Metformin Hcl

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

Mechanism Of Action

Metformin is an antihyperglycemic agent which improves glucose tolerance in patients with type 2 diabetes, lowering both basal and postprandial plasma glucose. Its pharmacologic mechanisms of action are different from other classes of oral antihyperglycemic agents. Metformin decreases hepatic glucose production, decreases intestinal absorption of glucose, and improves insulin sensitivity by increasing peripheral glucose uptake and utilization. Unlike sulfonylureas, metformin does not produce hypoglycemia in either patients with type 2 diabetes or normal subjects (except in special circumstances, see PRECAUTIONS) and does not cause hyperinsulinemia. With metformin therapy, insulin secretion remains unchanged while fasting plasma insulin levels and day-long plasma insulin response may actually decrease.

Pharmacokinetics And Drug Metabolism

The appearance of metformin in plasma from a FORTAMET® Extended-Release Tablet is slower and more prolonged compared to immediate-release metformin.

In a multiple-dose crossover study, 23 patients with type 2 diabetes mellitus were administered either FORTAMET® 2000 mg once a day (after dinner) or immediate-release (IR) metformin hydrochloride 1000 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. Results are presented in Table 1.

Table 1 : FORTAMET® vs . Immediate-Release Metformin Steady-State Pharmacokinetic Parameters at 4 Weeks

In four single-dose studies and one multiple-dose study, the bioavailability of FORTAMET® 2000 mg given once daily, in the evening, under fed conditions [as measured by the area under the plasma concentration versus time curve (AUC)] was similar to the same total daily dose administered as immediate-release metformin 1000 mg given twice daily. The geometric mean ratios (FORTAMET® / immediate-release metformin) of AUC0-24hr, AUC0-72h, and AUC0-inf. for these five studies ranged from 0.96 to 1.08.

In a single-dose, four-period replicate crossover design study, comparing two 500 mg FORTAMET® tablets to one 1000 mg FORTAMET® tablet administered in the evening with food to 29 healthy male subjects, two 500 mg FORTAMET® tablets were found to be equivalent to one 1000 mg FORTAMET® tablet.

In a study carried out with FORTAMET®, there was a dose-associated increase in metformin exposure over 24 hours following oral administration of 1000, 1500, 2000, and 2500 mg.

In three studies with FORTAMET® using different treatment regimens (2000 mg after dinner; 1000 mg after breakfast and after dinner; and 2500 mg after dinner), the pharmacokinetics of metformin as measured by AUC appeared linear following multiple-dose administration.

The extent of metformin absorption (as measured by AUC) from FORTAMET® increased by approximately 60% when given with food. When FORTAMET® was administered with food, Cmax was increased by approximately 30% and Tmax was more prolonged compared with the fasting state (6.1 versus 4.0 hours).

Distribution studies with FORTAMET® have not been conducted. However, the apparent volume of distribution (V/F) of metformin following single oral doses of immediate-release metformin 850 mg averaged 654 ± 358 L. Metformin is negligibly bound to plasma proteins, in contrast to sulfonylureas, which are more than 90% protein bound. Metformin partitions into erythrocytes, most likely as a function of time. At usual clinical doses and dosing schedules of immediate-release metformin, steady state plasma concentrations of metformin are reached within 24-48 hours and are generally < 1 μg/mL. During controlled clinical trials of immediate-release metformin, maximum metformin plasma levels did not exceed 5 μg/mL, even at maximum doses.

Metabolism studies with FORTAMET® have not been conducted. Intravenous single-dose studies in normal subjects demonstrate that metformin is excreted unchanged in the urine and does not undergo hepatic metabolism (no metabolites have been identified in humans) nor biliary excretion.

In healthy nondiabetic adults (N=18) receiving 2500 mg q.d. FORTAMET®, the percent of the metformin dose excreted in urine over 24 hours was 40.9% and the renal clearance was 542 ± 310 mL/min. After repeated administration of FORTAMET®, there is little or no accumulation of metformin in plasma, with most of the drug being eliminated via renal excretion over a 24-hour dosing interval. The t½ was 5.4 hours for FORTAMET®.

Renal clearance of metformin (Table 2) is approximately 3.5 times greater than creatinine clearance, which indicates that tubular secretion is the major route of metformin elimination. Following oral administration, approximately 90% of the absorbed drug is eliminated via the renal route within the first 24 hours, with a plasma elimination half-life of approximately 6.2 hours. In blood, the elimination halflife is approximately 17.6 hours, suggesting that the erythrocyte mass may be a compartment of distribution.

Special Populations

Limited data from controlled pharmacokinetic studies of immediate-release metformin in healthy elderly subjects suggest that total plasma clearance of metformin is decreased, the half-life is prolonged, and C is increased, compared to healthy young subjects. From these data, it appears that the change in metformin pharmacokinetics with aging is primarily accounted for by a change in renal function (Table 2). FORTAMET® treatment should not be initiated in patients ≥ 80 years of age unless measurement of creatinine clearance demonstrates that renal function is not reduced (see WARNINGS, PRECAUTIONS and DOSAGE AND ADMINISTRATION).

No pharmacokinetic data from studies of pediatric patients are currently available (see PRECAUTIONS).

Five studies indicated that with FORTAMET® treatment, the pharmacokinetic results for males and females were comparable.

Table 2 : Select Mean (±SD) Metformin Pharmacokinetic Parameters Following Single or Multiple Oral Doses of Immediate-Release Metformin

In patients with decreased renal function (based on measured creatinine clearance), the plasma and blood half-life of metformin is prolonged and the renal clearance is decreased in proportion to the decrease in creatinine clearance (Table 2; also see WARNINGS).

No pharmacokinetic studies of metformin have been conducted in patients with hepatic insufficiency.

No studies of metformin pharmacokinetic parameters according to race have been performed. In controlled clinical studies of immediate-release metformin in patients with type 2 diabetes, the antihyperglycemic effect was comparable in whites (n=249), blacks (n=51), and Hispanics (n=24).

Clinical Studies

In a double-blind, randomized, active-controlled, multicenter U.S. clinical study, which compared FORTAMET® q.d. to immediate-release metformin b.i.d., 680 patients with type 2 diabetes who had been taking metformin-containing medication at study entry were randomly assigned in equal numbers to double-blind treatment with either FORTAMET® or immediate-release metformin. Doses were adjusted during the first six weeks of treatment with study medication based on patients' FPG levels and were then held constant over a period of 20 weeks. The primary efficacy endpoint was the change in HbA from baseline to endpoint. The primary objective was to demonstrate the clinical non-inferiority of FORTAMET® compared to immediate-release metformin on the primary endpoint.

FORTAMET® and metformin patients had mean HbA1c changes from baseline to endpoint equal to +0.40 and +0.14, respectively (Table 3). The least-square (LS) mean treatment difference was 0.25 (95% CI = 0.14, 0.37) demonstrating that FORTAMET® was clinically similar to metformin according to the pre-defined criterion to establish efficacy.

Table 3 : FORTAMET® vs . Immediate-Release Metformin Switch Study: Summary of Mean Changes in HbA1c, Fasting Plasma Glucose, Body Weight, Body Mass Index, and Plasma Insulin

Footnote: Patients were taking metformin-containing medications at baseline that were prescribed by their personal physician.

The mean changes for FPG (Table 3) and plasma insulin (Table 3) were small for both FORTAMET® and immediate-release metformin, and were not clinically meaningful. Seventy-six (22%) and 49 (14%) of the FORTAMET® and immediate-release patients, respectively, discontinued prematurely from the trial. Eighteen (5%) patients on FORTAMET® withdrew because of a stated lack of efficacy, as compared with 8 patients (2%) on immediate-release metformin (p=0.047).

Results from this study also indicated that neither FORTAMET® nor immediate-release metformin were associated with weight gain or increases in body mass index.

A 24-week, double blind, placebo-controlled study of immediate-release metformin plus insulin, versus insulin plus placebo, was conducted in patients with type 2 diabetes who failed to achieve adequate glycemic control on insulin alone (Table 4). Patients randomized to receive immediate-release metformin plus insulin achieved a reduction in HbA of 2.10%, compared to a 1.56% reduction in HbA achieved by insulin plus placebo. The improvement in glycemic control was achieved at the final study visit with 16% less insulin, 93.0 U/day versus 110.6 U/day, immediate-release metformin plus insulin versus insulin plus placebo, respectively, p=0.04.

Table 4 : Combined Immediate-Release Metformin/lnsulin vs . Placebo/Insulin: Summary of Mean Changes from Baseline in HbA1c and Daily Insulin Dose

A second double-blind, placebo-controlled study (n=51), with 16 weeks of randomized treatment, demonstrated that in patients with type 2 diabetes controlled on insulin for 8 weeks with an average HbA1c of 7.46 ± 0.97%, the addition of immediate-release metformin maintained similar glycemic control (HbA1c 7.15 ± 0.61 versus 6.97 ± 0.62 for immediate-release metformin plus insulin and placebo plus insulin, respectively) with 19% less insulin versus baseline (reduction of 23.68 ± 30.22 versus an increase of 0.43 ± 25.20 units for immediate-release metformin plus insulin and placebo plus insulin, p < 0.01). In addition, this study demonstrated that the combination of immediate-release metformin plus insulin resulted in reduction in body weight of 3.11 ± 4.30 lbs, compared to an increase of 1.30 ± 6.08 lbs for placebo plus insulin, p=0.01.

No pediatric clinical studies have been conducted with FORTAMET®. In a double-blind, placebocontrolled study in pediatric patients aged 10 to 16 years with type 2 diabetes (mean FPG 182.2 mg/dL), treatment with immediate-release metformin (up to 2000 mg/day) for up to 16 weeks (mean duration of treatment 11 weeks) resulted in a significant mean net reduction in FPG of 64.3 mg/dL compared with placebo (Table 5).

Table 5 : Immediate-Release Metformin vs . Placebo (Pediatricsa): Summary of Mean Changes from Baseline* in Plasma Glucose and Body Weight at Final Visit

Fortamet®
(metformin hydrochloride) Extended-Release Tablets

Q1. Why do I need to take FORTAMET® ?

Your doctor has prescribed FORTAMET® to treat your type 2 diabetes, a condition in which blood sugar (blood glucose) is elevated. There are two types of diabetes. FORTAMET® is indicated for the most common type, known as type 2 diabetes.

Q2. Why is it important to control type 2 diabetes ?

Type 2 diabetes has multiple possible complications, including blindness, kidney failure, and circulatory and heart problems. Lowering your blood sugar to a normal level may prevent or delay these complications.

Q3. How is type 2 diabetes usually controlled?

High blood sugar can be lowered by diet and exercise, by a number of oral medications and by insulin injections. Your doctor may recommend that you try lifestyle modifications such as improved diet and exercise before initiating drug treatment for type 2 diabetes. Each patient will be treated individually by his or her physician, and should follow all treatment recommendations.

Q4. Does FORTAMET® work differently from other glucosecontrol medications ?

Yes. FORTAMET®, as well as other formulations of metformin, lowers the amount of sugar in your blood by controlling how much sugar is released by the liver. FORTAMET® (metformin hydrochloride) does not cause your body to produce more insulin. FORTAMET® rarely causes hypoglycemia (low blood sugar) and it does not usually cause weight gain when taken alone. However, if you do not eat enough, if you take other medications to lower blood sugar, or if you drink alcohol, you can develop hypoglycemia. Specifically, when FORTAMET® is taken together with a sulfonylurea or with insulin, hypoglycemia and weight gain are more likely to occur.

Q5. What happens if my blood sugar is still too high?

If your blood sugar is high, consult your physician. When blood sugar cannot be lowered enough by either FORTAMET® (metformin hydrochloride) Extended-Release Tablets or a sulfonylurea, the two medications can be effective when taken together. Other alternatives involve switching to other oral antidiabetic drugs (e.g., alpha glucoside inhibitors or glitazones). FORTAMET® may be stopped and replaced with other drugs and/or insulin. If you are unable to maintain your blood sugar with diet, exercise and glucose-control medications taken orally, then your doctor may prescribe injectable insulin to control your diabetes.

Q6. Why should I take FORTAMET® in addition to insulin if I am already on insulin alone?

Adding FORTAMET® to insulin can help you better control your blood sugar while reducing the insulin dose and possibly reducing your weight.

Q7. Can FORTAMET® cause side effects ?

FORTAMET®, like all blood sugar-lowering medications, can cause side effects in some patients. Most of these side effects are minor and will go away after you've taken FORTAMET® for a while. However, there are also serious but rare side effects related to FORTAMET® (see below).

Q8. What kind of side effects can FORTAMET® cause?

If side effects occur, they usually occur during the first few weeks of therapy. They are normally minor ones such as diarrhea, nausea, abdominal pain and upset stomach. FORTAMET® is generally taken with meals, which reduce these side effects.

Although these side effects are likely to go away, call your doctor if you have severe discomfort or if these effects last for more than a few weeks. Some patients may need to have their doses lowered or stop taking FORTAMET®, either temporarily or permanently. You should tell your doctor if the problems come back or start later on during the therapy.

WARNING: A rare number of people who have taken metformin have developed a serious condition called lactic acidosis. Properly functioning kidneys are needed to help prevent lactic acidosis. You should not take FORTAMET® if you have impaired kidney function, as measured by a blood test (see Q9-13).

Q9. Are there any serious side effects that FORTAMET® can cause?

FORTAMET® rarely causes serious side effects. The most serious side effect that FORTAMET® can cause is called lactic acidosis.

Q10. What is lactic acidosis and can it happen to me?

Lactic acidosis is caused by a build-up of lactic acid in the blood. Lactic acidosis associated with metformin is rare and has occurred mostly in people whose kidneys were not working normally. Lactic acidosis has been reported in about one in 33,000 patients taking metformin over the course of a year. Although rare, if lactic acidosis does occur, it can be fatal in up to half the cases.

It is also important for your liver to be working normally when you take FORTAMET®. Your liver helps to remove lactic acid from your bloodstream. Your doctor will monitor your diabetes and may perform blood tests on you from time to time to make sure your kidneys and your liver are functioning normally. There is no evidence that FORTAMET® causes harm to the kidneys or liver.

Q11. Are there other risk factors for lactic acidosis ?

Your risk of developing lactic acidosis from taking FORTAMET® is very low as long as your kidneys and liver are healthy. However, some factors can increase your risk because they can affect kidney and liver function. You should discuss your risk with your physician. You should not take FORTAMET® if:

• You have some forms of kidney or liver problems
• You have congestive heart failure which is treated with medications, e.g., digoxin (Lanoxin®) or furosemide (Lasix®)
• You drink alcohol excessively (all the time or short-term “binge” drinking)
• You are seriously dehydrated (have lost a large amount of body fluids)
• You are going to have, within a few days, certain x-ray tests with injectable contrast agents
• You are going to have surgery
• You develop a serious condition such as a heart attack, severe infection, or a stroke
• You are 80 years of age or older and have NOT had your kidney function tested

Q12. What are the symptoms of lactic acidosis ?

Some of the symptoms include feeling very weak, tired or uncomfortable, unusual muscle pain, trouble breathing, unusual or unexpected stomach discomfort, feeling cold, feeling dizzy or lightheaded, or suddenly developing a slow or irregular heartbeat. If you notice these symptoms, or if your medical condition has suddenly changed, stop taking FORTAMET® and call your doctor right away. Lactic acidosis is a medical emergency that must be treated in a hospital.

Q13. What does my doctor need to know to decrease my risk of lactic acidosis ?

Tell your doctor if you have an illness that results in severe vomiting, diarrhea and/or fever, or if your intake of fluids is generally reduced. These situations can lead to severe dehydration, and it may be necessary to stop taking FORTAMET® temporarily. You should let your doctor know if you are going to have any surgery or specialized x-ray procedures that require injection of contrast agents. FORTAMET® therapy will need to be stopped temporarily in such instances.

Q14. Can I take FORTAMET® with other medications ?

Remind your doctor and/or pharmacist that you are taking FORTAMET® when any new drug is prescribed or a change is made in how you take a drug already prescribed. FORTAMET® may interfere with the way some drugs work and some drugs may interfere with the action of FORTAMET®.

Q15. What if I become pregnant while taking FORTAMET® ?

Tell your doctor if you plan to become pregnant or have become pregnant. As with other oral glucosecontrol medications, you should not take FORTAMET® during pregnancy. Usually your doctor will prescribe insulin while you are pregnant.

Q16. How do I take FORTAMET® ?

FORTAMET® tablets should not be cut, crushed, or chewed and should be taken whole with a full glass of water once daily with the evening meal. Occasionally, the inactive ingredients of FORTAMET® may be eliminated as a soft mass in your stool that may look like the original tablet; this is not harmful and will not affect the way FORTAMET® works to control diabetes. FORTAMET® should be taken once a day with food. You will be started on a low dose of FORTAMET® and your dosage will be increased gradually until your blood sugar is controlled.

Q17. Where can I get more information about FORTAMET® ?

This leaflet is a summary of the most important information about FORTAMET®. If you have any questions or problems, you should talk to your doctor or other healthcare provider about type 2 diabetes as well as FORTAMET® and its side effects.

Dosage Forms And Strengths

GLUMETZA (metformin hydrochloride extended-release tablets) 500 mg are available as blue, film coated, ovalshaped tablets debossed with “GMZ” on one side and “500” on the other side.

GLUMETZA (metformin hydrochloride extended-release tablets) 1000 mg are available as white, film coated, ovalshaped tablets with “M1000” on one side.

Storage And Handling

GLUMETZA tablets - 500 mg are available as blue, film coated, oval-shaped tablets debossed with “GMZ” on one side and “500” on the other side.

GLUMETZA tablets 1000 mg are available as white, film coated, oval-shaped tablets with “M1000” on one side.

They are supplied as follows:

Store at 20° to 25°C (68° to 77°F); excursions permitted to 15° to 30°C (59° to 86°F); see [USP Controlled Room Temperature].

Manufactured for Santarus, Inc., a wholly owned subsidiary of Salix Pharmaceuticals, Raleigh, NC 27615. Revised: Sep 2014

Overdose of metformin hydrochloride has occurred, including ingestion of amounts greater than 50 grams. Hypoglycemia was reported in approximately 10% of cases, but no casual association with metformin hydrochloride has been established. Lactic acidosis has been reported in approximately 32% of metformin overdose cases [see WARNINGS AND PRECAUTIONS]. 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.

Avoid drinking alcohol. It lowers blood sugar and may increase your risk of lactic acidosis while taking metformin.

Your pharmacist can provide more information about metformin.

Remember, keep this and all other medicines out of the reach of children, never share your medicines with others, and use this medication only for the indication prescribed.

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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 PreferredTerm - 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

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 - ≤ 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 immediaterelease metformin in pediatric patients with type 2 diabetes, the profile of adverse reactions was similar to that observed in adults.

Read the entire FDA prescribing information for Fortamet (Metformin Hcl)

You should not use this medication if you are allergic to metformin, or if you are in a state of diabetic ketoacidosis (call your doctor for treatment with insulin).

If you need to have any type of x-ray or CT scan using a dye that is injected into your veins, you will need to temporarily stop taking metformin.

Before taking metformin, tell your doctor if you have liver disease or a history of heart disease.

Some people develop lactic acidosis while taking metformin. Early symptoms may get worse over time and this condition can be fatal. Get emergency medical help if you have even mild symptoms such as: muscle pain or weakness, numb or cold feeling in your arms and legs, trouble breathing, stomach pain, nausea with vomiting, slow or uneven heart rate, dizziness, or feeling very weak or tired.

Some people develop a life-threatening condition called lactic acidosis while taking metformin. You may be more likely to develop lactic acidosis if you have liver or kidney disease, congestive heart failure, a severe infection, if you are dehydrated, or if you drink large amounts of alcohol. Talk with your doctor about your individual risk.

You should not use this medication if you are allergic to metformin, or if you are in a state of diabetic ketoacidosis (call your doctor for treatment with insulin).

If you need to have any type of x-ray or CT scan using a dye that is injected into your veins, you will need to temporarily stop taking metformin.

To make sure you can safely take metformin, tell your doctor if you have any of these other conditions:

• liver disease; or
• a history of heart disease.

FDA pregnancy category B. This medication is not expected to be harmful to an unborn baby. Tell your doctor if you are pregnant or plan to become pregnant during treatment.

It is not known whether metformin passes into breast milk or if it could harm a nursing baby. You should not breast-feed while you are using metformin.

Metformin should not be given to a child younger than 10 years old. Extended-release metformin (Glucophage XR) should not be given to a child younger than 17 years old.