METFORMIN HYDROCHLORIDE tablet, film coated

United States - English - NLM (National Library of Medicine)

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Active ingredient:
METFORMIN HYDROCHLORIDE (UNII: 786Z46389E) (METFORMIN - UNII:9100L32L2N)
Available from:
NuCare Pharmaceuticals,Inc.
Administration route:
ORAL
Prescription type:
PRESCRIPTION DRUG
Therapeutic indications:
Metformin hydrochloride tablets, USP are indicated as an adjunct to diet and exercise to improve glycemic control in adults and pediatric patients 10 years of age and older with type 2 diabetes mellitus. Metformin hydrochloride tablets are contraindicated in patients with:  - Severe renal impairment (eGFR below 30 mL/min/1.73 m 2 ) [see Warnings and Precautions (5.1) ].   - Hypersensitivity to metformin.  - Acute or chronic metabolic acidosis, including diabetic ketoacidosis, with or without coma. Risk Summary Limited data with metformin hydrochloride 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 Considerat
Product summary:
Metformin Hydrochloride Tablets USP, 1,000 mg are supplied as white to off white, oval, biconvex, blackberry flavored, film coated tablets, bisected on both sides and debossed with L and 11 on either side of bisect line on one side. NDC 68071-2316-6 BOTTLES OF 60 Store at 20° to 25°C (68° to 77°F); excursions permitted between 15° to 30°C (59° to 86°F) [See USP Controlled Room Temperature]. Dispense in light-resistant containers.
Authorization status:
Abbreviated New Drug Application
Authorization number:
68071-2316-6

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METFORMIN HYDROCHLORIDE- metformin hydrochloride tablet, film coated

NuCare Pharmaceuticals,Inc.

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HIGHLIGHTS OF PRESCRIBING INFORMATION

These highlights do not include all the information needed to use METFORMIN HYDROCHLORIDE TABLETS

safely and effectively. See full prescribing information for METFORMIN HYDROCHLORIDE TABLETS.

METFORMIN HYDROCHLORIDE tablets, for oral use

Initial U.S. Approval: 1995

WARNING: LACTIC ACIDOSIS

See full prescribing information for complete boxed warning.

Postmarketing cases of metformin-associated lactic acidosis have resulted in death, hypothermia,

hypotension, and resistant bradyarrhythmias. Symptoms included malaise, myalgias, respiratory distress,

somnolence, and abdominal pain. Laboratory abnormalities included elevated blood lactate levels, anion

gap acidosis, increased lactate/pyruvate ratio; and metformin plasma levels generally >5 mcg/mL. ( 5.1)

Risk factors include renal impairment, concomitant use of certain drugs, age >65 years old,

radiological studies with contrast, surgery and other procedures, hypoxic states, excessive alcohol intake,

and hepatic impairment. Steps to reduce the risk of and manage metformin-associated lactic acidosis in

these high risk groups are provided in the Full Prescribing Information. ( 5.1)

If lactic acidosis is suspected, discontinue metformin hydrochloride and institute general supportive

measures in a hospital setting. Prompt hemodialysis is recommended. ( 5.1)

INDICATIONS AND USAGE

Metformin hydrochloride tablets, USP are a biguanide indicated as an adjunct to diet and exercise to improve glycemic

control in adults and pediatric patients 10 years of age and older with type 2 diabetes mellitus. ( 1)

DOSAGE AND ADMINISTRATION

Adult Dosage for Metformin Hydrochloride Tablets:

Starting dose: 500 mg orally twice a day or 850 mg once a day, with meals ( 2.1)

Increase the dose in increments of 500 mg weekly or 850 mg every 2 weeks, up to a maximum dose of 2,550 mg per

day, given in divided doses (2 .1)

Doses above 2,000 mg may be better tolerated given 3 times a day with meals ( 2.1)

Pediatric Dosage for Metformin Hydrochloride Tablets:

Starting dose: 500 mg orally twice a day, with meals ( 2.2)

Increase dosage in increments of 500 mg weekly up to a maximum of 2,000 mg per day, given in divided doses twice

daily ( 2.2)

Renal Impairment:

Prior to initiation, assess renal function with estimated glomerular filtration rate (eGFR) ( 2.3)

Do not use in patients with eGFR below 30 mL/minute/1.73 m

( 2.3)

Initiation is not recommended in patients with eGFR between 30 to 45 mL/minute/1.73 m

( 2.3)

Assess risk/benefit of continuing if eGFR falls below 45 mL/minute/1.73 m

( 2.3)

Discontinue if eGFR falls below 30 mL/minute/1.73 m

( 2.3)

Discontinuation for Iodinated Contrast Imaging Procedures:

Metformin hydrochloride tablets may need to be discontinued at time of, or prior to, iodinated contrast imaging

procedures ( 2.4)

DOSAGE FORMS AND STRENGTHS

Metformin hydrochloride tablets, USP: 500 mg, 850 mg, and 1,000 mg ( 3)

CONTRAINDICATIONS

Severe renal impairment (eGFR below 30 mL/min/1.73 m

) ( 4, 5.1)

Hypersensitivity to metformin ( 4)

Acute or chronic metabolic acidosis, including diabetic ketoacidosis, with or without coma. ( 4)

WARNINGS AND PRECAUTIONS

Lactic Acidosis: See boxed warning. ( 5.1)

Vitamin B

Deficiency: Metformin may lower vitamin B

levels. Measure hematological parameters annually and

vitamin B

at 2 to 3 year intervals and manage any abnormalities. ( 5.2)

Hypoglycemia with Concomitant Use with Insulin and Insulin Secretagogues: Increased risk of hypoglycemia when used

in combination with insulin and/or an insulin secretagogue. Lower dose of insulin or insulin secretagogue may be

required ( 5.3)

ADVERSE REACTIONS

For metformin hydrochloride, the most common adverse reactions (>5.0%) are diarrhea, nausea/vomiting, flatulence,

asthenia, indigestion, abdominal discomfort, and headache. ( 6.1)

To report SUSPECTED ADVERSE REACTIONS, contact Laurus Generics Inc. at 1-833-3-LAURUS (1-833-352-

8787) or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch

DRUG INTERACTIONS

Carbonic anhydrase inhibitors may increase risk of lactic acidosis. Consider more frequent monitoring ( 7)

Drugs that reduce metformin clearance (such as ranolazine, vandetanib, dolutegravir, and cimetidine) may increase the

accumulation of metformin. Consider the benefits and risks of concomitant use ( 7)

Alcohol can potentiate the effect of metformin on lactate metabolism. Warn patients against excessive alcohol intake (

USE IN SPECIFIC POPULATIONS

Females and Males of Reproductive Potential: Advise premenopausal females of the potential for an unintended

pregnancy. ( 8.3)

Geriatric Use: Assess renal function more frequently. ( 8.5)

Hepatic Impairment: Avoid use in patients with hepatic impairment. ( 8.7)

See 17 for PATIENT COUNSELING INFORMATION and FDA-approved patient labeling.

Revised: 11/2018

FULL PRESCRIBING INFORMATION: CONTENTS*

WARNING: LACTIC ACIDOSIS

1 INDICATIONS AND USAGE

2 DOSAGE AND ADMINISTRATION

2.1 Adult Dosage

2.2 Pediatric Dosage for Metformin Hydrochloride Tablets

2.3 Recommendations for Use in Renal Impairment

2.4 Discontinuation for Iodinated Contrast Imaging Procedures

3 DOSAGE FORMS AND STRENGTHS

4 CONTRAINDICATIONS

5 WARNINGS AND PRECAUTIONS

5.1 Lactic Acidosis

5.2 Vitamin B

Deficiency

5.3 Hypoglycemia with Concomitant Use with Insulin and Insulin Secretagogues

5.4 Macrovascular Outcomes

6 ADVERSE REACTIONS

6.1 Clinical Studies Experience

12

6.2 Postmarketing Experience

7 DRUG INTERACTIONS

8 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

8.2 Lactation

8.3 Females and Males of Reproductive Potential

8.4 Pediatric Use

8.5 Geriatric Use

8.6 Renal Impairment

8.7 Hepatic Impairment

10 OVERDOSAGE

11 DESCRIPTION

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

12.3 Pharmacokinetics

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

14 CLINICAL STUDIES

14.1 Metformin Hydrochloride

16 HOW SUPPLIED/STORAGE AND HANDLING

16.1 How Supplied

16.2 Storage

17 PATIENT COUNSELING INFORMATION

FULL PRESCRIBING INFORMATION

Sections or subsections omitted from the full prescribing information are not listed.

WARNING: LACTIC ACIDOSIS

Postmarketing cases of metformin-associated lactic acidosis have resulted in death,

hypothermia, hypotension, and resistant bradyarrhythmias. The onset of metformin-

associated lactic acidosis is often subtle, accompanied only by nonspecific symptoms such

as malaise, myalgias, respiratory distress, somnolence, and abdominal pain. Metformin-

associated lactic acidosis was characterized by elevated blood lactate levels (>5

mmol/Liter), anion gap acidosis (without evidence of ketonuria or ketonemia), an increased

lactate/pyruvate ratio; and metformin plasma levels generally >5 mcg/mL [see Warnings and

Precautions (5.1)].

Risk factors for metformin-associated lactic acidosis include renal impairment,

concomitant use of certain drugs (e.g. carbonic anhydrase inhibitors such as topiramate),

age 65 years old or greater, having a radiological study with contrast, surgery and other

procedures, hypoxic states (e.g., acute congestive heart failure), excessive alcohol intake,

and hepatic impairment.

Steps to reduce the risk of and manage metformin-associated lactic acidosis in these high

risk groups are provided [see Dosage and Administration (2.3), (2.7), Contraindications (4),

Warnings and Precautions (5.1)].

If metformin-associated lactic acidosis is suspected, immediately discontinue metformin

hydrochloride and institute general supportive measures in a hospital setting. Prompt

hemodialysis is recommended [see Warnings and Precautions (5.1)].

1 INDICATIONS AND USAGE

Metformin hydrochloride tablets, USP are indicated as an adjunct to diet and exercise to improve

glycemic control in adults and pediatric patients 10 years of age and older with type 2 diabetes mellitus.

2 DOSAGE AND ADMINISTRATION

2.1 Adult Dosage

Metformin Hydrochloride Tablets

The recommended starting dose of metformin hydrochloride tablets is 500 mg orally twice a day or

850 mg once a day, given with meals.

Increase the dose in increments of 500 mg weekly or 850 mg every 2 weeks on the basis of

glycemic control and tolerability, up to a maximum dose of 2,550 mg per day, given in divided

doses.

Doses above 2,000 mg may be better tolerated given 3 times a day with meals.

2.2 Pediatric Dosage for Metformin Hydrochloride Tablets

The recommended starting dose of metformin hydrochloride tablets for pediatric patients 10 years

of age and older is 500 mg orally twice a day, given with meals.

Increase dosage in increments of 500 mg weekly on the basis of glycemic control and tolerability,

up to a maximum of 2,000 mg per day, given in divided doses twice daily.

2.3 Recommendations for Use in Renal Impairment

Assess renal function prior to initiation of metformin hydrochloride tablets and periodically

thereafter.

Metformin hydrochloride tablets are contraindicated in patients with an estimated glomerular

filtration rate (eGFR) below 30 mL/minute/1.73 m

Initiation of metformin hydrochloride tablets in patients with an eGFR between 30 to 45

mL/minute/1.73 m

is not recommended.

In patients taking metformin hydrochloride tablets whose eGFR later falls below 45 mL/min/1.73 m

, assess the benefit risk of continuing therapy.

Discontinue metformin hydrochloride tablets if the patient’s eGFR later falls below 30

mL/minute/1.73 m

[see Warnings and Precautions (5.1)].

2.4 Discontinuation for Iodinated Contrast Imaging Procedures

Discontinue metformin hydrochloride tablets at the time of, or prior to, an iodinated contrast imaging

procedure in patients with an eGFR between 30 and 60 mL/min/1.73 m

; in patients with a history of

liver disease, alcoholism, or heart failure; or in patients who will be administered intra-arterial

iodinated contrast. Re-evaluate eGFR 48 hours after the imaging procedure; restart metformin

hydrochloride tablets if renal function is stable.

3 DOSAGE FORMS AND STRENGTHS

Metformin Hydrochloride Tablets, USP are available as:

Tablets: 500 mg white to off white, round, biconvex, blackberry flavored, film coated tablets with

'LL' debossed on one side and plain on the other side.

Tablets: 850 mg white to off white, round, biconvex, blackberry flavored, film coated tablets with

'L0' debossed on one side and plain on the other side.

Tablets: 1,000 mg white to off white, oval, biconvex, blackberry flavored, film coated tablets,

bisected on both sides and debossed with 'L' and '11' on either side of bisect line on one side.

4 CONTRAINDICATIONS

Metformin hydrochloride tablets are contraindicated in patients with:

Severe renal impairment (eGFR below 30 mL/min/1.73 m

) [see Warnings and Precautions (5.1)].

Hypersensitivity to metformin.

Acute or chronic metabolic acidosis, including diabetic ketoacidosis, with or without coma.

5 WARNINGS AND PRECAUTIONS

5.1 Lactic Acidosis

There have been postmarketing cases of metformin-associated lactic acidosis, including fatal cases.

These cases had a subtle onset and were accompanied by nonspecific symptoms such as malaise,

myalgias, abdominal pain, respiratory distress, or increased somnolence; however, hypotension and

resistant bradyarrhythmias have occurred with severe acidosis. Metformin-associated lactic acidosis

was characterized by elevated blood lactate concentrations (>5 mmol/L), anion gap acidosis (without

evidence of ketonuria or ketonemia), and an increased lactate: pyruvate ratio; metformin plasma levels

were generally >5 mcg/mL. Metformin decreases liver uptake of lactate increasing lactate blood levels

which may increase the risk of lactic acidosis, especially in patients at risk.

If metformin-associated lactic acidosis is suspected, general supportive measures should be instituted

promptly in a hospital setting, along with immediate discontinuation of metformin hydrochloride. In

metformin hydrochloride treated patients with a diagnosis or strong suspicion of lactic acidosis, prompt

hemodialysis is recommended to correct the acidosis and remove accumulated metformin (metformin

hydrochloride is dialyzable with a clearance of up to 170 mL/min under good hemodynamic conditions).

Hemodialysis has often resulted in reversal of symptoms and recovery.

Educate patients and their families about the symptoms of lactic acidosis and, if these symptoms occur,

instruct them to discontinue metformin hydrochloride and report these symptoms to their healthcare

provider.

For each of the known and possible risk factors for metformin-associated lactic acidosis,

recommendations to reduce the risk of and manage metformin-associated lactic acidosis are provided

below:

Renal impairment—The postmarketing metformin-associated lactic acidosis cases primarily

occurred in patients with significant renal impairment.

The risk of metformin accumulation and metformin-associated lactic acidosis increases with the

severity of renal impairment because metformin is substantially excreted by the kidney. Clinical

recommendations based upon the patient’s renal function include [see Dosage and Administration (2.1),

Clinical Pharmacology (12.3)]:

Before initiating metformin hydrochloride, obtain an estimated glomerular filtration rate (eGFR).

Metformin hydrochloride is contraindicated in patients with an eGFR less than 30 mL/min/1.73 m

[see Contraindications (4)].

Initiation of metformin hydrochloride is not recommended in patients with eGFR between 30 to

45 mL/min/1.73 m

Obtain an eGFR at least annually in all patients taking metformin hydrochloride. In patients at risk

for the development of renal impairment (e.g., the elderly), renal function should be assessed

more frequently.

In patients taking metformin hydrochloride whose eGFR falls below 45 mL/min/1.73 m

, assess

the benefit and risk of continuing therapy.

Drug interactions — The concomitant use of metformin hydrochloride with specific drugs may

increase the risk of metformin-associated lactic acidosis: those that impair renal function, result in

significant hemodynamic change, interfere with acid-base balance, or increase metformin

accumulation. Consider more frequent monitoring of patients.

Age 65 or greater — The risk of metformin-associated lactic acidosis increases with the patient’s

age because elderly patients have a greater likelihood of having hepatic, renal, or cardiac

impairment than younger patients. Assess renal function more frequently in elderly patients.

Radiologic studies with contrast — Administration of intravascular iodinated contrast agents in

metformin-treated patients has led to an acute decrease in renal function and the occurrence of lactic

acidosis. Stop metformin hydrochloride at the time of, or prior to, an iodinated contrast imaging

procedure in patients with an eGFR between 30 and 60 mL/min/1.73 m

; in patients with a history of

hepatic impairment, alcoholism or heart failure; or in patients who will be administered intra-arterial

iodinated contrast. Re-evaluate eGFR 48 hours after the imaging procedure, and restart metformin

hydrochloride if renal function is stable.

Surgery and other procedures — Withholding of food and fluids during surgical or other procedures

may increase the risk for volume depletion, hypotension, and renal impairment. Metformin

hydrochloride should be temporarily discontinued while patients have restricted food and fluid

intake.

Hypoxic states — Several of the postmarketing cases of metformin-associated lactic acidosis

occurred in the setting of acute congestive heart failure (particularly when accompanied by

hypoperfusion and hypoxemia). Cardiovascular collapse (shock), acute myocardial infarction,

sepsis, and other conditions associated with hypoxemia have been associated with lactic acidosis

and may cause prerenal azotemia. When such an event occurs, discontinue metformin hydrochloride.

Excessive alcohol intake — Alcohol potentiates the effect of metformin on lactate metabolism.

Patients should be warned against excessive alcohol intake while receiving metformin

hydrochloride.

Hepatic impairment — Patients with hepatic impairment have developed cases of metformin-

associated lactic acidosis. This may be due to impaired lactate clearance resulting in higher lactate

blood levels. Therefore, avoid use of metformin hydrochloride in patients with clinical or

laboratory evidence of hepatic disease.

5.2 Vitamin B

Deficiency

In metformin hydrochloride clinical trials of 29-week duration, a decrease to subnormal levels of

previously normal serum vitamin B

levels was observed in approximately 7% of patients. Such

decrease, possibly due to interference with B

absorption from the B

-intrinsic factor complex, may

be associated with anemia but appears to be rapidly reversible with discontinuation of metformin

hydrochloride or vitamin B

supplementation. Certain individuals (those with inadequate vitamin B

or calcium intake or absorption) appear to be predisposed to developing subnormal vitamin B

levels.

Measure hematologic parameters on an annual basis and vitamin B

at 2 to 3 year intervals in patients

on metformin hydrochloride and manage any abnormalities [see Adverse Reactions (6.1)].

5.3 Hypoglycemia with Concomitant Use with Insulin and Insulin Secretagogues

Insulin and insulin secretagogues (e.g., sulfonylurea) are known to cause hypoglycemia. Metformin

hydrochloride may increase the risk of hypoglycemia when combined with insulin and/or an insulin

secretagogue. Therefore, a lower dose of insulin or insulin secretagogue may be required to minimize

the risk of hypoglycemia when used in combination with metformin hydrochloride [see Drug Interactions

(7)].

5.4 Macrovascular Outcomes

There have been no clinical studies establishing conclusive evidence of macrovascular risk reduction

with metformin hydrochloride.

6 ADVERSE REACTIONS

The following adverse reactions are also discussed elsewhere in the labeling:

Lactic Acidosis [see Boxed Warning and Warnings and Precautions (5.1)]

Vitamin B

Deficiency [see Warnings and Precautions (5.2)]

Hypoglycemia [see Warnings and Precautions (5.3)]

6.1 Clinical Studies Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed

in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug

and may not reflect the rates observed in practice.

Metformin Hydrochloride

In a U.S. clinical trial of metformin hydrochloride in patients with type 2 diabetes mellitus, a total of 141

patients received metformin hydrochloride up to 2,550 mg per day. Adverse reactions reported in

greater than 5% of metformin hydrochloride treated patients and that were more common than in

placebo-treated patients, are listed in Table 1.

12

Table 1: Adverse Reactions from a Clinical Trial of Metformin Hydrochloride

Occurring >5% and More Common than Placebo in Patients with Type 2 Diabetes

Mellitus

Metformin Hydrochloride

(n=141)

Placebo

(n=145)

Diarrhea

Nausea/Vomiting

Flatulence

Asthenia

Indigestion

Abdominal Discomfort

Headache

Diarrhea led to discontinuation of metformin hydrochloride in 6% of patients. Additionally, the

following adverse reactions were reported in ≥1% to ≤5% of metformin hydrochloride treated patients

and were more commonly reported with metformin hydrochloride than placebo: abnormal stools,

hypoglycemia, myalgia, lightheaded, dyspnea, nail disorder, rash, sweating increased, taste disorder,

chest discomfort, chills, flu syndrome, flushing, palpitation.

In metformin hydrochloride clinical trials of 29-week duration, a decrease to subnormal levels of

previously normal serum vitamin B

levels was observed in approximately 7% of patients.

Pediatric Patients

In clinical trials with metformin hydrochloride in pediatric patients with type 2 diabetes mellitus, the

profile of adverse reactions was similar to that observed in adults.

6.2 Postmarketing Experience

The following adverse reactions have been identified during post approval use of metformin. Because

these reactions are reported voluntarily from a population of uncertain size, it is not always possible to

reliably estimate their frequency or establish a causal relationship to drug exposure.

Cholestatic, hepatocellular, and mixed hepatocellular liver injury have been reported with

postmarketing use of metformin.

7 DRUG INTERACTIONS

Table 3 presents clinically significant drug interactions with metformin hydrochloride.

Table 3: Clinically Significant Drug Interactions with Metformin Hydrochloride

Carbonic Anhydrase Inhibitors

Clinical Impact:

Carbonic anhydrase inhibitors frequently cause a decrease in serum

bicarbonate

induce

non-anion

gap,

hyperchloremic

metabolic

acidosis. Concomitant use of these drugs with metformin hydrochloride

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 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.

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.

Insulin Secretagogues or Insulin

Clinical Impact:

Coadministration of metformin hydrochloride 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, observe the patient closely for loss of blood glucose

control. When such drugs are withdrawn from a patient receiving

metformin hydrochloride, 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 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 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

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.

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 and any potential adverse effects on the breastfed child from metformin hydrochloride 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.

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