Jentadueto Drug Information

JENTADUETO XR is indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus. Limitations of Use JENTADUETO XR is not recommended in patients with type 1 diabetes mellitus. JENTADUETO XR has not been studied in patients with a history of pancreatitis.

It is unknown whether patients with a history of pancreatitis are at an increased risk for the development of pancreatitis while using JENTADUETO XR.

Recommended Dosage and Administration

The dosage of JENTADUETO XR should be individualized on the basis of both effectiveness and tolerability, while not exceeding the maximum recommended total daily dosage of linagliptin 5 mg and metformin hydrochloride (HCl) 2,000 mg. JENTADUETO XR should be given orally once daily with a meal. Dosage escalation should be gradual to reduce the gastrointestinal (GI) side effects associated with metformin use.

Recommended starting dosage: In patients currently not treated with metformin HCl, initiate JENTADUETO XR treatment with 5 mg linagliptin/1,000 mg metformin HCl extended-release once daily with a meal. In patients already treated with metformin HCl, start JENTADUETO XR with 5 mg of linagliptin total daily dosage and a similar total daily dosage of metformin HCl once daily with a meal. JENTADUETO XR should be swallowed whole.

The tablets must not be split, crushed, dissolved, or chewed. JENTADUETO XR 5 mg linagliptin/1,000 mg metformin HCl extended-release tablet should be taken as a single tablet once daily. Patients using 2.5 mg linagliptin/1,000 mg metformin HCl extended-release tablets should take two tablets together once daily.

Recommended Dosing in Renal Impairment

Assess renal function prior to initiation of JENTADUETO XR and periodically thereafter. JENTADUETO XR is contraindicated in patients with an estimated glomerular filtration rate (eGFR) below 30 mL/min/1.73 m 2. Initiation of JENTADUETO XR in patients with an eGFR between 30-45 mL/min/1.73 m 2 is not recommended.

In patients taking JENTADUETO XR whose eGFR later falls below 45 mL/min/1.73 m 2, assess benefit/risk of continuing therapy. Discontinue JENTADUETO XR if the patient's eGFR later falls below 30 mL/min/1.73 m 2.

Discontinuation for Iodinated Contrast Imaging Procedures Discontinue JENTADUETO 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 JENTADUETO 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. In the 3 placebo-controlled clinical studies, adverse reactions which occurred in ≥5% of patients receiving linagliptin + metformin (n=875) and were more common than in patients given placebo + metformin (n=539) included nasopharyngitis (5.7% vs 4.3%). In a 24-week factorial design trial, adverse reactions reported in ≥5% of patients receiving linagliptin + metformin and were more common than in patients given placebo are shown in Table 1.

Table 1 Adverse Reactions Reported in ≥5% of Patients Treated with Linagliptin + Metformin and Greater than with Placebo in a 24-week Factorial-Design Trial Other adverse reactions reported in clinical studies with treatment of linagliptin + metformin were hypersensitivity (e.g., urticaria, angioedema, or bronchial hyperreactivity), cough, decreased appetite, nausea, vomiting, pruritus, and pancreatitis. Other adverse reactions reported in clinical studies with treatment of linagliptin monotherapy were hypersensitivity (e.g., urticaria, angioedema, localized skin exfoliation, or bronchial hyperreactivity) and myalgia. In the clinical trial program, pancreatitis was reported in 15.2 cases per 10,000 patient year exposure while being treated with linagliptin compared with 3.7 cases per 10,000 patient year exposure while being treated with comparator (placebo and active comparator, sulfonylurea).

Three additional cases of pancreatitis were reported following the last administered dose of linagliptin. Metformin The most common (>5%) adverse reactions due to initiation of metformin therapy are diarrhea, nausea/vomiting, flatulence, abdominal discomfort, indigestion, asthenia, and headache. The incidence of hypoglycemia with plasma glucose <54 mg/dL was 8.1% in the linagliptin group (N=792) compared to 5.3% in the placebo group (N=263) when administered in combination with metformin and sulfonylurea in a 24-week trial.

Linagliptin The incidence of severe hypoglycemia (requiring assistance) was 1.7% in the linagliptin group (N=631) compared to 1.1% in the placebo group (N=630) when administered in combination with basal insulin in a 52-week trial. Laboratory Test Abnormalities in Clinical Trials of Linagliptin or Metformin Linagliptin Increase in Uric Acid: Changes in laboratory values that occurred more frequently in the linagliptin group and ≥1% more than in the placebo group were increases in uric acid (1.3% in the placebo group, 2.7% in the linagliptin group). Increase in Lipase: In a placebo-controlled clinical trial with linagliptin in type 2 diabetes mellitus patients with micro- or macroalbuminuria, a mean increase of 30% in lipase concentrations from baseline to 24 weeks was observed in the linagliptin arm compared to a mean decrease of 2% in the placebo arm.

Lipase levels above 3 times upper limit of normal were seen in 8.2% compared to 1.7% patients in the linagliptin and placebo arms, respectively. Increase in Amylase: In a cardiovascular safety trial comparing linagliptin versus glimepiride in patients with type 2 diabetes mellitus, amylase levels above 3 times upper limit of normal were seen in 1.0% compared to 0.5% of patients in the linagliptin and glimepiride arms, respectively. The clinical significance of elevations in lipase and amylase with linagliptin is unknown in the absence of potential signs and symptoms of pancreatitis.

Metformin Decrease in Vitamin B 12: In metformin clinical trials of 29-week duration, a decrease to subnormal levels of previously normal serum vitamin B 12 levels was observed in approximately 7% of patients.

Postmarketing Experience

The following adverse reactions have been identified during postapproval use. 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. Linagliptin Gastrointestinal Disorders: Acute pancreatitis, including fatal pancreatitis, mouth ulceration, stomatitis Immune System Disorders: Hypersensitivity reactions including anaphylaxis, angioedema, and exfoliative skin conditions Musculoskeletal and Connective Tissue Disorders: Rhabdomyolysis, severe and disabling arthralgia Skin and Subcutaneous Tissue Disorders: Bullous pemphigoid, rash Metformin Hepatobiliary Disorders: Cholestatic, hepatocellular, and mixed hepatocellular liver injury

Table 2 describes clinically relevant interactions with JENTADUETO XR. Table 2 Clinically Relevant Interactions with JENTADUETO XR Concomitant use of drugs that interfere with common renal tubular transport systems involved in the renal elimination of metformin (e.g., organic cationic transporter-2 / multidrug and toxin extrusion inhibitors such as ranolazine, vandetanib, dolutegravir, and cimetidine) could increase systemic exposure to metformin and may increase the risk for lactic acidosis.: May increase risk of lactic acidosis. Consider more frequent monitoring.

Drugs that Reduce Metformin Clearance: May increase risk of lactic acidosis. Consider benefits and risks of concomitant use. Alcohol: Can potentiate the effect of metformin on lactate metabolism.

Warn patients against excessive alcohol intake. Strong P-glycoprotein/CYP3A4 Inducer: Efficacy may be reduced when administered in combination (e.g., rifampin). Use of alternative treatments is strongly recommended.

Pregnancy Risk Summary The limited data with JENTADUETO XR and linagliptin use in pregnant women are not sufficient to inform a JENTADUETO XR-associated or linagliptin-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.

In animal reproduction studies, no adverse developmental effects were observed when the combination of linagliptin and metformin was administered to pregnant rats during the period of organogenesis at doses similar to the maximum recommended clinical dose, based on exposure. The estimated background risk of miscarriage for the indicated population is unknown. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is respectively.

Clinical Considerations Disease-associated maternal and/or embryo/fetal risk 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, stillbirth, and macrosomia related morbidity. Data Human Data Published data from postmarketing studies have not reported a clear association with metformin and major birth defects, miscarriage, or adverse maternal or fetal outcomes when metformin was used during pregnancy.

However, these studies cannot definitely establish the absence of any metformin-associated risk because of methodological limitations, including small sample size and inconsistent comparator groups. Animal Data Linagliptin and metformin, the components of JENTADUETO XR, were coadministered to pregnant Wistar Han rats during the period of organogenesis. At higher doses associated with maternal toxicity, the metformin component of the combination was associated with an increased incidence of fetal rib and scapula malformations at ≥9-times a 2,000 mg clinical dose, based on exposure.

Linagliptin No adverse developmental outcome was observed when linagliptin was administered to pregnant Wistar Han rats and Himalayan rabbits during the period of organogenesis at doses up to 240 mg/kg/day and 150 mg/kg/day, respectively. These doses represent approximately 943-times (rats) and 1,943-times (rabbits) the 5 mg maximum clinical dose, based on exposure. No adverse functional, behavioral, or reproductive outcome was observed in offspring following administration of linagliptin to Wistar Han rats from gestation day 6 to lactation day 21 at a dose 49-times the maximum recommended human dose, based on exposure.

Linagliptin crosses the placenta into the fetus following oral dosing in pregnant rats and rabbits. Metformin HCl Metformin HCl did not cause adverse developmental effects when administered to pregnant Sprague Dawley rats and rabbits at doses up to 600 mg/kg/day during the period of organogenesis. This represents an exposure of approximately 2-and 6-times a clinical dose of 2,000 mg, based on body surface area (mg/m 2 ) for rats and rabbits, respectively.

Pediatric Use Safety and effectiveness of JENTADUETO XR have not been established in pediatric patients.

JENTADUETO XR 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. hypersensitivity to linagliptin, metformin, or any of the excipients in JENTADUETO XR, reactions such as anaphylaxis, angioedema, exfoliative skin conditions, urticaria, or bronchial hyperreactivity have occurred with linagliptin.

In the event of an overdose with JENTADUETO XR, consider contacting the Poison Help line (1-800-222-1222) or a medical toxicologist for additional overdosage management recommendations. Overdose of metformin HCl has occurred, including ingestion of amounts greater than 50 grams. 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. Removal of linagliptin by hemodialysis or peritoneal dialysis is unlikely.