JANUMET® (sitagliptin and metformin hydrochloride) tablets

JANUMET® (sitagliptin and metformin hydrochloride) tablets

JANUMET® (sitagliptin and metformin hydrochloride) tablets

JANUMET (sitagliptin and metformin HCl) tablets for oral use contain two antihyperglycemic drugs: sitagliptin and metformin HCl.

Sitagliptin

Sitagliptin is an orally-active inhibitor of the dipeptidyl peptidase-4 (DPP-4) enzyme. Sitagliptin is present in JANUMET tablets in the form of sitagliptin phosphate monohydrate. Sitagliptin phosphate monohydrate is described chemically as 7-[(3R)-3-amino-1-oxo-4-(2,4,5-trifluorophenyl)butyl]-5,6,7,8-tetrahydro-3-(trifluoromethyl)-1,2,4-triazolo[4,3-a]pyrazine phosphate (1:1) monohydrate with an empirical formula of C16H15F6N5O•H3PO4•H2O and a molecular weight of 523.32.

Sitagliptin phosphate monohydrate is a white to off-white, crystalline, non-hygroscopic powder. It is soluble in water and N,N-dimethyl formamide; slightly soluble in methanol; very slightly soluble in ethanol, acetone, and acetonitrile; and insoluble in isopropanol and isopropyl acetate.

Metformin HCl

Metformin HCl (N,N-dimethylimidodicarbonimidic diamide hydrochloride) is not chemically or pharmacologically related to any other classes of oral antihyperglycemic agents. Metformin HCl is a white to off-white crystalline compound with a molecular formula of C4H11N5•HCl and a molecular weight of 165.63. Metformin HCl is freely soluble in water and is practically insoluble in acetone, ether, and chloroform. The pKa of metformin HCl is 12.4. The pH of a 1% aqueous solution of metformin HCl is 6.68.

JANUMET

JANUMET is available as film-coated tablets containing:

  • 64.25 mg sitagliptin monohydrate equivalent to 50 mg of sitagliptin and 389.93 mg of metformin equivalent to 500 mg metformin HCl (JANUMET 50/500).
  • 64.25 mg sitagliptin monohydrate equivalent to 50 mg of sitagliptin and 779.86 mg of metformin equivalent to 1000 mg metformin HCl (JANUMET 50/1000).

Each film-coated tablet of JANUMET contains the following inactive ingredients: microcrystalline cellulose, polyvinylpyrrolidone, sodium lauryl sulfate, and sodium stearyl fumarate. In addition, the film coating contains the following inactive ingredients: polyvinyl alcohol, polyethylene glycol, talc, titanium dioxide, red iron oxide, and black iron oxide.

INDICATIONS AND USAGE

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

Limitations of Use:

  • JANUMET should not be used in patients with type 1 diabetes mellitus.
  • JANUMET 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.

Mechanism of Action

JANUMET

JANUMET combines two antihyperglycemic agents with complementary mechanisms of action to improve glycemic control in patients with type 2 diabetes mellitus: sitagliptin, a dipeptidyl peptidase-4 (DPP- 4) inhibitor, and metformin HCl, a member of the biguanide class.

Sitagliptin

Sitagliptin is a DPP-4 inhibitor, which is believed to exert its actions in patients with type 2 diabetes by slowing the inactivation of incretin hormones. Concentrations of the active intact hormones are increased by sitagliptin, thereby increasing and prolonging the action of these hormones. Incretin hormones, including glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP), are released by the intestine throughout the day, and levels are increased in response to a meal. These hormones are rapidly inactivated by the enzyme DPP-4. The incretins are part of an endogenous system involved in the physiologic regulation of glucose homeostasis. When blood glucose concentrations are normal or elevated, GLP-1 and GIP increase insulin synthesis and release from pancreatic beta cells by intracellular signaling pathways involving cyclic AMP. GLP-1 also lowers glucagon secretion from pancreatic alpha cells, leading to reduced hepatic glucose production. By increasing and prolonging active incretin levels, sitagliptin increases insulin release and decreases glucagon levels in the circulation in a glucose-dependent manner. Sitagliptin demonstrates selectivity for DPP-4 and does not inhibit DPP-8 or DPP-9 activity in vitro at concentrations approximating those from therapeutic doses.

Metformin

Metformin is an antihyperglycemic agent which improves glucose tolerance in patients with type 2 diabetes mellitus, lowering both basal and postprandial plasma glucose. Metformin decreases hepatic glucose production, decreases intestinal absorption of glucose, and improves insulin sensitivity by increasing peripheral glucose uptake and utilization. With metformin therapy, insulin secretion remains unchanged while fasting insulin levels and day-long plasma insulin response may decrease.

DOSAGE AND ADMINISTRATION

  • Take JANUMET orally twice daily with meals.
  • Individualize the dosage of JANUMET on the basis of the patient’s current regimen, effectiveness, and tolerability.
  • The maximum recommended daily dose is 100 mg of sitagliptin and 2000 mg of metformin hydrochloride (HCl).
  • Do not split or divide JANUMET tablets.
  • The recommended starting dose in patients not currently treated with metformin is 50 mg sitagliptin and 500 mg metformin HCl twice daily, with gradual dose escalation recommended to reduce gastrointestinal side effects associated with metformin.
  • The starting dose in patients already treated with metformin should provide sitagliptin dosed as 50 mg twice daily (100 mg total daily dose) and the dose of metformin already being taken. For patients taking metformin HCl 850 mg twice daily, the recommended starting dose of JANUMET is 50 mg sitagliptin and 1000 mg metformin HCl twice daily.

Recommendations for Use in Renal Impairment

  • Assess renal function prior to initiation of JANUMET and periodically thereafter.
  • JANUMET is contraindicated in patients with an estimated glomerular filtration rate (eGFR) below 30 mL/min/1.73 m2
  • JANUMET is not recommended in patients with an eGFR between 30 and less than 45 mL/min/1.73 m2 because these patients require a lower dosage of sitagliptin than what is available in the fixed combination JANUMET product.

Discontinuation for Iodinated Contrast Imaging Procedures

Discontinue JANUMET 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 if renal function is stable

CONTRAINDICATIONS

JANUMET is contraindicated in patients with:

  • Severe renal impairment (eGFR below 30 mL/min/1.73 m2)
  • Acute or chronic metabolic acidosis, including diabetic ketoacidosis.
  • History of a serious hypersensitivity reaction to JANUMET, sitagliptin, or metformin, such as anaphylaxis or angioedema.

WARNINGS AND PRECAUTIONS

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.

Drug Interactions: The concomitant use of JANUMET with specific drugs may increase the risk of metformin-associatedlactic acidosis: those that impair renal function, result in significant hemodynamic change, interfere withacid-base balance or increase metformin accumulation. Therefore, considermore frequent monitoring of patients.

Radiological Studies with Contrast: Administration of intravascular iodinated contrast agents in metformin-treated patients has led to anacute decrease in renal function and the occurrence of lactic acidosis. Stop JANUMET at the time of, orprior 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 theimaging procedure, and restart JANUMET if renal function is stable.

Surgery and Other Procedures: Withholding of food and fluids during surgical or other procedures may increase the risk for volumedepletion, hypotension and renal impairment. JANUMET 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 ofacute congestive heart failure (particularly when accompanied by hypoperfusion and hypoxemia).Cardiovascular collapse (shock), acute myocardial infarction, sepsis, and other conditions associated withhypoxemia have been associated with lactic acidosis and may also cause prerenal azotemia. When suchevents occur, discontinue JANUMET.

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

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 in patients with clinical or laboratory evidence of hepatic disease.

Pancreatitis: There have been postmarketing reports of acute pancreatitis, including fatal and non-fatalhemorrhagic or necrotizing pancreatitis, in patients taking JANUMET. After initiation of JANUMET, patients should be observed carefully for signs and symptoms of pancreatitis. If pancreatitis is suspected, JANUMETshould promptly be discontinued and appropriate management should be initiated. It is unknown whetherpatients with a history of pancreatitis are at increased risk for the development of pancreatitis while usingJANUMET.

Heart Failure: An association between dipeptidyl peptidase-4 (DPP-4) inhibitor treatment and heart failure has beenobserved in cardiovascular outcomes trials for two other members of the DPP-4 inhibitor class. These trialsevaluated patients with type 2 diabetes mellitus and atherosclerotic cardiovascular disease.Consider therisks and benefits of JANUMET prior to initiating treatment in patients at risk for heart failure, such as thosewith a prior history of heart failure and a history of renal impairment, and observe these patients for signsand symptoms of heart failure during therapy. Advise patients of the characteristic symptoms of heart failureand to immediately report such symptoms. If heart failure develops, evaluate and manage according tocurrent standards of care and consider discontinuation of JANUMET.

Acute Renal Failure: There have been postmarketing reports of worsening renal function, including acute renal failure,sometimes requiring dialysis. Before initiation of therapy with JANUMET and at least annually thereafter, renal function should be assessed. In patients in whom development of renal dysfunction is anticipated, particularly in elderly patients, renal function should be assessed more frequently and JANUMET discontinued if evidence of renal impairment is present. JANUMET is contraindicated in patients with severe renal impairment.

Vitamin B12 Deficiency: In controlled clinical trials of metformin of 29 weeks duration, a decrease to subnormal levels ofpreviously normal serum vitamin B12 levels was observed in approximately 7% of patients. Such decrease, possibly due to interference with B12 absorption from the B12-intrinsic factor complex, may be associated with anemia but appears to be rapidly reversible with discontinuation of metformin or vitamin B12 supplementation. Certain individuals (those with inadequate vitamin B12 or calcium intake or absorption) appear to be predisposed to developing subnormal vitamin B12 levels. Measure hematologic parameters on an annual basis and vitamin B12 measurements at 2- to 3-year intervals in patients on JANUMET and manage any abnormalities.

Hypoglycemia with Concomitant Use with Insulin or Insulin Secretagogues: JANUMET may increase the risk of hypoglycemia when combined with insulin and/or an insulinsecretagogue (e.g., sulfonylurea) . A lower dose of insulin or insulinsecretagogue may be required to minimize the risk of hypoglycemia when used in combination withJANUMET

Hypersensitivity Reactions: There have been postmarketing reports of serious hypersensitivity reactions in patients treated withsitagliptin, one of the components of JANUMET. 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, assess for other potential causes for the event, and institute alternative treatment for diabetes.

Angioedema has also been reported with other DPP-4 inhibitors. Use caution in a patient with a history of angioedema with another DPP-4 inhibitor because it is unknown whether such patients will be predisposed to angioedema with JANUMET.

Severe and Disabling Arthralgia: There have been postmarketing reports of severe and disabling arthralgia in patients taking DPP-4inhibitors. The time to onset of symptoms following initiation of drug therapy varied from one day to years.

Patients experienced relief of symptoms upon discontinuation of the medication. A subset of patients experienced a recurrence of symptoms when restarting the same drug or a different DPP-4 inhibitor. Consider DPP-4 inhibitors as a possible cause for severe joint pain and discontinue drug if appropriate.

Bullous Pemphigoid: Postmarketing cases of bullous pemphigoid requiring hospitalization have been reported with DPP-4 inhibitor use. In reported cases, patients typically recovered with topical or systemic immunosuppressivetreatment and discontinuation of the DPP-4 inhibitor. Tell patients to report development of blisters orerosions while receiving JANUMET. If bullous pemphigoid is suspected, JANUMET should be discontinuedand referral to a dermatologist should be considered for diagnosis and appropriate treatment.

DRUG INTERACTIONS

Carbonic Anhydrase Inhibitors: Carbonic anhydrase inhibitors frequently cause a decrease in serumbicarbonate and induce non-anion gap, hyperchloremic metabolicacidosis. Concomitant use of these drugs with JANUMET may increasethe risk for lactic acidosis. Consider more frequent monitoring of these patients. Examples: Topiramate, zonisamide, acetazolamide or dichlorphenamide.

Drugs that Reduce Metformin Clearance: Concomitant use of drugs that interfere with common renal tubulartransport 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. Consider the benefits and risks of concomitant use with JANUMET. Examples: Ranolazine, vandetanib, dolutegravir, and cimetidine.

Alcohol: Alcohol is known to potentiate the effect of metformin on lactatemetabolism.Warn patients against alcohol intake while receiving JANUMET.

Insulin Secretagogues or Insulin: Coadministration of JANUMET with an insulin secretagogue (e.g.,sulfonylurea) or insulin may increase the risk of hypoglycemia. Patients receiving an insulin secretagogue or insulin may require lower doses of the insulin secretagogue or insulin.

Drugs Affecting Glycemic Control: Certain drugs tend to produce hyperglycemia and may lead to loss ofglycemic control. When such drugs are administered to a patient receiving JANUMET, observe the patient closely for loss of blood glucose control. When suchdrugs are withdrawn from a patient receiving JANUMET, observe thepatient closely for hypoglycemia.

Examples: Thiazides and other diuretics, corticosteroids, phenothiazines, thyroid products, estrogens, oral contraceptives, phenytoin, nicotinic acid, sympathomimetics, calcium channel blockers, and isoniazid.

USE IN SPECIFIC POPULATIONS

Pregnancy: The limited available data with JANUMET in pregnant women are not sufficient to inform a drugassociatedrisk for major birth defects and miscarriage. Published studies with metformin use during pregnancy have not reported a clear association with metformin and major birth defect or miscarriage risk. There are risks to the mother and fetus associated with poorly controlled diabetes in pregnancy.

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Poorly controlled diabetes in pregnancy increases the maternal risk for diabetic ketoacidosis, preeclampsia, spontaneous abortions, preterm delivery, and delivery complications. Poorly controlled diabetes increases the fetal risk for major birth defects, still birth, and macrosomia related morbidity.

Lactation: There is no information regarding the presence of JANUMET in human milk, the effects on thebreastfed infant, or the effects on milk production. Limited published studies report that metformin is presentin human milk. There are no reports of adverse effects on breastfed infants exposed to

metformin. There is no information on the effects of metformin on milk production. Sitagliptin is present in rat milk and therefore possibly present in human milk. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for JANUMET and any potential adverse effects on the breastfed infant from JANUMET or from the underlying maternal condition. Sitagliptin is secreted in the milk of lactating rats at a milk to plasma ratio of 4:1.

Geriatric Use: In general, dose selection for an elderly patient should be cautious, usually starting at the low end ofthe dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy and the higher risk of lactic acidosis. Renal function should beassessed more frequently in elderly patients.

Renal ImpairmentJANUMET is not recommended in patients with an eGFR between 30 and less than45 mL/min/1.73 m2 because these patients require a lower dosage of sitagliptin than what is available inthe fixed dose combination JANUMET product. JANUMET is contraindicated in severe renal impairment,patients with an eGFR below 30 mL/min/1.73 m2.

Hepatic Impairment: Use of metformin in patients with hepatic impairment has been associated with some cases of lacticacidosis. JANUMET is not recommended in patients with hepatic impairment.

OVERDOSAGE

In the event of overdose with JANUMET, contact the Poison Control Center. In the event of an overdose, it is reasonable to employ supportive measures, e.g., remove unabsorbed material from the gastrointestinal tract, employ clinical monitoring (including obtaining an electrocardiogram), and institute supportive therapy as indicated by the patient’s clinical status.

Sitagliptin is modestly dialyzable. In clinical studies, approximately 13.5% of the dose was removed over a 3- to 4-hour hemodialysis session. Prolonged hemodialysis may be considered if clinically appropriate. It is not known if sitagliptin is dialyzable by peritoneal dialysis.Overdose of metformin 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. Metformin is dialyzable with a clearance of up to 170 mL/min under good hemodynamic conditions. Therefore, hemodialysis may be useful for removal of accumulated drug from patients in whom metformin overdosage is suspected.

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