In clinical trials conducted in the U.S., over 1000 patients with type 2 diabetes mellitus have been treated with GLUMETZA 1500–2000 mg/day in active-controlled and placebo-controlled studies with the 500 mg dosage form.

In the 24-week active-controlled monotherapy trial, serious adverse events were reported in 3.6% (19/528) of the GLUMETZA-treated patients compared to 2.9% (5/174) of the patients treated with immediate-release metformin. During the 6-month open-label, uncontrolled, extension trial, an additional 10 (4.0%) GLUMETZA-treated patients reported a serious adverse event In the add-on to sulfonylurea study, a serious adverse event was reported in 2.1% (9/431) of the GLUMETZA+glyburide treated patients compared to 1.4% (2/144) of the placebo+glyburide treated patients. When the data from all clinical trials were combined, the most frequently (incidence ≥ 0.5 %) reported serious adverse events classified by system organ class were gastrointestinal disorders (1.0% of GLUMETZA-treated patients compared to 0% of patients not treated with GLUMETZA) and cardiac disorders (0.4% of GLUMETZA-treated patients compared to 0.5% of patients not treated with GLUMETZA). Only 2 serious adverse events (unstable angina [n=2] and pancreatitis [n=2]) were reported in more than one GLUMETZA-treated patient.

In the placebo-controlled study, patients receiving background glyburide (SU; sulfonylurea) therapy were randomized to receive add-on treatment of either one of three different regimens of GLUMETZA or placebo. In total, 431 patients received GLUMETZA + SU and 144 patients placebo + SU. Adverse events reported in greater than 5% of patients treated with GLUMETZA that were more common in the combined GLUMETZA + SU group than in the placebo + SU group are shown in Table 5.

In 0.7% of patients treated with GLUMETZA + SU, diarrhea was responsible for discontinuation of study medication compared to zero in the placebo + SU group.

Table 5: Treatment-Emergent Adverse Events Reported By > 5%* of Patients for the Combined Glumetza Group Versus Placebo Group

In the same study, the following adverse events were reported by 1-5% of patients for the combined Glumetza + SU group and these events occurred more commonly in the Glumetza-treated than in the placebo-treated patients:

Ear and labyrinth disorders: ear pain

Gastrointestinal disorders: vomiting NOS, dyspepsia, flatulence, abdominal pain upper, abdominal distension, abdominal pain NOS, toothache, loose stools

General disorders and administration site conditions: asthenia, chest pain

Immune system disorders: seasonal allergy

Infections and infestations: gastroenteritis viral NOS, tooth abscess, tonsillitis, fungal infection NOS

Injury, poisoning and procedural complications: muscle strain

Musculoskeletal and connective tissue disorders: pain in limb, myalgia, muscle cramp

Nervous system disorders: dizziness, tremor, sinus headache, hypoaesthesia

Respiratory, thoracic and mediastinal disorders: nasal congestion

Skin and subcutaneous tissue disorders: contusion

Vascular disorders: hypertension NOS

(Clinical Evaluation of Drug Interactions Conducted with metformin)

Glyburide — The influence of glyburide on GLUMETZA pharmacokinetics was assessed in a single-dose interaction study in healthy subjects. Co-administration of a single dose of 500 mg GLUMETZA and 5 mg glyburide did not result in any changes in metformin pharmacokinetics as AUC; Cmax as well as Tmax were unchanged. Changes in pharmacodynamics were not evaluated in this study (see DOSAGE AND ADMINISTRATION: Concomitant GLUMETZA and Oral Sulfonylurea Therapy).

Furosemide — A single-dose, metformin-furosemide drug interaction study in healthy subjects demonstrated that pharmacokinetic parameters of both compounds were affected by co-administration. Furosemide increased the metformin plasma and blood Cmax by 22% and blood AUC by 15%, without any significant change in metformin renal clearance. When administered with metformin, the Cmax 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 co-administered chronically.

Nifedipine — A single-dose, metformin-nifedipine drug interaction study in normal healthy volunteers demonstrated that co-administration of nifedipine increased plasma metformin Cmax 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, or 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 GLUMETZA 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 the 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 GLUMETZA, the patient should be closely observed for loss of blood glucose control. When such drugs are withdrawn from a patient receiving GLUMETZA, the patient should be observed closely for hypoglycemia. In healthy volunteers, the pharmacokinetics of metformin and propranolol, and metformin and ibuprofen were not affected when co-administered 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, as compared to the sulfonylureas, which are extensively bound to serum proteins.

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