Metformin ER 500 Mg: Package Insert and Label Information (Page 2 of 4)

7 DRUG INTERACTIONS

Table 3 presents clinically significant drug interactions with metformin hydrochloride extended-release tablets. Table 3: Clinically Significant Drug Interactions with Metformin Hydrochloride Extended-Release Tablets

Carbonic Anhydrase Inhibitors
Clinical Impact: Carbonic anhydrase inhibitors frequently cause a decrease in serum bicarbonate and induce non-anion gap, hyperchloremic metabolic acidosis. Concomitant use of these drugs with metformin hydrochloride extended-release tablets may increase the risk for lactic acidosis.
Intervention: Consider more frequent monitoring of these patients.
Examples: Topiramate, zonisamide, acetazolamide or dichlorphenamide.
Drugs that Reduce Metformin Hydrochloride Extended-Release Tablets Clearance
Clinical Impact: 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) could increase systemic exposure to metformin and may increase the risk for lactic acidosis [ see Clinical Pharmacology (12.3)].
Intervention: Consider the benefits and risks of concomitant use with metformin hydrochloride extended-release tablets.
Examples: Ranolazine, vandetanib, dolutegravir, and cimetidine.
Alcohol
Clinical Impact: Alcohol is known to potentiate the effect of metformin on lactate metabolism.
Intervention: Warn patients against excessive alcohol intake while receiving metformin hydrochloride extended-release tablets.
Insulin Secretagogues or Insulin
Clinical Impact: Coadministration of metformin hydrochloride extended-release tablets with an insulin secretagogue (e.g., sulfonylurea) or insulin may increase the risk of hypoglycemia.
Intervention: Patients receiving an insulin secretagogue or insulin may require lower doses of the insulin secretagogue or insulin.
Drugs Affecting Glycemic Control
Clinical Impact: Certain drugs tend to produce hyperglycemia and may lead to loss of glycemic control.
Intervention: When such drugs are administered to a patient receiving metformin hydrochloride extended-release tablets, observe the patient closely for loss of blood glucose control. When such drugs are withdrawn from a patient receiving metformin hydrochloride extended-release tablets, observe the patient closely for hypoglycemia.
Examples: Thiazides and other diuretics, corticosteroids, phenothiazines, thyroid products, estrogens, oral contraceptives, phenytoin, nicotinic acid, sympathomimetics, calcium channel blockers, and isoniazid.

8 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

Risk Summary
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 2550 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 HbA1C >7 and has been reported to be as high as 20 to 25% in women with a HbA1C >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.

Clinical Considerations
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.

Data

Human Data
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.


Animal Data
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 2550 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.

8.2 Lactation

Risk Summary
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.

Data 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.

8.3 Females and Males of Reproductive Potential

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.

8.4 Pediatric Use

Metformin Hydrochloride Extended-Release Tablets

Safety and effectiveness of metformin hydrochloride extended-release tabletsin pediatric patients have not been established.

8.5 Geriatric Use

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, although other reported clinical experience has not identified differences in responses between the elderly and 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) ].

8.6 Renal Impairment

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) ].

8.7 Hepatic Impairment

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) ].

10 OVERDOSAGE

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.

11 DESCRIPTION

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-structure-jpg

Metformin hydrochloride, USP 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 165.62. Metformin hydrochloride is freely soluble in water, slightly soluble in ethanol, practically insoluble in acetone and in methylene chloride. The pKa of metformin is 12.4. The pH of a 1% aqueous solution of metformin hydrochloride is 6.35.
Metformin hydrochloride extended-release tablets USP, contains 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 tablets contain the inactive ingredients hypromellose, magnesium stearate, and polyvinyl pyrrolidone
Metformin hydrochloride extended-release tablets USP, 750 mg tablets contain the inactive ingredients hypromellose, magnesium stearate, and polyvinyl pyrrolidone
Meets USP Dissolution Test 10

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

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.

12.3 Pharmacokinetics

Absorption
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 2000 mg administered once daily. Peak plasma levels are approximately 0.6, 1.1, 1.4 and 1.8 mcg/mL for 500, 1000, 1500, and 2000 mg once-daily doses, respectively. The extent of metformin absorption (as measured by AUC) from metformin hydrochloride extended-release tablets at a 2000 mg once-daily dose is similar to the same total daily dose administered as metformin hydrochloride tablets 1000 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 tablets 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 tablet 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.
Distribution
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.


Metabolism
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.

Elimination
Renal clearance (see Table 4) 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.

Specific Populations
Renal Impairment
In patients with decreased renal function the plasma and blood half-life of metformin is prolonged and the renal clearance is decreased (see Table 3) [see Dosage and Administration (2.3),Contraindications (4), Warnings and Precautions (5.1) and Use in Specific Populations (8.6) ].

Hepatic Impairment
No pharmacokinetic studies of metformin have been conducted in patients with hepatic impairment [see Warnings and Precautions (5.1) and Use in Specific Populations (8.7)].

Geriatrics 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 4). [see Warnings and Precautions (5.1)and Use in Specific Populations (8.5)].

Table 4: Select Mean (±S.D.) Metformin Pharmacokinetic Parameters Following Single or Multiple Oral Doses of Metformin Hydrochloride Tablets

a All doses given fasting except the first 18 doses of the multiple dose studies b Peak plasma concentration c Time to peak plasma concentration d Combined results (average means) of five studies: mean age 32 years (range 23 to 59 years) e Kinetic study done following dose 19, given fasting f Elderly subjects, mean age 71 years (range 65 to 81 years) g CL cr = creatinine clearance normalized to body surface area of 1.73 m 2
Subject Groups: Metformin Hydrochloride Tablets dose a (number of subjects) C max b (mcg/mL) T max c (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) d 1.60 (±0.38) 2.64 (±0.82) 552 (±139)
850 mg three times daily for 19 doses e (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 dosese (9) 1.90 (±0.62) 2.01 (±1.22) 550 (±160)
Elderly f , healthy nondiabetic adults:
850 mg single dose (12) 2.45 (±0.70) 2.71 (±1.05) 412 (±98)
Renal-impaired adults: 850 mg single dose
Mild (CLcr g 61 to 90 mL/min) (5) 1.86 (±0.52) 3.20 (±0.45) 384 (±122)
Moderate (CLcr 31 to 60 mL/min) (4) 4.12 (±1.83) 3.75 (±0.50) 108 (±57)
Severe (CLcr 10 to 30 mL/min) (6) 3.93 (±0.92) 4.01 (±1.10) 130 (±90)

Gender

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).

Race

No studies of metformin pharmacokinetic parameters according to race have been performed.

Drug Interactions

In Vivo Assessment of Drug Interactions

Table 5: Effect of Coadministered Drug on Plasma Metformin Systemic Exposure

* All metformin and coadministered drugs were given as single doses AUC = AUC (INF) Ratio of arithmetic means § At steady state with topiramate 100 mg every 12 hours and metformin 500 mg every 12 hours; AUC = AUC 0-12h
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 (5.9) and Drug Interactions (7.2).]
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 (7.1).]
Topiramate 100 mg § 500 mg § metformin 1.25 § 1.17

Table 6: Effect of Metformin on Coadministered Drug Systemic Exposure

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

*All metformin and coadministered drugs were given as single doses

+ AUC = AUC (INF) unless otherwise noted

‡ Ratio of arithmetic means, p-value of difference <0.05

§AUC (0-24 hr) reported

¶ Ratio of arithmetic means

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