• Watch the video on The Narcissist's Second Chance

Relationships with narcissists peter out slowly and tortuously. Narcissists do not provide closure.They stalk. They cajole, beg, promise, persuade, and, ultimately, succeed in doing the impossible yet again: sweep you off your feet, though you know better than to succumb to their spurious and superficial charms.

So, you go back to your "relationship" and hope for a better ending. You walk on eggshells. You become the epitome of submissiveness, a perfect Source of Narcissistic Supply, the ideal mate or spouse or partner or colleague. You keep your fingers crossed.

But how does the narcissist react to the resurrection of the bond?

It depends on whether you have re-entered the liaison from a position or strength - or of vulnerability and weakness.

The narcissist casts all interactions with other people in terms of conflicts or competitions to be won. He does not regard you as a partner - but as an adversary to be subjugated and defeated. Thus, as far as he is concerned, your return to the fold is a triumph, proof of his superiority and irresistibility.

If he perceives you as autonomous, dangerously independent, and capable of bailing out and abandoning him - the narcissist acts the part of the sensitive, loving, compassionate, and empathic counterpart. Narcissists respect strength, they are awed by it. As long as you maintain a "no nonsense" attitude, placing the narcissist on probation, he is likely to behave himself.

If, on the other hand, you have resumed contact because you have capitulated to his threats or because you are manifestly dependent on him financially or emotionally - the narcissist will pounce on your frailty and exploit your fragility to the maximum. Following a perfunctory honeymoon, he will immediately seek to control and abuse you.

 

In both cases, the narcissist's thespian reserves are exhausted and his true nature and feelings emerge. The facade crumbles and beneath it lurks the same old heartless falsity that is the narcissist. His gleeful smugness at having bent you to his wishes and rules, his all-consuming sense of entitlement, his sexual depravity, his aggression, pathological envy, and rage - all erupt uncontrollably.

The prognosis for the renewed affair is far worse if it follows a lengthy separation in which you have made a life for yourself with your own interests, pursuits, set of friends, needs, wishes, plans, and obligations, independent of your narcissistic ex and unrelated to him.

The narcissist cannot countenance your separateness. To him, you are a mere instrument of gratification or an extension of his bloated False Self. He resents your pecuniary wherewithal, is insanely jealous of your friends, refuses to accept your preferences or compromise his own, in envious and dismissive of your accomplishments.

Ultimately, the very fact that you have survived without his constant presence seems to deny him his much-needed Narcissistic Supply. He rides the inevitable cycle of idealisation and devaluation. He berates you, humiliates you publicly, threatens you, destabilises you by behaving unpredictably, fosters ambient abuse, and uses others to intimidate and humble you ("abuse by proxy").

You are then faced with a tough choice:

To leave again and give up all the emotional and financial investments that went into your attempt to resurrect the relationship - or to go on trying, subject to daily abuse and worse?

It is a well-known landscape. You have been here before. But this familiarity doesn't make it less nightmarish.

 

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next: The Cult of the Narcissist

If you're depressed despite normal efforts to treat your depression symptoms, a physical source of the depression should be considered.

Depression is a universally understood condition of sadness and despondency. Life has lost its luster and gloom prevails. Some sadness is an inherent part of weathering life's misfortunes. People normally recover from such low points and carry on. Other conditions of sadness may require lifestyle changes such as resolving a rocky marriage, dropping bad habits, or removing oppressive factors from one's life. Still other situations may require the counsel of a good friend or priest or minister - someone one can trust and discuss his or her troubles with.

However, sometimes people don't recover from life's setbacks. Or they become depressed over insignificant matters or for no reason at all. The feelings of sadness may simply slow them down or can debilitate them to the point where they weep continuously, cannot function in life, or may consider suicide

Looking for a Medical Cause for Depression

When a person remains depressed despite normal efforts to treat the depression, a physical source of the depression should be considered. This is particularly true in the case of debilitating or suicidal depression.

Physiological causes of depression are so common, in fact, that The American Assn. of Clinical Endocrinologists states, "The diagnosis of subclinical [without obvious signs] or clinical hypothyroidism must be considered in every patient with depression."

Physical sources of depression include:

• Nutritional deficiencies
• Lack of exercise
• Hypothyroidism
• Hyperthyroidism
• Fibromyalgia
• Candida (yeast infection)
• Poor adrenal function
• Other hormonal disorders including:
  • Cushing's Disease (excessive pituitary hormone production)
  • Addison's disease (low adrenal function)
  • High levels of parathyroid hormone
  • Low levels of pituitary hormones
• Hypoglycemia
• Food Allergies
• Heavy metals (such as mercury, lead, aluminum, cadmium, and thallium)
• Selenium toxicity
• Premenstrual syndrome
• Sleep disturbances
• Infections including:
  • AIDS
  • Influenza
  • Mononucleosis
  • Syphilis (late stage)
  • Tuberculosis
  • Viral hepatitis
  • Viral pneumonia
• Medical conditions including:
  • Heart problems
  • Lung disease
  • Diabetes
  • Multiple sclerosis
  • Rheumatoid arthritis
  • Chronic pain
  • Chronic inflammation
  • Cancer
  • Brain tumors
  • Head injury
  • Multiple sclerosis
  • Parkinson's disease
  • Stroke
  • Temporal lope epilepsy
  • Systemic lupus erythematosus
  • Liver disease
• Drugs including:
  • Tranquilizers and sedatives
  • Antipsychotic drugs
  • Amphetamines (withdrawal from)
  • Antihistamines
  • Beta-blockers
  • High blood pressure medications
  • Birth control pills
  • Anti-inflammatory agents
  • Corticosteroids (adrenal hormone agents
  • Cimetidine
  • Cycloserine (an antibiotic)
  • Indomethacin
  • Reserpine
  • Vinblastine
  • Vincristine

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The Importance of Exercise in Treating Depression Symptoms

A Duke University study points out the remarkable connection between depression and one's physical condition. A group of 156 elderly patients diagnosed with major depression were divided into three groups, including one whose only treatment was a brisk 30-minute walk or jog three times a week. After 16 weeks, 60.4% no longer met the criteria for a diagnosis of depression.

Duke University psychologist James Blumenthal published the results of his team's study in the Oct. 25, 1, issue of The Archives of Internal Medicine. "One of the conclusions we can draw from this," he said, "is that exercise may be just as effective as medication and may be a better alternative for certain patients.

Daily 30-minute walks are even better and faster-acting, according to a German study.

Nutritional Deficiencies As A Cause of Depression

A particular note should be made about nutritional deficiencies and their relationship to depression. According to the Encyclopedia of Natural Medicine, "A deficiency of any single nutrient can alter brain function and lead to depression, anxiety, and other mental disorders."

However, some nutritional deficiencies are more common than others.

Vitamin B₂ deficiency is not common but can be created, ironically enough, by certain antidepressant drugs called tricyclics>. This can lead to further depression.

Vitamin B₆ is commonly very low in people who are depressed. This is particularly true in people taking birth control pills or estrogen in other forms. Those who are deficient in this vitamin normally do well with B₆ supplements.

Vitamin B₉ is called folic acid and is the most common deficient vitamin. Studies have shown that 31-35% of depressed patients have folic acid deficiencies. The most common symptom of folic acid deficiency is, in fact, depression.

Vitamin B₁₂ works along with folic acid in a number of biochemical functions. Deficiency becomes more common over the age of 50. One study showed deficiency rates as follows: Between the ages of 60-69, 24%, ages 70-79, 32%, over 80, nearly 40%. Supplementation of folic acid and B₁₂ often produces dramatic results in people who are depressed because of deficiencies.

Vitamin C deficiency is not particularly common but can occur people with very poor diets or nonexistent intake of fruits and vegetables. Symptoms of a mild deficiency include fatigue, irritableness and "the blues." If not remedied, scurvy symptoms can develop.

Magnesium is a critical mineral used in sending messages along your nerves. By some estimates nearly 75% of Americans do not take in enough to meet minimum requirements. Magnesium deficiencies can result in muscle weakness and irritability.

Another deficiency can occur with amino acids, the building blocks that make up protein. One form of the amino acid methionine is called SAMe (S-adenosylmethionine). SAMe levels tend to be low in the elderly and in depressed people. SAMe supplements have been effective in alleviating depression. A common dosage of SAMe is to start with 1,600 mg a day - either 800 mg twice a day or 400 mg four times a day - for about two or three weeks, or until you start to feel the antidepressant effects. Then one gradually reduces the dosage to 800 mg or even 400-mg a day, based on one's depressive symptoms.

Tryptophan is another amino acid that affects depression. Many depressed people have low tryptophan levels. One supplement, 5-HTP, which contains a form of tryptophan, has been shown in numerous studies to be as effective as modern antidepressants (such as Prozac, , and Paxil) for less cost and with fewer and much milder side effects. A standard dosage of 5-HTP is 50-100 mg once or twice a day with meals.

Low fat diets can lead to depression if they are deficient in a specific fatty acid (the building block of fats) called omega-3. Omega-3 is common in certain seeds, canola oil, soybean oil, egg yolks, and cold-water ocean fish. Population studies in different countries have shown that decreased consumption of omega-3's correlates with increased rates of depression.

More information on the role of nutritional problems in depression.

Thyroid Problems Can Result in Depression

A study reported in the Feb. 28, 2000, issue of Archive of Internal Medicine revealed that, of more than 25,000 people given blood tests, 9.9% had thyroid problems they probably did not know about. Another 5.9% were being treated for thyroid problems. This means nearly 16% of the population had thyroid dysfunction. Depression is a common symptom of poor thyroid function.

Dr. Broda Barnes, author of Hypothyroidism: The Unsuspected Illness, estimated that as many as 40% of the public may have low thyroid function, much of which is not detectable by modern blood tests. He recommended a simple and more reliable body temperature test.

Dr. Barnes' self thyroid test, discussed in his book, is as follows: You take an old-fashioned mercury-type thermometer and shake it down and put it on the nightstand before going to bed (if you're going to do it on yourself - on someone else just shake it down below 95 degrees before you take the temp). In the morning on awakening, before arising or moving around, the person puts the thermometer snugly in his armpit for 10 minutes by the clock. If the temp is below 97.8, the person likely needs thyroid or, if they're on thyroid, they need more thyroid. The temp should be between 97.8-98.2. Dr. Barnes recommended Armour Thyroid which is natural. Most doctors don't use this test but alternative doctors do. You can get a list of them who will prescribe thyroid based on this test at the Broda Barnes Foundation at 203 261-2101.

A Note on Depression in the Elderly

A staggering number of the elderly are on antidepressant drugs because depression is rampant among the aged. While many factors can be involved - loss of loved ones, poor health, retirement, etc. - a primary cause of this epidemic is nutritional deficiencies. Not only do they eat poorly but they have trouble absorbing a number of vitamins (e.g. B₁₂) as their age increases.

Thyroid problems, as determined by blood tests, have been estimated to affect up to 20% of women over 60.

Lack of exercise, a common problem with seniors, can, as noted above, be a major source of depression.

Nutritional deficiencies, thyroid disorders, and enough exercise should be a top concern in any population of elderly people with "depression."

Summary

A host of physical ailments can lead to a condition of sadness, tearfulness, and hopelessness. These should be suspected and looked for in anyone who is depressed and has a known physical ailment or who experiences severe or unresolving depression.

next: Co-Occurrence of Depression With Cancer
~ depression library articles
~ all articles on depression

The following ADHD myths and factual responses have been collected from rebuttals to media articles about ADHD.

Myth #1: ADHD is a "phantom disorder".

FACT: The existence of a neurobiological disorder is not an issue to be decided by the media through public debate, but rather as a matter of scientific research. Scientific studies spanning 95 years summarized in the professional writings of Dr. Russell Barkley, Dr. Sam Goldstein, and others have consistently identified a group of individuals who have trouble with concentration, impulse control, and in some cases, hyperactivity. Although the name given to this group of individuals, our understanding of them, and the estimated prevalence of this group has changed a number of times over the past six decades, the symptoms have consistently been found to cluster together. Currently called Attention Deficit Hyperactivity Disorder, this syndrome has been recognized as a disability by the courts, the United States Department of Education, the Office for Civil Rights, the United States Congress, the National Institutes of Health, and all major professional medical, psychiatric, psychological, and educational associations.

Myth #2: Ritalin is like cocaine, and the failure to give youngsters drug holidays from Ritalin causes them to develop psychosis.

FACT: Methylphenidate (Ritalin) is a medically prescribed stimulant medication that is chemically different from cocaine. The therapeutic use of methylphenidate does NOT CAUSE addiction or dependence, and does not lead to psychosis. Some children have such severe ADD symptoms that it can be dangerous for them to have a medication holiday, for example a child who is so hyper and impulsive he'll run into traffic withoug stopping to look first. Hallucinations are an extremely rare side-effect of methylphenidate, and their occurrence has nothing to do with the presence or absence of medication holidays. Individuals with ADHD who are properly treated with stimulant medication such as Ritalin have a lower risk of developing problems with alcohol and other drugs than the general population. More importantly, fifty years of research has repeatedly shown that children, adolescents, and adults with ADHD safely benefit from treatment with methylphenidate.

Myth #3: No study has ever demonstrated that taking stimulant medications can cause any lasting behavioral or educational benefit to ADHD children.

FACT: Research has repeatedly shown that children, adolescents, and adults with ADHD benefit from therapeutic treatment with stimulant medications, which has been used safely and studied for more than 50 years. For example, The New York Times reviewed a recent study from Sweden showing positive long- term effects of stimulant medication therapy on children with ADHD. Readers interested in more studies on the effectiveness of ADHD medication should consult the professional writings of Dr. Russell Barkley, Drs. Gabrielle Weiss and Lily Hechtman, and Dr. Joseph Biederman.

Myth #4: ADHD kids are learning to make excuses, rather than take responsibility for their actions.

FACT: Therapists, educators, and physicians routinely teach children that ADHD is a challenge, not an excuse. Medication corrects their underlying chemical imbalance, giving them a fair chance of facing the challenges of growing up to become productive citizens. Accommodations for the disabled, as mandated by federal and state laws, are not ways of excusing them from meeting society's responsibilities, but rather make it possible for them to compete on a leveled playing field.

Myth #5: ADHD is basically due to bad parenting and lack of discipline, and all that ADHD children really need is old-fashioned discipline, not any of these phony therapies.

FACT: There are still some parent-bashers around who believe the century-old anachronism that child misbehavior is always a moral problem of the "bad child." Under this model, the treatment has been to "beat the Devil out of the child." Fortunately, most of us are more enlightened today. A body of family interaction research conducted by Dr. Russell Barkley and others has unequivocally demonstrated that simply providing more discipline without any other interventions worsens rather than improves the behavior of children with ADHD. One can't make a paraplegic walk by applying discipline. Similarly, one can't make a child with a biologically-based lack of self-control act better by simply applying discipline alone.

Myth #6: Ritalin is unsafe, causing serious weight loss, mood swings, Tourette's syndrome, and sudden, unexplained deaths.

FACT: Research has repeatedly shown that children, adolescents, and adults with ADHD benefit from treatment with Ritalin (also known as methylphenidate), which has been safely used for approximately 50 years. There are NO published cases of deaths from overdoses of Ritalin; if you take too much Ritalin, you will feel terrible and act strange for a few hours, but you will not die. This cannot be said about many other medications. The unexplained deaths cited in some articles are from a combination of Ritalin and other drugs, not from Ritalin alone. Further investigation of those cases has revealed that most of the children had unusual medical problems which contributed to their deaths. It is true that many children experience appetite loss, and some moodiness or "rebound effect" when Ritalin wears off. A very small number of children may show some temporary tics, but these do not become permanent. Ritalin does not permanently alter growth, and usually does not result in weight loss. Ritalin does not cause Tourette's syndrome, rather many youngsters with Tourette's also have ADHD. In some cases, Ritalin even leads to an improvement of the of tics in children who have ADHD and Tourette's.

Myth #7: Teachers around the country routinely push pills on any students who are even a little inattentive or overactive.

FACT: Teachers are well-meaning individuals who have the best interests of their students in mind. When they see students who are struggling to pay attention and concentrate, it is their responsibility to bring this to parents' attention, so parents can take appropriate action. The majority of teachers do not simply push pills- they provide information so that parents can seek out appropriate diagnostic help. We do agree with the position that teachers should not diagnose ADHD. However, being on the front lines with children, they collect information, raise the suspicion of ADHD, and bring the information to the attention of parents, who then need to have a full evaluation conducted outside the school. The symptoms of ADHD must be present in school and at home before a diagnosis is made; teachers do not have access to sufficient information about the child's functioning to make a diagnosis of ADHD or for that matter to make any kind of medical diagnosis.

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Myth #8: Efforts by teachers to help children who have attention problems can make more of a difference than medications such as Ritalin.

FACT: It would be nice if this were true, but recent scientific evidence from the multi-modal treatment trials sponsored by the National Institute of Mental Health suggests it is a myth. In these studies, stimulant medication alone was compared to stimulant medication plus a multi-modal psychological and educational treatment, as treatments for children with ADHD. The scientists found that the multi-modal treatment plus the medication was not much better than the medication alone. Teachers and therapists need to continue to do everything they can to help individuals with ADHD, but we need to realize that if we don't also alter the biological factors that affect ADHD, we won't see much change.

Myth #9: CH.A.D.D. is supported by drug companies, and along with many professionals, are simply in this field to make a quick buck on ADHD.

FACT: Thousands of parents and professionals volunteer countless hours daily to over 600 chapters of CH.A.D.D. around the U.S. and Canada on behalf of individuals with ADHD. CH.A.D.D. is very open about disclosing any contributions from drug companies. These contributions only support the organization's national conference, which consists of a series of educational presentations, 95% of which are on topics other than medications. None of the local chapters receive any of this money. It is a disgrace to impugn the honesty and efforts of all of these dedicated volunteers. CH.A.D.D. supports all known effective treatments for ADHD, including medication, and takes positions against unproven and costly remedies.

Myth #10: It is not possible to accurately diagnose ADD or ADHD in children or adults.

FACT: Although scientists have not yet developed a single medical test for diagnosing ADHD, clear-cut clinical diagnostic criteria have been developed, researched, and refined over several decades. The current generally accepted diagnostic criteria for ADHD are listed in the Diagnostic and Statistical Manual of Mental Disorders (DSM-IV) published by the American Psychiatric Association (1995). Using these criteria and multiple methods to collect comprehensive information from multiple informants, ADHD can be reliably diagnosed in children and adults.

Myth #11: Children outgrow ADD or ADHD.

FACT: ADHD is not found just in children. We have learned from a number of excellent follow-up studies conducted over the past few decades that ADHD often lasts a lifetime. Over 70% of children diagnosed as having ADHD will continue to manifest the full clinical syndrome in adolescence, and 15-50% will continue to manifest the full clinical syndrome in adulthood. If untreated, individuals with ADHD may develop a variety of secondary problems as they move through life, including depression, anxiety, substance abuse, academic failure, vocational problems, marital discord, and emotional distress. If properly treated, most individuals with ADHD live productive lives and cope reasonably well with their symptoms.

Myth #12: Methylphenidate prescriptions in the U.S. have increased 600%.

FACT: The production quotas for methylphenidate increased 6-fold; however that DEA production quota is a gross estimate based on a number of factors, including FDA estimates of need, drug inventories at hand, EXPORTS, and industry sales expectations. One cannot conclude that a 6-fold increase in production quotas translates to a 6-fold increase in the use of methylphenidate among U.S. children any more than one should conclude that Americans eat 6 times more bread because U.S. wheat production increased 6-fold even though much of the grain is stored for future use and export to countries that have no wheat production. Further, of the approximately 3.5 million children who meet the criteria for ADHD, only about 50% of them are diagnosed and have stimulant medication included in their treatment plan. The estimated number of children taking methylphenidate for ADD suggested in some media stories fails to note that methylphenidate is also prescribed for adults who have ADHD, people with narcolepsy, and geriatric patients who receive considerable benefit from it for certain conditions associated with old age such as memory functioning. (see Pediatrics, December 1996, Vol. 98, No. 6)

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Common Myths About ADHD

From a UK Perspective: With thanks to Michelle Richardson (ADHD Nurse), Ryegate Children's Centre.

Myth:

Children naturally outgrow ADHD.

Fact:

In some children, the overactive behavior of ADHD decreases during the teen years. But inattention often becomes more challenging during early high school years when students must organize homework assignments and complete complex projects. Some children do not experience any symptoms of ADHD in adulthood, while some experience fewer symptoms. Others have no change in their symptoms from childhood to adulthood.

Myth:

ADHD is caused by too much white sugar, preservatives, and other artificial food additives. Removing these things from a child's diet can cure the disorder.

Fact:

Studies have shown that very few children with ADHD are helped by special diets. Most of the children who do respond to diets are very young or have food allergies. Sugar and food additives have been ruled out as causes for ADHD.

Myth:

Poor parenting is responsible for ADHD behaviors in children.

Fact:

ADHD is a physical disorder caused by differences in how the child's brain works. Anxiety-producing factors, such as family conflicts or disruptions, can aggravate the disorder, but they do not cause it.

Common Myths About ADHD Stimulant Medications

Myth:

Children treated with stimulant medications will become addicted or will be more likely to abuse other drugs.

Fact:

Stimulant medications are not addictive when used as directed. Studies have shown adequate treatment of ADHD may reduce the risk of substance abuse.

Myth:

Children must be taken off stimulant medications by the time they become teenagers.

Fact:

About 80% of children who need medications will need them as teenagers.

Myth:

Stimulant medications stunt growth.

Fact:

While stimulant medications may cause an initial, mild slowing of growth, this effect is temporary. Children treated with ADHD stimulant medications ultimately reach their normal height.

Myth:

Children build up a tolerance to stimulant medication. They end up needing more and more of it.

Fact:

While your child's medication may need to be adjusted occasionally, there's no evidence that children become tolerant to medication or require more of it to be effective.

Other contributors to this article: Becky Booth, Wilma Fellman, LPC, Judy Greenbaum, Ph.D., Terry Matlen, ACSW, Geraldine Markel, Ph.D., Howard Morris, Arthur L. Robin, Ph.D., Angela Tzelepis, Ph.D.

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Brand Names: NovoLog, NovoLog FlexPen, NovoLog PenFill
Generic Name: insulin aspart

Pronounced:IN su lin AS part

NovoLog Insulin Aspart, full prescribing information

What is NovoLog and what is it used for?

NovoLog contains insulin aspart. Insulin is a hormone that works by lowering levels of glucose (sugar) in the blood. Insulin aspart is a fast-acting form of insulin.

NovoLog is used to treat type 1 (insulin-dependent) diabetes in adults and children who are at least 2 years old. It is usually given together with a long-acting insulin.

NovoLog may also be used for other purposes not listed.

Important information about NovoLog

NovoLog is a fast-acting insulin that begins to work very quickly. After using it, you should eat a meal within 5 to 10 minutes.

Take care to keep your blood sugar from getting too low, causing hypoglycemia. Symptoms of low blood sugar may include headache, nausea, hunger, confusion, drowsiness, weakness, dizziness, blurred vision, fast heartbeat, sweating, tremor, or trouble concentrating. Carry a piece of non-dietetic hard candy or glucose tablets with you in case you have low blood sugar. Also be sure your family and close friends know how to help you in an emergency.

Also watch for signs of blood sugar that is too high (hyperglycemia). These symptoms include increased thirst, loss of appetite, fruity breath odor, increased urination, nausea, vomiting, drowsiness, dry skin, and dry mouth. Check your blood sugar levels and ask your doctor how to adjust your insulin doses if needed

Never share an injection pen or cartridge with another person. Sharing injection pens or cartridges can allow disease such as hepatitis or HIV to pass from one person to another.

Before using NovoLog

Do not use NovoLog if you are allergic to insulin, or if you are having an episode of hypoglycemia (low blood sugar).

Before using NovoLog, tell your doctor if you have liver or kidney disease.

Tell your doctor about all other medications you use, including any oral (taken by mouth) diabetes medications.

NovoLog is only part of a complete program of treatment that may also include diet, exercise, weight control, foot care, eye care, dental care, and testing your blood sugar. Follow your diet, medication, and exercise routines very closely. Changing any of these factors can affect your blood sugar levels.

Your doctor will need to check your progress on a regular basis. Do not miss any scheduled appointments.

FDA pregnancy category B. NovoLog is not expected to be harmful to an unborn baby. Tell your doctor if you are pregnant or plan to become pregnant during treatment. It is not known whether NovoLog passes into breast milk or if it could harm a nursing baby. Do not use this medication without telling your doctor if you are breast-feeding a baby.

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How should I use NovoLog?

Use NovoLog exactly as it was prescribed for you. Do not use it in larger amounts or for longer than recommended by your doctor. Follow the directions on your prescription label.

NovoLog is given as an injection (shot) under your skin, using a needle and syringe or an insulin pump. Your doctor, nurse, or pharmacist will give you specific instructions on how and where to inject this medicine. Do not self-inject this medicine if you do not fully understand how to give the injection and properly dispose of used needles and syringes.

NovoLog is a fast-acting medication that begins to work very quickly. After using NovoLog, you should eat a meal within 5 to 10 minutes.

NovoLog should be thin, clear, and colorless. Do not use the medication if it has looks cloudy, has changed colors, or has any particles in it. Call your doctor for a new prescription.

Choose a different place in your injection skin area each time you use NovoLog. Do not inject into the same place two times in a row.

If you use this medication with an insulin pump, do not mix or dilute NovoLog with any other insulin. Call your doctor at once if you think your infusion pump is not working properly.

Use each disposable needle only one time. Throw away used needles in a puncture-proof container (ask your pharmacist where you can get one and how to dispose of it). Keep this container out of the reach of children and pets.

Some insulin needles can be used more than once, depending on needle brand and type. But a reused needle must be properly cleaned, recapped, and inspected for bending or breakage. Reusing needles also increases your risk of infection. Ask your doctor or pharmacist whether you are able to reuse your insulin needles.

Infusion pump tubing, catheters, and the needle location on your skin should be changed every 48 hours. Throw away any medication leftover in the reservoir.

Never share an injection pen or cartridge with another person. Sharing injection pens or cartridges can allow disease such as hepatitis or HIV to pass from one person to another.

Check your blood sugar carefully during a time of stress or illness, if you travel, exercise more than usual, or skip meals. These things can affect your glucose levels and your insulin dose needs may also change.

Watch for signs of blood sugar that is too high (hyperglycemia). These symptoms include increased thirst, loss of appetite, fruity breath odor, increased urination, nausea, vomiting, drowsiness, dry skin, and dry mouth. Check your blood sugar levels and ask your doctor how to adjust your insulin doses if needed.

Ask your doctor how to adjust your NovoLog dose if needed. Do not change your dose without first talking to your doctor. Carry an ID card or wear a medical alert bracelet stating that you have diabetes, in case of emergency. Any doctor, dentist, or emergency medical care provider who treats you should know that you are diabetic.

Storing unopened vials, cartridges, or injection pens: Keep in the carton and store in a refrigerator, protected from light. Throw away any insulin not used before the expiration date on the medicine label. Unopened vials, cartridges, or injection pens may also be stored at room temperature for up to 28 days, away from heat and bright light. Throw away any insulin not used within 28 days. Storing after your first use: Keep the "in-use" vials, cartridges, or injection pens at room temperature and use within 28 days. Do not refrigerate.

Do not freeze NovoLog, and throw away the medication if it has become frozen.

What happens if I miss a dose?

Since NovoLog is used before meals, you may not be on a timed dosing schedule. Whenever you use NovoLog, be sure to eat a meal within 5 to 10 minutes. Do not use extra NovoLog to make up a missed dose.

It is important to keep NovoLog on hand at all times. Get your prescription refilled before you run out of medicine completely.

What happens if I overdose?

Seek emergency medical attention if you think you have used too much of this medicine. An insulin overdose can cause life-threatening hypoglycemia.

Symptoms of severe hypoglycemia include extreme weakness, blurred vision, sweating, trouble speaking, tremors, stomach pain, confusion, seizure (convulsions), or coma.

What should I avoid while using NovoLog?

Do not change the brand of insulin aspart or syringe you are using without first talking to your doctor or pharmacist. Avoid drinking alcohol. Your blood sugar may become dangerously low if you drink alcohol while using NovoLog. Do not expose NovoLog to high heat. Throw the medication away if it becomes hotter than 98 degrees F.

NovoLog side effects

Get emergency medical help if you have any of these signs of insulin allergy: itching skin rash over the entire body, wheezing, trouble breathing, fast heart rate, sweating, or feeling like you might pass out.

Call your doctor if you have a serious side effect such as:

• swelling in your hands or feet; or
• low potassium (confusion, uneven heart rate, extreme thirst, increased urination, leg discomfort, muscle weakness or limp feeling).

Hypoglycemia, or low blood sugar, is the most common side effect of NovoLog. Symptoms of low blood sugar may include headache, nausea, hunger, confusion, drowsiness, weakness, dizziness, blurred vision, fast heartbeat, sweating, tremor, trouble concentrating, confusion, or seizure (convulsions). Watch for signs of low blood sugar. Carry a piece of non-dietetic hard candy or glucose tablets with you in case you have low blood sugar.

NovoLog can also cause hypokalemia (low potassium levels in the blood). Call your doctor at once if you have symptoms such as dry mouth, increased thirst, increased urination, uneven heartbeats, muscle pain or weakness, leg pain or discomfort, or confusion.

This is not a complete list of side effects and others may occur. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

What other drugs will affect NovoLog?

Using certain medicines can make it harder for you to tell when you have low blood sugar. Tell your doctor if you use any of the following:

• albuterol (Proventil, Ventolin);
• clonidine (Catapres);
• reserpine;
• guanethidine (Ismelin); or
• a beta-blocker such as atenolol (Tenormin), bisoprolol (Zebeta), labetalol (Normodyne, Trandate), metoprolol (Lopressor, Toprol), nadolol (Corgard), propranolol (Inderal, InnoPran), timolol (Blocadren) and others.

There are many other medicines that can increase or decrease the effects of NovoLog on lowering your blood sugar. Tell your doctor about all the prescription and over-the-counter medications you use. This includes vitamins, minerals, herbal products, and drugs prescribed by other doctors. Do not start using a new medication without telling your doctor. Keep a list with you of all the medicines you use and show this list to any doctor or other healthcare provider who treats you.

Where can I get more information?

• Your pharmacist can provide more information about NovoLog.
• Remember, keep this and all other medicines out of the reach of children, never share your medicines with others, and use NovoLog only for the indication prescribed.

last updated 10/2007

NovoLog Insulin Aspart, full prescribing information

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

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Learn about the types of music therapy and how music therapy is used in the treatment of various psychiatric disorders.

Music has soothed the souls of human beings for ages. It also has helped people recover from ailments since ancient times. Today, there is a widespread interest in the use of music therapy in treating psychiatric disorders. This article describes the various types of music therapy in use today and also offers insight into how music therapy can be incorporated into the management of psychiatric disorders and as an element of psychotherapy. (Altern Ther Health Med. 2004;11(6):52-53.)

Music is an ancient art that has soothed minds for centuries. Music helps people regain inner peace and is the voice that binds people together. It has been used to treat the sick since ancient times and frequently is used to cure depression. Songs offer people solace in adversity and joy in prosperity. They are sung on birthdays and even at the death of a loved one. Music is accepted as a universal means to express one's emotions. It was an essential component of ancient healing. A drum was beaten when treatment was offered to a patient, and a successful recovery was announced with trumpets.¹ Great philosophers have assigned important roles to music in the expression of their emotions and teachings.² Music was used to treat psychiatric illness in ancient Greek and Roman cultures.³ More recently, reports have indicated the usefulness of music therapy in managing psychiatric disorders.⁴ Music has been used in psychosis and neurosis and now is being used in addressing organic disorders such as dementia.^5,6 There is a wealth of literature on music therapy in all fields, but sadly, renowned psychiatry textbooks fail to mention music therapy as a treatment modality, and many contain no information about it at all. The purpose of this article is to offer insight into the various types of music therapy and review some of the literature on the use of music therapy in psychiatry.

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Background Music Therapy

Background music therapy is a form of therapy in which music is heard for an average of 8 to 12 hours per day as part of a hospital routine. It is transmitted via audiotapes and radio. The aim of this therapy is to create a calm environment amid the chaos in the hospital. This plays a useful role in allaying anxiety and relaxing patients in critical care.⁷

Contemplative Music

Contemplative music therapy helps patients appreciate the significance of music and art in general. Before music is played for patients, they are given a biography of the composer and other details about the music. This may be administered in a group setting or individually. This facilitates the uncovering of morbid experiences, termed communicative music therapy, and causes emotional enlivenment, termed reactive musical therapy. In contemplative therapy, both the music that soothes as well as the group setting and the group therapy used bring out morbid experiences of the patients. This therapy also aims to soothe agitation and alleviate sadness.⁸

Combined Music

In combined music therapy, music therapy is used in conjunction with other therapeutic procedures. Unlike background music therapy, it calls for the patient to select musical compositions that enhance therapeutic outcome and suit the patient. Sometimes in this form of music therapy, hypnosis is conducted while the subject listens to the music. This music is often accompanied by suggestion under hypnosis that improves the therapeutic outcome. In combined music therapy, the patient is asked to select music he likes as it will soothe him better, and here music is used as an adjuvant to various other therapies. The patient may or may not like the music chosen by the therapist and hence he is given the choice so that therapy is adhered to. This form of music therapy has been used in combination with cerebral electrosleep therapy and behavior therapy methods such as autogenic training.⁹

Executive Music

Executive music therapy consists of individual or group singing and playing musical instruments. Patients with long hospital stays are the best candidates for this form of therapy. It strengthens patients' self-confidence and their feelings of worth among others. Executive music therapy can be incorporated into the occupational therapy routine.¹⁰

Executive Iatromusic

In executive iatromusic therapy, a musician performs in children's psychiatric units. This form of therapy frequently is used in managing emotionally disturbed, mentally retarded, and dyslexic children.^11-13

Creative Music

In creative music therapy, patients write songs, compose music, and play instruments as a form of catharsis. Grief over a deceased loved one, oppression, and repressed feelings and fears often are well expressed in music and song.¹⁴

References

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The Use of Music Therapy in Psychiatric Disorders

Music therapy has been used effectively in both adults and children with psychiatric disorders. It has been used to modify the behavior of children with autism and pervasive developmental disorders with moderate success.¹⁵ It has been used to reduce agitation in patients with dementia by soothing them and eliminating the social isolation of these patients.^16,17 Music therapy has been used in patients with Parkinson's disease to improve motor skills and emotional problems.¹⁸ There is ample evidence of the usefulness of music therapy in alleviating grief and in combating bouts of depression.^19-21

Conclusions

Music no doubt plays a pivotal role in the lives of human beings. Incorporating music therapy into regular therapy programs for psychiatric disorders can help speed recovery and also help make therapy a more positive experience. Music therapy is a valuable but relatively unexplored asset in the field of psychiatry and psychotherapy.

References

1. Radin P. Music and medicine among primitive peoples. In: Schullian DM, Schoen M, eds. Music and Medicine. Freeport, NY: Books for Libraries; 1971:3-24.

2. The Internet Encyclopedia of Philosophy. Xunzi (Hsün Tzu). Available at: http://www.iep.utm.edu/x/xunzi.htm. Accessed Oct 19, 2005.

3. Meinecke, B. Music and medicine in classical antiquity. In: Schullian DM, Schoen M, eds. Music and Medicine. Freeport, NY: Books for Libraries; 1971:47-95.

4. Covington H. Therapeutic music for patients with psychiatric disorders. Holist Nurs Pract. 2001;15:59-69.

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5. Brotons M, Marti P. Music therapy with Alzheimer's patients and their caregivers: A pilot project. J Music Ther. 2003;40:138-150.

6. Gregory D. Music listening for maintaining attention of older adults with cognitive impairments. J Music Ther. 2002;39:244-264.

7. Richards K, Nagel C, Markie M, Elwell J, Barone C. Use of complementary and alternative therapies to promote sleep in critically ill patients. Crit Care Nurs Clin North Am. 2003;15:329-340.

8. Schmolz A. Zur Methode der Einzelmusiktherapie. In Musiktherapie by von Kohler & Jena, G. 1971, Pp 83-88.

9. Schultz LH. Autogenic Training. Stuttgart, Thieme, 1960.

10. Keen AW. Using Music as therapy tool to motivate troubled adolescents. Soc Work Health Care. 2004; 39: 361-373.

11. Rainey Perry MM. Relating improvisational music therapy with severely and multiply disabled children to communication development. J Music Ther. 2003;40:227-246.

12. Overy, K. Dyslexia and music. From timing deficits to musical interventions. Ann NY Acad Sci. 2003;999:497-505.

13. Layman DL, Hussey DL, Laing SJ. Music therapy assessment for severely emotionally disturbed children: A pilot study. J Music Ther. 2002;39:164-187.

14. O'Callahn CC. Pain, music creativity and music therapy in palliative care. AM J Hsop Palliative Care. 1996;13(2):43-49.

15. Brownell MD. Musically adapted social stories to modify behavior in students with autism: Four case studies. J Music Ther. 2002;39:117-144.

16. Lou MF. The use of music to decrease agitated behaviour of the demented elderly: The state of the science. Scand J Caring Sci. 2001;15:165-173.

17. Gotell E, Brown S, Ekman SL. Caregiver singing and background music in dementia care. West J Nurs Res. 2002;24:195-216.

18. Pacchetti C, Mancini F, Aglieri R, Fundaro C, Martignoni E, Nappi, G. Active music therapy in Parkinson's disease: An integrative method for motor and emotional rehabilitation. Psychosom Med. 2000;62:386-393.

19. Smeijsters H, van Den Hurk J. Music therapy helping to work through grief and finding a personal identity. J Music Ther. 1999;36:222-252.

20. Ernst E, Rand JL, Stevinson C. Complementary therapies for depression: an overview. Arch Gen Psychiatry. 1998;55:1026-1032.

21. Lai YM. Effects of music listening on depressed women in Taiwan. Issues Ment Health Nurs. 1999;20:229-246.

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Lindsey Kent MD PhD
Developmental Psychiatry Section, Douglas House 18 Trumpington Road, University of Cambridge, Cambridge, CB2 2AH, UK mailto:lk255@cam.ac.uk
Current Psychiatry Reports 2004, 6:143-148 (published 1 April 2004)

Abstract

In the past few years, interest in the molecular genetics of attention deficit hyperactivity disorder (ADHD) has grown enormously, with many groups searching for susceptibility genes, often through large collaborative efforts facilitated by the International ADHD Genetics Consortium. Association findings for several candidate genes within the dopaminergic system, the DRD4 and DRD5 receptor genes and the dopamine transporter gene, DAT1, have been well replicated, and the first of several ongoing genome linkage scan study results have been published. Current challenges in this field are to identify the actual functional variant(s) in these genes conferring susceptibility and other genetic and environmental risk factors for ADHD.

Lindsey Kent , MBChB., PhD. MRC Psych
University Lecturer
I am a child and adolescent psychiatrist with research interests in the biological underpinnings of Attention Deficit Hyperactivity Disorder and related conditions. My particular interests are concerned with the genetics of hyperactivity and attention disorders. In addition to searching for susceptibility genes, a further research aim is to identify meaningful biological phenotypes for ADHD, which may assist gene identification strategies. I am part of the international ADHD molecular genetic consortium and collaborate with a number of other research groups including the neuropsychiatric genetics groups in Trinity College Dublin and University of Wales, College of Medicine.

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Brand Name: Duetact
Generic Name: Pioglitazone Hydrochloride and Glimepiride

Contents:

Description
Pharmacology
Indications and Usage
Contraindications
Warnings
Precautions
Adverse Reactions
Overdose
Dosage and Administration
How Supplied
References
Ophthalmology Data

Duetact, pioglitazone hydrochloride and glimepiride patient information (in plain English)

• Thiazolidinediones, including pioglitazone, which is a component of Duetact, cause or exacerbate congestive heart failure in some patients (see Warnings, Pioglitazone hydrochloride). After initiation of Duetact, observe patients carefully for signs and symptoms of heart failure (including excessive, rapid weight gain, dyspnea, and/or edema). If these signs and symptoms develop, the heart failure should be managed according to the current standards of care. Furthermore, discontinuation of Duetact must be considered.
• Duetact is not recommended in patients with symptomatic heart failure. Initiation of Duetact in patients with established NYHA Class III or IV heart failure is contraindicated (see Contraindications and Warnings, Pioglitazone hydrochloride).

Description

Duetact™ (pioglitazone hydrochloride and glimepiride) tablets contain two oral antihyperglycemic agents used in the management of type 2 diabetes: pioglitazone hydrochloride and glimepiride. The concomitant use of pioglitazone and a sulfonylurea, the class of drugs that includes glimepiride, has been previously approved based on clinical trials in patients with type 2 diabetes inadequately controlled on a sulfonylurea. Additional efficacy and safety information about pioglitazone and glimepiride monotherapies may be found in the prescribing information for each individual drug.

Pioglitazone hydrochloride is an oral antihyperglycemic agent that acts primarily by decreasing insulin resistance. Pioglitazone is used in the management of type 2 diabetes. Pharmacological studies indicate that pioglitazone improves sensitivity to insulin in muscle and adipose tissue and inhibits hepatic gluconeogenesis. Pioglitazone improves glycemic control while reducing circulating insulin levels.

Pioglitazone ( ±)-5-[[4-[2-(5-ethyl-2-pyridinyl)ethoxy]phenyl]methyl]-2,4-thiazolidinedione monohydrochloride belongs to a different chemical class and has a different pharmacological action than the sulfonylureas, biguanides, or the α-glucosidase inhibitors. The molecule contains one asymmetric center, and the synthetic compound is a racemate. The two enantiomers of pioglitazone interconvert in vivo. The structural formula is as shown:

Pioglitazone Hydrochloride

Pioglitazone hydrochloride is an odorless, white crystalline powder that has a molecular formula of C₁₉H₂₀N₂O₃S-HC_l and a molecular weight of 392.90. It is soluble in N,N-dimethylformamide, slightly soluble in anhydrous ethanol, very slightly soluble in acetone and acetonitrile, practically insoluble in water, and insoluble in ether.

Glimepiride 1-[[p-[2-(3-ethyl-4-methyl-2-oxo-3-pyrroline-1-carboxamido)ethyl]phenyl] sulfonyl]-3-(trans-4-methylcyclohexyl)-urea is an oral blood glucose-lowering drug of the sulfonylurea class and is used in the management of type 2 diabetes. The molecule is the trans-isomer with respect to the cyclohexyl substituents. The chemical structure is as shown:

Glimepiride

Glimepiride is a white to yellowish-white crystalline, odorless, to practically odorless powder, that has a molecular formula of C₂4H₃₄N₄O₅S and a molecular weight of 490.62. It is soluble in dimethylsulfoxide, slightly soluble in acetone, very slightly soluble in acetonitrile and methanol, and practically insoluble in water.

Duetact is available as a tablet for oral administration containing 30 mg pioglitazone hydrochloride (as the base) with 2 mg glimepiride (30 mg/2 mg) or 30 mg pioglitazone hydrochloride (as the base) with 4 mg glimepiride (30 mg/4 mg) formulated with the following excipients: povidone USP, croscarmellose sodium NF, lactose monohydrate NF, magnesium stearate NF, hydroxypropyl cellulose NF, polysorbate 80 NF, and microcrystalline cellulose NF.

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Clinical Pharmacology

Mechanism of Action

Duetact

Duetact combines two antihyperglycemic agents with different mechanisms of action to improve glycemic control in patients with type 2 diabetes: pioglitazone hydrochloride, a member of the thiazolidinedione class, and glimepiride, a member of the sulfonylurea class. Thiazolidinediones are insulin-sensitizing agents that act primarily by enhancing peripheral glucose utilization, whereas sulfonylureas are insulin secretogogues that act primarily by stimulating release of insulin from functioning pancreatic beta cells.

Pioglitazone hydrochloride

Pioglitazone depends on the presence of insulin for its mechanism of action. Pioglitazone decreases insulin resistance in the periphery and in the liver resulting in increased insulin-dependent glucose disposal and decreased hepatic glucose output. Pioglitazone is a potent and highly selective agonist for peroxisome proliferator-activated receptor-gamma (PPARγ). PPAR receptors are found in tissues important for insulin action such as adipose tissue, skeletal muscle, and liver. Activation of PPARγ nuclear receptors modulates the transcription of a number of insulin responsive genes involved in the control of glucose and lipid metabolism.

In animal models of diabetes, pioglitazone reduces the hyperglycemia, hyperinsulinemia, and hypertriglyceridemia characteristic of insulin-resistant states such as type 2 diabetes. The metabolic changes produced by pioglitazone result in increased responsiveness of insulin-dependent tissues and are observed in numerous animal models of insulin resistance.

Since pioglitazone enhances the effects of circulating insulin (by decreasing insulin resistance), it does not lower blood glucose in animal models that lack endogenous insulin.

Glimepiride

The primary mechanism of action of glimepiride in lowering blood glucose appears to be dependent on stimulating the release of insulin from functioning pancreatic beta cells. In addition, extrapancreatic effects may also play a role in the activity of sulfonylureas such as glimepiride. This is supported by both preclinical and clinical studies demonstrating that glimepiride administration can lead to increased sensitivity of peripheral tissues to insulin. These findings are consistent with the results of a long-term, randomized, placebo-controlled trial in which glimepiride therapy improved postprandial insulin/C-peptide responses and overall glycemic control without producing clinically meaningful increases in fasting insulin/C-peptide levels. However, as with other sulfonylureas, the mechanism by which glimepiride lowers blood glucose during long-term administration has not been clearly established.

Pharmacokinetics and Drug Metabolism

Absorption and Bioavailability

Duetact

Bioequivalence studies were conducted following a single dose of the Duetact 30 mg/2 mg and 30 mg/4 mg tablets and concomitant administration of ACTOS (30 mg) and glimepiride (2 mg or 4 mg) under fasting conditions in healthy subjects.

Based on the area under the curve (AUC) and maximum concentration (C_max) of both pioglitazone and glimepiride, Duetact 30 mg/2 mg and 30 mg/4 mg were bioequivalent to ACTOS 30 mg concomitantly administered with glimepiride (2 mg or 4 mg, respectively) (Table 1).

Table 1. Mean (SD) Pharmacokinetic Parameters for Duetact

Regimen		N	AUC(0-inf) (ng· h/mL)	N	Cmax (ng/mL)	N	Tmax (h)	N	T1/2 (h)
30 mg/2 mg Duetact	pioglitazone	32	10116 (3641)	34	986 (433)	34	2.12 (1.10)	32	10.43 (5.08)
	glimepiride	34	871 (342)	34	168 (57.1)	34	2.53 (0.73)	34	8.23 (4.18)
30 mg pioglitazone + 2 mg glimepiride tablets	pioglitazone	32	11870 (3779)	34	1011 (406)	34	2.22 (1.38)	32	11.83 (4.39)
	glimepiride	34	863 (340)	34	190 (61.6)	34	2.29 (1.17)	34	6.47 (2.76)
30 mg/4 mg Duetact	pioglitazone	36	10676 (3031)	37	1103 (317)	37	1.84 (0.96)	36	9.64 (3.63)
	glimepiride	36	2435 (3063)	37	308 (110)	37	2.71 (0.67)	36	11.01 (5.34)
30 mg pioglitazone + 4 mg glimepiride tablets	pioglitazone	36	12179 (3481)	37	1188 (342)	37	2.17 (1.06)	36	10.47 (4.65)
	glimepiride	36	2432 (3217)	37	360 (133)	37	2.73 (1.15)	36	9.56 (4.32)

Food did not change the systemic exposures to glimepiride or pioglitazone following administration of Duetact. The presence of food did not significantly alter the time to peak serum concentration of glimepiride. However, for pioglitazone, there was a delay in time to peak concentration from 1.6 to 3.6 hours when administered with food. This food-induced delay in time to reach maximum serum concentration (T_max) was also associated with a 9% decrease in the maximum serum concentration (C_max) of pioglitazone. These changes are not likely to be clinically significant.

Pioglitazone hydrochloride

Following oral administration, in the fasting state, pioglitazone is first measurable in serum within 30 minutes, with peak concentrations observed within 2 hours. Food slightly delays the time to peak serum concentration to 3 to 4 hours, but does not alter the extent of absorption.

Glimepiride

After oral administration, glimepiride is completely (100%) absorbed from the GI tract. Studies with single oral doses in normal subjects and with multiple oral doses in patients with type 2 diabetes have shown significant absorption of glimepiride within 1 hour after administration and Cmax at 2 to 3 hours. When glimepiride was given with meals, the mean Tmax was slightly increased (12%) and the mean Cmax and the total area under the serum concentration-time curve (AUC) were slightly decreased (8% and 9%, respectively).

Distribution

Pioglitazone hydrochloride

The mean apparent volume of distribution (Vd/F) of pioglitazone following single-dose administration is 0.63 ± 0.41 (mean ± SD) L/kg of body weight. Pioglitazone is extensively protein bound (> 99%) in human serum, principally to serum albumin. Pioglitazone also binds to other serum proteins, but with lower affinity. Metabolites M-III and M-IV also are extensively bound (> 98%) to serum albumin.

Glimepiride

After intravenous (IV) dosing in normal subjects, Vd/F was 8.8 L (113 mL/kg), and the total body clearance (CL) was 47.8 mL/min. Protein binding was greater than 99.5%.

Metabolism

Pioglitazone hydrochloride

Pioglitazone is extensively metabolized by hydroxylation and oxidation; the metabolites also partly convert to glucuronide or sulfate conjugates. Metabolites M-II and M-IV (hydroxy derivatives of pioglitazone) and M-III (keto derivative of pioglitazone) are pharmacologically active in animal models of type 2 diabetes. In addition to pioglitazone, M-III and M-IV are the principal drug-related species found in human serum following multiple dosing. At steady-state, in both healthy volunteers and in patients with type 2 diabetes, pioglitazone comprises approximately 30% to 50% of the total peak serum concentrations and 20% to 25% of the total AUC.

In vitro data demonstrate that multiple CYP isoforms are involved in the metabolism of pioglitazone. The cytochrome P450 isoforms involved are CYP2C8 and, to a lesser degree, CYP3A4 with additional contributions from a variety of other isoforms including the mainly extrahepatic CYP1A1. In vivo studies of pioglitazone in combination with P450 inhibitors and substrates have been performed (see Precautions, Drug Interactions, Pioglitazone hydrochloride). Urinary 6ß-hydroxycortisol/cortisol ratios measured in patients treated with pioglitazone showed that pioglitazone is not a strong CYP3A4 enzyme inducer.

Glimepiride

Glimepiride is completely metabolized by oxidative biotransformation after either an IV or oral dose. The major metabolites are the cyclohexyl hydroxy methyl derivative (M1) and the carboxyl derivative (M2). CYP2C9 has been shown to be involved in the biotransformation of glimepiride to M1. M1 is further metabolized to M2 by one or several cytosolic enzymes. M1, but not M2, possesses about 1/3 of the pharmacological activity as compared to its parent in an animal model; however, whether the glucose-lowering effect of M1 is clinically meaningful is not clear.

Excretion and Elimination

Pioglitazone hydrochloride

Following oral administration, approximately 15% to 30% of the pioglitazone dose is recovered in the urine. Renal elimination of pioglitazone is negligible and the drug is excreted primarily as metabolites and their conjugates. It is presumed that most of the oral dose is excreted into the bile either unchanged or as metabolites and eliminated in the feces.

The mean serum half-life of pioglitazone and total pioglitazone ranges from 3 to 7 hours and 16 to 24 hours, respectively. Pioglitazone has an apparent clearance, CL/f, calculated to be 5 to 7 L/hr.

Glimepiride

When 14C-glimepiride was given orally, approximately 60% of the total radioactivity was recovered in the urine in 7 days and M1 (predominant) and M2 accounted for 80-90% of that recovered in the urine. Approximately 40% of the total radioactivity was recovered in feces and M1 and M2 (predominant) accounted for about 70% of that recovered in feces. No parent drug was recovered from urine or feces. After IV dosing in patients, no significant biliary excretion of glimepiride or its M1 metabolite has been observed.

Special Populations

Renal Insufficiency

Pioglitazone hydrochloride

The serum elimination half-life of pioglitazone, M-III and M-IV remains unchanged in patients with moderate (creatinine clearance 30 to 60 mL/min) to severe (creatinine clearance < 30 mL/min) renal impairment when compared to normal subjects. No dose adjustment in patients with renal dysfunction is recommended.

Glimepiride

A single-dose, open-label study was conducted in 15 patients with renal impairment. Glimepiride (3 mg) was administered to 3 groups of patients with different levels of mean creatinine clearance (CLcr); (Group I, CLcr = 77.7 mL/min, n = 5), (Group II, CLcr = 27.7 mL/min, n = 3), and (Group III, CLcr = 9.4 mL/min, n = 7). Glimepiride was found to be well tolerated in all 3 groups. The results showed that glimepiride serum levels decreased as renal function decreased. However, M1 and M2 serum levels (mean AUC values) increased 2.3 and 8.6 times from Group I to Group III. The apparent terminal half-life (T1/2) for glimepiride did not change, while the half-lives for M1 and M2 increased as renal function decreased. Mean urinary excretion of M1 plus M2 as percent of dose, however, decreased (44.4%, 21.9%, and 9.3% for Groups I to III).

A multiple-dose titration study was also conducted in 16 patients with type 2 diabetes and with renal impairment using doses ranging from 1-8 mg daily for 3 months. The results were consistent with those observed after single doses. All patients with a CLcr less than 22 mL/min had adequate control of their glucose levels with a dosage regimen of only 1 mg daily. The results from this study suggested that a starting dose of 1 mg glimepiride may be given to patients with type 2 diabetes and kidney disease, and the dose may be titrated based on fasting blood glucose levels (see Dosage and Administration, Special Patient Populations).

Hepatic Insufficiency

Pioglitazone hydrochloride

Compared with normal controls, subjects with impaired hepatic function (Child-Pugh Grade B/C) have an approximate 45% reduction in pioglitazone and total pioglitazone mean peak concentrations but no change in the mean AUC values.

Therapy with Duetact should not be initiated if the patient exhibits clinical evidence of active liver disease or serum transaminase levels (ALT) exceed 2.5 times the upper limit of normal (see Precautions, General: Pioglitazone hydrochloride, Hepatic Effects).

Glimepiride

No studies were performed in patients with hepatic insufficiency.

Elderly

Pioglitazone hydrochloride

In healthy elderly subjects, peak serum concentrations of pioglitazone and total pioglitazone are not significantly different, but AUC values are slightly higher and the terminal half-life values slightly longer than for younger subjects. These changes were not of a magnitude that would be considered clinically relevant.

Glimepiride

Comparison of glimepiride pharmacokinetics in patients with type 2 diabetes ≤65 years and those >65 years was performed in a study using a dosing regimen of 6 mg daily. There were no significant differences in glimepiride pharmacokinetics between the two age groups. The mean AUC at steady-state for the older patients was about 13% lower than that for the younger patients; the mean weight-adjusted clearance for the older patients was about 11% higher than that for the younger patients.

Pediatrics

No pharmacokinetic studies of Duetact were performed in pediatric patients.

Gender

Pioglitazone hydrochloride

As monotherapy and in combination with sulfonylurea, metformin, or insulin, pioglitazone improved glycemic control in both males and females. The mean C_max and AUC values were increased 20% to 60% in females. In controlled clinical trials, hemoglobin A1C (A1C) decreases from baseline were generally greater for females than for males (average mean difference in A1C 0.5%). Since therapy should be individualized for each patient to achieve glycemic control, no dose adjustment is recommended based on gender alone.

Glimepiride

There were no differences between males and females in the pharmacokinetics of glimepiride when adjustment was made for differences in body weight.

Ethnicity

Pioglitazone hydrochloride

Pharmacokinetic data among various ethnic groups are not available.

Glimepiride

No pharmacokinetic studies to assess the effects of race have been performed, but in placebo-controlled studies of glimepiride in patients with type 2 diabetes, the antihyperglycemic effect was comparable in whites (n = 536), blacks (n = 63), and Hispanics (n = 63).

Other Populations

Glimepiride

There were no important differences in glimepiride metabolism in subjects identified as phenotypically different drug-metabolizers by their metabolism of sparteine. The pharmacokinetics of glimepiride in morbidly obese patients were similar to those in the normal weight group, except for a lower C_max and AUC. However, since neither C_max nor AUC values were normalized for body surface area, the lower values of C_max and AUC for the obese patients were likely the result of their excess weight and not due to a difference in the kinetics of glimepiride.

Drug-Drug Interactions

Co-administration of pioglitazone (45 mg) and a sulfonylurea (5 mg glipizide) administered orally once daily for 7 days did not alter the steady-state pharmacokinetics of glipizide. Glimepiride and glipizide have similar metabolic pathways and are mediated by CYP2C9; therefore, drug-drug interaction between pioglitazone and glimepiride is considered unlikely. Specific pharmacokinetic drug interaction studies with Duetact have not been performed, although such studies have been conducted with the individual pioglitazone and glimepiride components.

Pioglitazone hydrochloride

The following drugs were studied in healthy volunteers with co-administration of pioglitazone 45 mg once daily. Results are listed below:

Oral Contraceptives: Co-administration of pioglitazone (45 mg once daily) and an oral contraceptive (1 mg norethindrone plus 0.035 mg ethinyl estradiol once daily) for 21 days, resulted in 11% and 11-14% decrease in ethinyl estradiol AUC (0-24h) and C_max respectively. There were no significant changes in norethindrone AUC (0-24h) and C_max. In view of the high variability of ethinyl estradiol pharmacokinetics, the clinical significance of this finding is unknown.

Midazolam: Administration of pioglitazone for 15 days followed by a single 7.5 mg dose of midazolam syrup resulted in a 26% reduction in midazolam C_max and AUC.

Nifedipine ER: Co-administration of pioglitazone for 7 days with 30 mg nifedipine ER administered orally once daily for 4 days to male and female volunteers resulted in a ratio of least square mean (90% CI) values for unchanged nifedipine of 0.83 (0.73 - 0.95) for C_max and 0.88 (0.80 - 0.96) for AUC. In view of the high variability of nifedipine pharmacokinetics, the clinical significance of this finding is unknown.

Ketoconazole: Co-administration of pioglitazone for 7 days with ketoconazole 200 mg administered twice daily resulted in a ratio of least square mean (90% CI) values for unchanged pioglitazone of 1.14 (1.06 - 1.23) for C_max, 1.34 (1.26 - 1.41) for AUC and 1.87 (1.71 - 2.04) for C_min.

Atorvastatin Calcium: Co-administration of pioglitazone for 7 days with atorvastatin calcium (LIPITOR®) 80 mg once daily resulted in a ratio of least square mean (90% CI) values for unchanged pioglitazone of 0.69 (0.57 - 0.85) for C_max, 0.76 (0.65 - 0.88) for AUC and 0.96 (0.87 - 1.05) for C_min. For unchanged atorvastatin, the ratio of least square mean (90% CI) values were 0.77 (0.66 - 0.90) for C_max, 0.86 (0.78 - 0.94) for AUC and 0.92 (0.82 - 1.02) for C_min.

Cytochrome P450: See Precautions, Drug Interactions, Pioglitazone hydrochloride

Gemfibrozil: Concomitant administration of gemfibrozil (oral 600 mg twice daily), an inhibitor of CYP2C8, with pioglitazone (oral 30 mg) in 10 healthy volunteers pre-treated for 2 days prior with gemfibrozil (oral 600 mg twice daily) resulted in pioglitazone exposure (AUC0-24) being 226% of the pioglitazone exposure in the absence of gemfibrozil (see Precautions, Drug Interactions, Pioglitazone hydrochloride).¹

Rifampin: Concomitant administration of rifampin (oral 600 mg once daily), an inducer of CYP2C8 with pioglitazone (oral 30 mg) in 10 healthy volunteers pre-treated for 5 days prior with rifampin (oral 600 mg once daily) resulted in a decrease in the AUC of pioglitazone by 54% (see Precautions, Drug Interactions, Pioglitazone hydrochloride).²

In other drug-drug interaction studies, pioglitazone had no significant effect on the pharmacokinetics of fexofenadine, metformin, digoxin, warfarin, ranitidine, or theophylline.

Glimepiride

The hypoglycemic action of sulfonylureas may be potentiated by certain drugs, including nonsteroidal anti-inflammatory drugs and other drugs that are highly protein bound, such as salicylates, sulfonamides, chloramphenicol, coumarins, probenecid, monoamine oxidase inhibitors, and beta adrenergic blocking agents. Due to the potential drug interaction between these drugs and glimepiride, the patient should be observed closely for hypoglycemia when these drugs are co-administered. Conversely, when these drugs are withdrawn, the patient should be observed closely for loss of glycemic control.

Certain drugs tend to produce hyperglycemia and may lead to loss of control. These drugs include the thiazides and other diuretics, corticosteroids, phenothiazines, thyroid products, estrogens, oral contraceptives, phenytoin, nicotinic acid, sympathomimetics, and isoniazid. Due to the potential drug interaction between these drugs and glimepiride, the patient should be observed closely for loss of glycemic control when these drugs are co-administered. Conversely, when these drugs are withdrawn, the patient should be observed closely for hypoglycemia.

Aspirin: Co-administration of aspirin (1 g three times daily) and glimepiride led to a 34% decrease in the mean glimepiride AUC and, therefore, a 34% increase in the mean CL/f. The mean C_max had a decrease of 4%. Blood glucose and serum C-peptide concentrations were unaffected and no hypoglycemic symptoms were reported. Pooled data from clinical trials showed no evidence of clinically significant adverse interactions with uncontrolled concurrent administration of aspirin and other salicylates.

Cimetidine/Ranitidine: Co-administration of either cimetidine (800 mg once daily) or ranitidine (150 mg twice daily) with a single 4-mg oral dose of glimepiride did not significantly alter the absorption and disposition of glimepiride, and no differences were seen in hypoglycemic symptomatology. Pooled data from clinical trials showed no evidence of clinically significant adverse interactions with uncontrolled concurrent administration of H2-receptor antagonists.

Propranolol: Concomitant administration of propranolol (40 mg three times daily) and glimepiride significantly increased C_max, AUC, and T1/2 of glimepiride by 23%, 22%, and 15%, respectively, and it decreased CL/f by 18%. The recovery of M1 and M2 from urine, however, did not change. The pharmacodynamic responses to glimepiride were nearly identical in normal subjects receiving propranolol and placebo. Pooled data from clinical trials in patients with type 2 diabetes showed no evidence of clinically significant adverse interactions with uncontrolled concurrent administration of beta-blockers. However, if beta-blockers are used, caution should be exercised and patients should be warned about the potential for hypoglycemia.

Warfarin: Concomitant administration of glimepiride (4 mg once daily) did not alter the pharmacokinetic characteristics of R- and S-warfarin enantiomers following administration of a single dose (25 mg) of racemic warfarin to healthy subjects. No changes were observed in warfarin plasma protein binding. Glimepiride treatment did result in a slight, but statistically significant, decrease in the pharmacodynamic response to warfarin. The reductions in mean area under the prothrombin time (PT) curve and maximum PT values during glimepiride treatment were very small (3.3% and 9.9%, respectively) and are unlikely to be clinically important.

Ramipril: The responses of serum glucose, insulin, C-peptide, and plasma glucagon to 2 mg glimepiride were unaffected by co-administration of ramipril (an ACE inhibitor) 5 mg once daily in normal subjects. No hypoglycemic symptoms were reported. Pooled data from clinical trials in patients with type 2 diabetes showed no evidence of clinically significant adverse interactions with uncontrolled concurrent administration of ACE inhibitors.

Miconazole: A potential interaction between oral miconazole and oral hypoglycemic agents leading to severe hypoglycemia has been reported. Whether this interaction also occurs with the intravenous, topical, or vaginal preparations of miconazole is not known. There is a potential interaction of glimepiride with inhibitors (e.g. fluconazole) and inducers (e.g. rifampicin) of cytochrome P450 2C9.

Although no specific interaction studies were performed with glimepiride, pooled data from clinical trials showed no evidence of clinically significant adverse interactions with uncontrolled concurrent administration of calcium-channel blockers, estrogens, fibrates, NSAIDS, HMG CoA reductase inhibitors, sulfonamides, or thyroid hormone.

Pharmacodynamics and Clinical Effects

Pioglitazone hydrochloride

Clinical studies demonstrate that pioglitazone improves insulin sensitivity in insulin-resistant patients. Pioglitazone enhances cellular responsiveness to insulin, increases insulin-dependent glucose disposal, improves hepatic sensitivity to insulin, and improves dysfunctional glucose homeostasis. In patients with type 2 diabetes, the decreased insulin resistance produced by pioglitazone results in lower plasma glucose concentrations, lower plasma insulin levels, and lower A1C values. Based on results from an open-label extension study, the glucose-lowering effects of pioglitazone appear to persist for at least one year. In controlled clinical studies, pioglitazone in combination with a sulfonylurea had an additive effect on glycemic control.

Patients with lipid abnormalities were included in placebo-controlled monotherapy clinical studies with pioglitazone. Overall, patients treated with pioglitazone had mean decreases in triglycerides, mean increases in HDL cholesterol, and no consistent mean changes in LDL cholesterol and total cholesterol compared to the placebo group. A similar pattern of results was seen in 16-week and 24-week combination therapy studies of pioglitazone with a sulfonylurea.

Glimepiride

A mild glucose-lowering effect first appeared following single oral doses as low as 0.5-0.6 mg in healthy subjects. The time required to reach the maximum effect (i.e., minimum blood glucose level [T_min]) was about 2 to 3 hours. In patients with type 2 diabetes, both fasting and 2-hour postprandial glucose levels were significantly lower with glimepiride (1, 2, 4, and 8 mg once daily) than with placebo after 14 days of oral dosing. The glucose-lowering effect in all active treatment groups was maintained over 24 hours.

In larger dose-ranging studies, blood glucose and A1C were found to respond in a dose-dependent manner over the range of 1 to 4 mg/day of glimepiride. Some patients, particularly those with higher fasting plasma glucose (FPG) levels, may benefit from doses of glimepiride up to 8 mg once daily. No difference in response was found when glimepiride was administered once or twice daily.

In two 14-week, placebo-controlled studies in 720 subjects, the average net reduction in A1C for patients treated with 8 mg of glimepiride once daily was 2.0% in absolute units compared with placebo-treated patients. In a long-term, randomized, placebo-controlled study of patients with type 2 diabetes unresponsive to dietary management, glimepiride therapy improved postprandial insulin/C-peptide responses, and 75% of patients achieved and maintained control of blood glucose and A1C. Efficacy results were not affected by age, gender, weight, or race. In long-term extension trials with previously-treated patients, no meaningful deterioration in mean fasting plasma glucose (FPG) or A1C levels was seen after 2 1/2 years of glimepiride therapy.

Glimepiride therapy is effective in controlling blood glucose without deleterious changes in the plasma lipoprotein profiles of patients treated for type 2 diabetes.

Clinical Studies

There have been no clinical efficacy studies conducted with Duetact. However, the efficacy and safety of the separate components have been previously established. The co-administration of pioglitazone and a sulfonylurea, including glimepiride, has been evaluated for efficacy and safety in two clinical studies. These clinical studies established an added benefit of pioglitazone in glycemic control of patients with inadequately controlled type 2 diabetes while on sulfonylurea therapy. Bioequivalence of Duetact with co-administered pioglitazone and glimepiride tablets was demonstrated at the 30 mg/2 mg and 30 mg/4 mg dosage strengths (see Clinical Pharmacology, Pharmacokinetics and Drug Metabolism, Absorption and Bioavailability).

Clinical Studies of Pioglitazone Add-On Therapy in Patients Not Adequately Controlled on a Sulfonylurea

Two treatment-randomized, controlled clinical studies in patients with type 2 diabetes were conducted to evaluate the safety and efficacy of pioglitazone plus a sulfonylurea. Both studies included patients receiving a sulfonylurea, either alone or in combination with another antihyperglycemic agent, who had inadequate glycemic control. Excluding the sulfonylurea agent, all other antihyperglycemic agents were discontinued prior to starting study treatment. In the first study, 560 patients were randomized to receive 15 mg or 30 mg of pioglitazone or placebo once daily in addition to their current sulfonylurea regimen for 16 weeks. In the second study, 702 patients were randomized to receive 30 mg or 45 mg of pioglitazone once daily in addition to their current sulfonylurea regimen for 24 weeks.

In the first study, the addition of pioglitazone 15 mg or 30 mg once daily to treatment with a sulfonylurea after 16 weeks significantly reduced the mean A1C by 0.88% and 1.28% and the mean FPG by 39.4 mg/dL and 57.9 mg/dL, respectively, from that observed with sulfonylurea treatment alone. In the second study, the mean reductions from baseline at Week 24 in A1C were 1.55% and 1.67% for the 30 mg and 45 mg doses, respectively. Mean reductions from baseline in FPG were 51.5 mg/dL and 56.1 mg/dL, respectively. Based on these reductions in A1C and FPG (Table 2), the addition of pioglitazone to sulfonylurea resulted in significant improvements in glycemic control irrespective of the sulfonylurea dosage.

Table 2. Glycemic Parameters in 16-Week and 24-Week Pioglitazone Hydrochloride + Sulfonylurea Combination Studies

Parameter	Placebo + sulfonylurea	Pioglitazone 15 mg + sulfonylurea		Pioglitazone 30 mg + sulfonylurea
16-Week Study
* significant change from baseline p ≤ 0.050 †significant difference from placebo plus sulfonylurea, p ≤ 0.050 (a) patients who achieved an A1C ≤ 6.1% or ≥ 0.6% decrease from baseline (b) patients who achieved a decrease in FPG by ≥ 30 mg/dL
A1C (%) Baseline mean Mean change from baseline at 16 weeks Difference in change from placebo + sulfonylurea	N=181 9.86 0.06	N=176 10.01 -0.82*† -0.88		N=182 9.93 -1.22*† -1.28
Responder rate (%) (a)	23.8	56.8		74.2
FPG (mg/dL) Baseline mean Mean change from baseline at 16 weeks Difference in change from placebo + sulfonylurea Responder rate (%) (b)	N=182 236 5.6 22.0	N=179 246.8 -33.8*† -39.4 55.3		N=186 238.9 -52.3*† -57.9 67.7
Parameter	Pioglitazone 30 mg + sulfonylurea		Pioglitazone 45 mg + sulfonylurea
24-Week Study
A1C (%) Baseline mean Mean change from baseline at 24 weeks	N=340 9.77 -1.55*		N=332 9.85 -1.67*
Responder rate (%) (a)	77.4		79.5
FPG (mg/dL) Baseline mean Mean change from baseline at 24 weeks	N=338 214.4 -51.5*		N=329 217.2 -56.1*
Responder rate (%) (b)	63.6		71.1

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Indications and Usage

Duetact is indicated as an adjunct to diet and exercise as a once-daily combination therapy to improve glycemic control in patients with type 2 diabetes who are already treated with a combination of pioglitazone and a sulfonylurea or whose diabetes is not adequately controlled with a sulfonylurea alone, or for those patients who have initially responded to pioglitazone alone and require additional glycemic control.

Management of type 2 diabetes should also include nutritional counseling, weight reduction as needed, and exercise. These efforts are important not only in the primary treatment of type 2 diabetes, but also to maintain the efficacy of drug therapy.

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Contraindications

Initiation of Duetact in patients with established New York Heart Association (NYHA) Class III or IV heart failure is contraindicated (see Boxed Warning).

In addition, Duetact is contraindicated in patients with:

1. Known hypersensitivity to pioglitazone, glimepiride or any other component of Duetact.
2. Diabetic ketoacidosis, with or without coma. This condition should be treated with insulin.

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Warnings

Glimepiride

SPECIAL WARNING ON INCREASED RISK OF CARDIOVASCULAR MORTALITY

The administration of oral hypoglycemic drugs has been reported to be associated with increased cardiovascular mortality as compared to treatment with diet alone or diet plus insulin. This warning is based on the study conducted by the University Group Diabetes Program (UGDP), a long-term, prospective clinical trial designed to evaluate the effectiveness of glucose-lowering drugs in preventing or delaying vascular complications in patients with non-insulin-dependent diabetes. The study involved 823 patients who were randomly assigned to one of four treatment groups (Diabetes, 19 supp. 2: 747-830, 1970).

UGDP reported that patients treated for 5 to 8 years with diet plus a fixed dose of tolbutamide (1.5 grams per day) had a rate of cardiovascular mortality approximately 2-1/2 times that of patients treated with diet alone. A significant increase in total mortality was not observed, but the use of tolbutamide was discontinued based on the increase in cardiovascular mortality, thus limiting the opportunity for the study to show an increase in overall mortality. Despite controversy regarding the interpretation of these results, the findings of the UGDP study provide an adequate basis for this warning. The patient should be informed of the potential risks and advantages of glimepiride tablets and of alternative modes of therapy.

Although only one drug in the sulfonylurea class (tolbutamide) was included in this study, it is prudent from a safety standpoint to consider that this warning may also apply to other oral hypoglycemic drugs in this class, in view of their close similarities in mode of action and chemical structure.

Pioglitazone hydrochloride

Cardiac Failure and Other Cardiac Effects

Pioglitazone, like other thiazolidinediones, can cause fluid retention when used alone or in combination with other antidiabetic agents, including insulin. Fluid retention may lead to or exacerbate heart failure. Patients should be observed for signs and symptoms of heart failure. If these signs and symptoms develop, the heart failure should be managed according to current standards of care. Furthermore, discontinuation or dose reduction of pioglitazone must be considered. Patients with NYHA Class III and IV cardiac status were not studied during pre-approval clinical trials and pioglitazone is not recommended in these patients (see Boxed Warning and Contraindications).

In one 16-week U.S. double-blind, placebo-controlled clinical trial involving 566 patients with type 2 diabetes, pioglitazone at doses of 15 mg and 30 mg in combination with insulin was compared to insulin therapy alone. This trial included patients with long-standing diabetes and a high prevalence of pre-existing medical conditions as follows: arterial hypertension (57.2%), peripheral neuropathy (22.6%), coronary heart disease (19.6%), retinopathy (13.1%), myocardial infarction (8.8%), vascular disease (6.4%), angina pectoris (4.4%), stroke and/or transient ischemic attack (4.1%), and congestive heart failure (2.3%).

In this study, two of the 191 patients receiving 15 mg pioglitazone plus insulin (1.1%) and two of the 188 patients receiving 30 mg pioglitazone plus insulin (1.1%) developed congestive heart failure compared with none of the 187 patients on insulin therapy alone. All four of these patients had previous histories of cardiovascular conditions including coronary artery disease, previous CABG procedures, and myocardial infarction. In a 24-week dose-controlled study in which pioglitazone was coadministered with insulin, 0.3% of patients (1/345) on 30 mg and 0.9% (3/345) of patients on 45 mg reported CHF as a serious adverse event.

Analysis of data from these studies did not identify specific factors that predict increased risk of congestive heart failure on combination therapy with insulin.

In type 2 diabetes and congestive heart failure (systolic dysfunction)

A 24-week post-marketing safety study was performed to compare pioglitazone (n=262) to glyburide (n=256) in uncontrolled diabetic patients (mean A1C 8.8% at baseline) with NYHA Class II and III heart failure and ejection fraction less than 40% (mean EF 30% at baseline). Over the course of the study, overnight hospitalization for congestive heart failure was reported in 9.9% of patients on pioglitazone compared to 4.7% of patients on glyburide with a treatment difference observed from 6 weeks. This adverse event associated with pioglitazone was more marked in patients using insulin at baseline and in patients over 64 years of age. No difference in cardiovascular mortality between the treatment groups was observed.

Pioglitazone should be initiated at the lowest approved dose if it is prescribed for patients with type 2 diabetes and systolic heart failure (NYHA Class II). If subsequent dose escalation is necessary, the dose should be increased gradually only after several months of treatment with careful monitoring for weight gain, edema, or signs and symptoms of CHF exacerbation (see Dosage and Administration, Special Patient Populations).

Prospective Pioglitazone Clinical Trial In Macrovascular Events (PROactive)

In PROactive, 5238 patients with type 2 diabetes and a prior history of macrovascular disease were treated with ACTOS (n=2605), force-titrated up to 45 mg once daily, or placebo (n=2633) (see Adverse Reactions). The percentage of patients who had an event of serious heart failure was higher for patients treated with ACTOS (5.7%, n=149) than for patients treated with placebo (4.1%, n=108). The incidence of death subsequent to a report of serious heart failure was 1.5% (n=40) in patients treated with ACTOS and 1.4% (n=37) in placebo-treated patients. In patients treated with an insulin-containing regimen at baseline, the incidence of serious heart failure was 6.3% (n=54/864) with ACTOS and 5.2% (n=47/896) with placebo. For those patients treated with a sulfonylurea-containing regimen at baseline, the incidence of serious heart failure was 5.8% (n=94/1624) with ACTOS and 4.4% (n=71/1626) with placebo.

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Precautions

General

Pioglitazone hydrochloride

Pioglitazone exerts its antihyperglycemic effect only in the presence of insulin. Therefore, Duetact should not be used in patients with type 1 diabetes or for the treatment of diabetic ketoacidosis.

Hypoglycemia: Patients receiving pioglitazone in combination with insulin or oral hypoglycemic agents may be at risk for hypoglycemia, and a reduction in the dose of the concomitant agent may be necessary.

Cardiovascular: In U.S. placebo-controlled clinical trials that excluded patients with New York Heart Association (NYHA) Class III and IV cardiac status, the incidence of serious cardiac adverse events related to volume expansion was not increased in patients treated with pioglitazone as monotherapy or in combination with sulfonylureas or metformin vs. placebo-treated patients. In insulin combination studies, a small number of patients with a history of previously existing cardiac disease developed congestive heart failure when treated with pioglitazone in combination with insulin (see Warnings, Pioglitazone hydrochloride, Cardiac Failure and Other Cardiac Effects). Patients with NYHA Class III and IV cardiac status were not studied in pre-approval pioglitazone clinical trials. Pioglitazone is not indicated in patients with NYHA Class III or IV cardiac status.

In postmarketing experience with pioglitazone, cases of congestive heart failure have been reported in patients both with and without previously known heart disease.

Edema: In all U.S. clinical trials with pioglitazone, edema was reported more frequently in patients treated with pioglitazone than in placebo-treated patients and appears to be dose related (see Adverse Reactions, Pioglitazone hydrochloride). In postmarketing experience, reports of initiation or worsening of edema have been received. Since thiazolidinediones, including pioglitazone, can cause fluid retention, which can exacerbate or lead to congestive heart failure, Duetact should be used with caution in patients at risk for heart failure. Patients should be monitored for signs and symptoms of heart failure (see Boxed Warning, Warnings, Pioglitazone hydrochloride, and Precautions, Information for Patients).

Weight Gain: Dose related weight gain was observed with pioglitazone alone and in combination with other hypoglycemic agents (Table 3). The mechanism of weight gain is unclear but probably involves a combination of fluid retention and fat accumulation.

Table 3. Weight Changes (kg) from Baseline During Double-Blind Clinical Trials with Pioglitazone

			Control Group (Placebo)	pioglitazone 15 mg	pioglitazone 30 mg	pioglitazone 45 mg
			Median (25th/75thpercentile)	Median (25th/75thpercentile)	Median (25th/75thpercentile)	Median (25th/75thpercentile)
Note: Trial durations of 16 to 26 weeks
Monotherapy			-1.4 (-2.7/0.0) n=256	0.9 (-0.5/3.4) n = 79	1.0 (-0.9/3.4) n=188	2.6 (0.2/5.4) n = 79
Combination Therapy		Sulfonylurea Metformin Insulin	-0.5 (-1.8/0.7) n=187 -1.4 (-3.2/0.3) n=160 0.2 (-1.4/1.4) n=182	2.0 (0.2/3.2) n=183 N/A 2.3 (0.5/4.3) n=190	3.1 (1.1/5.4) n=528 0.9 (-0.3/3.2) n=567 3.3 (0.9/6.3) n=522	4.1 (1.8/7.3) n=333 1.8 (-0.9/5.0) n=407 4.1 (1.4/6.8) n=338

Ovulation: Therapy with pioglitazone, like other thiazolidinediones, may result in ovulation in some premenopausal anovulatory women. Thus, adequate contraception in premenopausal women should be recommended while taking Duetact. This possible effect has not been investigated in clinical studies so the frequency of this occurrence is not known.

Hematologic: Across all clinical studies with pioglitazone, mean hemoglobin values declined by 2% to 4% in patients treated with pioglitazone. These changes primarily occurred within the first 4 to 12 weeks of therapy and remained relatively constant thereafter. These changes may be related to increased plasma volume and have rarely been associated with any significant hematologic clinical effects (see Adverse Reactions, Laboratory Abnormalities,Pioglitazone hydrochloride,Hematologic). Duetact may cause decreases in hemoglobin and hematocrit.

Hepatic Effects: In pre-approval clinical studies worldwide, over 4500 subjects were treated with pioglitazone. In U.S. clinical studies, over 4700 patients with type 2 diabetes received pioglitazone. There was no evidence of drug-induced hepatotoxicity or elevation of ALT levels in the clinical studies.

During pre-approval placebo-controlled clinical trials in the U.S., a total of 4 of 1526 (0.26%) patients treated with pioglitazone and 2 of 793 (0.25%) placebo-treated patients had ALT values ≥ 3 times the upper limit of normal. The ALT elevations in patients treated with pioglitazone were reversible and were not clearly related to therapy with pioglitazone.

In postmarketing experience with pioglitazone, reports of hepatitis and of hepatic enzyme elevations to 3 or more times the upper limit of normal have been received. Very rarely, these reports have involved hepatic failure with and without fatal outcome, although causality has not been established.

Pending the availability of the results of additional large, long-term controlled clinical trials and additional postmarketing safety data on pioglitazone, it is recommended that patients treated with Duetact undergo periodic monitoring of liver enzymes.

Serum ALT (alanine aminotransferase) levels should be evaluated prior to the initiation of therapy with Duetact in all patients and periodically thereafter per the clinical judgment of the health care professional. Liver function tests should also be obtained for patients if symptoms suggestive of hepatic dysfunction occur, e.g., nausea, vomiting, abdominal pain, fatigue, anorexia, or dark urine. The decision whether to continue the patient on therapy with Duetact should be guided by clinical judgment pending laboratory evaluations. If jaundice is observed, drug therapy should be discontinued.

Therapy with Duetact should not be initiated if the patient exhibits clinical evidence of active liver disease or the ALT levels exceed 2.5 times the upper limit of normal. Patients with mildly elevated liver enzymes (ALT levels at 1 to 2.5 times the upper limit of normal) at baseline or any time during therapy with Duetact should be evaluated to determine the cause of the liver enzyme elevation. Initiation or continuation of therapy with Duetact in patients with mildly elevated liver enzymes should proceed with caution and include appropriate clinical follow-up which may include more frequent liver enzyme monitoring. If serum transaminase levels are increased (ALT > 2.5 times the upper limit of normal), liver function tests should be evaluated more frequently until the levels return to normal or pretreatment values. If ALT levels exceed 3 times the upper limit of normal, the test should be repeated as soon as possible. If ALT levels remain > 3 times the upper limit of normal or if the patient is jaundiced, Duetact therapy should be discontinued.

Macular Edema: Macular edema has been reported in post-marketing experience in diabetic patients who were taking pioglitazone or another thiazolidinedione. Some patients presented with blurred vision or decreased visual acuity, but some patients appear to have been diagnosed on routine ophthalmologic examination. Some patients had peripheral edema at the time macular edema was diagnosed. Some patients had improvement in their macular edema after discontinuation of their thiazolidinedione. It is unknown whether or not there is a causal relationship between pioglitazone and macular edema. Patients with diabetes should have regular eye exams by an ophthalmologist, per the Standards of Care of the American Diabetes Association. Additionally, any diabetic who reports any kind of visual symptom should be promptly referred to an ophthalmologist, regardless of the patient's underlying medications or other physical findings (see Adverse Reactions).

Fractures: In a randomized trial (PROactive) in patients with type 2 diabetes (mean duration of diabetes 9.5 years), an increased incidence of bone fracture was noted in female patients taking pioglitazone. During a mean follow-up of 34.5 months, the incidence of bone fracture in females was 5.1% (44/870) for pioglitazone versus 2.5% (23/905) for placebo. This difference was noted after the first year of treatment and remained during the course of the study. The majority of fractures observed in female patients were nonvertebral fractures including lower limb and distal upper limb. No increase in fracture rates was observed in men treated with pioglitazone 1.7% (30/1735) versus placebo 2.1% (37/1728). The risk of fracture should be considered in the care of patients, especially female patients, treated with pioglitazone and attention should be given to assessing and maintaining bone health according to current standards of care.

General

Glimepiride

Hypoglycemia: All sulfonylurea drugs are capable of producing severe hypoglycemia. Proper patient selection, dosage, and instructions are important to avoid hypoglycemic episodes. Patients with impaired renal function may be more sensitive to the glucose-lowering effect of glimepiride. A starting dose of 1 mg of glimepiride once daily followed by appropriate dose titration is recommended in those patients (see Dosage and Administration, Special Patient Populations). Debilitated or malnourished patients, and those with adrenal, pituitary, or hepatic insufficiency are particularly susceptible to the hypoglycemic action of glucose-lowering drugs. Hypoglycemia may be difficult to recognize in the elderly and in people who are taking beta-adrenergic blocking drugs or other sympatholytic agents. Hypoglycemia is more likely to occur when caloric intake is deficient, after severe or prolonged exercise, when alcohol is ingested, or when more than one glucose-lowering drug is used. Combined use of glimepiride with insulin or metformin may increase the potential for hypoglycemia.

Loss of control of blood glucose: When a patient stabilized on any diabetic regimen is exposed to stress such as fever, trauma, infection, or surgery, a loss of control may occur. The effectiveness of any oral hypoglycemic drug, including Duetact, in lowering blood glucose to a desired level decreases in many patients over a period of time, which may be due to progression of the severity of the diabetes or to diminished responsiveness to the drug.

Laboratory Tests

FPG and A1C measurements should be performed periodically to monitor glycemic control and therapeutic response to Duetact.

Liver enzyme monitoring is recommended prior to initiation of therapy with Duetact in all patients and periodically thereafter per the clinical judgment of the health care professional (see Precautions, General:Pioglitazone hydrochloride, Hepatic Effects and Adverse Reactions, Laboratory Abnormalities,Pioglitazone hydrochloride, Serum Transaminase Levels).

Information for Patients

Patients should be instructed regarding the importance of adhering to dietary instructions, a regular exercise program, and regular testing of blood glucose and A1C. During periods of stress such as fever, trauma, infection, or surgery, medication requirements may change and patients should be reminded to seek medical advice promptly. Patients should also be informed of the potential risks and advantages of Duetact and of alternative modes of therapy.

Prior to initiation of Duetact therapy, the risks of hypoglycemia, its symptoms and treatment, and conditions that predispose to its development should be explained to patients and responsible family members (see Precautions, General: Pioglitazone hydrochloride and Glimepiride, Hypoglycemia). Combination therapy of Duetact with other antihyperglycemic agents may also cause hypoglycemia.

Patients who experience an unusually rapid increase in weight or edema or who develop shortness of breath or other symptoms of heart failure while on Duetact should immediately report these symptoms to their physician.

Patients should be told that blood tests for liver function will be performed prior to the start of therapy and periodically thereafter per the clinical judgment of the health care professional. Patients should be told to seek immediate medical advice for unexplained nausea, vomiting, abdominal pain, fatigue, anorexia, or dark urine.

Therapy with a thiazolidinedione, including the active pioglitazone component of the Duetact tablet, may result in ovulation in some premenopausal anovulatory women. As a result, these patients may be at an increased risk for pregnancy while taking Duetact. This possible effect has not been investigated in clinical studies so the frequency of this occurrence is not known. Thus, adequate contraception in premenopausal women should be recommended. Patients who become pregnant while on Duetact or are planning a pregnancy should be advised to discuss with their physician a regimen appropriate for maintaining adequate glycemic control (see Precautions, Pregnancy: Pregnancy Category C).

Patients should be told to take a single dose of Duetact once daily with the first main meal and instructed that any change in dosing should be made only if directed by their physician (see Dosage and Administration, Maximum Recommended Dose).

Drug Interactions

Pioglitazone hydrochloride

In vivo drug-drug interaction studies have suggested that pioglitazone may be a weak inducer of CYP 450 isoform 3A4 substrate.

An enzyme inhibitor of CYP2C8 (such as gemfibrozil) may significantly increase the AUC of pioglitazone and an enzyme inducer of CYP2C8 (such as rifampin) may significantly decrease the AUC of pioglitazone. Therefore, if an inhibitor or inducer of CYP2C8 is started or stopped during treatment with pioglitazone, changes in diabetes treatment may be needed based on clinical response (see Clinical Pharmacology, Drug-Drug Interactions, Pioglitazone hydrochloride).

Glimepiride

(see Clinical Pharmacology, Drug-Drug Interactions, Glimepiride)

Carcinogenesis, Mutagenesis, Impairment of Fertility

Duetact

No animal studies have been conducted with Duetact. The following data are based on findings in studies performed with pioglitazone or glimepiride individually.

Pioglitazone hydrochloride

A two-year carcinogenicity study was conducted in male and female rats at oral doses up to 63 mg/kg (approximately 14 times the maximum recommended human oral dose of 45 mg based on mg/m2). Drug-induced tumors were not observed in any organ except for the urinary bladder. Benign and/or malignant transitional cell neoplasms were observed in male rats at 4 mg/kg/day and above (approximately equal to the maximum recommended human oral dose based on mg/m2). A two-year carcinogenicity study was conducted in male and female mice at oral doses up to 100 mg/kg/day (approximately 11 times the maximum recommended human oral dose based on mg/m2). No drug-induced tumors were observed in any organ.

During prospective evaluation of urinary cytology involving more than 1800 patients receiving pioglitazone in clinical trials up to one year in duration, no new cases of bladder tumors were identified. In two 3 year studies in which pioglitazone was compared to placebo or glyburide, there were 16/3656 (0.44%) reports of bladder cancer in patients taking pioglitazone compared to 5/3679 (0.14%) in patients not taking pioglitazone. After excluding patients in whom exposure to study drug was less than one year at the time of diagnosis of bladder cancer, there were six cases (0.16%) on pioglitazone and two (0.05%) on placebo.

Pioglitazone hydrochloride was not mutagenic in a battery of genetic toxicology studies, including the Ames bacterial assay, a mammalian cell forward gene mutation assay (CHO/HPRT and AS52/XPRT), an in vitro cytogenetics assay using CHL cells, an unscheduled DNA synthesis assay, and an in vivo micronucleus assay.

No adverse effects upon fertility were observed in male and female rats at oral doses up to 40 mg/kg pioglitazone hydrochloride daily prior to and throughout mating and gestation (approximately 9 times the maximum recommended human oral dose based on mg/m²).

Glimepiride

Studies in rats at doses of up to 5000 ppm in complete feed (approximately 340 times the maximum recommended human dose, based on surface area) for 30 months showed no evidence of carcinogenesis. In mice, administration of glimepiride for 24 months resulted in an increase in benign pancreatic adenoma formation which was dose related and is thought to be the result of chronic pancreatic stimulation. The no-effect dose for adenoma formation in mice in this study was 320 ppm in complete feed, or 46-54 mg/kg body weight/day. This is about 35 times the maximum human recommended dose of 8 mg once daily based on surface area.

Glimepiride was non-mutagenic in a battery of in vitro and in vivo mutagenicity studies (Ames test, somatic cell mutation, chromosomal aberration, unscheduled DNA synthesis, mouse micronucleus test).

There was no effect of glimepiride on male mouse fertility in animals exposed up to 2500 mg/kg body weight (>1,700 times the maximum recommended human dose based on surface area). Glimepiride had no effect on the fertility of male and female rats administered up to 4000 mg/kg body weight (approximately 4,000 times the maximum recommended human dose based on surface area).

Animal Toxicology

Pioglitazone hydrochloride

Heart enlargement has been observed in mice (100 mg/kg), rats (4 mg/kg and above) and dogs (3 mg/kg) treated orally with pioglitazone hydrochloride (approximately 11, 1, and 2 times the maximum recommended human oral dose for mice, rats, and dogs, respectively, based on mg/m2). In a one-year rat study, drug-related early death due to apparent heart dysfunction occurred at an oral dose of 160 mg/kg/day (approximately 35 times the maximum recommended human oral dose based on mg/m2). Heart enlargement was seen in a 13-week study in monkeys at oral doses of 8.9 mg/kg and above (approximately 4 times the maximum recommended human oral dose based on mg/m2), but not in a 52-week study at oral doses up to 32 mg/kg (approximately 13 times the maximum recommended human oral dose based on mg/m2).

Glimepiride

Reduced serum glucose values and degranulation of the pancreatic beta cells were observed in beagle dogs exposed to 320 mg glimepiride/kg/day for 12 months (approximately 1,000 times the recommended human dose based on surface area). No evidence of tumor formation was observed in any organ. One female and one male dog developed bilateral subcapsular cataracts. Non-GLP studies indicated that glimepiride was unlikely to exacerbate cataract formation. Evaluation of the co-cataractogenic potential of glimepiride in several diabetic and cataract rat models was negative and there was no adverse effect of glimepiride on bovine ocular lens metabolism in organ culture.

Pregnancy

Pregnancy Category C

Duetact

Because current information strongly suggests that abnormal blood glucose levels during pregnancy are associated with a higher incidence of congenital anomalies, as well as increased neonatal morbidity and mortality, most experts recommend that insulin be used during pregnancy to maintain blood glucose levels as close to normal as possible. Duetact should not be used during pregnancy unless the potential benefit justifies the potential risk to the fetus.

There are no adequate and well-controlled studies in pregnant women with Duetact or its individual components. No animal studies have been conducted with the combined products in Duetact. The following data are based on findings in studies performed with pioglitazone or glimepiride individually.

Pioglitazone hydrochloride

Pioglitazone was not teratogenic in rats at oral doses up to 80 mg/kg or in rabbits given up to 160 mg/kg during organogenesis (approximately 17 and 40 times the maximum recommended human oral dose based on mg/m2, respectively). Delayed parturition and embryotoxicity (as evidenced by increased postimplantation losses, delayed development and reduced fetal weights) were observed in rats at oral doses of 40 mg/kg/day and above (approximately 10 times the maximum recommended human oral dose based on mg/m2). No functional or behavioral toxicity was observed in offspring of rats. In rabbits, embryotoxicity was observed at an oral dose of 160 mg/kg (approximately 40 times the maximum recommended human oral dose based on mg/m2). Delayed postnatal development, attributed to decreased body weight, was observed in offspring of rats at oral doses of 10 mg/kg and above during late gestation and lactation periods (approximately 2 times the maximum recommended human oral dose based on mg/m2).

Glimepiride

Teratogenic Effects: Glimepiride did not produce teratogenic effects in rats exposed orally up to 4000 mg/kg body weight (approximately 4,000 times the maximum recommended human dose based on surface area) or in rabbits exposed up to 32 mg/kg body weight (approximately 60 times the maximum recommended human dose based on surface area). Glimepiride has been shown to be associated with intrauterine fetal death in rats when given in doses as low as 50 times the human dose based on surface area and in rabbits when given in doses as low as 0.1 times the human dose based on surface area. This fetotoxicity, observed only at doses inducing maternal hypoglycemia, has been similarly noted with other sulfonylureas, and is believed to be directly related to the pharmacologic (hypoglycemic) action of glimepiride.

Nonteratogenic Effects: In some studies in rats, offspring of dams exposed to high levels of glimepiride during pregnancy and lactation developed skeletal deformities consisting of shortening, thickening, and bending of the humerus during the postnatal period. Significant concentrations of glimepiride were observed in the serum and breast milk of the dams as well as in the serum of the pups. These skeletal deformations were determined to be the result of nursing from mothers exposed to glimepiride.

Prolonged severe hypoglycemia (4 to 10 days) has been reported in neonates born to mothers who were receiving a sulfonylurea drug at the time of delivery. This has been reported more frequently with the use of agents with prolonged half-lives. Patients who are planning a pregnancy should consult their physician, and it is recommended that they change over to insulin for the entire course of pregnancy and lactation.

Nursing Mothers

No studies have been conducted with the combined components of Duetact. In studies performed with the individual components, pioglitazone was secreted in the milk of lactating rats and significant concentrations of glimepiride were observed in the serum and breast milk of the dams and serum of the pups. It is not known whether pioglitazone or glimepiride are secreted in human milk. However, other sulfonylureas are excreted in human milk. Because the potential for hypoglycemia in nursing infants may exist, and because of the effects on nursing animals, Duetact should not be administered to a woman breastfeeding. If Duetact is discontinued, and if diet alone is inadequate for controlling blood glucose, insulin therapy should be considered (see Precautions, Pregnancy: Pregnancy Category C, Glimepiride, Nonteratogenic Effects).

Pediatric Use

Safety and effectiveness of Duetact in pediatric patients have not been established.

Elderly Use

Pioglitazone hydrochloride

Approximately 500 patients in placebo-controlled clinical trials of pioglitazone were 65 and over. No significant differences in effectiveness and safety were observed between these patients and younger patients.

Glimepiride

In U.S. clinical studies of glimepiride, 608 of 1986 patients were 65 and over. No overall differences in safety or effectiveness were observed between these subjects and younger subjects, but greater sensitivity of some older individuals cannot be ruled out.

Comparison of glimepiride pharmacokinetics in patients with type 2 diabetes ≤65 years (n=49) and those >65 years (n=42) was performed in a study using a dosing regimen of 6 mg daily. There were no significant differences in glimepiride pharmacokinetics between the two age groups (see Clinical Pharmacology, Special Populations, Elderly: Glimepiride).

Glimepiride is known to be substantially excreted by the kidney, and the risk of toxic reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function.

Elderly patients are particularly susceptible to hypoglycemic action of glucose-lowering drugs. In elderly, debilitated, or malnourished patients, or in patients with renal and hepatic insufficiency, the initial dosing, dose increments, and maintenance dosage should be conservative based upon blood glucose levels prior to and after initiation of treatment to avoid hypoglycemic reactions. Hypoglycemia may be difficult to recognize in the elderly and in people who are taking beta-adrenergic blocking drugs or other sympatholytic agents (see Clinical Pharmacology, Special Populations, Renal Insufficiency: Glimepiride; PRECAUTIONS, General: Glimepiride, Hypoglycemia and Dosage and Administration, Special Patient Populations).

Adverse Reactions

The adverse events reported in at least 5% of patients in the controlled 16-week clinical studies between placebo plus a sulfonylurea and pioglitazone (15 mg and 30 mg combined) plus sulfonylurea-treatment arms were upper respiratory tract infection (15.5% and 16.6%), accidental injury (8.6% and 3.5%) and combined edema/peripheral edema (2.1% and 7.2%), respectively.

The incidence and type of adverse events reported in at least 5% of patients in any combined treatment group from the 24-week study comparing pioglitazone 30 mg plus a sulfonylurea and pioglitazone 45 mg plus a sulfonylurea are shown in Table 4; the rate of adverse events resulting in study discontinuation between the two treatment groups was 6.0% and 9.7%, respectively.

Table 4. Adverse Events That Occurred in ≥ 5% of Patients in Any Treatment Group During the 24-Week Study

Adverse Event	Pioglitazone 30 mg+ sulfonylurea N=351 n (%)	Pioglitazone 45 mg+ sulfonylurea N=351 n (%)
Hypoglycemia	47 (13.4)	55 (15.7)
Upper Respiratory Tract Infection	43 (12.3)	52 (14.8)
Weight Increased	32 (9.1)	47 (13.4)
Edema Lower Limb	20 (5.7)	43 (12.3)
Headache	25 (7.1)	14 (4.0)
Urinary Tract Infection	20 (5.7)	24 (6.8)
Diarrhea	21 (6.0)	15 (4.3)
Nausea	18 (5.1)	14 (4.0)
Pain in Limb	19 (5.4)	14 (4.0)

In U.S. double-blind studies, anemia was reported in ≤ 2% of patients treated with pioglitazone plus a sulfonylurea (see Precautions, General: Pioglitazone hydrochloride).

Pioglitazone hydrochloride

Over 8500 patients with type 2 diabetes have been treated with pioglitazone in randomized, double-blind, controlled clinical trials. This includes 2605 high-risk patients with type 2 diabetes treated with pioglitazone from the PROactive clinical trial. Over 6000 patients have been treated for 6 months or longer, and over 4500 patients for one year or longer. Over 3000 patients have received pioglitazone for at least 2 years.

Most clinical adverse events were similar between groups treated with pioglitazone in combination with a sulfonylurea and those treated with pioglitazone monotherapy. Other adverse events reported in at least 5% of patients in controlled clinical studies between placebo and pioglitazone monotherapy included myalgia (2.7% and 5.4%), tooth disorder (2.3% and 5.3%), diabetes mellitus aggravated (8.1% and 5.1%) and pharyngitis (0.8% and 5.1%), respectively.

In monotherapy studies, edema was reported for 4.8% (with doses from 7.5 mg to 45 mg) of patients treated with pioglitazone versus 1.2% of placebo-treated patients. Most of these events were considered mild or moderate in intensity (see Precautions, General: Pioglitazone hydrochloride, Edema).

Prospective Pioglitazone Clinical Trial In Macrovascular Events (PROactive)

In PROactive, 5238 patients with type 2 diabetes and a prior history of macrovascular disease were treated with ACTOS (n=2605), force-titrated up to 45 mg daily, or placebo (n=2633), in addition to standard of care. Almost all subjects (95%) were receiving cardiovascular medications (beta blockers, ACE inhibitors, ARBs, calcium channel blockers, nitrates, diuretics, aspirin, statins, fibrates). Patients had a mean age of 61.8 years, mean duration of diabetes 9.5 years, and mean A1C 8.1%. Average duration of follow-up was 34.5 months. The primary objective of this trial was to examine the effect of ACTOS on mortality and macrovascular morbidity in patients with type 2 diabetes mellitus who were at high risk for macrovascular events. The primary efficacy variable was the time to the first occurrence of any event in the cardiovascular composite endpoint (see table 5 below). Although there was no statistically significant difference between ACTOS and placebo for the 3-year incidence of a first event within this composite, there was no increase in mortality or in total macrovascular events with ACTOS.

Table 5. Number of First and Total Events for Each Component within the Cardiovascular Composite Endpoint

	Placebo N=2633		ACTOS N=2605
Cardiovascular Events	First Events (N)	Total events (N)	First Events (N)	Total events (N)
Any event	572	900	514	803
All-cause mortality	122	186	110	177
Non-fatal MI	118	157	105	131
Stroke	96	119	76	92
ACS	63	78	42	65
Cardiac intervention	101	240	101	195
Major leg amputation	15	28	9	28
Leg revascularization	57	92	71	115

Postmarketing reports of new onset or worsening diabetic macular edema with decreased visual acuity have also been received (see Precautions, General: Pioglitazone hydrochloride).

Glimepiride

Adverse events that occurred in controlled clinical trials with placebo and glimepiride monotherapy, other than hypoglycemia, headache and nausea, also included dizziness (0.3% and 1.7%) and asthenia (1.0% and 1.6%), respectively.

Gastrointestinal Reactions: Vomiting, gastrointestinal pain, and diarrhea have been reported with glimepiride, but the incidence in placebo-controlled trials was less than 1%. In rare cases, there may be an elevation of liver enzyme levels. In isolated instances, impairment of liver function (e.g. with cholestasis and jaundice), as well as hepatitis, which may also lead to liver failure have been reported with sulfonylureas, including glimepiride.

Dermatologic Reactions:Allergic skin reactions, e.g., pruritus, erythema, urticaria, and morbilliform or maculopapular eruptions, occur in less than 1% of glimepiride-treated patients. These may be transient and may disappear despite continued use of glimepiride. If those hypersensitivity reactions persist or worsen, the drug should be discontinued. Porphyria cutanea tarda, photosensitivity reactions, and allergic vasculitis have been reported with sulfonylureas.

Metabolic Reactions: Hepatic porphyria reactions and disulfiram-like reactions have been reported with sulfonylureas; however, no cases have yet been reported with glimepiride tablets. Cases of hyponatremia have been reported with glimepiride and all other sulfonylureas, most often in patients who are on other medications or have medical conditions known to cause hyponatremia or increase release of antidiuretic hormone. The syndrome of inappropriate antidiuretic hormone (SIADH) secretion has been reported with certain other sulfonylureas, and it has been suggested that these sulfonylureas may augment the peripheral (antidiuretic) action of ADH and/or increase release of ADH.

Hematologic Reactions: Leukopenia, agranulocytosis, thrombocytopenia, hemolytic anemia, aplastic anemia, and pancytopenia have been reported with sulfonylureas.

Other Reactions: Changes in accommodation and/or blurred vision may occur with the use of glimepiride. In placebo-controlled trials of glimepiride, the incidence of blurred vision with placebo was 0.7%, and with glimepiride, 0.4%. This is thought to be due to changes in blood glucose, and may be more pronounced when treatment is initiated. This condition is also seen in untreated diabetic patients, and may actually be reduced by treatment.

Laboratory Abnormalities

Pioglitazone hydrochloride

Hematologic:Pioglitazone may cause decreases in hemoglobin and hematocrit. The fall in hemoglobin and hematocrit with pioglitazone appears to be dose related. Across all clinical studies, mean hemoglobin values declined by 2% to 4% in patients treated with pioglitazone. These changes generally occurred within the first 4 to 12 weeks of therapy and remained relatively stable thereafter. These changes may be related to increased plasma volume associated with pioglitazone therapy and have rarely been associated with any significant hematologic clinical effects (see Precautions, General: Pioglitazone hydrochloride, Hematologic).

Serum Transaminase Levels: During all clinical studies in the U.S., 14 of 4780 (0.30%) patients treated with pioglitazone had ALT values ≥ 3 times the upper limit of normal during treatment. All patients with follow-up values had reversible elevations in ALT. In the population of patients treated with pioglitazone, mean values for bilirubin, AST, ALT, alkaline phosphatase, and GGT were decreased at the final visit compared with baseline. Fewer than 0.9% of patients treated with pioglitazone were withdrawn from clinical trials in the U.S. due to abnormal liver function tests.

In pre-approval clinical trials, there were no cases of idiosyncratic drug reactions leading to hepatic failure (see Precautions, General: Pioglitazone hydrochloride, Hepatic Effects).

CPK Levels: During required laboratory testing in clinical trials with pioglitazone, sporadic, transient elevations in creatine phosphokinase levels (CPK) were observed. An isolated elevation to greater than 10 times the upper limit of normal was noted in 9 patients (values of 2150 to 11400 IU/L). Six of these patients continued to receive pioglitazone, two patients had completed receiving study medication at the time of the elevated value and one patient discontinued study medication due to the elevation. These elevations resolved without any apparent clinical sequelae. The relationship of these events to pioglitazone therapy is unknown.

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Overdose

Pioglitazone hydrochloride

During controlled clinical trials, one case of overdose with pioglitazone was reported. A male patient took 120 mg per day for four days, then 180 mg per day for seven days. The patient denied any clinical symptoms during this period.

In the event of overdosage, appropriate supportive treatment should be initiated according to patient's clinical signs and symptoms.

Glimepiride

Overdosage of sulfonylureas, including glimepiride, can produce hypoglycemia. Mild hypoglycemic symptoms without loss of consciousness or neurologic findings should be treated aggressively with oral glucose and adjustments in drug dosage and/or meal patterns. Close monitoring should continue until the physician is assured that the patient is out of danger. Severe hypoglycemic reactions with coma, seizure, or other neurological impairment occur infrequently, but constitute medical emergencies requiring immediate hospitalization. If hypoglycemic coma is diagnosed or suspected, the patient should be given a rapid intravenous injection of concentrated (50%) glucose solution. This should be followed by a continuous infusion of a more dilute (10%) glucose solution at a rate that will maintain the blood glucose at a level above 100 mg/dL. Patients should be closely monitored for a minimum of 24 to 48 hours, because hypoglycemia may recur after apparent clinical recovery.

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Dosage and Administration

General

The use of antihyperglycemic therapy in the management of type 2 diabetes should be individualized on the basis of effectiveness and tolerability. Failure to follow an appropriate dosage regimen may precipitate hypoglycemia.

Dosage Recommendations

Selecting the starting dose of Duetact should be based on the patient's current regimen of pioglitazone and/or sulfonylurea. Those patients who may be more sensitive to antihyperglycemic drugs should be monitored carefully during dose adjustment. After initiation of Duetact, patients should be carefully monitored for adverse events related to fluid retention (see Boxed Warning and Warnings, Pioglitazone hydrochloride). It is recommended that a single dose of Duetact be administered once daily with the first main meal.

Starting dose for patients currently on glimepiride monotherapy

Based on the usual starting dose of pioglitazone (15 mg or 30 mg daily), Duetact may be initiated at 30 mg/2 mg or 30 mg/4 mg tablet strengths once daily, and adjusted after assessing adequacy of therapeutic response.

For patients with type 2 diabetes and systolic dysfunction, see Dosage and Administration, Special Patient Populations.

Starting dose for patients currently on pioglitazone monotherapy

Based on the usual starting doses of glimepiride (1 mg or 2 mg once daily), and pioglitazone 15 mg or 30 mg, Duetact may be initiated at 30 mg/2 mg once daily, and adjusted after assessing adequacy of therapeutic response.

For patients who are not currently on glimepiride and may be more sensitive to hypoglycemia, see Dosage and Administration, Special Patient Populations.

Starting dose for patients switching from combination therapy of pioglitazone plus glimepiride as separate tablets

Duetact may be initiated with 30 mg/2 mg or 30 mg/4 mg tablet strengths based on the dose of pioglitazone and glimepiride already being taken. Patients who are not controlled with 15 mg of pioglitazone in combination with glimepiride should be carefully monitored when switched to Duetact.

Starting dose for patients currently on a different sulfonylurea monotherapy or switching from combination therapy of pioglitazone plus a different sulfonylurea (e.g. glyburide, glipizide, chlorpropamide, tolbutamide, acetohexamide)

No exact dosage relationship exists between glimepiride and the other sulfonylurea agents. Therefore, based on the maximum starting dose of 2 mg glimepiride, Duetact should be limited initially to a starting dose of 30 mg/2 mg once daily, and adjusted after assessing adequacy of therapeutic response.

Any change in diabetic therapy should be undertaken with care and appropriate monitoring as changes in glycemic control can occur. Patients should be observed carefully for hypoglycemia (1-2 weeks) when being transferred to Duetact, especially from longer half-life sulfonylureas (e.g. chlorpropamide) due to potential overlapping of drug effect.

Sufficient time should be given to assess adequacy of therapeutic response. Ideally, the response to therapy should be evaluated using A1C, which is a better indicator of long-term glycemic control than FPG alone. A1C reflects glycemia over the past two to three months. In clinical use, it is recommended that patients be treated with Duetact for a period of time adequate to evaluate change in A1C (8-12 weeks) unless glycemic control as measured by FPG deteriorates.

Special Patient Populations

Duetact is not recommended for use in pregnancy, nursing mothers or for use in pediatric patients.

In elderly, debilitated, or malnourished patients, or in patients with renal or hepatic insufficiency, the initial dosing, dose increments, and maintenance dosage of Duetact should be conservative to avoid hypoglycemic reactions. These patients should be started at 1 mg of glimepiride prior to prescribing Duetact. During initiation of Duetact therapy and any subsequent dose adjustment, patients should be observed carefully for hypoglycemia (see PRECAUTIONS, General: Glimepiride, Hypoglycemia).

Therapy with Duetact should not be initiated if the patient exhibits clinical evidence of active liver disease or increased serum transaminase levels (ALT greater than 2.5 times the upper limit of normal) at start of therapy (see PRECAUTIONS, General: Pioglitazone hydrochloride, Hepatic Effects and CLINICAL PHARMACOLOGY, Special Populations, Hepatic Insufficiency: Pioglitazone hydrochloride). Liver enzyme monitoring is recommended in all patients prior to initiation of therapy with Duetact and periodically thereafter (see Precautions, General: Pioglitazone hydrochloride, Hepatic Effects and PRECAUTIONS, Laboratory Tests).

The lowest approved dose of Duetact therapy should be prescribed to patients with type 2 diabetes and systolic dysfunction only after titration from 15 mg to 30 mg of pioglitazone has been safely tolerated. If subsequent dose adjustment is necessary, patients should be carefully monitored for weight gain, edema, or signs and symptoms of CHF exacerbation (see Warnings, Pioglitazone hydrochloride, Cardiac Failure and Other Cardiac Effects).

Maximum Recommended Dose

Duetact tablets are available as a 30 mg pioglitazone plus 2 mg glimepiride or a 30 mg pioglitazone plus 4 mg glimepiride formulation for oral administration. The maximum recommended daily dose for pioglitazone is 45 mg and the maximum recommended daily dose for glimepiride is 8 mg

Duetact should therefore not be given more than once daily at any of the tablet strengths.

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How Supplied

Duetact is available in 30 mg pioglitazone plus 2 mg glimepiride or 30 mg pioglitazone plus 4 mg glimepiride tablets as follows:

30 mg/2 mg tablet: white to off-white, round, convex, uncoated tablet, debossed with 30/2 on one side and 4833G on the other, available in:

NDC 64764-302-30 Bottles of 30

NDC 64764-302-90 Bottles of 90

30 mg/4 mg tablet: white to off-white, round, convex, uncoated tablet, debossed with 30/4 on one side and 4833G on the other, available in:

NDC 64764-304-30 Bottles of 30

NDC 64764-304-90 Bottles of 90

Storage

Store at 25°C (77°F); excursions permitted to 15-30°C (59-86°F) [see USP Controlled Room Temperature]. Keep container tightly closed and protect from moisture and humidity.

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References

1. Deng, LJ, et al. Effect of gemfibrozil on the pharmacokinetics of pioglitazone. Eur J Clin Pharmacol 2005; 61: 831-836, Table 1.
2. Jaakkola, T, et al. Effect of rifampicin on the pharmacokinetics of pioglitazone. Br J Clin Pharmacol 2006; 61:1 70-78.

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Human Ophthalmology Data

Glimepiride

Ophthalmic examinations were carried out in over 500 subjects during long-term studies using the methodology of Taylor and West and Laties et al. No significant differences were seen between glimepiride and glyburide in the number of subjects with clinically important changes in visual acuity, intraocular tension, or in any of the five lens-related variables examined.

Ophthalmic examinations were carried out during long-term studies using the method of Chylack et al. No significant or clinically meaningful differences were seen between glimepiride and glipizide with respect to cataract progression by subjective LOCS II grading and objective image analysis systems, visual acuity, intraocular pressure, and general ophthalmic examination.

Rx only

ACTOS® and DuetactTM are trademarks of Takeda Pharmaceutical Company Limited and used under license by Takeda Pharmaceuticals America, Inc.

Distributed by:

Takeda Pharmaceuticals America, Inc.

Deerfield, IL 60015

© 2006 Takeda Pharmaceuticals America, Inc.

05-1140 September 2007

Last Updated: 09/07

Duetact, pioglitazone hydrochloride and glimepiride patient information (in plain English)

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

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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.

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Brand Name: Duetact
Generic Name: Pioglitazone Hydrochloride and Glimepiride

Duetact, pioglitazone hydrochloride and glimepiride full patient information

Why is Duetact Prescribed?

Duetact is used, along with diet and exercise, to treat people with type 2 diabetes. It contains two medications, pioglitazone and glimepiride, that work together to help keep blood sugar levels under control. Type 2 diabetes usually stems from the body's inability to make good use of insulin, the natural hormone that helps to transfer sugar out of the blood and into the cells, where it's converted to energy. Duetact works by improving your body's response to its own natural insulin supply. It also helps increase the amount of insulin produced by the pancreas.

Most Important Fact about Duetact

Always remember that Duetact is an aid to, not a substitute for, good diet and exercise. Failure to follow a sound diet and exercise plan can lead to serious complications, such as dangerously high or low blood sugar levels. Remember, too, that Duetact is not an oral form of insulin, and cannot be used in place of insulin.

How Should You Take Duetact?

Duetact should be taken once a day with the first meal of the day.

• If you miss a dose...
  Take it as soon as you remember. If you miss a dose on one day, skip it and go back to your regular schedule. Never take two doses at once.
• Storage instructions...
  Store at room temperature, away from moisture.

What Side Effects may Occur?

Side effects cannot be anticipated. If any develop or change in intensity, inform your doctor as soon as possible. Only your doctor can determine if it is safe for you to continue taking Duetact.

• Side effects may include:
  Diarrhea, headache, lower blood sugar, nausea, pain in legs, upper respiratory tract infection, urinary tract infection, weight gain

Why Should Duetact Not be Prescribed?

Do not take Duetact if you are allergic to any of its ingredient, or if you have diabetic ketoacidosis. This problem should be treated with insulin.

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Special Warnings about Duetact

Tell your doctor about all prescription, over-the-counter, and herbal medications you are taking to avoid an interaction with Duetact. Also, talk to your doctor about your complete medical history, including heart problems and all other type 2 diabetic medications you have taken.

In rare instances, pioglitazone, one of the medications in Duetact, causes swelling that can lead to congestive heart failure. Contact your doctor immediately if you develop symptoms of this problem, such as rapid weight gain, water retention or swelling, fatigue, and shortness of breath. Drug therapy with pioglitazone is not recommended for people with congestive heart failure.

During periods of stress—such as infection, fever, trauma, or dehydration due to diarrhea or vomiting—your medication requirements may change. Be sure to consult your doctor during such times.

For further recommendations, see the individual entries for pioglitazone and glimepiride.

Special Information if You Are Pregnant or Breastfeeding

Talk to your doctor if you are pregnant, planning to become pregnant, or nursing. Duetact is not recommended for pregnant women; blood sugar levels should be maintained with insulin during pregnancy. Also, Duetact may pass into breast milk. If you plan on breastfeeding, talk to your doctor about your options.

Recommended Dosage for Duetact

ADULTS

Duetact is taken as a single tablet once daily. The tablet strength your doctor prescribes will be based on the usual starting doses of the ingredients pioglitazone and glimepiride. The tablet is available in two strengths: 30 milligrams/2 milligrams and 30 milligrams/4 milligrams, with the first number being the amount of pioglitazone and the second number being the amount of glimepiride.

Overdosage

Any medication taken in excess can have serious consequences. If you suspect an overdose, seek medical attention immediately.

Last Updated: 09/07

Duetact, pioglitazone hydrochloride and glimepiride full patient information

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

back to:Browse all Medications for Diabetes

 

Brand Names: Byetta
Generic Name: exenatide (ex EN a tide)

Byetta, Exenatide, full prescribing information

What is Byetta and what is it used for?

Byetta (exenatide) is an injectable diabetes medicine that helps control blood sugar levels. This medication helps your pancreas produce insulin more efficiently.

Byetta is used to treat type 2 (non-insulin dependent) diabetes. Other diabetes medicines are sometimes used in combination with Byetta if needed.

Byetta may also be used for other purposes not listed in this medication guide.

Important information you need to have about Byetta

Do not use Byetta to treat type 1 (insulin-dependent) diabetes, or if you are in a state of diabetic ketoacidosis (call your doctor for treatment with insulin).

Before using Byetta, tell your doctor if you use any of these oral diabetes medications: acetohexamide (Dymelor), chlorpropamide (Diabinese), glimepiride (Amaryl), glipizide (Glucotrol), glyburide (DiaBeta), tolazamide (Tolinase), tolbutamide (Orinase).

You must use this medication within 60 minutes (1 hour) before eating a meal. If you miss a dose, use the medication as soon as you remember, but only if you have not yet eaten a meal. If you have already eaten a meal, wait until your next scheduled dose (1 hour before a meal) to use the medicine. Your Byetta doses should be spaced at least 6 hours apart. Do not use this medicine after eating a meal.

Stop using Byetta and call your doctor at once if you have severe pain in your upper stomach spreading to your back, with nausea, vomiting, and a fast heart rate. These could be symptoms of pancreatitis.

It is important to use Byetta regularly to get the most benefit. Get your prescription refilled before you run out of medicine completely.

Never share an injection pen or cartridge with another person. Sharing injection pens or cartridges can allow disease such as hepatitis or HIV to pass from one person to another.

To be sure this medication is helping your condition, you will need to check your blood sugar at home. Your blood will also need to be tested by your doctor on a regular basis. Do not miss any scheduled appointments.

If you are using any type of antibiotic or birth control pill, take these medicines at least 1 hour before you use Byetta.

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Before you take Byetta

Do not use Byetta to treat type 1 (insulin-dependent) diabetes, or if you are in a state of diabetic ketoacidosis (call your doctor for treatment with insulin).

If you have any of these other conditions, you may need a dose adjustment or special tests to safely use Byetta:

• kidney disease (or if you are on dialysis);
• problems with digestion; or
• severe stomach disorders (gastroparesis).

FDA pregnancy category C. It is not known whether Byetta is harmful to an unborn baby. Before using Byetta, Tell your doctor if you are pregnant or if you become pregnant during treatment. It is not known whether exenatide passes into breast milk or if it could be harmful to a nursing baby. Do not take Byetta without telling your doctor if you are breast-feeding a baby.

How should I use Byetta?

Use Byetta exactly as it was prescribed for you. Donot use the medication in larger amounts or use it for longer than recommended by your doctor. Follow the directions on your prescription label.

Your doctor may occasionally change your dose to make sure you get the best results from this medication. Your dose needs may change if you are ill, if you have a fever or infection, or if you have surgery or a medical emergency. Do not change your dose of Byetta without first talking to your doctor. Use only the diabetes medications prescribed for you.

Byetta is given as an injection under the skin, usually in the upper thigh, stomach area, or upper arm. Your doctor, nurse, or pharmacist will give you specific instructions on how and where to inject this medicine. Do not self-inject this medicine if you do not fully understand how to give the injection and properly dispose of used needles and syringes.

Byetta is usually injected twice a day, before the morning and evening meal. You must use this medication within 60 minutes (1 hour) before eating the meal. Your Byetta doses should be given at least 6 hours apart. Do not use this medicine after eating a meal.

It is important to use Byetta regularly to get the most benefit. Get your prescription refilled before you run out of medicine completely.

Byetta comes in a prefilled pen with a "Pen User Manual" showing instructions for using the pen and injecting the medicine. You must do a "New Pen Set-Up" one time only, when starting a new prefilled Byetta Pen. If you do this "New Pen Set-Up" before each injection, you will run out of medicine before 30 days.

Pen needles are not included with this medicine. Ask your doctor, diabetes counselor, or pharmacist which needle size is best for you.

Never share an injection pen or cartridge with another person. Sharing injection pens or cartridges can allow disease such as hepatitis or HIV to pass from one person to another.

To be sure this medication is helping your condition, you will need to check your blood sugar at home. Your blood will also need to be tested by your doctor on a regular basis. Do not miss any scheduled appointments.

Store unused Byetta injection pens in the refrigerator, protected from light. Do not freeze them, and throw away any pens that have become frozen. After your first use of a pen, it may then be stored at room temperature, away from heat and bright light.

Use the pen for only 30 days and then throw it away, even if it still has medicine in it. Do not use the medicine after the expiration date on the label has passed. Do not store the Byetta pen with the needle attached.

If the needle is left on, medicine may leak from the pen or air bubbles may form in the cartridge. Keep your Byetta pen, pen needles, and all medicines out of the reach of children.

What happens if I miss a dose?

Use the missed dose as soon as you remember, but only if you have not yet eaten a meal. If you have already eaten a meal, wait until your next scheduled dose (1 hour before a meal) to use the medicine. Do not use extra medicine to make up the missed dose.

What happens if I overdose?

Seek emergency medical attention if you think you have used too much of this medicine.

Overdose can cause severe nausea and vomiting, or signs of low blood sugar (headache, weakness, dizziness, confusion, irritability, hunger, fast heartbeat, sweating, and tremor).

What should I avoid while using Byetta?

Avoid drinking alcohol. It lowers blood sugar and may interfere with your diabetes treatment.

If you are using any type of antibiotic or birth control pill, take these medicines at least 1 hour before you use Byetta.

Byetta side effects

Get emergency medical help if you have any of these signs of an allergic reaction: hives; difficulty breathing; swelling of your face, lips, tongue, or throat. Stop using Byetta and call your doctor at once if you have severe pain in your upper stomach spreading to your back, with nausea, vomiting, and a fast heart rate. These could be symptoms of pancreatitis.

Less serious Byetta side effects may include:

• nausea, vomiting, heartburn, diarrhea;
• loss of appetite;
• weight loss; or
• dizziness, headache, or feeling jittery.

Know the signs of low blood sugar (hypoglycemia) and how to recognize them:

• hunger, headache, confusion, irritability;
• drowsiness, weakness, dizziness, tremors;
• sweating, fast heartbeat;
• seizure (convulsions); or
• fainting, coma (severe hypoglycemia can be fatal).

Always keep a source of sugar available in case you have symptoms of low blood sugar. Sugar sources include orange juice, glucose gel, candy, or milk. If you have severe hypoglycemia and cannot eat or drink, use an injection of glucagon. Your doctor can give you a prescription for a glucagon emergency injection kit and tell you how to give the injection.

This is not a complete list of side effects and others may occur. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

What other drugs will affect Byetta?

Before using Byetta, tell your doctor if you use any oral (taken by mouth) diabetes medications. You may need a dose adjustment:

• acetohexamide (Dymelor);
• chlorpropamide (Diabinese);
• glimepiride (Amaryl);
• glipizide (Glucotrol);
• glyburide (DiaBeta);
• tolazamide (Tolinase); or
• tolbutamide (Orinase).

Your doctor will tell you if any of your medication doses need to be changed.

There may be other drugs that can interact with Byetta. Tell your doctor about all the prescription and over-the-counter medications you use. This includes vitamins, minerals, herbal products, and drugs prescribed by other doctors. Do not start using a new medication without telling your doctor.

Where can I get more information?

• Your pharmacist can provide more information about Byetta.
• Remember, keep this and all other medicines out of the reach of children, never share your medicines with others, and use this medication only for the indication prescribed.

last updated 09/2007

Byetta, Exenatide, full prescribing information

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

back to: Browse all Medications for Diabetes

Brand Name: Byetta
Generic Name: Exenatide

Dosage Form: Injection

Contents:

Description
Clinical Pharmacology
Clinical Studies
Indications and Usage
Contraindications
Precautions
Adverse Reactions
Overdosage
Dosage and Administration
Storage
How Supplied

Byetta (Exenatide) Patient Information (in plain English)

Description

Byetta^® (exenatide) is a synthetic peptide that has incretin-mimetic actions and was originally identified in the lizard Heloderma suspectum. Byetta enhances glucose-dependent insulin secretion by the pancreatic beta-cell, suppresses inappropriately elevated glucagon secretion, and slows gastric emptying. Exenatide differs in chemical structure and pharmacological action from insulin, sulfonylureas (including D-phenylalanine derivatives and meglitinides), biguanides, thiazolidinediones, and alpha-glucosidase inhibitors.

Exenatide is a 39−amino acid peptide amide. Exenatide has the empirical formula C₁₈₄H₂₈₂N₅₀O₆₀S and molecular weight of 4186.6 Daltons. The amino acid sequence for exenatide is shown below.

H - His - Gly - Glu - Gly - Thr - Phe - Thr - Ser - Asp - Leu - Ser - Lys - Gln - Met - Glu - Glu - Glu - Ala - Val - Arg - Leu - Phe - Ile - Glu - Trp - Leu - Lys - Asn - Gly - Gly - Pro - Ser - Ser - Gly - Ala - Pro - Pro - Pro - Ser - NH2

Byetta is supplied for subcutaneous (SC) injection as a sterile, preserved isotonic solution in a glass cartridge that has been assembled in a pen-injector (pen). Each milliliter (mL) contains 250 micrograms (mcg) synthetic exenatide, 2.2 mg metacresol as an antimicrobial preservative, mannitol as a tonicity-adjusting agent, and glacial acetic acid and sodium acetate trihydrate in water for injection as a buffering solution at pH 4.5. Two prefilled pens are available to deliver unit doses of 5 mcg or 10 mcg. Each prefilled pen will deliver 60 doses to provide 30 days of twice daily administration (BID).

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Clinical Pharmacology

Mechanism of Action

Incretins, such as glucagon-like peptide-1 (GLP-1), enhance glucose-dependent insulin secretion and exhibit other antihyperglycemic actions following their release into the circulation from the gut. Exenatide is an incretin mimetic agent that mimics the enhancement of glucose-dependent insulin secretion and several other antihyperglycemic actions of incretins.

The amino acid sequence of exenatide partially overlaps that of human GLP-1. Exenatide has been shown to bind and activate the known human GLP-1 receptor in vitro. This leads to an increase in both glucose-dependent synthesis of insulin, and in vivo secretion of insulin from pancreatic beta cells, by mechanisms involving cyclic AMP and/or other intracellular signaling pathways. Exenatide promotes insulin release from beta cells in the presence of elevated glucose concentrations. When administered in vivo, exenatide mimics certain antihyperglycemic actions of GLP-1.

Byetta improves glycemic control by reducing fasting and postprandial glucose concentrations in patients with type 2 diabetes through the actions described below.

Glucose-dependent insulin secretion: Byetta has acute effects on pancreatic beta-cell responsiveness to glucose and leads to insulin release only in the presence of elevated glucose concentrations. This insulin secretion subsides as blood glucose concentrations decrease and approach euglycemia.

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First-phase insulin response: In healthy individuals, robust insulin secretion occurs during the first 10 minutes following intravenous (IV) glucose administration. This secretion, known as the "first-phase insulin response," is characteristically absent in patients with type 2 diabetes. The loss of the first-phase insulin response is an early beta-cell defect in type 2 diabetes. Administration of Byetta at therapeutic plasma concentrations restored first-phase insulin response to an IV bolus of glucose in patients with type 2 diabetes (Figure 1). Both first-phase insulin secretion and second-phase insulin secretion were significantly increased in patients with type 2 diabetes treated with Byetta compared with saline (p

Figure 1: Mean (+SEM) Insulin Secretion Rate During Infusion of Byetta or Saline in Patients With Type 2 Diabetes and During Infusion of Saline in Healthy Subjects

Glucagon secretion: In patients with type 2 diabetes, Byetta moderates glucagon secretion and lowers serum glucagon concentrations during periods of hyperglycemia. Lower glucagon concentrations lead to decreased hepatic glucose output and decreased insulin demand. However, Byetta does not impair the normal glucagon response to hypoglycemia.

Gastric emptying: Byetta slows gastric emptying, thereby reducing the rate at which meal-derived glucose appears in the circulation.

Food intake: In both animals and humans, administration of exenatide has been shown to reduce food intake.

Pharmacokinetics

Absorption

Following SC administration to patients with type 2 diabetes, exenatide reaches median peak plasma concentrations in 2.1 h. Mean peak exenatide concentration (C_max) was 211 pg/mL and overall mean area under the curve (AUC0-inf) was 1036 pg-h/mL following SC administration of a 10 mcg dose of Byetta. Exenatide exposure (AUC) increased proportionally over the therapeutic dose range of 5 mcg to 10 mcg. The Cmax values increased less than proportionally over the same range. Similar exposure is achieved with SC administration of Byetta in the abdomen, thigh, or arm.

Distribution

The mean apparent volume of distribution of exenatide following SC administration of a single dose of Byetta is 28.3 L.

Metabolism and Elimination

Nonclinical studies have shown that exenatide is predominantly eliminated by glomerular filtration with subsequent proteolytic degradation. The mean apparent clearance of exenatide in humans is 9.1 L/h and the mean terminal half-life is 2.4 h. These pharmacokinetic characteristics of exenatide are independent of the dose. In most individuals, exenatide concentrations are measurable for approximately 10 h post-dose.

Special Populations

Renal Insufficiency

In patients with mild to moderate renal impairment (creatinine clearance 30 to 80 mL/min), exenatide clearance was only mildly reduced; therefore, no dosage adjustment of Byetta is required in patients with mild to moderate renal impairment. However, in patients with end-stage renal disease receiving dialysis, mean exenatide clearance is reduced to 0.9 L/h compared with 9.1 L/h in healthy subjects (see PRECAUTIONS, General).

Hepatic Insufficiency

No pharmacokinetic study has been performed in patients with a diagnosis of acute or chronic hepatic insufficiency. Because exenatide is cleared primarily by the kidney, hepatic dysfunction is not expected to affect blood concentrations of exenatide (see Pharmacokinetics, Metabolism and Elimination).

Geriatric

Population pharmacokinetic analysis of patients (range from 22 to 73 years) suggests that age does not influence the pharmacokinetic properties of exenatide.

Pediatric

Exenatide has not been studied in pediatric patients.

Gender

Population pharmacokinetic analysis of male and female patients suggests that gender does not influence the distribution and elimination of exenatide.

Race

Population pharmacokinetic analysis of patients including Caucasian, Hispanic, and Black, suggests that race has no significant influence on the pharmacokinetics of exenatide.

Obesity

Population pharmacokinetic analysis of obese (BMI ≥30 kg/m2) and non-obese patients suggests that obesity has no significant effect on the pharmacokinetics of exenatide.

Drug Interactions

Digoxin

Coadministration of repeated doses of Byetta (10 mcg BID) decreased the C_max of oral digoxin (0.25 mg QD) by 17% and delayed the Tmax by approximately 2.5 h; however, the overall steady-state pharmacokinetic exposure (AUC) was not changed.

Lovastatin

Lovastatin AUC and Cmax were decreased approximately 40% and 28%, respectively, and Tmax was delayed about 4 h when Byetta (10 mcg BID) was administered concomitantly with a single dose of lovastatin (40 mg) compared with lovastatin administered alone. In the 30-week controlled clinical trials of Byetta, the use of Byetta in patients already receiving HMG CoA reductase inhibitors was not associated with consistent changes in lipid profiles compared to baseline.

Lisinopril

In patients with mild to moderate hypertension stabilized on lisinopril (5 to 20 mg/day), Byetta (10 mcg BID) did not alter steady-state Cmax or AUC of lisinopril. Lisinopril steady-state T_max was delayed by 2 h. There were no changes in 24-h mean systolic and diastolic blood pressure.

Acetaminophen

When 1000 mg acetaminophen elixir was given with 10 mcg Byetta (0 h) and 1 h, 2 h, and 4 h after Byetta injection, acetaminophen AUCs were decreased by 21%, 23%, 24%, and 14%, respectively; C_max was decreased by 37%, 56%, 54%, and 41%, respectively; T_max was increased from 0.6 h in the control period to 0.9 h, 4.2 h, 3.3 h, and 1.6 h, respectively. Acetaminophen AUC, C_max and Tmax were not significantly changed when acetaminophen was given 1 h before Byetta injection.

Warfarin

Coadministration of repeat doses of Byetta (5 mcg BID on days 1-2 and 10 mcg BID on days 3-9) in healthy volunteers, delayed warfarin (25 mg) Tmax by about 2 h. No clinically relevant effects on Cmax or AUC of S- and R-enantiomers of warfarin were observed. Byetta did not change the pharmacodynamic properties (as assessed by INR response) of warfarin.

Pharmacodynamics

Postprandial Glucose

In patients with type 2 diabetes, Byetta reduces the postprandial plasma glucose concentrations (Figure 2).

Figure 2: Mean (+SEM) Postprandial Plasma Glucose Concentrations on Day 1 of Byetta^a Treatment in Patients With Type 2 Diabetes Treated With Metformin, a Sulfonylurea, or Both (N = 54)

Fasting Glucose

In a single-dose crossover study in patients with type 2 diabetes and fasting hyperglycemia, an immediate insulin release followed injection of Byetta. Plasma glucose concentrations were significantly reduced with Byetta compared with placebo (Figure 3).

Figure 3: Mean (+SEM) Serum Insulin and Plasma Glucose Concentrations Following a One-Time Injection of Byetta^a or Placebo in Fasting Patients With Type 2 Diabetes (N = 12)

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Clinical Studies

Use with metformin and/or a sulfonylurea

Three 30-week, double-blind, placebo-controlled trials were conducted to evaluate the safety and efficacy of Byetta in patients with type 2 diabetes whose glycemic control was inadequate with metformin alone, a sulfonylurea alone, or metformin in combination with a sulfonylurea.

A total of 1446 patients were randomized in these three trials: 991 (68.5%) were Caucasian, 224 (15.5%) were Hispanic, and 174 (12.0%) were Black. Mean HbA1c values at baseline for the trials ranged from 8.2% to 8.7%. After a 4-week placebo lead-in period, patients were randomly assigned to receive Byetta 5 mcg BID, Byetta 10 mcg BID, or placebo BID before the morning and evening meals, in addition to their existing oral antidiabetic agent. All patients assigned to Byetta began a treatment initiation period with 5 mcg BID for 4 weeks. After 4 weeks, those patients either continued to receive Byetta 5 mcg BID or had their dose increased to 10 mcg BID. Patients assigned to placebo received placebo BID throughout the study.

The primary endpoint in each study was mean change from baseline HbA_1c at 30 weeks. Thirty-week study results are summarized in Table 1.

Table 1: Results of Thirty-Week Placebo-Controlled Trials of Byetta in Patients With Inadequate Glucose Control Despite the Use of Metformin, a Sulfonylurea, or Both

	Placebo BID	Byetta 5 mcg BID	Byetta 10 mcg* BID
*Byetta 5 mcg twice daily (BID) for 1 month followed by 10 mcg BID for 6 months before the morning and evening meals. †p ≤0.05, treatment vs. placebo cp ≤0.0001, treatment vs. placebo §Patients eligible for the analysis with baseline HbA1c>7%.
	In Combination With Metformin
Intent-to-Treat Population (N)	113	110	113
HbA1c (%), Mean
Baseline	8.2	8.3	8.2
Change at Week 30	+0.1	−0.4â€	−0.8c
Proportion Achieving HbA1c≤7% §	13.0%	31.6%â€	46.4%â€
Body Weight (kg), Mean
Baseline	99.9	100.0	100.9
Change at Week 30	−0.3	−1.6â€	−2.8c
	In Combination With a Sulfonylurea
Intent-to-Treat Population (N)	123	125	129
HbA1c (%), Mean
Baseline	8.7	8.5	8.6
Change at Week 30	+0.1	−0.5â€	−0.9c
Proportion Achieving HbA1c≤7% §	8.8%	32.6%â€	41.3%c
Body Weight (kg), Mean
Baseline	99.1	94.9	95.2
Change at Week 30	−0.6	−0.9	−1.6â€
	In Combination With Metformin and a Sulfonylurea
Intent-to-Treat Population (N)	247	245	241
HbA1c (%), Mean
Baseline	8.5	8.5	8.5
Change at Week 30	+0.2	−0.6c	−0.8c
Proportion Achieving HbA1c≤7% §	9.2%	27.4%c	33.5%c
Body Weight (kg), Mean
Baseline	99.1	96.9	98.4
Change at Week 30	−0.9	−1.6â€	−1.6â€

HbA_1c

The addition of Byetta to a regimen of metformin, a sulfonylurea, or both, resulted in statistically significant reductions from baseline HbA_1c at Week 30 compared with patients receiving placebo added to these agents in the three controlled trials (Table 1). In addition, a statistically significant dose-effect was observed between 5-mcg and 10-mcg Byetta groups for the change from baseline HbA_1c at Week 30 in the three studies.

Fasting and Postprandial Glucose

Long-term use of Byetta in combination with metformin, a sulfonylurea, or both, reduced both fasting and postprandial plasma glucose concentrations in a statistically significant, dose-dependent manner through Week 30. A statistically significant reduction from baseline in both mean fasting and postprandial glucose concentrations was observed at Week 30 in both Byetta groups compared with placebo in data combined from the three controlled trials. The change in fasting glucose concentration at Week 30 compared with baseline was −8 mg/dL for Byetta 5 mcg BID and −10 mg/dL for Byetta 10 mcg BID, compared with +12 mg/dL for placebo. The change in 2-h postprandial glucose concentration following administration of Byetta at Week 30 compared with baseline was −63 mg/dL for 5 mcg BID and −71 mg/dL for 10 mcg BID, compared with +11 mg/dL for placebo.

Proportion of Patients Achieving HbA_1c≤7%

Byetta in combination with metformin, a sulfonylurea, or both, resulted in a greater, statistically significant proportion of patients achieving an HbA1c≤7% at Week 30 compared with patients receiving placebo in combination with these agents (Table 1).

Body Weight

In the three controlled trials, a decrease from baseline body weight at Week 30 was associated with Byetta 10 mcg BID compared with placebo BID in patients with type 2 diabetes (Table 1).

One-Year Clinical Results

The cohort of 163 patients from the 30-week placebo-controlled trials who completed a total of 52 weeks of treatment with Byetta 10 mcg BID had HbA1c changes from baseline of −1.0% and −1.1% at 30 and 52 weeks of treatment, respectively, with accompanying changes from baseline in fasting plasma glucose of −14.0 mg/dL and −25.3 mg/dL, and body weight changes of −2.6 kg and −3.6 kg. This cohort had baseline values similar to those of the entire controlled-trial population.

Use with a thiazolidinedione

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In a randomized, double-blind, placebo-controlled trial of 16 weeks duration, Byetta (n=121) or placebo (n=112) was added to existing thiazolidinedione (pioglitazone or rosiglitazone) treatment, with or without metformin, in patients with type 2 diabetes with inadequate glycemic control. Randomization to Byetta or placebo was stratified based on whether the patients were receiving metformin. Patients assigned to placebo received placebo BID throughout the study. Byetta or placebo was injected subcutaneously before the morning and evening meals. Seventy-nine percent of patients were taking a thiazolidinedione and metformin and 21% were taking a thiazolidinedione alone. The majority of patients (84%) were Caucasian, 8% were Hispanic and 3% were Black. The mean baseline HbA1c values were similar for Byetta and placebo (7.9%). Byetta treatment was initiated at a dose of 5 mcg BID for 4 weeks then increased to 10 mcg BID for 12 more weeks.

Sixteen-week study results are summarized in Table 2. Compared to placebo, Byetta resulted in statistically significant reductions in HbA1c from baseline at Week 16. Treatment effects for HbA1c were similar in the two sub-groups defined by underlying treatment stratum (thiazolidinediones alone versus thiazolidinediones plus metformin). The change in fasting serum glucose concentration from baseline to Week 16 was statistically significant compared with placebo (−21 mg/dL for Byetta 10 mcg BID compared with +4 mg/dL for placebo).

Table 2: Results of 16-Week Placebo-Controlled Trial of Byetta in Patients With Inadequate Glucose Control Despite the Use of a Thiazolidinedione (TZD) or a Thiazolidinedione plus Metformin

Placebo BID	Byetta 10 mcg* BID
*Byetta 5 mcg twice daily (BID) for 1 month followed by 10 mcg BID for 3 months before the morning and evening meals. †p <0.0001, treatment vs. placebo cPatients eligible for the analysis with baseline HbA1c>7%.
	In Combination With a TZD or a TZD plus MET
Intent-to-Treat Population (N)	112	121
HbA1c (%), Mean
Baseline	7.9	7.9
Change at Week 16	+0.1	−0.8â€
Proportion Achieving HbA1c≤7%c	16.2%	62.3%â€
Body Weight (kg), Mean
Baseline	96.9	97.5
Change at Week 16	−0.2	−1.5â€

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Indications and Usage

Byetta is indicated as adjunctive therapy to improve glycemic control in patients with type 2 diabetes mellitus who are taking metformin, a sulfonylurea, a thiazolidinedione, a combination of metformin and a sulfonylurea, or a combination of metformin and a thiazolidinedione, but have not achieved adequate glycemic control.

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Contraindications

Byetta is contraindicated in patients with known hypersensitivity to exenatide or to any of the product components.

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Precautions

General

Byetta is not a substitute for insulin in insulin-requiring patients. Byetta should not be used in patients with type 1 diabetes or for the treatment of diabetic ketoacidosis.

Patients may develop anti-exenatide antibodies following treatment with Byetta, consistent with the potentially immunogenic properties of protein and peptide pharmaceuticals. Patients receiving Byetta should be observed for signs and symptoms of hypersensitivity reactions.

In a small proportion of patients, the formation of anti-exenatide antibodies at high titers could result in failure to achieve adequate improvement in glycemic control. If there is worsening glycemic control or failure to achieve targeted glycemic control, alternative antidiabetic therapy should be considered.

The concurrent use of Byetta with insulin, D-phenylalanine derivatives, meglitinides, or alpha-glucosidase inhibitors has not been studied.

Byetta is not recommended for use in patients with end-stage renal disease or severe renal impairment (creatinine clearance Pharmacokinetics, Special Populations). In patients with end-stage renal disease receiving dialysis, single doses of Byetta 5 mcg were not well tolerated due to gastrointestinal side effects.

There have been rare, spontaneously reported events of altered renal function, including increased serum creatinine, renal impairment, worsened chronic renal failure and acute renal failure, sometimes requiring hemodialysis. Some of these events occurred in patients receiving one or more pharmacologic agents known to affect renal function/hydration status and/or in patients experiencing nausea, vomiting, and/or diarrhea, with or without dehydration. Concomitant agents included angiotensin converting enzyme inhibitors, nonsteroidal anti-inflammatory drugs, and diuretics. Reversibility of altered renal function has been observed with supportive treatment and discontinuation of potentially causative agents, including exenatide. Exenatide has not been found to be directly nephrotoxic in preclinical or clinical studies.

Byetta has not been studied in patients with severe gastrointestinal disease, including gastroparesis. Its use is commonly associated with gastrointestinal adverse effects, including nausea, vomiting, and diarrhea. Therefore, the use of Byetta is not recommended in patients with severe gastrointestinal disease. The development of severe abdominal pain in a patient treated with Byetta should be investigated because it may be a warning sign of a serious condition.

Hypoglycemia

In the 30-week controlled clinical trials with Byetta, a hypoglycemia episode was recorded as an adverse event if the patient reported symptoms associated with hypoglycemia with an accompanying blood glucose DOSAGE AND ADMINISTRATION).

Table 3: Incidence (%) of Hypoglycemia* by Concomitant Antidiabetic Therapy

		Byetta			Byetta			Byetta
	Placebo BID	5 mcg BID	10 mcg BID	Placebo BID	5 mcg BID	10 mcg BID	Placebo BID	5 mcg BID	10 mcg BID
	With Metformin			With a Sulfonylurea			With MET/SFU
Byetta and placebo were administered before the morning and evening meals.
Abbreviations: BID, twice daily; MET/SFU, metformin and a sulfonylurea.
*In three 30-week placebo-controlled clinical trials.
N	113	110	113	123	125	129	247	245	241
Hypoglycemia	5.3%	4.5%	5.3%	3.3%	14.4%	35.7%	12.6%	19.2%	27.8%

 

When used as add-on to a thiazolidinedione, with or without metformin, the incidence of symptomatic mild to moderate hypoglycemia with Byetta was 11% compared to 7% with placebo.

Byetta did not alter the counter-regulatory hormone responses to insulin-induced hypoglycemia in a randomized, double-blind, controlled study in healthy subjects.

Information for Patients

Patients should be informed of the potential risks of Byetta. Patients should also be fully informed about self-management practices, including the importance of proper storage of Byetta, injection technique, timing of dosage of Byetta as well as concomitant oral drugs, adherence to meal planning, regular physical activity, periodic blood glucose monitoring and HbA1c testing, recognition and management of hypoglycemia and hyperglycemia, and assessment for diabetes complications.

Patients should be advised to inform their physicians if they are pregnant or intend to become pregnant.

Each dose of Byetta should be administered as a SC injection in the thigh, abdomen, or upper arm at any time within the 60-minute period before the morning and evening meals (or before the two main meals of the day, approximately 6 hours or more apart). Byetta should not be administered after a meal. If a dose is missed, the treatment regimen should be resumed as prescribed with the next scheduled dose.

The risk of hypoglycemia is increased when Byetta is used in combination with an agent that induces hypoglycemia, such as a sulfonylurea. The symptoms, treatment, and conditions that predispose development of hypoglycemia should be explained to the patient. While the patient's usual instructions for hypoglycemia management do not need to be changed, these instructions should be reviewed and reinforced when initiating Byetta therapy, particularly when concomitantly administered with a sulfonylurea (see PRECAUTIONS, Hypoglycemia).

Patients should be advised that treatment with Byetta may result in a reduction in appetite, food intake, and/or body weight, and that there is no need to modify the dosing regimen due to such effects. Treatment with Byetta may also result in nausea, particularly upon initiation of therapy (see ADVERSE REACTIONS).

The patient should read the "Information for the Patient" insert and the Pen User Manual before starting Byetta therapy and review them each time the prescription is refilled. The patient should be instructed on proper use and storage of the pen, emphasizing how and when to set up a new pen and noting that only one setup step is necessary at initial use. The patient should be advised not to share the pen and needles.

Patients should be informed that pen needles are not included with the pen and must be purchased separately. Patients should be advised which needle length and gauge should be used.

Drug Interactions

The effect of Byetta to slow gastric emptying may reduce the extent and rate of absorption of orally administered drugs. Byetta should be used with caution in patients receiving oral medications that require rapid gastrointestinal absorption. For oral medications that are dependent on threshold concentrations for efficacy, such as contraceptives and antibiotics, patients should be advised to take those drugs at least 1 h before Byetta injection. If such drugs are to be administered with food, patients should be advised to take them with a meal or snack when Byetta is not administered. The effect of Byetta on the absorption and effectiveness of oral contraceptives has not been characterized.

Warfarin

In a controlled clinical pharmacology study in healthy volunteers, a delay in warfarin Tmax of about 2 h was observed when warfarin was administered 30 min after Byetta. No clinically relevant effects on Cmax or AUC were observed. However, since market introduction there have been some spontaneously reported cases of increased INR (International Normalized Ratio) with concomitant use of warfarin and Byetta, sometimes associated with bleeding.

Carcinogenesis, Mutagenesis, Impairment of Fertility

A 104-week carcinogenicity study was conducted in male and female rats at doses of 18, 70, or 250 mcg/kg/day administered by bolus SC injection. Benign thyroid C-cell adenomas were observed in female rats at all exenatide doses. The incidences in female rats were 8% and 5% in the two control groups and 14%, 11%, and 23% in the low-, medium-, and high-dose groups with systemic exposures of 5, 22, and 130 times, respectively, the human exposure resulting from the maximum recommended dose of 20 mcg/day, based on plasma area under the curve (AUC).

In a 104-week carcinogenicity study in mice at doses of 18, 70, or 250 mcg/kg/day administered by bolus SC injection, no evidence of tumors was observed at doses up to 250 mcg/kg/day, a systemic exposure up to 95 times the human exposure resulting from the maximum recommended dose of 20 mcg/day, based on AUC.

Exenatide was not mutagenic or clastogenic, with or without metabolic activation, in the Ames bacterial mutagenicity assay or chromosomal aberration assay in Chinese hamster ovary cells. Exenatide was negative in the in vivo mouse micronucleus assay.

In mouse fertility studies with SC doses of 6, 68 or 760 mcg/kg/day, males were treated for 4 weeks prior to and throughout mating and females were treated 2 weeks prior to and throughout mating until gestation day 7. No adverse effect on fertility was observed at 760 mcg/kg/day, a systemic exposure 390 times the human exposure resulting from the maximum recommended dose of 20 mcg/day, based on AUC.

Pregnancy

Pregnancy Category C

Exenatide has been shown to cause reduced fetal and neonatal growth, and skeletal effects in mice at systemic exposures 3 times the human exposure resulting from the maximum recommended dose of 20 mcg/day, based on AUC. Exenatide has been shown to cause skeletal effects in rabbits at systemic exposures 12 times the human exposure resulting from the maximum recommended dose of 20 mcg/day, based on AUC. There are no adequate and well-controlled studies in pregnant women. Byetta should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

In female mice given SC doses of 6, 68, or 760 mcg/kg/day beginning 2 weeks prior to and throughout mating until gestation day 7, there were no adverse fetal effects at doses up to 760 mcg/kg/day, systemic exposures up to 390 times the human exposure resulting from the maximum recommended dose of 20 mcg/day, based on AUC.

In pregnant mice given SC doses of 6, 68, 460, or 760 mcg/kg/day from gestation day 6 through 15 (organogenesis), cleft palate (some with holes) and irregular skeletal ossification of rib and skull bones were observed at 6 mcg/kg/day, a systemic exposure 3 times the human exposure resulting from the maximum recommended dose of 20 mcg/kg/day, based on AUC.

In pregnant rabbits given SC doses of 0.2, 2, 22, 156, or 260 mcg/kg/day from gestation day 6 through 18 (organogenesis), irregular skeletal ossifications were observed at 2 mcg/kg/day, a systemic exposure 12 times the human exposure resulting from the maximum recommended dose of 20 mcg/day, based on AUC.

In pregnant mice given SC doses of 6, 68, or 760 mcg/kg/day from gestation day 6 through lactation day 20 (weaning), an increased number of neonatal deaths were observed on postpartum days 2-4 in dams given 6 mcg/kg/day, a systemic exposure 3 times the human exposure resulting from the maximum recommended dose of 20 mcg/day, based on AUC.

Nursing Mothers

It is not known whether exenatide is excreted in human milk. Many drugs are excreted in human milk and because of the potential for clinically significant adverse reactions in nursing infants from exenatide, a decision should be made whether to discontinue producing milk for consumption or discontinue the drug, taking into account the importance of the drug to the lactating woman. Studies in lactating mice have demonstrated that exenatide is present at low concentrations in milk (less than or equal to 2.5% of the concentration in maternal plasma following subcutaneous dosing). Caution should be exercised when Byetta is administered to a nursing woman.

Pediatric Use

Safety and effectiveness of Byetta have not been established in pediatric patients.

Geriatric Use

Byetta was studied in 282 patients 65 years of age or older and in 16 patients 75 years of age or older. No differences in safety or effectiveness were observed between these patients and younger patients.

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Adverse Reactions

Use with metformin and/or a sulfonylurea

In the three 30-week controlled trials of Byetta add-on to metformin and/or sulfonylurea, adverse events with an incidence ≥5% (excluding hypoglycemia; see Table 3) that occurred more frequently in Byetta-treated patients compared with placebo-treated patients are summarized in Table 4.

Table 4: Frequent Treatment-Emergent Adverse Events (≥5% Incidence and Greater Incidence With Byetta Treatment) Excluding Hypoglycemia*

Placebo BID N = 483 %	All Byetta BID N = 963 %
*In three 30-week placebo-controlled clinical trials.
Nausea	18	44
Vomiting	4	13
Diarrhea	6	13
Feeling Jittery	4	9
Dizziness	6	9
Headache	6	9
Dyspepsia	3	6

 

The adverse events associated with Byetta generally were mild to moderate in intensity. The most frequently reported adverse event, mild to moderate nausea, occurred in a dose-dependent fashion. With continued therapy, the frequency and severity decreased over time in most of the patients who initially experienced nausea. Adverse events reported in ≥1.0 to <5.0% of patients receiving Byetta and reported more frequently than with placebo included asthenia (mostly reported as weakness), decreased appetite, gastroesophageal reflux disease, and hyperhidrosis. Patients in the extension studies at 52 weeks experienced similar types of adverse events observed in the 30-week controlled trials.

The incidence of withdrawal due to adverse events was 7% for Byetta-treated patients and 3% for placebo-treated patients. The most common adverse events leading to withdrawal for Byetta-treated patients were nausea (3% of patients) and vomiting (1%). For placebo-treated patients, <1% withdrew due to nausea and 0% due to vomiting.

Use with a thiazolidinedione

In the 16-week placebo-controlled study of Byetta add-on to a thiazolidinedione, with or without metformin, the incidence and type of other adverse events observed were similar to those seen in the 30-week controlled clinical trials with metformin and/or a sulfonylurea. No serious adverse events were reported in the placebo arm. Two serious adverse events, namely chest pain (leading to withdrawal) and chronic hypersensitivity pneumonitis, were reported in the Byetta arm.

The incidence of withdrawal due to adverse events was 16% (19/121) for Byetta-treated patients and 2% (2/112) for placebo-treated patients. The most common adverse events leading to withdrawal for Byetta-treated patients were nausea (9%) and vomiting (5%). For placebo-treated patients, <1% withdrew due to nausea. Chills (n=4) and injection-site reactions (n=2) occurred only in Byetta-treated patients. The two patients who reported an injection-site reaction had high titers of anti-exenatide antibody.

Spontaneous Data

Since market introduction of Byetta, the following additional adverse reactions have been reported. Because these events are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

General: injection-site reactions; dysgeusia; somnolence, INR increased with concomitant warfarin use (some reports associated with bleeding).

Allergy/Hypersensitivity: generalized pruritus and/or urticaria, macular or papular rash, angioedema; rare reports of anaphylactic reaction.

Gastrointestinal: nausea, vomiting, and/or diarrhea resulting in dehydration; abdominal distension, abdominal pain, eructation, constipation, flatulence, acute pancreatitis.

Renal and Urinary Disorders: altered renal function, including acute renal failure, worsened chronic renal failure, renal impairment, increased serum creatinine (see PRECAUTIONS).

Immunogenicity

Consistent with the potentially immunogenic properties of protein and peptide pharmaceuticals, patients may develop anti-exenatide antibodies following treatment with Byetta. In most patients who develop antibodies, antibody titers diminish over time.

In the 30-week controlled trials of Byetta add-on to metformin and/or sulfonylurea, 38% of patients had low titer anti-exenatide antibodies at 30 weeks. For this group, the level of glycemic control (HbA1c) was generally comparable to that observed in those without antibody titers. An additional 6% of patients had higher titer antibodies at 30 weeks. In about half of this 6% (3% of the total patients given Byetta in the 30-week controlled studies), the glycemic response to Byetta was attenuated; the remainder had a glycemic response comparable to that of patients without antibodies.

In the 16-week trial of Byetta add-on to thiazolidinediones, with or without metformin, 9% of patients had higher titer antibodies at 16 weeks. Compared with patients who did not develop antibodies to Byetta, on average the glycemic response in patients with higher titer antibodies was attenuated.

The patient's glycemic response to Byetta should be monitored. If there is worsening glycemic control or failure to achieve targeted glycemic control, alternative antidiabetic therapy should be considered.

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Overdosage

In a clinical study of Byetta, three patients with type 2 diabetes each experienced a single overdose of 100 mcg SC (10 times the maximum recommended dose). Effects of the overdoses included severe nausea, severe vomiting, and rapidly declining blood glucose concentrations. One of the three patients experienced severe hypoglycemia requiring parenteral glucose administration. The three patients recovered without complication. In the event of overdose, appropriate supportive treatment should be initiated according to the patient's clinical signs and symptoms.

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Dosage and Administration

Byetta therapy should be initiated at 5 mcg per dose administered twice daily at any time within the 60-minute period before the morning and evening meals (or before the two main meals of the day, approximately 6 hours or more apart). Byetta should not be administered after a meal. Based on clinical response, the dose of Byetta can be increased to 10 mcg twice daily after 1 month of therapy. Each dose should be administered as a SC injection in the thigh, abdomen, or upper arm.

Byetta is recommended for use in patients with type 2 diabetes mellitus who are already receiving metformin, a sulfonylurea, a thiazolidinedione, a combination of metformin and a sulfonylurea, or a combination of metformin and a thiazolidinedione, and have suboptimal glycemic control. When Byetta is added to metformin or thiazolidinedione therapy, the current dose of metformin or thiazolidinedione can be continued as it is unlikely that the dose of metformin or thiazolidinedione will require adjustment due to hypoglycemia when used with Byetta. When Byetta is added to sulfonylurea therapy, a reduction in the dose of sulfonylurea may be considered to reduce the risk of hypoglycemia (see PRECAUTIONS, Hypoglycemia).

Byetta is a clear and colorless liquid and should not be used if particles appear or if the solution is cloudy or colored. Byetta should not be used past the expiration date. No data are available on the safety or efficacy of intravenous or intramuscular injection of Byetta.

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Storage

Prior to first use, Byetta must be stored refrigerated at 36°F to 46°F (2°C to 8°C). After first use, Byetta can be kept at a temperature not to exceed 77°F (25°C). Do not freeze. Do not use Byetta if it has been frozen. Byetta should be protected from light. The pen should be discarded 30 days after first use, even if some drug remains in the pen.

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How is Supplied

Byetta is supplied as a sterile solution for subcutaneous injection containing 250 mcg/mL exenatide. The following packages are available:

5 mcg per dose, 60 doses, 1.2 mL prefilled pen NDC 66780-210-07

10 mcg per dose, 60 doses, 2.4 mL prefilled pen NDC 66780-210-08

Rx ONLY

Manufactured for Amylin Pharmaceuticals, Inc., San Diego, CA 92121

Marketed by Amylin Pharmaceuticals, Inc. and Eli Lilly and Company
1-800-868-1190
http://www.Byetta.com

Byetta is a registered trademark of Amylin Pharmaceuticals, Inc.
© 2007 Amylin Pharmaceuticals, Inc. All rights reserved.

last updated 09/2007

Byetta (Exenatide) Patient Information (in plain English)

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

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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.

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