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Janumet XR

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Janumet XR

WARNINGS

Included as part of the PRECAUTIONS section.

PRECAUTIONS

Lactic Acidosis

Metformin hydrochloride

Lactic acidosis is a serious, metabolic complication that can occur due to metformin accumulation during treatment with JANUMET XR and 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 concentrations ( > 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 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 impairment, 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 JANUMET XR. In particular, treatment of the elderly should be accompanied by careful monitoring of renal function. JANUMET XR treatment should not be initiated in any patient unless measurement of creatinine clearance demonstrates that renal function is not reduced. In addition, JANUMET XR 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, JANUMET XR should generally be avoided in patients with clinical or laboratory evidence of hepatic impairment. Patients should be cautioned against excessive alcohol intake when taking JANUMET XR, because alcohol potentiates the effects of metformin on lactate metabolism. In addition, JANUMET XR should be temporarily discontinued prior to any intravascular radiocontrast study and for any surgical procedure necessitating restricted intake of food or fluids. Use of topiramate, a carbonic anhydrase inhibitor, in epilepsy and migraine prophylaxis may frequently cause dose-dependent metabolic acidosis (in controlled trials, 32% and 67% for adjunctive treatment in adults and pediatric patients, respectively, and 15 to 25% for monotherapy of epilepsy, with decrease in serum bicarbonate to less than 20 mEq/L; 3% and 11% for adjunctive treatment in adults and pediatric patients, respectively, and 1 to 7% for monotherapy of epilepsy, with decrease in serum bicarbonate to less than 17 mEq/L) and may exacerbate the risk of metformin-induced lactic acidosis. [See DRUG INTERACTIONS; CLINICAL PHARMACOLOGY] 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.

Patients should be educated to promptly report these symptoms to their physician should they occur. If present, JANUMET XR should be withdrawn until lactic acidosis is ruled out. Serum electrolytes, ketones, blood glucose, blood pH, lactate levels, and blood metformin levels may be useful. Once a patient is stabilized on any dose level of JANUMET XR, gastrointestinal symptoms, which are common during initiation of therapy, are unlikely to recur. 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 JANUMET XR 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. 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 JANUMET XR, 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 CONTRAINDICATIONS]

Pancreatitis

There have been postmarketing reports of acute pancreatitis, including fatal and non-fatal hemorrhagic or necrotizing pancreatitis, in patients taking sitagliptin with or without metformin. After initiation of JANUMET XR, patients should be observed carefully for signs and symptoms of pancreatitis. If pancreatitis is suspected, JANUMET XR should promptly be discontinued and appropriate management should be initiated. It is unknown whether patients with a history of pancreatitis are at increased risk for the development of pancreatitis while using JANUMET XR.

Impaired Hepatic Function

Since impaired hepatic function has been associated with some cases of lactic acidosis, JANUMET XR should generally be avoided in patients with clinical or laboratory evidence of hepatic disease.

Assessment of Renal Function

Metformin and sitagliptin are substantially excreted by the kidney.

Metformin hydrochloride

The risk of metformin accumulation and lactic acidosis increases with the degree of impairment of renal function. Therefore, JANUMET XR is contraindicated in patients with renal impairment.

Before initiation of JANUMET XR and at least annually thereafter, renal function should be assessed and verified as normal. In patients in whom development of renal dysfunction is anticipated (e.g., elderly), renal function should be assessed more frequently and JANUMET XR discontinued if evidence of renal impairment is present.

Sitagliptin

There have been postmarketing reports of worsening renal function in patients taking sitagliptin with or without metformin, including acute renal failure, sometimes requiring dialysis. Before initiation of therapy with JANUMET XR and at least annually thereafter, renal function should be assessed and verified as normal. In patients in whom development of renal dysfunction is anticipated, particularly in elderly patients, renal function should be assessed more frequently and JANUMET XR discontinued if evidence of renal impairment is present.

Vitamin B12 Levels

In controlled clinical trials of metformin of 29 weeks duration, a decrease to subnormal levels of previously normal serum Vitamin B12 levels, without clinical manifestations, was observed in approximately 7% of patients. Such decrease, possibly due to interference with B12 absorption from the B12-intrinsic factor complex, is, however, very rarely associated with anemia and appears to be rapidly reversible with discontinuation of metformin or Vitamin B12 supplementation. Measurement of hematologic parameters on an annual basis is advised in patients on JANUMET XR and any apparent abnormalities should be appropriately investigated and managed. [See ADVERSE REACTIONS]

Certain individuals (those with inadequate Vitamin B12 or calcium intake or absorption) appear to be predisposed to developing subnormal Vitamin B12 levels. In these patients, routine serum Vitamin B12 measurements at two-to three-year intervals may be useful.

Alcohol Intake

Alcohol potentiates the effect of metformin on lactate metabolism. Patients should be warned against excessive alcohol intake while receiving JANUMET XR.

Surgical Procedures

Use of JANUMET XR should be temporarily suspended for any surgical procedure (except minor procedures not associated with restricted intake of food and fluids) and should not be restarted until the patient's oral intake has resumed and renal function has been evaluated as normal.

Change in Clinical Status of Patients with Previously Controlled Type 2 Diabetes

A patient with type 2 diabetes previously well controlled on JANUMET XR who develops laboratory abnormalities or clinical illness (especially vague and poorly defined illness) should be evaluated promptly for evidence of ketoacidosis or lactic acidosis. Evaluation should include serum electrolytes and ketones, blood glucose and, if indicated, blood pH, lactate, pyruvate, and metformin levels. If acidosis of either form occurs, JANUMET XR must be stopped immediately and other appropriate corrective measures initiated.

Use with Medications Known to Cause Hypoglycemia

Sitagliptin

When sitagliptin was used in combination with a sulfonylurea or with insulin, medications known to cause hypoglycemia, the incidence of hypoglycemia was increased over that of placebo used in combination with a sulfonylurea or with insulin [see ADVERSE REACTIONS]. Therefore, patients also receiving an insulin secretagogue (e.g., sulfonylurea) or insulin may require a lower dose of the insulin secretagogue or insulin to reduce the risk of hypoglycemia [see DOSAGE AND ADMINISTRATION].

Metformin hydrochloride

Hypoglycemia does not occur in patients receiving metformin alone under usual circumstances of use, but could occur when caloric intake is deficient, when strenuous exercise is not compensated by caloric supplementation, or during concomitant use with other glucose-lowering agents (such as sulfonylureas and insulin) or ethanol. Elderly, debilitated, or malnourished patients, and those with adrenal or pituitary insufficiency or alcohol intoxication are particularly susceptible to hypoglycemic effects. Hypoglycemia may be difficult to recognize in the elderly, and in people who are taking β-adrenergic blocking drugs.

Concomitant Medications Affecting Renal Function or Metformin Disposition

Concomitant medication(s) that may affect renal function or result in significant hemodynamic change or may interfere with the disposition of metformin, such as cationic drugs that are eliminated by renal tubular secretion [see DRUG INTERACTIONS], should be used with caution.

Radiologic Studies with Intravascular Iodinated Contrast Materials

Intravascular contrast studies with iodinated materials (for example, intravenous urogram, intravenous cholangiography, angiography, and computed tomography (CT) scans with intravascular contrast materials) can lead to acute alteration of renal function and have been associated with lactic acidosis in patients receiving metformin [see CONTRAINDICATIONS]. Therefore, in patients in whom any such study is planned, JANUMET XR should be temporarily discontinued at the time of or prior to the procedure, and withheld for 48 hours subsequent to the procedure and reinstituted only after renal function has been reevaluated and found to be normal.

Hypoxic States

Cardiovascular collapse (shock) from whatever cause, acute congestive heart failure, acute myocardial infarction and other conditions characterized by hypoxemia have been associated with lactic acidosis and may also cause prerenal azotemia. When such events occur in patients on JANUMET XR therapy, the drug should be promptly discontinued.

Loss of Control of Blood Glucose

When a patient stabilized on any diabetic regimen is exposed to stress such as fever, trauma, infection, or surgery, a temporary loss of glycemic control may occur. At such times, it may be necessary to withhold JANUMET XR and temporarily administer insulin. JANUMET XR may be reinstituted after the acute episode is resolved.

Hypersensitivity Reactions

There have been postmarketing reports of serious hypersensitivity reactions in patients treated with sitagliptin, one of the components of JANUMET XR. These reactions include anaphylaxis, angioedema, and exfoliative skin conditions including Stevens-Johnson syndrome. Onset of these reactions occurred within the first 3 months after initiation of treatment with sitagliptin, with some reports occurring after the first dose. If a hypersensitivity reaction is suspected, discontinue JANUMET XR, assess for other potential causes for the event, and institute alternative treatment for diabetes. [See ADVERSE REACTIONS]

Use caution in a patient with a history of angioedema to another dipeptidyl peptidase-4 (DPP4) inhibitor because it is unknown whether such patients will be predisposed to angioedema with JANUMET XR.

Macrovascular Outcomes

There have been no clinical studies establishing conclusive evidence of macrovascular risk reduction with JANUMET XR or any other anti-diabetic drug.

Patient Counseling Information

See FDA-approved Medication Guide.

Instructions

Patients should be informed of the potential risks and benefits of JANUMET XR and of alternative modes of therapy. They should also be informed about the importance of adherence to dietary instructions, regular physical activity, periodic blood glucose monitoring and A1C testing, recognition and management of hypoglycemia and hyperglycemia, and assessment for diabetes complications. During periods of stress such as fever, trauma, infection, or surgery, medication requirements may change and patients should be advised to seek medical advice promptly.

The risks of lactic acidosis due to the metformin component, its symptoms, and conditions that predispose to its development, as noted in WARNINGS AND PRECAUTIONS, should be explained to patients. Patients should be advised to discontinue JANUMET XR immediately and to promptly notify their health practitioner if unexplained hyperventilation, myalgia, malaise, unusual somnolence, dizziness, slow or irregular heart beat, sensation of feeling cold (especially in the extremities) or other nonspecific symptoms occur. Gastrointestinal symptoms are common during initiation of metformin treatment and may occur during initiation of JANUMET XR therapy; however, patients should consult their physician if they develop unexplained symptoms. Although gastrointestinal symptoms that occur after stabilization are unlikely to be drug related, such an occurrence of symptoms should be evaluated to determine if it may be due to lactic acidosis or other serious disease.

Patients should be advised to notify their health practitioner or call the Poison Control Center immediately in case of JANUMET XR overdose.

Patients should be counseled against excessive alcohol intake, either acute or chronic, while receiving JANUMET XR.

Patients should be informed about the importance of regular testing of renal function and hematological parameters when receiving treatment with JANUMET XR.

Patients should be informed that acute pancreatitis has been reported during postmarketing use of JANUMET. Patients should be informed that persistent severe abdominal pain, sometimes radiating to the back, which may or may not be accompanied by vomiting, is the hallmark symptom of acute pancreatitis. Patients should be instructed to promptly discontinue JANUMET XR and contact their physician if persistent severe abdominal pain occurs [see WARNINGS AND PRECAUTIONS].

Patients should be informed that the incidence of hypoglycemia is increased when sitagliptin with or without metformin is added to an insulin secretagogue (e.g., sulfonylurea) or insulin therapy and that a lower dose of the insulin secretagogue or insulin may be required to reduce the risk of hypoglycemia.

Patients should be informed that allergic reactions have been reported during postmarketing use of sitagliptin, one of the components of JANUMET XR. If symptoms of allergic reactions (including rash, hives, and swelling of the face, lips, tongue, and throat that may cause difficulty in breathing or swallowing) occur, patients must stop taking JANUMET XR and seek medical advice promptly.

Patients should be informed that the tablets must be swallowed whole and never split, crushed or chewed.

Physicians should instruct their patients to read the Medication Guide before starting JANUMET XR therapy and to reread each time the prescription is renewed. Patients should be instructed to inform their doctor if they develop any bothersome or unusual symptom, or if any symptom persists or worsens.

Laboratory Tests

Response to all diabetic therapies should be monitored by periodic measurements of blood glucose and A1C levels, with a goal of decreasing these levels towards the normal range. A1C is especially useful for evaluating long-term glycemic control.

Initial and periodic monitoring of hematologic parameters (e.g., hemoglobin/hematocrit and red blood cell indices) and renal function (serum creatinine) should be performed, at least on an annual basis. While megaloblastic anemia has rarely been seen with metformin therapy, if this is suspected, Vitamin B12 deficiency should be excluded.

Nonclinical Toxicology

Carcinogenesis, Mutagenesis, Impairment of Fertility

JANUMET XR

No animal studies have been conducted with the combined products in JANUMET XR to evaluate carcinogenesis, mutagenesis or impairment of fertility. The following data are based on the findings in studies with sitagliptin and metformin individually. Sitagliptin

A two-year carcinogenicity study was conducted in male and female rats given oral doses of sitagliptin of 50, 150, and 500 mg/kg/day. There was an increased incidence of combined liver adenoma/carcinoma in males and females and of liver carcinoma in females at 500 mg/kg. This dose results in exposures approximately 60 times the human exposure at the maximum recommended daily adult human dose (MRHD) of 100 mg/day based on AUC comparisons. Liver tumors were not observed at 150 mg/kg, approximately 20 times the human exposure at the MRHD. A two-year carcinogenicity study was conducted in male and female mice given oral doses of sitagliptin of 50, 125, 250, and 500 mg/kg/day. There was no increase in the incidence of tumors in any organ up to 500 mg/kg, approximately 70 times human exposure at the MRHD. Sitagliptin was not mutagenic or clastogenic with or without metabolic activation in the Ames bacterial mutagenicity assay, a Chinese hamster ovary (CHO) chromosome aberration assay, an in vitro cytogenetics assay in CHO, an in vitro rat hepatocyte DNA alkaline elution assay, and an in vivo micronucleus assay.

In rat fertility studies with oral gavage doses of 125, 250, and 1000 mg/kg, males were treated for 4 weeks prior to mating, during mating, up to scheduled termination (approximately 8 weeks total), and females were treated 2 weeks prior to mating through gestation day 7. No adverse effect on fertility was observed at 125 mg/kg (approximately 12 times human exposure at the MRHD of 100 mg/day based on AUC comparisons). At higher doses, nondose-related increased resorptions in females were observed (approximately 25 and 100 times human exposure at the MRHD based on AUC comparison).

Metformin hydrochloride

Long-term carcinogenicity studies have been performed in Sprague Dawley rats at doses of 150, 300, and 450 mg/kg/day in males and 150, 450, 900, and 1200 mg/kg/day in females. These doses are approximately 2, 4, and 8 times in males, and 3, 7, 12, and 16 times in females of the maximum recommended human daily dose of 2000 mg based on body surface area comparisons. No evidence of carcinogenicity with metformin was found in either male or female rats. A carcinogenicity study was also performed in Tg.AC transgenic mice at doses up to 2000 mg applied dermally. No evidence of carcinogenicity was observed in male or female mice.

Genotoxicity assessments in the Ames test, gene mutation test (mouse lymphoma cells), chromosomal aberrations test (human lymphocytes) and in vivo mouse micronucleus tests were negative. Fertility of male or female rats was not affected by metformin when administered at doses up to 600 mg/kg/day, which is approximately 3 times the maximum recommended human daily dose based on body surface area comparisons.

Use In Specific Populations

Pregnancy

Pregnancy Category B

JANUMET XR

There are no adequate and well-controlled studies in pregnant women with JANUMET XR or its individual components; therefore, the safety of JANUMET XR in pregnant women is not known. JANUMET XR should be used during pregnancy only if clearly needed.

Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., maintains a registry to monitor the pregnancy outcomes of women exposed to JANUMET XR while pregnant. Health care providers are encouraged to report any prenatal exposure to JANUMET XR by calling the Pregnancy Registry at 1-800986-8999.

No animal studies have been conducted with the combined products in JANUMET XR to evaluate effects on reproduction. The following data are based on findings in studies performed with sitagliptin or metformin individually.

Sitagliptin

Reproduction studies have been performed in rats and rabbits. Doses of sitagliptin up to 125 mg/kg (approximately 12 times the human exposure at the maximum recommended human dose) did not impair fertility or harm the fetus. There are, however, no adequate and well-controlled studies with sitagliptin in pregnant women.

Sitagliptin administered to pregnant female rats and rabbits from gestation day 6 to 20 (organogenesis) was not teratogenic at oral doses up to 250 mg/kg (rats) and 125 mg/kg (rabbits), or approximately 30 and 20 times human exposure at the maximum recommended human dose (MRHD) of 100 mg/day based on AUC comparisons. Higher doses increased the incidence of rib malformations in offspring at 1000 mg/kg, or approximately 100 times human exposure at the MRHD.

Sitagliptin administered to female rats from gestation day 6 to lactation day 21 decreased body weight in male and female offspring at 1000 mg/kg. No functional or behavioral toxicity was observed in offspring of rats.

Placental transfer of sitagliptin administered to pregnant rats was approximately 45% at 2 hours and 80% at 24 hours postdose. Placental transfer of sitagliptin administered to pregnant rabbits was approximately 66% at 2 hours and 30% at 24 hours.

Metformin hydrochloride

Metformin was not teratogenic in rats and rabbits at doses up to 600 mg/kg/day, which represent 3 and 6 times the maximum recommended human daily dose of 2000 mg based on body surface area comparison for rats and rabbits, respectively. However, because animal reproduction studies are not always predictive of human response, metformin hydrochloride should not be used during pregnancy unless clearly needed.

Nursing Mothers

No studies in lactating animals have been conducted with the combined components of JANUMET XR. In studies performed with the individual components, both sitagliptin and metformin are secreted in the milk of lactating rats. It is not known whether sitagliptin or metformin are excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when JANUMET XR is administered to a nursing woman.

Pediatric Use

Safety and effectiveness of JANUMET XR in pediatric patients under 18 years have not been established.

Geriatric Use

JANUMET XR

Because sitagliptin and metformin are substantially excreted by the kidney, and because aging can be associated with reduced renal function, JANUMET XR should be used with caution as age increases. Care should be taken in dose selection and should be based on careful and regular monitoring of renal function. [See WARNINGS AND PRECAUTIONS; CLINICAL PHARMACOLOGY.]

Sitagliptin

Of the total number of subjects (N=3884) in premarketing Phase II and III clinical studies of sitagliptin, 725 patients were 65 years and over, while 61 patients were 75 years and over. No overall differences in safety or effectiveness were observed between subjects 65 years and over and younger subjects. While this and other reported clinical experience have not identified differences in responses between the elderly and younger patients, greater sensitivity of some older individuals cannot be ruled out.

Metformin hydrochloride

Controlled clinical studies of metformin did not include sufficient numbers of elderly patients to determine whether they respond differently from younger patients, although other reported clinical experience has not identified differences in responses between the elderly and young patients. Metformin should only be used in patients with normal renal function. The initial and maintenance dosing of metformin should be conservative in patients with advanced age, due to the potential for decreased renal function in this population. Any dose adjustment should be based on a careful assessment of renal function. [See CONTRAINDICATIONS; WARNINGS AND PRECAUTIONS; CLINICAL PHARMACOLOGY.]

Last reviewed on RxList: 2/24/2014
This monograph has been modified to include the generic and brand name in many instances.

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