Janumet Xr Drug Information

Recommended Dosing Take

JANUMET XR orally once daily with a meal. Patients taking two JANUMET XR tablets should take the two tablets together once daily. Individualize the dosage of JANUMET XR 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) extended-release. The recommended starting dose in patients not currently treated with metformin is 100 mg sitagliptin and 1000 mg metformin HCl extended-release once 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 100 mg sitagliptin and the previously prescribed dose of metformin.

For patients taking metformin HCl immediate-release 850 mg twice daily or 1000 mg twice daily, the recommended starting dose of JANUMET XR is two 50 mg sitagliptin and 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. Do not split, crush or chew JANUMET XR tablets.

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 m 2. Discontinue JANUMET XR if the patient's eGFR later falls below 30 mL/min/1.73 m 2 . Initiation of JANUMET XR in patients with an eGFR between 30 and 45 mL/min/1.73 m 2 is not recommended. In patients taking JANUMET XR whose eGFR later falls below 45 mL/min/1.73 m 2, assess the benefit risk of continuing therapy and limit dose of the sitagliptin component to 50 mg once daily.

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 m 2 ; 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 .

Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. Sitagliptin and Metformin Immediate-Release Coadministration in Patients with Type 2 Diabetes Inadequately Controlled on Diet and Exercise Table 1 summarizes the most common (≥5% of patients) adverse reactions reported (regardless of investigator assessment of causality) in a 24-week placebo-controlled factorial study in which sitagliptin and metformin immediate-release were coadministered to patients with type 2 diabetes inadequately controlled on diet and exercise. Table 1: Sitagliptin and Metformin Immediate-Release Coadministered to Patients with Type 2 Diabetes Inadequately Controlled on Diet and Exercise: Adverse Reactions Reported (Regardless of Investigator Assessment of Causality) in ≥5% of Patients Receiving Combination Therapy (and Greater than in Patients Receiving Placebo) Intent-to-treat population.

Number of Patients (%) Placebo Sitagliptin 100 mg once daily Metformin HCl Immediate-Release 500 mg or 1000 mg twice daily Data pooled for the patients given the lower and higher doses of metformin. Sitagliptin 50 mg twice daily + Metformin HCl Immediate- Release 500 mg or 1000 mg twice daily N = 176 N = 179 N = 364 N = 372 Diarrhea 7 5 28 28 Upper Respiratory Tract Infection 9 8 19 23 Headache 5 2 14 22 Sitagliptin Add-on Therapy in Patients with Type 2 Diabetes Inadequately Controlled on Metformin Immediate-Release Alone In a 24-week placebo-controlled trial of sitagliptin 100 mg administered once daily added to a twice daily metformin immediate-release regimen, there were no adverse reactions reported regardless of investigator assessment of causality in ≥5% of patients and more commonly than in patients given placebo. Discontinuation of therapy due to clinical adverse reactions was similar to the placebo treatment group (sitagliptin and metformin immediate-release, 1.9%; placebo and metformin immediate-release, 2.5%). Gastrointestinal Adverse Reactions The incidences of pre-selected gastrointestinal adverse experiences in patients treated with sitagliptin and metformin immediate-release were similar to those reported for patients treated with metformin immediate-release alone.

See Table 2. Table 2: Pre-selected Gastrointestinal Adverse Reactions (Regardless of Investigator Assessment of Causality) Reported in Patients with Type 2 Diabetes Receiving Sitagliptin and Metformin Immediate-Release Number of Patients (%) Study of Sitagliptin and Metformin Immediate-Release in Patients Inadequately Controlled on Diet and Exercise Study of Sitagliptin Add-on in Patients Inadequately Controlled on Metformin Immediate-Release Alone Placebo Sitagliptin 100 mg once daily Metformin HCl Immediate-Release 500 mg or 1000 mg twice daily Data pooled for the patients given the lower and higher doses of metformin. Sitagliptin 50 mg bid + Metformin HCl Immediate- Release 500 mg or 1000 mg twice daily Placebo and Metformin HCL Immediate- Release ≥1500 mg daily Sitagliptin 100 mg once daily and Metformin HCl Immediate- Release ≥1500 mg daily N = 176 N = 179 N = 364 N = 372 N = 237 N = 464 Diarrhea 7 5 28 28 6 11 Nausea 2 2 20 18 2 6 Vomiting 1 0 2 8 2 5 Abdominal Pain Abdominal discomfort was included in the analysis of abdominal pain in the study of initial therapy. 4 6 14 11 9 10 Sitagliptin in Combination with Metformin Immediate-Release and Glimepiride In a 24-week placebo-controlled study of sitagliptin 100 mg as add-on therapy in patients with type 2 diabetes inadequately controlled on metformin immediate-release and glimepiride (sitagliptin, N=116; placebo, N=113), the adverse reactions reported regardless of investigator assessment of causality in ≥5% of patients treated with sitagliptin and more commonly than in patients treated with placebo were: hypoglycemia ( Table 3 ) and headache (6.9%, 2.7%). Sitagliptin in Combination with Metformin Immediate-Release and Rosiglitazone In a placebo-controlled study of sitagliptin 100 mg as add-on therapy in patients with type 2 diabetes inadequately controlled on metformin immediate-release and rosiglitazone (sitagliptin, N=181; placebo, N=97), the adverse reactions reported regardless of investigator assessment of causality through Week 18 in ≥5% of patients treated with sitagliptin and more commonly than in patients treated with placebo were: upper respiratory tract infection (sitagliptin, 5.5%; placebo, 5.2%) and nasopharyngitis (6.1%, 4.1%). Through Week 54, the adverse reactions reported regardless of investigator assessment of causality in ≥5% of patients treated with sitagliptin and more commonly than in patients treated with placebo were: upper respiratory tract infection (sitagliptin, 15.5%; placebo, 6.2%), nasopharyngitis (11.0%, 9.3%), peripheral edema (8.3%, 5.2%), and headache (5.5%, 4.1%). Sitagliptin in Combination with Metformin Immediate-Release and Insulin In a 24-week placebo-controlled study of sitagliptin 100 mg as add-on therapy in patients with type 2 diabetes inadequately controlled on metformin immediate-release and insulin (sitagliptin, N=229; placebo, N=233), the only adverse reaction reported regardless of investigator assessment of causality in ≥5% of patients treated with sitagliptin and more commonly than in patients treated with placebo was hypoglycemia ( Table 3 ). Hypoglycemia In the above studies (N=5), adverse reactions of hypoglycemia were based on all reports of symptomatic hypoglycemia; a concurrent glucose measurement was not required although most (77%) reports of hypoglycemia were accompanied by a blood glucose measurement ≤70 mg/dL. When the combination of sitagliptin and metformin immediate-release was coadministered with a sulfonylurea or with insulin, the percentage of patients reporting at least one adverse reaction of hypoglycemia was higher than that observed with placebo and metformin immediate-release coadministered with a sulfonylurea or with insulin ( Table 3 ). Table 3: Incidence and Rate of Hypoglycemia Adverse reactions of hypoglycemia were based on all reports of symptomatic hypoglycemia; a concurrent glucose measurement was not required: Intent-to-treat population. (Regardless of Investigator Assessment of Causality) in Placebo-Controlled Clinical Studies of Sitagliptin in Combination with Metformin Immediate-Release Coadministered with Glimepiride or Insulin Add-On to Glimepiride + Metformin Immediate-Release (24 weeks) Sitagliptin 100 mg + Metformin Immediate-Release + Glimepiride Placebo + Metformin Immediate-Release + Glimepiride N = 116 N = 113 Overall (%) 19 1 Rate (episodes/patient-year) Based on total number of events (i.e., a single patient may have had multiple events). 0.82 0.02 Severe (%) Severe events of hypoglycemia were defined as those events requiring medical assistance or exhibiting depressed level/loss of consciousness or seizure. 0 0 Add-On to Insulin + Metformin Immediate-Release (24 weeks) Sitagliptin 100 mg + Metformin Immediate-Release + Insulin Placebo + Metformin Immediate-Release + Insulin N = 229 N = 233 Overall (%) 35 19 Rate (episodes/patient-year) 0.98 0.61 Severe (%) 1 1 The overall incidence of reported adverse reactions of hypoglycemia in patients with type 2 diabetes inadequately controlled on diet and exercise was 0.6% in patients given placebo, 0.6% in patients given sitagliptin alone, 0.8% in patients given metformin immediate-release alone, and 1.6% in patients given sitagliptin in combination with metformin immediate-release. In patients with type 2 diabetes inadequately controlled on metformin immediate-release alone, the overall incidence of adverse reactions of hypoglycemia was 1.3% in patients given add-on sitagliptin and 2.1% in patients given add-on placebo.

In the study of sitagliptin and add-on combination therapy with metformin immediate-release and rosiglitazone, the overall incidence of hypoglycemia was 2.2% in patients given add-on sitagliptin and 0.0% in patients given add-on placebo through Week 18. Through Week 54, the overall incidence of hypoglycemia was 3.9% in patients given add-on sitagliptin and 1.0% in patients given add-on placebo. In an additional 30-week placebo-controlled study of patients with type 2 diabetes inadequately controlled with metformin comparing the maintenance of sitagliptin 100 mg versus withdrawal of sitagliptin when initiating basal insulin therapy, the event rate and incidence of documented symptomatic hypoglycemia (blood glucose measurement ≤70 mg/dL) did not differ between the sitagliptin and placebo groups. Vital Signs and Electrocardiograms With the combination of sitagliptin and metformin immediate-release, no clinically meaningful changes in vital signs or in electrocardiogram parameters (including the QTc interval) were observed.

Pancreatitis In a pooled analysis of 19 double-blind clinical trials that included data from 10,246 patients randomized to receive sitagliptin 100 mg/day (N=5429) or corresponding (active or placebo) control (N=4817), the incidence of acute pancreatitis was 0.1 per 100 patient-years in each group (4 patients with an event in 4708 patient-years for sitagliptin and 4 patients with an event in 3942 patient-years for control). Sitagliptin The most common adverse experience in sitagliptin monotherapy reported regardless of investigator assessment of causality in ≥5% of patients and more commonly than in patients given placebo was nasopharyngitis. Metformin Extended-Release In a 24-week clinical trial in which extended-release metformin or placebo was added to glyburide therapy, the most common (>5% and greater than placebo) adverse reactions in the combined treatment group were hypoglycemia (13.7% vs. 4.9%), diarrhea (12.5% vs. 5.6%), and nausea (6.7% vs. 4.2%). Laboratory Tests Sitagliptin The incidence of laboratory adverse reactions was similar in patients treated with sitagliptin and metformin immediate-release (7.6%) compared to patients treated with placebo and metformin (8.7%). In most but not all studies, a small increase in white blood cell count (approximately 200 cells/microL difference in WBC vs. placebo; mean baseline WBC approximately 6600 cells/microL) was observed due to a small increase in neutrophils. This change in laboratory parameters is not considered to be clinically relevant.

Metformin In controlled clinical trials of metformin of 29 weeks duration, a decrease to subnormal levels of previously normal serum vitamin B 12 levels, without clinical manifestations, was observed in approximately 7% of patients. Such decrease, possibly due to interference with B 12 absorption from the B 12 -intrinsic factor complex, is, however, very rarely associated with anemia and appears to be rapidly reversible with discontinuation of metformin or vitamin B 12 supplementation.

Postmarketing Experience Additional adverse reactions have been identified during postapproval use of

sitagliptin with metformin, sitagliptin, or metformin. Because these reactions are reported voluntarily from a population of uncertain size, it is generally not possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Hypersensitivity reactions including anaphylaxis, angioedema, rash, urticaria, cutaneous vasculitis, and exfoliative skin conditions including Stevens-Johnson syndrome ; upper respiratory tract infection; hepatic enzyme elevations; acute pancreatitis, including fatal and non-fatal hemorrhagic and necrotizing pancreatitis ; worsening renal function, including acute renal failure (sometimes requiring dialysis) and tubulointerstitial nephritis; severe and disabling arthralgia; bullous pemphigoid; constipation; vomiting; headache; myalgia; pain in extremity; back pain; pruritus; mouth ulceration; stomatitis; cholestatic, hepatocellular, and mixed hepatocellular liver injury; rhabdomyolysis.

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. Therefore, consider more frequent monitoring of patients.

Pregnancy Risk Summary The limited available data with JANUMET XR in pregnant women are not sufficient to inform a drug-associated risk 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 . No adverse developmental effects were observed when sitagliptin was administered to pregnant rats and rabbits during organogenesis at oral doses up to 30-times and 20-times, respectively, the 100 mg clinical dose, based on AUC. No adverse developmental effects were observed when metformin was administered to pregnant Sprague Dawley rats and rabbits during organogenesis at doses up to 2- and 6-times, respectively, a 2000 mg clinical dose, based on body surface area . The estimated background risk of major birth defects is 6-10% in women with pre-gestational diabetes with a Hemoglobin A1c >7% and has been reported to be as high as 20-25% in women with a Hemoglobin A1c >10%. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively. Clinical Considerations Disease-Associated Maternal and/or Embryo/Fetal Risk Poorly controlled diabetes in pregnancy increases the maternal risk for diabetic ketoacidosis, pre-eclampsia, spontaneous abortions, preterm delivery, and delivery complications.

Poorly controlled diabetes increases the fetal risk for major birth defects, still birth, and macrosomia related morbidity. Data Human Data Published data from post-marketing studies do not report a clear association with metformin and major birth defects, miscarriage, or adverse maternal or fetal outcomes when metformin is used during pregnancy. However, these studies cannot definitely establish the absence of any risk because of methodological limitations, including small sample size and inconsistent comparator groups.

Animal Data Sitagliptin and Metformin No animal reproduction studies were conducted with the coadministration of sitagliptin and metformin. Sitagliptin In embryo-fetal development studies, sitagliptin administered to pregnant rats and rabbits during organogenesis (gestation day 6 to 20) did not adversely affect developmental outcomes at oral doses up to 250 mg/kg (30-times the 100 mg clinical dose) and 125 mg/kg (20-times the 100 mg clinical dose), respectively, based on AUC. Higher doses in rats associated with maternal toxicity increased the incidence of rib malformations in offspring at 1000 mg/kg, or approximately 100-times the clinical dose, based on AUC. Placental transfer of sitagliptin was observed in pregnant rats and rabbits. Sitagliptin administered to female rats from gestation day 6 to lactation day 21 caused no functional or behavioral toxicity in offspring of rats at doses up to 1000 mg/kg.

Metformin Metformin did not cause adverse developmental effects when administered to pregnant Sprague Dawley rats and rabbits up to 600 mg/kg/day during the period of organogenesis. This represents an exposure of about 2- and 6-times a 2000 mg clinical dose based on body surface area (mg/m 2 ) for rats and rabbits, respectively.

Pediatric Use The safety and effectiveness of JANUMET XR have not been established in pediatric patients. Three 20-week double-blind, placebo-controlled studies each with 34-week extensions were conducted to evaluate the efficacy and safety of sitagliptin in 410 pediatric patients aged 10 to 17 years with inadequately controlled type 2 diabetes, with or without insulin therapy (HbA1c 6.5-10% for patients not on insulin, HbA1c 7-10% for patients on insulin). At study entry, patients in study 1 were not treated with oral antihyperglycemic agents; patients in studies 2 and 3 were on maximally tolerated metformin therapy. The primary efficacy endpoint was the change from baseline in HbA1c after 20 weeks of therapy.

The pre-specified primary efficacy analyses included data from study 1 and pooled data from studies 2 and 3, regardless of glycemic rescue or treatment discontinuation. In both efficacy analyses, the effect of treatment with sitagliptin was not significantly different from placebo. In study 1, the mean baseline HbA1c was 7.5%, and 12% of patients were on insulin therapy.

At week 20, the change from baseline in HbA1c in patients treated with sitagliptin (N=95) was 0.06% compared to 0.23% in patients treated with placebo (N=95), a difference of -0.17% (95% CI: -0.62, 0.28). In studies 2 and 3, the mean baseline HbA1c was 8.0%, 15% of patients were on insulin and 72% were on metformin HCl doses of greater than 1,500 mg daily. At week 20, the change from baseline in HbA1c in patients treated with sitagliptin (N=107) was -0.23% compared to 0.09% in patients treated with placebo (N=113), a difference of -0.33% (95% CI: -0.70, 0.05).

is contraindicated in patients with: Severe renal impairment (eGFR below 30 mL/min/1.73 m 2 ) . Acute or chronic metabolic acidosis, including diabetic ketoacidosis. History of a serious hypersensitivity reaction to JANUMET XR, sitagliptin, or metformin such as anaphylaxis or angioedema. Severe renal impairment: eGFR below 30 mL/min/1.73 m 2. Metabolic acidosis, including diabetic ketoacidosis.

History of a serious hypersensitivity reaction (e.g., anaphylaxis or angioedema) to JANUMET XR, sitagliptin, or metformin.

In the event of overdose with JANUMET XR, 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.