Avandamet Side Effects, and Drug Interactions - Rosiglitazone Maleate and Metformin

Avandamet Side Effects, and Drug Interactions - Rosiglitazone Maleate and Metformin

SIDE EFFECTS

The incidence and types of adverse events reported in controlled, 26-week clinical trials in association with rosiglitazone maleate in combination with doses of metformin hydrochloride of 2,500 mg/day in comparison to adverse reactions reported in association with rosiglitazone and metformin monotherapies are shown in Table 4.

Reports of hypoglycemia in patients treated with rosiglitazone and maximum metformin combination therapy were more frequent than in patients treated with rosiglitazone or metformin monotherapies. In double-blind studies, hypoglycemia was reported by 3.0% of patients receiving rosiglitazone in combination with maximum doses of metformin, by 1.3% of patients receiving metformin monotherapy, by 0.6% of patients receiving rosiglitazone as monotherapy, and by 0.2% of patients receiving placebo.

There were a small number of patients treated with rosiglitazone who had adverse events of anemia and edema. Overall, these events 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. Overall, the types of adverse experiences reported when rosiglitazone was used in combination with metformin were similar to those during monotherapy with rosiglitazone. Reports of anemia (7.1%) were greater in patients treated with a combination of rosiglitazone and metformin compared to monotherapy with rosiglitazone.

Lower pre-treatment hemoglobin/hematocrit levels in patients enrolled in the metformin combination clinical trials may have contributed to the higher reporting rate of anemia in these studies (see ADVERSE REACTIONS, Laboratory Abnormalities, Hematologic).

In 26-week double-blind, fixed-dose studies, edema was reported with higher frequency in the rosiglitazone plus insulin combination trials (insulin, 5.4%; and rosiglitazone in combination with insulin, 14.7%). 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 (see WARNINGS, Cardiac Failure and Other Cardiac Effects).

In postmarketing experience with rosiglitazone maleate, adverse events potentially related to volume expansion (e.g., congestive heart failure, pulmonary edema, and pleural effusions) have been reported. (See also GLUCOPHAGE prescribing information, ADVERSE REACTIONS.)

Decreases in mean hemoglobin and hematocrit occurred in a dose-related fashion in 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. White blood cell counts also decreased slightly in 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 (see CLINICAL STUDIES).

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 (see PRECAUTIONS, Hepatic Effects).

Rosiglitazone maleate

Drugs Metabolized by Cytochrome P450: In vitro drug metabolism studies suggest that rosiglitazone does not inhibit any of the major P450 enzymes at clinically relevant concentrations. In vitro data demonstrate that rosiglitazone is predominantly metabolized by CYP2C8, and to a lesser extent, 2C9.

Rosiglitazone (4 mg twice daily) was shown to have no clinically relevant effect on the pharmacokinetics of nifedipine and oral contraceptives (ethinyl estradiol and norethindrone), which are predominantly metabolized by CYP3A4.

Metformin hydrochloride

Furosemide: A single-dose, metformin-furosemide drug interaction study in healthy subjects demonstrated that pharmacokinetic parameters of both compounds were affected by coadministration. Furosemide increased the metformin plasma and blood C_max by 22% and blood AUC by 15%, without any significant change in metformin renal clearance. When administered with metformin, the C_max and AUC of furosemide were 31% and 12% smaller, respectively, than when administered alone, and the terminal half-life was decreased by 32%, without any significant change in furosemide renal clearance. No information is available about the interaction of metformin and furosemide when coadministered chronically.

Nifedipine

A single-dose, metformin-nifedipine drug interaction study in normal healthy volunteers demonstrated that coadministration of nifedipine increased plasma metformin C_max and AUC by 20% and 9%, respectively, and increased the amount excreted in the urine. Tmax and half-life were unaffected. Nifedipine appears to enhance the absorption of metformin. Metformin had minimal effects on nifedipine.

Cationic Drugs: Cationic drugs (e.g., amiloride, digoxin, morphine, procainamide, quinidine, quinine, ranitidine, triamterene, trimethoprim, and vancomycin) that are eliminated by renal tubular secretion theoretically have the potential for interaction with metformin by competing for common renal tubular transport systems. Such interaction between metformin and oral cimetidine has been observed in normal healthy volunteers in both single- and multiple-dose, metformin-cimetidine drug interaction studies, with a 60% increase in peak metformin plasma and whole blood concentrations and a 40% increase in plasma and whole blood metformin AUC. There was no change in elimination half-life in the single-dose study. Metformin had no effect on cimetidine pharmacokinetics. Although such interactions remain theoretical (except for cimetidine), careful patient monitoring and dose adjustment of AVANDAMET and/or the interfering drug is recommended in patients who are taking cationic medications that are excreted via the proximal renal tubular secretory system.

Other

Certain drugs tend to produce hyperglycemia and may lead to loss of glycemic control. These drugs include thiazides and other diuretics, corticosteroids, phenothiazines, thyroid products, estrogens, oral contraceptives, phenytoin, nicotinic acid, sympathomimetics, calcium channel blocking drugs, and isoniazid. When such drugs are administered to a patient receiving AVANDAMET, the patient should be closely observed to maintain adequate glycemic control.

In healthy volunteers, the pharmacokinetics of metformin and propranolol and metformin and ibuprofen were not affected when coadministered in single-dose interaction studies. Metformin is negligibly bound to plasma proteins and is therefore, less likely to interact with highly protein-bound drugs such as salicylates, sulfonamides, chloramphenicol, and probenecid.