Fortamet

Dosage Forms & Strengths

tablet, immediate-release

• 500mg
• 850mg
• 1000mg

tablet, extended-release

• 500mg
• 750mg
• 1000mg

oral solution

• 100mg/mL

Type 2 Diabetes Mellitus

Monotherapy or with sulfonylurea

Immediate-release tablet or solution

• Initial: 500 mg PO q12hr or 850 mg PO qDay with meals; increase q2Weeks
• Maintenance: 1500-2550 mg/day PO divided q8-12hr with meal
• Not to exceed 2550 mg/day

Extended-release

• Glucophage XR: 500 mg PO qDay with dinner; titrate by 500 mg/day qWeek; not to exceed 2000 mg/day
• Fortamet: 500-1000 mg PO qDay; titrate by 500 mg/day qWeek; not to exceed 2500 mg/day
• Glumetza: 1000 mg PO qDay; titrate by 500 mg/day qWeek; not to exceed 2000 mg/day

Type 2 Diabetes Prevention (Off-label)

850 mg PO qDay

Target dosing: 850 mg PO q12hr

Dosage Modifications

Hepatic impairment: Avoid use; risk of lactic acidosis

Renal impairment

• Obtain eGFR before starting metformin
• eGFR <30 mL/min/1.73 m²: Contraindicated
• eGFR 30-45 mL/min/1.73 m²: Not recommended to initiate treatment
• Monitor eGFR at least annually or more often for those at risk for renal impairment (eg, elderly)
• If eGFR falls below 45mL/min/1.73 m² while taking metformin, risks and benefits of continuing therapy should be evaluated
• If eGFR falls below 30 mL/min/1.73 m²: while taking metformin, discontinue the drug

Polycystic Ovary Syndrome (Orphan)

Orphan designation for treatment of pediatric polycystic ovary syndrome

Sponsor

• EffRx Pharmaceuticals SA; Wolleraustrass 41 B; 8807 Freienbach (SZ); SWITZERLAND

Dosage Forms & Strengths

tablet, immediate-release

• 500mg
• 850mg
• 1000mg

tablet, extended-release

• 500mg
• 750mg
• 1000mg

oral solution

• 100mg/mL

Type 2 Diabetes Mellitus

Immediate-release (10-16 years)

• Initial: 500 mg PO q12hr
• Maintenance: Titrate qWeek by 500 mg; no more than 2000 mg/day in divided doses

Immediate-release (≥17 years)

• Initial: 500 mg PO q12hr or 850 mg PO qDay with meals; increase q2Weeks
• Maintenance: 1500-2550 mg/day PO divided q8-12hr with meal
• No more than 2550 mg/day

Extended-release (<17 years)

• Safety and efficacy not established

Extended-release (≥17 years)

• Glucophage XR: 500 mg PO qDay with dinner; titrate by 500 mg/day qWeek; not to exceed 2000 mg/day
• Fortamet: 500-1000 mg PO qDay; titrate by 500 mg/day qWeek; not to exceed 2500 mg/day

Dosage Modifications

Renal impairment

• Obtain eGFR before initiating metformin
• eGFR <30 mL/min/1.73 m²: Contraindicated
• eGFR 30-45 mL/min/1.73 m²: Initiating not recommended
• Obtain GFR at least annually in all patients taking metformin; assess eGFR more frequently in patients at increased risk for renal impairment (eg, elderly)
• If eGFR falls to <45 mL/min/1.73 m² during treatment: Assess the benefits and risks of continuing treatment
• If eGFR falls to <30 mL/min/1.73 m² during treatment: Discontinue

Elderly patients are more likely to have decreased renal function; contraindicated in patients with renal impairment, carefully monitor renal function in the elderly and use with caution as age increases

Not for use in patients >80 years unless normal renal function establishedInitial and maintenance dosing of metformin should be conservative in patients with advanced age due to the potential for decreased renal function in this population

Controlled clinical studies of metformin did not include sufficient numbers of elderly patients to determine whether they respond differently from younger patients

FORTAMET® (metformin hydrochloride) Extended-Release Tablets contain an oral antihyperglycemic drug used in the management of type 2 diabetes. Metformin hydrochloride (N, Ndimethylimidodicarbonimidic diamide hydrochloride) is a member of the biguanide class of oral antihyperglycemics and is not chemically or pharmacologically related to any other class of oral antihyperglycemic agents. The empirical formula of metformin hydrochloride is C4H11N5•HCl and its molecular weight is 165.63. Its structural formula is:

Metformin hydrochloride 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 hydrochloride is 6.68.

FORTAMET® Extended-Release Tablets are designed for once-a-day oral administration and deliver 500 mg or 1000 mg of metformin hydrochloride. In addition to the active ingredient metformin hydrochloride, each tablet contains the following inactive ingredients: candellila 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.

FORTAMET® meets USP Dissolution Test 5.

System Components And Performance

FORTAMET® was developed as an extended-release formulation of metformin hydrochloride and designed for once-a-day oral administration using the patented single-composition osmotic technology (SCOT™). The tablet is similar in appearance to other film-coated oral administered tablets but it consists of an osmotically active core formulation that is surrounded by a semipermeable membrane. Two laser drilled exit ports exist in the membrane, one on either side of the tablet. The core formulation is composed primarily of drug with small concentrations of excipients. The semipermeable membrane is permeable to water but not to higher molecular weight components of biological fluids. Upon ingestion, water is taken up through the membrane, which in turn dissolves the drug and excipients in the core formulation. The dissolved drug and excipients exit through the laser drilled ports in the membrane. The rate of drug delivery is constant and dependent upon the maintenance of a constant osmotic gradient across the membrane. This situation exists so long as there is undissolved drug present in the core tablet. Following the dissolution of the core materials, the rate of drug delivery slowly decreases until the osmotic gradient across the membrane falls to zero at which time delivery ceases. The membrane coating remains intact during the transit of the dosage form through the gastrointestinal tract and is excreted in the feces.

Tell your doctor if you are breastfeeding or plan to breastfeed. It is not known if Fortamet is excreted in human breastmilk or if it will harm your nursing baby.

Metformin is used to treat high blood sugar levels that are caused by a type of diabetes mellitus or sugar diabetes called type 2 diabetes. With this type of diabetes, insulin produced by the pancreas is not able to get sugar into the cells of the body where it can work properly. Using metformin alone, with a type of oral antidiabetic medicine called a sulfonylurea, or with insulin, will help to lower blood sugar when it is too high and help restore the way you use food to make energy.

Many people can control type 2 diabetes with diet and exercise. Following a specially planned diet and exercise will always be important when you have diabetes, even when you are taking medicines. To work properly, the amount of metformin you take must be balanced against the amount and type of food you eat and the amount of exercise you do. If you change your diet or exercise, you will want to test your blood sugar to find out if it is too low. Your doctor will teach you what to do if this happens.

Metformin does not help patients does not help patients who have insulin-dependent or type 1 diabetes because they cannot produce insulin from their pancreas gland. Their blood glucose is best controlled by insulin injections.

This medicine is available only with your doctor's prescription.

WARNING/CAUTION: Even though it may be rare, some people may have very bad and sometimes deadly side effects when taking a drug. Tell your doctor or get medical help right away if you have any of the following signs or symptoms that may be related to a very bad side effect:

• Signs of an allergic reaction, like rash; hives; itching; red, swollen, blistered, or peeling skin with or without fever; wheezing; tightness in the chest or throat; trouble breathing or talking; unusual hoarseness; or swelling of the mouth, face, lips, tongue, or throat.
• Very bad belly pain.
• Fever or chills.
• Sore throat.
• It is common to have stomach problems like upset stomach, throwing up, or loose stools (diarrhea) when you start taking Fortamet. If you have stomach problems later during care, call your doctor right away. This may be a sign of an acid health problem in the blood (lactic acidosis).
• Low blood sugar can happen. The chance of low blood sugar may be raised when this medicine is used with other drugs for high blood sugar (diabetes). Signs may be dizziness, headache, feeling sleepy, feeling weak, shaking, a fast heartbeat, confusion, hunger, or sweating. Call your doctor right away if you have any of these signs. Follow what you have been told to do if you get low blood sugar. This may include taking glucose tablets, liquid glucose, or some fruit juices.

All drugs may cause side effects. However, many people have no side effects or only have minor side effects. Call your doctor or get medical help if any of these side effects or any other side effects bother you or do not go away:

• Loose stools (diarrhea).
• Gas.
• Upset stomach or throwing up.
• Feeling tired or weak.

These are not all of the side effects that may occur. If you have questions about side effects, call your doctor. Call your doctor for medical advice about side effects.

You may report side effects to the FDA at 1-800-FDA-1088. You may also report side effects at http://www.fda.gov/medwatch.

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

Fortamet® is contraindicated in patients with:

1. Renal disease or renal dysfunction (e.g., as suggested by serum creatinine levels ≥1.5 mg/dL [males], ≥1.4 mg/dL [females] or abnormal creatinine clearance) which may also result from conditions such as cardiovascular collapse (shock), acute myocardial infarction, and septicemia (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.

Fortamet® should be temporarily discontinued in patients undergoing radiologic studies involving intravascular administration of iodinated contrast materials, because use of such products may result in acute alteration of renal function (see also PRECAUTIONS).

Lactic Acidosis:

Lactic acidosis is a rare, but serious, metabolic complication that can occur due to metformin accumulation during treatment with Fortamet® (metformin hydrochloride) Extended-Release Tablets; when it occurs, it is fatal in approximately 50% of cases. Lactic acidosis may also occur in association with a number of pathophysiologic conditions, including diabetes mellitus, and whenever there is significant tissue hypoperfusion and hypoxemia. Lactic acidosis is characterized by elevated blood lactate levels (>5 mmol/ L), decreased blood pH, electrolyte disturbances with an increased anion gap, and an increased lactate/pyruvate ratio. When metformin is implicated as the cause of lactic acidosis, metformin plasma levels >5 μg/mL are generally found.

The reported incidence of lactic acidosis in patients receiving metformin hydrochloride is very low (approximately 0.03 cases/1000 patient-years, with approximately 0.015 fatal cases/1000 patient-years). Reported cases have occurred primarily in diabetic patients with significant renal insufficiency, including both intrinsic renal disease and renal hypoperfusion, often in the setting of multiple concomitant medical/ surgical problems and multiple concomitant medications. Patients with congestive heart failure requiring pharmacologic management, in particular those with unstable or acute congestive heart failure who are at risk of hypoperfusion and hypoxemia, are at increased risk of lactic acidosis. The risk of lactic acidosis increases with the degree of renal dysfunction and the patient's age. The risk of lactic acidosis may, therefore, be significantly decreased by regular monitoring of renal function in patients taking Fortamet® (metformin hydrochloride) Extended-Release Tablets and by use of the minimum effective dose of Fortamet®. In particular, treatment of the elderly should be accompanied by careful monitoring of renal function. Fortamet® treatment should not be initiated in patients ≥80 years of age unless measurement of creatinine clearance demonstrates that renal function is not reduced, as these patients are more susceptible to developing lactic acidosis. In addition, Fortamet® should be promptly withheld in the presence of any condition associated with hypoxemia, dehydration, or sepsis. Because impaired hepatic function may significantly limit the ability to clear lactate, Fortamet® should generally be avoided in patients with clinical or laboratory evidence of hepatic disease. Patients should be cautioned against excessive alcohol intake, either acute or chronic, when taking Fortamet®, since alcohol potentiates the effects of metformin hydrochloride on lactate metabolism. In addition, Fortamet® should be temporarily discontinued prior to any intravascular radiocontrast study and for any surgical procedure (see also PRECAUTIONS).

The onset of lactic acidosis often is subtle, and accompanied only by nonspecific symptoms such as malaise, myalgias, respiratory distress, increasing somnolence, and nonspecific abdominal distress. There may be associated hypothermia, hypotension, and resistant bradyarrhythmias with more marked acidosis. The patient and the patient's physician must be aware of the possible importance of such symptoms and the patient should be instructed to notify the physician immediately if they occur (see also PRECAUTIONS). Fortamet® should be withdrawn until the situation is clarified. Serum electrolytes, ketones, blood glucose and, if indicated, blood pH, lactate levels, and even blood metformin levels may be useful. Once a patient is stabilized on any dose level of Fortamet®, gastrointestinal symptoms, which are common during initiation of therapy, are unlikely to be drug related. Later occurrence of gastrointestinal symptoms could be due to lactic acidosis or other serious disease.

Levels of fasting venous plasma lactate above the upper limit of normal but less than 5 mmol/L in patients taking Fortamet® do not necessarily indicate impending lactic acidosis and may be explainable by other mechanisms, such as poorly controlled diabetes or obesity, vigorous physical activity, or technical problems in sample handling (see also PRECAUTIONS).

Lactic acidosis should be suspected in any diabetic patient with metabolic acidosis lacking evidence of ketoacidosis (ketonuria and ketonemia).

Lactic acidosis is a medical emergency that must be treated in a hospital setting. In a patient with lactic acidosis who is taking Fortamet®, the drug should be discontinued immediately and general supportive measures promptly instituted. Because metformin hydrochloride is dialyzable (with a clearance of up to 170 mL/min under good hemodynamic conditions), prompt hemodialysis is recommended to correct the acidosis and remove the accumulated metformin. Such management often results in prompt reversal of symptoms and recovery (see also CONTRAINDICATIONS and PRECAUTIONS).

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 immediate-release 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.

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.

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 - ≤5.0% of immediate-release 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.

Store at 20º-25°C (68º-77°F) Excursions permitted to 15° - 30°C (59° - 86°F) [See USP Controlled Room Temperature]. Keep tightly closed (protect from moisture). Protect from light. Avoid excessive heat and humidity.

Distributed by:
Shionogi Inc.
Florham Park, NJ 07932

Manufactured by:
Watson Laboratories - Florida
Ft. Lauderdale, FL 33314

LactMed Record Number

173

Last Revision Date

20170905

Disclaimer

Information presented in this database is not meant as a substitute for professional judgment. You should consult your healthcare provider for breastfeeding advice related to your particular situation. The U.S. government does not warrant or assume any liability or responsibility for the accuracy or completeness of the information on this Site.