JANUMET XR

JANUMET XR- sitagliptin phosphate and metformin hydrochloride tablet, film coated, extended release
Merck Sharp & Dohme Corp.

WARNING: LACTIC ACIDOSIS

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), Drug Interactions (7), and Use in Specific Populations (8.6, 8.7)].

If metformin-associated lactic acidosis is suspected, immediately discontinue JANUMET XR and institute general supportive measures in a hospital setting. Prompt hemodialysis is recommended [see Warnings and Precautions (5.1)].

1 INDICATIONS AND USAGE

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

Limitations of Use

JANUMET XR should not be used in patients with type 1 diabetes mellitus or for the treatment of diabetic ketoacidosis.

JANUMET XR has not been studied in patients with a history of pancreatitis. It is unknown whether patients with a history of pancreatitis are at increased risk for the development of pancreatitis while using JANUMET XR. [See Warnings and Precautions (5.2).]

2 DOSAGE AND ADMINISTRATION

2.1 Recommended Dosing

The dose of JANUMET XR 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 (HCl). Initial combination therapy or maintenance of combination therapy should be individualized and left to the discretion of the health care provider.

  • In patients not currently treated with metformin, the recommended total daily starting dose of JANUMET XR is 100 mg sitagliptin and 1000 mg metformin HCl extended-release. Patients with inadequate glycemic control on this dose of metformin can be titrated gradually, to reduce gastrointestinal side effects associated with metformin, up to the maximum recommended daily dose.
  • In patients already treated with metformin, the recommended total daily starting dose of JANUMET XR is 100 mg sitagliptin and the previously prescribed dose of metformin.
  • For patients taking metformin immediate-release 850 mg twice daily or 1000 mg twice daily, the recommended starting dose of JANUMET XR is two 50 mg sitagliptin/1000 mg metformin HCl extended-release tablets taken together once daily.
  • Maintain the same total daily dose of sitagliptin and metformin when changing between JANUMET (sitagliptin and metformin HCl immediate-release) and JANUMET XR. Patients with inadequate glycemic control on this dose of metformin can be titrated gradually, to reduce gastrointestinal side effects associated with metformin, up to the maximum recommended daily dose.

JANUMET XR should be administered with food to reduce the gastrointestinal side effects associated with the metformin component. JANUMET XR should be given once daily with a meal preferably in the evening. JANUMET XR should be swallowed whole. The tablets must not be split, crushed, or chewed before swallowing. There have been reports of incompletely dissolved JANUMET XR tablets being eliminated in the feces. It is not known whether this material seen in feces contains active drug. If a patient reports repeatedly seeing tablets in feces, the health care provider should assess adequacy of glycemic control [see Patient Counseling Information (17)].

The 100 mg sitagliptin/1000 mg metformin HCl extended-release tablet should be taken as a single tablet once daily. Patients using two JANUMET XR tablets (such as two 50 mg sitagliptin/500 mg metformin HCl extended-release tablets or two 50 mg sitagliptin/1000 mg metformin HCl extended-release tablets) should take the two tablets together once daily.

No studies have been performed specifically examining the safety and efficacy of JANUMET XR in patients previously treated with other oral antihyperglycemic agents and switched to JANUMET XR. Any change in therapy of type 2 diabetes should be undertaken with care and appropriate monitoring as changes in glycemic control can occur.

2.2 Recommendations for Use in Renal Impairment

Assess renal function prior to initiation of JANUMET XR and periodically thereafter.

JANUMET XR is contraindicated in patients with an estimated glomerular filtration rate (eGFR) below 30 mL/min/1.73 m2. Discontinue JANUMET XR if the patient’s eGFR later falls below 30 mL/min/1.73 m2 [see Contraindications (4) and Warnings and Precautions (5.1)].

Initiation of JANUMET XR in patients with an eGFR between 30 and 45 mL/min/1.73 m2 is not recommended.

In patients taking JANUMET XR whose eGFR later falls below 45 mL/min/1.73 m2 , assess the benefit risk of continuing therapy and limit dose of the sitagliptin component to 50 mg once daily.

2.3 Discontinuation for Iodinated Contrast Imaging Procedures

Discontinue JANUMET XR at the time of, or prior to, an iodinated contrast imaging procedure in patients with an eGFR between 30 and 60 mL/min/1.73 m2 ; in patients with a history of liver disease, alcoholism, or heart failure; or in patients who will be administered intra-arterial iodinated contrast. Re-evaluate eGFR 48 hours after the imaging procedure; restart JANUMET XR if renal function is stable [see Warnings and Precautions (5.1)].

3 DOSAGE FORMS AND STRENGTHS

Tablets:

  • 100 mg/1000 mg tablets are blue, bi-convex oval, film-coated tablets with “81″ debossed on one side.
  • 50 mg/500 mg tablets are light blue, bi-convex oval, film-coated tablets with “78″ debossed on one side.
  • 50 mg/1000 mg tablets are light green, bi-convex oval, film-coated tablets with “80″ debossed on one side.

4 CONTRAINDICATIONS

JANUMET XR is contraindicated in patients with:

5 WARNINGS AND PRECAUTIONS

5.1 Lactic Acidosis

There have been postmarketing cases of metformin-associated lactic acidosis, including fatal cases. These cases had a subtle onset and were accompanied by nonspecific symptoms such as malaise, myalgias, abdominal pain, respiratory distress, or increased somnolence; however, hypothermia, hypotension and resistant bradyarrhythmias have occurred with severe acidosis. Metformin-associated lactic acidosis was characterized by elevated blood lactate concentrations (>5 mmol/Liter), anion gap acidosis (without evidence of ketonuria or ketonemia), and an increased lactate/pyruvate ratio; metformin plasma levels were generally >5 mcg/mL. Metformin decreases liver uptake of lactate increasing lactate blood levels which may increase the risk of lactic acidosis, especially in patients at risk.

If metformin-associated lactic acidosis is suspected, general supportive measures should be instituted promptly in a hospital setting, along with immediate discontinuation of JANUMET XR. In JANUMET XR-treated patients with a diagnosis or strong suspicion of lactic acidosis, prompt hemodialysis is recommended to correct the acidosis and remove accumulated metformin (metformin HCl is dialyzable, with a clearance of up to 170 mL/min under good hemodynamic conditions). Hemodialysis has often resulted in reversal of symptoms and recovery.

Educate patients and their families about the symptoms of lactic acidosis, and if these symptoms occur instruct them to discontinue JANUMET XR and report these symptoms to their health care provider.

For each of the known and possible risk factors for metformin-associated lactic acidosis, recommendations to reduce the risk of and manage metformin-associated lactic acidosis are provided below:

Renal Impairment: The postmarketing metformin-associated lactic acidosis cases primarily occurred in patients with significant renal impairment. The risk of metformin accumulation and metformin-associated lactic acidosis increases with the severity of renal impairment because metformin is substantially excreted by the kidney. Clinical recommendations based upon the patient’s renal function include [see Dosage and Administration (2.2), Clinical Pharmacology (12.3)]:

  • Before initiating JANUMET XR, obtain an estimated glomerular filtration rate (eGFR).
  • JANUMET XR is contraindicated in patients with an eGFR less than 30 mL/min/1.73 m2. Discontinue JANUMET XR if the patient’s eGFR later falls below 30 mL/min/1.73 m2 [see Contraindications (4)].
  • Initiation of JANUMET XR is not recommended in patients with eGFR between 30 and 45 mL/min/1.73 m2.
  • In patients taking JANUMET XR whose eGFR later falls below 45 mL/min/1.73 m2 , assess the benefit and risk of continuing therapy.
  • Obtain an eGFR at least annually in all patients taking JANUMET XR. In patients at increased risk for the development of renal impairment (e.g., the elderly), renal function should be assessed more frequently.

Drug Interactions

The concomitant use of JANUMET XR with specific drugs may increase the risk of metformin-associated lactic acidosis: those that impair renal function, result in significant hemodynamic change, interfere with acid-base balance or increase metformin accumulation [see Drug Interactions (7)]. Therefore, consider more frequent monitoring of patients.

Age 65 or Greater

The risk of metformin-associated lactic acidosis increases with the patient’s age because elderly patients have a greater likelihood of having hepatic, renal, or cardiac impairment than younger patients. Assess renal function more frequently in elderly patients [see Use in Specific Populations (8.5)].

Radiological Studies with Contrast

Administration of intravascular iodinated contrast agents in metformin-treated patients has led to an acute decrease in renal function and the occurrence of lactic acidosis. Stop JANUMET XR at the time of, or prior to, an iodinated contrast imaging procedure in patients with an eGFR between 30 and 60 mL/min/1.73 m2 ; in patients with a history of hepatic impairment, alcoholism, or heart failure; or in patients who will be administered intra-arterial iodinated contrast. Re-evaluate eGFR 48 hours after the imaging procedure, and restart JANUMET XR if renal function is stable.

Surgery and Other Procedures

Withholding of food and fluids during surgical or other procedures may increase the risk for volume depletion, hypotension and renal impairment. JANUMET XR should be temporarily discontinued while patients have restricted food and fluid intake.

Hypoxic States

Several of the postmarketing cases of metformin-associated lactic acidosis occurred in the setting of acute congestive heart failure (particularly when accompanied by hypoperfusion and hypoxemia). Cardiovascular collapse (shock), acute myocardial infarction, sepsis, and other conditions associated with hypoxemia have been associated with lactic acidosis and may also cause prerenal azotemia. When such events occur, discontinue JANUMET XR.

Excessive Alcohol Intake

Alcohol potentiates the effect of metformin on lactate metabolism and this may increase the risk of metformin-associated lactic acidosis. Warn patients against excessive alcohol intake while receiving JANUMET XR.

Hepatic Impairment

Patients with hepatic impairment have developed with cases of metformin-associated lactic acidosis. This may be due to impaired lactate clearance resulting in higher lactate blood levels. Therefore, avoid use of JANUMET XR in patients with clinical or laboratory evidence of hepatic disease.

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