Drug Name

Avandia (Rosiglitazone)

Generic Name

Rosiglitazone (ROE-zi-GLI-ta-zone)

Manufacturer / Distributor

GlaxoSmithKline

Looks like

Rosiglitazone is available with a prescription under the brand name Avandia. Other brand or generic formulations may also be available. Ask your pharmacist any questions you have about Avandia, especially if it is new to you.

• Avandia 2 mg - pink, five-sided, film-coated tablets
• Avandia 4 mg - orange, five-sided, film-coated tablets
• Avandia 8 mg - red-brown, five-sided, film-coated tablets

Dosage Form

Tablets

Route Of Administration

ORAL

Imprint Code

SB;2 / SB;4 / SB;8

Size

10mm / 10mm / 12mm

Alternatives

Type 2 Diabetes
Januvia, Glucophage, Glyburide, Actos, Glipizide

Drug Uses

Avandia is an anti-diabetic drug (thiazolidinedione-type, also called "glitazones") used with a proper diet and exercise program to control high blood sugar in patients with type 2 diabetes (non-insulin-dependent diabetes).
Avandia works by helping to restore your body's proper response to insulin, thereby lowering your blood sugar. Effectively controlling high blood sugar helps prevent heart disease, strokes, kidney disease, blindness, and circulation problems, as well as sexual function problems (impotence).
Avandia is used either alone or in combination with other anti-diabetic medications (e.g., metformin, sulfonylureas, insulin).

Drug class

Avandia is an oral drug that reduces the amount of sugar (glucose) in the blood. It is used for treating patients with type 2 diabetes and is in a class of anti-diabetic drugs called thiazolidinediones. The other member of this class is pioglitazone (Actos). Insulin is a hormone produced by the pancreas that is important for controlling the levels of glucose in the blood. Insulin stimulates the cells of the body to remove glucose from the blood and thereby lowers the level of glucose in the blood. Patients with type II diabetes cannot make enough insulin. As a result, the cells in their bodies do not remove enough glucose from the blood, and the level of glucose rises.
Avandia often is referred to as an "insulin sensitizer" because it attaches to the insulin receptors on cells throughout the body and causes the cells to become more sensitive (more responsive) to insulin and remove more glucose from the blood. At least some insulin must be produced by the pancreas in order for Avandia to work).

Contains

Each pentagonal film-coated TILTAB tablet contains rosiglitazone maleate equivalent to rosiglitazone, 2 mg, 4 mg, or 8 mg, for oral administration.
Inactive ingredients are:

• Hypromellose 2910,
• lactose monohydrate,
• magnesium stearate,
• microcrystalline cellulose,
• polyethylene glycol 3000,
• sodium starch glycolate,
• titanium dioxide,
• triacetin,
• and 1 or more of the following: Synthetic red and yellow iron oxides and talc.

Chemical formula

Chemically, rosiglitazone maleate is (±)-5-[[4-[2-(methyl-2-pyridinylamino)ethoxy]phenyl]methyl]-2,4-thiazolidinedione, (Z)-2-butenedioate (1:1) with a molecular weight of 473.52 (357.44 free base). The molecule has a single chiral center and is present as a racemate. Due to rapid interconversion, the enantiomers are functionally indistinguishable. The structural formula of rosiglitazone maleate is:

The molecular formula is C18H19N3O3S*C4H4O4. Rosiglitazone maleate is a white to off-white solid with a melting point range of 122 to 123C. The pKa values of rosiglitazone maleate are 6.8 and 6.1. It is readily soluble in ethanol and a buffered aqueous solution with pH of 2.3; solubility decreases with increasing pH in the physiological range.

Mechanism of Action

Rosiglitazone, a member of the thiazolidinedione class of antidiabetic agents, improves glycemic control by improving insulin sensitivity. Rosiglitazone is a highly selective and potent agonist for the peroxisome proliferator-activated receptor-gamma (PPAR?). In humans, PPAR receptors are found in key target tissues for insulin action such as adipose tissue, skeletal muscle, and liver. Activation of PPAR? nuclear receptors regulates the transcription of insulin-responsive genes involved in the control of glucose production, transport, and utilization. In addition, PPAR?-responsive genes also participate in the regulation of fatty acid metabolism.
Insulin resistance is a common feature characterizing the pathogenesis of type 2 diabetes. The antidiabetic activity of rosiglitazone has been demonstrated in animal models of type 2 diabetes in which hyperglycemia and/or impaired glucose tolerance is a consequence of insulin resistance in target tissues. Rosiglitazone reduces blood glucose concentrations and reduces hyperinsulinemia in the ob/ob obese mouse, db/db diabetic mouse, and fa/fa fatty Zucker rat.
In animal models, rosiglitazone's antidiabetic activity was shown to be mediated by increased sensitivity to insulin's action in the liver, muscle, and adipose tissues. The expression of the insulin-regulated glucose transporter GLUT-4 was increased in adipose tissue. Rosiglitazone did not induce hypoglycemia in animal models of type 2 diabetes and/or impaired glucose tolerance.

How Taken

Take rosiglitazone exactly as directed by your doctor. If you do not understand these instructions, ask your pharmacist, nurse, or doctor to explain them to you.
Take each dose with a full glass of water.
Rosiglitazone can be taken with or without food or meals.
It is important to take rosiglitazone regularly to get the most benefit.
Your doctor may want you to have blood or urine tests or other medical evaluations during treatment with rosiglitazone to monitor blood sugar levels, liver function, or other factors.
Usually, liver function is monitored with blood tests at the start of treatment, every two months for the first year of treatment, and periodically thereafter during treatment with rosiglitazone. Notify your doctor immediately if you develop nausea, vomiting, abdominal pain, unusual fatigue, loss of appetite, yellow skin or eyes, or dark urine. These symptoms may be early signs of liver problems.
Although rosiglitazone does not usually cause hypoglycemia (low blood sugar), hypoglycemia may result from skipped meals, excessive exercise, or alcohol consumption. Know the signs and symptoms of hypoglycemia, which include headache, drowsiness, weakness, dizziness, fast heartbeat, sweating, tremor, and nausea. Carry a piece of non-dietetic hard candy or glucose tablets with you to treat episodes of low blood sugar.

Dosage and Administration

The management of antidiabetic therapy should be individualized. All patients should start Avandia at the lowest recommended dose. Further increases in the dose of Avandia should be accompanied by careful monitoring for adverse events related to fluid retention.
Avandia may be administered either at a starting dose of 4 mg as a single daily dose or divided and administered in the morning and evening. For patients who respond inadequately following 8 to 12 weeks of treatment, as determined by reduction in FPG, the dose may be increased to 8 mg daily as monotherapy or in combination with metformin, sulfonylurea, or sulfonylurea plus metformin. Reductions in glycemic parameters by dose and regimen are described under CLINICAL STUDIES. Avandia may be taken with or without food.

Monotherapy
The usual starting dose of Avandia is 4 mg administered either as a single dose once daily or in divided doses twice daily. In clinical trials, the 4 mg twice daily regimen resulted in the greatest reduction in FPG and HbA1c.

Combination Therapy
When Avandia is added to existing therapy, the current dose(s) of the agent(s) can be continued upon initiation of Avandia therapy.

Sulfonylurea
When used in combination with sulfonylurea, the usual starting dose of Avandia is 4 mg administered as either a single dose once daily or in divided doses twice daily. If patients report hypoglycemia, the dose of the sulfonylurea should be decreased.

Metformin
The usual starting dose of Avandia in combination with metformin is 4 mg administered as either a single dose once daily or in divided doses twice daily. It is unlikely that the dose of metformin will require adjustment due to hypoglycemia during combination therapy with Avandia.

Insulin
For patients stabilized on insulin, the insulin dose should be continued upon initiation of therapy with Avandia. Avandia should be dosed at 4 mg daily. Doses of Avandia greater than 4 mg daily in combination with insulin are not currently indicated. It is recommended that the insulin dose be decreased by 10% to 25% if the patient reports hypoglycemia or if FPG concentrations decrease to less than 100 mg/dL. Further adjustments should be individualized based on glucose-lowering response.

Sulfonylurea Plus Metformin
The usual starting dose of Avandia in combination with a sulfonylurea plus metformin is 4 mg administered as either a single dose once daily or divided doses twice daily. If patients report hypoglycemia, the dose of the sulfonylurea should be decreased.

Usual Starting Dose

The usual starting dose of Avandia either alone or in combination with insulin or another diabetes drug is 4 milligrams once a day or 2 milligrams twice a day. If your sugar levels remain too high after 12 weeks of treatment, the doctor may increase your dose to 8 milligrams once a day or 4 milligrams twice a day.

Usual Maintenance Dose

The dose of Avandia should not exceed 8 mg daily, as a single dose or divided twice daily. The 8 mg daily dose has been shown to be safe and effective in clinical studies as monotherapy and in combination with metformin, sulfonylurea, or sulfonylurea plus metformin. Doses of Avandia greater than 4 mg daily in combination with insulin are not currently indicated.

Missed Dose

Take the missed dose as soon as you remember. If you do not remember until the next day, skip the dose you missed and take only your next regularly scheduled dose.
Do not take a double dose.

Overdose

Limited data are available with regard to overdosage in humans. In clinical studies in volunteers, Avandia has been administered at single oral doses of up to 20 mg and was well-tolerated. In the event of an overdose, appropriate supportive treatment should be initiated as dictated by the patient's clinical status.
Seek emergency medical attention if you think you have used too much of this medicine. Contact 1-800-222-1222 (the American Association of Poison Control Centers), your local poison control center ( http://www.aapcc.org/findyour.htm ), or emergency room immediately.

Storage

Store Avandia at 77 degrees F (25 degrees C). Brief storage at temperatures between 59 and 86 degrees F (15 and 30 degrees C) is permitted. Do not store Avandia in the bathroom. Store away from heat, moisture, and light. Keep Avandia out of the reach of children and away from pets.

How Supplied

Each pentagonal film-coated TILTAB tablet contains rosiglitazone as the maleate as follows: 2 mg?pink, debossed with SB on one side and 2 on the other; 4 mg?orange, debossed with SB on one side and 4 on the other; 8 mg?red-brown, debossed with SB on one side and 8 on the other.

2 mg bottles of 60 - NDC 0029-3158-18

4 mg bottles of 30 - NDC 0029-3159-13

4 mg bottles of 90 - NDC 0029-3159-00

8 mg bottles of 30 - NDC 0029-3160-13

8 mg bottles of 90 - NDC 0029-3160-59

What is the most important information I should know about Avandia (Rosiglitazone)?

Thiazolidinediones, including rosiglitazone, cause or exacerbate congestive heart failure in some patients. After initiation of Avandia, and after dose increases, 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 current standards of care. Furthermore, discontinuation or dose reduction of Avandia must be considered.
Avandia is not recommended in patients with symptomatic heart failure. Initiation of Avandia in patients with established NYHA Class III or IV heart failure is contraindicated.
Usually, liver function is monitored with blood tests at the start of treatment, every two months for the first year of treatment, and periodically thereafter during treatment with rosiglitazone. Notify your doctor immediately if you develop nausea, vomiting, abdominal pain, unusual fatigue, loss of appetite, yellow skin or eyes, or dark urine. These symptoms may be early signs of liver problems.
Notify your doctor immediately if you experience an unusually rapid increase in weight or edema (water retention), shortness of breath, or chest pain during treatment with rosiglitazone. These may be early symptoms of heart problems.
Rosiglitazone usually does not cause hypoglycemia (low blood sugar). However, hypoglycemia may occur as a result of skipped meals, excessive exercise, or alcohol consumption while taking rosiglitazone. Know the signs and symptoms of hypoglycemia, which include:

• headache,
• drowsiness,
• weakness,
• dizziness,
• fast heartbeat,
• sweating,
• tremor, and nausea.

Carry non-dietetic hard candy or glucose tablets with you to treat episodes of low blood sugar.
Always remember that Avandia is an aid to, not a substitute for, good diet, weight loss, 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 Avandia is not an oral form of insulin, and cannot be used in place of insulin.

What should I discuss with my doctor before taking Avandia (Rosiglitazone)?

Do not take rosiglitazone without first talking to your doctor if you have liver disease.
Before taking this medication, tell your doctor if you

• have heart failure or heart disease;
• have edema (water retention or swelling);
• have type 1 diabetes mellitus;
• have a serious infection, illness, or injury; or
• need surgery.

You may not be able to take rosiglitazone, or you may need a dosage adjustment or special monitoring during treatment if you have any of the conditions listed above.
Treatment with rosiglitazone may cause resumption of fertility by allowing for the return of ovulation (production of eggs) in certain women with insulin resistance who were not ovulating before treatment with rosiglitazone. Talk to your doctor about adequate forms of birth control while taking rosiglitazone if birth control is desired.
Contact your doctor if you develop a fever or an infection, require surgery, or if you experience a serious injury. Illness or injury may cause a loss of blood sugar control and insulin (or an adjustment of a current insulin dose) may be required for a period of time.
Rosiglitazone is in the FDA pregnancy category C. This means that it is not known whether rosiglitazone will harm an unborn baby. Generally, insulin is the drug of choice for controlling diabetes during pregnancy. Do not take rosiglitazone without first talking to your doctor if you are pregnant or could become pregnant during treatment.
It is not known whether rosiglitazone passes into breast milk. Do not take rosiglitazone without first talking to your doctor if you are breast-feeding a baby.
The safety and effectiveness of rosiglitazone have not been established for children.

Absorption

The absolute bioavailability of rosiglitazone is 99%. Peak plasma concentrations are observed about 1 hour after dosing. Administration of rosiglitazone with food resulted in no change in overall exposure (AUC), but there was an approximately 28% decrease in Cmax and a delay in Tmax (1.75 hours). These changes are not likely to be clinically significant; therefore, Avandia may be administered with or without food.

Distribution

The mean (CV%) oral volume of distribution (Vss/F) of rosiglitazone is approximately 17.6 (30%) liters, based on a population pharmacokinetic analysis. Rosiglitazone is approximately 99.8% bound to plasma proteins, primarily albumin.

Metabolism

Rosiglitazone is extensively metabolized with no unchanged drug excreted in the urine. The major routes of metabolism were N-demethylation and hydroxylation, followed by conjugation with sulfate and glucuronic acid. All the circulating metabolites are considerably less potent than parent and, therefore, are not expected to contribute to the insulin-sensitizing activity of rosiglitazone.
In vitro data demonstrate that rosiglitazone is predominantly metabolized by Cytochrome P450 (CYP) isoenzyme 2C8, with CYP2C9 contributing as a minor pathway.

Excretion

Following oral or intravenous administration of [14C]rosiglitazone maleate, approximately 64% and 23% of the dose was eliminated in the urine and in the feces, respectively. The plasma half-life of [14C]related material ranged from 103 to 158 hours.

Special Populations

Geriatric

Results of the population pharmacokinetic analysis (n = 716 <65 years; n = 331 ?65 years) showed that age does not significantly affect the pharmacokinetics of rosiglitazone.

Pediatric

Pharmacokinetic parameters of rosiglitazone in pediatric patients were established using a population pharmacokinetic analysis with sparse data from 96 pediatric patients in a single pediatric clinical trial including 33 males and 63 females with ages ranging from 10 to 17 years (weights ranging from 35 to 178.3 kg). Population mean CL/F and V/F of rosiglitazone were 3.15 L/hr and 13.5 L, respectively. These estimates of CL/F and V/F were consistent with the typical parameter estimates from a prior adult population analysis.

Gender

Results of the population pharmacokinetics analysis showed that the mean oral clearance of rosiglitazone in female patients (n = 405) was approximately 6% lower compared to male patients of the same body weight (n = 642).
As monotherapy and in combination with metformin, Avandia improvedglycemic control in both males and females. In metformin combination studies, efficacy was demonstrated with no gender differences in glycemic response.
In monotherapy studies, a greater therapeutic response was observed in females; however, in more obese patients, gender differences were less evident. For a given body mass index (BMI), females tend to have a greater fat mass than males. Since the molecular target PPAR? is expressed in adipose tissues, this differentiating characteristic may account, at least in part, for the greater response to Avandia in females. Since therapy should be individualized, no dose adjustments are necessary based on gender alone.

Race

Results of a population pharmacokinetic analysis including subjects of Caucasian, black, and other ethnic origins indicate that race has no influence on the pharmacokinetics of rosiglitazone.

Renal Insufficiency

There are no clinically relevant differences in the pharmacokinetics of rosiglitazone in patients with mild to severe renal impairment or in hemodialysis-dependent patients compared to subjects with normal renal function. No dosage adjustment is therefore required in such patients receiving Avandia. Since metformin is contraindicated in patients with renal impairment, coadministration of metformin with Avandia is contraindicated in these patients.

Hepatic Impairment

Unbound oral clearance of rosiglitazone was significantly lower in patients with moderate to severe liver disease (Child-Pugh Class B/C) compared to healthy subjects. As a result, unbound Cmax and AUC0-inf were increased 2- and 3-fold, respectively. Elimination half-life for rosiglitazone was about 2 hours longer in patients with liver disease, compared to healthy subjects.
Therapy with Avandia should not be initiated if the patient exhibits clinical evidence of active liver disease or increased serum transaminase levels (ALT >2.5X upper limit of normal) at baseline.

Possible side effects

Heart failure. Avandia can cause your body to keep extra fluid (fluid retention), which leads to swelling and weight gain. Extra body fluid can make some heart problems worse or leadto heart failure.

Swelling (edema) from fluid retention. Call your doctor right away if you have symptoms such as:

• swelling or fluid retention, especially in the ankles or legs
• shortness of breath or trouble breathing, especially when you lie down
• an unusually fast increase in weight
• unusual tiredness

Low blood sugar (hypoglycemia). Lightheadedness, dizziness, shakiness or hunger may mean that your blood sugar is too low. This can happen if you skip meals, if you use another medicine that lowers blood sugar, or if you have certain medical problems. Call your doctor if low blood sugar levels are a problem for you.

Fractures, usually in the hand, upper arm or foot, in females. Talk to your doctor for advice on how to keep your bones healthy.

Weight gain. Avandia can cause weight gain that may be due to fluid retention or extra body fat. Weight gain can be a serious problem for people with certain conditions including heart problems. Call your doctor if you have an unusually fast increase in weight.

Low red blood cell count (anemia).

Ovulation (release of egg from an ovary in a woman) leading to pregnancy. Ovulation may happen in premenopausal women who do not have regular monthly periods. This can increase the chance of pregnancy.

Liver problems. It is important for your liver to be working normally when you take Avandia. Your doctor should do blood tests to check your liver before you start taking Avandia and during treatment as needed.Call your doctor right away if you have unexplained symptoms such as:

• nausea or vomiting
• stomach pain
• unusual or unexplained tiredness
• loss of appetite
• dark urine
• yellowing of your skin or the whites of your eyes.

The most common side effects of Avandia included cold-like symptoms, injury, and headache.

What other drugs will affect Avandia (Rosiglitazone)?

You may be more likely to have hyperglycemia (high blood sugar) if you are taking Avandia with other drugs that raise blood sugar. Drugs that can raise blood sugar include:

• isoniazid;
• diuretics (water pills);
• steroids (prednisone and others);
• phenothiazines (Compazine and others);
• thyroid medicine (Synthroid and others);
• birth control pills and other hormones;
• seizure medicines (Dilantin and others); and
• diet pills or medicines to treat asthma, colds or allergies.

You may be more likely to have hypoglycemia (low blood sugar) if you are taking Avandia with other drugs that lower blood sugar. Drugs that can lower blood sugar include:

• nonsteroidal anti-inflammatory drugs (NSAIDs);
• aspirin or other salicylates (including Pepto-Bismol);
• sulfa drugs (Bactrim and others);
• a monoamine oxidase inhibitor (MAOI);
• beta-blockers (Tenormin and others); or
• probenecid (Benemid).

Some medications may interact with Avandia. Tell your doctor if you are using any of the following drugs:

• gemfibrozil (Gemcor); or
• rifampin (Rifater, Rifadin, Rimactane).

If you are using any of these drugs, you may not be able to take Avandia, or you may require a dosage adjustment or special monitoring.
There may be other drugs not listed that can affect Avandia. 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.

What should I avoid while taking Avandia (Rosiglitazone)?

Follow your diet, medication, and exercise routines very closely. Changing any of these factors can affect your blood sugar levels.
Avoid alcohol. It lowers blood sugar and may interfere with your diabetes treatment.
Tell your doctor and dentist that you are taking this medication before you undergo any surgery.
Do not take any over-the-counter cough, cold, allergy, pain, or weight-loss medications without first talking to your doctor.

Contraindications

Initiation of Avandia in patients with established New York Heart Association (NYHA) Class III or IV heart failure is contraindicated.
Avandia is contraindicated in patients with known hypersensitivity to this product or any of its components.

Warnings

Avandia, like other thiazolidinediones, alone or in combination with other antidiabetic agents, can cause fluid retention, which may exacerbate or lead to 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 rosiglitazone must be considered. In combination with insulin, thiazolidinediones may also increase the risk of other cardiovascular adverse events. Avandia should be discontinued if any deterioration in cardiac status occurs.
Patients with congestive heart failure (CHF) NYHA Class I and II treated with Avandia have an increased risk of cardiovascular events.
Patients treated with combination Avandia and insulin should be monitored for cardiovascular adverse events. This combination therapy should be discontinued in patients who do not respond as manifested by a reduction in HbA1c or insulin dose after 4 to 5 months of therapy or who develop any significant adverse events.

Precautions

Due to its mechanism of action, Avandia is active only in the presence of endogenous insulin. Therefore, Avandia should not be used in patients with type 1 diabetes or for the treatment of diabetic ketoacidosis.

Hypoglycemia
Patients receiving Avandia in combination with other hypoglycemic agents may be at risk for hypoglycemia, and a reduction in the dose of the concomitant agent may be necessary.

Edema
Avandia should be used with caution in patients with edema. In a clinical study in healthy volunteers who received 8 mg of Avandia once daily for 8 weeks, there was a statistically significant increase in median plasma volume compared to placebo.
Since thiazolidinediones, including rosiglitazone, can cause fluid retention, which can exacerbate or lead to congestive heart failure, Avandia should be used with caution in patients at risk for heart failure. Patients should be monitored for signs and symptoms of heart failure.
In controlled clinical trials of patients with type 2 diabetes, mild to moderate edema was reported in patients treated with Avandia, and may be dose related. Patients with ongoing edema are more likely to have adverse events associated with edema if started on combination therapy with insulin and Avandia.

Macular Edema
Macular edema has been reported in postmarketing experience in some diabetic patients who were taking Avandia 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. Most patients had peripheral edema at the time macular edema was diagnosed. Some patients had improvement in their macular edema after discontinuation of their thiazolidinedione. 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.

Fractures
In a 4- to 6-year comparative study (ADOPT) of glycemic control with monotherapy in drug-naive patients recently diagnosed with type 2 diabetes mellitus, an increased incidence of bone fracture was noted in female patients taking Avandia. Over the 4- to 6-year period, the incidence of bone fracture in females was 9.3% (60/645) for Avandia versus 3.5% (21/605) for glyburide and 5.1% (30/590) for metformin. This increased incidence was noted after the first year of treatment and persisted during the course of the study. The majority of the fractures in the women who received Avandia occurred in the upper arm, hand, and foot. These sites of fracture are different from those usually associated with postmenopausal osteoporosis (e.g., hip or spine). No increase in fracture rates was observed in men treated with Avandia. The risk of fracture should be considered in the care of patients, especially female patients, treated with Avandia, and attention given to assessing and maintaining bone health according to current standards of care.

Weight Gain
Dose-related weight gain was seen with Avandia alone and in combination with other hypoglycemic agents. The mechanism of weight gain is unclear but probably involves a combination of fluid retention and fat accumulation.

Hematologic
Across all controlled clinical studies in adults, decreases in hemoglobin and hematocrit (mean decreases in individual studies ?1.0 gram/dL and ?3.3%, respectively) were observed for Avandia alone and in combination with other hypoglycemic agents. The changes occurred primarily during the first 3 months following initiation of therapy with Avandia or following a dose increase in Avandia. White blood cell counts also decreased slightly in adult patients treated with Avandia. Small decreases in hemoglobin and hematocrit have also been reported in pediatric patients treated with Avandia. The observed changes may be related to the increased plasma volume observed with treatment with Avandia and may be dose related.

Ovulation
Therapy with Avandia, like other thiazolidinediones, may result in ovulation in some premenopausal anovulatory women. As a result, these patients may be at an increased risk for pregnancy while taking Avandia. Thus, adequate contraception in premenopausal women should be recommended. This possible effect has not been specifically investigated in clinical studies so the frequency of this occurrence is not known.
Although hormonal imbalance has been seen in preclinical studies, the clinical significance of this finding is not known. If unexpected menstrual dysfunction occurs, the benefits of continued therapy with Avandia should be reviewed.

Hepatic Effects
Another drug of the thiazolidinedione class, troglitazone, was associated with idiosyncratic hepatotoxicity, and very rare cases of liver failure, liver transplants, and death were reported during clinical use. In pre-approval controlled clinical trials in patients with type 2 diabetes, troglitazone was more frequently associated with clinically significant elevations in liver enzymes (ALT >3X upper limit of normal) compared to placebo. Very rare cases of reversible jaundice were also reported.

Information For Patients

Carcinogenesis/ Mutagenesis/ Impairment of Fertility

A 2-year carcinogenicity study was conducted in Charles River CD-1 mice at doses of 0.4, 1.5, and 6 mg/kg/day in the diet (highest dose equivalent to approximately 12 times human AUC at the maximum recommended human daily dose). Sprague-Dawley rats were dosed for 2 years by oral gavage at doses of 0.05, 0.3, and 2 mg/kg/day (highest dose equivalent to approximately 10 and 20 times human AUC at the maximum recommended human daily dose for male and female rats, respectively).
Rosiglitazone was not carcinogenic in the mouse. There was an increase in incidence of adipose hyperplasia in the mouse at doses ?1.5 mg/kg/day (approximately 2 times human AUC at the maximum recommended human daily dose). In rats, there was a significant increase in the incidence of benign adipose tissue tumors (lipomas) at doses ?0.3 mg/kg/day (approximately 2 times human AUC at the maximum recommended human daily dose). These proliferative changes in both species are considered due to the persistent pharmacological overstimulation of adipose tissue.
Rosiglitazone was not mutagenic or clastogenic in the in vitro bacterial assays for gene mutation, the in vitro chromosome aberration test in human lymphocytes, the in vivo mouse micronucleus test, and the in vivo/in vitro rat UDS assay. There was a small (about 2-fold) increase in mutation in the in vitro mouse lymphoma assay in the presence of metabolic activation.
Rosiglitazone had no effects on mating or fertility of male rats given up to 40 mg/kg/day (approximately 116 times human AUC at the maximum recommended human daily dose). Rosiglitazone altered estrous cyclicity (2 mg/kg/day) and reduced fertility (40 mg/kg/day) of female rats in association with lower plasma levels of progesterone and estradiol (approximately 20 and 200 times human AUC at the maximum recommended human daily dose, respectively). No such effects were noted at 0.2 mg/kg/day (approximately 3 times human AUC at the maximum recommended human daily dose). In juvenile rats dosed from 27 days of age through to sexual maturity (at up to 40 mg/kg/day), there was no effect on male reproductive performance, or on estrous cyclicity, mating performance or pregnancy incidence in females (approximately 68 times human AUC at the maximum recommended daily dose). In monkeys, rosiglitazone (0.6 and 4.6 mg/kg/day; approximately 3 and 15 times human AUC at the maximum recommended human daily dose, respectively) diminished the follicular phase rise in serum estradiol with consequential reduction in the luteinizing hormone surge, lower luteal phase progesterone levels, and amenorrhea. The mechanism for these effects appears to be direct inhibition of ovarian steroidogenesis.

Animal Toxicology

Heart weights were increased in mice (3 mg/kg/day), rats (5 mg/kg/day), and dogs (2 mg/kg/day) with rosiglitazone treatments (approximately 5, 22, and 2 times human AUC at the maximum recommended human daily dose, respectively). Effects in juvenile rats were consistent with those seen in adults. Morphometric measurement indicated that there was hypertrophy in cardiac ventricular tissues, which may be due to increased heart work as a result of plasma volume expansion.

Pregnancy

Pregnancy Category C. All pregnancies have a background risk of birth defects, loss, or other adverse outcome regardless of drug exposure. This background risk is increased in pregnancies complicated by hyperglycemia and may be decreased with good metabolic control. It is essential for patients with diabetes or history of gestational diabetes to maintain good metabolic control before conception and throughout pregnancy. Careful monitoring of glucose control is essential in such patients. Most experts recommend that insulin monotherapy be used during pregnancy to maintain blood glucose levels as close to normal as possible.

Human Data
Rosiglitazone has been reported to cross the human placenta and be detectable in fetal tissue. The clinical significance of these findings is unknown. There are no adequate and well controlled studies in pregnant women. Avandia should not be used during pregnancy.

Animal Studies
There was no effect on implantation or the embryo with rosiglitazone treatment during early pregnancy in rats, but treatment during mid-late gestation was associated with fetal death and growth retardation in both rats and rabbits. Teratogenicity was not observed at doses up to 3 mg/kg in rats and 100 mg/kg in rabbits (approximately 20 and 75 times human AUC at the maximum recommended human daily dose, respectively). Rosiglitazone caused placental pathology in rats (3 mg/kg/day). Treatment of rats during gestation through lactation reduced litter size, neonatal viability, and postnatal growth, with gro