HIGHLIGHTS OF PRESCRIBING INFORMATION
`
`
` These highlights do not include all the information needed to use
` FORTAMET safely and effectively. See full prescribing information for
`
` FORTAMET.
`
`
`FORTAMET® (metformin hydrochloride) extended-release 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 FORTAMET and
`
`institute general supportive measures in a hospital setting.
`
`
`
` Prompt hemodialysis is recommended. (5.1)
`
`
`•
`
`
`--------------------------- INDICATIONS AND USAGE -------------------------­
`
`
`
`
`
`FORTAMET is a biguanide indicated as an adjunct to diet and exercise to
`
`
`
`improve glycemic control in adults with type 2 diabetes mellitus. (1)
`
`
`
`
`---------------------- DOSAGE AND ADMINISTRATION ---------------------­
`
`
`
`
`Swallow FORTAMET tablets whole and never crush, cut or chew (2.1)
`
`
`
`•
`Starting dose: 500 mg orally once daily with the evening meal (2.1)
`
`
`
`•
`Increase the dose in increments of 500 mg weekly, up to a maximum of
`
`
`
`•
`2,000 mg once daily with the evening meal (2.1)
`
`
`Patients receiving metformin hydrochloride (HCl) tablets may be
`
`
`
`
`switched to FORTAMET once daily at the same total daily dose, up to
`
`
`
`2,000 mg once daily (2.1)
`
`Renal Impairment:
`
`Prior to initiation, assess renal function with estimated glomerular
`
`
`
`
`•
`filtration rate (eGFR) (2.2)
`
`o Do not use in patients with eGFR below 30 mL/minute/1.73 m2 (2.2)
`
`
`
`
`
`o Initiation is not recommended in patients with eGFR between 30 to 45
`
`
`mL/minute/1.73 m2 (2.2)
`
`
`
`
`o Assess risk/benefit of continuing if eGFR falls below 45
`
`mL/minute/1.73 m2 (2.2)
`
`
`
`o Discontinue if eGFR falls below 30 mL/minute/1.73 m2 (2.2)
`
`
`
`
`
`Discontinuation for Iodinated Contrast Imaging Procedures:
`
`
`
`FULL PRESCRIBING INFORMATION: CONTENTS*
`WARNING: LACTIC ACIDOSIS
`
`
`1 INDICATIONS AND USAGE
`
`2 DOSAGE AND ADMINISTRATION
`
`2.1 Adult Dosage and Administration
`
`
`2.2 Recommendations for Use in Renal Impairment
`
`
`2.3 Discontinuation for Iodinated Contrast Imaging Procedures
`
`
`
`3 DOSAGE FORMS AND STRENGTHS
`
`4 CONTRAINDICATIONS
`
`
`5 WARNINGS AND PRECAUTIONS
`5.1 Lactic Acidosis
`
`5.2 Vitamin B12 Deficiency
`
`
`
`5.3 Hypoglycemia with Concomitant Use with Insulin andInsulin
`
`Secretagogues
`
`5.4 Macrovascular Outcomes
`
`
`6 ADVERSE REACTIONS
`
`
`6.1 Clinical Studies Experience
`
`
`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
`
`Reference ID: 4347556
`
`
`•
`
`FORTAMET may need to be discontinued at time of, or prior to,
`
`
`
`iodinated contrast imaging procedures (2.3)
`
`--------------------- DOSAGE FORMS AND STRENGTHS -------------------­
`
`
`
`
`Extended-Release Tablets: 500 mg and 1,000 mg (3)
`
`
`------------------------------ CONTRAINDICATIONS ----------------------------­
`
`
`
`
`Severe renal impairment (eGFR below 30 mL/min/1.73 m2) (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 B12 Deficiency: Metformin may lower vitamin B12 levels.
`
`
`
`
`
`
`•
`Measure hematological parameters annually and vitamin B12 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 ----------------------------­
`
`
`
`
`Common adverse reactions are diarrhea, nausea/vomiting, abdominal pain,
`
`
`
`
`constipation, abdomen distention, dyspepsia/heartburn, flatulence, dizziness,
`
`headache, upper respiratory infection, taste disturbance. (6.1)
`
`
`
`To report SUSPECTED ADVERSE REACTIONS, contact Teva
`
`
`Pharmaceuticals USA, Inc. at 1-888-838-2872 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 (7)
`
`------------------------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
`
`
`
`
`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
`
`
`
`16 HOW SUPPLIED/STORAGE AND HANDLING
`
`16.1 How Supplied
`
`16.2 Storage
`17 PATIENT COUNSELING INFORMATION
`
`
`*Sections or subsections omitted from the full prescribing information are not
`
`listed.
`
`
`
`
`
`

`

`
`
` FULL PRESCRIBING INFORMATION
`
`
`
`
` 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 (2.2), Contraindications (4), Warnings and Precautions (5.1)].
`
`
`If metformin-associated lactic acidosis is suspected, immediately discontinue FORTAMET and institute general
`
`
`supportive measures in a hospital setting. Prompt hemodialysis is recommended [see Warnings and Precautions
`
`
` (5.1)].
`
`
`1 INDICATIONS AND USAGE
`
`
`FORTAMET is indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes
`
`
`
`mellitus.
`
`
`2 DOSAGE AND ADMINISTRATION
`
`
`
`2.1 Adult Dosage and Administration
`
`
`
`
`
`•
`
`• Swallow FORTAMET whole and never crush, cut or chew.
`
`
`
`• The recommended starting dose of FORTAMET is 500 mg orally once daily with the evening meal.
`
`
`
`
`
`Increase the dose in increments of 500 mg weekly on the basis of glycemic control and tolerability, up to a maximum
`
`
`
`
`
`•
`of 2,000 mg once daily with the evening meal.
`
`If glycemic control is not achieved with FORTAMET 2,000 mg once daily, consider a trial of FORTAMET 1,000
`
`
`
`mg twice daily.
`
`• Patients receiving metformin hydrochloride (HCl) may be switched to FORTAMET once daily at the same total daily
`
`
`
`
`
`
`
`dose, up to 2,000 mg once daily.
`
`
`
`2.2 Recommendations for Use in Renal Impairment
`
`
`
`
`• Assess renal function prior to initiation of FORTAMET and periodically thereafter.
`
`
`
`
`
`
`• FORTAMET is contraindicated in patients with an estimated glomerular filtration rate (eGFR) below 30
`
`
`
`
`mL/minute/1.73 m2.
`
`Initiation of FORTAMET in patients with an eGFR between 30 to 45 mL/minute/1.73 m2 is not recommended.
`
`
`
`
`In patients taking FORTAMET whose eGFR later falls below 45 mL/min/1.73 m2, assess the benefit risk of
`
`
`
`
`
`continuing therapy.
`• Discontinue FORTAMET if the patient’s eGFR later falls below 30 mL/minute/1.73 m2 [see Contraindications (4)
`
`
`
`
`
`
`and Warnings and Precautions (5.1)].
`
`
`
`•
`
`•
`
`
`
`
`2.3 Discontinuation for Iodinated Contrast Imaging Procedures
`
`
`
`
`Discontinue FORTAMET 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 m2; in patients with a history of liver disease, alcoholism, or heart failure; or in patients
`
`
`
`Reference ID: 4347556
`
`

`

`
`who will be administered intra-arterial iodinated contrast. Re-evaluate eGFR 48 hours after the imaging procedure; restart
`
`
`FORTAMET if renal function is stable.
`
`
`
`3 DOSAGE FORMS AND STRENGTHS
`
`
`
`
`FORTAMET is available as:
`
`
`
`
`
`• Extended-release tablets: 500 mg white-colored, unscored tablets imprinted with Andrx logo and 574 on one side.
`
`
`
`
`
`• Extended-release tablets: 1,000 mg white-colored, unscored tablets imprinted with Andrx logo and 575 on one side.
`
`
`
`4 CONTRAINDICATIONS
`
`
`
`
`FORTAMET is contraindicated in patients with:
`
`• Severe renal impairment (eGFR below 30 mL/min/1.73 m2) [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 FORTAMET. In FORTAMET treated patients with a diagnosis
`or strong suspicion of lactic acidosis, prompt hemodialysis is recommended to correct the acidosis and remove
`
`
`
`
`
`accumulated metformin (metformin HCl 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 FORTAMET 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 (2.2), Clinical Pharmacology (12.3)]:
`
`
`o Before initiating FORTAMET, obtain an estimated glomerular filtration rate (eGFR).
`
`
`
`
`o FORTAMET is contraindicated in patients with an eGFR less than 30 mL/min/1.73 m2 [see
`
`
`
` Contraindications (4)].
`
`
`o
` Initiation of FORTAMET is not recommended in patients with eGFR between 30 to 45 mL/min/1.73 m2.
`
`
`
`
`
`
`Reference ID: 4347556
`
`

`

`
`o Obtain an eGFR at least annually in all patients taking FORTAMET. In patients at risk for the
`
`
`
`
` development of renal impairment (e.g., the elderly), renal function should be assessed more frequently.
`
`
`o
` In patients taking FORTAMET whose eGFR falls below 45 mL/min/1.73 m2, assess the benefit and risk of
`
`
` continuing therapy.
`
`
`
`
`
`
`
` • Drug interactions — The concomitant use of FORTAMET 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 [see Drug Interactions (7)]. 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 FORTAMET 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 m2; 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 FORTAMET 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. FORTAMET 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 FORTAMET.
`
`• Excessive alcohol intake — Alcohol potentiates the effect of metformin on lactate metabolism. Patients should be
`
`
`
`
`warned against excessive alcohol intake while receiving FORTAMET.
`
`
`• 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 FORTAMET in patients with clinical or laboratory evidence of hepatic disease.
`
`
`
`
`
`5.2 Vitamin B12 Deficiency
`
`
`
`
`In clinical trials of 29-week duration with metformin HCl tablets, a decrease to subnormal levels of previously normal
`
`
`
`
`
`
`
`serum vitamin B12 levels was observed in approximately 7% of patients. Such decrease, possibly due to interference with
`
`
`
`B12 absorption from the B12-intrinsic factor complex, may be associated with anemia but appears to be rapidly reversible
`
`with discontinuation of metformin or vitamin B12 supplementation. Certain individuals (those with inadequate vitamin B12
`
`
`or calcium intake or absorption) appear to be predisposed to developing subnormal vitamin B12 levels. Measure
`
`hematologic parameters on an annual basis and vitamin B12 at 2 to 3 year intervals in patients on FORTAMET 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. FORTAMET 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 FORTAMET
`
`
`[see Drug Interactions (7)].
`
`
`5.4 Macrovascular Outcomes
`
`
`There have been no clinical studies establishing conclusive evidence of macrovascular risk reduction with FORTAMET.
`
`
`
`
`6 ADVERSE REACTIONS
`
`
`The following adverse reactions are also discussed elsewhere in the labeling:
`
`
`Reference ID: 4347556
`
`

`

` • Lactic Acidosis [see Boxed Warning and Warnings and Precautions (5.1)]
`
` • Vitamin B12 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.
`
`
`
`
`In placebo-controlled trials, 781 patients were administered metformin HCl extended-release tablets. Adverse reactions
`
`
`
`
`
`
`reported in greater than 5% of the patients treated with metformin HCl extended-release tablets and that were more
`
`
`common than in placebo-treated patients are listed in Table 1.
`
`
`
`
`
`
`Table 1: Adverse Reactions from Clinical Trials of Metformin HCl Extended-Release Tablets Occurring >5% and
`
`More Common than Placebo in Patients with Type 2 Diabetes Mellitus
`
` Metformin HCl Extended-Release Tablets
`
`
`
` Adverse Reaction
`
` (n=781)
`
` 10%
` 7%
`
`
`
` Placebo
`
` (n=195)
`
` 3%
`
` 2%
`
` Diarrhea
`
` Nausea/Vomiting
`
`
`
`
`Diarrhea led to the discontinuation of metformin HCl extended-release tablets in 0.6% of patients. Additionally, the
`
`
`
`
`
`
`
`
`following adverse reactions were reported in 1.0% to 5.0% of patients treated with metformin HCl extended-release
`
`
`
`
`tablets and were more commonly reported than in placebo-treated patients: abdominal pain, constipation, abdomen
`
`
`
`
`distention, dyspepsia/heartburn, flatulence, dizziness, headache, upper respiratory infection, taste disturbance.
`
`
`
`
`Laboratory Tests
`
`
`
`Vitamin B12 Concentrations
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
` In clinical trials of 29-week duration with metformin HCl tablets, a decrease to subnormal levels of previously normal
`
` serum vitamin B12 levels was observed in approximately 7% of patients.
`
`
` 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 2 presents clinically significant drug interactions with FORTAMET.
`
` Table 2: Clinically Significant Drug Interactions with FORTAMET
`
`Carbonic Anhydrase Inhibitors
`
` Carbonic anhydrase inhibitors frequently cause a decrease in serum bicarbonate
`
`
`
` and induce non-anion gap, hyperchloremic metabolic acidosis. Concomitant use
` of these drugs with FORTAMET may increase the risk for lactic acidosis.
`
`
`
`
` Intervention: Consider more frequent monitoring of these patients.
`
` Examples: Topiramate, zonisamide, acetazolamide or dichlorphenamide.
`Drugs that Reduce FORTAMET Clearance
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
` Clinical Impact:
`
`Reference ID: 4347556
`
`

`

`
`
` 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 FORTAMET.
`
`
` 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 FORTAMET.
`Insulin Secretagogues or Insulin
`
`
` Clinical Impact: Coadministration of FORTAMET 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.
`When such drugs are administered to a patient receiving FORTAMET, observe
`
`
` the patient closely for loss of blood glucose control. When such drugs are
` withdrawn from a patient receiving FORTAMET, observe the patient closely for
`
` hypoglycemia.
`
` Thiazides and other diuretics, corticosteroids, phenothiazines, thyroid products,
`
` estrogens, oral contraceptives, phenytoin, nicotinic acid, sympathomimetics,
`
` calcium channel blockers, and isoniazid.
`
`
`
`
`
` Intervention:
`
`
`
` Examples:
`
`
`8 USE IN SPECIFIC POPULATIONS
`
`
`8.1 Pregnancy
`
`
`Risk Summary
`
`
`
`
`
`Limited data with FORTAMET 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.
`
`
`
`
`
`Reference ID: 4347556
`
`

`

`
`
` 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 HCl 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 FORTAMET and any potential adverse effects on the breastfed child from
`
`
`FORTAMET 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 FORTAMET may result in
`
`ovulation in some anovulatory women.
`
`
`8.4 Pediatric Use
`
`
`
`
`Safety and effectiveness of FORTAMET in pediatric patients have not been established.
`
`
`8.5 Geriatric Use
`
`
`
`Controlled clinical studies of FORTAMET 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)].
`
`
`
`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. FORTAMET is contraindicated in severe renal impairment, patients with an
`estimated glomerular filtration rate (eGFR) below 30 mL/min/1.73 m2 [see Dosage and Administration (2.2),
`
`
`
`
`Contraindications (4), Warnings and Precautions (5.1), and Clinical Pharmacology (12.3)].
`
`
`Reference ID: 4347556
`
`

`

`
`
`8.7 Hepatic Impairment
`
`
`
`
`Use of metformin in patients with hepatic impairment has been associated with some cases of lactic acidosis.
`
`
`
`FORTAMET is not recommended in patients with hepatic impairment [see Warnings and Precautions (5.1)].
`
`
`10 OVERDOSAGE
`
`
`
`
`Overdose of metformin HCl 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
`
`
`
`
`
`
`
`FORTAMET extended-release tablets contain the biguanidine antihyperglycemic agent, metformin, in the form of
`
`
`
`
`
`
`monohydrochloride salt. The chemical name of metformin HCl is N, N-dimethylimidodicarbonimidic diamide
`
`
`
`
`hydrochloride with a molecular formula of C4H11N5•HCl and a molecular weight of 165.63. Its structural formula is:
`
`
`
`
`
`
`
`
`
`
`
`
`
`Metformin HCl is a white to off-white crystalline powder that is freely soluble in water and is practically insoluble in
`
`acetone, ether, and chloroform. The pKa of metformin is 12.4. The pH of a 1% aqueous solution of metformin HCl is
`
`6.68.
`
`
`
`
`FORTAMET tablets deliver 500 mg or 1,000 mg of metformin HCl, which is equivalent to 389.93 mg or 779.86 mg
`
`
`metformin, respectively. In addition to the active ingredient metformin HCl, each tablet contains the following inactive
`
`ingredients: candelilla wax, cellulose acetate, hypromellose, magnesium stearate, polyethylene glycols (PEG 400, PEG
`
`8000), polysorbate 80, povidone, sodium lauryl sulfate, synthetic black iron oxides, titanium dioxide, and triacetin.
`
`
`
`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
`
`
`
`
`
`In a multiple-dose crossover study, 23 patients with type 2 diabetes mellitus were administered either FORTAMET 2,000
`
`
`mg once a day (after dinner) or metformin HCl tablets 1,000 mg twice a day (after breakfast and after dinner). After 4
`
`
`weeks of treatment, steady-state pharmacokinetic parameters, area under the concentration-time curve (AUC), time to
`peak plasma concentration (Tmax), and maximum concentration (Cmax) were evaluated. The appearance of metformin in
`
`
`
`
`Reference ID: 4347556
`
`

`

`
` plasma from FORTAMET is slower and more prolonged compared to metformin HCl tablets. Results are presented in
`
`
` Table 3.
`
`
`
`
`
`
`
` Table 3
`
`
`
` FORTAMET vs.
`
` Metformin HCl Tablets
`
` Steady-State Pharmacokinetic Parameters at 4 Weeks
`
`
` FORTAMET
`
`
`
` Pharmacokinetic
`Metformin HCl tablets*
`
` 2,000 mg
`
`
` Parameters
`2,000 mg
`
` (administered q.d.
`
`
` (mean ± SD)
`(1,000 mg b.i.d.)
`
` after dinner)
`
` 26,811 ± 7055
` AUC0-24hr (ng•hr/mL)
`
`
`
` 6 (3-10)
`
`
` Tmax (hr)
` 2849 ± 797
`
`
` Cmax (ng/mL)
`
`
` *Immediate-release metformin HCl tablets
`
`In four single-dose studies and one multiple-dose study, the bioavailability of FORTAMET 2,000 mg given once daily, in
`
` the evening, under fed conditions [as measured by AUC] was similar to the same total daily dose administered as
` metformin HCl tablets 1,000 mg given twice daily. The geometric mean ratios (FORTAMET/ metformin HCL tablets) of
`
`
`
`AUC0-24hr, AUC0-72hr, and AUC0-inf for these five studies ranged from 0.96 to 1.08.
`
`
`
`
`
` 27,371 ± 5,781
`
` 3 (1-8)
` 1820 ± 370
`
`
`