Jentadueto Xr Drug Information
Generic name: LINAGLIPTIN AND METFORMIN HYDROCHLORIDE
Dipeptidyl Peptidase 4 Inhibitor [EPC]
Uses of Jentadueto Xr
is indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus. JENTADUETO XR is a combination of linagliptin, a dipeptidyl peptidase-4 (DPP-4) inhibitor and metformin hydrochloride (HCl), a biguanide, indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus Limitations of Use Not recommended in patients with type 1 diabetes mellitus Has not been studied in patients with a history of pancreatitis 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.
Dosage & Administration of 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. In patients already treated with linagliptin and metformin HCl or JENTADUETO, switch to JENTADUETO XR containing 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.
Side Effects of Jentadueto Xr
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. Linagliptin/Metformin The safety of concomitantly administered linagliptin (daily dosage 5 mg) and metformin (mean daily dosage of approximately 1,800 mg) has been evaluated in 2,816 patients with type 2 diabetes mellitus treated for ≥12 weeks in clinical trials. Three placebo-controlled trials with linagliptin + metformin were conducted: 2 studies were 24 weeks in duration, 1 trial was 12 weeks in duration.
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 Adverse Reactions Placebo (%) n=72 Linagliptin Monotherapy (%) n=142 Metformin Monotherapy (%) n=291 Combination of Linagliptin with Metformin (%) n=286 Nasopharyngitis 1.4 5.6 2.7
Diarrhea 2.8 3.5 3.8 6.3 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. Linagliptin Adverse reactions reported in ≥2% of patients treated with linagliptin 5 mg and more commonly than in patients treated with placebo included: nasopharyngitis (7.0% vs 6.1%), diarrhea (3.3% vs 3.0%), and cough (2.1% vs 1.4%). Rates for other adverse reactions for linagliptin 5 mg vs placebo when linagliptin was used in combination with specific antidiabetic agents were: urinary tract infection (3.1% vs 0%) and hypertriglyceridemia (2.4% vs 0%) when linagliptin was used as add-on to sulfonylurea; hyperlipidemia (2.7% vs 0.8%) and weight increased (2.3% vs 0.8%) when linagliptin was used as add-on to pioglitazone; and constipation (2.1% vs 1%) when linagliptin was used as add-on to basal insulin therapy. 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. 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%). Other Adverse Reactions Hypoglycemia Linagliptin/Metformin In a 24-week factorial design trial, hypoglycemia was reported in 4 (1.4%) of 286 subjects treated with linagliptin + metformin, 6 (2.1%) of 291 subjects treated with metformin, and 1 (1.4%) of 72 subjects treated with placebo.
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
Warnings & Cautions for Jentadueto Xr
Lactic Acidosis Metformin
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 generally >5 mcg/mL. Metformin decreases liver uptake of lactate increasing lactate blood levels which may increase 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 JENTADUETO XR. In JENTADUETO 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 is dialyzable, with 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 JENTADUETO XR and report these symptoms to their healthcare 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 : Before initiating JENTADUETO XR, obtain an estimated glomerular filtration rate (eGFR). JENTADUETO XR is contraindicated in patients with an eGFR less than 30 mL/min/1.73 m 2 . Initiation of JENTADUETO XR is not recommended in patients with eGFR between 30 – 45 mL/min/1.73 m 2. Obtain an eGFR at least annually in all patients taking JENTADUETO XR. In patients at increased risk for the development of renal impairment (e.g., the elderly), renal function should be assessed more frequently. In patients taking JENTADUETO XR whose eGFR later falls below 45 mL/min/1.73 m 2, assess the benefit and risk of continuing therapy.
Drug Interactions: The concomitant use of JENTADUETO 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. 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.
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 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 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 JENTADUETO 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. JENTADUETO 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 JENTADUETO 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 JENTADUETO XR. Hepatic Impairment: Patients with hepatic impairment have developed cases of metformin-associated lactic acidosis. This may be due to impaired lactate clearance resulting in higher lactate blood levels.
Therefore, avoid use of JENTADUETO XR in patients with clinical or laboratory evidence of hepatic disease.
Pancreatitis Acute pancreatitis, including fatal pancreatitis, has been reported in patients treated
with linagliptin. In the CARMELINA trial , acute pancreatitis was reported in 9 (0.3%) patients treated with linagliptin and in 5 (0.1%) patients treated with placebo. Two patients treated with linagliptin in the CARMELINA trial had acute pancreatitis with a fatal outcome.
There have been postmarketing reports of acute pancreatitis, including fatal pancreatitis, in patients treated with linagliptin. Take careful notice of potential signs and symptoms of pancreatitis. If pancreatitis is suspected, promptly discontinue JENTADUETO XR and initiate appropriate management.
It is unknown whether patients with a history of pancreatitis are at increased risk for the development of pancreatitis while using JENTADUETO XR.
Hypoglycemia with
Concomitant Use with Insulin and Insulin Secretagogues Insulin secretagogues and insulin are known to cause hypoglycemia. The risk of hypoglycemia is increased when JENTADUETO XR is used in combination with an insulin secretagogue (e.g., sulfonylurea) or insulin . Therefore, a lower dosage of the insulin secretagogue or insulin may be required to reduce the risk of hypoglycemia when used in combination with JENTADUETO XR.
Hypersensitivity Reactions
There have been postmarketing reports of serious hypersensitivity reactions in patients treated with linagliptin. These reactions include anaphylaxis, angioedema, and exfoliative skin conditions. Onset of these reactions occurred predominantly within the first 3 months after initiation of treatment with linagliptin, with some reports occurring after the first dose.
If a serious hypersensitivity reaction is suspected, discontinue JENTADUETO XR, assess for other potential causes for the event, and institute alternative treatment for diabetes mellitus. Angioedema has also been reported with other dipeptidyl peptidase-4 (DPP-4) inhibitors. Use caution in a patient with a history of angioedema to another DPP-4 inhibitor because it is unknown whether such patients will be predisposed to angioedema with JENTADUETO XR.
Vitamin B 12 Deficiency
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 metformin-treated patients. Such decrease, possibly due to interference with B 12 absorption from the B 12 -intrinsic factor complex, may be associated with anemia but appears to be rapidly reversible with discontinuation of metformin or vitamin B 12 supplementation. Certain individuals (those with inadequate vitamin B 12 or calcium intake or absorption) appear to be predisposed to developing subnormal vitamin B 12 levels.
Measure hematologic parameters on an annual basis and vitamin B 12 at 2 to 3 year intervals in patients on JENTADUETO XR and manage any abnormalities.
Severe and Disabling Arthralgia
There have been postmarketing reports of severe and disabling arthralgia in patients taking linagliptin. 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 Bullous pemphigoid was reported in 7 (0.2%) patients treated with
linagliptin compared to none in patients treated with placebo in the CARMELINA trial , and 3 of these patients were hospitalized due to 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 immunosuppressive treatment and discontinuation of the DPP-4 inhibitor.
Tell patients to report development of blisters or erosions while receiving JENTADUETO XR. If bullous pemphigoid is suspected, JENTADUETO XR should be discontinued and referral to a dermatologist should be considered for diagnosis and appropriate treatment.
Heart Failure
An association between DPP-4 inhibitor treatment and heart failure has been observed in cardiovascular outcomes trials for two other members of the DPP-4 inhibitor class. These trials evaluated patients with type 2 diabetes mellitus and atherosclerotic cardiovascular disease. Consider the risks and benefits of JENTADUETO XR prior to initiating treatment in patients at risk for heart failure, such as those with a prior history of heart failure and a history of renal impairment, and observe these patients for signs and symptoms of heart failure during therapy.
Advise patients of the characteristic symptoms of heart failure and to immediately report such symptoms. If heart failure develops, evaluate and manage according to current standards of care and consider discontinuation of JENTADUETO XR.
Drug Interactions with Jentadueto Xr
Table 2 describes clinically relevant interactions with JENTADUETO XR. Table 2 Clinically Relevant Interactions with JENTADUETO XR Carbonic Anhydrase Inhibitors Clinical Impact Topiramate or other carbonic anhydrase inhibitors (e.g., zonisamide, acetazolamide or dichlorphenamide) frequently cause a decrease in serum bicarbonate and induce non-anion gap, hyperchloremic metabolic acidosis. Concomitant use of these drugs with JENTADUETO XR may increase the risk of lactic acidosis. Intervention Consider more frequent monitoring of these patients.
Drugs that Reduce Metformin Clearance Clinical Impact 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 . Intervention Consider the benefits and risks of concomitant use. Alcohol Clinical Impact Alcohol is known to potentiate the effect of metformin on lactate metabolism. Intervention Warn patients against excessive alcohol intake while receiving JENTADUETO XR. Insulin or Insulin Secretagogues Clinical Impact The risk of hypoglycemia is increased when JENTADUETO XR is used in combination with an insulin secretagogue (e.g., sulfonylurea) or insulin.
Intervention Coadministration of JENTADUETO XR with an insulin secretagogue (e.g., sulfonylurea) or insulin may require lower dosages of the insulin secretagogue or insulin to reduce the risk of hypoglycemia. Drugs Affecting Glycemic Control Clinical Impact Certain drugs tend to produce hyperglycemia and may lead to loss of glycemic control. These drugs include the thiazides and other diuretics, corticosteroids, phenothiazines, thyroid products, estrogens, oral contraceptives, phenytoin, nicotinic acid, sympathomimetics, calcium channel blocking drugs, and isoniazid.
Intervention When such drugs are administered to a patient receiving JENTADUETO XR, the patient should be closely observed to maintain adequate glycemic control. When such drugs are withdrawn from a patient receiving JENTADUETO XR, the patient should be observed closely for hypoglycemia. Inducers of P-glycoprotein or CYP3A4 Enzymes Clinical Impact Rifampin decreased linagliptin exposure, suggesting that the efficacy of linagliptin may be reduced when administered in combination with a strong P-gp or CYP3A4 inducer.
Intervention Use of alternative treatments is strongly recommended when linagliptin is to be administered with a strong P-gp or CYP3A4 inducer. Carbonic Anhydrase Inhibitors: 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 Safety for Jentadueto Xr
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 major birth defects is 6% to 10% in women with pre-gestational diabetes with a HbA1c>7 and has been reported to be as high as 20% to 25% in women with HbA1c>10. 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 2% to 4% and 15% to 20%, 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. No adverse developmental outcome was observed at doses similar to the maximum recommended clinical dose, based on exposure. 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 of Jentadueto Xr
Pediatric Use Safety and effectiveness of JENTADUETO XR have not been established in pediatric patients. Effectiveness of linagliptin was not demonstrated in a 26-week randomized, double-blind, placebo-controlled trial (NCT03429543) in 157 pediatric patients aged 10 to 17 years with inadequately controlled type 2 diabetes mellitus.
Contraindications for 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. Severe renal impairment (eGFR below 30 mL/min/1.73 m 2 ) Metabolic acidosis, including diabetic ketoacidosis Hypersensitivity to linagliptin, metformin, or any of the excipients in JENTADUETO XR
Overdosage Information for Jentadueto Xr
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.
Clinical Studies of Jentadueto Xr
Glycemic Control Trials in Adults with Type 2 Diabetes Mellitus Initial Combination
Therapy with Linagliptin and Metformin A total of 791 patients with type 2 diabetes mellitus and inadequate glycemic control on diet and exercise participated in the 24-week, randomized, double-blind, portion of this placebo-controlled factorial trial designed to assess the efficacy of linagliptin as initial therapy with metformin. Patients on an antihyperglycemic agent (52%) underwent a drug washout period of 4 weeks' duration. After the washout period and after completing a 2-week single-blind placebo run-in period, patients with inadequate glycemic control (A1C ≥7.0% to ≤10.5%) were randomized.
Patients with inadequate glycemic control (A1C ≥7.5% to <11.0%) not on antihyperglycemic agents at trial entry (48%) immediately entered the 2-week single-blind placebo run-in period and then were randomized. Randomization was stratified by baseline A1C (<8.5% vs ≥8.5%) and use of a prior oral antidiabetic drug (none vs monotherapy). Patients were randomized in a 1:2:2:2:2:2 ratio to either placebo or one of 5 active-treatment arms. Approximately equal numbers of patients were randomized to receive initial therapy with 5 mg of linagliptin once daily, 500 mg or 1,000 mg of metformin twice daily, or 2.5 mg of linagliptin twice daily in combination with 500 mg or 1,000 mg of metformin twice daily.
Patients who failed to meet specific glycemic goals during the trial were treated with sulfonylurea, thiazolidinedione, or insulin rescue therapy. Initial therapy with the combination of linagliptin and metformin provided significant improvements in A1C, and fasting plasma glucose (FPG) compared to placebo, to metformin alone, and to linagliptin alone (Table 7, Figure 1). The adjusted mean treatment difference in A1C from baseline to week 24 (LOCF) was -0.5% (95% CI -0.7, -0.3; p<0.0001) for linagliptin 2.5 mg/metformin 1,000 mg twice daily compared to metformin 1,000 mg twice daily; -1.1% (95% CI -1.4, -0.9; p<0.0001) for linagliptin 2.5 mg/metformin 1,000 mg twice daily compared to linagliptin 5 mg once daily; -0.6% (95% CI -0.8, -0.4; p<0.0001) for linagliptin 2.5 mg/metformin 500 mg twice daily compared to metformin 500 mg twice daily; and -0.8% (95% CI -1.0, -0.6; p<0.0001) for linagliptin 2.5 mg/metformin 500 mg twice daily compared to linagliptin 5 mg once daily. Lipid effects were generally neutral.
No meaningful change in body weight was noted in any of the 6 treatment groups. Table 7 Glycemic Parameters at Final Visit (24-Week Trial) for Linagliptin and Metformin, Alone and in Combination in Randomized Patients with Type 2 Diabetes Mellitus Inadequately Controlled on Diet and Exercise** Placebo Linagliptin 5 mg Once Daily* Metformin 500 mg Twice Daily Linagliptin 2.5 mg Twice Daily* + Metformin 500 mg Twice Daily Metformin 1,000 mg Twice Daily Linagliptin 2.5 mg Twice Daily* + Metformin 1,000 mg Twice Daily *Total daily dosage of linagliptin is equal to 5 mg **Full analysis population using last observation on trial ***Metformin 500 mg twice daily, n=140; Linagliptin 2.5 mg twice daily + Metformin 500 mg twice daily, n=136; Metformin 1,000 mg twice daily, n=137; Linagliptin 2.5 mg twice daily + Metformin 1,000 mg twice daily, n=138 ****HbA1c: ANCOVA model included treatment and number of prior OADs as class-effects, as well as baseline HbA1c as continuous covariates. FPG: ANCOVA model included treatment and number of prior OADs as class-effects, as well as baseline HbA1c and baseline FPG as continuous covariates.
A1C (%) Number of patients n=65 n=135 n=141 n=137 n=138 n=140 Baseline (mean) 8.7 8.7 8.7 8.7 8.5
Change from baseline (adjusted mean****) 0.1 -0.5 -0.6 -1.2 -1.1 -1.6 Difference
from placebo (adjusted mean) (95% CI) -- -0.6 (-0.9, -0.3) -0.8 (-1.0, -0.5) -1.3 (-1.6, -1.1) -1.2 (-1.5, -0.9) -1.7 (-2.0, -1.4) Patients achieving A1C <7%*** 7 14 26 41 42 74 Patients (%) receiving rescue medication 29.2 11.1 13.5 7.3 8.0
FPG (mg/dL) Number of patients n=61 n=134 n=136 n=135 n=132 n=136 Baseline
(mean) 203 195 191 199 191 196 Change from baseline (adjusted mean****) 10 -9 -16 -33 -32 -49 Difference from placebo (adjusted mean) (95% CI) -- -19 (-31, -6) -26 (-38, -14) -43 (-56, -31) -42 (-55, -30) -60 (-72, -47) Figure 1 Adjusted Mean Change from Baseline for A1C (%) over 24 Weeks with Linagliptin and Metformin, Alone and in Combination in Patients with Type 2 Diabetes Mellitus Inadequately Controlled with Diet and Exercise - FAS completers. Figure 1 Initial Combination Therapy with Linagliptin and Metformin vs Linagliptin in Treatment-Naïve Patients A total of 316 patients with type 2 diabetes mellitus diagnosed within the previous 12 months and treatment-naïve (no antidiabetic therapy for 12 weeks prior to randomization) and inadequate glycemic control (A1C ≥8.5% to ≤12.0%) participated in a 24-week, randomized, double-blind, trial designed to assess the efficacy of linagliptin in combination with metformin vs linagliptin. Patients were randomized (1:1), after a 2-week run-in period, to either linagliptin 5 mg plus metformin (1,500 to 2,000 mg per day, n=159) or linagliptin 5 mg plus placebo, (n=157) administered once daily.
Patients in the linagliptin and metformin treatment group were up-titrated to a maximum tolerated dosage of metformin (1,000 to 2,000 mg per day) over a three-week period. Initial therapy with the combination of linagliptin and metformin provided statistically significant improvements in A1C compared to linagliptin (Table 8). The mean difference between groups in A1C change from baseline was -0.8% with 2-sided 95% confidence interval (-1.23%, -0.45%). Table 8 Glycemic Parameters at 24 Weeks in Trial Comparing Linagliptin in Combination with Metformin to Linagliptin in Treatment-Naïve Patients* Linagliptin 5 mg + Metformin Linagliptin 5 mg + Placebo † p<0.0001 compared to linagliptin, †† p=0.0054 compared to linagliptin *Full analysis set population **A1C: MMRM model included treatment, continuous baseline A1C, baseline A1C by visit interaction, visit by treatment interaction, baseline renal impairment by treatment interaction and baseline renal impairment by treatment by visit interaction. FPG: MMRM model included treatment, continuous baseline A1C, continuous baseline FPG, baseline FPG by visit interaction, visit by treatment interaction, baseline renal impairment by treatment interaction and baseline renal impairment by treatment by visit interaction.
A1C (%)* Number of patients n=153 n=150 Baseline (mean) 9.8
Change from baseline (adjusted mean) -2.9 -2 Difference from linagliptin (adjusted mean**)
(95% CI) -0.84 † (-1.23, -0.45) -- Patients achieving A1C <7%* 82 45 FPG (mg/dL)* Number of patients n=153 n=150 Baseline (mean) 196 198 Change from baseline (adjusted mean) -54 -35 Difference from linagliptin (adjusted mean**) (95% CI) -18 †† (-31, -5.5) -- The adjusted mean changes for A1C (%) from baseline over time for linagliptin and metformin as compared to linagliptin alone were maintained throughout the 24-week treatment period. Using the completers analysis the respective adjusted means for A1C (%) changes from baseline for linagliptin and metformin as compared to linagliptin alone were -1.9 and -1.3 at week 6, -2.6 and -1.8 at week 12, -2.7 and -1.9 at week 18, and -2.7 and -1.9 at week 24. Changes in body weight from baseline were not clinically significant in either treatment group. Add-On Combination Therapy with Metformin A total of 701 patients with type 2 diabetes mellitus participated in a 24-week, randomized, double-blind, placebo-controlled trial designed to assess the efficacy of linagliptin in combination with metformin.
Patients already on metformin (n=491) at a dosage of at least 1,500 mg per day were randomized after completing a 2-week, open-label, placebo run-in period. Patients on metformin and another antihyperglycemic agent (n=207) were randomized after a run-in period of approximately 6 weeks on metformin (at a dosage of at least 1,500 mg per day) in monotherapy. Patients were randomized to the addition of either linagliptin 5 mg or placebo, administered once daily.
Patients who failed to meet specific glycemic goals during the studies were treated with glimepiride rescue. In combination with metformin, linagliptin provided statistically significant improvements in A1C, FPG, and 2-hour PPG compared with placebo (Table 9). Rescue glycemic therapy was used in 7.8% of patients treated with linagliptin 5 mg and in 18.9% of patients treated with placebo. A similar decrease in body weight was observed for both treatment groups.
Table 9 Glycemic Parameters in Placebo-Controlled Trial for Linagliptin in Combination with Metformin* Linagliptin 5 mg + Metformin Placebo + Metformin * Full analysis population using last observation on trial **Linagliptin 5 mg + Metformin, n=485; Placebo + Metformin, n=163 ***HbA1c: ANCOVA model included treatment and number of prior oral OADs as class-effects, as well as baseline HbA1c as continuous covariates. FPG: ANCOVA model included treatment and number of prior OADs as class-effects, as well as baseline HbA1c and baseline FPG as continuous covariates. PPG: ANCOVA model included treatment and number of prior OADs as class-effects, as well as baseline HbA1c and baseline postprandial glucose after two hours as covariate.
A1C (%) Number of patients n=513 n=175 Baseline (mean) 8.1
Change from baseline (adjusted mean***) -0.5 0.15 Difference from placebo + metformin
(adjusted mean) (95% CI) -0.6 (-0.8, -0.5) -- Patients achieving A1C <7%** 127 15 FPG (mg/dL) Number of patients n=495 n=159 Baseline (mean) 169 164 Change from baseline (adjusted mean***) -11 11 Difference from placebo + metformin (adjusted mean) (95% CI) -21 (-27, -15) -- 2-hour PPG (mg/dL) Number of patients n=78 n=21 Baseline (mean) 270 274 Change from baseline (adjusted mean***) -49 18 Difference from placebo + metformin (adjusted mean) (95% CI) -67 (-95, -40) -- Active-Controlled Trial vs Glimepiride in Combination with Metformin The efficacy of linagliptin was evaluated in a 104-week double-blind, glimepiride-controlled non-inferiority trial in type 2 diabetic patients with insufficient glycemic control despite metformin therapy. Patients being treated with metformin only entered a run-in period of 2 weeks' duration, whereas patients pretreated with metformin and one additional antihyperglycemic agent entered a run-in treatment period of 6 weeks' duration with metformin monotherapy (dosage of ≥1,500 mg per day) and washout of the other agent. After an additional 2-week placebo run-in period, those with inadequate glycemic control (A1C 6.5% to 10%) were randomized 1:1 to the addition of linagliptin 5 mg once daily or glimepiride.
Randomization was stratified by baseline HbA1c (<8.5% vs ≥8.5%), and the previous use of antidiabetic drugs (metformin alone vs metformin plus one other OAD). Patients receiving glimepiride were given an initial dosage of 1 mg/day and then electively titrated over the next 12 weeks to a maximum dosage of 4 mg/day as needed to optimize glycemic control. Thereafter, the glimepiride dosage was to be kept constant, except for down-titration to prevent hypoglycemia. After 52 weeks and 104 weeks, linagliptin and glimepiride both had reductions from baseline in A1C (52 weeks: -0.4% for linagliptin, -0.6% for glimepiride; 104 weeks: -0.2% for linagliptin, -0.4% for glimepiride) from a baseline mean of 7.7% (Table 10). The mean difference between groups in A1C change from baseline was 0.2% with 2-sided 97.5% confidence interval (0.1%, 0.3%) for the intent-to-treat population using last observation carried forward.
These results were consistent with the completers analysis. Table 10 Glycemic Parameters at 52 and 104 Weeks in Trial Comparing Linagliptin to Glimepiride as Add-On Therapy in Patients Inadequately Controlled on Metformin** Week 52 Week 104 Linagliptin 5 mg + Metformin Glimepiride + Metformin (mean glimepiride dosage 3 mg) Linagliptin 5 mg + Metformin Glimepiride + Metformin (mean glimepiride dosage 3 mg) *p<0.0001 vs glimepiride; † p=0.0012 vs glimepiride **Full analysis population using last observation on trial ***HbA1c: ANCOVA model included treatment and number of prior OADs as class-effects, as well as baseline HbA1c as continuous covariates. FPG: ANCOVA model included treatment and number of prior OADs as class-effects, as well as baseline HbA1c and baseline FPG as continuous covariates.
A1C (%) Number of patients n=764 n=755 n=764 n=755 Baseline (mean) 7.7 7.7 7.7
Change from baseline (adjusted mean***) -0.4 -0.6 -0.2 -0.4 Difference from glimepiride
(adjusted mean) (97.5% CI) 0.2 -- 0.2 -- FPG (mg/dL) Number of patients n=733 n=725 n=733 n=725 Baseline (mean) 164 166 164 166 Change from baseline (adjusted mean***) -8* -15 -2 † -9 Patients treated with linagliptin had a mean baseline body weight of 86 kg and were observed to have an adjusted mean decrease in body weight of 1.1 kg at 52 weeks and 1.4 kg at 104 weeks. Patients on glimepiride had a mean baseline body weight of 87 kg and were observed to have an adjusted mean increase from baseline in body weight of 1.4 kg at 52 weeks and 1.3 kg at 104 weeks (treatment difference p<0.0001 for both timepoints). Add-On Combination Therapy with Metformin and a Sulfonylurea A total of 1,058 patients with type 2 diabetes mellitus participated in a 24-week, randomized, double-blind, placebo-controlled trial designed to assess the efficacy of linagliptin in combination with a sulfonylurea and metformin. The most common sulfonylureas used by patients in the trial were glimepiride (31%), glibenclamide (26%), and gliclazide (26% ). Patients on a sulfonylurea and metformin were randomized to receive linagliptin 5 mg or placebo, each administered once daily.
Patients who failed to meet specific glycemic goals during the trial were treated with pioglitazone rescue. Glycemic end points measured included A1C and FPG. In combination with a sulfonylurea and metformin, linagliptin provided statistically significant improvements in A1C and FPG compared with placebo (Table 11). In the entire trial population (patients on linagliptin in combination with a sulfonylurea and metformin), a mean reduction from baseline relative to placebo in A1C of -0.6% and in FPG of -13 mg/dL was seen. Rescue therapy was used in 5.4% of patients treated with linagliptin 5 mg and in 13% of patients treated with placebo.
Change from baseline in body weight did not differ significantly between the groups. Table 11 Glycemic Parameters at Final Visit (24-Week Trial) for Linagliptin in Combination with Metformin and Sulfonylurea* Linagliptin 5 mg + Metformin + SU Placebo + Metformin + SU SU=sulfonylurea *Full analysis population using last observation on trial **Linagliptin 5 mg + Metformin + SU, n=742; Placebo + Metformin + SU, n=247 ***HbA1c: ANCOVA model included treatment as class-effects and baseline HbA1c as continuous covariates. FPG: ANCOVA model included treatment as class-effects, as well as baseline HbA1c and baseline FPG as continuous covariates.
A1C (%) Number of patients n=778 n=262 Baseline (mean) 8.2
Change from baseline (adjusted mean***) -0.7 -0.1 Difference from placebo (adjusted mean)
(95% CI) -0.6 (-0.7, -0.5) -- Patients achieving A1C <7%** 217 20 FPG (mg/dL) Number of patients n=739 n=248 Baseline (mean) 159 163 Change from baseline (adjusted mean***) -5 8 Difference from placebo (adjusted mean) (95% CI) -13 (-18, -7) --
Linagliptin Cardiovascular Safety Trials in Patients with Type 2 Diabetes Mellitus
CARMELINA The cardiovascular risk of linagliptin was evaluated in CARMELINA, a multi-national, multi-center, placebo-controlled, double-blind, parallel group trial comparing linagliptin (N=3,494) to placebo (N=3,485) in adult patients with type 2 diabetes mellitus and a history of established macrovascular and/or renal disease. The trial compared the risk of major adverse cardiovascular events (MACE) between linagliptin and placebo when these were added to standard of care treatments for diabetes mellitus and other cardiovascular risk factors. The trial was event driven, the median duration of follow-up was 2.2 years and vital status was obtained for 99.7% of patients.
Patients were eligible to enter the trial if they were adults with type 2 diabetes mellitus, with HbA1c of 6.5% to 10%, and had either albuminuria and previous macrovascular disease (39% of enrolled population), or evidence of impaired renal function by eGFR and Urinary Albumin Creatinine Ratio (UACR) criteria (42% of enrolled population), or both (18% of enrolled population). At baseline the mean age was 66 years and the population was 63% male, 80% White, 9% Asian, 6% Black or African American and 36% were of Hispanic or Latino ethnicity. Mean HbA1c was 8.0% and mean duration of type 2 diabetes mellitus was 15 years. The trial population included 17% patients ≥75 years of age and 62% patients with renal impairment defined as eGFR <60 mL/min/1.73 m 2. The mean eGFR was 55 mL/min/1.73 m 2 and 27% of patients had mild renal impairment (eGFR 60 to 90 mL/min/1.73 m 2 ), 47% of patients had moderate renal impairment (eGFR 30 to <60 mL/min/1.73 m 2 ) and 15% of patients had severe renal impairment (eGFR <30 mL/min/1.73 m 2 ). Patients were taking at least one antidiabetic drug (97%), and the most common were insulin and analogues (57%), metformin (54%) and sulfonylurea (32%). Patients were also taking antihypertensives (96%), lipid lowering drugs (76%) with 72% on statin, and aspirin (62%). The primary endpoint, MACE, was the time to first occurrence of one of three composite outcomes which included cardiovascular death, non-fatal myocardial infarction or non-fatal stroke.
The trial was designed as a non-inferiority trial with a pre-specified risk margin of 1.3 for the hazard ratio of MACE. The results of CARMELINA, including the contribution of each component to the primary composite endpoint, are shown in Table 12. The estimated hazard ratio for MACE associated with linagliptin relative to placebo was 1.02 with a 95% confidence interval of. The upper bound of this confidence interval, 1.17, excluded the risk margin of 1.3. The Kaplan-Meier curve depicting time to first occurrence of MACE is shown in Figure 2. Table 12 Major Adverse Cardiovascular Events (MACE) by Treatment Group in the CARMELINA Trial Linagliptin 5 mg n = 3,494 Placebo n = 3,485 Hazard Ratio Number of Subjects (%) Incidence Rate per 1,000 PY* Number of Subjects (%) Incidence Rate per 1,000 PY* (95% CI) *PY=patient years **A patient may have experienced more than one component; therefore, the sum of the components is larger than the number of patients who experienced the composite outcome. Composite of first event of CV death, non-fatal myocardial infarction (MI), or non-fatal stroke (MACE) 434 57.7 420 56.3 1.02 CV death** 255 32.6 264 34.0 0.96 Non-fatal MI** 156 20.6 135 18.0 1.15 Non-fatal stroke** 65 8.5 73 9.6 0.88 Figure 2 Kaplan-Meier: Time to First Occurrence of MACE in the CARMELINA Trial Figure 2 CAROLINA The cardiovascular risk of linagliptin was evaluated in CAROLINA, a multi-center, multi-national, randomized, double-blind parallel group trial comparing linagliptin (N=3,023) to glimepiride (N=3,010) in adult patients with type 2 diabetes mellitus and a history of established cardiovascular disease and/or multiple cardiovascular risk factors.
The trial compared the risk of major adverse cardiovascular events (MACE) between linagliptin and glimepiride when these were added to standard of care treatments for diabetes mellitus and other cardiovascular risk factors. The trial was event driven, the median duration of follow-up was 6.23 years and vital status was obtained for 99.3% of patients. Patients were eligible to enter the trial if they were adults with type 2 diabetes mellitus with insufficient glycemic control (defined as HbA1c of 6.5% to 8.5% or 6.5% to 7.5% depending on whether treatment-naïve, on monotherapy or on combination therapy), and were defined to be at high cardiovascular risk with previous vascular disease, evidence of vascular related end-organ damage, age ≥70 years, and/or two cardiovascular risk factors (duration of diabetes mellitus >10 years, systolic blood pressure >140 mmHg, current smoker, LDL cholesterol ≥135 mg/dL). At baseline, the mean age was 64 years and the population was 60% male, 73% White, 18% Asian, 5% Black or African American, and 17% were of Hispanic or Latino ethnicity.
The mean HbA1c was 7.15% and mean duration of type 2 diabetes was 7.6 years. The trial population included 34% patients ≥70 years of age and 19% patients with renal impairment defined as eGFR <60 mL/min/1.73m 2. The mean eGFR was 77 mL/min/1.73m 2. Patients were taking at least one antidiabetic drug (91%) and the most common were metformin (83%) and sulfonylurea (28%). Patients were also taking antihypertensives (89%), lipid lowering drugs (70%) with 65% on statin, and aspirin (47%). The primary endpoint, MACE, was the time to first occurrence of one of three composite outcomes which included cardiovascular death, non-fatal myocardial infarction or non-fatal stroke. The trial was designed as a non-inferiority trial with a pre-specified risk margin of 1.3 for the upper bound of the 95% CI for the hazard ratio of MACE. The results of CAROLINA, including the contribution of each component to the primary composite endpoint, are shown in Table 13. The Kaplan-Meier curve depicting time to first occurrence of MACE is shown in Figure 3. Table 13 Major Adverse Cardiovascular Events (MACE) by Treatment Group in the CAROLINA Trial Linagliptin 5 mg n=3,023 Glimepiride (1 mg to 4 mg) n=3,010 Hazard Ratio Number of Subjects (%) Incidence Rate per 1,000 PY* Number of Subjects (%) Incidence Rate per 1,000 PY* (95% CI) *PY=patient years **A patient may have experienced more than one component; therefore, the sum of the components is larger than the number of patients who experienced the composite outcome Composite of first event of CV death, non-fatal myocardial infarction (MI), or non-fatal stroke (MACE) 356 20.7 362 21.2 0.98 CV death** 169 9.2 168 9.2 1.00 Non-fatal MI** 145 8.3 142 8.2 1.01 Non-fatal stroke** 91 5.2 104 6.0 0.87 Figure 3 Time to First Occurrence of 3P-MACE in CAROLINA Figure 3
Drug information sourced from the FDA. This content is for informational purposes only and does not constitute medical advice. Consult a healthcare professional before making any medication decisions.
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