Complete SPL Sections
WARNING: LACTIC ACIDOSIS
Boxed Warning Section
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 in the full prescribing information [see Dosage and Administration (2.2), Contraindications (4), Warnings and Precautions (5.1), and Drug Interactions (7)] . If metformin-associated lactic acidosis is suspected, immediately discontinue metformin hydrochloride extended-release tablets and institute general supportive measures in a hospital setting. Prompt hemodialysis is recommended [see Warnings and Precautions (5.1)] .
1 INDICATIONS AND USAGE
Indications & Usage Section
Metformin hydrochloride extended-release tablets, USP are indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus.
2 DOSAGE AND ADMINISTRATION
Dosage & Administration Section
3 DOSAGE FORMS AND STRENGTHS
Dosage Forms & Strengths Section
Metformin hydrochloride extended-release tablets, USP 500 mg are available as white to off-white, circular, biconvex, film-coated tablets imprinted with “305” in black ink on one side and plain on the other side. Metformin hydrochloride extended-release tablets, USP 1,000 mg are available as white to off-white, circular, biconvex, film-coated tablets imprinted with “306” in black ink on one side and plain on the other side.
4 CONTRAINDICATIONS
Contraindications Section
Metformin hydrochloride extended-release tablets are contraindicated in patients with: · Severe renal impairment (eGFR below 30 mL/minute/1.73 m 2 ) [see Warnings and Precautions (5.1)] . · Known hypersensitivity to metformin. · Acute or chronic metabolic acidosis, including diabetic ketoacidosis, with or without coma.
5 WARNINGS AND PRECAUTIONS
Warnings And Precautions Section
6 ADVERSE REACTIONS
Adverse Reactions Section
The following adverse reactions are discussed in more detail in other sections of the labeling: · Lactic Acidosis [see Boxed Warning and Warnings and Precautions (5.1)] · Vitamin B 12 Deficiency [see Warnings and Precautions (5.2)] · Hypoglycemia [see Warnings and Precautions (5.3)]
7 DRUG INTERACTIONS
Drug Interactions Section
Table 2 presents clinically significant drug interactions with metformin hydrochloride extended-release tablets. Table 2: Clinically Significant Drug Interactions with Metformin Hydrochloride Extended-Release Tablets Carbonic Anhydrase Inhibitors Clinical Impact: Carbonic anhydrase inhibitors frequently cause a decrease in serum bicarbonate and induce non-anion gap, hyperchloremic metabolic acidosis. Concomitant use of these drugs with metformin hydrochloride extended-release tablets may increase the risk for lactic acidosis. Intervention: Consider more frequent monitoring of these patients. Examples: Topiramate, zonisamide, acetazolamide or dichlorphenamide. Drugs that Reduce Metformin Hydrochloride Extended-Release Tablets Clearance Clinical Impact: Concomitant use of drugs that interfere with common renal tubular transport systems involved in the renal elimination of metformin (e.g., organic cationic transporter-2 [OCT2] / multidrug and toxin extrusion [MATE] inhibitors) could increase systemic exposure to metformin and may increase the risk for lactic acidosis [see Clinical Pharmacology (12.3)] . Intervention: Consider the benefits and risks of concomitant use with metformin hydrochloride extended-release tablets. Examples: Ranolazine, vandetanib, dolutegravir, and cimetidine. Alcohol Clinical Impact: Alcohol is known to potentiate the effect of metformin on lactate metabolism. Intervention: Warn patients against excessive alcohol intake while receiving metformin hydrochloride extended-release tablets. Insulin Secretagogues or Insulin Clinical Impact: Coadministration of metformin hydrochloride extended-release tablets with an insulin secretagogue (e.g., sulfonylurea) or insulin may increase the risk of hypoglycemia. Intervention: Patients receiving an insulin secretagogue or insulin may require lower doses of the insulin secretagogue or insulin. Drugs Affecting Glycemic Control Clinical Impact: Certain drugs tend to produce hyperglycemia and may lead to loss of glycemic control. Intervention: When such drugs are administered to a patient receiving metformin hydrochloride extended-release tablets, observe the patient closely for loss of blood glucose control. When such drugs are withdrawn from a patient receiving metformin hydrochloride extended-release tablets, observe the patient closely for hypoglycemia. Examples: Thiazides and other diuretics, corticosteroids, phenothiazines, thyroid products, estrogens, oral contraceptives, phenytoin, nicotinic acid, sympathomimetics, calcium channel blockers, and isoniazid.
8 USE IN SPECIFIC POPULATIONS
Use In Specific Populations Section
10 OVERDOSAGE
Overdosage Section
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/minute under good hemodynamic conditions. Therefore, hemodialysis may be useful for removal of accumulated drug from patients in whom metformin overdosage is suspected.
11 DESCRIPTION
Description Section
Metformin hydrochloride extended-release tablets contain the biguanide antihyperglycemic agent metformin in the form of monohydrochloride salt. The chemical name of metformin hydrochloride is N,N-dimethylimidodicarbonimidic diamide hydrochloride. The structural formula is as shown: Metformin hydrochloride is a white crystalline compound with a molecular formula of C 4 H 11 N 5 •HCl and a molecular weight of 165.62. Metformin hydrochloride 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. Metformin hydrochloride extended-release tablets, USP contain 500 mg or 1,000 mg of metformin hydrochloride, USP, which is equivalent to 389.93 mg or 779.86 mg metformin, respectively. Each tablet contains anhydrous citric acid, colloidal silicon dioxide, dibutyl sebacate, ethylcellulose, magnesium stearate, povidone, sodium bicarbonate and sodium lauryl sulfate. The imprinting ink contains ammonium hydroxide, iron oxide black, N-butyl alcohol, propylene glycol and shellac glaze. FDA approved dissolution specifications differ from USP
12 CLINICAL PHARMACOLOGY
Clinical Pharmacology Section
13 NONCLINICAL TOXICOLOGY
Nonclinical Toxicology Section
14 CLINICAL STUDIES
Clinical Studies Section
In a multicenter, randomized, double-blind, active-controlled, dose-ranging, parallel group study conducted in patients type 2 diabetes mellitus, metformin hydrochloride extended-release tablets1,500 mg once daily, metformin hydrochloride extended-release tablets 1,500 per day in divided doses (500 mg in the morning and 1,000 mg in the evening), and metformin hydrochloride extended-release tablets 2,000 mg once daily were compared to immediate-release metformin HCl tablets 1,500 mg per day in divided doses (500 mg in the morning and 1,000 mg in the evening). This study included patients (n=338) who were newly diagnosed with diabetes, patients treated only with diet and exercise, patients treated with a single antidiabetic medication (sulfonylureas, alpha-glucosidase inhibitors, thiazolidinediones, or meglitinides), and patients (n=368) receiving metformin HCl tablets up to 1,500 mg/day plus a sulfonylurea at a dose equal to or less than one-half the maximum dose. Patients who were enrolled on monotherapy or combination antidiabetic therapy underwent a 6-week washout. Patients randomized to metformin hydrochloride extended-release tabletsbegan titration from 1,000 mg/day up to their assigned treatment dose over 3 weeks. Patients randomized to immediate-release metformin initiated 500 mg twice daily for 1 week followed by 500 mg with breakfast and 1,000 mg with dinner for the second week. The 3-week treatment period was followed by an additional 21-week period at the randomized dose. The results are presented in Table 4. Table 5: Mean Changes from Baseline in HbA1c and Fasting Plasma Glucose at Week 24 Comparing Metformin Hydrochloride Extended-Release Tablets versus Metformin HCl Tablets* in Patients with Type 2 Diabetes Mellitus Metformin Hydrochloride E xtended-Release Tablets Metformin HCl Tablets* 1,500 mg in Divided Doses (n=174) 1,500 mg Once Daily (n = 178) 1,500 mg in Divided doses (n = 182) 2,000 mg O nce Daily (n = 172) HbA1c (%), N 169 175 159 170 Baseline 8.2 8.5 8.3 8.7 Mean Change at Final Visit -0.7 -0.7 -1.1 -0.7 Mean Difference from Metformin HCl Tablets* (98.4% CI) 0 (-0.3, 0.3) 0 (-0.3, 0.3) -0.4 (-0,7, -0.1) N/A Fasting Plasma Glucose (mg/dL), N 175 179 170 172 Baseline 190 192.3 184 197 Mean Change at Final Visit -39 -32 -42 -32 Mean Difference from Metformin HCl Tablets* (95% CI) -6 (-15, 2) 0 (-8, 9) -10 (-19, -1) N/A *Immediate-release metformin HCl tablets Mean baseline body weight was 88.2 kg, 90.5 kg, 87.7 kg and 88.7 kg in the metformin hydrochloride extended-release tablets 1,500 mg once daily, metformin hydrochloride extended-release tablets 1,500 mg in divided doses, metformin hydrochloride extended-release tablets 2,000 mg once daily and metformin HCl tablets 1,500 mg in divided doses arms, respectively. Mean change in body weight from baseline to week 24 was -0.9 kg, -0.7 kg, -1.1 kg, and -0.9 kg in the metformin hydrochloride extended-release tablets 1,500 mg once daily, metformin hydrochloride extended-release tablets 1,500 mg in divided doses, metformin hydrochloride extended-release tablets 2,000 mg once daily and metformin HCl tablets 1,500 mg in divided doses arms, respectively. A double-blind, randomized, placebo-controlled (glyburide add-on) multicenter study enrolled patients with type 2 diabetes mellitus who were newly diagnosed or treated with diet and exercise (n=144), or who were receiving monotherapy with metformin, sulfonylureas, alpha-glucosidase inhibitors, thiazolidinediones, or meglitinides, or treated with combination therapy consisting of metformin HCl/glyburide at doses up to 1,000 mg metformin + 10 mg glyburide per day (or equivalent doses of glipizide or glimepiride up to half the maximum therapeutic dose) (n=431). All patients were stabilized on glyburide for a 6-week run-in period, and then randomized to 1 of 4 treatments: placebo + glyburide (glyburide alone); metformin hydrochloride extended-release tablets 1,500 mg once a day + glyburide, metformin hydrochloride extended-release tablets 2,000 mg once a day + glyburide, or metformin hydrochloride extended-release tablets 1,000 mg twice a day + glyburide. A 3-week metformin hydrochloride extended-release tablets titration period was followed by a 21-week maintenance treatment period. Use of insulin and oral hypoglycemic agents other than the study drugs were prohibited. The results are presented in Table 5. Table 6: Mean Changes from Baseline in HbA1c and Fasting Plasma Glucose at Week 24 for the Metformin Hydrochloride Extended-Release Tablets + Glyburide Groups and Placebo+ Glyburide Treatment Group in Patients with Type 2 Diabetes Mellitus Metformin Hydrochloride Extended-Release Tablets + Glyburide* Placebo + Glyburide* (n = 144) 1,500 mg Once Daily (n=144) 1,000 mg Twice Daily (n=141) 2,000 mg Once Daily (n=146) HbA1c (%), N 136 136 144 141 Baseline 7.9 7.8 7.7 8.1 Mean Change at Final Visit -0.7 -0.8 -0.7 -0.1 Mean Difference from Glyburide Alone (95% CI) -0.8 a (-1.0, -0.6) -0.9 a (-1.1, -0.7) -0.8 a (-1.0, -0.6) N/A Fasting Plasma Glucose (mg/dL), N 143 141 145 144 Baseline 163 163 159 164 Mean Change at Final Visit -14 -16 -9 16 Mean Difference from Glyburide Alone (95% CI) -29.2 a (-39, -20) -31.2 a (-41, -22) -24.9 a (-35, -15) N/A * Glyburide was administered as 10 mg at breakfast and 5 mg at dinner. a p-value for pairwise comparison
16 HOW SUPPLIED/STORAGE AND HANDLING
How Supplied Section
Metformin hydrochloride extended-release tablets, USP - 500 mg are available as white to off-white, circular, biconvex, film-coated tablets imprinted with "305" in black ink on one side and plain on the other side. Metformin hydrochloride extended-release tablets, USP - 1,000 mg are available as white to off-white, circular, biconvex, film-coated tablets imprinted with "306" in black ink on one side and plain on the other side. They are supplied as follows: 500 mg tablets: Bottles of 30 with Child Resistant Cap…....................NDC 47335-305-83 Bottles of 100 with Child Resistant Cap…..................NDC 47335-305-88 Bottles of 1000.................................................………..NDC 47335-305-18 1,000 mg tablets: Bottles of 30 with Child Resistant Cap…....................NDC 47335-306-83 Bottles of 90 with Child Resistant Cap…....................NDC 47335-306-81 Bottles of 100 with Child Resistant Cap…..................NDC 47335-306-88 Bottles of 1000.................................................………..NDC 47335-306-18 Storage Store at 20° to 25°C (68° to 77°F); excursions permitted between 15° and 30°C (59° and 86°F) [see USP Controlled Room Temperature].
17 PATIENT COUNSELING INFORMATION
Information For Patients Section
Advise the patient to read the FDA-approved patient labeling (Patient Information). Lactic Acidosis: Explain the risks of lactic acidosis, its symptoms, and conditions that predispose to its development. Advise patients to discontinue metformin hydrochloride extended-release tablets immediately and to promptly notify their healthcare provider if unexplained hyperventilation, myalgias, malaise, unusual somnolence or other nonspecific symptoms occur. Counsel patients against excessive alcohol intake and inform patients about importance of regular testing of renal function while receiving metformin hydrochloride extended-release tablets. Instruct patients to inform their doctor that they are taking metformin hydrochloride extended-release tablets prior to any surgical or radiological procedure, as temporary discontinuation may be required [see Warnings and Precautions (5.1)]. Hypoglycemia: Inform patients that hypoglycemia may occur when metformin hydrochloride extended-release tablets are coadministered with oral sulfonylureas and insulin. Explain to patients receiving concomitant therapy the risks of hypoglycemia, its symptoms and treatment, and conditions that predispose to its development [see Warnings and Precautions (5.3)]. Vitamin B12 Deficiency: Inform patients about importance of regular hematological parameters while receiving metformin hydrochloride extended-release tablets [see Warnings and Precautions (5.2)]. Females of Reproductive Age: Inform females that treatment with metformin hydrochloride extended-release tablets may result in ovulation in some premenopausal anovulatory women which may lead to unintended pregnancy [see Use in Specific Populations (8.3)]. Administration Information: Inform patients that metformin hydrochloride extended-release tablets must be swallowed whole and not crushed, cut, or chewed, and that the inactive ingredients may occasionally be eliminated in the feces as a soft mass that may resemble the original tablet.
SPL PATIENT PACKAGE INSERT SECTION
SPL PATIENT PACKAGE INSERT SECTION
Dispense with Patient Information available at: https://www.sunpharma.com/usa/products PARIENT INFORMATION Metformin Hydrochloride (met-FOR-min HYE-droe-KLOR-ide) Extended-Release Tablets USP, for oral use What is the most important information I should know about metformin hydrochloride extended-release tablets? Metformin hydrochloride extended-release tablets can cause serious side effects, including: Lactic acidosis. Metformin hydrochloride, the medicine in metformin hydrochloride extended-release tablets, can cause a rare, but serious side effect called lactic acidosis (a buildup of lactic acid in the blood) that can cause death. Lactic acidosis is a medical emergency and must be treated in the hospital. Stop taking metformin hydrochloride extended-release tablets and call your doctor right away if you get any of the following symptoms of lactic acidosis: feel very weak and tired have unusual sleepiness or sleep longer than usual have unusual (not normal) muscle pain feel cold, especially in your arms and legs have trouble breathing feel dizzy or lightheaded have unexplained stomach or intestinal problems with nausea and vomiting, or diarrhea have a slow or irregular heartbeat You have a higher chance of getting lactic acidosis if you: have severe kidney problems. See “ Do not take metformin hydrochloride extended-release tablets if you ” have liver problems. drink a lot of alcohol (very often or short-term "binge" drinking). get dehydrated (lose a large amount of body fluids). This can happen if you are sick with a fever, vomiting, or diarrhea. Dehydration can also happen when you sweat a lot with activity or exercise and do not drink enough fluids. have certain x-ray tests with injectable dyes or contrast agents. have surgery or other procedure for which you need to restrict the amount of food and liquid you eat and drink. have congestive heart failure. have a heart attack, severe infection, or stroke. are 65 years of age or older. Tell your doctor if you have any of the problems in the list above. Tell your doctor that you are taking metformin hydrochloride extended-release tablets before you have surgery or x-ray tests. Your doctor may need to stop metformin hydrochloride extended-release tablets for a while if you have surgery or certain x-ray tests. Metformin hydrochloride extended-release tablets can have other serious side effects. See “What are the possible side effects of metformin hydrochloride extended-release tablets?”. What are metformin hydrochloride extended-release tablets? Metformin hydrochloride extended-release tablets are a prescription medicine that contains metformin hydrochloride. Metformin hydrochloride extended-release tablets are used with diet and exercise to help control high blood sugar (hyperglycemia) in adults with type 2 diabetes. It is not known if metformin hydrochloride extended-release tablets are safe and effective in children. Do not take metformin hydrochloride extended-release tablets if you: • have severe kidney problems. • are allergic to metformin hydrochloride or any of the ingredients in metformin hydrochloride extended-release tablets. See the end of this Patient Information leaflet for a complete list of ingredients in metformin hydrochloride extended-release tablets. • have a condition called metabolic acidosis, including diabetic ketoacidosis (high levels of certain acids called “ketones” in your blood or urine). Before taking metformin hydrochloride extended-release tablets tell your doctor about all of your medical conditions, including if you: • have a history or risk for diabetic ketoacidosis. See “ Do not take metformin hydrochloride extended-release tablets if you: ”. • have kidney problems. • have liver problems. • have heart problems, including congestive heart failure. • are 65 years of age or older. • drink alcohol very often, or drink a lot of alcohol in short-term “binge” drinking. • are taking insulin or a sulfonylurea medicine. • are pregnant or plan to become pregnant. It is not known if metformin hydrochloride extended-release tablets can harm your unborn baby. If you are pregnant, talk with your doctor about the best way to control your blood sugar while you are pregnant. • are a woman who has not gone through menopause (premenopausal) who does not have periods regularly or at all. Metformin hydrochloride extended-release tablets can cause the release of an egg from an ovary in a woman (ovulation). This can increase your chance of getting pregnant. • are breastfeeding or plan to breastfeed. Metformin hydrochloride can pass into your breast milk. Talk with your doctor about the best way to feed your baby while you take metformin hydrochloride extended-release tablets. Tell your doctor about all the medicines you take, including prescription and over-the-counter medicines, vitamins and herbal supplements. Know the medicines you take. Keep a list of them to show your doctor and pharmacist. Talk to your doctor before you start any new medicine. Metformin hydrochloride extended-release tablets may affect the way other medicines work, and other medicines may affect how metformin hydrochloride extended-release tablets work. How should I take metformin hydrochloride extended-release tablets? • Take metformin hydrochloride extended-release tablets exactly as your doctor tells you. • Metformin hydrochloride extended-release tablets should be taken 1 time each day with your evening meal to help decrease an upset stomach. • Swallow metformin hydrochloride extended-release tablets whole. Do not crush, cut, or chew the tablets. • You may sometimes pass a soft mass in your stools (bowel movement) that looks like metformin hydrochloride extended-release tablets. This is normal and will not affect the way metformin hydrochloride extended-release tablets work. • When your body is under some type of stress, such as fever, trauma (such as a car accident), infection, or surgery, the amount of diabetes medicine that you need may change. Tell your doctor right away if you have any of these problems. • Your doctor should do blood tests to check how well your kidneys are working before and during your treatment with metformin hydrochloride extended-release tablets. • Your doctor will check your diabetes with regular blood tests, including your blood sugar levels and your hemoglobin A1C. • Low blood sugar (hypoglycemia) can happen more often when metformin hydrochloride extended-release tablets are taken with certain other diabetes medicines. Talk to your doctor about how to prevent, recognize, and manage low blood sugar. See “ What are the possible side effects of metformin hydrochloride extended-release tablets? ”. • Check your blood sugar as your doctor tells you to. • Stay on your prescribed diet and exercise program while taking metformin hydrochloride extended-release tablets. • If you miss a dose of metformin hydrochloride extended-release tablets, take your next dose at the normal schedule. Do not take 2 doses of metformin hydrochloride extended-release tablets on the same day. • If you take too many metformin hydrochloride extended-release tablets, call your doctor or go to the nearest hospital emergency room right away. What should I avoid while taking metformin hydrochloride extended-release tablets? Do not drink a lot of alcoholic drinks while taking metformin hydrochloride extended-release tablets. This means you should not binge drink for short periods, and you should not drink a lot of alcohol on a regular basis. Alcohol can increase the chance of getting lactic acidosis. What are the possible side effects of metformin hydrochloride extended-release tablets? Metformin hydrochloride extended-release tablets can cause serious side effects, including: • See “ What is the most important information I should know about metformin hydrochloride extended-release tablets? ” • Low vitamin B 12 (vitamin B 12 deficiency). Using metformin hydrochloride extended-release tablets may cause a decrease i...
PACKAGE LABEL.PRINCIPAL DISPLAY PANEL
PACKAGE LABEL.PRINCIPAL DISPLAY PANEL
NDC 47335-305-88 Metformin Hydrochloride Extended-Release Tablets, USP 500 mg ONCE DAILY PHARMACIST: Dispense with Patient Information. Rx only 100 Tablets SUN PHARMA NDC 47335-306-88 Metformin Hydrochloride Extended-Release Tablets, USP 1, 000 mg ONCE DAILY PHARMACIST: Dispense with Patient Information. Rx only 100 Tablets SUN PHARMA