Avandamet Side Effects

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.

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:

Back or joint pain; cold-like symptoms; diarrhea; dizziness; headache; indigestion; nausea; stomach upset; tiredness.

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; unusual hoarseness); blurred vision or other vision changes; chest, jaw, or arm pain or discomfort; dark urine; fainting; fast or difficult breathing; feeling of being unusually cold; fever, chills, or persistent sore throat; general feeling of being unwell; lightheadedness; muscle pain or weakness; numbness of an arm or leg; 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 or dizziness; sudden, unexplained weight gain; swelling of the hands, ankles, legs, or feet; symptoms of low blood sugar (eg, anxiety, increased sweating, dizziness or drowsiness, headache, chills, tremors, increased hunger); unusual bone pain (especially in the hand, foot, or upper arm); unusual stomach pain or discomfort; unusual tiredness or weakness; yellowing of the eyes or skin.

This is not a complete list of all side effects that may occur. If you have questions about side effects, contact your health care provider. Call your doctor for medical advice about side effects. To report side effects to the appropriate agency, please read the Guide to Reporting Problems to FDA.

Top

Avandamet Side Effects - for the Professional

Avandamet

Clinical Trial Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

The incidence and types of adverse events reported in controlled, 26-week clinical trials of rosiglitazone administered in combination with metformin 2,500 mg/day in comparison to adverse reactions reported in association with rosiglitazone and metformin monotherapies are shown in Table 7. Overall, the types of adverse reactions without regard to causality reported when rosiglitazone was used in combination with metformin were similar to those reported during monotherapy with rosiglitazone.

Table 7. Adverse Events (≥5% for Rosiglitazone Plus Metformin) Reported by Patients in 26-week Double-blind Clinical Trials of Rosiglitazone Added to Metformin Therapy

	Rosiglitazone + Metformin	Rosiglitazone	Placebo	Metformin
	N = 338	N = 2,526	N = 601	N = 225
Preferred term	%	%	%	%
Upper respiratory tract infection	16.0	9.9	8.7	8.9
Diarrhea	12.7	2.3	3.3	15.6
Injury	8.0	7.6	4.3	7.6
Anemia	7.1	1.9	0.7	2.2
Headache	6.5	5.9	5.0	8.9
Sinusitis	6.2	3.2	4.5	5.3
Fatigue	5.9	3.6	5.0	4.0
Back pain	5.0	4.0	3.8	4.0
Viral infection	5.0	3.2	4.0	3.6
Arthralgia	5.0	3.0	4.0	2.2

Reports of hypoglycemia in patients treated with rosiglitazone added to maximum metformin therapy in double-blind trials 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.

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.

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 trials [see Adverse Reactions (6.2)].

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 trials of rosiglitazone added to insulin, edema was reported with higher frequency (rosiglitazone in combination with insulin, 14.7%; insulin, 5.4%) [see Warnings and Precautions (5.2)].

In trials in which rosiglitazone was added to insulin, rosiglitazone increased the risk of congestive heart failure. The use of rosiglitazone in combination with insulin may increase the risk of myocardial infarction [see Warnings and Precautions (5.2, 5.3)].

In a trial in which insulin was added to Avandamet, no myocardial ischemia was observed in the insulin group (N = 158), and no congestive heart failure was reported in either group. There was one myocardial ischemic event and one sudden death in the group receiving Avandamet plus insulin (N = 161). [See Warnings and Precautions (5.2).]

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

A long-term, 4- to 6-year trial (ADOPT) compared the use of rosiglitazone (n = 1,456), glyburide (n = 1,441), and metformin (n = 1,454) as monotherapy in patients recently diagnosed with type 2 diabetes who were not previously treated with antidiabetic medication. Table 8 presents adverse reactions without regard to causality; rates are expressed per 100 patient-years (PY) exposure to account for the differences in exposure to trial medication across the 3 treatment groups.

In ADOPT, fractures were reported in a greater number of women treated with rosiglitazone (9.3%, 2.7/100 patient-years) compared to glyburide (3.5%, 1.3/100 patient-years) or metformin (5.1%, 1.5/100 patient-years). The majority of the fractures in the women who received rosiglitazone were reported in the upper arm, hand, and foot. [See Warnings and Precautions (5.9).] The observed incidence of fractures for male patients was similar among the 3 treatment groups.

Table 8. On-Therapy Adverse Events (≥5 Events/100 Patient-Years [PY]) in Any Treatment Group Reported in a 4- to 6-Year Clinical Trial of Rosiglitazone as Monotherapy (ADOPT)

	Rosiglitazone	Glyburide	Metformin
	N = 1,456	N = 1,441	N = 1,454
	PY = 4,954	PY = 4,244	PY = 4,906
Nasopharyngitis	6.3	6.9	6.6
Back pain	5.1	4.9	5.3
Arthralgia	5.0	4.8	4.2
Hypertension	4.4	6.0	6.1
Upper respiratory tract infection	4.3	5.0	4.7
Hypoglycemia	2.9	13.0	3.4
Diarrhea	2.5	3.2	6.8

Laboratory Abnormalities

Hematologic: Decreases in mean hemoglobin and hematocrit occurred in a dose-related fashion in adult patients treated with rosiglitazone (mean decreases in individual trials as much as 1.0 gram/dL hemoglobin and as much as 3.3% hematocrit). The changes occurred primarily during the first 3 months following initiation of rosiglitazone therapy or following an increase in rosiglitazone dose. The time course and magnitude of decreases were similar in patients treated with a combination of rosiglitazone and other hypoglycemic agents or monotherapy with rosiglitazone. Pre-treatment levels of hemoglobin and hematocrit were lower in patients in metformin combination trials and may have contributed to the higher reporting rate of anemia. In a single trial 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 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 in adults [see Clinical Pharmacology (12.2)].

Serum Transaminase Levels: In pre-approval clinical trials in 4,598 patients treated with rosiglitazone encompassing approximately 3,600 patient years of exposure, and in a long-term 4- to 6-year trial in 1,456 patients treated with rosiglitazone (4,954 patient-years exposure), there was no evidence of drug-induced hepatotoxicity.

In pre-approval controlled trials, 0.2% of patients treated with rosiglitazone had reversible elevations in ALT >3X the upper limit of normal compared to 0.2% on placebo and 0.5% on active comparators. The ALT elevations in patients treated with rosiglitazone were reversible. 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 pre-approval clinical trials, there were no cases of idiosyncratic drug reactions leading to hepatic failure. [See Warnings and Precautions (5.7).]

In the 4- to 6-year ADOPT trial, patients treated with rosiglitazone (4,954 patient-years exposure), glyburide (4,244 patient-years exposure) or metformin (4,906 patient-years exposure) as monotherapy, had the same rate of ALT increase to >3X upper limit of normal (0.3 per 100 patient-years exposure).

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 patients receiving thiazolidinedione therapy, serious adverse events with or without a fatal outcome, potentially related to volume expansion (e.g., congestive heart failure, pulmonary edema, and pleural effusions) have been reported [see Boxed Warning and Warnings and Precautions (5.2)].

There are postmarketing reports with rosiglitazone of hepatitis, hepatic enzyme elevations to 3 or more times the upper limit of normal, and hepatic failure with and without fatal outcome, although causality has not been established.

There are postmarketing reports with rosiglitazone of rash, pruritus, urticaria, angioedema, anaphylactic reaction, Stevens-Johnson syndrome, and new onset or worsening diabetic macular edema with decreased visual acuity [see Warnings and Precautions (5.8)].

Top

Side Effects by Body System - for Healthcare Professionals

General

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

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

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.

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.

Hematologic

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

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

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

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

Ocular

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

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.

Top

Disclaimer: Every effort has been made to ensure that the information provided is accurate, up-to-date, and complete, but no guarantee is made to that effect. In addition, the drug information contained herein may be time sensitive and should not be utilized as a reference resource beyond the date hereof. This information does not endorse drugs, diagnose patients, or recommend therapy. This drug information is a reference resource designed as supplement to, and not a substitute for, the expertise, skill , knowledge, and judgement of healthcare practitioners in patient care. The absence of a warning for a given drug or drug combination in no way should be construed to indicate that the drug of drug combination is safe, effective, or appropriate for any given patient. Drugs.com does not assume any responsibility for any aspect of healthcare administered with the aid of information provided. The information contained herein is not intended to cover all possible uses, directions, precautions, warnings, drug interactions, allergic reactions, or adverse effects. If you have questions about the drugs you are taking, check with your doctor, nurse, or pharmacist.