Avandamet Side Effects - Avandamet Side Effects

Avandamet Side Effects

Avandamet Side Effects
Generic name: metformin/rosiglitazone
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Please note - some side effects for Avandamet may not be reported. Always consult your doctor or healthcare specialist for medical advice. You may also report side effects to the FDA at http://www.fda.gov/medwatch/ or 1-800-FDA-1088 (1-800-332-1088).

Side Effects of Avandamet - for the consumer

Avandamet

All medicines may cause side effects, but many people have no, or minor, side effects. Check with your doctor if any of these most COMMON side effects persist or become bothersome when using Avandamet:

Cold symptoms; diarrhea; headache; indigestion; mild weight gain; nausea; stomach upset.

Seek medical attention right away if any of these SEVERE side effects occur when using Avandamet:

Severe allergic reactions (rash; hives; itching; difficulty breathing; tightness in the chest; swelling of the mouth, face, lips, or tongue); blurred vision or other vision changes; bone pain; chest pain or discomfort; dark urine; dizziness or lightheadedness; fainting; fast or difficult breathing; feeling of being unusually cold; fever, chills, or persistent sore throat; general feeling of being unwell; muscle pain or weakness; numbness of an arm or leg; pale stools; persistent loss of appetite; red, swollen, blistered, or peeling skin; severe or persistent nausea or vomiting; shortness of breath; slow or irregular heartbeat; sudden severe headache, dizziness, or vomiting; sudden unexplained weight gain; swelling of the hands, ankles, or feet; unusual bone pain; unusual drowsiness; unusual stomach pain or discomfort; unusual tiredness or weakness; yellowing of the eyes or skin.

For the professional

Avandamet

The incidence and types of adverse events reported in a controlled, 32-week double-blind clinical trial of Avandamet in drug-naïve patients (n = 468) are shown in Table 8.

The incidence and types of adverse events reported in controlled, 26-week clinical trials of rosiglitazone maleate administered in combination with metformin hydrochloride 2,500 mg/day in comparison to adverse reactions reported in association with rosiglitazone and metformin monotherapies are shown in Table 9. Overall, the types of adverse experiences reported when rosiglitazone was used in combination with metformin were similar to those reported during monotherapy with rosiglitazone.

In the double-blind trial evaluating Avandamet in drug-naïve patients, mild (no intervention required) to moderate (minor intervention required) symptomatic hypoglycemia was reported by 18/155 (12%) of patients treated with Avandamet, 14/154 (9%) with metformin, and 13/159 (8%) with rosiglitazone. Approximately half of these episodes were accompanied by a simultaneous capillary glucose measurement, and the rate of confirmed hypoglycemia (blood glucose≤50 mg/dL) was low in this clinical study: 0.6% (1/155) for Avandamet, 1.3% (2/154) for metformin and 0% with rosiglitazone. No hypoglycemic episode led to withdrawal with Avandamet treatment, and no patients required medical intervention due to hypoglycemia.

Reports of hypoglycemia in patients treated with rosiglitazone added to maximum metformin therapy in double-blind studies were more frequent (3.0%) than in patients treated with rosiglitazone (0.6%) or metformin monotherapies (1.3%) or placebo (0.2%). Overall, anemia and edema were generally mild to moderate in severity and usually did not require discontinuation of treatment with rosiglitazone.

In the double-blind trial in drug-naïve patients, the incidence of edema was 6% on Avandamet compared to 7% on rosiglitazone and 3% on metformin.

In the double-blind trial in drug-naïve patients, the incidence of anemia was 4% in patients treated with Avandamet compared to either rosiglitazone (2%) or metformin (0%). Reports of anemia (7.1%) were greater in patients treated with rosiglitazone added to metformin compared to monotherapy with rosiglitazone. Lower pre-treatment hemoglobin/hematocrit levels in patients enrolled in the metformin and rosiglitazone combination therapy clinical trials may have contributed to the higher reporting rate of anemia in these studies.

Edema was reported in 4.8% of patients receiving rosiglitazone compared to 1.3% on placebo, and 2.2% on metformin monotherapy and 4.4% on rosiglitazone in combination with maximum doses of metformin.
Combination with Insulin

The safety profile for Avandamet plus insulin was consistent with that of the individual components (rosiglitazone or metformin) and with that of rosiglitazone used in combination with insulin.

The incidence of hypoglycemia (confirmed by fingerstick blood glucose concentration ≤50 mg/dL) was 14% for patients on Avandamet plus insulin compared to 10% for patients on insulin monotherapy.

The incidence of edema was 7% when insulin was added to Avandamet compared to 3% with insulin monotherapy. This trial excluded patients with pre-existing heart failure or new or worsening edema on Avandamet therapy.

However, in 26-week double-blind, fixed-dose studies of rosiglitazone added to insulin, edema was reported with higher frequency (rosiglitazone in combination with insulin, 14.7%; insulin, 5.4%). Reports of new-onset or exacerbation of congestive heart failure occurred at rates of 1% for insulin alone, and 2% (4 mg) and 3% (8 mg) for insulin in combination with rosiglitazone. There were too few events to confirm a dose relationship; however, the incidence of heart failure appeared higher with rosiglitazone 8 mg daily.

The incidence of anemia was 2% for Avandamet in combination with insulin compared to 1% for insulin monotherapy.
Postmarketing Experience

In addition to adverse reactions reported from clinical trials, the events described below have been identified during post-approval use of Avandamet or its individual components. Because these events are reported voluntarily from a population of unknown size, it is not possible to reliably estimate their frequency or to always establish a causal relationship to drug exposure.

In postmarketing experience in patients receiving thiazolidinedione therapy, serious adverse events with or without a fatal outcome, potentially related to volume expansion (e.g., heart failure, pulmonary edema, and pleural effusions) have been reported.

Rash, pruritus, urticaria, angioedema, anaphylactic reaction, and Stevens-Johnson syndrome have been reported rarely.

Reports of new onset or worsening diabetic macular edema with decreased visual acuity have also been received.

Laboratory Abnormalities
Hematologic

Decreases in mean hemoglobin and hematocrit occurred in a dose-related fashion in adult patients treated with rosiglitazone maleate (mean decreases in individual studies up to 1.0 gram/dL hemoglobin and up to 3.3% hematocrit). The time course and magnitude of decreases were similar in patients treated with a combination of rosiglitazone and other hypoglycemic agents or rosiglitazone monotherapy. Pre-treatment levels of hemoglobin and hematocrit were lower in patients in metformin combination studies and may have contributed to the higher reporting rate of anemia. In a single study in pediatric patients, decreases in hemoglobin and hematocrit (mean decreases of 0.29 g/dL and 0.95%, respectively) were reported with rosiglitazone. White blood cell counts also decreased slightly in adult patients treated with rosiglitazone. Decreases in hematologic parameters may be related to increased plasma volume observed with rosiglitazone treatment.

In controlled clinical trials of metformin hydrochloride of 29 weeks’ duration, a decrease to subnormal levels of previously normal serum vitamin B12 levels, without clinical manifestations, was observed in approximately 7% of patients. Such a decrease, possibly due to interference with B12 absorption from the B12-intrinsic factor complex, is, however, very rarely associated with anemia and appears to be rapidly reversible with discontinuation of metformin or vitamin B12 supplementation.
Lipids

Changes in serum lipids have been observed following treatment with rosiglitazone maleate in adults. Small changes in serum lipid parameters were reported in children treated with rosiglitazone for 24 weeks.
Serum Transaminase Levels

In clinical studies in 4,598 patients treated with rosiglitazone maleate encompassing approximately 3,600 patient years of exposure, there was no evidence of drug-induced hepatotoxicity or elevated ALT levels.

In controlled trials, 0.2% of patients treated with rosiglitazone maleate had reversible elevations in ALT >3X the upper limit of normal compared to 0.2% on placebo and 0.5% on active comparators. Hyperbilirubinemia was found in 0.3% of patients treated with rosiglitazone compared with 0.9% treated with placebo and 1% in patients treated with active comparators.

In the clinical program including long-term, open-label experience, the rate per 100 patient years of exposure of ALT increase to >3X the upper limit of normal was 0.35 for patients treated with rosiglitazone maleate, 0.59 for placebo-treated patients, and 0.78 for patients treated with active comparator agents.

In pre-approval clinical trials, there were no cases of idiosyncratic drug reactions leading to hepatic failure. In postmarketing experience with rosiglitazone maleate, reports of hepatic enzyme elevations 3 or more times the upper limit of normal and hepatitis have been received.
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By body system

General side effects

Metformin-rosiglitazone has been generally well tolerated. Viral infection, injury, headache, back pain, fatigue, and arthralgia were reported slightly more frequently than placebo in clinical trials.

Metabolic side effects

Lactic acidosis is a medical emergency requiring immediate evaluation and treatment. The case fatality rate may be as high as 50.3%. Patients taking metformin who present with even vague medical illnesses such as myalgia, malaise, somnolence, abdominal discomfort, and so forth, should be evaluated for a metabolic etiology like lactic acidosis.

Signs and symptoms of severe acidosis may include vomiting, abdominal pain, nausea, dyspnea, hypothermia, hypotension, and bradycardia.

Laboratory evaluation of metformin-induced lactic acidosis generally includes determination of the following: blood glucose concentration, lactic acid concentration, serum electrolytes, blood pH, metformin concentration, and exclusion of ketoacidosis.

If lactic acidosis is present, immediate institution of general supportive care is indicated. Prompt hemodialysis is also generally recommended in order to correct the acidosis and remove metformin. Hemodialysis often results in rapid improvement. Some investigators have suggested that dialysis with a bicarbonate-buffered dialysate may be particularly effective.

Metabolic side effects of metformin have included lactic acidosis, which is a potentially fatal metabolic complication of biguanide therapy. The incidence of lactic acidosis has been about 1.5 cases per 10,000 patient years. The incidence may be lower with current recommended doses and less frequent use in the elderly. The risk of lactic acidosis is particularly high in patients with underlying renal insufficiency. Cases of lactic acidosis occurring in patients with normal renal function have been rarely reported. Concomitant cardiovascular or liver disease, sepsis, and hypoxia may also increase the risk of lactic acidosis. Hypoglycemia occurs uncommonly in patients receiving metformin as monotherapy. Strenuous exercise, decreased caloric intake, general debilitation, adrenal insufficiency, pituitary insufficiency, and ethanol use may increase the risk of hypoglycemia. Metabolic side effects of rosiglitazone have included increases in total cholesterol, LDL, and HDL and decreases in free fatty acids. Dose related weight gain has been reported in patients treated with rosiglitazone alone and in combination with other hypoglycemic agents.

Cardiovascular side effects

Healthy volunteers receiving rosiglitazone 8 mg once daily for 8 weeks experienced a statistically significant increase in median plasma volume compared to placebo. Patients with ongoing edema are more likely to have adverse events associated with edema if started on combination therapy with insulin and rosiglitazone.

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

In a 26-week study, 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 congestive heart failure occurred at a rate of 1% for insulin alone, and 2% (4 mg) and 3% (8 mg) for insulin in combination with rosiglitazone.

Cardiovascular side effects of rosiglitazone have included mild to moderate edema. Patients with congestive heart failure have experienced new or worsening edema. Compared to patients receiving placebo, patients with congestive heart failure (CHF) receiving rosiglitazone also experienced more cardiovascular deaths, more CHF worsening, more new or worsening dyspnea, more increases in CHF medication and cardiovascular hospitalization, more myocardial infarctions, and angina.

Hematologic side effects

Hematologic side effects have included decreases of previously normal levels of serum vitamin B12 to subnormal levels. Across all controlled clinical studies in adults, decreases in hemoglobin and hematocrit (mean decreases in individual studies of approximately 1.0 gram/dL and 3.3%, respectively) were observed for rosiglitazone maleate alone and in combination with other hypoglycemic agents.

Gastrointestinal side effects

Gastrointestinal side effects have included nausea, anorexia, metallic taste, diarrhea, dyspepsia, flatulence, and abdominal pain. Diarrhea has been reported by 12.7% of patients in clinical trials.

Respiratory side effects

Respiratory side effects have included reports of upper respiratory tract infection in 16% and sinusitis in 6.2% of patients in clinical trials. Patients with congestive heart failure have experienced new or worsening dyspnea.

Hypersensitivity side effects

Hypersensitivity side effects have included rare postmarketing reports of urticaria and angioedema. Postmarketing experience has included rare reports of anaphylactic reactions.

Ocular side effects

Ocular side effects have included changes in accommodation and blurred vision. New onset or worsening (diabetic) macular edema with decreased visual acuity has been reported very rarely in postmarketing experience with rosiglitazone. In some cases, symptoms improved following discontinuation of rosiglitazone. Physicians should consider the possibility of macular edema if a patient reports decreased visual acuity.

Musculoskeletal side effects

Musculoskeletal side effects have included an increased incidence of bone fracture in female patients. The majority of the fractures in the women who received rosiglitazone 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 rosiglitazone.

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