Detailed information on the usage, dosage, and side-effects of various psychiatric medications such as antidepressants, antipsychotics and antianxiety medications.

Saphris (Asenapine) Uses, Dosage, Side-Effects

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Saphris (Asenapine) Full Prescribing Information

Brand Name: Saphris®
Generic Name: asenapine

Saphris (asenapine) is an antipsychotic medication used for the treatment of bipolar disorder and schizophrenia. Uses, dosage, side effects of Saphris.

Contents:

Indications and Usage
Dosage and Administration
Dosage Forms and Strengths
Contraindications
Warnings and Precautions
Adverse Reactions
Drug Interactions
Use in Specific Populations
Drug Abuse and Dependence
Overdose
Description
Clinical Pharmacology
Nonclinical Toxicology
Clinical Studies
How Supplied
Patient Counseling Information

Asenapine (Saphris) Patient Information Sheet (in plain English)

Warning: Increased Mortality in Elderly Patients with Dementia-Related Psychosis

Elderly patients with dementia-related psychosis treated with antipsychotic drugs are at an increased risk of death. Analyses of 17 placebo-controlled trials (modal duration of 10 weeks), largely in patients taking atypical antipsychotic drugs, revealed a risk of death in the drug-treated patients of between 1.6 to 1.7 times that seen in placebo-treated patients. Over the course of a typical 10-week controlled trial, the rate of death in drug-treated patients was about 4.5%, compared to a rate of about 2.6% in the placebo group. Although the causes of death were varied, most of the deaths appeared to be either cardiovascular (e.g., heart failure, sudden death) or infectious (e.g., pneumonia) in nature. Observational studies suggest that, similar to atypical antipsychotic drugs, treatment with conventional antipsychotic drugs may increase mortality. The extent to which the findings of increased mortality in observational studies may be attributed to the antipsychotic drug as opposed to some characteristic(s) of the patients is not clear. SAPHRIS® (asenapine) is not approved for the treatment of patients with dementia-related psychosis [see Warnings and Precautions (5.1)].

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1 Indications and Usage

1.1 Schizophrenia

SAPHRIS is indicated for the acute treatment of schizophrenia in adults [see Clinical Studies (14.1)]i. The physician who elects to use SAPHRIS for extended periods in schizophrenia should periodically re-evaluate the long-term risks and benefits of the drug for the individual patient [see Dosage and Administration (2.1)].

1.2 Bipolar Disorder

SAPHRIS is indicated for the acute treatment of manic or mixed episodes associated with bipolar I disorder with or without psychotic features in adults [see Clinical Studies (14.2)]. If SAPHRIS is used for extended periods in bipolar disorder, the physician should periodically re-evaluate the long-term risks and benefits of the drug for the individual patient [see Dosage and Administration (2.2)].

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2 Dosage and Administration

2.1 Schizophrenia

Usual Dose for Acute Treatment in Adults: The recommended starting and target dose of SAPHRIS is 5 mg given twice daily. In controlled trials, there was no suggestion of added benefit with the higher dose, but there was a clear increase in certain adverse reactions. The safety of doses above 10 mg twice daily has not been evaluated in clinical studies.

Maintenance Treatment: While there is no body of evidence available to answer the question of how long the schizophrenic patient should remain on SAPHRIS, it is generally recommended that responding patients be continued beyond the acute response.

2.2 Bipolar Disorder

Usual Dose for Acute Treatment in Adults: The recommended starting dose of SAPHRIS, and the dose maintained by 90% of the patients studied, is 10 mg twice daily. The dose can be decreased to 5 mg twice daily if there are adverse effects.

In controlled trials, the starting dose for SAPHRIS was 10 mg twice daily. On the second and subsequent days of the trials, the dose could be lowered to 5 mg twice daily, based on tolerability, but less than 10% of patients had their dose reduced. The safety of doses above 10 mg twice daily has not been evaluated in clinical trials.

Maintenance Treatment: While there is no body of evidence available to answer the question of how long the bipolar patient should remain on SAPHRIS, it is generally recommended that responding patients be continued beyond the acute response.

2.3 Administration Instructions

SAPHRIS is a sublingual tablet. To ensure optimal absorption, patients should be instructed to place the tablet under the tongue and allow it to dissolve completely. The tablet will dissolve in saliva within seconds. SAPHRIS sublingual tablets should not be crushed, chewed, or swallowed [see Clinical Pharmacology (12.3)]. Patients should be instructed to not eat or drink for 10 minutes after administration [see Clinical Pharmacology (12.3) and Patient Counseling Information (17.1)].

2.4 Dosage in Special Populations

In a study of subjects with hepatic impairment who were treated with a single dose of SAPHRIS 5 mg, there were increases in asenapine exposures (compared to subjects with normal hepatic function), that correlated with the degree of hepatic impairment. While the results indicated that no dosage adjustments are required in patients with mild (Child-Pugh A) or moderate (Child-Pugh B) hepatic impairment, there was a 7-fold increase (on average) in asenapine concentrations in subjects with severe hepatic impairment (Child-Pugh C) compared to the concentrations of those in subjects with normal hepatic function. Therefore, SAPHRIS is not recommended in patients with severe hepatic impairment [see Use in Special Populations (8.7)]. Dosage adjustments are not routinely required on the basis of age, gender, race, or renal impairment status [see Use in Specific Populations (8.4, 8.5, 8.6) and Clinical Pharmacology (12.3)].

2.5 Switching from Other Antipsychotics

There are no systematically collected data to specifically address switching patients with schizophrenia or bipolar mania from other antipsychotics to SAPHRIS or concerning concomitant administration with other antipsychotics. While immediate discontinuation of the previous antipsychotic treatment may be acceptable for some patients with schizophrenia, more gradual discontinuation may be most appropriate for others. In all cases, the period of overlapping antipsychotic administration should be minimized.

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3 Dosage Forms and Strengths

  • SAPHRIS 5 mg tablets are round, white to off-white sublingual tablets, with "5" on one side.
  • SAPHRIS 10 mg tablets are round, white to off-white sublingual tablets, with "10" on one side.

4 Contraindications

None

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5 Warnings and Precautions

5.1 Increased Mortality in Elderly Patients with Dementia-Related Psychosis

Elderly patients with dementia-related psychosis treated with antipsychotic drugs are at an increased risk of death. SAPHRIS is not approved for the treatment of patients with dementia-related psychosis [see Boxed Warning].

5.2 Cerebrovascular Adverse Events, Including Stroke, in Elderly Patients with Dementia-Related Psychosis

In placebo-controlled trials with risperidone, aripiprazole, and olanzapine in elderly subjects with dementia, there was a higher incidence of cerebrovascular adverse reactions (cerebrovascular accidents and transient ischemic attacks) including fatalities compared to placebo-treated subjects. SAPHRIS is not approved for the treatment of patients with dementia-related psychosis [see also Boxed Warning and Warnings and Precautions (5.1)].

5.3 Neuroleptic Malignant Syndrome

A potentially fatal symptom complex sometimes referred to as Neuroleptic Malignant Syndrome (NMS) has been reported in association with administration of antipsychotic drugs, including SAPHRIS. Clinical manifestations of NMS are hyperpyrexia, muscle rigidity, altered mental status, and evidence of autonomic instability (irregular pulse or blood pressure, tachycardia, diaphoresis, and cardiac dysrhythmia). Additional signs may include elevated creatine phosphokinase, myoglobinuria (rhabdomyolysis), and acute renal failure.

The diagnostic evaluation of patients with this syndrome is complicated. It is important to exclude cases where the clinical presentation includes both serious medical illness (e.g. pneumonia, systemic infection) and untreated or inadequately treated extrapyramidal signs and symptoms (EPS). Other important considerations in the differential diagnosis include central anticholinergic toxicity, heat stroke, drug fever, and primary central nervous system pathology.

The management of NMS should include: 1) immediate discontinuation of antipsychotic drugs and other drugs not essential to concurrent therapy; 2) intensive symptomatic treatment and medical monitoring; and 3) treatment of any concomitant serious medical problems for which specific treatments are available. There is no general agreement about specific pharmacological treatment regimens for NMS.

If a patient requires antipsychotic drug treatment after recovery from NMS, the potential reintroduction of drug therapy should be carefully considered. The patient should be carefully monitored, since recurrences of NMS have been reported.

5.4 Tardive Dyskinesia

A syndrome of potentially irreversible, involuntary, dyskinetic movements can develop in patients treated with antipsychotic drugs. Although the prevalence of the syndrome appears to be highest among the elderly, especially elderly women, it is impossible to rely upon prevalence estimates to predict, at the inception of antipsychotic treatment, which patients are likely to develop the syndrome. Whether antipsychotic drug products differ in their potential to cause Tardive Dyskinesia (TD) is unknown.

The risk of developing TD and the likelihood that it will become irreversible are believed to increase as the duration of treatment and the total cumulative dose of antipsychotic drugs administered to the patient increase. However, the syndrome can develop, although much less commonly, after relatively brief treatment periods at low doses.

There is no known treatment for established cases of TD, although the syndrome may remit, partially or completely, if antipsychotic treatment is withdrawn. Antipsychotic treatment, itself, however, may suppress (or partially suppress) the signs and symptoms of the syndrome and thereby may possibly mask the underlying process. The effect that symptomatic suppression has upon the long-term course of the syndrome is unknown.

Given these considerations, SAPHRIS should be prescribed in a manner that is most likely to minimize the occurrence of TD. Chronic antipsychotic treatment should generally be reserved for patients who suffer from a chronic illness that (1) is known to respond to antipsychotic drugs, and (2) for whom alternative, equally effective, but potentially less harmful treatments are not available or appropriate. In patients who do require chronic treatment, the smallest dose and the shortest duration of treatment producing a satisfactory clinical response should be sought. The need for continued treatment should be reassessed periodically.

If signs and symptoms of TD appear in a patient on SAPHRIS, drug discontinuation should be considered. However, some patients may require treatment with SAPHRIS despite the presence of the syndrome.

5.5 Hyperglycemia and Diabetes Mellitus

Hyperglycemia, in some cases extreme and associated with ketoacidosis or hyperosmolar coma or death, has been reported in patients treated with atypical antipsychotics. In clinical trials of SAPHRIS, the occurrence of any adverse reaction related to glucose metabolism was less than 1% in both the SAPHRIS and placebo treatment groups. Assessment of the relationship between atypical antipsychotic use and glucose abnormalities is complicated by the possibility of an increased background risk of diabetes mellitus in patients with schizophrenia and the increasing incidence of diabetes mellitus in the general population. Given these confounders, the relationship between atypical antipsychotic use and hyperglycemia-related adverse reactions is not completely understood. However, epidemiological studies, which did not include SAPHRIS, suggest an increased risk of treatment-emergent hyperglycemia-related adverse reactions in patients treated with the atypical antipsychotics included in these studies.

Patients with an established diagnosis of diabetes mellitus who are started on atypical antipsychotics should be monitored regularly for worsening of glucose control. Patients with risk factors for diabetes mellitus (e.g., obesity, family history of diabetes) who are starting treatment with atypical antipsychotics should undergo fasting blood glucose testing at the beginning of treatment and periodically during treatment. Any patient treated with atypical antipsychotics should be monitored for symptoms of hyperglycemia including polydipsia, polyuria, polyphagia, and weakness. Patients who develop symptoms of hyperglycemia during treatment with atypical antipsychotics should undergo fasting blood glucose testing. In some cases, hyperglycemia has resolved when the atypical antipsychotic was discontinued; however, some patients required continuation of anti-diabetic treatment despite discontinuation of the antipsychotic drug.

5.6 Weight Gain

In short-term schizophrenia and bipolar mania trials, there were differences in mean weight gain between SAPHRIS-treated and placebo-treated patients. In short-term, placebo-controlled schizophrenia trials, the mean weight gain was 1.1 kg for SAPHRIS-treated patients compared to 0.1 kg for placebo-treated patients. The proportion of patients with a ≥7% increase in body weight (at Endpoint) was 4.9% for SAPHRIS-treated patients versus 2% for placebo-treated patients. In short-term, placebo-controlled bipolar mania trials, the mean weight gain for SAPHRIS-treated patients was 1.3 kg compared to 0.2 kg for placebo-treated patients. The proportion of patients with a ≥7% increase in body weight (at Endpoint) was 5.8% for SAPHRIS-treated patients versus 0.5% for placebo-treated patients.

In a 52-week, double-blind, comparator-controlled trial of patients with schizophrenia or schizoaffective disorder, the mean weight gain from baseline was 0.9 kg. The proportion of patients with a ≥7% increase in body weight (at Endpoint) was 14.7%. Table 1 provides the mean weight change from baseline and the proportion of patients with a weight gain of ≥7% categorized by Body Mass Index (BMI) at baseline:

TABLE 1: Weight Change Results Categorized by BMI at Baseline: Comparator-Controlled 52-Week Study in Schizophrenia.

  BMI < 23
SAPHRIS
N=295
BMI 23 - ≤ 27
SAPHRIS
N=290
BMI > 27
SAPHRIS
N=302
Mean change from Baseline (kg) 1.7 1 0
% with ≥ 7% increase in body weight 22% 13% 9%

5.7 Orthostatic Hypotension, Syncope, and Other Hemodynamic Effects

SAPHRIS may induce orthostatic hypotension and syncope in some patients, especially early in treatment, because of its α1-adrenergic antagonist activity. In short-term schizophrenia trials, syncope was reported in 0.2% (1/572) of patients treated with therapeutic doses (5 mg or 10 mg twice daily) of SAPHRIS, compared to 0.3% (1/378) of patients treated with placebo. In short-term bipolar mania trials, syncope was reported in 0.3% (1/379) of patients treated with therapeutic doses (5 mg or 10 mg twice daily) of SAPHRIS, compared to 0% (0/203) of patients treated with placebo. During clinical trials with SAPHRIS, including long-term trials without comparison to placebo, syncope was reported in 0.6% (11/1953) of patients treated with SAPHRIS.

Four normal volunteers in clinical pharmacology studies treated with either intravenous, oral, or sublingual SAPHRIS experienced hypotension, bradycardia, and sinus pauses. These spontaneously resolved in 3 cases, but the fourth subject received external cardiac massage. The risk of this sequence of hypotension, bradycardia, and sinus pause might be greater in nonpsychiatric patients compared to psychiatric patients who are possibly more adapted to certain effects of psychotropic drugs.

Patients should be instructed about nonpharmacologic interventions that help to reduce the occurrence of orthostatic hypotension (e.g., sitting on the edge of the bed for several minutes before attempting to stand in the morning and slowly rising from a seated position). SAPHRIS should be used with caution in (1) patients with known cardiovascular disease (history of myocardial infarction or ischemic heart disease, heart failure or conduction abnormalities), cerebrovascular disease, or conditions which would predispose patients to hypotension (dehydration, hypovolemia, and treatment with antihypertensive medications); and (2) in the elderly. SAPHRIS should be used cautiously when treating patients who receive treatment with other drugs that can induce hypotension, bradycardia, respiratory or central nervous system depression [see Drug Inrteactions (7)]. Monitoring of orthostatic vital signs should be considered in all such patients, and a dose reduction should be considered if hypotension occurs.

5.8 Leukopenia, Neutropenia, and Agranulocytosis

In clinical trial and postmarketing experience, events of leukopenia/neutropenia have been reported temporally related to antipsychotic agents, including SAPHRIS. Agranulocytosis (including fatal cases) has been reported with other agents in the class.

Possible risk factors for leukopenia/neutropenia include pre-existing low white blood cell count (WBC) and history of drug induced leukopenia/neutropenia. Patients with a pre-existing low WBC or a history of drug induced leukopenia/neutropenia should have their complete blood count (CBC) monitored frequently during the first few months of therapy and SAPHRIS should be discontinued at the first sign of decline in WBC in the absence of other causative factors.

Patients with neutropenia should be carefully monitored for fever or other symptoms or signs of infection and treated promptly if such symptoms or signs occur. Patients with severe neutropenia (absolute neutrophil count <1000/mm3) should discontinue SAPHRIS and have their WBC followed until recovery.

5.9 QT Prolongation

The effects of SAPHRIS on the QT/QTc interval were evaluated in a dedicated QT study. This trial involved SAPHRIS doses of 5 mg, 10 mg, 15 mg, and 20 mg twice daily, and placebo, and was conducted in 151 clinically stable patients with schizophrenia, with electrocardiographic assessments throughout the dosing interval at baseline and steady state. At these doses, SAPHRIS was associated with increases in QTc interval ranging from 2 to 5 msec compared to placebo. No patients treated with SAPHRIS experienced QTc increases ≥60 msec from baseline measurements, nor did any patient experience a QTc of ≥500 msec.

Electrocardiogram (ECG) measurements were taken at various time points during the SAPHRIS clinical trial program (5 mg or 10 mg twice daily doses). Post-baseline QT prolongations exceeding 500 msec were reported at comparable rates for SAPHRIS and placebo in these short-term trials. There were no reports of Torsade de Pointes or any other adverse reactions associated with delayed ventricular repolarization.

The use of SAPHRIS should be avoided in combination with other drugs known to prolong QTc including Class 1A antiarrhythmics (e.g., quinidine, procainamide) or Class 3 antiarrhythmics (e.g., amiodarone, sotalol), antipsychotic medications (e.g., ziprasidone, chlorpromazine, thioridazine), and antibiotics (e.g., gatifloxacin, moxifloxacin). SAPHRIS should also be avoided in patients with a history of cardiac arrhythmias and in other circumstances that may increase the risk of the occurrence of torsade de pointes and/or sudden death in association with the use of drugs that prolong the QTc interval, including bradycardia; hypokalemia or hypomagnesemia; and presence of congenital prolongation of the QT interval.

5.10 Hyperprolactinemia

Like other drugs that antagonize dopamine D2 receptors, SAPHRIS can elevate prolactin levels, and the elevation can persist during chronic administration. Hyperprolactinemia may suppress hypothalamic GnRH, resulting in reduced pituitary gonadotropin secretion. This, in turn, may inhibit reproductive function by impairing gonadal steroidogenesis in both female and male patients. Galactorrhea, amenorrhea, gynecomastia, and impotence have been reported in patients receiving prolactin-elevating compounds. Long-standing hyperprolactinemia when associated with hypogonadism may lead to decreased bone density in both female and male subjects. In SAPHRIS clinical trials, the incidences of adverse events related to abnormal prolactin levels were 0.4% versus 0% for placebo [see Adverse Reactions (6.2)].

Tissue culture experiments indicate that approximately one-third of human breast cancers are prolactin-dependent in vitro, a factor of potential importance if the prescription of these drugs is considered in a patient with previously-detected breast cancer. Neither clinical studies nor epidemiologic studies conducted to date have shown an association between chronic administration of this class of drugs and tumorigenesis in humans, but the available evidence is too limited to be conclusive.

5.11 Seizures

Seizures were reported in 0% and 0.3% (0/572, 1/379) of patients treated with doses of 5 mg and 10 mg twice daily of SAPHRIS, respectively, compared to 0% (0/503, 0/203) of patients treated with placebo in short-term schizophrenia and bipolar mania trials, respectively. During clinical trials with SAPHRIS, including long-term trials without comparison to placebo, seizures were reported in 0.3% (5/1953) of patients treated with SAPHRIS. As with other antipsychotic drugs, SAPHRIS should be used with caution in patients with a history of seizures or with conditions that potentially lower the seizure threshold, e.g., Alzheimer's dementia. Conditions that lower the seizure threshold may be more prevalent in patients 65 years or older.

5.12 Potential for Cognitive and Motor Impairment

Somnolence was reported in patients treated with SAPHRIS. It was usually transient with the highest incidence reported during the first week of treatment. In short-term, fixed-dose, placebo-controlled schizophrenia trials, somnolence was reported in 15% (41/274) of patients on SAPHRIS 5 mg twice daily and in 13% (26/208) of patients on SAPHRIS 10 mg twice daily compared to 7% (26/378) of placebo patients. In short-term, placebo-controlled bipolar mania trials of therapeutic doses (5-10 mg twice daily), somnolence was reported in 24% (90/379) of patients on SAPHRIS compared to 6% (13/203) of placebo patients. During clinical trials with SAPHRIS, including long-term trials without comparison to placebo, somnolence was reported in 18% (358/1953) of patients treated with SAPHRIS. Somnolence (including sedation) led to discontinuation in 0.6% (12/1953) of patients in short-term, placebo-controlled trials.

Patients should be cautioned about performing activities requiring mental alertness, such as operating hazardous machinery or operating a motor vehicle, until they are reasonably certain that SAPHRIS therapy does not affect them adversely.

5.13 Body Temperature Regulation

Disruption of the body's ability to reduce core body temperature has been attributed to antipsychotic agents. In the short-term placebo-controlled trials for both schizophrenia and acute bipolar disorder, the incidence of adverse reactions suggestive of body temperature increases was low (≤ 1%) and comparable to placebo. During clinical trials with SAPHRIS, including long-term trials without comparison to placebo, the incidence of adverse reactions suggestive of body temperature increases (pyrexia and feeling hot) was ≤ 1%. Appropriate care is advised when prescribing SAPHRIS for patients who will be experiencing conditions that may contribute to an elevation in core body temperature, e.g., exercising strenuously, exposure to extreme heat, receiving concomitant medication with anticholinergic activity, or being subject to dehydration.

5.14 Suicide

The possibility of a suicide attempt is inherent in psychotic illnesses and bipolar disorder, and close supervision of high-risk patients should accompany drug therapy. Prescriptions for SAPHRIS should be written for the smallest quantity of tablets consistent with good patient management in order to reduce the risk of overdose.

5.15 Dysphagia

Esophageal dysmotility and aspiration have been associated with antipsychotic drug use. Dysphagia was reported in 0.2% and 0% (1/572, 0/379) of patients treated with therapeutic doses (5-10 mg twice daily) of SAPHRIS as compared to 0% (0/378, 0/203) of patients treated with placebo in short-term schizophrenia and bipolar mania trials, respectively. During clinical trials with SAPHRIS, including long-term trials without comparison to placebo, dysphagia was reported in 0.1% (2/1953) of patients treated with SAPHRIS.

Aspiration pneumonia is a common cause of morbidity and mortality in elderly patients, in particular those with advanced Alzheimer's dementia. SAPHRIS is not indicated for the treatment of dementia-related psychosis, and should not be used in patients at risk for aspiration pneumonia [see also Warnings and Precautions (5.1)].

5.16 Use in Patients with Concomitant Illness

Clinical experience with SAPHRIS in patients with certain concomitant systemic illnesses is limited [see Clinical Pharmacology (12.3)].

SAPHRIS has not been evaluated in patients with a recent history of myocardial infarction or unstable heart disease. Patients with these diagnoses were excluded from premarketing clinical trials. Because of the risk of orthostatic hypotension with SAPHRIS, caution should be observed in cardiac patients [see Warnings and Precautions (5.6)].

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6 Adverse Reactions

6.1 Overall Adverse Reactions Profile

The following adverse reactions are discussed in more detail in other sections of the labeling:

The most common adverse reactions (≥5% and at least twice the rate on placebo) in schizophrenia were akathisia, oral hypoesthesia, and somnolence.

The most common adverse reactions (≥5% and at least twice the rate on placebo) in bipolar disorder were somnolence, dizziness, extrapyramidal symptoms other than akathisia, and weight increased.

The information below is derived from a clinical trial database for SAPHRIS consisting of over 3350 patients and/or normal subjects exposed to one or more sublingual doses of SAPHRIS.Of these subjects, 1953 (1480 in schizophrenia and 473 in acute bipolar mania) were patients who participated in multiple-dose effectiveness trials of therapeutic doses (5 or 10 mg twice daily, with a total experience of approximately 611 patient-years). A total of 486 SAPHRIS-treated patients were treated for at least 24 weeks and 293 SAPHRIS-treated patients had at least 52 weeks of exposure.

The stated frequencies of adverse reactions represent the proportion of individuals who experienced a treatment-emergent adverse event of the type listed. A reaction was considered treatment emergent if it occurred for the first time or worsened while receiving therapy following baseline evaluation. The figures in the tables and tabulations cannot be used to predict the incidence of side effects in the course of usual medical practice where patient characteristics and other factors differ from those that prevailed in the clinical trials. Similarly, the cited frequencies cannot be compared with figures obtained from other clinical investigations involving different treatment, uses, and investigators. The cited figures, however, do provide the prescriber with some basis for estimating the relative contribution of drug and nondrug factors to the adverse reaction incidence in the population studied.

6.2 Clinical Studies Experience

Adult Patients with Schizophrenia: The following findings are based on the short-term placebo-controlled premarketing trials for schizophrenia (a pool of three 6-week fixed-dose trials and one 6-week flexible-dose trial) in which sublingual SAPHRIS was administered in doses ranging from 5 to 10 mg twice daily.

Adverse Reactions Associated with Discontinuation of Treatment: A total of 9% of SAPHRIS-treated subjects and 10% of placebo subjects discontinued due to adverse reactions. There were no drug-related adverse reactions associated with discontinuation in subjects treated with SAPHRIS at the rate of at least 1% and at least twice the placebo rate.

Adverse Reactions Occurring at an Incidence of 2% or More in SAPHRIS-Treated Schizophrenic Patients: Adverse reactions associated with the use of SAPHRIS (incidence of 2% or greater, rounded to the nearest percent, and SAPHRIS incidence greater than placebo) that occurred during acute therapy (up to 6-weeks in patients with schizophrenia) are shown in Table 2.

TABLE 2: Adverse Reactions Reported in 2% or More of Subjects in one of the SAPHRIS Dose Groups and Which Occurred at Greater Incidence Than in the Placebo group in 6-Week Schizophrenia Trials

System Organ Class / Preferred Term Placebo
N= 378
SAPHRIS
5 mg
twice
daily
N= 274
SAPHRIS
10 mg
twice
daily
N= 208
All
SAPHRIS §
5 or 10
mg twice
daily
N=572
Gastrointestinal disorders        
Constipation 6% 7% 4% 5%
Dry Mouth 1% 3% 1% 2%
Oral hypoesthesia 1% 6% 7% 5%
Salivary hypersecretion 0% <1% 4% 2%
Stomach discomfort 1% <1% 3% 2%
Vomiting 5% 4% 7% 5%
General disorders        
Fatigue 3% 4% 3% 3%
Irritability <1% 2% 1% 2%
Investigations        
Weight Increased <1% 2% 2% 3%
Metabolism disorders        
Increased appetite <1% 3% 0% 2%
Nervous system disorders        
Akathisia* 3% 4% 11% 6%
Dizziness 4% 7% 3% 5%
Extrapyramidal symptoms
(excluding akathisia)†
7% 9% 12% 10%
Somnolencec 7% 15% 13% 13%
Psychiatric disorders        
Insomnia 13% 16% 15% 15%
Vascular disorders        
Hypertension 2% 2% 3% 2%
*Akathisia includes: akathisia and hyperkinesia.
†Extrapyramidal symptoms included dystonia, oculogyration, dyskinesia, tardive dyskinesia, muscle rigidity, parkinsonism, tremor, and extrapyramidal disorder (excluding akathisia).
cSomnolence includes the following events: somnolence, sedation, and hypersomnia.
§Also includes the Flexible-dose trial (N=90).

Dose-Related Adverse Reactions: Of all the adverse reactions listed in Table 2, the only apparent dose-related adverse reaction was akathisia.

Adult Patients with Bipolar Mania: The following findings are based on the short-term placebo-controlled trials for bipolar mania (a pool of two 3-week flexible-dose trials) in which sublingual SAPHRIS was administered in doses of 5 mg or 10 mg twice daily.

Adverse Reactions Associated with Discontinuation of Treatment: Approximately 10% (38/379) of SAPHRIS-treated patients in short-term, placebo-controlled trials discontinued treatment due to an adverse reaction, compared with about 6% (12/203) on placebo. The most common adverse reactions associated with discontinuation in subjects treated with SAPHRIS (rates at least 1% and at least twice the placebo rate) were anxiety (1.1%) and oral hypoesthesia (1.1%) compared to placebo (0%).

Adverse Reactions Occurring at an Incidence of 2% or More Among SAPHRIS-Treated Bipolar Patients: Adverse reactions associated with the use of SAPHRIS (incidence of 2% or greater, rounded to the nearest percent, and SAPHRIS incidence greater than placebo) that occurred during acute therapy (up to 3-weeks in patients with bipolar mania) are shown in Table 3.

TABLE 3: Adverse Reactions Reported in 2% or More of Subjects in one of the SAPHRIS Dose Groups and Which Occurred at Greater Incidence Than in the Placebo Group in 3-Week Bipolar Mania Trials

System Organ Class / Preferred Term Placebo
(N=203)
SAPHRIS
5 or 10 mg twice daily*
(N=379)
Gastrointestinal disorders
Dry Mouth 1% 3%
Dyspepsia 2% 4%
Oral hypoesthesia <1% 4%
Toothache 2% 3%
General disorders
Fatigue 2% 4%
Investigations
Weight increased <1% 5%
Metabolism disorders
Increased appetite 1% 4%
Musculoskeletal and connective tissue disorders
Arthralgia 1% 3%
Pain in extremity <1% 2%
Nervous system disorders
Akathisia 2% 4%
Dizziness 3% 11%
Dysgeusia <1% 3%
Headache 11% 12%
Other extrapyramidal symptoms
(excluding akathisia)†
2% 7%
Somnolencec 6% 24%
Psychiatric disorders
Anxiety 2% 4%
Depression 1% 2%
Insomnia 5% 6%

*SAPHRIS 5 to 10 mg twice daily with flexible dosing.
†Extrapyramidal symptoms included: dystonia, blepharospasm, torticollis, dyskinesia, tardive dyskinesia, muscle rigidity,
parkinsonism, gait disturbance, masked facies, and tremor (excluding akathisia).
cSomnolence includes the following events: somnolence, sedation, and hypersomnia.

Dystonia: Antipsychotic Class Effect: Symptoms of dystonia, prolonged abnormal contractions of muscle groups, may occur in susceptible individuals during the first few days of treatment. Dystonic symptoms include: spasm of the neck muscles, sometimes progressing to tightness of the throat, swallowing difficulty, difficulty breathing, and/or protrusion of the tongue. While these symptoms can occur at low doses, they occur more frequently and with greater severity with high potency and at higher doses of first generation antipsychotic drugs. An elevated risk of acute dystonia is observed in males and younger age groups.

Extrapyramidal Symptoms: In the short-term, placebo-controlled schizophrenia and bipolar mania trials, data was objectively collected on the Simpson Angus Rating Scale for extrapyramidal symptoms (EPS), the Barnes Akathisia Scale (for akathisia) and the Assessments of Involuntary Movement Scales (for dyskinesias). The mean change from baseline for the all-SAPHRIS 5 mg or 10 mg twice daily treated group was comparable to placebo in each of the rating scale scores.In the short-term, placebo-controlled schizophrenia trials, the incidence of reported EPS-related events, excluding events related to akathisia, for SAPHRIS-treated patients was 10% versus 7% for placebo; and the incidence of akathisia-related events for SAPHRIS-treated patients was 6% versus 3% for placebo. In short-term placebo-controlled bipolar mania trials, the incidence of EPS-related events, excluding events related to akathisia, for SAPHRIS-treated patients was 7% versus 2% for placebo; and the incidence of akathisia-related events for SAPHRIS-treated patients was 4% versus 2% for placebo.

Laboratory Test Abnormalities:

Glucose: The effects on fasting serum glucose levels in the short-term schizophrenia and bipolar mania trials revealed no clinically relevant mean changes [see also Warnings and Precautions (5.5)]. In the short-term placebo-controlled schizophrenia trials, the mean increase in fasting glucose levels for SAPHRIS-treated patients was 3.2 mg/dL compared to a decrease of 1.6 mg/dL for placebo-treated patients. The proportion of patients with fasting glucose elevations ≥126 mg/dL (at Endpoint), was 7.4% for SAPHRIS-treated patients versus 6% for placebo-treated patients. In the short-term, placebo-controlled bipolar mania trials, the mean decreases in fasting glucose levels for both SAPHRIS-treated and placebo-treated patients were 0.6 mg/dL. The proportion of patients with fasting glucose elevations ≥126 mg/dL (at Endpoint), was 4.9% for SAPHRIS-treated patients versus 2.2% for placebo-treated patients.

In a 52-week, double-blind, comparator-controlled trial of patients with schizophrenia and schizoaffective disorder, the mean increase from baseline of fasting glucose was 2.4 mg/dL.

Lipids: The effects on total cholesterol and fasting triglycerides in the short-term schizophrenia and bipolar mania trials revealed no clinically relevant mean changes. In short-term, placebo-controlled schizophrenia trials, the mean increase in total cholesterol levels for SAPHRIS-treated patients was 0.4 mg/dL compared to a decrease of 3.6 mg/dL for placebo-treated patients. The proportion of patients with total cholesterol elevations ≥240 mg/dL (at Endpoint) was 8.3% for SAPHRIS-treated patients versus 7% for placebo-treated patients. In short-term, placebo-controlled bipolar mania trials, the mean increase in total cholesterol levels for SAPHRIS-treated patients was 1.1 mg/dL compared to a decrease of 1.5 mg/dL in placebo-treated patients. The proportion of patients with total cholesterol elevations ≥240 mg/dL (at Endpoint) was 8.7% for SAPHRIS-treated patients versus 8.6% for placebo-treated patients. In short-term, placebo-controlled schizophrenia trials, the mean increase in triglyceride levels for SAPHRIS-treated patients was 3.8 mg/dL compared to a decrease of 13.5 mg/dL for placebo-treated patients. The proportion of patients with elevations in triglycerides ≥200 mg/dL (at Endpoint) was 13.2% for SAPHRIS-treated patients versus 10.5% for placebo-treated patients. In short-term, placebo-controlled bipolar mania trials, the mean decrease in triglyceride levels for SAPHRIS-treated patients was 3.5 mg/dL versus 17.9 mg/dL for placebo-treated subjects. The proportion of patients with elevations in triglycerides ≥200 mg/dL (at Endpoint) was 15.2% for SAPHRIS-treated patients versus 11.4% for placebo-treated patients.

In a 52-week, double-blind, comparator-controlled trial of patients with schizophrenia and schizoaffective disorder, the mean decrease from baseline of total cholesterol was 6 mg/dL and the mean decrease from baseline of fasting triglycerides was 9.8 mg/dL.

Transaminases: Transient elevations in serum transaminases (primarily ALT) in the short-term schizophrenia and bipolar mania trials were more common in treated patients but mean changes were not clinically relevant. In short-term, placebo-controlled schizophrenia trials, the mean increase in transaminase levels for SAPHRIS-treated patients was 1.6 units/L compared to a decrease of 0.4 units/L for placebo-treated patients. The proportion of patients with transaminase elevations ≥3 times ULN (at Endpoint) was 0.9% for SAPHRIS-treated patients versus 1.3% for placebo-treated patients. In short-term, placebo-controlled bipolar mania trials, the mean increase in transaminase levels for SAPHRIS-treated patients was 8.9 units/L compared to a decrease of 4.9 units/L in placebo-treated patients. The proportion of patients with transaminase elevations ≥3 times upper limit of normal (ULN) (at Endpoint) was 2.5% for SAPHRIS-treated patients versus 0.6% for placebo-treated patients. No cases of more severe liver injury were seen.

In a 52-week, double-blind, comparator-controlled trial of patients with schizophrenia and schizoaffective disorder, the mean increase from baseline of ALT was 1.7 units/L.

Prolactin: The effects on prolactin levels in the short-term schizophrenia and bipolar mania trials revealed no clinically relevant changes in mean change in baseline. In short-term, placebo-controlled schizophrenia trials, the mean decreases in prolactin levels were 6.5 ng/mL for SAPHRIS-treated patients compared to 10.7 ng/mL for placebo-treated patients. The proportion of patients with prolactin elevations ≥4 times ULN (at Endpoint) were 2.6% for SAPHRIS-treated patients versus 0.6% for placebo-treated patients. In short-term, placebo-controlled bipolar mania trials, the mean increase in prolactin levels was 4.9 ng/mL for SAPHRIS-treated patients compared to a decrease of 0.2 ng/mL for placebo-treated patients. The proportion of patients with prolactin elevations =≥4 times ULN (at Endpoint) were 2.3% for SAPHRIS-treated patients versus 0.7% for placebo-treated patients.

In a long-term (52-week), double-blind, comparator-controlled trial of patients with schizophrenia and schizoaffective disorder, the mean decrease in prolactin from baseline for SAPHRIS-treated patients was 26.9 ng/mL.

Other Adverse Reactions Observed During the Premarketing Evaluation of SAPHRIS: Following is a list of MedDRA terms that reflect adverse reactions reported by patients treated with sublingual SAPHRIS at multiple doses of ≥5 mg twice daily during any phase of a trial within the database of adult patients. The reactions listed are those that could be of clinical importance, as well as reactions that are plausibly drug-related on pharmacologic or other grounds. Reactions already listed in other parts of Adverse Reactions (6), or those considered in Warnings and Precautions (5) or Overdosage (10) are not included. Although the reactions reported occurred during treatment with SAPHRIS, they were not necessarily caused by it. Reactions are further categorized by MedDRA system organ class and listed in order of decreasing frequency according to the following definitions: those occurring in at least 1/100 patients (only those not already listed in the tabulated results from placebo-controlled trials appear in this listing); those occurring in 1/100 to 1/1000 patients; and those occurring in fewer than 1/1000 patients.

  • Blood and lymphatic disorders: <1/1000 patients:thrombocytopenia;≥1/1000 patients and <1/100 patients:anemia
  • Cardiac disorders: ≥1/1000 patients and <1/100 patients: tachycardia, temporary bundle branch block
  • Eye disorders: ≥1/1000 patients and <1/100 patients: accommodation disorder
  • Gastrointestinal disorders: ≥1/1000 patients and <1/100 patients: oral paraesthesia, glossodynia, swollen tongue
  • General disorders: <1/1000 patients: idiosyncratic drug reaction
  • Investigations:≥1/1000 patients and <1/100 patients:hyponatremia
  • Nervous system disorders: ≥1/1000 patients and <1/100 patients: dysarthria
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7 Drug Interactions

The risks of using SAPHRIS in combination with other drugs have not been extensively evaluated. Given the primary CNS effects of SAPHRIS, caution should be used when it is taken in combination with other centrally-acting drugs or alcohol.

Because of its α1-adrenergic antagonism with potential for inducing hypotension, SAPHRIS may enhance the effects of certain antihypertensive agents.

7.1 Potential for Other Drugs to Affect SAPHRIS

Asenapine is cleared primarily through direct glucuronidation by UGT1A4 and oxidative metabolism by cytochrome P450isoenzymes (predominantly CYP1A2). The potential effects of inhibitors of several of these enzyme pathways on asenapine clearance were studied.

TABLE 4: Summary of Effect of Coadministered Drugs on Exposure to Asenapine in Healthy Volunteers

Coadministered drug (Postulated effect on CYP450/UGT)

Dose schedules

Effect on asenapine pharmacokinetics

Recommendation

Coadministered drug

Asenapine

Cmax

AUC0-β


Fluvoxamine
(CYP1A2 inhibitor)

25 mg twice daily for
8 days

5 mg Single Dose

+13%

+29%

Coadminister with caution*

Paroxetine
(CYP2D6 inhibitor)

20 mg once daily for
9 days

5 mg Single Dose

-13%

-9%

No SAPHRIS dose adjustment required [see Drug Interactions (7.2)]

Imipramine (CYP1A2/2C19/3A4 inhibitor)

75 mg Single Dose

5 mg Single Dose

+17%

+10%

No SAPHRIS dose adjustment required

Cimetidine (CYP3A4/2D6/1A2 inhibitor)

800 mg twice daily for
8 days

5 mg Single Dose

-13%

+1%

No SAPHRIS dose adjustment required

Carbamazepine
(CYP3A4 inducer)

400 mg twice daily for
15 days

5 mg Single Dose

-16%

-16%

No SAPHRIS dose adjustment required

Valproate
(UGT1A4 inhibitor)

500 mg twice daily for
9 days

5 mg Single Dose

2%

-1%

No SAPHRIS dose adjustment required

*The full therapeutic dose of fluvoxamine would be expected to cause a greater increase in asenapine plasma concentrations. AUC: Area under the curve.

7.2 Potential for SAPHRIS to Affect Other Drugs

Coadministration with CYP2D6 Substrates: In vitro studies indicate that asenapine weakly inhibits CYP2D6.

Following coadministration of dextromethorphan and SAPHRIS in healthy subjects, the ratio of dextrorphan/dextromethorphan (DX/DM) as a marker of CYP2D6 activity was measured. Indicative of CYP2D6 inhibition, treatment with SAPHRIS 5 mg twice daily decreased the DX/DM ratio to 0.43. In the same study, treatment with paroxetine 20 mg daily decreased the DX/DM ratio to 0.032. In a separate study, coadministration of a single 75-mg dose of imipramine with a single 5-mg dose of SAPHRIS did not affect the plasma concentrations of the metabolite desipramine (a CYP2D6 substrate). Thus, in vivo, SAPHRIS appears to be at most a weak inhibitor of CYP2D6. Coadministration of a single 20-mg dose of paroxetine (a CYP2D6 substrate and inhibitor) during treatment with 5 mg SAPHRIS twice daily in 15 healthy male subjects resulted in an almost 2-fold increase in paroxetine exposure. Asenapine may enhance the inhibitory effects of paroxetine on its own metabolism.

SAPHRIS should be coadministered cautiously with drugs that are both substrates and inhibitors for CYP2D6.

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8 Use in Specific Populations

8.1 Pregnancy

Pregnancy Category C: There are no adequate and well-controlled studies of SAPHRIS in pregnant women. In animal studies, asenapine increased post-implantation loss and decreased pup weight and survival at doses similar to or less than recommended clinical doses. In these studies there was no increase in the incidence of structural abnormalities caused by asenapine. SAPHRIS should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

Asenapine was not teratogenic in reproduction studies in rats and rabbits at intravenous doses up to 1.5 mg/kg in rats and 0.44 mg/kg in rabbits. These doses are 0.7 and 0.4 times, respectively, the maximum recommended human dose (MRHD) of 10 mg twice daily given sublingually on a mg/m2 basis. Plasma levels of asenapine were measured in the rabbit study, and the area under the curve (AUC) at the highest dose tested was 2 times that in humans receiving the MRHD.

In a study in which rats were treated from day 6 of gestation through day 21 postpartum with intravenous doses of asenapine of 0.3, 0.9, and 1.5 mg/kg/day (0.15, 0.4, and 0.7 times the MRHD of 10 mg twice daily given sublingually on a mg/m2 basis), increases in post-implantation loss and early pup deaths were seen at all doses, and decreases in subsequent pup survival and weight gain were seen at the two higher doses. A cross-fostering study indicated that the decreases in pup survival were largely due to prenatal drug effects. Increases in post-implantation loss and decreases in pup weight and survival were also seen when pregnant rats were dosed orally with asenapine.

8.2 Labor and Delivery

The effect of SAPHRIS on labor and delivery in humans is unknown.

8.3 Nursing Mothers

Asenapine is excreted in milk of rats during lactation. It is not known whether asenapine or its metabolites are excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when SAPHRIS is administered to a nursing woman. It is recommended that women receiving SAPHRIS should not breast feed.

8.4 Pediatric Use

Safety and effectiveness in pediatric patients have not been established.

8.5 Geriatric Use

Clinical studies of SAPHRIS in the treatment of schizophrenia and bipolar mania did not include sufficient numbers of patients aged 65 and over to determine whether or not they respond differently than younger patients. Of the approximately 2250 patients in premarketing clinical studies of SAPHRIS, 1.1% (25) were 65 years of age or over. Multiple factors that might increase the pharmacodynamic response to SAPHRIS, causing poorer tolerance or orthostasis, could be present in elderly patients, and these patients should be monitored carefully.

Elderly patients with dementia-related psychosis treated with SAPHRIS are at an increased risk of death compared to placebo. SAPHRIS is not approved for the treatment of patients with dementia-related psychosis [see Boxed Warning].

8.6 Renal Impairment

The exposure of asenapine following a single dose of 5 mg was similar among subjects with varying degrees of renal impairment and subjects with normal renal function [see Clinical Pharmacology (12.3)].

8.7 Hepatic Impairment

In subjects with severe hepatic impairment who were treated with a single dose of SAPHRIS 5 mg, asenapine exposures (on average), were 7-fold higher than the exposures observed in subjects with normal hepatic function. Thus, SAPHRIS is not recommended in patients with severe hepatic impairment (Child-Pugh C) [see Dosage and Administration (2.4) and Clinical Pharmacology (12.3)].

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9 Drug Abuse and Dependence

9.1 Controlled Substance

SAPHRIS is not a controlled substance.

9.2 Abuse

SAPHRIS has not been systematically studied in animals or humans for its abuse potential or its ability to induce tolerance or physical dependence. Thus, it is not possible to predict the extent to which a CNS-active drug will be misused, diverted and/or abused once it is marketed. Patients should be evaluated carefully for a history of drug abuse, and such patients should be observed carefully for signs that they are misusing or abusing SAPHRIS (e.g., drug-seeking behavior, increases in dose).

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10 Overdosage

Human Experience: In premarketing clinical studies involving more than 3350 patients and/or healthy subjects, accidental or intentional acute overdosage of SAPHRIS was identified in 3 patients. Among these few reported cases of overdose, the highest estimated ingestion of SAPHRIS was 400 mg. Reported adverse reactions at the highest dosage included agitation and confusion.

Management of Overdosage: There is no specific antidote to SAPHRIS. The possibility of multiple drug involvement should be considered. An electrocardiogram should be obtained and management of overdose should concentrate on supportive therapy, maintaining an adequate airway, oxygenation and ventilation, and management of symptoms.

Hypotension and circulatory collapse should be treated with appropriate measures, such as intravenous fluids and/or sympathomimetic agents (epinephrine and dopamine should not be used, since beta stimulation may worsen hypotension in the setting of SAPHRIS-induced alpha blockade). In case of severe extrapyramidal symptoms, anticholinergic medication should be administered. Close medical supervision and monitoring should continue until the patient recovers.

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11 Description

SAPHRIS is a psychotropic agent that is available for sublingual administration. Asenapine belongs to the class dibenzo-oxepino pyrroles. The chemical designation is (3aRS,12bRS)-5-Chloro-2-methyl-2,3,3a,12b-tetrahydro-1Hdibenzo[2,3:6,7]oxepino[4,5-c]pyrrole (2Z)-2-butenedioate (1:1). Its molecular formula is C17H16ClNO·C4H4O4 and its molecular weight is 401.84 (free base:285.8). The chemical structure is:

Saphris Chemical Structure

Asenapine is a white- to off-white powder.

SAPHRIS is supplied for sublingual administration in tablets containing 5 mg or 10 mg asenapine; inactive ingredients include gelatin and mannitol.

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12 Clinical Pharmacology

12.1 Mechanism of Action

The mechanism of action of asenapine, as with other drugs having efficacy in schizophrenia and bipolar disorder, is unknown. It has been suggested that the efficacy of asenapine in schizophrenia is mediated through a combination of antagonist activity at D2 and 5-HT2A receptors.

12.2 Pharmacodynamics

Asenapine exhibits high affinity for serotonin 5-HT1A, 5-HT1B, 5-HT2A, 5-HT2B, 5-HT2C, 5-HT5, 5-HT6, and 5-HT7 receptors (Ki values of 2.5, 4.0, 0.06, 0.16, 0.03, 1.6, 0.25, and 0.13 nM), dopamine D2, D3, D4, and D1 receptors (Ki values of 1.3, 0.42, 1.1, and 1.4 nM), α1 and α2-adrenergic receptors (Ki values of 1.2 and 1.2 nM), and histamine H1 receptors (Ki value 1.0 nM), and moderate affinity for H2 receptors (Ki value of 6.2 nM). In in vitro assays asenapine acts as an antagonist at these receptors. Asenapine has no appreciable affinity for muscarinic cholinergic receptors (e.g., Ki value of 8128 nM for M1).

12.3 Pharmacokinetics

Following a single 5-mg dose of SAPHRIS, the mean Cmax was approximately 4 ng/mL and was observed at a mean tmax of 1 hr. Elimination of asenapine is primarily through direct glucuronidation by UGT1A4 and oxidative metabolism by cytochrome P450 isoenzymes (predominantly CYP1A2). Following an initial more rapid distribution phase, the mean terminal half-life is approximately 24 hrs. With multiple-dose twice-daily dosing, steady-state is attained within 3 days. Overall, steady-state asenapine pharmacokinetics are similar to single-dose pharmacokinetics.

Absorption: Following sublingual administration, asenapine is rapidly absorbed with peak plasma concentrations occurring within 0.5 to 1.5 hours. The absolute bioavailability of sublingual asenapine at 5 mg is 35%. Increasing the dose from 5 to 10 mg twice daily (a two-fold increase) results in less than linear (1.7 times) increases in both the extent of exposure and maximum concentration. The absolute bioavailability of asenapine when swallowed is low (<2% with an oral tablet formulation).

The intake of water several (2 or 5) minutes after asenapine administration resulted in decreased asenapine exposure. Therefore, eating and drinking should be avoided for 10 minutes after administration [see Dosage and Administration (2.3)].

Distribution: Asenapine is rapidly distributed and has a large volume of distribution (approximately 20 - 25 L/kg), indicating extensive extravascular distribution. Asenapine is highly bound (95%) to plasma proteins, including albumin and α1-acid glycoprotein.

Metabolism and Elimination: Direct glucuronidation by UGT1A4 and oxidative metabolism by cytochrome P450 isoenzymes (predominantly CYP1A2) are the primary metabolic pathways for asenapine.

Asenapine is a high clearance drug with a clearance after intravenous administration of 52 L/h. In this circumstance, hepatic clearance is influenced primarily by changes in liver blood flow rather than by changes in the intrinsic clearance, i.e., the metabolizing enzymatic activity. Following an initial more rapid distribution phase, the terminal half life of asenapine is approximately 24 hours. Steady-state concentrations of asenapine are reached within 3 days of twice daily dosing.

After administration of a single dose of [14C]-labeled asenapine, about 90% of the dose was recovered; approximately 50% was recovered in urine, and 40% recovered in feces. About 50% of the circulating species in plasma have been identified.The predominant species was asenapine N+-glucuronide; others included N-desmethylasenapine, N-desmethylasenapine N-carbamoyl glucuronide, and unchanged asenapine in smaller amounts. SAPHRIS activity is primarily due to the parent drug.

In vitro studies indicate that asenapine is a substrate for UGT1A4, CYP1A2 and to a lesser extent CYP3A4 and CYP2D6. Asenapine is a weak inhibitor of CYP2D6. Asenapine does not cause induction of CYP1A2 or CYP3A4 activities in cultured human hepatocytes. Coadministration of asenapine with known inhibitors, inducers or substrates of these metabolic pathways has been studied in a number of drug-drug interaction studies [see Drug Interactions (7)].

Smoking: A population pharmacokinetic analysis indicated that smoking, which induces CYP1A2, had no effect on the clearance of asenapine in smokers. In a crossover study in which 24 healthy male subjects (who were smokers) were administered a single 5-mg sublingual dose, concomitant smoking had no effect on the pharmacokinetics of asenapine.

Food: A crossover study in 26 healthy male subjects was performed to evaluate the effect of food on the pharmacokinetics of a single 5-mg dose of asenapine. Consumption of food immediately prior to sublingual administration decreased asenapine exposure by 20%; consumption of food 4 hours after sublingual administration decreased asenapine exposure by about 10%. These effects are probably due to increased hepatic blood flow.

In clinical trials establishing the efficacy and safety of SAPHRIS, patients were instructed to avoid eating for 10 minutes following sublingual dosing. There were no other restrictions with regard to the timing of meals in these trials [see Dosage and Administration (2.3) and Patient Counseling Information (17.1)].

Water: In clinical trials establishing the efficacy and safety of SAPHRIS, patients were instructed to avoid drinking for 10 minutes following sublingual dosing. The effect of water administration following 10 mg sublingual SAPHRIS dosing was studied at different time points of 2, 5, 10, and 30 minutes in 15 healthy male subjects. The exposure of asenapine following administration of water 10 minutes after sublingual dosing was equivalent to that when water was administered 30 minutes after dosing. Reduced exposure to asenapine was observed following water administration at 2 minutes (19% decrease) and 5 minutes (10% decrease) [see Dosage and Administration (2.3) and Patient Counseling Information (17.1)].

Special Populations:

Hepatic Impairment:The effect of decreased hepatic function on the pharmacokinetics of asenapine, administered as a single 5-mg sublingual dose, was studied in 30 subjects (8 each in those with normal hepatic function and Child-Pugh A and B groups, and 6 in the Child Pugh C group). In subjects with mild or moderate hepatic impairment (Child-Pugh A or B), asenapine exposure was 12% higher than that in subjects with normal hepatic function, indicating that dosage adjustment is not required for these subjects. In subjects with severe hepatic impairment, asenapine exposures were on average 7 times higher than the exposures of those in subjects with normal hepatic function. Thus, SAPHRIS is not recommended in patients with severe hepatic impairment (Child-Pugh C) [see Dosage in Specific Populations (2.4) and Use in Specific Populations (8.7) and Warnings and Precautions (5.14)].

Renal Impairment: The effect of decreased renal function on the pharmacokinetics of asenapine was studied in subjects with mildly (creatinine clearance (CrCl) 51 to 80 mL/min; N=8), moderately (CrCl 30 to 50 mL/min; N=8), and severely (CrCl lessthan 30 mL/min but not on dialysis; N=8) impaired renal function and compared to normal subjects (CrCl greater than 80 mL/min; N=8). The exposureof asenapine following a single dose of 5 mg was similar among subjects with varying degrees of renal impairment and subjects with normal renal function. Dosage adjustment based upon degree of renal impairment is not required. The effect of renal function on the excretion of other metabolites and the effect of dialysis on the pharmacokinetics of asenapine has not been studied [see Use in Specific Populations (8.6)].

Geriatric Patients: In elderly patients with psychosis (65-85 years of age), asenapine concentrations were on average 30 to 40% higher compared to younger adults. When the range of exposures in the elderly was examined, the highest exposure for asenapine was up to 2-fold higher than the highest exposure in younger subjects. In a population pharmacokinetic analysis, a decrease in clearance with increasing age was observed, implying a 30% higher exposure in elderly as compared to adult patients [see Use in Specific Populations (8.5)].

Gender: The potential difference in asenapine pharmacokinetics between males and females was not studied in a dedicated trial. In a population pharmacokinetic analysis, no significant differences between genders were observed.

Race: In a population pharmacokinetic analysis, no effect of race on asenapine concentrations was observed. In a dedicated study, the pharmacokinetics of SAPHRIS were similar in Caucasian and Japanese subjects.

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13 Nonclinical Toxicology

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

Carcinogenesis: In a lifetime carcinogenicity study in CD-1 mice asenapine was administered subcutaneously at doses up to those resulting in plasma levels (AUC) estimated to be 5 times those in humans receiving the MRHD of 10 mg twice daily. The incidence of malignant lymphomas was increased in female mice, with a no-effect dose resulting in plasma levels estimated to be 1.5 times those in humans receiving the MRHD.The mouse strain used has a high and variable incidence of malignant lymphomas, and the significance of these results to humans is unknown.There were no increases in other tumor types in female mice. In male mice, there were no increases in any tumors.

In a lifetime carcinogenicity study in Sprague-Dawley rats, asenapine did not cause any increases in tumors when administered subcutaneously at doses up to those resulting in plasma levels (AUC) estimated to be 5 times those in humans receiving the MRHD.

Mutagenesis: No evidence for genotoxic potential of asenapine was found in the in vitro bacterial reverse mutation assay, the in vitro forward gene mutation assay in mouse lymphoma cells, the in vitro chromosomal aberration assays in human lymphocytes, the in vitro sister chromatid exchange assay in rabbit lymphocytes, or the in vivo micronucleus assay in rats.

Impairment of Fertility: Asenapine did not impair fertility in rats when tested at doses up to 11 mg/kg twice daily given orally. This dose is 10 times the maximum recommended human dose of 10 mg twice daily given sublingually on a mg/m2 basis.

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14 Clinical Studies

14.1 Schizophrenia

The efficacy of SAPHRIS in the treatment of schizophrenia in adults was evaluated in three fixed-dose, short-term (6 week), randomized, double-blind, placebo-controlled, and active-controlled (haloperidol, risperidone, and olanzapine) trials of adult patients who met DSM-IV criteria for schizophrenia and were having an acute exacerbation of their schizophrenic illness. In two of the three trials SAPHRIS demonstrated superior efficacy to placebo. In a third trial, SAPHRIS could not be distinguished from placebo; however, an active control in that trial was superior to placebo.

In the two positive trials for SAPHRIS, the primary efficacy rating scale was the Positive and Negative Syndrome Scale (PANSS), which assesses the symptoms of schizophrenia. The primary endpoint was change from baseline to endpoint on the PANSS total score. The results of the SAPHRIS trials in schizophrenia follow:

In trial 1, a 6-week trial (n=174), comparing SAPHRIS (5 mg twice daily) to placebo, SAPHRIS 5 mg twice daily was statistically superior to placebo on the PANSS total score.

In trial 2, a 6-week trial (n=448), comparing two fixed doses of SAPHRIS (5 mg and 10 mg twice daily) to placebo, SAPHRIS 5 mg twice daily was statistically superior to placebo on the PANSS total score. SAPHRIS 10 mg twice daily showed no added benefit compared to 5 mg twice daily and was not significantly different from placebo.

An examination of population subgroups did not reveal any clear evidence of differential responsiveness on the basis of age, gender or race.

14.2 Bipolar Disorder

The efficacy of SAPHRIS in the treatment of acute mania was established in two similarly designed 3-week, randomized, double-blind, placebo-controlled, and active-controlled (olanzapine) trials of adult patients who met DSM-IV criteria for Bipolar I Disorder with an acute manic or mixed episode with or without psychotic features.

The primary rating instrument used for assessing manic symptoms in these trials was the Young Mania Rating Scale (YMRS). Patients were also assessed on the Clinical Global Impression - Bipolar (CGI-BP) scale. In both trials, all patients randomized to SAPHRIS were initially administered 10 mg twice daily, and the dose could be adjusted within the dose range of 5 to 10 mg twice daily from Day 2 onward based on efficacy and tolerability. Ninety percent of patients remained on the 10 mg twice daily dose. SAPHRIS was statistically superior to placebo on the YMRS total score and the CGI-BP Severity of Illness score (mania) in both studies.

An examination of subgroups did not reveal any clear evidence of differential responsiveness on the basis of age, gender or race.

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16 How Supplied / Storage and Handling

SAPHRIS (asenapine) sublingual tablets are supplied as:

5 mg Tablets:

Round, white- to off-white sublingual tablets, with "5" on one side.
Child-resistant packaging
Box of 60 - 6 blisters with 10 tablets - NDC 0052-0118-06
Hospital Unit Dose
Box of 100 - 10 blisters with 10 tablets - NDC 0052-0118-90

10 mg Tablets:

Round, white- to off-white sublingual tablets, with "10" on one side.
Child-resistant packaging
Box of 60 - 6 blisters with 10 tablets - NDC 0052-0119-06
Hospital Unit Dose
Box of 100 - 10 blisters with 10 tablets - NDC 0052-0119-90

Storage

Store at 15°-30° C (59°-86° F) [see USP Controlled Room Temperature].

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17 Patient Counseling Information

17.1 Tablet Administration

Saphris Tablet Administration Information

[see Drug Interactions (7) and Clinical Pharmacology (12.3)].

17.2 Interference with Cognitive and Motor Performance

Patients should be cautioned about performing activities requiring mental alertness, such as operating hazardous machinery or operating a motor vehicle, until they are reasonably certain that SAPHRIS therapy does not affect them adversely [see Warnings and Precautions (5.12)].

17.3 Neuroleptic Malignant Syndrome

Patients and caregivers should be counseled that a potentially fatal symptom complex sometimes referred to as Neuroleptic Malignant Syndrome (NMS) has been reported in association with administration of antipsychotic drugs. Signs and symptoms of NMS include hyperpyrexia, muscle rigidity, altered mental status, and evidence of autonomic instability (irregular pulse or blood pressure, tachycardia, diaphoresis, and cardiac dysrhythmia) [see Warnings and Precautions (5.3)].

17.4 Orthostatic Hypotension

Patients should be advised of the risk of orthostatic hypotension (symptoms include feeling dizzy or lightheaded upon standing) especially early in treatment, and also at times of re-initiating treatment or increases in dose [see Warnings and Precautions (5.7)].

17.5 Pregnancy and Nursing

Patients should be advised to notify their physician if they become pregnant or intend to become pregnant during therapy with SAPHRIS. Patients should be advised not to breast feed if they are taking SAPHRIS [see Use in Special Populations (8.1, 8.3)].

17.6 Concomitant Medication and Alcohol

Patients should be advised to inform their physicians if they are taking, or plan to take, any prescription or over-the-counter medications since there is a potential for interactions. Patients should be advised to avoid alcohol while taking SAPHRIS [see Drug Interactions (7)].

17.7 Heat Exposure and Dehydration

Patients should be advised regarding appropriate care in avoiding overheating and dehydration [see Warnings and Precautions (5.13)].

Manufactured by Catalent UK Swindon Zydis Ltd., Blagrove, Swindon, Wiltshire, SN5 8RU, UK.

Distributed by Schering Corporation, a subsidiary of Schering-Plough Corporation,

Kenilworth, NJ 07033 USA.

U.S. Patent No. 5,763,476.

© 2009, Schering Corporation. All rights reserved.

Shering-Plough

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Last Revised: 8/2009

Asenapine (Saphris) Patient Information Sheet (in plain English)

Detailed Info on Signs, Symptoms, Causes, Treatments of Bipolar Disorder

Detailed Info on Signs, Symptoms, Causes, Treatments of Schizophrenia


The information in this monograph is not intended to cover all possible uses, directions, precautions, drug interactions or adverse effects. This information is generalized and is not intended as specific medical advice. If you have questions about the medicines you are taking or would like more information, check with your doctor, pharmacist, or nurse. Last updated 3/03.

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Intuniv (Guanfacine) Patient Information

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Find out why ADHD medication, Intuniv, is prescribed, side effects of Intuniv, Intuniv warnings, how Intuniv should be taken, more - in plain English.

Generic Name: Guanfacine
Brand Name: Intuniv

Pronounced: in-TOO-niv

Full Intuniv (Guanfacine) prescribing information

Read the Patient Information that comes with INTUNIVTM before you start taking it and each time you get a refill. There may be new information. This leaflet does not take the place of talking with your doctor about your medical condition or your treatment.

What is INTUNIV?

INTUNIV is a prescription medicine used to treat the symptoms of attention deficit/hyperactivity disorder (ADHD).

INTUNIV is not a central nervous system (CNS) stimulant.

INTUNIV should be used as a part of a total treatment program for ADHD that may include counselling or other therapies.

It is not known if INTUNIV is effective:

  • for use longer than 9 weeks

It is not known if INTUNIV is safe or effective:

  • in children younger than 6 years old
  • in adults

What should I tell my doctor before taking INTUNIV?

Before you take INTUNIV, tell your doctor if you:

  • have heart problems or a low heart rate
  • have fainted
  • have low blood pressure
  • have liver or kidney problems
  • have any other medical conditions
  • are pregnant or plan to become pregnant. It is not known if INTUNIV will harm your unborn baby. Talk to your doctor if you are pregnant or plan to become pregnant.
  • are breast-feeding or plan to breast-feed. It is not known if INTUNIV passes into your breast milk. You and your doctor should decide if you will take INTUNIV or breastfeed.

Tell your doctor about all of the medicines you take, including prescription and non-prescription medicines, vitamins, and herbal supplements.

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INTUNIV may affect the way other medicines work, and other medicines may affect how INTUNIV works.

Especially tell your doctor if you take:

  • ketoconazole
  • medicines that can affect enzyme metabolism
  • valproic acid
  • high blood pressure medicine
  • sedatives
  • benzodiazepines
  • barbiturates
  • antipsychotics

Ask your doctor or pharmacist for a list of these medicines, if you are not sure.

Know the medicines you take. Keep a list of them and show it to your doctor and pharmacist when you get a new medicine.

How should I take INTUNIV?

  • Take INTUNIV exactly as your doctor tells you.
  • Your doctor may change your dose. Do not change your dose of INTUNIV without talking to your doctor.
  • Do not stop taking INTUNIV without talking to your doctor.
  • INTUNIV should be taken 1 time a day.
  • INTUNIV should be swallowed whole with a small amount of water, milk, or other liquid.
  • Do not crush, chew, or break INTUNIV. Tell your doctor if you can not swallow INTUNIV whole.
  • Do not take INTUNIV with a high-fat meal.
  • Your doctor will check your blood pressure and heart rate while you take INTUNIV.
  • If you take too much INTUNIV, call your local Poison Control Center or go to the nearest emergency room right away.

What should I avoid while taking INTUNIV?

  • Do not drive, operate heavy machinery, or do other dangerous activities until you know how INTUNIV affects you. INTUNIV can slow your thinking and motor skills.
  • Do not drink alcohol or take other medicines that make you sleepy or dizzy while taking INTUNIV until you talk with your doctor. INTUNIV taken with alcohol or medicines that cause sleepiness or dizziness may make your sleepiness or dizziness worse.

What are the possible side effects of INTUNIV?

INTUNIV may cause serious side effects including:

  • low blood pressure
  • low heart rate
  • fainting
  • sleepiness
  • tiredness
  • drowsiness

Get medical help right away, if you have any of the symptoms listed above.

The most common side effects of INTUNIV include:

  • sleepiness
  • drowsiness
  • low blood pressure
  • headache
  • nausea
  • stomach pain
  • dry mouth
  • dizziness
  • irritability
  • constipation
  • not hungry (decreased appetite)

Tell the doctor if you have any side effect that bothers you or that does not go away.

These are not all the possible side effects of INTUNIV. For more information, ask your doctor or pharmacist.

Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

How should I store INTUNIV?

  • Store INTUNIV between 590F to 860F (15oC to 30oC)

Keep INTUNIV and all medicines out of the reach of children.

General Information about INTUNIV

Medicines are sometimes prescribed for purposes other than those listed in a Patient Information Leaflet. Do not use INTUNIV for a condition for which it was not prescribed. Do not give INTUNIV to other people, even if they have the same symptoms that you have. It may harm them.

This leaflet summarizes the most important information about INTUNIV. If you would like more information, talk with your doctor. You can ask your pharmacist or doctor for information about INTUNIV that is written for health professionals.

For more information, go to www.INTUNIV.com or call 1-800-828-2088.

What are the ingredients in INTUNIV?

Active ingredient: guanfacine hydrochloride

Inactive ingredients: hypromellose, methacrylic acid copolymer, lactose, povidone, crospovidone, microcrystalline cellulose, fumaric acid, and glycerol behenate. In addition, the 3mg and 4mg tablets also contain green pigment blend PB-1763.

Manufactured for Shire US Inc., Wayne, PA 19087.

INTUNIV is a trademark of Shire LLC.

©2009 Shire Pharmaceuticals Inc.

This product is covered by US patents including 5,854,290; 6,287,599; 6,811,794.

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Version: August 2009

Full Intuniv (Guanfacine) prescribing information

back to: Psychiatric Medication Patient Information Index

Lamotrigine Full Prescribing Information

PDF

Brand Name: Lamictal
Generic Name: Lamotrigine

Lamotrigine (Lamictal) is an anticonvulsant drug used to treat bipolar disorder (mood stabilizer) and epilepsy. Uses, dosage, side effects of Lamictal.

Contents:

Description
Clinical Pharmacology
Indications and Usage
Contraindications
Warnings
Precautions
Drug Interactions
Adverse Reactions
Overdose
Dosage
Supplied

Lamictal Patient Information (in plain English)

WARNING

SERIOUS RASHES REQUIRING HOSPITALIZATION AND DISCONTINUATION OF TREATMENT HAVE BEEN REPORTED IN ASSOCIATION WITH THE USE OF LAMICTAL. THE INCIDENCE OF THESE RASHES, WHICH HAVE INCLUDED STEVENS-JOHNSON SYNDROME, IS APPROXIMATELY 0.8% (8 PER 1,000) IN PEDIATRIC PATIENTS (AGE <16 YEARS) RECEIVING LAMICTAL AS ADJUNCTIVE THERAPY FOR EPILEPSY AND 0.3% (3 PER 1,000) IN ADULTS ON ADJUNCTIVE THERAPY FOR EPILEPSY. IN CLINICAL TRIALS OF BIPOLAR AND OTHER MOOD DISORDERS, THE RATE OF SERIOUS RASH WAS 0.08% (0.8 PER 1,000) IN ADULT PATIENTS RECEIVING LAMICTAL AS INITIAL MONOTHERAPY AND 0.13% (1.3 PER 1,000) IN ADULT PATIENTS RECEIVING LAMICTAL AS ADJUNCTIVE THERAPY. IN A PROSPECTIVELY FOLLOWED COHORT OF 1,983 PEDIATRIC PATIENTS WITH EPILEPSY TAKING ADJUNCTIVE LAMICTAL, THERE WAS 1 RASH-RELATED DEATH. IN WORLDWIDE POSTMARKETING EXPERIENCE, RARE CASES OF TOXIC EPIDERMAL NECROLYSIS AND/OR RASH-RELATED DEATH HAVE BEEN REPORTED IN ADULT AND PEDIATRIC PATIENTS, BUT THEIR NUMBERS ARE TOO FEW TO PERMIT A PRECISE ESTIMATE OF THE RATE.

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BECAUSE THE RATE OF SERIOUS RASH IS GREATER IN PEDIATRIC PATIENTS THAN IN ADULTS, IT BEARS EMPHASIS THAT LAMICTAL IS APPROVED ONLY FOR USE IN PEDIATRIC PATIENTS BELOW THE AGE OF 16 YEARS WHO HAVE SEIZURES ASSOCIATED WITH THE LENNOX-GASTAUT SYNDROME OR IN PATIENTS WITH PARTIAL SEIZURES (SEE INDICATIONS). OTHER THAN AGE, THERE ARE AS YET NO FACTORS IDENTIFIED THAT ARE KNOWN TO PREDICT THE RISK OF OCCURRENCE OR THE SEVERITY OF RASH ASSOCIATED WITH LAMICTAL. THERE ARE SUGGESTIONS, YET TO BE PROVEN, THAT THE RISK OF RASH MAY ALSO BE INCREASED BY (1) COADMINISTRATION OF LAMICTAL WITH VALPROATE (INCLUDES VALPROIC ACID AND DIVALPROEX SODIUM), (2) EXCEEDING THE RECOMMENDED INITIAL DOSE OF LAMICTAL, OR (3) EXCEEDING THE RECOMMENDED DOSE ESCALATION FOR LAMICTAL. HOWEVER, CASES HAVE BEEN REPORTED IN THE ABSENCE OF THESE FACTORS.

NEARLY ALL CASES OF LIFE-THREATENING RASHES ASSOCIATED WITH LAMICTAL HAVE OCCURRED WITHIN 2 TO 8 WEEKS OF TREATMENT INITIATION. HOWEVER, ISOLATED CASES HAVE BEEN REPORTED AFTER PROLONGED TREATMENT (E.G., 6 MONTHS). ACCORDINGLY, DURATION OF THERAPY CANNOT BE RELIED UPON AS A MEANS TO PREDICT THE POTENTIAL RISK HERALDED BY THE FIRST APPEARANCE OF A RASH.

ALTHOUGH BENIGN RASHES ALSO OCCUR WITH LAMICTAL, IT IS NOT POSSIBLE TO PREDICT RELIABLY WHICH RASHES WILL PROVE TO BE SERIOUS OR LIFE THREATENING. ACCORDINGLY, LAMICTAL SHOULD ORDINARILY BE DISCONTINUED AT THE FIRST SIGN OF RASH, UNLESS THE RASH IS CLEARLY NOT DRUG RELATED. DISCONTINUATION OF TREATMENT MAY NOT PREVENT A RASH FROM BECOMING LIFE THREATENING OR PERMANENTLY DISABLING OR DISFIGURING.

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Description

LAMICTAL (lamotrigine), an antiepileptic drug (AED) of the phenyltriazine class, is chemically unrelated to existing antiepileptic drugs. Its chemical name is 3,5-diamino-6-(2,3-dichlorophenyl)-as-triazine, its molecular formula is C9H7N5Cl2, and its molecular weight is 256.09. Lamotrigine is a white to pale cream-colored powder and has a pKa of 5.7. Lamotrigine is very slightly soluble in water (0.17 mg/mL at 25°C) and slightly soluble in 0.1 M HCl (4.1 mg/mL at 25°C). The structural formula is:

Lamictal structural formula

LAMICTAL Tablets are supplied for oral administration as 25-mg (white), 100-mg (peach), 150-mg (cream), and 200-mg (blue) tablets. Each tablet contains the labeled amount of lamotrigine and the following inactive ingredients: lactose; magnesium stearate; microcrystalline cellulose; povidone; sodium starch glycolate; FD&C Yellow No. 6 Lake (100-mg tablet only); ferric oxide, yellow (150-mg tablet only); and FD&C Blue No. 2 Lake (200-mg tablet only).

LAMICTAL Chewable Dispersible Tablets are supplied for oral administration. The tablets contain 2 mg (white), 5 mg (white), or 25 mg (white) of lamotrigine and the following inactive ingredients: blackcurrant flavor, calcium carbonate, low-substituted hydroxypropylcellulose, magnesium aluminum silicate, magnesium stearate, povidone, saccharin sodium, and sodium starch glycolate.

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Clinical Pharmacology

Mechanism of Action: The precise mechanism(s) by which lamotrigine exerts its anticonvulsant action are unknown. In animal models designed to detect anticonvulsant activity, lamotrigine was effective in preventing seizure spread in the maximum electroshock (MES) and pentylenetetrazol (scMet) tests, and prevented seizures in the visually and electrically evoked after-discharge (EEAD) tests for antiepileptic activity. The relevance of these models to human epilepsy, however, is not known.

One proposed mechanism of action of LAMICTAL, the relevance of which remains to be established in humans, involves an effect on sodium channels. In vitro pharmacological studies suggest that lamotrigine inhibits voltage-sensitive sodium channels, thereby stabilizing neuronal membranes and consequently modulating presynaptic transmitter release of excitatory amino acids (e.g., glutamate and aspartate).

LAMICTAL also displayed inhibitory properties in the kindling model in rats both during kindling development and in the fully kindled state. The relevance of this animal model to specific types of human epilepsy is unclear.

The mechanisms by which lamotrigine exerts its therapeutic action in Bipolar Disorder have not been established.

Pharmacological Properties: Although the relevance for human use is unknown, the following data characterize the performance of LAMICTAL in receptor binding assays. Lamotrigine had a weak inhibitory effect on the serotonin 5-HT3 receptor (IC50 = 18 µM). It does not exhibit high affinity binding (IC50>100 µM) to the following neurotransmitter receptors: adenosine A1 and A2; adrenergic a1, a2, and b; dopamine D1 and D2; g-aminobutyric acid (GABA) A and B; histamine H1; kappa opioid; muscarinic acetylcholine; and serotonin 5-HT2. Studies have failed to detect an effect of lamotrigine on dihydropyridine-sensitive calcium channels. It had weak effects at sigma opioid receptors (IC50 = 145 µM). Lamotrigine did not inhibit the uptake of norepinephrine, dopamine, or serotonin, (IC50>200 µM) when tested in rat synaptosomes and/or human platelets in vitro.

Effect of Lamotrigine on N-Methyl d-Aspartate-Receptor Mediated Activity:

Lamotrigine did not inhibit N-methyl d-aspartate (NMDA)-induced depolarizations in rat cortical slices or NMDA-induced cyclic GMP formation in immature rat cerebellum, nor did lamotrigine displace compounds that are either competitive or noncompetitive ligands at this glutamate receptor complex (CNQX, CGS, TCHP). The IC50 for lamotrigine effects on NMDA-induced currents (in the presence of 3 µM of glycine) in cultured hippocampal neurons exceeded 100 µM.

Folate Metabolism: In vitro, lamotrigine was shown to be an inhibitor of dihydrofolate reductase, the enzyme that catalyzes the reduction of dihydrofolate to tetrahydrofolate. Inhibition of this enzyme may interfere with the biosynthesis of nucleic acids and proteins. When oral daily doses of lamotrigine were given to pregnant rats during organogenesis, fetal, placental, and maternal folate concentrations were reduced. Significantly reduced concentrations of folate are associated with teratogenesis (see PRECAUTIONS: Pregnancy). Folate concentrations were also reduced in male rats given repeated oral doses of lamotrigine. Reduced concentrations were partially returned to normal when supplemented with folinic acid.

Accumulation in Kidneys: Lamotrigine was found to accumulate in the kidney of the male rat, causing chronic progressive nephrosis, necrosis, and mineralization. These findings are attributed to a-2 microglobulin, a species- and sex-specific protein that has not been detected in humans or other animal species.

Melanin Binding: Lamotrigine binds to melanin-containing tissues, e.g., in the eye and pigmented skin. It has been found in the uveal tract up to 52 weeks after a single dose in rodents.

Cardiovascular: In dogs, lamotrigine is extensively metabolized to a 2-N-methyl metabolite. This metabolite causes dose-dependent prolongations of the PR interval, widening of the QRS complex, and, at higher doses, complete AV conduction block. Similar cardiovascular effects are not anticipated in humans because only trace amounts of the 2-N-methyl metabolite (<0.6% of lamotrigine dose) have been found in human urine (see Drug Disposition). However, it is conceivable that plasma concentrations of this metabolite could be increased in patients with a reduced capacity to glucuronidate lamotrigine (e.g., in patients with liver disease).

Pharmacokinetics and Drug Metabolism: The pharmacokinetics of lamotrigine have been studied in patients with epilepsy, healthy young and elderly volunteers, and volunteers with chronic renal failure. Lamotrigine pharmacokinetic parameters for adult and pediatric patients and healthy normal volunteers are summarized in Tables 1 and 2.

Table 1. Mean* Pharmacokinetic Parameters in Healthy Volunteers and Adult Patients With Epilepsy

Adult Study Population

Number of Subjects

Tmax: Time of Maximum Plasma Concentration (h)

t ½: Elimination Half-life (h)

Cl/F: Apparent Plasma Clearance (mL/min/kg)

Healthy volunteers taking no other medications:

Single-dose LAMICTAL

179

2.2(0.25-12.0)

32.8(14.0-103.0)

0.44(0.12-1.10)

Multiple-dose LAMICTAL

36

1.7(0.5-4.0)

25.4(11.6-61.6)

0.58(0.24-1.15)

Healthy volunteers taking valproate:

Single-dose LAMICTAL

6

1.8(1.0-4.0)

48.3(31.5-88.6)

0.30(0.14-0.42)

Multiple-dose LAMICTAL

18

1.9(0.5-3.5)

70.3(41.9-113.5)

0.18(0.12-0.33)

Patients with epilepsy taking valproate only:

Single-dose LAMICTAL

4

4.8(1.8-8.4)

58.8(30.5-88.8)

0.28(0.16-0.40)

Patients with epilepsy taking carbamazepine, phenytoin, phenobarbital, or primidone† plus valproate:

Single-dose LAMICTAL

25

3.8 (1.0-10.0)

27.2 (11.2-51.6)

0.53 (0.27-1.04)

Patients with epilepsy taking carbamazepine, phenytoin, phenobarbital, or primidone†:

Single-dose LAMICTAL

24

2.3(0.5-5.0)

14.4(6.4-30.4)

1.10(0.51-2.22)

Multiple-dose LAMICTAL

17

2.0(0.75-5.93)

12.6(7.5-23.1)

1.21(0.66-1.82)

*The majority of parameter means determined in each study had coefficients of variation between 20% and 40% for half-life and Cl/F and between 30% and 70% for Tmax. The overall mean values were calculated from individual study means that were weighted based on the number of volunteers/patients in each study. The numbers in parentheses below each parameter mean represent the range of individual volunteer/patient values across studies. Examples of EIAEDs are carbamazepine, phenobarbital, phenytoin, and primidone.

Absorption: Lamotrigine is rapidly and completely absorbed after oral administration with negligible first-pass metabolism (absolute bioavailability is 98%). The bioavailability is not affected by food. Peak plasma concentrations occur anywhere from 1.4 to 4.8 hours following drug administration. The lamotrigine chewable/dispersible tablets were found to be equivalent, whether they were administered as dispersed in water, chewed and swallowed, or swallowed as whole, to the lamotrigine compressed tablets in terms of rate and extent of absorption.

Distribution: Estimates of the mean apparent volume of distribution (Vd/F) of lamotrigine following oral administration ranged from 0.9 to 1.3 L/kg. Vd/F is independent of dose and is similar following single and multiple doses in both patients with epilepsy and in healthy volunteers.

Protein Binding: Data from in vitro studies indicate that lamotrigine is approximately 55% bound to human plasma proteins at plasma lamotrigine concentrations from 1 to 10 mcg/mL (10 mcg/mL is 4 to 6 times the trough plasma concentration observed in the controlled efficacy trials). Because lamotrigine is not highly bound to plasma proteins, clinically significant interactions with other drugs through competition for protein binding sites are unlikely. The binding of lamotrigine to plasma proteins did not change in the presence of therapeutic concentrations of phenytoin, phenobarbital, or valproate. Lamotrigine did not displace other AEDs (carbamazepine, phenytoin, phenobarbital) from protein binding sites.

Drug Disposition: Lamotrigine is metabolized predominantly by glucuronic acid conjugation; the major metabolite is an inactive 2-N-glucuronide conjugate. After oral administration of 240 mg of 14C-lamotrigine (15 mCi) to 6 healthy volunteers, 94% was recovered in the urine and 2% was recovered in the feces. The radioactivity in the urine consisted of unchanged lamotrigine (10%), the 2-N-glucuronide (76%), a 5-N-glucuronide (10%), a 2-N-methyl metabolite (0.14%), and other unidentified minor metabolites (4%).

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Drug Interactions

The apparent clearance of lamotrigine is affected by the coadministration of certain medications. Since lamotrigine is metabolized predominantly by glucuronic acid conjugation, drugs that induce or inhibit glucuronidation may affect the apparent clearance of lamotrigine.

Carbamazepine, phenytoin, phenobarbital, and primidone have been shown to increase the apparent clearance of lamotrigine (see DOSAGE AND ADMINISTRATION and PRECAUTIONS: Drug Interactions). Most clinical experience is derived from patients taking these AEDs.

Oral contraceptives and rifampin have also been shown to increase the apparent clearance of lamotrigine (see PRECAUTIONS: Drug Interactions).

Valproate decreases the apparent clearance of lamotrigine (i.e., more than doubles the elimination half-life of lamotrigine), whether given with or without carbamazepine, phenytoin, phenobarbital, or primidone. Accordingly, if lamotrigine is to be administered to a patient receiving valproate, lamotrigine must be given at a reduced dosage, of no more than half the dose used in patients not receiving valproate, even in the presence of drugs that increase the apparent clearance of lamotrigine (see DOSAGE AND ADMINISTRATION and PRECAUTIONS: Drug Interactions).

Oxcarbazepine and levetiracetam do not affect the apparent clearance of lamotrigine PRECAUTIONS: Drug Interactions).

In vitro inhibition experiments indicated that the formation of the primary metabolite of lamotrigine, the 2-N-glucuronide, was not significantly affected by co-incubation with clozapine, fluoxetine, phenelzine, risperidone, sertraline, or trazodone, and was minimally affected by co-incubation with amitriptyline, bupropion, clonazepam, haloperidol, or lorazepam. In addition, bufuralol metabolism data from human liver microsomes suggested that lamotrigine does not inhibit the metabolism of drugs eliminated predominantly by CYP2D6.

LAMICTAL has no effects on the pharmacokinetics of lithium (see PRECAUTIONS: Drug Interactions).

The pharmacokinetics of LAMICTAL were not changed by co-administration of bupropion (see PRECAUTIONS: Drug Interactions).

Enzyme Induction: The effects of lamotrigine on the induction of specific families of mixed-function oxidase isozymes have not been systematically evaluated.

Following multiple administrations (150 mg twice daily) to normal volunteers taking no other medications, lamotrigine induced its own metabolism, resulting in a 25% decrease in t ½ and a 37% increase in Cl/F at steady state compared to values obtained in the same volunteers following a single dose. Evidence gathered from other sources suggests that self-induction by LAMICTAL may not occur when LAMICTAL is given as adjunctive therapy in patients receiving carbamazepine, phenytoin, phenobarbital, primidone, or rifampin.

Dose Proportionality: In healthy volunteers not receiving any other medications and given single doses, the plasma concentrations of lamotrigine increased in direct proportion to the dose administered over the range of 50 to 400 mg. In 2 small studies (n = 7 and 8) of patients with epilepsy who were maintained on other AEDs, there also was a linear relationship between dose and lamotrigine plasma concentrations at steady state following doses of 50 to 350 mg twice daily.

Elimination: (see Table 1).

Special Populations: Patients With Renal Insufficiency: Twelve volunteers with chronic renal failure (mean creatinine clearance = 13 mL/min; range = 6 to 23) and another 6 individuals undergoing hemodialysis were each given a single 100-mg dose of LAMICTAL. The mean plasma half-lives determined in the study were 42.9 hours (chronic renal failure), 13.0 hours (during hemodialysis), and 57.4 hours (between hemodialysis) compared to 26.2 hours in healthy volunteers. On average, approximately 20% (range = 5.6 to 35.1) of the amount of lamotrigine present in the body was eliminated by hemodialysis during a 4-hour session.

Hepatic Disease: The pharmacokinetics of lamotrigine following a single 100-mg dose of LAMICTAL were evaluated in 24 subjects with moderate to severe hepatic dysfunction and compared with 12 subjects without hepatic impairment. The median apparent clearance of lamotrigine was 0.31, 0.24, or 0.10 mL/kg/min in patients with Grade A, B, or C (Child-Pugh Classification) hepatic impairment, respectively, compared to 0.34 mL/kg/min in the healthy controls. Median half-life of lamotrigine was 36, 60, or 110 hours in patients with Grade A, B, or C hepatic impairment, respectively, versus 32 hours in healthy controls.

Age: Pediatric Patients: The pharmacokinetics of LAMICTAL following a single 2-mg/kg dose were evaluated in 2 studies of pediatric patients (n = 29 for patients aged 10 months to 5.9 years and n = 26 for patients aged 5 to 11 years). Forty-three patients received concomitant therapy with other AEDS and 12 patients received LAMICTAL as monotherapy. Lamotrigine pharmacokinetic parameters for pediatric patients are summarized in Table 2.

Population pharmacokinetic analyses involving patients aged 2 to 18 years demonstrated that lamotrigine clearance was influenced predominantly by total body weight and concurrent AED therapy. The oral clearance of lamotrigine was higher, on a body weight basis, in pediatric patients than in adults. Weight-normalized lamotrigine clearance was higher in those subjects weighing less than 30 kg, compared with those weighing greater than 30 kg. Accordingly, patients weighing less than 30 kg may need an increase of as much as 50% in maintenance doses, based on clinical response, as compared with subjects weighing more than 30 kg being administered the same AEDs (see DOSAGE AND ADMINISTRATION). These analyses also revealed that, after accounting for body weight, lamotrigine clearance was not significantly influenced by age. Thus, the same weight-adjusted doses should be administered to children irrespective of differences in age. Concomitant AEDs which influence lamotrigine clearance in adults were found to have similar effects in children.

Table 2. Mean Pharmacokinetic Parameters in Pediatric Patients With Epilepsy

Pediatric Study Population

Number of Subjects

Tmax (h)

t ½ (h)

Cl/F (mL/min/kg)

Ages 10 months-5.3 years
Patients taking carbamazepine, phenytoin, phenobarbital, or primidone*

10

3.0(1.0-5.9)

7.7(5.7-11.4)

3.62(2.44-5.28)

Patients taking antiepileptic drugs (AEDs) with no known effect on the apparent clearance of
lamotrigine

7

5.2(2.9-6.1)

19.0(12.9-27.1)

1.2(0.75-2.42)

Patients taking valproate only*

8

2.9(1.0-6.0)

44.9(29.5-52.5)

0.47(0.23-0.77)

Ages 5-11 years
Patients taking carbamazepine, phenytoin, phenobarbital, or primidone*

7

1.6(1.0-3.0)

7.0(3.8-9.8)

2.54(1.35-5.58)

Patients taking carbamazepine, phenytoin, phenobarbital, or primidone* plus valproate

8

3.3(1.0-6.4)

19.1(7.0-31.2)

0.89(0.39-1.93)

Patients taking valproate only

3

4.5(3.0-6.0)

65.8(50.7-73.7)

0.24(0.21-0.26)

Ages 13-18 years
Patients taking carbamazepine phenytoin, phenobarbital, or primidone*

11

†

†

1.3

Patients taking carbamazepine, phenytoin, phenobarbital, or primidone* plus valproate

8

†

†

0.5

Patients taking valproate only

4

†

†

0.3

*Two subjects were included in the calculation for mean Tmax.

† Parameter not estimated.

Elderly: The pharmacokinetics of lamotrigine following a single 150-mg dose of LAMICTAL were evaluated in 12 elderly volunteers between the ages of 65 and 76 years (mean creatinine clearance = 61 mL/min, range = 33 to 108 mL/min). The mean half-life of lamotrigine in these subjects was 31.2 hours (range, 24.5 to 43.4 hours), and the mean clearance was 0.40 mL/min/kg (range, 0.26 to 0.48 mL/min/kg).

Gender: The clearance of lamotrigine is not affected by gender.

Race: The apparent oral clearance of lamotrigine was 25% lower in non-Caucasians than Caucasians.

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Clinical Studies

Epilepsy: The results of controlled clinical trials established the efficacy of LAMICTAL as monotherapy in adults with partial onset seizures already receiving treatment with a single enzyme-inducing antiepileptic drug (EIAED), as adjunctive therapy in adults and pediatric patients age 2 to 16 with partial seizures, and as adjunctive therapy in the generalized seizures of Lennox-Gastaut syndrome in pediatric and adult patients.

Monotherapy With LAMICTAL in Adults With Partial Seizures Already Receiving Treatment With Carbamazepine, Phenytoin, Phenobarbital, or Primidone as the Single AED: The effectiveness of monotherapy with LAMICTAL was established in a multicenter, double-blind clinical trial enrolling 156 adult outpatients with partial seizures. The patients experienced at least 4 simple partial, complex partial, and/or secondarily generalized seizures during each of 2 consecutive 4-week periods while receiving carbamazepine or phenytoin monotherapy during baseline. LAMICTAL (target dose of 500 mg/day) or valproate (1,000 mg/day) was added to either carbamazepine or phenytoin monotherapy over a 4-week period. Patients were then converted to monotherapy with LAMICTAL or valproate during the next 4 weeks, then continued on monotherapy for an additional 12-week period.

Study endpoints were completion of all weeks of study treatment or meeting an escape criterion. Criteria for escape relative to baseline were: (1) doubling of average monthly seizure count, (2) doubling of highest consecutive 2-day seizure frequency, (3) emergence of a new seizure type (defined as a seizure that did not occur during the 8-week baseline) that is more severe than seizure types that occur during study treatment, or (4) clinically significant prolongation of generalized-tonic-clonic (GTC) seizures. The primary efficacy variable was the proportion of patients in each treatment group who met escape criteria.

The percentage of patients who met escape criteria was 42% (32/76) in the LAMICTAL group and 69% (55/80) in the valproate group. The difference in the percentage of patients meeting escape criteria was statistically significant (p = 0.0012) in favor of LAMICTAL. No differences in efficacy based on age, sex, or race were detected.

Patients in the control group were intentionally treated with a relatively low dose of valproate; as such, the sole objective of this study was to demonstrate the effectiveness and safety of monotherapy with LAMICTAL, and cannot be interpreted to imply the superiority of LAMICTAL to an adequate dose of valproate.

Adjunctive Therapy With LAMICTAL in Adults With Partial Seizures: The effectiveness of LAMICTAL as adjunctive therapy (added to other AEDs) was established in 3 multicenter, placebo-controlled, double-blind clinical trials in 355 adults with refractory partial seizures. The patients had a history of at least 4 partial seizures per month in spite of receiving one or more AEDs at therapeutic concentrations and, in 2 of the studies, were observed on their established AED regimen during baselines that varied between 8 to 12 weeks. In the third, patients were not observed in a prospective baseline. In patients continuing to have at least 4 seizures per month during the baseline, LAMICTAL or placebo was then added to the existing therapy. In all 3 studies, change from baseline in seizure frequency was the primary measure of effectiveness. The results given below are for all partial seizures in the intent-to-treat population (all patients who received at least one dose of treatment) in each study, unless otherwise indicated. The median seizure frequency at baseline was 3 per week while the mean at baseline was 6.6 per week for all patients enrolled in efficacy studies.

One study (n = 216) was a double-blind, placebo-controlled, parallel trial consisting of a 24-week treatment period. Patients could not be on more than 2 other anticonvulsants and valproate was not allowed. Patients were randomized to receive placebo, a target dose of 300 mg/day of LAMICTAL, or a target dose of 500 mg/day of LAMICTAL. The median reductions in the frequency of all partial seizures relative to baseline were 8% in patients receiving placebo, 20% in patients receiving 300 mg/day of LAMICTAL, and 36% in patients receiving 500 mg/day of LAMICTAL. The seizure frequency reduction was statistically significant in the 500-mg/day group compared to the placebo group, but not in the 300-mg/day group.

A second study (n = 98) was a double-blind, placebo-controlled, randomized, crossover trial consisting of two 14-week treatment periods (the last 2 weeks of which consisted of dose tapering) separated by a 4-week washout period. Patients could not be on more than 2 other anticonvulsants and valproate was not allowed. The target dose of LAMICTAL was 400 mg/day. When the first 12 weeks of the treatment periods were analyzed, the median change in seizure frequency was a 25% reduction on LAMICTAL compared to placebo (p<0.001).

The third study (n = 41) was a double-blind, placebo-controlled, crossover trial consisting two 12-week treatment periods separated by a 4-week washout period. Patients could not be o more than 2 other anticonvulsants. Thirteen patients were on concomitant valproate; these patients received 150 mg/day of LAMICTAL. The 28 other patients had a target dose of 300 mg/day of LAMICTAL. The median change in seizure frequency was a 26% reduction o LAMICTAL compared to placebo (p<0.01).

No differences in efficacy based on age, sex, or race, as measured by change in seizure frequency, were detected.

Adjunctive Therapy With LAMICTAL in Pediatric Patients With Partial Seizures: The effectiveness of LAMICTAL as adjunctive therapy in pediatric patients with partial seizures was established in a multicenter, double-blind, placebo-controlled trial in 199 patients aged 2 to 16 years (n = 98 on LAMICTAL, n = 101 on placebo). Following an 8-week baseline phase, patients were randomized to 18 weeks of treatment with LAMICTAL or placebo added to their current AED regimen of up to 2 drugs. Patients were dosed based on body weight and valproate use. Target doses were designed to approximate 5 mg/kg per day for patients taking valproate (maximum dose, 250 mg/day) and 15 mg/kg per day for the patients not taking valproate (maximum dose, 750 mg per day). The primary efficacy endpoint was percentage change from baseline in all partial seizures. For the intent-to-treat population, the median reduction of all partial seizures was 36% in patients treated with LAMICTAL and 7% on placebo, a difference that was statistically significant (p<0.01).

Adjunctive Therapy With LAMICTAL in Pediatric and Adult Patients With Lennox-Gastaut Syndrome: The effectiveness of LAMICTAL as adjunctive therapy in patients with Lennox-Gastaut syndrome was established in a multicenter, double-blind, placebo-controlled trial in 169 patients aged 3 to 25 years (n = 79 on LAMICTAL, n = 90 on placebo). Following a 4-week single-blind, placebo phase, patients were randomized to 16 weeks of treatment with LAMICTAL or placebo added to their current AED regimen of up to 3 drugs. Patients were dosed on a fixed-dose regimen based on body weight and valproate use. Target doses were designed to approximate 5 mg/kg per day for patients taking valproate (maximum dose, 200 mg/day) and 15 mg/kg per day for patients not taking valproate (maximum dose, 400 mg/day). The primary efficacy endpoint was percentage change from baseline in major motor seizures (atonic, tonic, major myoclonic, and tonic-clonic seizures). For the intent-to-treat population, the median reduction of major motor seizures was 32% in patients treated with LAMICTAL and 9% on placebo, a difference that was statistically significant (p<0.05). Drop attacks were significantly reduced by LAMICTAL (34%) compared to placebo (9%), as were tonic-clonic seizures (36% reduction versus 10% increase for LAMICTAL and placebo, respectively).

Bipolar Disorder: The effectiveness of LAMICTAL in the maintenance treatment of Bipolar I Disorder was established in 2 multicenter, double-blind, placebo-controlled studies in adult patients who met DSM-IV criteria for Bipolar I Disorder. Study 1 enrolled patients with a current or recent (within 60 days) depressive episode as defined by DSM-IV and Study 2 included patients with a current or recent (within 60 days) episode of mania or hypomania as defined by DSM-IV. Both studies included a cohort of patients (30% of 404 patients in Study 1 and 28% of 171 patients in Study 2) with rapid cycling Bipolar Disorder (4 to 6 episodes per year).

In both studies, patients were titrated to a target dose of 200 mg of LAMICTAL, as add-on therapy or as monotherapy, with gradual withdrawal of any psychotropic medications during an 8- to 16-week open-label period. Overall 81% of 1,305 patients participating in the open-label period were receiving 1 or more other psychotropic medications, including benzodiazepines, selective serotonin reuptake inhibitors (SSRIs), atypical antipsychotics (including olanzapine), valproate, or lithium, during titration of LAMICTAL. Patients with a CGI-severity score of 3 or less maintained for at least 4 continuous weeks, including at least the final week on monotherapy with LAMICTAL, were randomized to a placebo-controlled, double-blind treatment period for up to 18 months. The primary endpoint was TIME (time to intervention for a mood episode or one that was emerging, time to discontinuation for either an adverse event that was judged to be related to Bipolar Disorder, or for lack of efficacy). The mood episode could be depression, mania, hypomania, or a mixed episode.

In Study 1, patients received double-blind monotherapy with LAMICTAL, 50 mg/day (n = 50), LAMICTAL 200 mg/day (n = 124), LAMICTAL 400 mg/day (n = 47), or placebo (n = 121). LAMICTAL (200- and 400-mg/day treatment groups combined) was superior to placebo in delaying the time to occurrence of a mood episode. Separate analyses of the 200 and 400 mg/day dose groups revealed no added benefit from the higher dose.

In Study 2, patients received double-blind monotherapy with LAMICTAL (100 to 400 mg/day, n = 59), or placebo (n = 70). LAMICTAL was superior to placebo in delaying time to occurrence of a mood episode. The mean LAMICTAL dose was about 211 mg/day. Although these studies were not designed to separately evaluate time to the occurrence of depression or mania, a combined analysis for the 2 studies revealed a statistically significant benefit for LAMICTAL over placebo in delaying the time to occurrence of both depression and mania, although the finding was more robust for depression.

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Indications and Usage

Epilepsy:

Adjunctive Use: LAMICTAL is indicated as adjunctive therapy for partial seizures in adults and pediatric patients ( 2 years of age).

LAMICTAL is also indicated as adjunctive therapy for the generalized seizures of Lennox-Gastaut syndrome in adult and pediatric patients ( 2 years of age).

Monotherapy Use: LAMICTAL is indicated for conversion to monotherapy in adults with partial seizures who are receiving treatment with carbamazepine, phenytoin, phenobarbital, primidone, or valproate as the single AED.

Safety and effectiveness of LAMICTAL have not been established (1) as initial monotherapy, (2) for conversion to monotherapy from AEDs other than carbamazepine, phenytoin, phenobarbital, primidone, or valproate, or (3) for simultaneous conversion to monotherapy from 2 or more concomitant AEDs (see DOSAGE AND ADMINISTRATION).

Bipolar Disorder: LAMICTAL is indicated for the maintenance treatment of Bipolar I Disorder to delay the time to occurrence of mood episodes (depression, mania, hypomania, mixed episodes) in patients treated for acute mood episodes with standard therapy. The effectiveness of LAMICTAL in the acute treatment of mood episodes has not been established.

The effectiveness of LAMICTAL as maintenance treatment was established in 2 placebo-controlled trials of 18 months' duration in patients with Bipolar I Disorder as defined by DSM-IV (see CLINICAL STUDIES, Bipolar Disorder). The physician who elects to use LAMICTAL for periods extending beyond 18 months should periodically re-evaluate the long-term usefulness of the drug for the individual patient.

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Contraindications

LAMICTAL is contraindicated in patients who have demonstrated hypersensitivity to the drug or its ingredients.

Warnings

SEE BOX WARNING REGARDING THE RISK OF SERIOUS RASHES REQUIRING HOSPITALIZATION AND DISCONTINUATION OF LAMICTAL. ALTHOUGH BENIGN RASHES ALSO OCCUR WITH LAMICTAL, IT IS NOT POSSIBLE TO PREDICT RELIABLY WHICH RASHES WILL PROVE TO BE SERIOUS OR LIFE THREATENING. ACCORDINGLY, LAMICTAL SHOULD ORDINARILY BE DISCONTINUED AT THE FIRST SIGN OF RASH, UNLESS THE RASH IS CLEARLY NOT DRUG RELATED. DISCONTINUATION OF TREATMENT MAY NOT PREVENT A RASH FROM BECOMING LIFE THREATENING OR PERMANENTLY DISABLING OR DISFIGURING.

Serious Rash: Pediatric Population: The incidence of serious rash associated with hospitalization and discontinuation of LAMICTAL in a prospectively followed cohort of pediatric patients with epilepsy receiving adjunctive therapy was approximately 0.8% (16 of 1,983). When 14 of these cases were reviewed by 3 expert dermatologists, there was considerable disagreement as to their proper classification. To illustrate, one dermatologist considered none of the cases to be Stevens-Johnson syndrome; another assigned 7 of the 14 to this diagnosis. There was 1 rash-related death in this 1,983 patient cohort. Additionally, there have been rare cases of toxic epidermal necrolysis with and without permanent sequelae and/or death in US and foreign postmarketing experience. It bears emphasis, accordingly, that LAMICTAL is only approved for use in those patients below the age of 16 who have partial seizures or generalized seizures associated with the Lennox-Gastaut syndrome (see INDICATIONS).

There is evidence that the inclusion of valproate in a multidrug regimen increases the risk of serious, potentially life-threatening rash in pediatric patients. In pediatric patients who used valproate concomitantly, 1.2% (6 of 482) experienced a serious rash compared to 0.6% (6 of 952) patients not taking valproate.

Adult Population: Serious rash associated with hospitalization and discontinuation of LAMICTAL occurred in 0.3% (11 of 3,348) of adult patients who received LAMICTAL in premarketing clinical trials of epilepsy. In the bipolar and other mood disorders clinical trials, the rate of serious rash was 0.08% (1 of 1,233) of adult patients who received LAMICTAL as initial monotherapy and 0.13% (2 of 1,538) of adult patients who received LAMICTAL as adjunctive therapy. No fatalities occurred among these individuals. However, in worldwide postmarketing experience, rare cases of rash-related death have been reported, but their numbers are too few to permit a precise estimate of the rate.

Among the rashes leading to hospitalization were Stevens-Johnson syndrome, toxic epidermal necrolysis, angioedema, and a rash associated with a variable number of the following systemic manifestations: fever, lymphadenopathy, facial swelling, hematologic, and hepatologic abnormalities.

There is evidence that the inclusion of valproate in a multidrug regimen increases the risk of serious, potentially life-threatening rash in adults. Specifically, of 584 patients administered LAMICTAL with valproate in epilepsy clinical trials, 6 (1%) were hospitalized in association with rash; in contrast, 4 (0.16%) of 2,398 clinical trial patients and volunteers administered LAMICTAL in the absence of valproate were hospitalized.

Other examples of serious and potentially life-threatening rash that did not lead to hospitalization also occurred in premarketing development. Among these, 1 case was reported to be Stevens-Johnson - like.

Hypersensitivity Reactions: Hypersensitivity reactions, some fatal or life threatening, have also occurred. Some of these reactions have included clinical features of multiorgan failure/dysfunction, including hepatic abnormalities and evidence of disseminated intravascular coagulation. It is important to note that early manifestations of hypersensitivity (e.g., fever, lymphadenopathy) may be present even though a rash is not evident. If such signs or symptoms are present, the patient should be evaluated immediately. LAMICTAL should be discontinued if an alternative etiology for the signs or symptoms cannot be established.

Prior to initiation of treatment with LAMICTAL, the patient should be instructed that a rash or other signs or symptoms of hypersensitivity (e.g., fever, lymphadenopathy) may herald a serious medical event and that the patient should report any such occurrence to a physician immediately.

Acute Multiorgan Failure: Multiorgan failure, which in some cases has been fatal or irreversible, has been observed in patients receiving LAMICTAL. Fatalities associated with multiorgan failure and various degrees of hepatic failure have been reported in 2 of 3,796 adult patients and 4 of 2,435 pediatric patients who received LAMICTAL in clinical trials. No such fatalities have been reported in bipolar patients in clinical trials. Rare fatalities from multiorgan failure have also been reported in compassionate plea and postmarketing use. The majority of these deaths occurred in association with other serious medical events, including status epilepticus and overwhelming sepsis, and hantavirus making it difficult to identify the initial cause.

Additionally, 3 patients (a 45-year-old woman, a 3.5-year-old boy, and an 11-year-old girl) developed multiorgan dysfunction and disseminated intravascular coagulation 9 to 14 days after LAMICTAL was added to their AED regimens. Rash and elevated transaminases were also present in all patients and rhabdomyolysis was noted in 2 patients. Both pediatric patients were receiving concomitant therapy with valproate, while the adult patient was being treated with carbamazepine and clonazepam. All patients subsequently recovered with supportive care after treatment with LAMICTAL was discontinued.

Blood Dyscrasias: There have been reports of blood dyscrasias that may or may not be associated with the hypersensitivity syndrome. These have included neutropenia, leukopenia, anemia, thrombocytopenia, pancytopenia, and, rarely, aplastic anemia and pure red cell aplasia. Withdrawal Seizures: As with other AEDs, LAMICTAL should not be abruptly discontinued. In patients with epilepsy there is a possibility of increasing seizure frequency. In clinical trials in patients with Bipolar Disorder, 2 patients experienced seizures shortly after abrupt withdrawal of LAMICTAL. However, there were confounding factors that may have contributed to the occurrence of seizures in these bipolar patients. Unless safety concerns require a more rapid withdrawal, the dose of LAMICTAL should be tapered over a period of at least 2 weeks (see DOSAGE AND ADMINISTRATION).

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Precautions

Dermatological Events (see BOX WARNING, WARNINGS): Serious rashes associated with hospitalization and discontinuation of LAMICTAL have been reported. Rare deaths have been reported, but their numbers are too few to permit a precise estimate of the rate. There are suggestions, yet to be proven, that the risk of rash may also be increased by (1) coadministration of LAMICTAL with valproate, (2) exceeding the recommended initial dose of LAMICTAL, or (3) exceeding the recommended dose escalation for LAMICTAL. However, cases have been reported in the absence of these factors.

In epilepsy clinical trials, approximately 10% of all patients exposed to LAMICTAL developed a rash. In the Bipolar Disorder clinical trials, 14% of patients exposed to LAMICTAL developed a rash. Rashes associated with LAMICTAL do not appear to have unique identifying features. Typically, rash occurs in the first 2 to 8 weeks following treatment initiation. However, isolated cases have been reported after prolonged treatment (e.g., 6 months). Accordingly, duration of therapy cannot be relied upon as a means to predict the potential risk heralded by the first appearance of a rash.

Although most rashes resolved even with continuation of treatment with LAMICTAL, it is not possible to predict reliably which rashes will prove to be serious or life threatening.

ACCORDINGLY, LAMICTAL SHOULD ORDINARILY BE DISCONTINUED AT THE FIRST SIGN OF RASH, UNLESS THE RASH IS CLEARLY NOT DRUG RELATED. DISCONTINUATION OF TREATMENT MAY NOT PREVENT A RASH FROM BECOMING LIFE THREATENING OR PERMANENTLY DISABLING OR DISFIGURING.

It is recommended that LAMICTAL not be restarted in patients who discontinued due to rash associated with prior treatment with LAMICTAL unless the potential benefits clearly outweigh the risks. If the decision is made to restart a patient who has discontinued LAMICTAL, the need to restart with the initial dosing recommendations should be assessed. The greater the interval of time since the previous dose, the greater consideration should be given to restarting with the initial dosing recommendations. If a patient has discontinued LAMICTAL for a period of more than 5 half-lives, it is recommended that initial dosing recommendations and guidelines be followed. The half-life of LAMICTAL is affected by other concomitant medications (see CLINICAL PHARMACOLOGY: Pharmacokinetics and Drug Metabolism, and DOSAGE AND ADMINISTRATION).

Use in Patients With Epilepsy:

Sudden Unexplained Death in Epilepsy (SUDEP): During the premarketing development of LAMICTAL, 20 sudden and unexplained deaths were recorded among a cohort of 4,700 patients with epilepsy (5,747 patient-years of exposure).

Some of these could represent seizure-related deaths in which the seizure was not observed, e.g., at night. This represents an incidence of 0.0035 deaths per patient-year. Although this rate exceeds that expected in a healthy population matched for age and sex, it is within the range of estimates for the incidence of sudden unexplained deaths in patients with epilepsy not receiving LAMICTAL (ranging from 0.0005 for the general population of patients with epilepsy, to 0.004 for a recently studied clinical trial population similar to that in the clinical development program for LAMICTAL, to 0.005 for patients with refractory epilepsy). Consequently, whether these figures are reassuring or suggest concern depends on the comparability of the populations reported upon to the cohort receiving LAMICTAL and the accuracy of the estimates provided. Probably most reassuring is the similarity of estimated SUDEP rates in patients receiving LAMICTAL and those receiving another antiepileptic drug that underwent clinical testing in a similar population at about the same time. Importantly, that drug is chemically unrelated to LAMICTAL. This evidence suggests, although it certainly does not prove, that the high SUDEP rates reflect population rates, not a drug effect.

Status Epilepticus: Valid estimates of the incidence of treatment emergent status epilepticus among patients treated with LAMICTAL are difficult to obtain because reporters participating in clinical trials did not all employ identical rules for identifying cases. At a minimum, 7 of 2,343 adult patients had episodes that could unequivocally be described as status. In addition, a number of reports of variably defined episodes of seizure exacerbation (e.g., seizure clusters, seizure flurries, etc.) were made.

Use in Patients With Bipolar Disorder:

Acute Treatment of Mood Episodes: Safety and effectiveness of LAMICTAL in the acute treatment of mood episodes has not been established.

Children and Adolescents (less than 18 years of age): Treatment with antidepressants is associated with an increased risk of suicidal thinking and behavior in children and adolescents with major depressive disorder and other psychiatric disorders. It is not known whether LAMICTAL is associated with a similar risk in this population (see PRECAUTIONS: Clinical Worsening and Suicide Risk Associated With Bipolar Disorder).

Safety and effectiveness of LAMICTAL in patients below the age of 18 years with mood disorders have not been established.

Clinical Worsening and Suicide Risk Associated With Bipolar Disorder: Patients with bipolar disorder may experience worsening of their depressive symptoms and/or the emergence of suicidal ideation and behaviors (suicidality) whether or not they are taking medications for bipolar disorder. Patients should be closely monitored for clinical worsening (including development of new symptoms) and suicidality, especially at the beginning of a course of treatment, or at the time of dose changes.

In addition, patients with a history of suicidal behavior or thoughts, those patients exhibiting a significant degree of suicidal ideation prior to commencement of treatment, and young adults, are at an increased risk of suicidal thoughts or suicide attempts, and should receive careful monitoring during treatment.

Patients (and caregivers of patients) should be alerted about the need to monitor for any worsening of their condition (including development of new symptoms) and /or the emergence of suicidal ideation/behavior or thoughts of harming themselves and to seek medical advice immediately if these symptoms present.

Consideration should be given to changing the therapeutic regimen, including possibly discontinuing the medication, in patients who experience clinical worsening (including development of new symptoms) and/or the emergence of suicidal ideation/behavior especially if these symptoms are severe, abrupt in onset, or were not part of the patient's presenting symptoms.

Prescriptions for LAMICTAL should be written for the smallest quantity of tablets consistent with good patient management, in order to reduce the risk of overdose. Overdoses have been reported for LAMICTAL, some of which have been fatal (see OVERDOSAGE).

Addition of LAMICTAL to a Multidrug Regimen That Includes Valproate (Dosage Reduction): Because valproate reduces the clearance of lamotrigine, the dosage of lamotrigine in the presence of valproate is less than half of that required in its absence (see DOSAGE AND ADMINISTRATION).

Use in Patients With Concomitant Illness: Clinical experience with LAMICTAL in patients with concomitant illness is limited. Caution is advised when using LAMICTAL in patients with diseases or conditions that could affect metabolism or elimination of the drug, such as renal, hepatic, or cardiac functional impairment.

Hepatic metabolism to the glucuronide followed by renal excretion is the principal route of elimination of lamotrigine (see CLINICAL PHARMACOLOGY).

A study in individuals with severe chronic renal failure (mean creatinine clearance = 13 mL/min) not receiving other AEDs indicated that the elimination half-life of unchanged lamotrigine is prolonged relative to individuals with normal renal function. Until adequate numbers of patients with severe renal impairment have been evaluated during chronic treatment with LAMICTAL, it should be used with caution in these patients, generally using a reduced maintenance dose for patients with significant impairment.

Because there is limited experience with the use of LAMICTAL in patients with impaired liver function, the use in such patients may be associated with as yet unrecognized risks (see CLINICAL PHARMACOLOGY and DOSAGE AND ADMINISTRATION).

Binding in the Eye and Other Melanin-Containing Tissues: Because lamotrigine binds to melanin, it could accumulate in melanin-rich tissues over time. This raises the possibility that lamotrigine may cause toxicity in these tissues after extended use. Although ophthalmological testing was performed in one controlled clinical trial, the testing was inadequate to exclude subtle effects or injury occurring after long-term exposure. Moreover, the capacity of available tests to detect potentially adverse consequences, if any, of lamotrigine's binding to melanin is unknown.

Accordingly, although there are no specific recommendations for periodic ophthalmological monitoring, prescribers should be aware of the possibility of long-term ophthalmologic effects.

Information for Patients: Prior to initiation of treatment with LAMICTAL, the patient should be instructed that a rash or other signs or symptoms of hypersensitivity (e.g., fever, lymphadenopathy) may herald a serious medical event and that the patient should report any such occurrence to a physician immediately. In addition, the patient should notify his or her physician if worsening of seizure control occurs.

Patients should be advised that LAMICTAL may cause dizziness, somnolence, and other symptoms and signs of central nervous system (CNS) depression. Accordingly, they should be advised neither to drive a car nor to operate other complex machinery until they have gained sufficient experience on LAMICTAL to gauge whether or not it adversely affects their mental and/or motor performance.

Patients should be advised to notify their physicians if they become pregnant or intend to become pregnant during therapy. Patients should be advised to notify their physicians if they intend to breast-feed or are breast-feeding an infant.

Women should be advised to notify their physician if they plan to start or stop use of oral contraceptives or other female hormonal preparations. They should also be advised to promptly notify their physician if they experience changes in menstrual pattern (e.g., break-through bleeding) while receiving LAMICTAL in combination with these medications.

Patients should be advised to notify their physician if they stop taking LAMICTAL for any reason and not to resume LAMICTAL without consulting their physician.

Patients should be informed of the availability of a patient information leaflet, and they should be instructed to read the leaflet prior to taking LAMICTAL. See PATIENT INFORMATION at the end of this labeling for the text of the leaflet provided for patients.

Laboratory Tests: The value of monitoring plasma concentrations of LAMICTAL has not been established. Because of the possible pharmacokinetic interactions between LAMICTAL and other drugs including AEDs, (see Table 3), monitoring of the plasma levels of LAMICTAL and concomitant drugs may be indicated, particularly during dosage adjustments. In general, clinical judgment should be exercised regarding monitoring of plasma levels of LAMICTAL and other drugs and whether or not dosage adjustments are necessary.

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Drug Interactions

Effects of Lamotrigine on the Pharmacokinetics of Other Drugs: (see Table 3).

LAMICTAL Added to Carbamazepine: LAMICTAL has no appreciable effect on steady-state carbamazepine plasma concentration. Limited clinical data suggest there is a higher incidence of dizziness, diplopia, ataxia, and blurred vision in patients receiving carbamazepine with LAMICTAL than in patients receiving other AEDs with LAMICTAL (see ADVERSE REACTIONS). The mechanism of this interaction is unclear. The effect of lamotrigine on plasma concentrations of carbamazepine-epoxide is unclear. In a small subset of patients (n = 7) studied in a placebo-controlled trial, lamotrigine had no effect on carbamazepine-epoxide plasma concentrations, but in a small, uncontrolled study (n = 9), carbamazepine-epoxide levels were seen to increase.

LAMICTAL Added to Oxcarbazepine: The AUC and Cmax of oxcarbazepine and its active 10-monohydroxy oxcarbazepine metabolite were not significantly different following the addition of oxcarbazepine (600 mg twice daily) to LAMICTAL (200 mg once daily) in healthy male volunteers (n = 13) compared to healthy male volunteers receiving oxcarbazepine alone (n = 13). Limited clinical data suggest a higher incidence of headache, dizziness, nausea, and somnolence with coadministration of LAMICTAL and oxcarbazepine compared to LAMICTAL alone or oxcarbazepine alone.

LAMICTAL Added to Levetiracetam: Potential drug interactions between levetiracetam and lamotrigine were assessed by evaluating serum concentrations of both agents during placebo-controlled clinical trials. These data indicate that lamotrigine does not influence the pharmacokinetics of levetiracetam.

LAMICTAL Added to Valproate: When LAMICTAL was administered to 18 health volunteers receiving valproate in a pharmacokinetic study, the trough steady-state valproate concentrations in plasma decreased by an average of 25% over a 3-week period, and then stabilized. However, adding LAMICTAL to the existing therapy did not cause a change in plasma valproate concentrations in either adult or pediatric patients in controlled clinical trials

LAMICTAL Added to Lithium: The pharmacokinetics of lithium were not altered in healthy subjects (n = 20) by co-administration of 100 mg/day lamotrigine for 6 days.

LAMICTAL Added to Phenytoin: LAMICTAL has no appreciable effect on steady-state phenytoin plasma concentrations in patients with epilepsy.

LAMICTAL Added to Olanzapine: The AUC and Cmax of olanzapine were similar following the addition of olanzapine (15 mg once daily) to LAMICTAL (200 mg once daily) in healthy male volunteers (n = 16) compared to the AUC and Cmax in healthy male volunteers receiving olanzapine alone (n = 16).

Results of in vitro experiments suggest that lamotrigine does not reduce the clearance of drugs eliminated predominantly by CYP2D6 (see CLINICAL PHARMACOLOGY).

Effects of Other Drugs on the Pharmacokinetics of Lamotrigine: (see Table 3).

Valproate Added to LAMICTAL: The addition of valproate increases lamotrigine steady-state concentrations in normal volunteers by slightly more than 2-fold. In one study, maximal inhibition of lamotrigine clearance was reached at valproate doses between 250 mg/day and 500 mg/day and did not increase as the valproate dose was further increased.

Carbamazepine, Phenytoin, Phenobarbital, or Primidone Added to LAMICTAL: The addition of these AEDs decreases lamotrigine steady-state concentrations by approximately 40%.

Oxcarbazepine Added to LAMICTAL: The AUC and Cmax of lamotrigine were similar following the addition of oxcarbazepine (600 mg twice daily) to LAMICTAL (200 mg once daily) in healthy male volunteers (n = 13) compared to healthy male volunteers receiving LAMICTAL alone (n = 13). Limited clinical data suggest a higher incidence of headache, dizziness, nausea, and somnolence with coadministration of LAMICTAL and oxcarbazepine compared to LAMICTAL alone or oxcarbazepine alone.

Levetiracetam Added to LAMICTAL: Potential drug interactions between levetiracetam and lamotrigine were assessed by evaluating serum concentrations of both agents during placebo-controlled clinical trials. These data indicate that levetiracetam does not influence the pharmacokinetics of lamotrigine.

Bupropion Added to LAMICTAL: The pharmacokinetics of a 100-mg single dose of lamotrigine in 12 healthy volunteers were not changed by co-administration of bupropion at 300 mg/day starting 11 days before the lamotrigine dose.

Olanzapine Added to LAMICTAL: The AUC and Cmax of lamotrigine was reduced on average by 24% and 20%, respectively, following the addition of olanzapine (15 mg once daily) to LAMICTAL (200 mg once daily) in healthy male volunteers (n = 16) compared to healthy male volunteers receiving LAMICTAL alone (n = 12). This reduction in lamotrigine plasma concentrations is not expected to be clinically relevant.

Other Psychotropic Drugs Added to LAMICTAL: Results of in vitro experiments suggest that clearance of lamotrigine is unlikely to be reduced by concomitant administration of amitriptyline, clonazepam, clozapine, fluoxetine, haloperidol, lorazepam, phenelzine, risperidone, sertraline, or trazodone (see CLINICAL PHARMACOLOGY: Pharmacokinetics and Drug Metabolism).

Rifampin Added to LAMICTAL: In a study in 10 male volunteers, rifampin (600 mg/day for 5 days) significantly increased the apparent clearance of a single 25 mg dose of lamotrigine by approximately 2-fold (AUC decreased by approximately 40%).

Interactions With Folate Inhibitors: Lamotrigine is an inhibitor of dihydrofolate reductase. Prescribers should be aware of this action when prescribing other medications that inhibit folate metabolism.

Interactions With Oral Contraceptives: Effect of Oral Contraceptives on LAMICTAL: In a study in 16 female volunteers, an oral contraceptive preparation containing 30 mcg ethinylestradiol and 150 mcg levonorgestrel increased the apparent clearance of lamotrigine (300 mg/day) by approximately two fold with a mean decrease in AUC of 52% and in Cmax of 39%. In this study, trough serum lamotrigine concentrations gradually increased and were approximately 2-fold higher on average at the end of the week of the inactive preparation compared to trough lamotrigine concentrations at the end of the active hormone cycle.

Gradual transient increases in lamotrigine levels will occur during the week of no active hormone preparation (pill-free week) for women not also taking a drug that increases the clearance of lamotrigine (carbamazepine, phenytoin, phenobarbital, primidone, or rifampin). The increase in lamotrigine levels will be greater if the dose of LAMICTAL is increased in the few days before or during the pill-free week.

Dosage adjustments may be necessary for women receiving oral contraceptive preparations (see DOSAGE AND ADMINISTRATION: Women and Oral Contraceptives).

Effect of LAMICTAL on Oral Contraceptives: Co-administration of LAMICTAL (300 mg/day) in 16 female volunteers did not affect the pharmacokinetics of the ethinylestradiol component of an oral contraceptive preparation containing 30 mcg ethinylestradiol and 150 mcg levonorgestrel. There was a mean decrease in the AUC and Cmax of the levonorgestrel component of 19% and 12%, respectively. Measurement of serum progesterone indicated that there was no hormonal evidence of ovulation in any of the 16 volunteers, although measurement of serum FSH, LH, and estradiol indicated that there was some loss of suppression of the hypothalamic- pituitary-ovarian axis.

The effects of doses of LAMICTAL other than 300 mg/day have not been studied.

The clinical significance of the observed hormonal changes on ovulatory activity is unknown. However, the possibility of decreased contraceptive efficacy in some patients cannot be excluded. Therefore, patients should be instructed to promptly report changes in their menstrual pattern (e.g., break-through bleeding).

Interactions With Other Hormonal Contraceptives or Hormone Replacement Therapy: The effect of other hormonal contraceptive preparations or hormone replacement therapy on the pharmacokinetics of lamotrigine has not been evaluated, although the effect may be similar to oral contraceptive preparations. Therefore, as for oral contraceptives, dosage adjustments may be necessary (see DOSAGE AND ADMINISTRATION: Women and Oral Contraceptives).

The net effects of drug interactions with LAMICTAL are summarized in Table 3.

Table 3. Summary of Drug Interactions With LAMICTAL
Drug
Drug
Plasma Concentration With
Adjunctive LAMICTAL *
Lamotrigine Plasma Concentration
With Adjunctive Drugs **/*
Phenytoin (PHT)
  down
Carbamazepine (CBZ)
  down
CBZ epoxide #
?
Valproate
down up
Valproate + PHT
and/or CBZ
Not assessed  
Oxcarbazepine
   
10-monohydroxy oxcarbazepine metabolite §
 
Levetiracetam
   
Lithium
  Not assessed
Bupropion
Not assessed  
Olanzapine
  #
Rifampin
Not assessed down
Ethinylestradiol/ levonorgesterol ¶
# down
*From adjunctive clinical trials and volunteer studies.
**/* Net effects were estimated by comparing the mean clearance values obtained in adjunctive clinical trials and volunteers studies.
# Not administered, but an active metabolite of carbamazepine
§ Not administered, but an active metabolite of oxcarbazepine
=No significant effect.
? =Conflicting data.
# Slight decrease, not expected to be clinically relevant.
The effect of other hormonal contraceptive preparations or hormone replacement therapy on the pharmacokinetics of lamotrigine has not been evaluated, although the effect may be similar.
# Modest decrease in levonorgestrel (see PRECAUTIONS: Drug Interactions: Effect of LAMICTAL on Oral Contraceptives).

Drug/Laboratory Test Interactions: None known.

Carcinogenesis, Mutagenesis, Impairment of Fertility: No evidence of carcinogenicity was seen in 1 mouse study or 2 rat studies following oral administration of lamotrigine for up to 2 years at maximum tolerated doses (30 mg/kg per day for mice and 10 to 15 mg/kg per day for 2 2 rats, doses that are equivalent to 90 mg/m2 and 60 to 90 mg/m2 , respectively). Steady-state plasma concentrations ranged from 1 to 4 mcg/mL in the mouse study and 1 to 10 mcg/mL in the rat study. Plasma concentrations associated with the recommended human doses of 300 to 500 mg/day are generally in the range of 2 to 5 mcg/mL, but concentrations as high as 19 mcg/mL have been recorded.

Lamotrigine was not mutagenic in the presence or absence of metabolic activation when tested in 2 gene mutation assays (the Ames test and the in vitro mammalian mouse lymphoma assay). In 2 cytogenetic assays (the in vitro human lymphocyte assay and the in vivo rat bone marrow assay), lamotrigine did not increase the incidence of structural or numerical chromosomal abnormalities.

No evidence of impairment of fertility was detected in rats given oral doses of lamotrigine up to 2.4 times the highest usual human maintenance dose of 8.33 mg/kg per day or 0.4 times the human dose on a mg/m 2 basis. The effect of lamotrigine on human fertility is unknown.

Pregnancy: Teratogenic Effects: Pregnancy Category C. No evidence of teratogenicity was found in mice, rats, or rabbits when lamotrigine was orally administered to pregnant animals during the period of organogenesis at doses up to 1.2, 0.5, and 1.1 times, respectively, on a mg/m 2 basis, the highest usual human maintenance dose (i.e., 500 mg/day). However, maternal toxicity and secondary fetal toxicity producing reduced fetal weight and/or delayed ossification were seen in mice and rats, but not in rabbits at these doses. Teratology studies were also conducted using bolus intravenous administration of the isethionate salt of lamotrigine in rats and rabbits. In rat dams administered an intravenous dose at 0.6 times the highest usual human maintenance dose, the incidence of intrauterine death without signs of teratogenicity was increased.

A behavioral teratology study was conducted in rats dosed during the period of organogenesis. At day 21 postpartum, offspring of dams receiving 5 mg/kg per day or higher displayed a significantly longer latent period for open field exploration and a lower frequency of rearing. In a swimming maze test performed on days 39 to 44 postpartum, time to completion was increased in offspring of dams receiving 25 mg/kg per day. These doses represent 0.1 and 0.5 times the clinical dose on a mg/m basis, respectively.

Lamotrigine did not affect fertility, teratogenesis, or postnatal development when rats were dosed prior to and during mating, and throughout gestation and lactation at doses equivalent to 0.4 times the highest usual human maintenance dose on a mg/m2 basis.

When pregnant rats were orally dosed at 0.1, 0.14, or 0.3 times the highest human maintenance dose (on a mg/m2 basis) during the latter part of gestation (days 15 to 20), maternal toxicity and fetal death were seen. In dams, food consumption and weight gain were reduced, and the gestation period was slightly prolonged (22.6 vs. 22.0 days in the control group). Stillborn pups were found in all 3 drug-treated groups with the highest number in the high-dose group. Postnatal death was also seen, but only in the 2 highest doses, and occurred between day 1 and 20. Some of these deaths appear to be drug-related and not secondary to the maternal toxicity. A no-observed-effect level (NOEL) could not be determined for this study.

Although LAMICTAL was not found to be teratogenic in the above studies, lamotrigine decreases fetal folate concentrations in rats, an effect known to be associated with teratogenesis in animals and humans. There are no adequate and well-controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human response, this drug should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

Non-Teratogenic Effects: As with other antiepileptic drugs, physiological changes during pregnancy may affect lamotrigine concentrations and/or therapeutic effect. There have been reports of decreased lamotrigine concentrations during pregnancy and restoration of pre-partum concentrations after delivery. Dosage adjustments may be necessary to maintain clinical response.

Pregnancy Exposure Registry: To facilitate monitoring fetal outcomes of pregnant women exposed to lamotrigine, physicians are encouraged to register patients, before fetal outcome (e.g., ultrasound, results of amniocentesis, birth, etc.) is known, and can obtain information by calling the Lamotrigine Pregnancy Registry at (800) 336-2176 (toll-free). Patients can enroll themselves in the North American Antiepileptic Drug Pregnancy Registry by calling (888) 233- 2334 (toll-free).

Labor and Delivery: The effect of LAMICTAL on labor and delivery in humans is unknown.

Use in Nursing Mothers: Preliminary data indicate that lamotrigine passes into human milk. Because the effects on the infant exposed to LAMICTAL by this route are unknown, breast-feeding while taking LAMICTAL is not recommended.

Pediatric Use: LAMICTAL is indicated as adjunctive therapy for partial seizures in patients above 2 years of age and for the generalized seizures of Lennox-Gastaut syndrome. Safety and effectiveness for other uses in patients with epilepsy below the age of 16 years have not been established (see BOX WARNING).

Safety and effectiveness in patients below the age of 18 years with Bipolar Disorder has not been established.

Geriatric Use: Clinical studies of LAMICTAL for epilepsy and in Bipolar Disorder did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.

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Adverse Reactions

SERIOUS RASH REQUIRING HOSPITALIZATION AND DISCONTINUATION OF LAMICTAL, INCLUDING STEVENS-JOHNSON SYNDROME AND TOXIC EPIDERMAL NECROLYSIS, HAVE OCCURRED IN ASSOCIATION WITH THERAPY WITH LAMICTAL. RARE DEATHS HAVE BEEN REPORTED, BUT THEIR NUMBERS ARE TOO FEW TO PERMIT A PRECISE ESTIMATE OF THE RATE (see BOX WARNING).

Epilepsy:

Most Common Adverse Events in All Clinical Studies: Adjunctive Therapy in Adults With Epilepsy: The most commonly observed ( 5%) adverse experiences seen in association with LAMICTAL during adjunctive therapy in adults and not seen at an equivalent frequency among placebo-treated patients were: dizziness, ataxia, somnolence, headache, diplopia, blurred vision, nausea, vomiting, and rash. Dizziness, diplopia, ataxia, blurred vision, nausea, and vomiting were dose related. Dizziness, diplopia, ataxia, and blurred vision occurred more commonly in patients receiving carbamazepine with LAMICTAL than in patients receiving other AEDs with LAMICTAL. Clinical data suggest a higher incidence of rash, including serious rash, in patients receiving concomitant valproate than in patients not receiving valproate (see WARNINGS).

Approximately 11% of the 3,378 adult patients who received LAMICTAL as adjunctive therapy in premarketing clinical trials discontinued treatment because of an adverse experience. The adverse events most commonly associated with discontinuation were rash (3.0%), dizziness (2.8%), and headache (2.5%).

In a dose response study in adults, the rate of discontinuation of LAMICTAL for dizziness, ataxia, diplopia, blurred vision, nausea, and vomiting was dose related.

Monotherapy in Adults With Epilepsy: The most commonly observed ( 5%) adverse experiences seen in association with the use of LAMICTAL during the monotherapy phase of the controlled trial in adults not seen at an equivalent rate in the control group were vomiting, coordination abnormality, dyspepsia, nausea, dizziness, rhinitis, anxiety, insomnia, infection, pain, weight decrease, chest pain, and dysmenorrhea. The most commonly observed ( 5%) adverse experiences associated with the use of LAMICTAL during the conversion to monotherapy (add-on) period, not seen at an equivalent frequency among low-dose valproate-treated patients, were dizziness, headache, nausea, asthenia, coordination abnormality, vomiting, rash, somnolence, diplopia, ataxia, accidental injury, tremor, blurred vision, insomnia, nystagmus, diarrhea, lymphadenopathy, pruritus, and sinusitis.

Approximately 10% of the 420 adult patients who received LAMICTAL as monotherapy in premarketing clinical trials discontinued treatment because of an adverse experience. The adverse events most commonly associated with discontinuation were rash (4.5%), headache (3.1%), and asthenia (2.4%).

Adjunctive Therapy in Pediatric Patients With Epilepsy: The most commonly observed ( 5%) adverse experiences seen in association with the use of LAMICTAL as adjunctive treatment in pediatric patients and not seen at an equivalent rate in the control group were infection, vomiting, rash, fever, somnolence, accidental injury, dizziness, diarrhea, abdominal pain, nausea, ataxia, tremor, asthenia, bronchitis, flu syndrome, and diplopia.

In 339 patients age 2 to 16 years, 4.2% of patients on LAMICTAL and 2.9% of patients on placebo discontinued due to adverse experiences. The most commonly reported adverse experiences that led to discontinuation were rash for patients treated with LAMICTAL and deterioration of seizure control for patients treated with placebo.

Approximately 11.5% of the 1,081 pediatric patients who received LAMICTAL as adjunctive therapy in premarketing clinical trials discontinued treatment because of an adverse experience. The adverse events most commonly associated with discontinuation were rash (4.4%), reaction aggravated (1.7%), and ataxia (0.6%).

Incidence in Controlled Clinical Studies of Epilepsy: The prescriber should be aware that the figures in Tables 4, 5, 6, and 7 cannot be used to predict the frequency of adverse experiences in the course of usual medical practice where patient characteristics and other factors may differ from those prevailing during clinical studies. Similarly, the cited frequencies cannot be directly compared with figures obtained from other clinical investigations involving different treatments, uses, or investigators. An inspection of these frequencies, however, does provide the prescriber with one basis to estimate the relative contribution of drug and nondrug factors to the adverse event incidences in the population studied.

Incidence in Controlled Adjunctive Clinical Studies in Adults With Epilepsy: Table 4 lists treatment-emergent signs and symptoms that occurred in at least 2% of adult patients with epilepsy treated with LAMICTAL in placebo-controlled trials and were numerically more common in the patients treated with LAMICTAL. In these studies, either LAMICTAL or placebo was added to the patient's current AED therapy. Adverse events were usually mild to moderate in intensity.

Table 4. Treatment-Emergent Adverse Event Incidence in Placebo-Controlled Adjunctive Trials in Adult Patients With Epilepsy * (Events in at least 2% of patients treated with LAMICTAL and numerically more frequent than in the placebo group.)

Body System/
Adverse Experience **/*
Percent of Patients
Receiving Adjunctive
LAMICTAL
(n = 711)
Percent of Patients
Receiving Adjunctive
Placebo
(n = 419)
Body as a whole
Headache
29 1
Flu syndrome
7 6
Fever
6 4
Abdominal pain
5 4
Neck pain
2 1
Reaction aggravated
(seizure exacerbation)
2 1
Digestive
Nausea
19 10
Vomiting
9 4
Diarrhea
6 4
Dyspepsia
5 2
Constipation
4 3
Tooth disorder
3 2
Anorexia
2 1
Musculoskeletal
Arthralgia
2 0
Nervous
Dizziness
38 13
Ataxia
22 6
Somnolence
14 7
Incoordination
6 2
Insomnia
6 2
Tremor
4 1
Depression
4 3
Anxiety
4 3
Convulsion
3 1
Irritability
3 2
Speech disorder
3 0
Concentration
disturbance
2 1
Respiratory
Rhinitis
14 9
Pharyngitis
10 9
Cough increased
8 6
Skin and appendages
Rash
10 5
Pruritus
3 2
Special senses
Diplopia
28 7
Blurred vision
16 5
Vision abnormality
3 1
Urogenital
Female patients only
(n = 365) (n = 207)
Dysmenorrhea
7 6
Vaginitis
4 1
Amenorrhea
2 1
*Patients in these adjunctive studies were receiving 1 to 3 of the following concomitant AEDs (carbamazepine, phenytoin, phenobarbital, or primidone) in addition to LAMICTAL or placebo. Patients may have reported multiple adverse experiences during the study or at discontinuation; thus, patients may be included in more than one category.
**/* Adverse experiences reported by at least 2% of patients treated with LAMICTAL are included.

In a randomized, parallel study comparing placebo and 300 and 500 mg/day of LAMICTAL, some of the more common drug-related adverse events were dose related (see Table 5).

Table 5. Dose-Related Adverse Events From a Randomized, Placebo-Controlled Trial in Adults With Epilepsy
Percent of Patients Experiencing Adverse Experiences

Adverse Experience

Placebo
(n = 73)
LAMICTAL
300 mg
(n = 71)
LAMICTAL
500 mg
(n = 72)
Ataxia
10 10 28 * **/*
Blurred vision
10 11 25 * **/*
Diplopia
8 24 * 49 * **/*
Dizziness
27 31 54 * **/*
Nausea
11 18 25 *
Vomiting
4 11 18 *
*Significantly greater than placebo group (p<0.05).
**/* Significantly greater than group receiving LAMICTAL 300 mg (p<0.05).

Other events that occurred in more than 1% of patients but equally or more frequently in the placebo group included: asthenia, back pain, chest pain, flatulence, menstrual disorder, myalgia, paresthesia, respiratory disorder, and urinary tract infection.

The overall adverse experience profile for LAMICTAL was similar between females and males, and was independent of age. Because the largest non-Caucasian racial subgroup was only 6% of patients exposed to LAMICTAL in placebo-controlled trials, there are insufficient data to support a statement regarding the distribution of adverse experience reports by race. Generally, females receiving either adjunctive LAMICTAL or placebo were more likely to report adverse experiences than males. The only adverse experience for which the reports on LAMICTAL were greater than 10% more frequent in females than males (without a corresponding difference by gender on placebo) was dizziness (difference = 16.5%). There was little difference between females and males in the rates of discontinuation of LAMICTAL for individual adverse experiences.

Incidence in a Controlled Monotherapy Trial in Adults With Partial Seizures: Table 6 lists treatment-emergent signs and symptoms that occurred in at least 5% of patients with epilepsy treated with monotherapy with LAMICTAL in a double-blind trial following discontinuation of either concomitant carbamazepine or phenytoin not seen at an equivalent frequency in the control group.

Table 6. Treatment-Emergent Adverse Event Incidence in Adults With Partial Seizures in a Controlled Monotherapy Trial * (Events in at least 5% of patients treated with LAMICTAL and numerically more frequent than in the valproate group.)
Body System/
Adverse Experience **/*
Percent of Patients
Receiving LAMICTAL Monotherapy #
(n = 43)
Percent of
Patients Receiving
Low-Dose Valproate §
Monotherapy
(n = 44)
Body as a whole
Pain
5 0
Infection
5 2
Chest pain
5 2
Digestive
Vomiting
9 0
Dyspepsia
7 2
Nausea
7 2
Metabolic and nutritional
Weight decrease
5 2
Nervous
Coordination
abnormality
7 0
Dizziness
7 0
Anxiety
5 0
Insomnia
5 2
Respiratory
Rhinitis
7 2
Urogenital (female
patients only)
(n = 21) (n = 28)
Dysmenorrhea
5 0
*Patients in these studies were converted to LAMICTAL or valproate monotherapy from adjunctive therapy with carbamazepine or phenytoin. Patients may have reported multiple adverse experiences during the study; thus, patients may be included in more than one category.
**/* Adverse experiences reported by at least 5% of patients are included.
# Up to 500 mg/day.
§ 1,000 mg/day.

Adverse events that occurred with a frequency of less than 5% and greater than 2% of patients receiving LAMICTAL and numerically more frequent than placebo were:

Body as a Whole: Asthenia, fever.

Digestive: Anorexia, dry mouth, rectal hemorrhage, peptic ulcer.

Metabolic and Nutritional: Peripheral edema.

Nervous System: Amnesia, ataxia, depression, hypesthesia, libido increase, decreased reflexes, increased reflexes, nystagmus, irritability, suicidal ideation.

Respiratory: Epistaxis, bronchitis, dyspnea.

Skin and Appendages: Contact dermatitis, dry skin, sweating.

Special Senses: Vision abnormality.

Incidence in Controlled Adjunctive Trials in Pediatric Patients With Epilepsy: Table 7 lists adverse events that occurred in at least 2% of 339 pediatric patients who received LAMICTAL up to 15 mg/kg per day or a maximum of 750 mg per day. Reported adverse events were classified using COSTART terminology.

Table 7. Treatment-Emergent Adverse Event Incidence in Placebo-Controlled Adjunctive Trials in Pediatric Patients With Epilepsy (Events in at least 2% of patients treated with LAMICTAL and numerically more frequent than in the placebo group.)
Body System/
Adverse Experience
Percent of Patients Receiving LAMICTAL
(n = 168)
Percent of Patients
Receiving Placebo
(n = 171)
Body as a whole
Infection
20 17
Fever
15 14
Accidental injury
14 12
Abdominal pain
10 5
Asthenia
8 4
Flu syndrome
7 6
Pain
5 4
Facial edema
2 1
Photosensitivity
2 0
Cardiovascular
Hemorrhage
2 1
Digestive
Vomiting
20 16
Diarrhea
11 9
Nausea
10 2
Constipation
4 2
Dyspepsia
2 1
Tooth disorder
2 1
Hemic and lymphatic
Lymphadenopathy
2 1
Metabolic and nutritional
Edema
2 0
Nervous system
Somnolence
17 15
Dizziness
14 4
Ataxia
11 3
Tremor
10 1
Emotional lability
4 2
Gait abnormality
4 2
Thinking abnormality
3 2
Convulsions
2 1
Nervousness
2 1
Vertigo
2 1
Respiratory
Pharyngitis
14 11
Bronchitis
7 5
Increased cough
7 6
Sinusitis
2 1
Bronchospasm
2 1
Skin
Rash
14 12
Eczema
2 1
Pruritus
2 1
Special senses
Diplopia
5 1
Blurred vision
4 1
Ear disorder
2 1
Visual abnormality
2 0
Urogenital


Male and female patients
Urinary tract infection
3 0
Male patients only
n = 93 n = 92
Penis disorder
2 0

Bipolar Disorder: The most commonly observed (>/=5%) adverse experiences seen in association with the use of LAMICTAL as monotherapy (100 to 400 mg/day) in Bipolar Disorder in the 2 double-blind, placebo-controlled trials of 18 months' duration, and numerically more frequent than in placebo-treated patients are included in Table 8. Adverse events that occurred in at least 5% of patients and were numerically more common during the dose escalation phase of LAMICTAL in these trials (when patients may have been receiving concomitant medications) compared to the monotherapy phase were: headache (25%), rash (11%), dizziness (10%), diarrhea (8%), dream abnormality (6%), and pruitus (6%).

During the monotherapy phase of the double-blind, placebo-controlled trials of 18 months' duration, 13% of 227 patients who received LAMICTAL (100 to 400 mg/day), 16% of 190 patients who received placebo, and 23% of 166 patients who received lithium discontinued therapy because of an adverse experience. The adverse events which most commonly led to discontinuation of LAMICTAL were rash (3%) and mania/hypomania/mixed mood adverse events (2%). Approximately 16% of 2,401 patients who received LAMICTAL (50 to 500 mg/day) for Bipolar Disorder in premarketing trials discontinued therapy because of an adverse experience; most commonly due to rash (5%) and mania/hypomania/mixed mood adverse events (2%).

Incidence in Controlled Clinical Studies of LAMICTAL for the Maintenance Treatment of Bipolar I Disorder: Table 8 lists treatment-emergent signs and symptoms that occurred in at least 5% of patients with Bipolar Disorder treated with LAMICTAL monotherapy (100 to 400 mg/day), following the discontinuation of other psychotropic drugs, in 2 double-blind, placebo-controlled trials of 18 months' duration and were numerically more frequent than in the placebo group.

Table 8. Treatment-Emergent Adverse Event Incidence in 2 Placebo-Controlled Trials in Adults With Bipolar I Disorder * (Events in at least 5% of patients treated with LAMICTAL monotherapy and numerically more frequent than in the placebo group.)
Body System/
Adverse Experience **/*
Percent of Patients Receiving LAMICTAL
n = 227
Percent of Patients Receiving
Placebo n = 190
General
Back pain
8 6
Fatigue
8 5
Abdominal pain
6 3
Digestive
Nausea
14 11
Constipation
5 2
Vomiting
5 2
Nervous System
Insomnia
10 6
Somnolence
9 7
Xerostomia (dry mouth)
6 4
Respiratory
Rhinitis
7 4
Exacerbation of cough
5 3
Pharyngitis
5 4
Skin
Rash
(non-serious) #
7 5
* Patients in these studies were converted to LAMICTAL (100 to 400 mg/day) or placebo monotherapy from add-on therapy with other psychotropic medications. Patients may have reported multiple adverse experiences during the study; thus, patients may be included in more than one category.
**/* Adverse experiences reported by at least 5% of patients are included.
# In the overall bipolar and other mood disorders clinical trials, the rate of serious rash was 0.08% (1 of 1,233) of adult patients who received LAMICTAL as initial monotherapy and 0.13% (2 of 1,538) of adult patients who received LAMICTAL as adjunctive therapy (see WARNINGS ).

These adverse events were usually mild to moderate in intensity.

Other events that occurred in 5% or more patients but equally or more frequently in the placebo group included: dizziness, mania, headache, infection, influenza, pain, accidental injury, diarrhea, and dyspepsia.

Adverse events that occurred with a frequency of less than 5% and greater than 1% of patients receiving LAMICTAL and numerically more frequent than placebo were:

General: Fever, neck pain.

Cardiovascular: Migraine.

Digestive: Flatulence.

Metabolic and Nutritional: Weight gain, edema.

Musculoskeletal: Arthralgia, myalgia.

Nervous System: Amnesia, depression, agitation, emotional lability, dyspraxia, abnormal thoughts, dream abnormality, hypoesthesia.

Respiratory: Sinusitis.

Urogenital: Urinary frequency.

Adverse Events Following Abrupt Discontinuation: In the 2 maintenance trials, there was no increase in the incidence, severity or type of adverse events in Bipolar Disorder patients after abruptly terminating LAMICTAL therapy. In clinical trials in patients with Bipolar Disorder, 2 patients experienced seizures shortly after abrupt withdrawal of LAMICTAL. However, there were confounding factors that may have contributed to the occurrence of seizures in these bipolar patients (see DOSAGE AND ADMINISTRATION).

Mania/Hypomania/Mixed Episodes: During the double-blind, placebo-controlled clinical trials in Bipolar I Disorder in which patients were converted to LAMICTAL monotherapy (100 to 400 mg/day) from other psychotropic medications and followed for durations up to 18 months, the rate of manic or hypomanic or mixed mood episodes reported as adverse experiences was 5% for patients treated with LAMICTAL (n = 227), 4% for patients treated with lithium (n = 166), and 7% for patients treated with placebo (n = 190). In all bipolar controlled trials combined, adverse events of mania (including hypomania and mixed mood episodes) were reported in 5% of patients treated with LAMICTAL (n = 956), 3% of patients treated with lithium (n = 280), and 4% of patients treated with placebo (n = 803).

The overall adverse event profile for LAMICTAL was similar between females and males, between elderly and nonelderly patients, and among racial groups.

Other Adverse Events Observed During All Clinical Trials For Pediatric and Adult Patients With Epilepsy or Bipolar Disorder and Other Mood Disorders: LAMICTAL has been administered to 6,694 individuals for whom complete adverse event data was captured during all clinical trials, only some of which were placebo controlled. During these trials, all adverse events were recorded by the clinical investigators using terminology of their own choosing. To provide a meaningful estimate of the proportion of individuals having adverse events, similar types of events were grouped into a smaller number of standardized categories using modified COSTART dictionary terminology. The frequencies presented represent the proportion of the 6,694 individuals exposed to LAMICTAL who experienced an event of the type cited on at least one occasion while receiving LAMICTAL. All reported events are included except those already listed in the previous tables or elsewhere in the labeling, those too general to be informative, and those not reasonably associated with the use of the drug.

Events are further classified within body system categories and enumerated in order of decreasing frequency using the following definitions: frequent adverse events are defined as those occurring in at least 1/100 patients; infrequent adverse events are those occurring in 1/100 to 1/1,000 patients; rare adverse events are those occurring in fewer than 1/1,000 patients.

Body as a Whole: Infrequent: Allergic reaction, chills, halitosis, and malaise. Rare: Abdomen enlarged, abscess, and suicide/suicide attempt.

Cardiovascular System: Infrequent: Flushing, hot flashes, hypertension, palpitations, postural hypotension, syncope, tachycardia, and vasodilation. Rare: Angina pectoris, atrial fibrillation, deep thrombophlebitis, ECG abnormality, and myocardial infarction.

Dermatological: Infrequent: Acne, alopecia, hirsutism, maculopapular rash, skin discoloration, and urticaria. Rare: Angioedema, erythema, exfoliative dermatitis, fungal dermatitis, herpes zoster, leukoderma, multiforme erythema, petechial rash, pustular rash, seborrhea, Stevens-Johnson syndrome, and vesiculobullous rash.

Digestive System: Infrequent: Dysphagia, eructation, gastritis, gingivitis, increased appetite, increased salivation, liver function tests abnormal, and mouth ulceration. Rare: Gastrointestinal hemorrhage, glossitis, gum hemorrhage, gum hyperplasia, hematemesis, hemorrhagic colitis, hepatitis, melena, stomach ulcer, stomatitis, thirst, and tongue edema.

Endocrine System: Rare: Goiter and hypothyroidism.

Hematologic and Lymphatic System: Infrequent: Ecchymosis and leukopenia. Rare: Anemia, eosinophilia, fibrin decrease, fibrinogen decrease, iron deficiency anemia, leukocytosis, lymphocytosis, macrocytic anemia, petechia, and thrombocytopenia.

Metabolic and Nutritional Disorders: Infrequent: Aspartate transaminase increased. Rare: Alcohol intolerance, alkaline phosphatase increase, alanine transaminase increase, bilirubinemia, general edema, gamma glutamyl transpeptidase increase, and hyperglycemia.

Musculoskeletal System: Infrequent: Arthritis, leg cramps, myasthenia, and twitching. Rare: Bursitis, joint disorder, muscle atrophy, pathological fracture, and tendinous contracture.

Nervous System: Frequent: Confusion and paresthesia. Infrequent: Akathisia, apathy, aphasia, CNS depression, depersonalization, dysarthria, dyskinesia, euphoria, hallucinations, hostility, hyperkinesia, hypertonia, libido decreased, memory decrease, mind racing, movement disorder, myoclonus, panic attack, paranoid reaction, personality disorder, psychosis, sleep disorder, stupor, and suicidal ideation. Rare: Cerebellar syndrome, cerebrovascular accident, cerebral sinus thrombosis, choreoathetosis, CNS stimulation, delirium, delusions, dysphoria, dystonia, extrapyramidal syndrome, faintness, grand mal convulsions, hemiplegia, hyperalgesia, hyperesthesia, hypokinesia, hypotonia, manic depression reaction, muscle spasm, neuralgia, neurosis, paralysis, and peripheral neuritis.

Respiratory System: Infrequent: Yawn. Rare: Hiccup and hyperventilation. Special Senses: Frequent: Amblyopia. Infrequent: Abnormality of accommodation, conjunctivitis, dry eyes, ear pain, photophobia, taste perversion, and tinnitus. Rare: Deafness, lacrimation disorder, oscillopsia, parosmia, ptosis, strabismus, taste loss, uveitis, and visual field defect.

Urogenital System: Infrequent: Abnormal ejaculation, breast pain, hematuria, impotence, menorrhagia, polyuria, urinary incontinence, and urine abnormality. Rare: Acute kidney failure, anorgasmia, breast abscess, breast neoplasm, creatinine increase, cystitis, dysuria, epididymitis, female lactation, kidney failure, kidney pain, nocturia, urinary retention, urinary urgency, and vaginal moniliasis.

Postmarketing and Other Experience: In addition to the adverse experiences reported during clinical testing of LAMICTAL, the following adverse experiences have been reported in patients receiving marketed LAMICTAL and from worldwide noncontrolled investigational use. These adverse experiences have not been listed above, and data are insufficient to support an estimate of their incidence or to establish causation.

Blood and Lymphatic: Agranulocytosis, aplastic anemia, disseminated intravascular coagulation, hemolytic anemia, neutropenia, pancytopenia, red cell aplasia.

Gastrointestinal: Esophagitis.

Hepatobiliary Tract and Pancreas: Pancreatitis.

Immunologic: Lupus-like reaction, vasculitis.

Lower Respiratory: Apnea.

Musculoskeletal: Rhabdomyolysis has been observed in patients experiencing hypersensitivity reactions.

Neurology: Exacerbation of parkinsonian symptoms in patients with pre-existing Parkinson s disease, tics.

Non-site Specific: Hypersensitivity reaction, multiorgan failure, progressive immunosuppression.

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Drug Abuse and Alcohol Dependence

The abuse and dependence potential of LAMICTAL have not been evaluated in human studies.

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Overdosage

Human Overdose Experience: Overdoses involving quantities up to 15 g have been reported for LAMICTAL, some of which have been fatal. Overdose has resulted in ataxia, nystagmus, increased seizures, decreased level of consciousness, coma, and intraventricular conduction delay.

Management of Overdose: There are no specific antidotes for LAMICTAL. Following a suspected overdose, hospitalization of the patient is advised. General supportive care is indicated, including frequent monitoring of vital signs and close observation of the patient. If indicated, emesis should be induced or gastric lavage should be performed; usual precautions should be taken to protect the airway. It should be kept in mind that lamotrigine is rapidly absorbed (see CLINICAL PHARMACOLOGY). It is uncertain whether hemodialysis is an effective means of removing lamotrigine from the blood. In 6 renal failure patients, about 20% of the amount of lamotrigine in the body was removed by hemodialysis during a 4-hour session. A Poison Control Center should be contacted for information on the management of overdosage of LAMICTAL.

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Dosage and Administration

Epilepsy:

Adjunctive Use: LAMICTAL is indicated as adjunctive therapy for partial seizures in adults and pediatric patients ( 2 years of age). LAMICTAL is also indicated as adjunctive therapy for the generalized seizures of Lennox-Gastaut syndrome in adult and pediatric patients ( 2 years of age).

Monotherapy Use: LAMICTAL is indicated for conversion to monotherapy in adults with partial seizures who are receiving treatment with carbamazepine, phenytoin, phenobarbital, primidone, or valproate as the single AED.

Safety and effectiveness of LAMICTAL have not been established (1) as initial monotherapy, (2) for conversion to monotherapy from non enzyme-inducing AEDs (e.g., valproate), or (3) for simultaneous conversion to monotherapy from 2 or more concomitant AEDs.

Safety and effectiveness in pediatric patients below the age of 16 years other than those with partial seizures and the generalized seizures of Lennox-Gastaut syndrome have not been established (see BOX WARNING).

Bipolar Disorder: LAMICTAL is indicated for the maintenance treatment of Bipolar I Disorder to delay the time to occurrence of mood episodes (depression, mania, hypomania, mixed episodes) in patients treated for acute mood episodes with standard therapy. The effectiveness of LAMICTAL in the acute treatment of mood episodes has not been established.

General Dosing Considerations for Epilepsy and Bipolar Disorder Patients: The risk of nonserious rash is increased when the recommended initial dose and/or the rate of dose escalation of LAMICTAL is exceeded. There are suggestions, yet to be proven, that the risk of severe, potentially life-threatening rash may be increased by (1) coadministration of LAMICTAL with valproate, (2) exceeding the recommended initial dose of LAMICTAL, or (3) exceeding the recommended dose escalation for LAMICTAL. However, cases have been reported in the absence of these factors (see BOX WARNING). Therefore, it is important that the dosing recommendations be followed closely.

It is recommended that LAMICTAL not be restarted in patients who discontinued due to rash associated with prior treatment with LAMICTAL, unless the potential benefits clearly outweigh the risks. If the decision is made to restart a patient who has discontinued LAMICTAL, the need to restart with the initial dosing recommendations should be assessed. The greater the interval of time since the previous dose, the greater consideration should be given to restarting with the initial dosing recommendations. If a patient has discontinued LAMICTAL for a period of more than 5 half-lives, it is recommended that initial dosing recommendations and guidelines be followed. The half-life of LAMICTAL is affected by other concomitant medications (see CLINICAL PHARMACOLOGY: Pharmacokinetics and Drug Metabolism).

Women and Oral Contraceptives: Starting LAMICTAL in Women Taking Oral Contraceptives: Although oral contraceptives have been shown to increase the clearance of lamotrigine (see PRECAUTIONS: Drug Interactions), no adjustments to the recommended dose escalation guidelines for LAMICTAL should be necessary solely based on the use of oral contraceptives. Therefore, dose escalation should follow the recommended guidelines based on whether LAMICTAL is added to valproate, whether LAMICTAL is added to carbamazepine, phenytoin, phenobarbital, primidone, or rifampin, or whether LAMICTAL is added in the absence of valproate, carbamazepine, phenytoin, phenobarbital, primidone, or rifampin.

Adjustments to the Maintenance Dose of LAMICTAL:

(1) Taking or Starting Oral Contraceptives: For women not taking carbamazepine, phenytoin, phenobarbital, primidone, or rifampin, the maintenance dose of LAMICTAL may need to be increased, by as much as 2 fold over the recommended target maintenance dose, according to clinical response (see PRECAUTIONS: Drug Interactions). For women taking LAMICTAL in addition to carbamazepine, phenytoin, phenobarbital, primidone, or rifampin, no adjustment should be necessary.

(2) Stopping Oral Contraceptives: For women not taking carbamazepine, phenytoin, phenobarbital, primidone, or rifampin, the maintenance dose of LAMICTAL may need to be decreased by as much as 50% of the maintenance dose with concurrent oral contraceptives, according to clinical response (see PRECAUTIONS: Drug Interactions). For women taking LAMICTAL in addition to carbamazepine, phenytoin, phenobarbital, primidone or rifampin, no adjustment should be necessary.

Women and Other Hormonal Contraceptive Preparations or Hormone Replacement Therapy: Although the effect of other hormonal contraceptive preparations or hormone replacement therapy on the pharmacokinetics of lamotrigine has not been evaluated, the effect may be similar to oral contraceptives (see PRECAUTIONS: Drug Interactions). Therefore, similar adjustments to the dosage of LAMICTAL may be needed, based on clinical response.

Patients With Hepatic Impairment: Experience in patients with hepatic impairment is limited. Based on a clinical pharmacology study in 24 patients with moderate to severe liver dysfunction (see CLINICAL PHARMACOLOGY), the following general recommendations can be made. Initial, escalation, and maintenance doses should generally be reduced by approximately 50% in patients with moderate (Child-Pugh Grade B) and 75% in patients with severe (Child-Pugh Grade C) hepatic impairment. Escalation and maintenance doses should be adjusted according to clinical response.

Patients With Renal Functional Impairment: Initial doses of LAMICTAL should be based on patients' AED regimen (see above); reduced maintenance doses may be effective for patients with significant renal functional impairment (see CLINICAL PHARMACOLOGY). Few patients with severe renal impairment have been evaluated during chronic treatment with LAMICTAL. Because there is inadequate experience in this population, LAMICTAL should be used with caution in these patients.

Epilepsy:

Adjunctive Therapy With LAMICTAL for Epilepsy: This section provides specific dosing recommendations for patients 2 to 12 years of age and patients greater than 12 years of age. Within each of these age-groups, specific dosing recommendations are provided depending upon whether or not the patient is receiving valproate (Tables 9 and 10 for patients 2 to 12 years of age, Tables 11 and 12 for patients greater than 12 years of age). In addition, the section provides a discussion of dosing for those patients receiving concomitant AEDs that have not been systematically evaluated in combination with LAMICTAL.

Patients 2 to 12 Years of Age: LAMICTAL Added to an Antiepileptic Drug Regimen Containing Valproate: Recommended dosing guidelines are summarized in Table 9.

LAMICTAL Added to Carbamazepine, Phenytoin, Phenobarbital, or Primidone: Recommended dosing guidelines are summarized in Table 10.

LAMICTAL Added to Oxcarbazepine or Levetiracetam, or to Antiepileptic Drugs for Which the Interaction With Lamotrigine is Not Known: Oxcarbazepine and levetiracetam do not affect the apparent clearance of lamotrigine. Specific dosing guidelines for the addition of LAMICTAL to oxcarbazepine or levetiracetam have not been studied in clinical trials. The effect of AEDs other than those already specified on the metabolism of LAMICTAL is not currently known. Therefore, no specific dosing guidelines can be provided. Conservative starting doses and dose escalations (as with concomitant valproate) would be prudent; maintenance dosing would be expected to fall between the maintenance dose with valproate, which decreases the apparent clearance of lamotrigine, and the maintenance dose without valproate, but with carbamazepine, phenytoin, phenobarbital, or primidone, which increase the apparent clearance of lamotrigine.

Note that the starting doses and dose escalations listed in Tables 9 and 10 are different than those used in clinical trials; however, the maintenance doses are the same as in clinical trials. Smaller starting doses and slower dose escalations than those used in clinical trials are recommended because of the suggestions that the risk of rash may be decreased by smaller starting doses and slower dose escalations. Therefore, maintenance doses will take longer to reach in clinical practice than in clinical trials. It may take several weeks to months to achieve an individualized maintenance dose. Maintenance doses in patients weighing less than 30 kg, regardless of age or concomitant AED, may need to be increased as much as 50%, based on clinical response.

The smallest available strength of LAMICTAL Chewable Dispersible Tablets is 2 mg, and only whole tablets should be administered. If the calculated dose cannot be achieved using whole tablets, the dose should be rounded down to the nearest whole tablet (see HOW SUPPLIED and PATIENT INFORMATION for a description of the available sizes of LAMICTAL Chewable Dispersible Tablets).

Table 9. LAMICTAL Added to an Antiepileptic Regimen Containing Valproate in Patients 2 to 12 Years of Age
Weeks
1 and 2
0.15 mg/kg/day in 1 or 2 divided doses, rounded down to the nearest whole tablet. Only whole tablets should be used for dosing.
Weeks
3 and 4
0.3 mg/kg/day in 1 or 2 divided doses, rounded down to the nearest whole tablet.

Weight based dosing can be achieved by using the following guide:

If the patient's weight is Give this daily dose, using the most appropriate combination of LAMICTAL 2-mg and 5-mg tablets
Greater than And less than Weeks 1 and 2 Weeks 3 and 4
6.7 kg 14 kg 2 mg every other day 2 mg every day
14.1 kg 27 kg 2 mg every day 4 mg every day
27.1 kg 34 kg 4 mg every day 8 mg every day
34.1 kg 40 kg 5 mg every day 10 mg every day
Usual maintenance dose: 1 to 5 mg/kg/day (maximum 200 mg/day in 1 or 2 divided doses). To achieve the usual maintenance dose, subsequent doses should be increased every 1 to 2 weeks as follows: calculate 0.3 mg/kg/day, round this amount down to the nearest whole tablet, and add this amount to the previously administered daily dose. The usual maintenance dose in patients adding LAMICTAL to valproate alone ranges from 1 to 3 mg/kg/day. Maintenance doses in patients weighing less than 30 kg may need to be increased by as much as 50%, based on clinical response.

 

Table 10. LAMICTAL Added to Enzyme-Inducing Antiepileptic Drugs (Without Valproate) in Patients 2 to 12 Years of Age
Weeks 1 and 2 0.6 mg/kg/day in 2 divided doses, rounded down to the nearest whole tablet.
Weeks 3 and 4 1.2 mg/kg/day in 2 divided doses, rounded down to the nearest whole tablet.
Usual maintenance dose: 5 to 15 mg/kg/day (maximum 400 mg/day in 2 divided doses). To achieve the usual maintenance dose, subsequent doses should be increased every 1 to 2 weeks as follows: calculate 1.2 mg/kg/day, round this amount down to the nearest whole tablet, and add this amount to the previously administered daily dose. Maintenance doses in patients weighing less than 30 kg may need to be increased by as much as 50%, based on clinical response.

* Rifampin has also been shown to increase the apparent clearance of lamotrigine (see PRECAUTIONS: Drug Interactions).

Patients Over 12 Years of Age: LAMICTAL Added to an Antiepileptic Drug Regimen Containing Valproate: Recommended dosing guidelines are summarized in Table 11.

LAMICTAL Added to Carbamazepine, Phenytoin, Phenobarbital, or Primidone: Recommended dosing guidelines are summarized in Table 12.

LAMICTAL Added to Oxcarbazepine or Levetiracetam, or to Antiepileptic Drugs for Which the Interaction With Lamotrigine is Not Known: Oxcarbazepine and levetiracetam do not affect the apparent clearance of lamotrigine. Specific dosing guidelines for the addition of LAMICTAL to oxcarbazepine or levetiracetam have not been studied in clinical trials. The effect of AEDs other than those already specified on the metabolism of LAMICTAL is not currently known. Therefore, no specific dosing guidelines can be provided. Conservative starting doses and dose escalations (as with concomitant valproate) would be prudent; maintenance dosing would be expected to fall between the maintenance dose with valproate, which decreases the apparent clearance of lamotrigine, and the maintenance dose without valproate, but with carbamazepine, phenytoin, phenobarbital, or primidone, which increase the apparent clearance of lamotrigine.

Table 11. LAMICTAL Added to an Antiepileptic Drug Regimen Containing Valproate in Patients Over 12 Years of Age
Weeks 1 and 2 25 mg every other day
Weeks 3 and 4 25 mg every day
Usual maintenance dose: 100 to 400 mg/day (1 or 2 divided doses). To achieve maintenance, doses may be increased by 25 to 50 mg/day every 1 to 2 weeks. The usual maintenance dose in patients adding LAMICTAL to valproate alone ranges from 100 to 200 mg/day.

 

Table 12. LAMICTAL Added to Enzyme-Inducing Antiepileptic Drugs (Without Valproate) in Patients Over 12 Years of Age
Weeks 1 and 2 50 mg/day
Weeks 3 and 4 100 mg/day in 2 divided doses
Usual maintenance dose: 300 to 500 mg/day (in 2 divided doses). To achieve maintenance, doses may be increased by 100 mg/day every 1 to 2 weeks.

* Rifampin has also been shown to increase the apparent clearance of lamotrigine (see PRECAUTIONS: Drug Interactions).

Conversion From Adjunctive Therapy With Carbamazepine, Phenytoin, Phenobarbital, Primidone, or Valproate as the Single AED to Monotherapy With LAMICTAL in Patients 16 Years of Age With Epilepsy: The goal of the transition regimen is to effect the conversion to monotherapy with LAMICTAL under conditions that ensure adequate seizure control while mitigating the risk of serious rash associated with the rapid titration of LAMICTAL.

The recommended maintenance dose of LAMICTAL as monotherapy is 500 mg/day given in 2 divided doses.

To avoid an increased risk of rash, the recommended initial dose and subsequent dose escalations of LAMICTAL should not be exceeded (see BOX WARNING).

Conversion From Adjunctive Therapy With Carbamazepine, Phenytoin, Phenobarbital, or Primidone to Monotherapy With LAMICTAL: After achieving a dose of 500 mg/day of LAMICTAL according to the guidelines in Table 12, the concomitant AED should be withdrawn by 20% decrements each week over a 4-week period. The regimen for the withdrawal of the concomitant AED is based on experience gained in the controlled monotherapy clinical trial.

Conversion from Adjunctive Therapy With Valproate to Monotherapy With LAMICTAL: The conversion regimen involves 4 steps. First, achieve a dose of 200 mg/day of LAMICTAL according to the guidelines in Table 11. Second, while keeping the LAMICTAL dose at 200 mg/day, valproate should be gradually decreased to a dose of 500 mg/day by decrements no greater than 500 mg/day per week. This dosage regimen is then maintained for 1 week. Third, LAMICTAL should then be increased to 300 mg/day while valproate is simultaneously decreased to 250 mg/day. This regimen should be maintained for 1 week. Fourth, valproate should then be discontinued completely and LAMICTAL increased by 100 mg/day every week until the recommended monotherapy dose of 500 mg/day is reached (see Table 13).

Table 13. Conversion From Adjunctive Therapy With Valproate to Monotherapy With LAMICTAL in Patients 16 Years of Age
Step 1 Achieve a dose of 200 mg/day according to guidelines in Table 11 (if not already on 200 mg/day). Maintain previous stable dose
Step 2 Maintain at 200 mg/day. Decrease to 500 mg/day by decrements no greater than 500 mg/day per week and the maintain the dose of 500 mg/day for 1 week.
Step 3 Increase to 300 mg/day and maintain for 1 week. Simultaneously decrease to 250 mg/day and maintain fo 1 week.
Step 4 Increase by 100 mg/day every week to achieve maintenance dose of 500 mg/day. Simultaneously decrease to 250 mg/day and maintain for 1 week.

Conversion from Adjunctive Therapy With Antiepileptic Drugs Other Than Carbamazepine, Phenytoin, Phenobarbital, Primidone, or Valproate to Monotherapy With LAMICTAL: No specific dosing guidelines can be provided for conversion to monotherapy with LAMICTAL with AEDs other than carbamazepine, phenobarbital, phenytoin, primidone, or valproate.

Usual Maintenance Dose for Epilepsy: The usual maintenance doses identified in Tables 9-12 are derived from dosing regimens employed in the placebo-controlled adjunctive studies in which the efficacy of LAMICTAL was established. In patients receiving multidrug regimens employing carbamazepine, phenytoin, phenobarbital, or primidone without valproate, maintenance doses of adjunctive LAMICTAL as high as 700 mg/day have been used. In patients receiving valproate alone, maintenance doses of adjunctive LAMICTAL as high as 200 mg/day have been used. The advantage of using doses above those recommended in Tables 9-13 has not been established in controlled trials.

Discontinuation Strategy for Patients With Epilepsy: For patients receiving LAMICTAL in combination with other AEDs, a reevaluation of all AEDs in the regimen should be considered if a change in seizure control or an appearance or worsening of adverse experiences is observed.

If a decision is made to discontinue therapy with LAMICTAL, a step-wise reduction of dose over at least 2 weeks (approximately 50% per week) is recommended unless safety concerns require a more rapid withdrawal (see PRECAUTIONS).

Discontinuing carbamazepine, phenytoin, phenobarbital, or primidone should prolong the half-life of lamotrigine; discontinuing valproate should shorten the half-life of lamotrigine.

Target Plasma Levels for Patients With Epilepsy: A therapeutic plasma concentration range has not been established for lamotrigine. Dosing of LAMICTAL should be based on therapeutic response.

Bipolar Disorder: The goal of maintenance treatment with LAMICTAL is to delay the time to occurrence of mood episodes (depression, mania, hypomania, mixed episodes) in patients treated for acute mood episodes with standard therapy. The target dose of LAMICTAL is 200 mg/day (100 mg/day in patients taking valproate, which decreases the apparent clearance of lamotrigine, and 400 mg/day in patients not taking valproate and taking either carbamazepine, phenytoin, phenobarbital, primidone, or rifampin, which increase the apparent clearance of lamotrigine). In the clinical trials, doses up to 400 mg/day as monotherapy were evaluated, however, no additional benefit was seen at 400 mg/day compared to 200 mg/day (see CLINICAL STUDIES: Bipolar Disorder). Accordingly, doses above 200 mg/day are not recommended. Treatment with LAMICTAL is introduced, based on concurrent medications, according to the regimen outlined in Table 14. If other psychotropic medications are withdrawn following stabilization, the dose of LAMICTAL should be adjusted. For patients discontinuing valproate, the dose of LAMICTAL should be doubled over a 2-week period in equal weekly increments (see Table 15). For patients discontinuing carbamazepine, phenytoin, phenobarbital, primidone, or rifampin, the dose of LAMICTAL should remain constant for the first week and then should be decreased by half over a 2-week period in equal weekly decrements (see Table 15). The dose of LAMICTAL may then be further adjusted to the target dose (200 mg) as clinically indicated.

If other drugs are subsequently introduced, the dose of LAMICTAL may need to be adjusted. In particular, the introduction of valproate requires reduction in the dose of LAMICTAL (see CLINICAL PHARMACOLOGY: Drug Interactions).

To avoid an increased risk of rash, the recommended initial dose and subsequent dose escalations of LAMICTAL should not be exceeded (see BOX WARNING).

Table 14. Escalation Regimen for LAMICTAL for Patients With Bipolar Disorder


For Patients Not Taking Carbamazepine (or Other Enzyme- Inducing Drugs) or Valproate

For Patients Taking Valproate

For Patients Taking Carbamazepine (or Other Enzyme-Inducing Drugs) and Not Taking Valproate

Weeks 1 and 2

25 mg daily

25 mg every other day

50 mg daily

Weeks 3 and 4

50 mg daily

25 mg daily

100 mg daily, in divided doses

Week 5

100 mg daily

50 mg daily

200 mg daily, in divided doses

Week 6

200 mg daily

100 mg daily

300 mg daily, in divided doses

Week 7

200 mg daily

100 mg daily

up to 400 mg daily, in divided doses

*See CLINICAL PHARMACOLOGY: Drug Interactions and PRECAUTIONS: Drug
Interactions for a description of known drug interactions.
†Carbamazepine, phenytoin, phenobarbital, primidone, and rifampin have been shown to increase the apparent clearance of lamotrigine.
cValproate has been shown to decrease the apparent clearance of lamotrigine.

Table 15. Adjustments to LAMICTAL Dosing for Patients With Bipolar Disorder Following Discontinuation of Psychotropic Medications


Discontinuation of Psychotropic Drugs (excluding Carbamazepine, Phenytoin, Phenobarbital, Primidone, Rifampin†, or Valproatec)

After Discontinuation of Valproate c

After Discontinuation of Carbamazepine, Phenytoin, Phenobarbital Primidone, or Rifampin†

Current LAMICTAL Dose (mg/day) 100

Current LAMICTAL dose (mg/day) 400

Week 1

Maintain current LAMICTAL dose

150

400

Week 2

Maintain current LAMICTAL dose

200

300

Week 3 onward

Maintain current LAMICTAL dose

200

200

*See CLINICAL PHARMACOLOGY: Drug Interactions and PRECAUTIONS: Drug
Interactions for a description of known drug interactions.
†Carbamazepine, phenytoin, phenobarbital, primidone, and rifampin have been shown to
increase the apparent clearance of lamotrigine.
c)Valproate has been shown to decrease the apparent clearance of lamotrigine.

There is no body of evidence available to answer the question of how long the patient should remain on LAMICTAL therapy. Systematic evaluation of the efficacy of LAMICTAL in patients with either depression or mania who responded to standard therapy during an acute 8 to 16 week treatment phase and were then randomized to LAMICTAL or placebo for up to 76 weeks of observation for affective relapse demonstrated a benefit of such maintenance treatment (see CLINICAL STUDIES: Bipolar Disorder). Nevertheless, patients should be periodically reassessed to determine the need for maintenance treatment.

Discontinuation Strategy in Bipolar Disorder: As with other AEDs, LAMICTAL should not be abruptly discontinued. In the controlled clinical trials, there was no increase in the incidence, type, or severity of adverse experiences following abrupt termination of LAMICTAL. In clinical trials in patients with bipolar disorder, 2 patients experienced seizures shortly after abrupt withdrawal of LAMICTAL. However, there were confounding factors that may have contributed to the occurrence of seizures in these bipolar patients. Discontinuation of LAMICTAL should involve a step-wise reduction of dose over at least 2 weeks (approximately 50% per week) unless safety concerns require a more rapid withdrawal.

Administration of LAMICTAL Chewable Dispersible Tablets: LAMICTAL Chewable Dispersible Tablets may be swallowed whole, chewed, or dispersed in water or diluted fruit juice. If the tablets are chewed, consume a small amount of water or diluted fruit juice to aid in swallowing.

To disperse LAMICTAL Chewable Dispersible Tablets, add the tablets to a small amount of liquid (1 teaspoon, or enough to cover the medication). Approximately 1 minute later, when the tablets are completely dispersed, swirl the solution and consume the entire quantity immediately. No attempt should be made to administer partial quantities of the dispersed tablets.

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How Supplied

LAMICTAL Tablets, 25-mg

White, scored, shield-shaped tablets debossed with "LAMICTAL" and "25"

bottles of 100 (NDC 0173-0633-02).

Store at 25 C (77 F); excursions permitted to 15-30 C (59-86 F) [see USP Controlled Room Temperature] in a dry place.

LAMICTAL Tablets, 100-mg

Peach, scored, shield-shaped tablets debossed with "LAMICTAL" and "100"

bottles of 100 (NDC 0173-0642-55).

LAMICTAL Tablets, 150-mg

Cream, scored, shield-shaped tablets debossed with "LAMICTAL" and "150"

bottles of 60 (NDC 0173-0643-60).

LAMICTAL Tablets, 200-mg

Blue, scored, shield-shaped tablets debossed with "LAMICTAL" and "200"

bottles of 60 (NDC 0173-0644-60).

Store at 25 C (77 F); excursions permitted to 15-30 C (59-86 F) [see USP Controlled Room Temperature] in a dry place and protect from light.

LAMICTAL Chewable Dispersible Tablets, 2-mg

White to off-white, round tablets debossed with "LTG" over "2" 

bottles of 30 (NDC 0173- 0699-00).
ORDER DIRECTLY FROM GlaxoSmithKline 1-800-334-4153.

LAMICTAL Chewable Dispersible Tablets, 5-mg

White to off-white, caplet-shaped tablets debossed with "GX CL2"

bottles of 100 (NDC 0173-0526-00).

LAMICTAL Chewable Dispersible Tablets, 25-mg

White, super elliptical-shaped tablets debossed with "GX CL5"

bottles of 100 (NDC 0173- 0527-00).

Store at 25 C (77 F); excursions permitted to 15-30 C (59-86 F) [see USP Controlled Room Temperature] in a dry place.

LAMICTAL Starter Kit for Patients Taking Valproate 25-mg,

White, scored, shield-shaped tablets debossed with "LAMICTAL" and "25"

blisterpack of 35 tablets (NDC 0173-0633-10).

Store at 25 C (77 F); excursions permitted to 15-30 C (59-86 F) [see USP Controlled Room Temperature] in a dry place.

LAMICTAL Starter Kit for Patients Taking Carbamazepine, Phenytoin, Phenobarbital, Primidone, or Rifampin and Not Taking Valproate

25-mg, white, scored, shield-shaped tablets debossed with "LAMICTAL" and "25"

and 100-mg, peach, scored, shield-shaped tablets debossed with "LAMICTAL" and "100

blisterpack of 84, 25-mg tablets" and 14, 100-mg tablets (NDC 0173-0594-01)

Store at 25 C (77 F); excursions permitted to 15-30 C (59-86 F) [see USP Controlled Room Temperature] in a dry place and protect from light.

LAMICTAL Starter Kit for Patients Not Taking Carbamazepine, Phenytoin, Phenobarbital, Primidone, Rifampin, or Valproate

[FOR USE IN BIPOLAR PATIENTS ONLY]

25-mg, white, scored, shield-shaped tablets debossed with "LAMICTAL" and "25"

and 100-mg, peach, scored, shield-shaped tablets debossed with "LAMICTAL" and "100" 

blisterpack of 42, 25-mg tablets and 7, 100-mg tablets (NDC 0173-0594-02).

Store at 25 C (77 F); excursions permitted to 15-30 C (59-86 F) [see USP Controlled Room Temperature] in a dry place and protect from light.

Patient Information

Information for the Patient

® LAMICTAL (lamotrigine) Tablets ® LAMICTAL (lamotrigine) Chewable Dispersible Tablets

ALWAYS CHECK THAT YOU RECEIVE LAMICTAL

Patients prescribed LAMICTAL (lah-MICK-tall) have sometimes been given the wrong medicine in error because many medicines have names similar to LAMICTAL. Taking the wrong medication can cause serious health problems. When your healthcare provider gives you a prescription for LAMICTAL

  • make sure you can read it clearly.
  • talk to your pharmacist to check that you are given the correct medicine.
  • check the tablets you receive against the pictures of the tablets below. The pictures show actual tablet shape and size and the wording describes the color and printing that is on each strength of LAMICTAL Tablets and Chewable Dispersible Tablets.

Please read this leaflet carefully before you take LAMICTAL and read the leaflet provided with any refill, in case any information has changed. This leaflet provides a summary of the information about your medicine. Please do not throw away this leaflet until you have finished your medicine. This leaflet does not contain all the information about LAMICTAL and is not meant to take the place of talking with your doctor. If you have any questions about LAMICTAL, ask your doctor or pharmacist.

Information About Your Medicine:

The name of your medicine is LAMICTAL (lamotrigine). The decision to use LAMICTAL is one that you and your doctor should make together. When taking lamotrigine, it is important to follow your doctor's instructions.

1. The Purpose of Your Medicine:

For Patients With Epilepsy: LAMICTAL is intended to be used either alone or in combination with other medicines to treat seizures in people aged 2 years or older.

For Patients With Bipolar Disorder: LAMICTAL is used as maintenance treatment of Bipolar I Disorder to delay the time to occurrence of mood episodes in people aged 18 years or older treated for acute mood episodes with standard therapy.

If you are taking LAMICTAL to help prevent extreme mood swings, you may not experience the full effect for several weeks. Occasionally, the symptoms of depression or bipolar disorder may include thoughts of harming yourself or committing suicide. Tell your doctor immediately or go to the nearest hospital if you have any distressing thoughts or experiences during this initial period or at any other time. Also contact your doctor if you experience any worsening of your condition or develop other new symptoms at any time during your treatment.

Some medicines used to treat depression have been associated with suicidal thoughts and suicidal behavior in children or teenagers. LAMICTAL is not approved for treating children or teenagers with mood disorders such as bipolar disorder or depression.

2. Who Should Not Take LAMICTAL:

You should not take LAMICTAL if you had an allergic reaction to it in the past.

3. Side Effects to Watch for:

  • Most people who take LAMICTAL tolerate it well. Common side effects with LAMICTAL include dizziness, headache, blurred or double vision, lack of coordination, sleepiness, nausea, vomiting, insomnia, and rash. LAMICTAL may cause other side effects not listed in this leaflet. If you develop any side effects or symptoms you are concerned about or need more information, call your doctor.
  • Although most patients who develop rash while receiving LAMICTAL have mild to moderate symptoms, some individuals may develop a serious skin reaction that requires hospitalization. Rarely, deaths have been reported. These serious skin reactions are most likely to happen within the first 8 weeks of treatment with LAMICTAL. Serious skin reactions occur more often in children than in adults.
  • Rashes may be more likely to occur if you: (1) take LAMICTAL in combination with ® ® valproate [DEPAKENE (valproic acid) or DEPAKOTE (divalproex sodium)], (2) take a higher starting dose of LAMICTAL than your doctor prescribed, or (3) increase your dose of LAMICTAL faster than prescribed.
  • It is not possible to predict whether a mild rash will develop into a more serious reaction.

Therefore, if you experience a skin rash, hives, fever, swollen lymph glands, painful sores in the mouth or around the eyes, or swelling of lips or tongue, tell a doctor immediately, since these symptoms may be the first signs of a serious reaction. A doctor should evaluate your condition and decide if you should continue taking LAMICTAL.

4. The Use of LAMICTAL During Pregnancy and Breast-feeding:

The effects of LAMICTAL during pregnancy are not known at this time. If you are pregnant or are planning to become pregnant, talk to your doctor. Some LAMICTAL passes into breast milk and the effects of this on infants are unknown. Therefore, if you are breast-feeding, you should discuss this with your doctor to determine if you should continue to take LAMICTAL.

5. Use of Birth Control Pills or Other Female Hormonal Products:

  • Do not start or stop using birth control pills or other female hormonal products until you have consulted your doctor.

  • Tell your doctor as soon as possible if you experience changes in your menstrual pattern (e.g., break-through bleeding) while taking LAMICTAL and birth control pills or other female hormonal products.

6. How to Use LAMICTAL:

  • It is important to take LAMICTAL exactly as instructed by your doctor. The dose of LAMICTAL must be increased slowly. It may take several weeks or months before your final dosage can be determined by your doctor, based on your response.

  • Do not increase your dose of LAMICTAL or take more frequent doses than those indicated by your doctor. Contact your doctor, if you stop taking LAMICTAL for any reason. Do not restart without consulting your doctor.

  • If you miss a dose of LAMICTAL, do not double your next dose.

  • Always tell your doctor and pharmacist if you are taking any other prescription or over-the-counter medicines. Tell your doctor before you start any other medicines.

  • Do NOT stop taking LAMICTAL or any of your other medicines unless instructed by your doctor.

  • Use caution before driving a car or operating complex, hazardous machinery until you know if LAMICTAL affects your ability to perform these tasks.

  • If you have epilepsy, tell your doctor if your seizures get worse or if you have any new types of seizures.

7. How to Take LAMICTAL:

LAMICTAL Tablets should be swallowed whole. Chewing the tablets may leave a bitter taste. LAMICTAL Chewable Dispersible Tablets may be swallowed whole, chewed, or mixed in water or diluted fruit juice. If the tablets are chewed, consume a small amount of water or diluted fruit juice to aid in swallowing.

To disperse LAMICTAL Chewable Dispersible Tablets, add the tablets to a small amount of liquid (1 teaspoon, or enough to cover the medication) in a glass or spoon. Approximately 1 minute later, when the tablets are completely dispersed, mix the solution and take the entire amount immediately.

8. Storing Your Medicine:

Store LAMICTAL at room temperature away from heat and light. Always keep your medicines out of the reach of children.

This medicine was prescribed for your use only to treat seizures or to treat Bipolar Disorder. Do not give the drug to others.

If your doctor decides to stop your treatment, do not keep any leftover medicine unless your doctor tells you to. Throw away your medicine as instructed.

Manufactured for
GlaxoSmithKline
Research Triangle Park,
NC 27709
by DSM Pharmaceuticals, Inc.
Greenville, NC 27834
or GlaxoSmithKline
Research Triangle Park, NC 27709

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Last updated: August, 2005

Lamictal Patient Information (in plain English)

Detailed Info on Signs, Symptoms, Causes, Treatments of Bipolar Disorder


The information in this monograph is not intended to cover all possible uses, directions, precautions, drug interactions or adverse effects. This information is generalized and is not intended as specific medical advice. If you have questions about the medicines you are taking or would like more information, check with your doctor, pharmacist, or nurse.

back to: Psychiatric Medications Pharmacology Homepage

Intuniv (Guanfacine) Full Prescribing Information

PDF

Brand Name: Intuniv

Intuniv Extended Release Tablets, an ADHD medication for the treatment of Attention-Deficit/Hyperactivity Disorder (ADHD) in children and adolescents. Usage, dosage, side effects.

Contents:

Indications and Usage
Dosage and Administration
Dosage Forms and Strengths
Contraindications
Warnings and Precautions
Adverse Reactions
Drug Interactions
Use in Specific Populations
Drug Abuse and Dependence
Overdosage
Description
Clinical Pharmacology
Nonclinical Toxicology
Clinical Studies
How Supplied/Storage and Handling

Intuniv (Guanfacine) Patient Information (in plain English)

Indications and Usage

INTUNIV™ is indicated for the treatment of Attention Deficit Hyperactivity Disorder (ADHD). The efficacy of INTUNIV was studied for the treatment of ADHD in two controlled clinical trials (8 and 9 weeks in duration) in children and adolescents ages 6- 17 who met DSM-IV® criteria for ADHD [see Clinical Studies]. The effectiveness of INTUNIV for longer-term use (more than 9 weeks) has not been systematically evaluated in controlled trials.

A diagnosis of ADHD implies the presence of hyperactive-impulsive and/or inattentive symptoms that cause impairment and were present before the age of 7 years. The symptoms must cause clinically significant impairment, e.g., in social, academic, or occupational functioning, and be present in two or more settings, e.g., school (or work) and at home. The symptoms must not be better accounted for by another mental disorder. For the Inattentive Type, at least six of the following symptoms must have persisted for at least 6 months: lack of attention to details/careless mistakes; lack of sustained attention; poor listener; failure to follow through on tasks; poor organization; avoids tasks requiring sustained mental effort; loses things; easily distracted; forgetful. For the Hyperactive-Impulsive Type, at least six of the following symptoms must have persisted for at least 6 months: fidgeting/squirming; leaving seat; inappropriate running/climbing; difficulty with quiet activities; "on the go"; excessive talking; blurting answers; can't wait turn; intrusive. The Combined Type requires both inattentive and hyperactive-impulsive criteria to be met.

Special Diagnostic Considerations

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Specific etiology of this syndrome is unknown, and there is no single diagnostic test. Adequate diagnosis requires the use not only of medical but also of special psychological, educational, and social resources. Learning may or may not be impaired. The diagnosis must be based upon a complete history and evaluation of the patient and not solely on the presence of the required number of DSM-IV® characteristics.

Need for Comprehensive Treatment Program

INTUNIV is indicated as an integral part of a total treatment program for ADHD that may include other measures (psychological, educational, and social) for patients with this syndrome. Drug treatment may not be indicated for all patients with this syndrome. INTUNIV is not intended for use in patients who exhibit symptoms secondary to environmental factors and/or other primary psychiatric disorders, including psychosis. Appropriate educational/vocational placement is essential and psychosocial intervention is often helpful. When remedial measures alone are insufficient, the decision to prescribe INTUNIV will depend upon the physician's assessment of the chronicity and severity of the patient's symptoms and on the level of functional impairment.

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Dosage and Administration

General Dosing Information

INTUNIV is an extended-release tablet and should be dosed once daily. Tablets should not be crushed, chewed or broken before swallowing because this will increase the rate of guanfacine release. Do not administer with high fat meals, due to increased exposure.

Do not substitute for immediate-release guanfacine tablets on a mg-mg basis, because of differing pharmacokinetic profiles. INTUNIV has a delayed Tmax, reduced Cmax and lower bioavailability compared to those of the same dose of immediate-release guanfacine [see Clinical Pharmacology].

Dose Selection

If switching from immediate-release guanfacine, discontinue that treatment, and titrate with INTUNIV according to the following recommended schedule.

Begin at a dose of 1 mg/day, and adjust in increments of no more than 1 mg/week.

Maintain the dose within the range of 1-4 mg once daily, depending on clinical response and tolerability. In clinical trials, patients were randomized to doses of 1 mg, 2 mg, 3 mg or 4 mg and received INTUNIV once daily in the morning [see Clinical Studies].

Clinically relevant improvements were observed beginning at doses in the range 0.05- 0.08 mg/kg once daily. Efficacy increased with increasing weight-adjusted dose (mg/kg). If well tolerated, doses up to 0.12 mg/kg once daily may provide additional benefit. Doses above 4 mg/day have not been studied.

In clinical trials, there were dose-related and exposure-related risks for several clinically significant adverse reactions (hypotension, bradycardia, sedative events). Thus, consideration should be given to dosing INTUNIV on a mg/kg basis, in order to balance the exposure-related potential benefits and risks of treatment.

Maintenance Treatment

The effectiveness of INTUNIV for longer-term use (more than 9 weeks) has not been systematically evaluated in controlled trials. Therefore the physician electing to use INTUNIV for extended periods should periodically re-evaluate the long-term usefulness of the drug for the individual patient.

Discontinuation

In a pharmacodynamic study in healthy young adult volunteers receiving INTUNIV (4 mg once daily) or placebo, the effects of abrupt discontinuation were compared to tapering. There were greater mean increases in systolic and diastolic blood pressure and heart rate after abrupt discontinuation of INTUNIV, but these changes generally reflected a return to original baseline and were not meaningfully different for the two discontinuation strategies. However, infrequent, transient elevations in blood pressure above original baseline (i.e., rebound) have been reported to occur upon abrupt discontinuation of guanfacine. To minimize these effects, the dose should generally be tapered in decrements of no more than 1 mg every 3 to 7 days.

Missed Doses

When reinitiating patients to the previous maintenance dose after two or more missed consecutive doses, physicians should consider titration based on patient tolerability.

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Dosage Forms and Strengths

1 mg, 2 mg, 3 mg and 4 mg extended-release tablets

  1 mg 2 mg 3 mg 4 mg
Color White/off-white White/off-white Green Green
Shape Round Caplet Round Caplet

Debossment (top/bottom)

503 / 1mg 503 / 2mg 503 / 3mg 503 / 4mg

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Contraindications

Patients with a history of hypersensitivity to INTUNIV, its inactive ingredients [see Description], or other products containing guanfacine (e.g. TENEX®) should not take INTUNIV.

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Warnings and Precautions

Hypotension, Bradycardia, and Syncope

Treatment with INTUNIV can cause decreases in blood pressure and heart rate. In the pediatric, short-term (8-9 weeks), controlled trials, the maximum mean changes from baseline in systolic blood pressure, diastolic blood pressure, and pulse were −5 mm Hg, −3 mm Hg, and −6 bpm, respectively, for all dose groups combined (generally one week after reaching target doses of 1 mg/day, 2 mg/day, 3 mg/day or 4 mg/day). These changes were dose dependent. Decreases in blood pressure and heart rate were usually modest and asymptomatic; however, hypotension and bradycardia can occur. Hypotension was reported as an adverse event for 6% of the INTUNIV group and 4% of the placebo group. Orthostatic hypotension was reported for 1% of the INTUNIV group and none in the placebo group. In long-term, open label studies, (mean exposure of approximately 10 months), maximum decreases in systolic and diastolic blood pressure occurred in the first month of therapy. Decreases were less pronounced over time. Syncope occurred in 1% of pediatric subjects in the clinical program. The majority of these cases occurred in the long-term, open-label studies.

Measure heart rate and blood pressure prior to initiation of therapy, following dose increases, and periodically while on therapy. Use INTUNIV with caution in patients with a history of hypotension, heart block, bradycardia, or cardiovascular disease, because it can decrease blood pressure and heart rate. Use caution in treating patients who have a history of syncope or may have a condition that predisposes them to syncope, such as hypotension, orthostatic hypotension, bradycardia, or dehydration. Use INTUNIV with caution in patients treated concomitantly with antihypertensives or other drugs that can reduce blood pressure or heart rate or increase the risk of syncope. Advise patients to avoid becoming dehydrated or overheated.

Sedation and Somnolence

Somnolence and sedation were commonly reported adverse reactions in clinical studies (38% for INTUNIV vs. 12% for placebo) in children and adolescents with ADHD, especially during initial use [see Adverse Reactions]. Before using INTUNIV with other centrally active depressants (such as phenothiazines, barbiturates, or benzodiazepines), consider the potential for additive sedative effects. Caution patients against operating heavy equipment or driving until they know how they respond to treatment with INTUNIV. Advise patients to avoid use with alcohol.

Other Guanfacine-Containing Products

Guanfacine, the active ingredient in INTUNIV, is also approved as an antihypertensive. Do not use INTUNIV in patients concomitantly taking other guanfacine-containing products (e.g., Tenex).

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Adverse Reactions

The following serious adverse reactions are described elsewhere in the labelling:

The most common adverse reactions with INTUNIV are: somnolence/sedation, abdominal pain, dizziness, hypotension/decreased blood pressure, dry mouth, and constipation.

Twelve percent (12%) of patients receiving INTUNIV discontinued from the clinical studies due to adverse events, compared to 4% in the placebo group. The most common adverse reactions leading to discontinuation of INTUNIV-treated patients from the studies were somnolence/sedation (6%) and fatigue (2%). Less common adverse reactions leading to discontinuation (occurring in approximately 1% of patients) included: hypotension/decreased blood pressure, headache, and dizziness.

Clinical Trial Experience

Short Term Clinical Studies

Common Adverse Reactions - Two short-term, placebo-controlled, double-blind pivotal studies (Studies 1 and 2) were conducted in children and adolescents with ADHD, using fixed doses of INTUNIV (1, 2, 3, and 4 mg/day). The most commonly reported adverse reactions (occurring in ≥ 2% of patients) that were considered drug-related and reported in a greater percentage of patients taking INTUNIV compared to patients taking placebo are shown in Table 1. Adverse reactions that were dose-related include: somnolence, sedation, abdominal pain, dizziness, hypotension/decreased blood pressure, dry mouth and constipation.

Table 1: Percentage of Patients Experiencing Common (≥ 2%) Adverse Reactions in Short-Term Studies 1 and 2

Adverse Reaction Term

Placebo
(N=149)

All Doses of
INTUNIV
(N=513)

Somnolencea 12% 38%
Headache 19% 24%
Fatigue 3% 14%
Abdominal pain (upper) 7% 10%
Nausea 2% 6%
Lethargy 3% 6%
Dizziness 4% 6%
Irritability 4% 6%

Hypotension/Decreased
blood pressure

4% 6%
Decreased appetite 3% 5%
Dry mouth 1% 4%
Constipation 1% 3%
a: The somnolence term includes somnolence, sedation, and hypersomnia.

Less Common Adverse Reactions - Less common adverse reactions (< 2%) reported in pivotal Studies 1 and 2 that occurred in more than one patient taking INTUNIV and were more common than in the placebo group are listed below.

Table 2: Less Common Adverse Reactions (< 2%) in Short-Term Studies 1 and 2
Body System Adverse Reaction
Cardiac Atrioventricular block, bradycardia, sinus arrhythmia
Gastrointestinal
Dyspepsia
General Asthenia, chest pain
Investigations Increased alanine aminotransferase, increased blood pressure,increased weight
Nervous system Postural dizziness
Renal Increased urinary frequency, enuresis
Respiratory Asthma
Vascular Orthostatic hypotension, pallor

In addition, the following less common (< 2%) psychiatric disorders occurred in more than one patient receiving INTUNIV and were more common than in the placebo group. The relationship to INTUNIV could not be determined because these events may also occur as symptoms in pediatric patients with ADHD: agitation, anxiety, depression, emotional lability, nightmares or interrupted sleep.

Long Term Clinical Studies

Common Adverse Reactions

Patients from the two short-term, placebo-controlled studies 1 and 2 were eligible to participate in one of two long-term, flexible-dose, open-label studies. The mean duration of exposure of the 446 patients who received open-label treatment was approximately 10 months. The distribution of patients among the doses prior to tapering off upon completion of the study was 37%, 33%, 27% and 3% on 4 mg, 3 mg, 2 mg and 1 mg, respectively.

The most common adverse reactions (≥ 5%) reported during open label treatment are shown in Table 3.

Table 3: Percentage of Patients Experiencing Common (≥ 5%) Adverse Reactions during Long-Term (Up to 10 months), Flexible-dose, Open-Label Follow-up from Studies 1 and 2

Adverse Reaction Term

All Doses of INTUNIV
(N=446)

Somnolencea 45%
Headache
26%
Fatigue 15%
Abdominal pain (upper) 11%
Hypotension / Decreased Blood Pressure 10%
Vomiting 9%
Dizziness 7%
Nausea 7%
Weight increased 7%
Irritability 6%
a: The somnolence term includes somnolence, sedation, and hypersomnia.

Adverse Reactions Leading to Discontinuation - Eighteen percent (18%) of patients receiving INTUNIV discontinued from long-term studies due to adverse events. The most frequent adverse reactions leading to discontinuation (≥ 2%) were somnolence (3%), syncopal events (2%), increased weight (2%), depression (2%), and fatigue (2%). Other adverse reactions leading to discontinuation in the long-term studies (occurring in approximately 1% of patients) included: hypotension/decreased blood pressure, sedation, headache, and lethargy.

Serious Adverse Reactions - In long-term open label studies, serious adverse reactions occurring in more than one patient were syncope (2%) and convulsion (0.4%).

Less Common Adverse Reactions - Adverse reactions that occurred in < 5% of patients but ≥ 2% in open-label, long-term studies that are considered possibly related to INTUNIV include: syncopal events, constipation, stomach discomfort, hypertension/increased blood pressure, decreased appetite, diarrhea, dry mouth, lethargy, and insomnia.

Effects on Height, Weight, and Body Mass Index (BMI)

Patients taking INTUNIV demonstrated similar growth compared to normative data. Patients taking INTUNIV had a mean increase in weight of 1 kg (2 lbs) compared to those receiving placebo over a comparative treatment period. Patients receiving INTUNIV for at least 12 months in open-label studies gained an average of 8 kg (17 lbs) in weight and 8 cm (3 in) in height. The height, weight, and BMI percentile remained stable in patients at 12 months in the long-term studies compared to when they began receiving INTUNIV.

Laboratory Tests

In short and long-term studies, no clinically important effects were identified on any laboratory parameters.

Effects on Heart Rate and QT Interval

The effect of two dose levels of immediate-release guanfacine (4 mg and 8 mg) on the QT interval was evaluated in a double-blind, randomized, placebo- and active-controlled, cross-over study in healthy adults.

A dose-dependent decrease in heart rate was observed during the first 12 hours, at time of maximal concentrations. The mean change in heart rate was -13 bpm at 4 mg and -22 bpm at 8 mg.

An apparent increase in mean QTc was observed for both doses. However, guanfacine does not appear to interfere with cardiac repolarization of the form associated with proarrhythmic drugs. This finding has no known clinical relevance.

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Drug Interactions

CYP3A4/5 Inhibitors

Use caution when INTUNIV is administered to patients taking ketoconazole and other strong CYP3A4/5 inhibitors, since elevation of plasma guanfacine concentration increases the risk of adverse events such as hypotension, bradycardia, and sedation. There was a substantial increase in the rate and extent of guanfacine exposure when administered with ketoconazole; the guanfacine exposure increased 3-fold (AUC).

CYP3A4 Inducers

When patients are taking INTUNIV concomitantly with a CYP3A4 inducer, an increase in the dose of INTUNIV within the recommended dose range may be considered. There was a significant decrease in the rate and extent of guanfacine exposure when co-administered with rifampin, a CYP3A4 inducer. The exposure to guanfacine decreased by 70% (AUC).

Valproic Acid

Co-administration of guanfacine and valproic acid can result in increased concentrations of valproic acid. The mechanism of this interaction is unknown, although both guanfacine (via a Phase I metabolite, 3-hydroxy guanfacine) and valproic acid are metabolized by glucuronidation, possibly resulting in competitive inhibition. When INTUNIV is coadministered with valproic acid, monitor patients for potential additive CNS effects, and consider monitoring serum valproic acid concentrations. Adjustments in the dose of valproic acid may be indicated when co-administered with INTUNIV.

Antihypertensive Drugs

Use caution when INTUNIV is administered concomitantly with antihypertensive drugs, due to the potential for additive pharmacodynamic effects (e.g., hypotension, syncope) [see Warnings and Precautions].

CNS Depressant Drugs

Caution should be exercised when INTUNIV is administered concomitantly with CNS depressant drugs (e.g. alcohol, sedative/hypnotics, benzodiazepines, barbiturates, and antipsychotics) due to the potential for additive pharmacodynamic effects (e.g., sedation, somnolence) [see Warnings and Precautions].

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Use in Specific Populations

Pregnancy

Pregnancy Category B

Rat experiments have shown that guanfacine crosses the placenta. However, administration of guanfacine to rats and rabbits at 6 and 4 times, respectively, the maximum recommended human dose of 4 mg/day on a mg/m2 basis resulted in no evidence of harm to the fetus. Higher doses (20 times the maximum recommended human dose in both rabbits and rats) were associated with reduced fetal survival and maternal toxicity. There are no adequate and well-controlled studies of guanfacine in pregnant women. Because animal reproduction studies are not always predictive of human response, this drug should be used during pregnancy only if clearly needed.

Nursing Mothers

It is not known whether guanfacine is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when INTUNIV is administered to a nursing woman. Experiments with rats have shown that guanfacine is excreted in the milk.

Pediatric Use

The safety and efficacy of INTUNIV in pediatric patients less than 6 years of age have not been established. For children and adolescents 6 years and older, efficacy beyond 9 weeks and safety beyond 2 years of treatment have not been established [see Adverse Reactions and Clinical Studies].

Geriatric Use

The safety and efficacy of INTUNIV in geriatric patients have not been established.

Use in Patients with Renal or Hepatic Impairment

Renal Impairment

The impact of renal impairment on the pharmacokinetics of guanfacine in children was not assessed. In adult patients with impaired renal function, the cumulative urinary excretion of guanfacine and the renal clearance diminished as renal function decreased. In patients on hemodialysis, the dialysis clearance was about 15% of the total clearance. The low dialysis clearance suggests that the hepatic elimination (metabolism) increases as renal function decreases. It may be necessary to adjust the dose in patients with significant impairment of renal function.

Hepatic Impairment

The impact of hepatic impairment on PK of guanfacine in children was not assessed. Guanfacine in adults is cleared both by the liver and the kidney, and approximately 50% of the clearance of guanfacine is hepatic. It may be necessary to adjust the dose in patients with significant impairment of hepatic function.

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Drug Abuse and Dependence

Controlled Substance

INTUNIV is not a controlled substance and has no known potential for abuse or dependence.

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Overdosage

Symptoms

Two cases of accidental overdose of INTUNIV were reported in clinical trials in pediatric ADHD patients. These reports included adverse reactions of sedation and bradycardia in one patient and somnolence and dizziness in the other patient.

During post-marketing surveillance of guanfacine as an antihypertensive treatment for adults, drowsiness, lethargy, bradycardia and hypotension have been observed following overdose. Similar symptoms have been described in voluntary reports to the American Association of Poison Control Center's National Poison Data System. Miosis of the pupils may be noted on examination. No fatal overdoses of guanfacine have been reported in published literature.

Treatment

Consult a Certified Poison Control Center for up to date guidance and advice. Gastric lavage may be indicated if performed soon after ingestion. Activated charcoal may be useful in limiting absorption. Guanfacine is not dialyzable in clinically significant amounts (2.4%).

Management of INTUNIV overdose should include monitoring for and the treatment of hypotension, bradycardia, lethargy and respiratory depression. Children and adolescents who develop lethargy should be observed for the development of more serious toxicity including coma, bradycardia and hypotension for up to 24 hours, due to the possibility of delayed onset hypotension.

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Description

INTUNIV is a once-daily, extended-release formulation of guanfacine hydrochloride (HCl) in a matrix tablet formulation for oral administration only. The chemical designation is N-amidino-2-(2,6-dichlorophenyl) acetamide monohydrochloride. The molecular formula is C9H9Cl2 N3O·HCl corresponding to a molecular weight of 282.55. The chemical structure is:

Intuniv structural formula

Guanfacine HCl is a white to off-white crystalline powder, sparingly soluble in water (approximately 1 mg/mL) and alcohol and slightly soluble in acetone. The only organic solvent in which it has relatively high solubility is methanol (>30 mg/mL). Each tablet contains guanfacine HCl equivalent to 1 mg, 2 mg, 3 mg, or 4 mg of guanfacine base. The tablets also contain hypromellose, methacrylic acid copolymer, lactose, povidone, crospovidone, microcrystalline cellulose, fumaric acid, and glyceryl behenate. In addition, the 3mg and 4mg tablets also contain green pigment blend PB-1763.

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Clinical Pharmacology

Mechanism of Action

Guanfacine is a selective alpha2A-adrenergic receptor agonist. Guanfacine is not a central nervous system (CNS) stimulant. The mechanism of action of guanfacine in ADHD is not known.

Pharmacodynamics

Guanfacine is a selective alpha2A-adrenergic receptor agonist in that it has a 15-20 times higher affinity for this receptor subtype than for the alpha2B or alpha2C subtypes.

Guanfacine is a known antihypertensive agent. By stimulating alpha2A-adrenergic receptors, guanfacine reduces sympathetic nerve impulses from the vasomotor center to the heart and blood vessels. This results in a decrease in peripheral vascular resistance and a reduction in heart rate.

Pharmacokinetics

Absorption and Distribution

Guanfacine is readily absorbed and approximately 70% bound to plasma proteins independent of drug concentration. After oral administration of INTUNIV the time to peak plasma concentration is approximately 5 hours in children and adolescents with ADHD.

Immediate-release guanfacine and INTUNIV have different pharmacokinetic characteristics; dose substitution on a milligram for milligram basis will result in differences in exposure.

A comparison across studies suggests that the Cmax is 60% lower and AUC0-β 43% lower, respectively, for INTUNIV compared to immediate-release guanfacine. Therefore, the relative bioavailability of INTUNIV to immediate-release guanfacine is 58%. The mean pharmacokinetic parameters in adults following the administration of INTUNIV 1 mg once daily and immediate-release guanfacine 1mg once daily are summarized in Table 4.

Table 4: Pharmacokinetic Parameters in Adults
Parameter INTUNIV
1 mg once daily
(n=52)
Immediate-release
guanfacine
1 mg once daily
(n=12)
Cmax (ng/mL) 1.0 ± 0.3 2.5 ± 0.6
AUC0-β (ng.h/mL) 32 ± 9 56 ± 15
tmax (h) 6.0 (4.0 - 8.0) 3.0 (1.5-4.0)
t ½ (h) 18 ± 4 16 ± 3
Note: Values are mean +/- SD, except for tmax which is median (range)

Exposure to guanfacine was higher in children (ages 6-12) compared to adolescents (ages 13-17) and adults. After oral administration of multiple doses of INTUNIV 4 mg, the Cmax was 10 ng/mL compared to 7 ng/mL and the AUC was 162 ng h/mL compared to 116 ng h/mL in children (ages 6-12) and adolescents (ages 13-17), respectively. These differences are probably attributable to the lower body weight of children compared to adolescents and adults.

The pharmacokinetics were affected by intake of food when a single dose of INTUNIV 4 mg was administered with a high-fat breakfast. The mean exposure increased (Cmax ~75% and AUC ~40%) compared to dosing in a fasted state.

Dose Proportionality

Following administration of INTUNIV in single doses of 1 mg, 2 mg, 3 mg, and 4 mg to adults, Cmax and AUC0-β of guanfacine were proportional to dose.

Metabolism and Elimination

In vitro studies with human liver microsomes and recombinant CYP's demonstrated that guanfacine was primarily metabolized by CYP3A4. In pooled human hepatic microsomes, guanfacine did not inhibit the activities of the major cytochrome P450 isoenzymes (CYP1A2, CYP2C8, CYP2C9, CYP2C19, CYP2D6 or CYP3A4/5). Guanfacine is a substrate of CYP3A4/5 and exposure is affected by CYP3A4/5 inducers/inhibitors.

Renal and Hepatic Impairment

The impact of renal impairment on PK of guanfacine in children was not assessed [see Use in Specific Populations].

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Nonclinical Toxicology

Carcinogenesis, Mutagenesis, Impairment of Fertility

No carcinogenic effect of guanfacine was observed in studies of 78 weeks in mice or 102 weeks in rats at doses up to 6-7 times the maximum recommended human dose of 4 mg/day on a mg/ m2 basis.

Guanfacine was not genotoxic in a variety of test models, including the Ames test and an in vitro chromosomal aberration test; however, a marginal increase in numerical aberrations (polyploidy) was observed in the latter study.

No adverse effects were observed in fertility studies in male and female rats at doses up to 30 times the maximum recommended human dose on a mg/ m2 basis.

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Clinical Studies

Safety and Efficacy Studies

The efficacy of INTUNIV in the treatment of ADHD was established in 2 placebocontrolled trials in children and adolescents ages 6-17. Study 1 evaluated 2 mg, 3 mg and 4 mg of INTUNIV dosed once daily in an 8-week, double-blind, placebo-controlled, parallel-group, fixed dose design (n=345). Study 2 evaluated 1 mg, 2 mg, 3 mg and 4 mg of INTUNIV dosed once daily in a 9-week, double-blind, placebo-controlled, parallel-group, fixed-dose design (n=324). In Studies 1 and 2, patients were randomized to a fixed dose of INTUNIV. Doses were titrated in increments of up to 1 mg/week. The lowest dose of 1 mg used in Study 2 was assigned only to patients less than 50 kg (110 lbs). Patients who weighed less than 25 kg (55 lbs) were not included in either study.

Signs and symptoms of ADHD were evaluated on a once weekly basis using the clinician administered and scored ADHD Rating Scale-IV (ADHD-RS), which includes both hyperactive/impulsive and inattentive subscales. In both studies, the primary outcome was the change from baseline to endpoint in mean ADHD-RS scores.

The mean reductions in ADHD-RS scores at endpoint were statistically significantly greater for INTUNIV compared to placebo for Studies 1 and 2. Placebo-adjusted changes from baseline were statistically significant for each of the 2 mg, 3 mg, and 4 mg INTUNIV randomized treatment groups in both studies, as well as the 1 mg INTUNIV treatment group (for patients 55-110 lbs) that was included only in Study 2.

Dose-responsive efficacy was evident, particularly when data were examined on a weight-adjusted (mg/kg) basis. When evaluated over the dose range of 0.01-0.17 mg/kg/day, clinically relevant improvements were observed beginning at doses in the range 0.05-0.08 mg/kg/day. Doses up to 0.12 mg/kg/day were shown to provide additional benefit.

Controlled, long-term efficacy studies (>9 weeks) have not been conducted.

Subgroup analyses were performed to identify any differences in response based on gender or age (6-12 vs. 13-17). Analyses of the primary outcome did not suggest any differential responsiveness on the basis of gender. Analyses by age subgroup revealed a statistically significant treatment effect only in the 6-12 age subgroup. Due to the relatively small proportion of adolescent patients (ages 13-17) enrolled into these studies (approximately 25%), these data may not be sufficient to demonstrate efficacy in the adolescent subgroup. In these studies, patients were randomized to a fixed dose of INTUNIV rather than optimized by body weight. Therefore, it is likely that some adolescent patients were randomized to a dose that resulted in relatively low plasma guanfacine concentrations compared to the younger sub-group. Over half (55%) of the adolescent patients received doses of 0.01-0.04mg/kg. In studies in which systematic pharmacokinetic data were obtained, there was a strong inverse correlation between body weight and plasma guanfacine concentrations.

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How Supplied/Storage and Handling

INTUNIV is supplied in 1 mg, 2 mg, 3 mg, and 4 mg strength extended-release tablets

in 100 count bottles.

  1 mg 2 mg 3 mg 4 mg
Color White/off-white White/off-white Green Green
Shape Round Caplet Round Caplet
Debossment
(top/bottom)
503 / 1mg 503 / 2mg 503 / 3mg 503 / 4mg
NDC number 54092-513-02 54092-515-02 54092-517-02 54092-519-02

Storage - Store at 25°C (77°F); excursions permitted to 15° to 30°C (59° to 86°F). See USP Controlled Room Temperature.

Manufactured for Shire US Inc., Wayne, PA 19087.

INTUNIV is a trademark of Shire LLC.

©2009 Shire Pharmaceuticals Inc.

This product is covered by US patents including

5,854,290; 6,287,599; 6,811,794.

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Version: August 2009

Detailed Info on Signs, Symptoms, Causes, Treatments of Attention-Deficit/Hyperactivity Disorder

Intuniv (Guanfacine) Patient Information (in plain English)

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The information in this monograph is not intended to cover all possible uses, directions, precautions, drug interactions or adverse effects. This information is generalized and is not intended as specific medical advice. If you have questions about the medicines you are taking or would like more information, check with your doctor, pharmacist, or nurse.

Cymbalta (Duloxetine) Medication Guide

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Brand Name: Cymbalta
Generic Name: Duloxetine

Warning

Suicidality in Children and Adolescents - Antidepressants increased the risk of suicidal thinking and behavior (suicidality) in short-term studies in children and adolescents with major depressive disorder (MDD) and other psychiatric disorders. Anyone considering the use of Cymbalta or any other antidepressant in a child or adolescent must balance this risk with the clinical need. Patients who are started on therapy should be observed closely for clinical worsening, suicidality, or unusual changes in behavior. Families and caregivers should be advised of the need for close observation and communication with the prescriber. Cymbalta is not approved for use in pediatric patients. (See WARNINGS and PRECAUTIONS, Pediatric Use.) Pooled analyses of short-term (4 to 16 weeks) placebo-controlled trials of 9 antidepressant drugs (SSRIs and others) in children and adolescents with major depressive disorder (MDD), obsessive compulsive disorder (OCD), or other psychiatric disorders (a total of 24 trials involving over 4400 patients) have revealed a greater risk of adverse events representing suicidal thinking or behavior (suicidality) during the first few months of treatment in those receiving antidepressants. The average risk of such events in patients receiving antidepressants was 4%, twice the placebo risk of 2%. No suicides occurred in these trials.

Cymbalta Prescribing Information

About Using Antidepressants in Children and Teenagers

What is the most important information I should know if my child is being prescribed an antidepressant?

Parents or guardians need to think about 4 important things when their child is prescribed an antidepressant:

1. There is a risk of suicidal thoughts or actions
2. How to try to prevent suicidal thoughts or actions in your child
3. You should watch for certain signs if your child is taking an antidepressant
4. There are benefits and risks when using antidepressants

1. There is a Risk of Suicidal Thoughts or Actions

Children and teenagers sometimes think about suicide, and many report trying to kill themselves.

Antidepressants increase suicidal thoughts and actions in some children and teenagers. But suicidal thoughts and actions can also be caused by depression, a serious medical condition that is commonly treated with antidepressants. Thinking about killing yourself or trying to kill yourself is called suicidality or being suicidal.

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A large study combined the results of 24 different studies of children and teenagers with depression or other illnesses. In these studies, patients took either a placebo (sugar pill) or an antidepressant for 1 to 4 months. No one committed suicide in these studies, but some patients became suicidal. On sugar pills, 2 out of every 100 became suicidal. On the antidepressants, 4 out of every 100 patients became suicidal.

For some children and teenagers, the risks of suicidal actions may be especially high. These include patients with

- Bipolar illness (sometimes called manic-depressive illness)
- A family history of bipolar illness
- A personal or family history of attempting suicide

If any of these are present, make sure you tell your health care provider before your child takes an antidepressant.

2. How to Try to Prevent Suicidal Thoughts and Actions

To try to prevent suicidal thoughts and actions in your child, pay close attention to changes in her or his moods or actions, especially if the changes occur suddenly. Other important people in your child's life can help by paying attention as well (e.g., your child, brothers and sisters, teachers, and other important people). The changes to look out for are listed in Section 3, on what to watch for.
Whenever an antidepressant is started or its dose is changed, pay close attention to your child.
After starting an antidepressant, your child should generally see his or her health care provider

- Once a week for the first 4 weeks
- Every 2 weeks for the next 4 weeks
- After taking the antidepressant for 12 weeks
- After 12 weeks, follow your health care provider's advice about how often to come back
- More often if problems or questions arise (see Section 3)

You should call your child's health care provider between visits if needed.

3. You Should Watch for Certain Signs If Your Child is Taking an Antidepressant

Contact your child's health care provider right away if your child exhibits any of the following signs for the first time, or if they seem worse, or worry you, your child, or your child's teacher:

- Thoughts about suicide or dying
- Attempts to commit suicide
- New or worse depression
- New or worse anxiety
- Feeling very agitated or restless
- Panic attacks
- Difficulty sleeping (insomnia)
- New or worse irritability
- Acting aggressive, being angry, or violent
- Acting on dangerous impulses
- An extreme increase in activity and talking
- Other unusual changes in behavior or mood

Never let your child stop taking an antidepressant without first talking to his or her health care provider. Stopping an antidepressant suddenly can cause other symptoms.

4. There are Benefits and Risks When Using Antidepressants

Antidepressants are used to treat depression and other illnesses. Depression and other illnesses can lead to suicide. In some children and teenagers, treatment with an antidepressant increases suicidal thinking or actions. It is important to discuss all the risks of treating depression and also the risks of not treating it. You and your child should discuss all treatment choices with your health care provider, not just the use of antidepressants.

Other side effects can occur with antidepressants (see section below).
Of all the antidepressants, only fluoxetine (Prozac®) has been FDA approved to treat pediatric depression.

For obsessive compulsive disorder in children and teenagers, FDA has approved only fluoxetine (Prozac®), sertraline (Zoloft®), fluvoxamine, and clomipramine (Anafranil®).

Your health care provider may suggest other antidepressants based on the past experience of your child or other family members.

Is this all I need to know if my child is being prescribed an antidepressant?

No. This is a warning about the risk for suicidality. Other side effects can occur with antidepressants. Be sure to ask your health care provider to explain all the side effects of the particular drug he or she is prescribing. Also ask about drugs to avoid when taking an antidepressant. Ask your health care provider or pharmacist where to find more information.

Prozac® is a registered trademark of Eli Lilly and Company.

Zoloft® is a registered trademark of Pfizer Pharmaceuticals.
Anafranil® is a registered trademark of Mallinckrodt Inc.
This Medication Guide has been approved by the US Food and Drug Administration for all antidepressants.
Literature revised September 22, 2005
Eli Lilly and Company
Indianapolis, IN 46285, USA
www.Cymbalta.com

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Cymbalta Prescribing Information

Detailed Info on Signs, Symptoms, Causes, Treatments of Depression


The information in this monograph is not intended to cover all possible uses, directions, precautions, drug interactions or adverse effects. This information is generalized and is not intended as specific medical advice. If you have questions about the medicines you are taking or would like more information, check with your doctor, pharmacist, or nurse. This page last reviewed 11/05.

Copyright © 2005 Healthyplace Inc. All rights reserved.

back to: Psychiatric Medications Pharmacology Homepage