Pregnancy

Pregnancy Teratogenic Effects: Pregnancy Category B Recent information strongly suggests that abnormal blood glucose levels during pregnancy are associated with a higher incidence of congenital abnormalities. Most experts recommend that insulin be used during pregnancy to maintain blood glucose levels as close to normal as possible. Because animal reproduction studies are not always predictive of human response, GLUCOPHAGE and GLUCOPHAGE XR should not be used during pregnancy unless clearly needed. There are no adequate and well-controlled studies in pregnant women with GLUCOPHAGE or GLUCOPHAGE XR. Metformin was not teratogenic in rats and rabbits at doses up to 600 mg/kg/day. This represents an exposure of about 2 and 6 times the maximum recommended human daily dose of 2000 mg based on body surface area comparisons for rats and rabbits, respectively. Determination of fetal concentrations demonstrated a partial placental barrier to metformin.

Drug Interactions

Drug Interactions (Clinical Evaluation of Drug Interactions Conducted with GLUCOPHAGE) Glyburide—In a single-dose interaction study in type 2 diabetes patients, coadministration of metformin and glyburide did not result in any changes in either metformin pharmacokinetics or pharmacodynamics. Decreases in glyburide AUC and Cmax were observed, but were highly variable. The single-dose nature of this study and the lack of correlation between glyburide blood levels and pharmacodynamic effects, makes the clinical significance of this interaction uncertain (see DOSAGE AND ADMINISTRATION: Concomitant GLUCOPHAGE or GLUCOPHAGE XR and Oral Sulfonylurea Therapy in Adult Patients ). 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 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 coadministered chronically. Nifedipine—A single-dose, metformin-nifedipine drug interaction study in normal healthy volunteers demonstrated that coadministration 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. Drugs that reduce metformin clearance— Concomitant use of drugs that interfere with common renal tubular transport systems involved in the renal elimination of metformin (e.g., organic cationic transporter-2 [OCT2] / multidrug and toxin extrusion [MATE] inhibitors such as ranolazine, vandetanib, dolutegravir, and cimetidine) could increase systemic exposure to metformin and may increase the risk for lactic acidosis. Consider the benefits and risks of concomitant use. 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. 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, as compared to the sulfonylureas, which are extensively bound to serum proteins. 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 GLUCOPHAGE or GLUCOPHAGE XR, the patient should be closely observed for loss of blood glucose control. When such drugs are withdrawn from a patient receiving GLUCOPHAGE or GLUCOPHAGE XR, the patient should be observed closely for hypoglycemia. Carbonic anhydrase inhibitors—Topiramate or other carbonic anhydrase inhibitors (e.g., zonisamide, acetazolamide or dichlorphenamide) frequently cause a decrease in serum bicarbonate and induce non-anion gap, hyperchloremic metabolic acidosis. Concomitant use of these drugs with GLUCOPHAGE or GLUCOPHAGE XR may increase the risk for lactic acidosis. Consider more frequent monitoring of these patients. Alcohol—Alcohol is known to potentiate the effect of metformin on lactate metabolism. Warn patients against excessive alcohol intake while receiving GLUCOPHAGE OR GLUCOPHAGE XR.

Indications And Usage

INDICATIONS AND USAGE GLUCOPHAGE (metformin hydrochloride) Tablets is indicated as an adjunct to diet and exercise to improve glycemic control in adults and children with type 2 diabetes mellitus. GLUCOPHAGE XR (metformin hydrochloride) Extended-Release Tablets is indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus.

Clinical Studies

Clinical Studies GLUCOPHAGE In a double-blind, placebo-controlled, multicenter US clinical trial involving obese patients with type 2 diabetes whose hyperglycemia was not adequately controlled with dietary management alone (baseline fasting plasma glucose [FPG] of approximately 240 mg/dL), treatment with GLUCOPHAGE (up to 2550 mg/day) for 29 weeks resulted in significant mean net reductions in fasting and postprandial plasma glucose (PPG) and hemoglobin A1c (HbA1c) of 59 mg/dL, 83 mg/dL, and 1.8%, respectively, compared to the placebo group (see Table 2). Table 2: GLUCOPHAGE vs Placebo Summary of Mean Changes from Baseline* in Fasting Plasma Glucose, HbA1c, and Body Weight, at Final Visit (29-week study) GLUCOPHAGE (n=141) Placebo (n=145) p-Value * All patients on diet therapy at Baseline ** Not statistically significant FPG (mg/dL) Baseline Change at FINAL VISIT 241.5 –53.0 237.7 6.3 NS** 0.001 Hemoglobin A1c (%) Baseline Change at FINAL VISIT 8.4 –1.4 8.2 0.4 NS** 0.001 Body Weight (lbs) Baseline Change at FINAL VISIT 201.0 –1.4 206.0 –2.4 NS** NS** A 29-week, double-blind, placebo-controlled study of GLUCOPHAGE and glyburide, alone and in combination, was conducted in obese patients with type 2 diabetes who had failed to achieve adequate glycemic control while on maximum doses of glyburide (baseline FPG of approximately 250 mg/dL) (see Table 3). Patients randomized to the combination arm started therapy with GLUCOPHAGE 500 mg and glyburide 20 mg. At the end of each week of the first 4 weeks of the trial, these patients had their dosages of GLUCOPHAGE increased by 500 mg if they had failed to reach target fasting plasma glucose. After week 4, such dosage adjustments were made monthly, although no patient was allowed to exceed GLUCOPHAGE 2500 mg. Patients in the GLUCOPHAGE only arm (metformin plus placebo) followed the same titration schedule. At the end of the trial, approximately 70% of the patients in the combination group were taking GLUCOPHAGE 2000 mg/glyburide 20 mg or GLUCOPHAGE 2500 mg/glyburide 20 mg. Patients randomized to continue on glyburide experienced worsening of glycemic control, with mean increases in FPG, PPG, and HbA1c of 14 mg/dL, 3 mg/dL, and 0.2%, respectively. In contrast, those randomized to GLUCOPHAGE (up to 2500 mg/day) experienced a slight improvement, with mean reductions in FPG, PPG, and HbA1c of 1 mg/dL, 6 mg/dL, and 0.4%, respectively. The combination of GLUCOPHAGE and glyburide was effective in reducing FPG, PPG, and HbA1c levels by 63 mg/dL, 65 mg/dL, and 1.7%, respectively. Compared to results of glyburide treatment alone, the net differences with combination treatment were –77 mg/dL, –68 mg/dL, and –1.9%, respectively (see Table 3). Table 3: Combined GLUCOPHAGE/Glyburide (Comb) vs Glyburide (Glyb) or GLUCOPHAGE (GLU) Monotherapy: Summary of Mean Changes from Baseline* in Fasting Plasma Glucose, HbA1c, and Body Weight, at Final Visit (29-week study) p-values Comb (n=213) Glyb (n=209) GLU (n=210) Glyb vs Comb GLU vs Comb GLU vs Glyb * All patients on glyburide, 20 mg/day, at Baseline ** Not statistically significant Fasting Plasma Glucose (mg/dL) Baseline Change at FINAL VISIT 250.5 –63.5 247.5 13.7 253.9 –0.9 NS** 0.001 NS** 0.001 NS** 0.025 Hemoglobin A1c (%) Baseline Change at FINAL VISIT 8.8 –1.7 8.5 0.2 8.9 –0.4 NS** 0.001 NS** 0.001 0.007 0.001 Body Weight (lbs) Baseline Change at FINAL VISIT 202.2 0.9 203.0 –0.7 204.0 –8.4 NS** 0.011 NS** 0.001 NS** 0.001 The magnitude of the decline in fasting blood glucose concentration following the institution of GLUCOPHAGE Tablets therapy was proportional to the level of fasting hyperglycemia. Patients with type 2 diabetes with higher fasting glucose concentrations experienced greater declines in plasma glucose and glycosylated hemoglobin. In clinical studies, GLUCOPHAGE, alone or in combination with a sulfonylurea, lowered mean fasting serum triglycerides, total cholesterol, and LDL cholesterol levels, and had no adverse effects on other lipid levels (see Table 4). Table 4: Summary of Mean Percent Change From Baseline of Major Serum Lipid Variables at Final Visit (29-week studies) GLUCOPHAGE vs Placebo Combined GLUCOPHAGE/Glyburide vs Monotherapy GLUCOPHAGE (n=141) Placebo (n=145) GLUCOPHAGE (n=210) GLUCOPHAGE/ Glyburide (n=213) Glyburide (n=209) Total Cholesterol (mg/dL) Baseline Mean % Change at FINAL VISIT 211.0 –5% 212.3 1% 213.1 –2% 215.6 –4% 219.6 1% Total Triglycerides (mg/dL) Baseline Mean % Change at FINAL VISIT 236.1 –16% 203.5 1% 242.5 –3% 215.0 –8% 266.1 4% LDL-Cholesterol (mg/dL) Baseline Mean % Change at FINAL VISIT 135.4 –8% 138.5 1% 134.3 –4% 136.0 –6% 137.5 3% HDL-Cholesterol (mg/dL) Baseline Mean % Change at FINAL VISIT 39.0 2% 40.5 –1% 37.2 5% 39.0 3% 37.0 1% In contrast to sulfonylureas, body weight of individuals on GLUCOPHAGE tended to remain stable or even decrease somewhat (see Tables 2 and 3). A 24-week, double-blind, placebo-controlled study of GLUCOPHAGE plus insulin versus insulin plus placebo was conducted in patients with type 2 diabetes who failed to achieve adequate glycemic control on insulin alone (see Table 5). Patients randomized to receive GLUCOPHAGE plus insulin achieved a reduction in HbA1c of 2.10%, compared to a 1.56% reduction in HbA1c achieved by insulin plus placebo. The improvement in glycemic control was achieved at the final study visit with 16% less insulin, 93.0 U/day vs 110.6 U/day, GLUCOPHAGE plus insulin versus insulin plus placebo, respectively, p=0.04. Table 5: Combined GLUCOPHAGE/Insulin vs Placebo/Insulin Summary of Mean Changes from Baseline in HbA1c and Daily Insulin Dose GLUCOPHAGE/ Insulin (n=26) Placebo/ Insulin (n=28) Treatment Difference Mean ± SE a Statistically significant using analysis of covariance with baseline as covariate (p=0.04) Not significant using analysis of variance (values shown in table) b Statistically significant for insulin (p=0.04) Hemoglobin A1c (%) Baseline Change at FINAL VISIT 8.95 –2.10 9.32 –1.56 –0.54 ± 0.43a Insulin Dose (U/day) Baseline Change at FINAL VISIT 93.12 –0.15 94.64 15.93 –16.08 ± 7.77b A second double-blind, placebo-controlled study (n=51), with 16 weeks of randomized treatment, demonstrated that in patients with type 2 diabetes controlled on insulin for 8 weeks with an average HbA1c of 7.46 ± 0.97%, the addition of GLUCOPHAGE maintained similar glycemic control (HbA1c 7.15 ± 0.61 vs 6.97 ± 0.62 for GLUCOPHAGE plus insulin and placebo plus insulin, respectively) with 19% less insulin versus baseline (reduction of 23.68 ± 30.22 vs an increase of 0.43 ± 25.20 units for GLUCOPHAGE plus insulin and placebo plus insulin, p<0.01). In addition, this study demonstrated that the combination of GLUCOPHAGE plus insulin resulted in reduction in body weight of 3.11 ± 4.30 lbs, compared to an increase of 1.30 ± 6.08 lbs for placebo plus insulin, p=0.01. GLUCOPHAGE XR A 24-week, double-blind, placebo-controlled study of GLUCOPHAGE XR, taken once daily with the evening meal, was conducted in patients with type 2 diabetes who had failed to achieve glycemic control with diet and exercise (HbA1c 7.0%-10.0%, FPG 126-270 mg/dL). Patients entering the study had a mean baseline HbA1c of 8.0% and a mean baseline FPG of 176 mg/dL. After 12 weeks treatment, mean HbA1c had increased from baseline by 0.1% and mean FPG decreased from baseline by 2 mg/dL in the placebo group, compared with a decrease in mean HbA1c of 0.6% and a decrease in mean FPG of 23 mg/dL in patients treated with GLUCOPHAGE XR 1000 mg once daily. Subsequently, the treatment dose was increased to 1500 mg once daily if HbA1c was ≥7.0% but <8.0% (patients with HbA1c ≥8.0% were discontinued from the study). At the final visit (24-week), mean HbA1c had increased 0.2% from baseline in placebo patients and decreased 0.6% with GLUCOPHAGE XR. A 16-week, double-blind, placebo-controlled, dose-response study of GLUCOPHAGE XR, taken once daily with the evening meal or twice daily with meals, was conducted in patients with type 2 diabetes who had failed to achieve glycemic control with diet and exercise (HbA1c 7.0%-11.0%, FPG 126-280 mg/dL). Changes in glycemic control and body weight are shown in Table 6. Table 6: Summary of Mean Changes from Baseline* in HbA1c, Fasting Plasma Glucose, and Body Weight at Final Visit (16-week study) GLUCOPHAGE XR Placebo 500 mg Once Daily 1000 mg Once Daily 1500 mg Once Daily 2000 mg Once Daily 1000 mg Twice Daily * All patients on diet therapy at Baseline a All comparisons versus Placebo ** Not statistically significant Hemoglobin A1c (%) (n=115) (n=115) (n=111) (n=125) (n=112) (n=111) Baseline 8.2 8.4 8.3 8.4 8.4 8.4 Change at FINAL VISIT –0.4 –0.6 –0.9 –0.8 –1.1 0.1 p-valuea <0.001 <0.001 <0.001 <0.001 <0.001 – FPG (mg/dL) (n=126) (n=118) (n=120) (n=132) (n=122) (n=113) Baseline 182.7 183.7 178.9 181.0 181.6 179.6 Change at FINAL VISIT –15.2 –19.3 –28.5 –29.9 –33.6 7.6 p-valuea <0.001 <0.001 <0.001 <0.001 <0.001 – Body Weight (lbs) (n=125) (n=119) (n=117) (n=131) (n=119) (n=113) Baseline 192.9 191.8 188.3 195.4 192.5 194.3 Change at FINAL VISIT –1.3 –1.3 –0.7 –1.5 –2.2 –1.8 p-valuea NS** NS** NS** NS** NS** – Compared with placebo, improvement in glycemic control was seen at all dose levels of GLUCOPHAGE XR Extended-Release Tablets and treatment was not associated with any significant change in weight (see DOSAGE AND ADMINISTRATION for dosing recommendations for GLUCOPHAGE and GLUCOPHAGE XR). A 24-week, double-blind, randomized study of GLUCOPHAGE XR, taken once daily with the evening meal, and GLUCOPHAGE Tablets, taken twice daily (with breakfast and evening meal), was conducted in patients with type 2 diabetes who had been treated with GLUCOPHAGE 500 mg twice daily for at least 8 weeks prior to study entry. The GLUCOPHAGE dose had not necessarily been titrated to achieve a specific level of glycemic control prior to study entry. Patients qualified for the study if HbA1c was ≤8.5% and FPG was ≤200 mg/dL. Changes in glycemic control and body weight are shown in Table 7. Table 7: Summary of Mean Changes from Baseline* in HbA1c, Fasting Plasma Glucose, and Body Weight at Week 12 and at Final Visit (24-week study) GLUCOPHAGE 500 mg Twice Daily GLUCOPHAGE XR 1000 mg Once Daily 1500 mg Once Daily * All patients on GLUCOPHAGE 500 mg twice daily at Baseline a n=68 Hemoglobin A1c (%) (n=67) (n=72) (n=66) Baseline 7.06 6.99 7.02 Change at 12 Weeks 0.14 0.23 0.04 (95% CI) (–0.03, 0.31) (0.10, 0.36) (–0.08, 0.15) Change at FINAL VISIT 0.14a 0.27 0.13 (95% CI) (–0.04, 0.31) (0.11, 0.43) (–0.02, 0.28) FPG (mg/dL) (n=69) (n=72) (n=70) Baseline 127.2 131.0 131.4 Change at 12 Weeks 12.9 9.5 3.7 (95% CI) (6.5, 19.4) (4.4, 14.6) (–0.4, 7.8) Change at FINAL VISIT 14.0 11.5 7.6 (95% CI) (7.0, 21.0) (4.4, 18.6) (1.0, 14.2) Body Weight (lbs) (n=71) (n=74) (n=71) Baseline 210.3 202.8 192.7 Change at 12 Weeks 0.4 0.9 0.7 (95% CI) (–0.4, 1.5) (0.0, 2.0) (–0.4, 1.8) Change at FINAL VISIT 0.9 1.1 0.9 (95% CI) (–0.4, 2.2) (–0.2, 2.4) (–0.4, 2.0) After 12 weeks of treatment, there was an increase in mean HbA1c in all groups; in the GLUCOPHAGE XR 1000 mg group, the increase from baseline of 0.23% was statistically significant (see DOSAGE AND ADMINISTRATION). Changes in lipid parameters in the previously described placebo-controlled dose-response study of GLUCOPHAGE XR are shown in Table 8. Table 8: Summary of Mean Percent Changes from Baseline* in Major Lipid Variables at Final Visit (16-week study) GLUCOPHAGE XR Placebo 500 mg Once Daily 1000 mg Once Daily 1500 mg Once Daily 2000 mg Once Daily 1000 mg Twice Daily * All patients on diet therapy at Baseline Total Cholesterol (mg/dL) (n=120) (n=113) (n=110) (n=126) (n=117) (n=110) Baseline 210.3 218.1 214.6 204.4 208.2 208.6 Mean % Change at FINAL VISIT 1.0% 1.7% 0.7% –1.6% –2.6% 2.6% Total Triglycerides (mg/dL) (n=120) (n=113) (n=110) (n=126) (n=117) (n=110) Baseline 220.2 211.9 198.0 194.2 179.0 211.7 Mean % Change at FINAL VISIT 14.5% 9.4% 15.1% 14.9% 9.4% 10.9% LDL-Cholesterol (mg/dL) (n=119) (n=113) (n=109) (n=126) (n=117) (n=107) Baseline 131.0 134.9 135.8 125.8 131.4 131.9 Mean % Change at FINAL VISIT –1.4% –1.6% –3.5% –3.3% –5.5% 3.2% HDL-Cholesterol (mg/dL) (n=120) (n=108) (n=108) (n=125) (n=117) (n=108) Baseline 40.8 41.6 40.6 40.2 42.4 39.4 Mean % Change at FINAL VISIT 6.2% 8.6% 5.5% 6.1% 7.1% 5.8% Changes in lipid parameters in the previously described study of GLUCOPHAGE and GLUCOPHAGE XR are shown in Table 9. Table 9: Summary of Mean Percent Changes from Baseline* in Major Lipid Variables at Final Visit (24-week study) GLUCOPHAGE GLUCOPHAGE XR 500 mg Twice Daily 1000 mg Once Daily 1500 mg Once Daily * All patients on GLUCOPHAGE 500 mg twice daily at Baseline Total Cholesterol (mg/dL) (n=68) (n=70) (n=66) Baseline 199.0 201.9 201.6 Mean % Change at FINAL VISIT 0.1% 1.3% 0.1% Total Triglycerides (mg/dL) (n=68) (n=70) (n=66) Baseline 178.0 169.2 206.8 Mean % Change at FINAL VISIT 6.3% 25.3% 33.4% LDL-Cholesterol (mg/dL) (n=68) (n=70) (n=66) Baseline 122.1 126.2 115.7 Mean % Change at FINAL VISIT −1.3% −3.3% −3.7% HDL-Cholesterol (mg/dL) (n=68) (n=70) (n=65) Baseline 41.9 41.7 44.6 Mean % Change at FINAL VISIT 4.8% 1.0% –2.1%

Overdosage

Adverse Reactions

Mechanism

Contraindications

Nursing Mothers