RIVA SITAGLIPTIN/METFORMIN

1 Dosing Considerations • The dosage of RIVA SITAGLIPTIN/METFORMIN should be individualized on the basis of the patient’s current regimen, effectiveness, and tolerability while not exceeding the maximum recommended daily dose of 100 mg sitagliptin and 2000 mg metformin hydrochloride.

Dose escalation should be gradual to reduce the gastrointestinal side effects associated with metformin use. Factors that may increase the risk of lactic acidosis should be reviewed before considering initiation of metformin-containing products in patients with renal impairment.

73 m2 is 50 mg and 1000 mg, respectively. , sulfonylurea), a lower dose of insulin or the insulin secretagogue may be considered to reduce the risk of hypoglycemia (see 7 WARNINGS AND PRECAUTIONS and 8 ADVERSE REACTIONS). RIVA SITAGLIPTIN/METFORMIN (sitagliptin and metformin hydrochloride) Page 6 of 64 • Concomitant Use with Medication(s) that May Decrease Renal Function Caution should be exercised when using concomitant medication(s) that may decrease renal function (like diuretics, particularly loop diuretics) or may interfere with the disposition of metformin, such as cationic drugs, that are eliminated by renal tubular secretion, due to the increased risk of developing lactic acidosis during co-administration (see 9 DRUG INTERACTIONS).

2 Recommended Dose and Dosage Adjustment RIVA SITAGLIPTIN/METFORMIN is available in the following dosage strengths: • 50 mg sitagliptin/500 mg metformin hydrochloride • 50 mg sitagliptin/1000 mg metformin hydrochloride One RIVA SITAGLIPTIN/METFORMIN tablet should be taken orally twice a day with meals to reduce the risk of gastrointestinal side effects associated with metformin use.

Tablets are to be swallowed whole. In patients on metformin (alone or in combination with a sulfonylurea, pioglitazone, or insulin), the recommended total daily dose of RIVA SITAGLIPTIN/METFORMIN is 100 mg sitagliptin and the nearest therapeutically appropriate dose of metformin already being taken.

In patients already treated with sitagliptin and metformin, switching to RIVA SITAGLIPTIN/METFORMIN may be initiated at the dose of sitagliptin and metformin already being taken.

Renal Impairment:

Renal function must be assessed prior to initiation of RIVA SITAGLIPTIN/METFORMIN and periodically thereafter because there is a dosage adjustment based upon renal function. 73 m2 (see 7 WARNINGS AND PRECAUTIONS, Monitoring and Laboratory Tests).

). For a complete listing, see the 6 DOSAGE FORMS, STRENGTHS, COMPOSITION AND PACKAGING section. • During pregnancy and breastfeeding (see 7 WARNINGS AND PRECAUTIONS, Special populations). • During period around administration of iodinated contrast materials, because the use of such products may result in acute alteration of renal function (see 7 WARNINGS AND PRECAUTIONS).

3 SERIOUS WARNINGS AND PRECAUTIONS BOX Serious Warnings and Precautions Lactic Acidosis • Lactic acidosis is a rare, but serious, metabolic complication that can occur due to metformin accumulation during treatment with RIVA SITAGLIPTIN/METFORMIN (see 7 WARNINGS AND PRECAUTIONS, Endocrine and Metabolism – Lactic Acidosis).

• Patients should be cautioned against excessive alcohol intake, either acute or chronic, when taking RIVA SITAGLIPTIN/METFORMIN, since alcohol intake potentiates the effect of metformin on lactate metabolism (see 7 WARNINGS AND PRECAUTIONS, Endocrine and Metabolism – Lactic Acidosis).

1 Dosing Considerations • The dosage of RIVA SITAGLIPTIN/METFORMIN should be individualized on the basis of the patient’s current regimen, effectiveness, and tolerability while not exceeding the maximum recommended daily dose of 100 mg sitagliptin and 2000 mg metformin hydrochloride.

Dose escalation should be gradual to reduce the gastrointestinal side effects associated with metformin use. Factors that may increase the risk of lactic acidosis should be reviewed before considering initiation of metformin-containing products in patients with renal impairment.

73 m2 is 50 mg and 1000 mg, respectively. , sulfonylurea), a lower dose of insulin or the insulin secretagogue may be considered to reduce the risk of hypoglycemia (see 7 WARNINGS AND PRECAUTIONS and 8 ADVERSE REACTIONS). RIVA SITAGLIPTIN/METFORMIN (sitagliptin and metformin hydrochloride) Page 6 of 64 • Concomitant Use with Medication(s) that May Decrease Renal Function Caution should be exercised when using concomitant medication(s) that may decrease renal function (like diuretics, particularly loop diuretics) or may interfere with the disposition of metformin, such as cationic drugs, that are eliminated by renal tubular secretion, due to the increased risk of developing lactic acidosis during co-administration (see

, Endocrine and Metabolism, and Special Populations). 2 CONTRAINDICATIONS • Unstable and/or insulin-dependent (type 1) diabetes mellitus. • Acute or chronic metabolic acidosis, including diabetic ketoacidosis, with or without coma, history of ketoacidosis with or without coma.

• In patients with a history of lactic acidosis, irrespective of precipitating factors (see 7 WARNINGS AND PRECAUTIONS). 73 m2)], end-stage renal disease, in patients on dialysis or when renal function is not known (see 7 WARNINGS AND PRECAUTIONS).

• In excessive alcohol intake, acute or chronic. • In patients suffering from severe hepatic dysfunction, since severe hepatic dysfunction has been associated with some cases of lactic acidosis, RIVA SITAGLIPTIN/METFORMIN should not be used in patients with clinical or laboratory evidence of hepatic disease.

RIVA SITAGLIPTIN/METFORMIN (sitagliptin and metformin hydrochloride) Page 5 of 64 • In cases of cardiovascular collapse and in disease states associated with hypoxemia such as cardiorespiratory insufficiency, which are often associated with hyperlactacidemia.

• During stress conditions, such as severe infections, trauma or surgery and the recovery phase thereafter. • In patients suffering from severe dehydration or shock. • Known hypersensitivity to sitagliptin, metformin or to any ingredient in the formulation, including any non-medicinal ingredient, or component of the container (see 7 WARNINGS AND PRECAUTIONS and

• Unstable and/or insulin-dependent (type 1) diabetes mellitus. • Acute or chronic metabolic acidosis, including diabetic ketoacidosis, with or without coma, history of ketoacidosis with or without coma. • In patients with a history of lactic acidosis, irrespective of precipitating factors (see 7 WARNINGS AND PRECAUTIONS).

73 m2)], end-stage renal disease, in patients on dialysis or when renal function is not known (see 7 WARNINGS AND PRECAUTIONS). • In excessive alcohol intake, acute or chronic. • In patients suffering from severe hepatic dysfunction, since severe hepatic dysfunction has been associated with some cases of lactic acidosis, RIVA SITAGLIPTIN/METFORMIN should not be used in patients with clinical or laboratory evidence of hepatic disease.

RIVA SITAGLIPTIN/METFORMIN (sitagliptin and metformin hydrochloride) Page 5 of 64 • In cases of cardiovascular collapse and in disease states associated with hypoxemia such as cardiorespiratory insufficiency, which are often associated with hyperlactacidemia.

• During stress conditions, such as severe infections, trauma or surgery and the recovery phase thereafter. • In patients suffering from severe dehydration or shock. • Known hypersensitivity to sitagliptin, metformin or to any ingredient in the formulation, including any non-medicinal ingredient, or component of the container (see 7 WARNINGS AND PRECAUTIONS and 8 ADVERSE REACTIONS).

For a complete listing, see the 6 DOSAGE FORMS, STRENGTHS, COMPOSITION AND PACKAGING section. • During pregnancy and breastfeeding (see 7 WARNINGS AND PRECAUTIONS, Special populations). • During period around administration of iodinated contrast materials, because the use of such products may result in acute alteration of renal function (see 7 WARNINGS AND PRECAUTIONS).