Fortamet

FORTAMET^® (metformin hydrochloride) Extended-Release Tablets are supplied as biconvex-shaped, film-coated extended-release tablets containing 500 mg or 1000 mg of metformin hydrochloride.

NDC 59630-574-60: 500 mg extended-release, white-colored tablets imprinted with Andrx logo and 574 on one side: bottles of 60.

NDC 59630-575-60: 1000 mg extended-release, white-colored tablets imprinted with Andrx logo and 575 on one side: bottles of 60.

Storage

Store at 20° to 25°C (68° to 77°F) Excursions permitted to 15° to 30°C (59° to 86°F). Keep tightly closed (protect from moisture). Protect from light. Avoid excessive heat and humidity.

Manufactured by: Actavis Laboratories FL, Inc. Fort Lauderdale, FL 33314 USA. Revised: Nov 2017

FORTAMET^® is indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus.

There is no fixed dosage regimen for the management of hyperglycemia in patients with type 2 diabetes with FORTAMET^® or any other pharmacologic agent. Dosage of FORTAMET^® must be individualized on the basis of both effectiveness and tolerance, while not exceeding the maximum recommended daily dose. The maximum recommended daily dose of FORTAMET^® Extended-Release Tablets in adults is 2500 mg.

FORTAMET^® should be taken with a full glass of water once daily with the evening meal. FORTAMET^® should be started at a low dose, with gradual dose escalation, both to reduce gastrointestinal side effects and to permit identification of the minimum dose required for adequate glycemic control of the patient.

During treatment initiation and dose titration (see Recommended Dosing Schedule), fasting plasma glucose should be used to determine the therapeutic response to FORTAMET^® and identify the minimum effective dose for the patient. Thereafter, glycosylated hemoglobin should be measured at intervals of approximately three months. The therapeutic goal should be to decrease both fasting plasma glucose and glycosylated hemoglobin levels to normal or near normal by using the lowest effective dose of FORTAMET^® , either when used as monotherapy or in combination with sulfonylurea or insulin.

Monitoring of blood glucose and glycosylated hemoglobin will also permit detection of primary failure, i.e., inadequate lowering of blood glucose at the maximum recommended dose of medication, and secondary failure, i.e., loss of an adequate blood glucose lowering response after an initial period of effectiveness.

Short-term administration of FORTAMET^® may be sufficient during periods of transient loss of control in patients usually well-controlled on diet alone.

Recommended Dosing Schedule

The usual starting dose of FORTAMET^® is 1000 mg taken with a full glass of water once daily with the evening meal, although 500 mg may be utilized when clinically appropriate. Dosage increases should be made in increments of 500 mg weekly, up to a maximum of 2500 mg once daily with the evening meal (see Clinical Studies).

In randomized trials, patients currently treated with immediate-release metformin were switched to FORTAMET^®. Results of this trial suggest that patients receiving immediate-release metformin treatment may be safely switched to FORTAMET^® once daily at the same total daily dose, up to 2500 mg once daily. Following a switch from immediate-release metformin to FORTAMET^®, glycemic control should be closely monitored and dosage adjustments made accordingly (see Clinical Studies).

Pediatrics

There is no pediatric information available for FORTAMET^®.

Concomitant FORTAMET^® And Oral Sulfonylurea Therapy In Adult Patients

If patients have not responded to four weeks of the maximum dose of FORTAMET^® monotherapy, consideration should be given to gradual addition of an oral sulfonylurea while continuing FORTAMET^® at the maximum dose, even if prior primary or secondary failure to a sulfonylurea has occurred. Clinical and pharmacokinetic drug-drug interaction data are currently available only for metformin plus glyburide (also known as glibenclamide). With concomitant FORTAMET^® and sulfonylurea therapy, the desired control of blood glucose may be obtained by adjusting the dose of each drug. However, attempts should be made to identify the minimum effective dose of each drug to achieve this goal. With concomitant FORTAMET^® and sulfonylurea therapy, the risk of hypoglycemia associated with sulfonylurea therapy continues and may be increased. Appropriate precautions should be taken (see Package Insert Of The Respective Sulfonylurea).

If patients have not satisfactorily responded to one to three months of concomitant therapy with the maximum dose of FORTAMET^® and the maximum dose of an oral sulfonylurea, consider therapeutic alternatives including switching to insulin with or without FORTAMET^®.

Concomitant FORTAMET^® And Insulin Therapy In Adult Patients

The current insulin dose should be continued upon initiation of FORTAMET^® therapy. FORTAMET^® therapy should be initiated at 500 mg once daily in patients on insulin therapy. For patients not responding adequately, the dose of FORTAMET^® should be increased by 500 mg after approximately 1 week and by 500 mg every week thereafter until adequate glycemic control is achieved. The maximum recommended daily dose for FORTAMET^® Extended-Release Tablet is 2500 mg. It is recommended that the insulin dose be decreased by 10% to 25% when fasting plasma glucose concentrations decrease to less than 120 mg/dL in patients receiving concomitant insulin and FORTAMET^®. Further adjustment should be individualized based on glucose-lowering response.

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 – 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 WARNINGS and PRECAUTIONS).

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 who will be administered intra-arterial iodinated contrast. Reevaluate eGFR 48 hours after the imaging procedure; restart FORTAMET^® if renal function is stable.

Specific Patient Populations

FORTAMET^® is not recommended for use in pregnancy, and is not recommended in patients below the age of 17 years.

The initial and maintenance dosing of FORTAMET^® should be conservative in patients with advanced age, due to the potential for decreased renal function in this population. Any dosage adjustment should be based on a careful assessment of renal function.

Monitoring of renal function is necessary to aid in prevention of lactic acidosis, particularly in the elderly (see WARNINGS).

FORTAMET^® is contraindicated in patients with:

1. Severe renal impairment (eGFR below 30 mL/min/1.73 m² ) (see WARNINGS and PRECAUTIONS).
2. Known hypersensitivity to metformin.
3. Acute or chronic metabolic acidosis, including diabetic ketoacidosis, with or without coma. Diabetic ketoacidosis should be treated with insulin.

WARNINGS

Lactic Acidosis

Postmarketing cases of metformin-associated lactic acidos is 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 PRECAUTIONS).

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, CONTRAINDICATIONS, and PRECAUTIONS).

If metformin-associated lactic acidosis is suspected, immediately discontinue FORTAMET^® and institute general supportive measures in a hospital setting. Prompt hemodialysis is recommended (see PRECAUTIONS).

PRECAUTIONS

General

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 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 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 and CLINICAL PHARMACOLOGY):

• Before initiating FORTAMET^®, obtain an estimated glomerular filtration rate (eGFR)
• FORTAMET^® is contraindicated in patients with an eGFR less than 30 mL/min/1.73 m² (see CONTRAINDICATIONS).
• Initiation of FORTAMET^® is not recommended in patients with eGFR between 30-45 mL/min/1.73 m².
• 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.
• 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. 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 is known to potentiate the effect of metformin on lactate metabolism. Patients, therefore, should be warned against excessive alcohol intake, acute or chronic, while receiving FORTAMET^®.

Hepatic Impairment

Patients with hepatic impairment have developed cases of metforminassociated 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.

Vitamin B₁₂ Levels

In controlled clinical trials of immediate-release metformin of 29 weeks duration, a decrease to subnormal levels of previously normal serum Vitamin B₁₂ levels, without clinical manifestations, was observed in approximately 7% of patients. Such decrease, possibly due to interference with B₁₂ absorption from the B₁₂ -intrinsic factor complex, is, however, very rarely associated with anemia and appears to be rapidly reversible with discontinuation of immediate-release metformin or Vitamin B₁₂ supplementation. Measurement of hematologic parameters on an annual basis is advised in patients on FORTAMET^® and any apparent abnormalities should be appropriately investigated and managed (see PRECAUTIONS: Laboratory Tests ). Certain individuals (those with inadequate Vitamin B₁₂ or calcium intake or absorption) appear to be predisposed to developing subnormal Vitamin B₁₂ levels. In these patients, routine serum Vitamin B₁₂ measurements at two- to three-year intervals may be useful.

Hypoglycemia

Hypoglycemia does not occur in patients receiving FORTAMET^® alone under usual circumstances of use, but could occur when caloric intake is deficient, when strenuous exercise is not compensated by caloric supplementation, or during concomitant use with other glucose-lowering agents (such as sulfonylureas and insulin) or ethanol. Elderly, debilitated, or malnourished patients, and those with adrenal or pituitary insufficiency or alcohol intoxication are particularly susceptible to hypoglycemic effects. Hypoglycemia may be difficult to recognize in the elderly, and in people who are taking beta-adrenergic blocking drugs.

Macrovascular Outcomes

There have been no clinical studies establishing conclusive evidence of macrovascular risk reduction with FORTAMET^® or any other anti-diabetic drug.

Information For Patients

Patients should be informed of the potential risks and benefits of FORTAMET^® and of alternative modes of therapy. They should also be informed about the importance of adherence to dietary instructions, of a regular exercise program, and of regular testing of blood glucose, glycosylated hemoglobin, renal function, and hematologic parameters.

The risks of lactic acidosis, its symptoms, and conditions that predispose to its development, as noted in the WARNINGS and PRECAUTIONS sections, should be explained to patients. Patients should be advised to discontinue FORTAMET^® immediately and to promptly notify their health practitioner if unexplained hyperventilation, myalgia, malaise, unusual somnolence, or other nonspecific symptoms occur. Once a patient is stabilized on any dose level of FORTAMET^® , gastrointestinal symptoms, which are common during initiation of metformin therapy, are unlikely to be drug related. Later occurrence of gastrointestinal symptoms could be due to lactic acidosis or other serious disease.

Patients should be counseled against excessive alcohol intake, either acute or chronic, while receiving FORTAMET^®.

FORTAMET^® alone does not usually cause hypoglycemia, although it may occur when FORTAMET^® is used in conjunction with oral sulfonylureas and insulin. When initiating combination therapy, the risks of hypoglycemia, its symptoms and treatment, and conditions that predispose to its development should be explained to patients and responsible family members (see PATIENT INFORMATION).

Patients should be informed that FORTAMET^® must be swallowed whole and not chewed, cut, or crushed, and that the inactive ingredients may occasionally be eliminated in the feces as a soft mass that may resemble the original tablet (see PATIENT INFORMATION).

Laboratory Tests

Response to all diabetic therapies should be monitored by periodic measurements of fasting blood glucose and glycosylated hemoglobin levels, with a goal of decreasing these levels toward the normal range. During initial dose titration, fasting glucose can be used to determine the therapeutic response. Thereafter, both glucose and glycosylated hemoglobin should be monitored. Measurements of glycosylated hemoglobin may be especially useful for evaluating long-term control (see also DOSAGE AND ADMINISTRATION).

Initial and periodic monitoring of hematologic parameters (e.g., hemoglobin/hematocrit and red blood cell indices) and renal function (serum creatinine) should be performed, at least on an annual basis. While megaloblastic anemia has rarely been seen with immediate-release metformin therapy, if this is suspected, Vitamin B₁₂ deficiency should be excluded.

Instruct patients to inform their doctor that they are taking FORTAMET^® prior to any surgical or radiological procedure, as temporary discontinuation of FORTAMET^® may be required until renal function has been confirmed to be normal (see PRECAUTIONS).

Carcinogenesis, Mutagenesis, Impairment Of Fertility

Long-term carcinogenicity studies with metformin have been performed in rats (dosing duration of 104 weeks) and mice (dosing duration of 91 weeks) at doses up to and including 900 mg/kg/day and 1500 mg/kg/day, respectively. These doses are both approximately four times the maximum recommended human daily dose of 2000 mg based on body surface area comparisons. No evidence of carcinogenicity with metformin was found in either male or female mice. Similarly, there was no tumorigenic potential observed with metformin in male rats. There was, however, an increased incidence of benign stromal uterine polyps in female rats treated with 900 mg/kg/day.

There was no evidence of mutagenic potential of metformin in the following in vitro tests: Ames test (S. typhimurium), gene mutation test (mouse lymphoma cells), or chromosomal aberrations test (human lymphocytes). Results in the in vivo mouse micronucleus test were also negative.

Fertility of male or female rats was unaffected by metformin when administered at doses as high as 600 mg/kg/day, which is approximately three times the maximum recommended human daily dose based on body surface area comparisons.

Pregnancy

Teratogenic Effects

Pregnancy Category B

Recent information strongly suggests that abnormal blood glucose levels during pregnancy are associated with a higher incidence of congenital abnormalities. Most experts recommend that insulin be used during pregnancy to maintain blood glucose levels as close to normal as possible. Because animal reproduction studies are not always predictive of human response, FORTAMET^® should not be used during pregnancy unless clearly needed.

There are no adequate and well-controlled studies in pregnant women with immediate-release metformin or FORTAMET^®. Metformin was not teratogenic in rats and rabbits at doses up to 600 mg/kg/day. This represents an exposure of about two and six times the maximum recommended human daily dose of 2000 mg based on body surface area comparisons for rats and rabbits, respectively. Determination of fetal concentrations demonstrated a partial placental barrier to metformin.

Nursing Mothers

Studies in lactating rats show that metformin is excreted into milk and reaches levels comparable to those in plasma. Similar studies have not been conducted in nursing mothers. Because the potential for hypoglycemia in nursing infants may exist, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother. If FORTAMET^® is discontinued, and if diet alone is inadequate for controlling blood glucose, insulin therapy should be considered.

Pediatric Use

No pediatric clinical studies have been conducted with FORTAMET^®. The safety and effectiveness of immediate-release metformin for the treatment of type 2 diabetes have been established in pediatric patients ages 10 to 16 years (studies have not been conducted in pediatric patients below the age of 10 years). Use of immediate-release metformin in this age group is supported by evidence from adequate and well-controlled studies of immediate-release metformin in adults with additional data from a controlled clinical study in pediatric patients ages 10 to 16 years with type 2 diabetes, which demonstrated a similar response in glycemic control to that seen in adults (see CLINICAL PHARMACOLOGY: Pediatric Clinical Studies ). In this study, adverse effects were similar to those described in adults (see ADVERSE REACTIONS: Pediatric Patients ). A maximum daily dose of 2000 mg of immediate-release metformin is recommended.

The safety and efficacy of FORTAMET^® has not been evaluated in pediatric patients.

Geriatric Use

Of the 389 patients who received FORTAMET^® in controlled Phase III clinical studies, 26.5% [103/389] were 65 years and older. No overall differences in effectiveness or safety were observed between these patients and younger patients.

Controlled clinical studies of immediate-release metformin 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, PRECAUTIONS, and DOSAGE AND ADMINISTRATION).

SIDE EFFECTS

FORTAMET^® Clinical Studies

In the controlled clinical studies of FORTAMET^® in patients with type 2 diabetes, a total of 424 patients received FORTAMET^® therapy (up to 2500 mg/day) and 430 patients received immediaterelease metformin. Adverse reactions reported in ≥5% of the FORTAMET^® or immediate-release metformin patients are listed in Table 6. These pooled results show that the most frequently reported adverse reactions in the FORTAMET^® group were infection, diarrhea, and nausea. Similar incidences of these adverse reactions were seen in the immediate-release metformin group.

Table 6 Number and Percentage of Patients With the Most Common (Incidence ≥5%) Treatment-Emergent Signs or Symptoms by Body System and Preferred Term - Pooled Phase II and III Studies

The most frequent adverse events thought to be related to FORTAMET^® were diarrhea, nausea, dyspepsia, flatulence, and abdominal pain. The frequency of dyspepsia was 4.2% in the FORTAMET^® group compared to 5.1% in the immediate-release group, the frequency of flatulence was 3.5% in the FORTAMET^® group compared to 3.7% in the immediate-release group, and the frequency of abdominal pain was 3.3% in the FORTAMET^® group compared to 4.4% in the immediate-release group.

In the controlled studies, 4.7% of patients treated with FORTAMET^® and 4.9% of patients treated with immediate-release metformin were discontinued due to adverse events.

Immediate-Release Metformin

Immediate-Release Metformin Phase III Clinical Studies

In a U.S. double-blind clinical study of immediate-release metformin in patients with type 2 diabetes, a total of 141 patients received immediate-release metformin therapy (up to 2550 mg per day) and 145 patients received placebo. Adverse reactions reported in greater than 5% of the immediate-release metformin patients, and that were more common in immediate-release metformin than placebo-treated patients, are listed in Table 7.

Table 7 Most Common Adverse Reactions (>5.0%) in a Placebo-Controlled Clinical Study of Immediate-Release Metformin Monotherapy*

Diarrhea led to discontinuation of study medication in 6% of patients treated with immediate-release metformin. Additionally, the following adverse reactions were reported in ≥1.0 to ≤5.0% of immediaterelease metformin patients and were more commonly reported with immediate-release metformin than placebo: abnormal stools, hypoglycemia, myalgia, lightheaded, dyspnea, nail disorder, rash, sweating increased, taste disorder, chest discomfort, chills, flu syndrome, flushing, palpitation.

Pediatric Patients

No pediatric clinical studies have been conducted with FORTAMET^®. In clinical trials with immediate-release metformin in pediatric patients with type 2 diabetes, the profile of adverse reactions was similar to that observed in adults.

Cholestatic, hepatocellular, and mixed hepatocellular liver injury have been reported with postmarketing use of metformin.

DRUG INTERACTIONS

(Clinical Evaluation Of Drug Interactions Conducted With Immediate-Release Metformin)

Glyburide

In a single-dose interaction study in type 2 diabetes patients, coadministration of metformin and glyburide did not result in any changes in either metformin pharmacokinetics or pharmacodynamics. Decreases in glyburide AUC and Cmax were observed, but were highly variable. The single-dose nature of this study and the lack of correlation between glyburide blood levels and pharmacodynamic effects, makes the clinical significance of this interaction uncertain (see DOSAGE AND ADMINISTRATION: Concomitant FORTAMET^® And Oral Sulfonylurea Therapy In Adult Patients).

Furosemide

A single-dose, metformin-furosemide drug interaction study in healthy subjects demonstrated that pharmacokinetic parameters of both compounds were affected by coadministration. Furosemide increased the metformin plasma and blood Cmax by 22% and blood AUC by 15%, without any significant change in metformin renal clearance.

When administered with metformin, the Cmax and AUC of furosemide were 31% and 12% smaller, respectively, than when administered alone, and the terminal half-life was decreased by 32%, without any significant change in furosemide renal clearance. No information is available about the interaction of metformin and furosemide when coadministered chronically.

Nifedipine

A single-dose, metformin-nifedipine drug interaction study in normal healthy volunteers demonstrated that coadministration of nifedipine increased plasma metformin Cmax and AUC by 20% and 9%, respectively, and increased the amount excreted in the urine. Tmax and half-life were unaffected. Nifedipine appears to enhance the absorption of metformin. Metformin had minimal effects on nifedipine.

Drugs That Reduce Metformin Clearance

Concomitant use of drugs that interfere with common renal tubular transport systems involved in the renal elimination of metformin (e.g., organic cationic transporter-2 [OCT2] / multidrug and toxin extrusion [MATE] inhibitors such as ranolazine, vandetanib, dolutegravir, and cimetidine) could increase systemic exposure to metformin and may increase the risk for lactic acidosis. Consider the benefits and risks of concomitant use. Such interaction between metformin and oral cimetidine has been observed in normal healthy volunteers in both single- and multiple-dose, metformin-cimetidine drug interaction studies, with a 60% increase in peak metformin plasma and whole blood concentrations and a 40% increase in plasma and whole blood metformin AUC.

There was no change in elimination half-life in the single-dose study. Metformin had no effect on cimetidine pharmacokinetics.

In healthy volunteers, the pharmacokinetics of metformin and propranolol, and metformin and ibuprofen were not affected when coadministered in single-dose interaction studies.

Metformin is negligibly bound to plasma proteins and is, therefore, less likely to interact with highly protein-bound drugs such as salicylates, sulfonamides, chloramphenicol, and probenecid, as compared to the sulfonylureas, which are extensively bound to serum proteins.

Other

Certain drugs tend to produce hyperglycemia and may lead to loss of glycemic control. These drugs include the thiazides and other diuretics, corticosteroids, phenothiazines, thyroid products, estrogens, oral contraceptives, phenytoin, nicotinic acid, sympathomimetics, calcium channel blocking drugs, and isoniazid. When such drugs are administered to a patient receiving FORTAMET^®, the patient should be closely observed for loss of blood glucose control. When such drugs are withdrawn from a patient receiving FORTAMET^®, the patient should be observed closely for hypoglycemia.

In healthy volunteers, the pharmacokinetics of metformin and propranolol, and metformin and ibuprofen were not affected when coadministered in single-dose interaction studies.

Metformin is negligibly bound to plasma proteins and is, therefore, less likely to interact with highly protein-bound drugs such as salicylates, sulfonamides, chloramphenicol, and probenecid, as compared to the sulfonylureas, which are extensively bound to serum proteins.

Carbonic Anhydrase Inhibitors

Topiramate or other carbonic anhydrase inhibitors (e.g., zonisamide, acetazolamide or dichlorphenamide) frequently causes 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. Consider more frequent monitoring of these patients.

Alcohol

Alcohol is known to potentiate the effect of metformin on lactate metabolism. Warn patients against excessive alcohol intake while receiving FORTAMET^®.

Teratogenic Effects

Pregnancy Category B

Recent information strongly suggests that abnormal blood glucose levels during pregnancy are associated with a higher incidence of congenital abnormalities. Most experts recommend that insulin be used during pregnancy to maintain blood glucose levels as close to normal as possible. Because animal reproduction studies are not always predictive of human response, FORTAMET^® should not be used during pregnancy unless clearly needed.

There are no adequate and well-controlled studies in pregnant women with immediate-release metformin or FORTAMET^®. Metformin was not teratogenic in rats and rabbits at doses up to 600 mg/kg/day. This represents an exposure of about two and six times the maximum recommended human daily dose of 2000 mg based on body surface area comparisons for rats and rabbits, respectively. Determination of fetal concentrations demonstrated a partial placental barrier to metformin.

FORTAMET^® Clinical Studies

In the controlled clinical studies of FORTAMET^® in patients with type 2 diabetes, a total of 424 patients received FORTAMET^® therapy (up to 2500 mg/day) and 430 patients received immediaterelease metformin. Adverse reactions reported in ≥5% of the FORTAMET^® or immediate-release metformin patients are listed in Table 6. These pooled results show that the most frequently reported adverse reactions in the FORTAMET^® group were infection, diarrhea, and nausea. Similar incidences of these adverse reactions were seen in the immediate-release metformin group.

Table 6 Number and Percentage of Patients With the Most Common (Incidence ≥5%) Treatment-Emergent Signs or Symptoms by Body System and Preferred Term - Pooled Phase II and III Studies

The most frequent adverse events thought to be related to FORTAMET^® were diarrhea, nausea, dyspepsia, flatulence, and abdominal pain. The frequency of dyspepsia was 4.2% in the FORTAMET^® group compared to 5.1% in the immediate-release group, the frequency of flatulence was 3.5% in the FORTAMET^® group compared to 3.7% in the immediate-release group, and the frequency of abdominal pain was 3.3% in the FORTAMET^® group compared to 4.4% in the immediate-release group.

In the controlled studies, 4.7% of patients treated with FORTAMET^® and 4.9% of patients treated with immediate-release metformin were discontinued due to adverse events.

Immediate-Release Metformin

Immediate-Release Metformin Phase III Clinical Studies

In a U.S. double-blind clinical study of immediate-release metformin in patients with type 2 diabetes, a total of 141 patients received immediate-release metformin therapy (up to 2550 mg per day) and 145 patients received placebo. Adverse reactions reported in greater than 5% of the immediate-release metformin patients, and that were more common in immediate-release metformin than placebo-treated patients, are listed in Table 7.

Table 7 Most Common Adverse Reactions (>5.0%) in a Placebo-Controlled Clinical Study of Immediate-Release Metformin Monotherapy*

Diarrhea led to discontinuation of study medication in 6% of patients treated with immediate-release metformin. Additionally, the following adverse reactions were reported in ≥1.0 to ≤5.0% of immediaterelease metformin patients and were more commonly reported with immediate-release metformin than placebo: abnormal stools, hypoglycemia, myalgia, lightheaded, dyspnea, nail disorder, rash, sweating increased, taste disorder, chest discomfort, chills, flu syndrome, flushing, palpitation.

Pediatric Patients

No pediatric clinical studies have been conducted with FORTAMET^®. In clinical trials with immediate-release metformin in pediatric patients with type 2 diabetes, the profile of adverse reactions was similar to that observed in adults.

Cholestatic, hepatocellular, and mixed hepatocellular liver injury have been reported with postmarketing use of metformin.

Hypoglycemia has not been seen even with ingestion of up to 85 grams of immediate-release metformin, although lactic acidosis has occurred in such circumstances (see WARNINGS). 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.