Rosiglitazone

Rosiglitazone may cause serious side effects. See "Drug Precautions". Some serious side effects include:

• New or worse heart failure 
• Heart attack
• Swelling (edema) 
• Weight gain
• Liver problems. 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
• Macular edema (a diabetic eye disease with swelling in the back of the eye) 
• Fractures (broken bones), usually in the hand, upper arm or foot 
• Low red blood cell count (anemia)
• Low blood sugar (hypoglycemia)
• Ovulation (release of egg from an ovary in a woman) leading to pregnancy 

The most common side effects of rosiglitazone reported in clinical trials included cold-like symptoms and headache.

This is not a complete list of rosiglitazone side effects. Ask your doctor or pharmacist for more information.

Follow all directions on your prescription label. Your doctor may occasionally change your dose to make sure you get the best results. Do not take this medicine in larger or smaller amounts or for longer than recommended.

You may take the medicine with or without food.

Your blood sugar will need to be checked often, and you may need other blood tests at your doctor's office.

Low blood sugar (hypoglycemia) can happen to everyone who has diabetes. Symptoms include headache, hunger, sweating, pale skin, irritability, dizziness, feeling shaky, or trouble concentrating. Always keep a source of sugar with you in case you have low blood sugar. Sugar sources include fruit juice, hard candy, crackers, raisins, and non-diet soda. Be sure your family and close friends know how to help you in an emergency.

If you have severe hypoglycemia and cannot eat or drink, use a glucagon injection. Your doctor can prescribe a glucagon emergency injection kit and tell you how to use it.

Check your blood sugar carefully during times of stress, travel, illness, surgery or medical emergency, vigorous exercise, or if you drink alcohol or skip meals. These things can affect your glucose levels and your dose needs may also change. Do not change your medication dose or schedule without your doctor's advice.

Use rosiglitazone regularly to get the most benefit. Get your prescription refilled before you run out of medicine completely.

Rosiglitazone is only part of a treatment program that may also include diet, exercise, weight control, blood sugar testing, and special medical care. Follow your doctor's instructions very closely.

Store at room temperature away from moisture, heat, and light. Keep the bottle tightly closed when not in use.

Take rosiglitazone only as directed by your doctor. Do not use more of it, do not use it more often, and do not use it for a longer time than your doctor ordered.

rosiglitazone should come with a Medication Guide. It is very important that you read and understand this information. Ask your doctor if you have any questions.

rosiglitazone may be taken with or without food.

Carefully follow the special diet your doctor gave you. This is the most important part of controlling your diabetes and will help the medicine work properly. Also, exercise regularly and test for sugar in your blood or urine as directed.

Dosing

The dose of rosiglitazone will be different for different patients. Follow your doctor's orders or the directions on the label. The following information includes only the average doses of rosiglitazone. If your dose is different, do not change it unless your doctor tells you to do so.

The amount of medicine that you take depends on the strength of the medicine. Also, the number of doses you take each day, the time allowed between doses, and the length of time you take the medicine depend on the medical problem for which you are using the medicine.

• For oral dosage form (tablets):
  • For type 2 diabetes:
    • Adults—At first, 4 milligrams (mg) per day, taken as a single dose or divided into two doses. Your doctor may adjust your dose as needed. However, the dose is usually not more than 8 mg per day.
    • Children—Use and dose must be determined by your doctor.

Missed Dose

If you miss a dose of rosiglitazone, take it as soon as possible. However, if it is almost time for your next dose, skip the missed dose and go back to your regular dosing schedule. Do not double doses.

Storage

Store the medicine in a closed container at room temperature, away from heat, moisture, and direct light. Keep from freezing.

Keep out of the reach of children.

Do not keep outdated medicine or medicine no longer needed.

Ask your healthcare professional how you should dispose of any medicine you do not use.

• If you have an allergy to rosiglitazone or any other part of this medicine.
• If you are allergic to any drugs like this one, any other drugs, foods, or other substances. Tell your doctor about the allergy and what signs you had, like rash; hives; itching; shortness of breath; wheezing; cough; swelling of face, lips, tongue, or throat; or any other signs.
• If you have any of these health problems: Acidic blood problem or type 1 diabetes.
• If you are using insulin.
• If you are breast-feeding or plan to breast-feed.

This is not a list of all drugs or health problems that interact with rosiglitazone.

Tell your doctor and pharmacist about all of your drugs (prescription or OTC, natural products, vitamins) and health problems. You must check to make sure that it is safe for you to take this medicine with all of your drugs and health problems. Do not start, stop, or change the dose of any drug without checking with your doctor.

• Tell all of your health care providers that you take rosiglitazone. This includes your doctors, nurses, pharmacists, and dentists.
• Do not drive if your blood sugar has been low. There is a greater chance of you having a crash.
• Check your blood sugar as you have been told by your doctor.
• Have blood work checked as you have been told by the doctor. Talk with the doctor.
• Have an eye exam as you have been told by your doctor.
• Talk with your doctor before you drink alcohol.
• Follow the diet and workout plan that your doctor told you about.
• It may be harder to control your blood sugar during times of stress like when you have a fever, an infection, an injury, or surgery. A change in level of physical activity or exercise and a change in diet may also affect your blood sugar. Talk with your doctor.
• This medicine may raise the chance of broken bones. The chance may be higher in women. Broken bones were seen after people took this medicine for 1 year. Most of the broken bones happened in the upper arm, hand, or foot. Talk with your doctor about how to keep your bones healthy or if you have any questions.
• If you are 65 or older, use rosiglitazone with care. You could have more side effects.
• There is a chance of pregnancy in women of childbearing age who have not been ovulating. If you want to avoid pregnancy, use birth control that you can trust while taking this medicine.
• Tell your doctor if you are pregnant or plan on getting pregnant. You will need to talk about the benefits and risks of using rosiglitazone while you are pregnant.

• If your symptoms or health problems do not get better or if they become worse, call your doctor.
• Do not share your drugs with others and do not take anyone else's drugs.
• Keep a list of all your drugs (prescription, natural products, vitamins, OTC) with you. Give this list to your doctor.
• Talk with the doctor before starting any new drug, including prescription or OTC, natural products, or vitamins.
• This medicine comes with an extra patient fact sheet called a Medication Guide. Read it with care. Read it again each time this medicine is refilled. If you have any questions about rosiglitazone, please talk with the doctor, pharmacist, or other health care provider.
• If you think there has been an overdose, call your poison control center or get medical care right away. Be ready to tell or show what was taken, how much, and when it happened.

This information should not be used to decide whether or not to take this medicine or any other medicine. Only the healthcare provider has the knowledge and training to decide which medicines are right for a specific patient. This information does not endorse any medicine as safe, effective, or approved for treating any patient or health condition. This is only a brief summary of general information about rosiglitazone. It does NOT include all information about the possible uses, directions, warnings, precautions, interactions, adverse effects, or risks that may apply to this medicine. This information is not specific medical advice and does not replace information you receive from the healthcare provider. You must talk with the healthcare provider for complete information about the risks and benefits of using rosiglitazone.

Review Date: October 4, 2017

17.1 Patient Advice

Patients should be informed of the following:

• Rosiglitazone maleate is not recommended for patients with symptoms of heart failure.

• Patients with more severe heart failure (NYHA Class 3 or 4) cannot start Rosiglitazone maleate as the risks exceed any potential benefits in such patients.

• Results of a set of clinical studies suggest that treatment with Rosiglitazone Maleate is associated with an increased risk for myocardial ischemic events, such as angina or myocardial infarction (heart attack), especially in patients taking insulin or nitrates. Because this risk has not been confirmed or excluded in different long-term trials, definitive conclusions regarding this risk await completion of an adequately-designed cardiovascular outcome study.

• Rosiglitazone maleate is not recommended for patients who are taking nitrates or insulin.

• There are multiple medications available to treat type 2 diabetes, and each patient with diabetes is unique. The benefits and risks of each available diabetes medication should be taken into account when choosing a particular diabetes medication for a given patient.

• There have been no clinical studies establishing conclusive evidence of macrovascular risk reduction with Rosiglitazone maleateor any other oral antidiabetic drug.

• Management of type 2 diabetes should include diet control. Caloric restriction, weight loss, and exercise are essential for the proper treatment of the diabetic patient because they help improve insulin sensitivity. This is important not only in the primary treatment of type 2 diabetes, but in maintaining the efficacy of drug therapy.

• It is important to adhere to dietary instructions and to regularly have blood glucose and glycosylated hemoglobin tested. It can take 2 weeks to see a reduction in blood glucose and 2 to 3 months to see the full effect of Rosiglitazone maleat.

• Blood will be drawn to check their liver function prior to the start of therapy and periodically thereafter per the clinical judgment of the healthcare professional. Patients with unexplained symptoms of nausea, vomiting, abdominal pain, fatigue, anorexia, or dark urine should immediately report these symptoms to their physician.

• 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 Rosiglitazone maleate should immediately report these symptoms to their physician.

• Rosiglitazone maleate can be taken with or without meals.

• When using Rosiglitazoe maleate in combination with other hypoglycemic agents, the risk of hypoglycemia, its symptoms and treatment, and conditions that predispose to its development should be explained to patients and their family members.

• Therapy with Rosiglitazone maleate, like other thiazolidinediones, may result in ovulation in some Rosiglitazone maleate[see Warnings and Precautions (5.10)  and Use in Specific Populations (8.1 )]. 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.

(roh si GLI ta zone)

Thiazolidinedione antidiabetic agent that lowers blood glucose by improving target cell response to insulin, without increasing pancreatic insulin secretion. It has a mechanism of action that is dependent on the presence of insulin for activity. Rosiglitazone is an agonist for peroxisome proliferator-activated receptor-gamma (PPARgamma). Activation of nuclear PPARgamma receptors influences the production of a number of gene products involved in glucose and lipid metabolism. PPARgamma is abundant in the cells within the renal collecting tubules; fluid retention results from stimulation by thiazolidinediones which increases sodium reabsorption.

Distribution

Vdss (apparent): 17.6 L

Metabolism

Hepatic (99%) via CYP2C8; minor metabolism via CYP2C9

Excretion

Urine (~64%) and feces (~23%) as metabolites

Type 2 diabetes: Adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus (noninsulin dependent, NIDDM); may be used as monotherapy or in combination with metformin or a sulfonylurea.

Limitations of use: Should not be used in patients with type 1 diabetes mellitus or diabetic ketoacidosis; use with insulin is not recommended.

Store at 25°C (77°F); excursions are permitted between 15°C and 30°C (59°F and 86°F). Protect from light.

Concerns related to adverse effects:

• Edema: Dose-related edema may occur. Use with caution in patients with edema; may increase plasma volume and/or cause fluid retention. Monitor for signs/symptoms of heart failure.

• Fractures: Increased incidence of bone fractures in females treated with rosiglitazone was observed during analysis of long-term trial; majority of fractures occurred in the upper arm, hand and foot (differing from the hip or spine fractures usually associated with postmenopausal osteoporosis). Consider risk of fracture prior to initiation and during use. According to the American Diabetes Association guidelines, thiazolidinediones should be avoided in patients with fracture risk factors (ADA 2016a).

• Heart failure/cardiac effects: [US Boxed Warning]: Thiazolidinediones, including rosiglitazone, may cause or exacerbate congestive heart failure; closely monitor for signs and symptoms of congestive heart failure (eg, rapid weight gain, dyspnea, edema), particularly after initiation or dose increases. If heart failure develops, treat accordingly and consider dose reduction or discontinuation. Not recommended for use in any patient with symptomatic heart failure. Initiation of therapy is contraindicated in patients with NYHA class III or IV heart failure. A higher frequency of cardiovascular events has been noted in patients with NYHA class I or II heart failure treated with rosiglitazone. Use may also be associated with an increased risk of angina and MI. Use with caution in patients at risk for cardiovascular events and monitor closely. Discontinue if any deterioration in cardiac status occurs.

• Hematologic effects: May decrease hemoglobin, hematocrit, and/or WBC count (slight); effects may be related to increased plasma volume and/or dose-related. Changes in hemoglobin and hematocrit generally occurred during the first 3 months after initiation of therapy and after dose increases. Use with caution in patients with anemia.

• Hypoglycemia: The risk of hypoglycemia is increased when rosiglitazone is combined with other hypoglycemic agents; dosage adjustment of concomitant hypoglycemic agents may be necessary. Monitor blood glucose and HbA1c as clinically necessary.

• Macular edema: Has been reported with thiazolidinedione use, including rosiglitazone; some patients with macular edema presented with blurred vision or decreased visual acuity, and most had peripheral edema at time of diagnosis. In addition to regular ophthalmic exams, diabetic patients with visual symptoms should receive prompt ophthalmic evaluation. Improvement in macular edema may occur with discontinuation of therapy.

• Weight gain: Dose-related weight gain observed with use; mechanism unknown but likely associated with fluid retention and fat accumulation.

Disease-related concerns:

• Diabetes, type 1: Mechanism requires the presence of endogenous insulin; therefore, use in type 1 diabetes (insulin dependent, IDDM) or diabetic ketoacidosis is not recommended. Use with insulin is not recommended; may increase the risk of heart failure.

• Hepatic impairment: Use with caution in patients with elevated transaminases (AST or ALT); do not initiate in patients with active liver disease or ALT >2.5 times the upper limit of normal (ULN) at baseline; evaluate patients with ALT ≤2.5 times ULN at baseline or during therapy for cause of enzyme elevation; during therapy, if ALT >3 times ULN, reevaluate levels promptly and discontinue if elevation persists or if jaundice occurs at any time during use. Idiosyncratic hepatotoxicity has been reported with another thiazolidinedione agent (troglitazone); avoid use in patients who previously experienced jaundice during troglitazone therapy.

• Ischemic heart disease: Do not initiate in patients with stable ischemic heart disease due to an increased risk of cardiovascular complications (Fihn 2012).

• Stress-related states: It may be necessary to discontinue therapy and administer insulin if the patient is exposed to stress (fever, trauma, infection, surgery).

Concurrent drug therapy issues:

• Drug-drug interactions: Potentially significant interactions may exist, requiring dose or frequency adjustment, additional monitoring, and/or selection of alternative therapy. Consult drug interactions database for more detailed information.

Special populations:

• Premenopausal/anovulatory females: Use with caution in premenopausal, anovulatory women; may result in a resumption of ovulation, increasing the risk of pregnancy. Use of adequate contraception in premenopausal women is recommended.

Adverse effects were observed in initial animal reproduction studies. Rosiglitazone has been found to cross the placenta during the first trimester of pregnancy. Inadvertent use early in pregnancy has not been shown to increase the risk of adverse fetal effects, although in the majority of cases, the medication was stopped as soon as pregnancy was detected (Chan 2005; Kalyoncu 2005; Yaris 2004).

Thiazolidinediones may cause ovulation in anovulatory premenopausal women, increasing the risk of pregnancy. Adequate contraception in premenopausal women is recommended.

In women with diabetes, maternal hyperglycemia can be associated with congenital malformations as well as adverse effects in the fetus, neonate, and the mother (ACOG 2005; ADA 2017c; Kitzmiller 2008; Metzger 2007). To prevent adverse outcomes, prior to conception and throughout pregnancy maternal blood glucose and HbA1c should be kept as close to target goals as possible but without causing significant hypoglycemia (ACOG 2013; ADA 2017c; Blumer 2013; Kitzmiller 2008).

Agents other than rosiglitazone are currently recommended to treat diabetes in pregnant women (ADA 2017c).

Applies to rosiglitazone: oral tablet

General

The most commonly reported adverse reports included upper respiratory tract infections, injury, and headache.[Ref]

Cardiovascular

Major Adverse Cardiovascular Events:
Overall data from long-term rosiglitazone trials including the RECORD, ADOPT, and DREAM trials (rosiglitazone n=6311; control n=7756) showed no difference in overall mortality or major adverse cardiovascular events; however, a meta-analysis of shorter-term trials suggests and increased risk for myocardial infarction with rosiglitazone compared with placebo.

The RECORD trial (Rosiglitazone evaluated for Cardiac Outcomes and Regulation of Glycemia in Diabetes) revealed no significant difference in cardiovascular hospitalization or cardiovascular death (primary outcome) among patients with type 2 diabetes receiving rosiglitazone add-on therapy (n=2220) compared with active control (n=2227); however, there was a significant difference in the incidence of CHF (secondary endpoint). Patients randomized were those who had failed metformin or sulfonylurea monotherapy; mean age: 58 years; 52% male. Following randomization to add-on rosiglitazone or active control (add-on metformin for those inadequately controlled on sulfonylurea or add-on sulfonylurea for those inadequately controlled on metformin) patients were treated to a target glycosylated hemoglobin (HbA1c) of 7% or less. Heart failure was reported in 61 patients receiving add-on rosiglitazone and 29 patients receiving active control.

In a retrospective analysis of 42 clinical trials (mean duration 6 months), rosiglitazone was associated with an increased risk of myocardial ischemia compared with combined active or placebo control (2% versus 1.53%). These events included angina pectoris, angina dyspnea, myocardial infarction, coronary thrombosis, myocardial ischemia, coronary artery disease, and coronary artery disorder. There was an increased risk with combination insulin therapy and in patients receiving nitrates for known coronary heart disease.

Cardiovascular Events in Patients with NYHA Class I and II Heart Failure:
An increased risk of cardiovascular events was observed in a 52-week trial in patients with NYHA Class I and II Heart Failure who were receiving rosiglitazone (n=110) compared with placebo (n=114). These events included: cardiovascular deaths (5% vs 4%), worsening CHF (6% vs 4%), new or worsening edema (25% vs 9%), new or worsening dyspnea (26% vs 17%), increases in CHF medication (33% vs 18%), and cardiovascular hospitalization (19% vs 13%).

Edema:
-Dose-related edema was reported in rosiglitazone clinical trials. In patients receiving rosiglitazone 8 mg in combination with a sulfonylurea, the incidence of edema was 12.4%. In rosiglitazone monotherapy trials, edema was reported in 4.8% of patients (dose not specified). Healthy volunteers receiving rosiglitazone 8 mg once daily for 8 weeks experienced a statistically significant increase in median plasma volume compared with placebo.

Concomitant Administration with Insulin:
-Edema was reported with higher frequency in the rosiglitazone plus insulin combination trials (insulin, 5.4%; and rosiglitazone with insulin 14.7%). Reports of new onset or exacerbation of CHF occurred at a rate of 1% for insulin alone, 2% (4 mg) and 3% (8 mg) for insulin in combination with rosiglitazone. The coadministration of rosiglitazone and insulin is not recommended.[Ref]

Common (1% to 10%): Edema, hypertension,
Frequency not reported: Cardiovascular deaths, congestive heart failure (CHF), myocardial infarction, angina, angina pectoris, angina dyspnea, myocardial infarction, coronary thrombosis, myocardial ischemia, coronary artery disease, coronary artery disorder[Ref]

Hematologic

Anemia was reported in 1.9% of patients receiving rosiglitazone as monotherapy. In combination therapy with metformin, a sulfonylurea, or metformin plus a sulfonylurea, the incidence of anemia was 7.1%, 2.3%, and 6.7%, respectively. Laboratory findings have shown dose-related decreases in hemoglobin and hematocrit; mean decreases in hemoglobin were 1 g/dL and up to 3.3% in hematocrit. These changes primarily occurred during the first 3 months or following a dose increase. They may be related to increased plasma volume.[Ref]

Common (1% to 10%): Anemia
Frequency not reported: Decrease in WBC counts[Ref]

Hepatic

Uncommon (0.1% to 1%): Hyperbilirubinemia, ALT elevations
Postmarketing reports: Hepatitis, hepatic enzyme elevations greater than 3 times the upper limit of normal, hepatic failure[Ref]

Metabolic

Common (1% to 10%): Hyperglycemia, hypoglycemia, hypocholesterolemia
Uncommon (0.1% to 1%): Weight gain
Frequency not reported: Increases in waist and hip circumference[Ref]

The mechanism of weight gain is unclear, although it probably is due to a combination of fluid retention and fat accumulation. In the ADOPT monotherapy trial, median weight change at 4 years was plus 3.5 kg.[Ref]

Endocrine

Frequency not reported: Resumption of ovulation in premenopausal, anovulatory women, hormonal imbalance[Ref]

Hypersensitivity

Postmarketing reports: Anaphylactic reaction, urticaria, angioedema[Ref]

Dermatologic

Postmarketing reports: Rash, pruritus, urticaria, angioedema, Stevens-Johnson syndrome[Ref]

Ocular

Postmarketing reports: Diabetic macular edema with decreased visual acuity[Ref]

Respiratory

Common (1% to 10%): Upper respiratory tract infection, sinusitis
Frequency not reported: Dyspnea
Postmarketing reports: Pulmonary edema, pleural effusions[Ref]

Musculoskeletal

Common (1% to 10%): Back pain
Frequency not reported: Fractures[Ref]

Long-term clinical trials have shown an increased incidence of bone fracture in patients receiving drug compared with glyburide or metformin. This increased incidence appeared after the first year and persisted during the trials. The majority of fractures were observed in women and occurred in the upper arm, hand, and foot.[Ref]

Gastrointestinal

Common (1% to 10%): Diarrhea[Ref]

Other

Common (1% to 10%): Injury, fatigue[Ref]

Some side effects of rosiglitazone may not be reported. Always consult your doctor or healthcare specialist for medical advice. You may also report side effects to the FDA.