The safety of concomitantly administered linagliptin and metformin has been evaluated in
more than 2800 patients with type 2 diabetes mellitus treated for >12 weeks in clinical trials1,2
- 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.
- Adverse reactions reported in ≥2% of patients treated with linagliptin 5 mg and more commonly than in patients with placebo included: nasopharyngitis (7.0% vs 6.1%), diarrhea (3.3% vs 3.0%), and cough (2.1% vs 1.4%).
- In the clinical trial program, pancreatitis was reported in 15.2 cases per 10,000 patient-years of exposure while being treated with linagliptin compared with 3.7 cases per 10,000 patient-years of 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.
- The most common adverse reactions due to initiation of metformin are diarrhea, nausea/vomiting, flatulence, asthenia, indigestion, abdominal discomfort, and headache.
- Long-term treatment with metformin has been associated with a decrease in vitamin B12 absorption, which may very rarely result in clinically significant vitamin B12 deficiency (e.g., megaloblastic anemia).
- In a 24-week factorial-design study, 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.
- When linagliptin was administered in combination with metformin and a sulfonylurea, 181 (22.9%) of 792 patients reported hypoglycemia compared with 39 (14.8%) of 263 patients administered placebo in combination with metformin and sulfonylurea.
- In the study of patients receiving linagliptin as add-on therapy to a stable dose of insulin for up to 52 weeks, no significant difference in the incidence of investigator-reported hypoglycemia was noted compared with placebo (31.4% vs 32.9%, respectively).
- In a study of linagliptin compared with placebo as add-on to pre-existing antidiabetic therapy in patients with severe renal impairment, the incidence of hypoglycemia was higher in patients treated with linagliptin (63%) vs in patients treated with placebo (49%). Severe hypoglycemic events were reported in 4.4% of patients treated with linagliptin vs 4.6% of patients treated with placebo in this trial.
- Changes in laboratory findings were similar in patients treated with linagliptin/metformin compared to patients treated with placebo plus metformin.
- Changes in laboratory values that occurred more frequently in the linagliptin/metformin group and ≥1% more than in the placebo group were not detected.
- No clinically meaningful changes in vital signs were observed in patients treated with linagliptin.
INDICATION AND IMPORTANT LIMITATIONS OF USE
JENTADUETO and JENTADUETO XR tablets are indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus when treatment with both linagliptin and metformin is appropriate.
JENTADUETO and JENTADUETO XR should not be used in patients with type 1 diabetes or for the treatment of diabetic ketoacidosis.
JENTADUETO and JENTADUETO XR have not been studied in patients with a history of pancreatitis, and it is unknown if using JENTADUETO or JENTADUETO XR increases the risk of developing pancreatitis in these patients.
IMPORTANT SAFETY INFORMATION
WARNING: LACTIC ACIDOSIS
Postmarketing cases of metformin-associated lactic acidosis have resulted in death, hypothermia, hypotension, and resistant bradyarrhythmias. Symptoms included malaise, myalgias, respiratory distress, somnolence, and abdominal pain. Laboratory abnormalities included elevated blood lactate levels, anion gap acidosis, increased lactate/pyruvate ratio; and metformin plasma levels generally >5 mcg/mL.
Risk factors include renal impairment, concomitant use of certain drugs, age ≥ 65 years old, radiological studies with contrast, surgery and other procedures, hypoxic states, excessive alcohol intake, and hepatic impairment. Steps to reduce the risk of and manage metformin-associated lactic acidosis in these high risk groups are provided in the Full Prescribing Information.
If lactic acidosis is suspected, discontinue JENTADUETO or JENTADUETO XR and institute general supportive measures in a hospital setting. Prompt hemodialysis is recommended.
JENTADUETO and JENTADUETO XR are contraindicated in patients with:
- Severe renal impairment (eGFR below 30 mL/min/1.73 m2).
- Acute or chronic metabolic acidosis, including diabetic ketoacidosis.
- A history of hypersensitivity reaction to linagliptin, such as anaphylaxis, angioedema, exfoliative skin conditions, urticaria, or bronchial hyperreactivity.
- Hypersensitivity to metformin.
WARNINGS AND PRECAUTIONS
There have been 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.
If lactic acidosis is suspected, immediately discontinue JENTADUETO or JENTADUETO XR and institute general supportive measures promptly in a hospital setting. Prompt hemodialysis is recommended to correct the acidosis.
Educate patients and their families about the symptoms of lactic acidosis and if these symptoms occur instruct them to discontinue JENTADUETO or JENTADUETO XR and promptly notify their healthcare provider.
Risk factors for lactic acidosis and recommendations to reduce the risk include:
- Renal Impairment: Metformin-associated lactic acidosis cases primarily occurred in patients with significant renal impairment. Obtain eGFR prior to initiating and annually or more frequently in patients at increased risk of developing renal impairment.
- Drug Interactions: Consider more frequent monitoring when JENTADUETO or JENTADUETO XR is administered with drugs that impair renal function, result in hemodynamic change, interfere with acid-base balance, or increase metformin accumulation.
- Age 65 or Greater: Assess renal function more frequently in elderly patients.
- Radiological Studies with Contrast: Stop JENTADUETO or 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 m2; in patients with a history of hepatic impairment, alcoholism, or heart failure; or in patients who will be administered intra-arterial iodinated contrast. Re-evaluate eGFR 48 hours after the imaging procedure, and restart JENTADUETO or JENTADUETO XR if renal function is stable.
- Surgery and Other Procedures: Discontinue JENTADUETO or JENTADUETO XR while patients have restricted food and fluid intake during surgical or other procedures.
- Hypoxic States: Discontinue JENTADUETO or JENTADUETO XR in conditions associated with hypoxemia.
- Excessive Alcohol Intake: Warn patients against excessive alcohol intake while taking JENTADUETO or JENTADUETO XR.
- Hepatic Impairment: Avoid use of JENTADUETO or JENTADUETO XR in patients with hepatic disease.
There have been reports of acute pancreatitis, including fatal pancreatitis, in patients taking linagliptin. Take careful notice of potential signs and symptoms of pancreatitis. If pancreatitis is suspected, promptly discontinue JENTADUETO or 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 or JENTADUETO XR.
Use with Medications Known to Cause Hypoglycemia
Insulin secretagogues and insulin are known to cause hypoglycemia. The use of linagliptin in combination with an insulin secretagogue (e.g., sulfonylurea) was associated with a higher rate of hypoglycemia compared with placebo in a clinical trial. A lower dose of the insulin secretagogue or insulin may be required to reduce the risk of hypoglycemia when used in combination with JENTADUETO or JENTADUETO XR.
There have been reports of serious hypersensitivity reactions in patients treated with linagliptin (one of the components of JENTADUETO or JENTADUETO XR). These reactions include anaphylaxis, angioedema, and exfoliative skin conditions. Onset of these reactions occurred 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 or JENTADUETO XR, assess for other potential causes for the event, and institute alternative treatment for diabetes.
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 or JENTADUETO XR.
Vitamin B12 Levels
Vitamin B12 deficiency: Metformin may lower Vitamin B12 levels. Monitor hematologic parameters annually.
Severe and Disabling Arthralgia
Severe and disabling arthralgia has been reported in patients taking DPP-4 inhibitors. Consider as a possible cause for severe joint pain and discontinue drug if appropriate.
There have been reports of bullous pemphigoid requiring hospitalization in patients taking DPP-4 inhibitors. Tell patients to report development of blisters or erosions. If bullous pemphigoid is suspected, discontinue JENTADUETO or JENTADUETO XR.
There have been no clinical studies establishing conclusive evidence of macrovascular risk reduction with linagliptin or metformin.
- In a 24-week factorial design study, adverse reactions reported in ≥5% of patients treated with JENTADUETO and more commonly than in patients treated with placebo were nasopharyngitis and diarrhea.
- In a 24-week factorial design study, 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. In the placebo-controlled studies, hypoglycemia was more commonly reported in patients treated with the combination of linagliptin and metformin with SU (22.9%) compared with those treated with the combination of placebo and metformin with SU (14.8%).
- In the clinical trial program, pancreatitis was reported in 15.2 cases per 10,000 patient-years exposure while being treated with linagliptin compared with 3.7 cases per 10,000 patient-years 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.
Carbonic Anhydrase Inhibitors: The concomitant use of carbonic anhydrase inhibitors (e.g. topiramate) and metformin may increase the risk of lactic acidosis. Consider more frequent monitoring.
Drugs that Reduce Metformin Clearance: Drugs that are eliminated by renal tubular secretion (such as ranolazine, vandetanib, dolutegravir, and cimetidine) could increase the risk for lactic acidosis. Consider more frequent monitoring.
Alcohol: Alcohol is known to potentiate the effect of metformin on lactate metabolism. Warn patients against excessive alcohol intake while taking JENTADUETO or JENTADUETO XR.
Inducers of P-glycoprotein and CYP3A4 Enzymes: The efficacy of JENTADUETO or JENTADUETO XR may be reduced when administered in combination with a strong P-glycoprotein inducer or CYP3A4 inducer (e.g. rifampin). Use of alternative treatments is strongly recommended.
USE IN SPECIFIC POPULATIONS
- There are no adequate and well-controlled studies of JENTADUETO or JENTADUETO XR in pregnant women. JENTADUETO or JENTADUETO XR should be used during pregnancy only if clearly needed.
- It is not known whether linagliptin is excreted in human milk. Metformin is excreted in human milk in low concentrations. Consider the benefits of breastfeeding along with the mother’s clinical need for JENTADUETO or JENTADUETO XR and any potential adverse effects on the breastfed child from JENTADUETO or JENTADUETO XR or from the mother’s underlying condition.
- Discuss the potential for unintended pregnancy with premenopausal women as therapy with metformin may result in ovulation in some anovulatory women.
- The safety and effectiveness of JENTADUETO or JENTADUETO XR in patients under the age of 18 has not been established.
- JENTADUETO or JENTADUETO XR should be used with caution as age increases, as aging can be associated with reduced renal function.
JDJDXR PROF ISI 22MAR2017
Please see Prescribing Information for JENTADUETO, including Boxed Warning regarding risk of lactic acidosis and Medication Guide.
Please see Prescribing Information for JENTADUETO XR, including Boxed Warning regarding risk of lactic acidosis and Medication Guide.