Limited data with metformin hydrochloride extended-release tablets in pregnant women are not sufficient to determine a drug-associated risk for major birth defects or miscarriage. Published studies with metformin use during pregnancy have not reported a clear association with metformin and major birth defect or miscarriage risk [see Data]. There are risks to the mother and fetus associated with poorly controlled diabetes mellitus in pregnancy [see Clinical Considerations].
No adverse developmental effects were observed when metformin was administered to pregnant Sprague Dawley rats and rabbits during the period of organogenesis at doses up to 2- and 5-times, respectively, a 2,550 mg clinical dose, based on body surface area [see Data].
The estimated background risk of major birth defects is 6% to 10% in women with pre-gestational diabetes mellitus with an HbA 1C > 7 and has been reported to be as high as 20% to 25% in women with a HbA 1C > 10. The estimated background risk of miscarriage for the indicated population is unknown. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively.
Disease-associated maternal and/or embryo/fetal risk
Poorly-controlled diabetes mellitus in pregnancy increases the maternal risk for diabetic ketoacidosis, pre-eclampsia, spontaneous abortions, preterm delivery, stillbirth and delivery complications. Poorly controlled diabetes mellitus increases the fetal risk for major birth defects, stillbirth, and macrosomia related morbidity.
Published data from post-marketing studies have not reported a clear association with metformin and major birth defects, miscarriage, or adverse maternal or fetal outcomes when metformin was used during pregnancy. However, these studies cannot definitely establish the absence of any metformin-associated risk because of methodological limitations, including small sample size and inconsistent comparator groups.
Metformin hydrochloride did not adversely affect development outcomes when administered to pregnant rats and rabbits at doses up to 600 mg/kg/day. This represents an exposure of about 2 and 5 times a 2,550 mg clinical dose based on body surface area comparisons for rats and rabbits, respectively. Determination of fetal concentrations demonstrated a partial placental barrier to metformin.
Limited published studies report that metformin is present in human milk [see Data]. However, there is insufficient information to determine the effects of metformin on the breastfed infant and no available information on the effects of metformin on milk production. Therefore, the developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for metformin hydrochloride extended-release tablets and any potential adverse effects on the breastfed child from metformin hydrochloride extended-release tablets or from the underlying maternal condition.
Published clinical lactation studies report that metformin is present in human milk which resulted in infant doses approximately 0.11% to 1% of the maternal weight-adjusted dosage and a milk/plasma ratio ranging between 0.13 and 1. However, the studies were not designed to definitely establish the risk of use of metformin during lactation because of small sample size and limited adverse event data collected in infants.
Discuss the potential for unintended pregnancy with premenopausal women as therapy with metformin hydrochloride extended-release tablets may result in ovulation in some anovulatory women.
Metformin Hydrochloride Extended-Release Tablets
Safety and effectiveness of metformin hydrochloride extended-release tablets in pediatric patients have not been established.
Controlled clinical studies of metformin hydrochloride extended-release tablets did not include sufficient numbers of elderly patients to determine whether they respond differently from younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy and the higher risk of lactic acidosis. Assess renal function more frequently in elderly patients [see Warnings and Precautions (5.1)] .
Metformin is substantially excreted by the kidney, and the risk of metformin accumulation and lactic acidosis increases with the degree of renal impairment. Metformin hydrochloride extended-release tablets are contraindicated in severe renal impairment, patients with an estimated glomerular filtration rate (eGFR) below 30 mL/min/1.73 m 2 [see Dosage and Administration (2.3), Contraindications (4), Warnings and Precautions (5.1), and Clinical Pharmacology (12.3)] .
Use of metformin in patients with hepatic impairment has been associated with some cases of lactic acidosis. Metformin hydrochloride extended-release tablets are not recommended in patients with hepatic impairment. [see Warnings and Precautions (5.1)] .
Overdose of metformin hydrochloride has occurred, including ingestion of amounts greater than 50 grams. Hypoglycemia was reported in approximately 10% of cases, but no causal association with metformin has been established. Lactic acidosis has been reported in approximately 32% of metformin overdose cases [see Warnings and Precautions (5.1)] . Metformin is dialyzable with a clearance of up to 170 mL/min under good hemodynamic conditions. Therefore, hemodialysis may be useful for removal of accumulated drug from patients in whom metformin overdosage is suspected.
Metformin hydrochloride extended-release tablets, USP contain the antihyperglycemic agent metformin, which is a biguanide, in the form of monohydrochloride. The chemical name of metformin hydrochloride is N,N -dimethylimidodicarbonimidic diamide hydrochloride. The structural formula is as shown below:
Metformin hydrochloride is a white to off-white crystalline compound with a molecular formula of C 4 H 11 N 5 ∙ HCl and a molecular weight of 165.63. It is freely soluble in water and is practically insoluble in acetone, ether, and chloroform. The pK a of metformin is 12.4. The pH of a 1% aqueous solution of metformin hydrochloride is 6.68.
Metformin hydrochloride extended-release tablets, USP contain 500 mg or 750 mg of metformin hydrochloride, which is equivalent to 389.93 mg, 584.90 mg metformin base, respectively.
Metformin hydrochloride extended-release tablets USP, 500 mg and 750 mg contain the inactive ingredients carboxymethylcellulose sodium, copovidone, hypromellose, magnesium stearate and microcrystalline cellulose.
The USP dissolution test is pending.
Metformin is an antihyperglycemic agent which improves glucose tolerance in patients with type 2 diabetes mellitus, lowering both basal and postprandial plasma glucose. Metformin decreases hepatic glucose production, decreases intestinal absorption of glucose, and improves insulin sensitivity by increasing peripheral glucose uptake and utilization. With metformin therapy, insulin secretion remains unchanged while fasting insulin levels and day-long plasma insulin response may decrease.
Following a single oral dose of metformin hydrochloride extended-release tablets, C max is achieved with a median value of 7 hours and a range of 4 to 8 hours. Peak plasma levels are approximately 20% lower compared to the same dose of metformin hydrochloride tablets, however, the extent of absorption (as measured by AUC) is comparable to metformin hydrochloride tablets.
At steady state, the AUC and C max are less than dose proportional for metformin hydrochloride extended-release tablets within the range of 500 to 2,000 mg administered once daily. Peak plasma levels are approximately 0.6, 1.1, 1.4 and 1.8 mcg/mL for 500, 1,000, 1,500, and 2,000 mg once-daily doses, respectively. The extent of metformin absorption (as measured by AUC) from metformin hydrochloride extended-release tablets at a 2,000 mg once-daily dose is similar to the same total daily dose administered as metformin hydrochloride tablets 1,000 mg twice daily. After repeated administration of metformin hydrochloride extended-release tablets, metformin did not accumulate in plasma.
Effect of food: Food decreases the extent of absorption and slightly delays the absorption of metformin, as shown by approximately a 40% lower mean peak plasma concentration (C max ), a 25% lower area under the plasma concentration versus time curve (AUC), and a 35-minute prolongation of time to peak plasma concentration (T max ) following administration of a single 850 mg tablet of metformin hydrochloride with food, compared to the same tablet strength administered fasting.
Although the extent of metformin absorption (as measured by AUC) from the metformin hydrochloride extended-release tablets increased by approximately 50% when given with food, there was no effect of food on C max and T max of metformin. Both high and low fat meals had the same effect on the pharmacokinetics of metformin hydrochloride extended-release tablets.
The apparent volume of distribution (V/F) of metformin following single oral doses of metformin hydrochloride tablets 850 mg averaged 654 ± 358 L. Metformin is negligibly bound to plasma proteins. Metformin partitions into erythrocytes, most likely as a function of time.
Intravenous single-dose studies in normal subjects demonstrate that metformin is excreted unchanged in the urine and does not undergo hepatic metabolism (no metabolites have been identified in humans) nor biliary excretion.
Renal clearance (see Table 3) is approximately 3.5 times greater than creatinine clearance, which indicates that tubular secretion is the major route of metformin elimination. Following oral administration, approximately 90% of the absorbed drug is eliminated via the renal route within the first 24 hours, with a plasma elimination half-life of approximately 6.2 hours. In blood, the elimination half-life is approximately 17.6 hours, suggesting that the erythrocyte mass may be a compartment of distribution.
In patients with decreased renal function the plasma and blood half-life of metformin is prolonged and the renal clearance is decreased (see Table 2) [See Dosage and Administration (2.3), Contraindications (4), Warnings and Precautions (5.1) and Use in Specific Populations (8.6)] .
Limited data from controlled pharmacokinetic studies of metformin hydrochloride tablets in healthy elderly subjects suggest that total plasma clearance of metformin is decreased, the half-life is prolonged, and C max is increased, compared to healthy young subjects. It appears that the change in metformin pharmacokinetics with aging is primarily accounted for by a change in renal function (see Table 3) . [See Warnings and Precautions (5.1) and Use in Specific Populations (8.5)] .
|Subject Groups: Metformin Hydrochloride Tablets Dose * (number of subjects)||C max †(mcg/mL)||T max ‡(hrs)||Renal Clearance (mL/min)|
|Healthy, nondiabetic adults:|
|500 mg single dose (24)||1.03 (± 0.33)||2.75 (± 0.81)||600 (± 132)|
|850 mg single dose (74) §||1.60 (± 0.38)||2.64 (± 0.82)||552 (± 139)|
|850 mg three times daily for 19 doses ¶ (9)||2.01 (± 0.42)||1.79 (± 0.94)||642 (± 173)|
|Adults with type 2 diabetes mellitus:|
|850 mg single dose (23)||1.48 (± 0.5)||3.32 (± 1.08)||491 (± 138)|
|850 mg three times daily for 19 doses ¶ (9)||1.90 (± 0.62)||2.01 (± 1.22)||550 (± 160)|
|Elderly #, healthy nondiabetic adults:|
|850 mg single dose (12)||2.45 (± 0.70)||2.71 (± 1.05)||412 (± 98)|
|850 mg single dose|
|Mild (CL cr Þ 61 to 90 mL/min) (5)||1.86 (± 0.52)||3.20 (± 0.45)||384 (± 122)|
|Moderate (CL cr 31 to 60 mL/min) (4)||4.12 (± 1.83)||3.75 (± 0.50)||108 (± 57)|
|Severe (CL cr 10 to 30 mL/min) (6)||3.93 (± 0.92)||4.01 (± 1.10)||130 (± 90)|
After administration of a single oral metformin hydrochloride 500 mg tablet with food, geometric mean metformin C max and AUC differed less than 5% between pediatric type 2 diabetic patients (12 to 16 years of age) and gender- and weight-matched healthy adults (20 to 45 years of age), all with normal renal function.
Metformin pharmacokinetic parameters did not differ significantly between normal subjects and patients with type 2 diabetes mellitus when analyzed according to gender (males = 19, females = 16).
No studies of metformin pharmacokinetic parameters according to race have been performed.
In Vivo Assessment of Drug Interactions
|Coadministered Drug||Dose of Coadministered Drug *||Dose of Metformin *||Geometric Mean Ratio (ratio with/without coadministered drug) No Effect = 1.00|
|AUC †||C max|
|No dosing adjustments required for the following:|
|Glyburide||5 mg||850 mg||metformin||0.91 ‡||0.93 ‡|
|Furosemide||40 mg||850 mg||metformin||1.09 ‡||1.22 ‡|
|Nifedipine||10 mg||850 mg||metformin||1.16||1.21|
|Propranolol||40 mg||850 mg||metformin||0.90||0.94|
|Ibuprofen||400 mg||850 mg||metformin||1.05 ‡||1.07 ‡|
|Cationic drugs eliminated by renal tubular secretion may reduce metformin elimination [See Warnings and Precautions (5.1) and Drug Interactions (7).]|
|Cimetidine||400 mg||850 mg||metformin||1.40||1.61|
|Carbonic anhydrase inhibitors may cause metabolic acidosis [See Warnings and Precautions (5.1) and Drug Interactions (7).]|
|Topiramate||100 mg §||500 mg §||metformin||1.25 §||1.17|
|Coadministered Drug||Dose of Coadministered Drug *||Dose of Metformin *||Geometric Mean Ratio (ratio with/without metformin) No Effect = 1.00|
|AUC †||C max|
|No dosing adjustments required for the following:|
|Glyburide||5 mg||850 mg||glyburide||0.78 ‡||0.63 ‡|
|Furosemide||40 mg||850 mg||furosemide||0.87 ‡||0.69 ‡|
|Nifedipine||10 mg||850 mg||nifedipine||1.10 §||1.08|
|Propranolol||40 mg||850 mg||propranolol||1.01 §||1.02|
|Ibuprofen||400 mg||850 mg||ibuprofen||0.97 ¶||1.01 ¶|
|Cimetidine||400 mg||850 mg||cimetidine||0.95 §||1.01|
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