FDA label 1c042875-bd4e-49d6-818c-e5a15fa769d7

WARNINGS Lactic Acidosis: Lactic acidosis is a rare, but serious, metabolic complication that can occur due to metformin accumulation during treatment with metformin; 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 (greater than 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 greater than 5 µg/mL are generally found. The reported incidence of lactic acidosis in patients receiving metformin hydrochloride tablets, USP is very low (approximately 0.03 cases/1000 patient-years, with approximately 0.015 fatal cases/1000 patient-years). In more than 20,000 patient-years exposure to metformin in clinical trials, there were no reports of lactic acidosis. 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 metformin and by use of the minimum effective dose of metformin. In particular, treatment of the elderly should be accompanied by careful monitoring of renal function. Metformin hydrochloride tablets, USP treatment should not be initiated in patients greater than or equal to 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, metformin 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, metformin 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 metformin hydrochloride tablets, USP since alcohol potentiates the effects of metformin hydrochloride tablets, USP on lactate metabolism. In addition, metformin 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). Metformin hydrochloride tablets, USP 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 metformin, 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 metformin 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 metformin, the drug should be discontinued immediately and general supportive measures promptly instituted. Because metformin hydrochloride tablets, USP are 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).

WARNING A small number of people who have taken metformin have developed a serious condition called lactic acidosis. Lactic acidosis is caused by a buildup of lactic acid in the blood. This happens more often in people with kidney problems. Most people with kidney problems should not take metformin. (See “What are the side effects of metformin?”) Who should not take metformin? Some conditions increase your chance of getting lactic acidosis, or cause other problems if you take metformin. Most of the conditions listed below can increase your chance of getting lactic acidosis. Do not take metformin if you: - have kidney problems - have liver problems - have heart failure that is treated with medicines, such as Lanoxin® (digoxin) or Lasix® (furosemide) - drink a lot of alcohol. This means you binge drink for short periods or drink all the time - are seriously dehydrated (have lost a lot of water from your body) - are going to have an x-ray procedure with injection of dyes (contrast agents) - are going to have surgery - develop a serious condition, such as heart attack, severe infection, or a stroke - are 80 years or older and you have NOT had your kidney function tested Tell your doctor if you are pregnant or plan to become pregnant. Metformin may not be right for you. Talk with your doctor about your choices. You should also discuss your choices with your doctor if you are nursing a child. Can metformin hydrochloride tablets, USP be used in children? Metformin hydrochloride tablets, USP has been shown to effectively lower glucose levels in children (ages 10 to 16 years) with type 2 diabetes. Metformin hydrochloride tablets, USP have not been studied in children younger than 10 years old. Metformin hydrochloride tablets, USP have not been studied in combination with other oral glucose-control medicines in children. If you have any questions about the use of metformin hydrochloride tablets, USP in children, talk with your doctor or healthcare provider. How should I take metformin hydrochloride tablets, USP? Your doctor will tell you how much medicine to take and when to take it. You will probably start out with a low dose of the medicine. Your doctor may slowly increase your dose until your blood sugar is better controlled. You should take metformin with meals. Your doctor may have you take other medicines along with metformin to control your blood sugar. These medicines may include insulin shots. Taking metformin hydrochloride tablets, USP with insulin may help you better control your blood sugar while reducing the insulin dose. Continue your excercise and diet program and test your blood sugar regularly while taking metformin. 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 metformin causes harm to the liver or kidneys. Tell your doctor if you - have an illness that causes severe vomiting, diarrhea or fever, or if you drink a much lower amount of liquid than normal. These conditions can lead to severe dehydration (loss of water in your body). You may need to stop taking metformin for a short time. - plan to have surgery or an x-ray procedure with injection of dye (contrast agent). You may need to stop taking metformin hydrochloride tablets for a short time. - start to take other medicines or change how you take a medicine. Metformin can affect how well other drugs work, and some drugs can affect how well metformin works. Some medicines may cause high blood sugar. What should I avoid while taking metformin hydrochloride tablets, USP? Do not drink a lot of alcoholic drinks while taking metformin. 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 side effects of metformin? Lactic Acidosis. In rare cases, metformin can cause a serious side effect called lactic acidosis. This is caused by a buildup of lactic acid in your blood. This build-up can cause serious damage. Lactic acidosis caused by 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 people who develop it. It is also important for your liver to be working normally when you take metformin. Your liver helps remove lactic acid from your blood. Make sure you tell your doctor before you use metformin if you have kidney or liver problems. You should also stop using metformin and call your doctor right away if you have signs of lactic acidosis. Lactic acidosis is a medical emergency that must be treated in a hospital. Signs of lactic acidosis are: - feeling very weak, tired, or uncomfortable - unusual muscle pain - trouble breathing - unusual or unexpected stomach discomfort - feeling cold - feeling dizzy or lightheaded - suddenly developing a slow or irregular heartbeat If your medical condition suddenly changes, stop taking metformin and call your doctor right away. This may be a sign of lactic acidosis or another serious side effect. Other Side Effects. Common side effects of metformin include diarrhea, nausea, and upset stomach. These side effects generally go away after you take the medicine for a while. Taking your medicine with meals can help reduce these side effects. Tell your doctor if the side effects bother you a lot, last for more than a few weeks, come back after they've gone away, or start later in therapy. You may need a lower dose or need to stop taking the medicine for a short period or for good. About 3 out of every 100 people who take metformin have an unpleasant metallic taste when they start taking the medicine. It lasts for a short time. Metformin rarely cause hypoglycemia (low blood sugar) by themselves. However, hypoglycemia can happen if you do not eat enough, if you drink alcohol, or if you take other medicines to lower blood sugar. General advice about prescription medicines If you have questions or problems, talk with your doctor or other healthcare provider. You can ask your doctor or pharmacist for the information about metformin that is written for health care professionals. Medicines are sometimes prescribed for purposes other than those listed in a patient information leaflet. Do not use metformin for a condition for which it was not prescribed. Do not share your medicine with other people. CARACO PHARMACEUTICAL LABORATORIES, LTD. Manufactured by: Sun Pharmaceutical Ind. Ltd. Halol-Baroda Highway, Halol-389 350, Gujarat, India. Distributed by: Caraco Pharmaceutical Laboratories, Ltd. 1150 Elijah McCoy Drive, C.S. No: 5249T34 Iss 3/10 Detroit, MI 48202

ADVERSE REACTIONS In a U.S. double-blind clinical study of metformin in patients with type 2 diabetes, a total of 141 patients received metformin therapy (up to 2550 mg per day) and 145 patients received placebo. Adverse reactions reported in greater than 5% of the metformin patients, and that were more common in metformin than placebotreated patients, are listed in Table 7. Table 7. Most Common Adverse Reactions (greater than5.0%) in a Placebo-Controlled Clinical Study of Metformin Monotherapy* Metformin Monotherapy n=141 Metformin Monotherapy n=141 Adverse Reaction % of Patients % of Patients Diarrhea 53.2 11.7 Nausea/Vomiting 25.5 8.3 Flatulence 12.1 5.5 Asthenia 9.2 5.5 Indigestion 7.1 4.1 Abdominal Discomfort 6.4 4.8 Headache 5.7 4.8 * Reactions that were more common in metformin- than placebo-treated patients * Reactions that were more common in metformin- than placebo-treated patients * Reactions that were more common in metformin- than placebo-treated patients Diarrhea led to discontinuation of study medication in 6% of patients treated with metformin. Additionally, the following adverse reactions were reported in greater than or equal to 1.0- less than or equal to 5.0% of metformin patients and were more commonly reported with 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 In clinical trials with metformin hydrochloride tablets, USP in pediatric patients with type 2 diabetes, the profile of adverse reactions was similar to that observed in adults.

ADVERSE REACTIONS Ingestion of L-tryptophan and/or choline at high doses of up to 15 grams daily is generally well tolerated. The most common adverse reactions of higher doses — from 15 to 30 grams daily — are nausea, abdominal cramps, and diarrhea. Some patients may experience these symptoms at lower doses. The total combined amount of amino acids in each AppTrim capsule does not exceed 400 mg.

<table ID="if374e918-2c75-4c7f-85df-49f4a647cb56" border="6" width="100%"> <caption>Table 7. Most Common Adverse Reactions (greater than5.0%) in a Placebo-Controlled Clinical Study of Metformin Monotherapy*</caption> <tbody> <tr> <td> </td> <td>Metformin Monotherapy n=141 </td> <td>Metformin Monotherapy n=141 </td> </tr> <tr> <td>Adverse Reaction </td> <td>% of Patients </td> <td>% of Patients </td> </tr> <tr> <td>Diarrhea </td> <td>53.2 </td> <td>11.7 </td> </tr> <tr> <td>Nausea/Vomiting </td> <td>25.5 </td> <td>8.3 </td> </tr> <tr> <td>Flatulence </td> <td>12.1 </td> <td>5.5 </td> </tr> <tr> <td>Asthenia </td> <td>9.2 </td> <td>5.5 </td> </tr> <tr> <td>Indigestion </td> <td>7.1 </td> <td>4.1 </td> </tr> <tr> <td>Abdominal Discomfort </td> <td>6.4 </td> <td>4.8 </td> </tr> <tr> <td>Headache </td> <td>5.7 </td> <td>4.8 </td> </tr> <tr> <td>* Reactions that were more common in metformin- than placebo-treated patients </td> <td>* Reactions that were more common in metformin- than placebo-treated patients </td> <td>* Reactions that were more common in metformin- than placebo-treated patients </td> </tr> </tbody> </table>