"The US Food and Drug Administration (FDA) has approved a once-daily oral combination of linagliptin and metformin hydrochloride (Jentadueto XR, Boehringer Ingelheim and Eli Lilly & Co) for treating adults with type 2 diabetes."...
There have been postmarketing reports of acute pancreatitis, including fatal and non-fatal hemorrhagic or necrotizing pancreatitis, in patients taking JANUVIA. After initiation of JANUVIA, patients should be observed carefully for signs and symptoms of pancreatitis. If pancreatitis is suspected, JANUVIA should promptly be discontinued and appropriate management should be initiated. It is unknown whether patients with a history of pancreatitis are at increased risk for the development of pancreatitis while using JANUVIA.
Assessment of renal function is recommended prior to initiating JANUVIA and periodically thereafter. A dosage adjustment is recommended in patients with moderate or severe renal insufficiency and in patients with ESRD requiring hemodialysis or peritoneal dialysis. [See DOSAGE AND ADMINISTRATION; CLINICAL PHARMACOLOGY] Caution should be used to ensure that the correct dose of JANUVIA is prescribed for patients with moderate (creatinine clearance ≥ 30 to <50 mL/min) or severe (creatinine clearance <30 mL/min) renal impairment.
There have been postmarketing reports of worsening renal function, including acute renal failure, sometimes requiring dialysis. A subset of these reports involved patients with renal insufficiency, some of whom were prescribed inappropriate doses of sitagliptin. A return to baseline levels of renal insufficiency has been observed with supportive treatment and discontinuation of potentially causative agents. Consideration can be given to cautiously reinitiating JANUVIA if another etiology is deemed likely to have precipitated the acute worsening of renal function.
JANUVIA has not been found to be nephrotoxic in preclinical studies at clinically relevant doses, or in clinical trials.
Use With Medications Known To Cause Hypoglycemia
When JANUVIA was used in combination with a sulfonylurea or with insulin, medications known to cause hypoglycemia, the incidence of hypoglycemia was increased over that of placebo used in combination with a sulfonylurea or with insulin. [See ADVERSE REACTIONS] Therefore, a lower dose of sulfonylurea or insulin may be required to reduce the risk of hypoglycemia. [See DOSAGE AND ADMINISTRATION]
There have been postmarketing reports of serious hypersensitivity reactions in patients treated with JANUVIA. These reactions include anaphylaxis, angioedema, and exfoliative skin conditions including Stevens-Johnson syndrome. Onset of these reactions occurred within the first 3 months after initiation of treatment with JANUVIA, with some reports occurring after the first dose. If a hypersensitivity reaction is suspected, discontinue JANUVIA, assess for other potential causes for the event, and institute alternative treatment for diabetes. [See ADVERSE REACTIONS]
Angioedema has also been reported with other dipeptidyl peptidase-4 (DPP-4) inhibitors. Use caution in a patient with a history of angioedema with another DPP-4 inhibitor because it is unknown whether such patients will be predisposed to angioedema with JANUVIA.
There have been no clinical studies establishing conclusive evidence of macrovascular risk reduction with JANUVIA or any other anti-diabetic drug.
Patient Counseling Information
See FDA-Approved Patient Labeling (Medication Guide).
Patients should be informed of the potential risks and benefits of JANUVIA and of alternative modes of therapy. Patients should also be informed about the importance of adherence to dietary instructions, regular physical activity, periodic blood glucose monitoring and A1C testing, recognition and management of hypoglycemia and hyperglycemia, and assessment for diabetes complications. During periods of stress such as fever, trauma, infection, or surgery, medication requirements may change and patients should be advised to seek medical advice promptly.
Patients should be informed that acute pancreatitis has been reported during postmarketing use of JANUVIA. Patients should be informed that persistent severe abdominal pain, sometimes radiating to the back, which may or may not be accompanied by vomiting, is the hallmark symptom of acute pancreatitis. Patients should be instructed to promptly discontinue JANUVIA and contact their physician if persistent severe abdominal pain occurs [see WARNINGS AND PRECAUTIONS].
Patients should be informed that the incidence of hypoglycemia is increased when JANUVIA is added to a sulfonylurea or insulin and that a lower dose of the sulfonylurea or insulin may be required to reduce the risk of hypoglycemia.
Patients should be informed that allergic reactions have been reported during postmarketing use of JANUVIA. If symptoms of allergic reactions (including rash, hives, and swelling of the face, lips, tongue, and throat that may cause difficulty in breathing or swallowing) occur, patients must stop taking JANUVIA and seek medical advice promptly.
Physicians should instruct their patients to read the Medication Guide before starting JANUVIA therapy and to reread each time the prescription is renewed. Patients should be instructed to inform their doctor or pharmacist if they develop any unusual symptom, or if any known symptom persists or worsens.
Patients should be informed that response to all diabetic therapies should be monitored by periodic measurements of blood glucose and A1C levels, with a goal of decreasing these levels towards the normal range. A1C is especially useful for evaluating long-term glycemic control. Patients should be informed of the potential need to adjust dose based on changes in renal function tests over time.
Carcinogenesis, Mutagenesis, Impairment Of Fertility
A two-year carcinogenicity study was conducted in male and female rats given oral doses of sitagliptin of 50, 150, and 500 mg/kg/day. There was an increased incidence of combined liver adenoma/carcinoma in males and females and of liver carcinoma in females at 500 mg/kg. This dose results in exposures approximately 60 times the human exposure at the maximum recommended daily adult human dose (MRHD) of 100 mg/day based on AUC comparisons. Liver tumors were not observed at 150 mg/kg, approximately 20 times the human exposure at the MRHD. A two-year carcinogenicity study was conducted in male and female mice given oral doses of sitagliptin of 50, 125, 250, and 500 mg/kg/day. There was no increase in the incidence of tumors in any organ up to 500 mg/kg, approximately 70 times human exposure at the MRHD. Sitagliptin was not mutagenic or clastogenic with or without metabolic activation in the Ames bacterial mutagenicity assay, a Chinese hamster ovary (CHO) chromosome aberration assay, an in vitro cytogenetics assay in CHO, an in vitro rat hepatocyte DNA alkaline elution assay, and an in vivo micronucleus assay.
In rat fertility studies with oral gavage doses of 125, 250, and 1000 mg/kg, males were treated for 4 weeks prior to mating, during mating, up to scheduled termination (approximately 8 weeks total) and females were treated 2 weeks prior to mating through gestation day 7. No adverse effect on fertility was observed at 125 mg/kg (approximately 12 times human exposure at the MRHD of 100 mg/day based on AUC comparisons). At higher doses, nondose-related increased resorptions in females were observed (approximately 25 and 100 times human exposure at the MRHD based on AUC comparison).
Use In Specific Populations
Pregnancy Category B
Reproduction studies have been performed in rats and rabbits. Doses of sitagliptin up to 125 mg/kg (approximately 12 times the human exposure at the maximum recommended human dose) did not impair fertility or harm the fetus. There are, however, no adequate and well-controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human response, this drug should be used during pregnancy only if clearly needed. Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., maintains a registry to monitor the pregnancy outcomes of women exposed to JANUVIA while pregnant. Health care providers are encouraged to report any prenatal exposure to JANUVIA by calling the Pregnancy Registry at 1-800-986-8999.
Sitagliptin administered to pregnant female rats and rabbits from gestation day 6 to 20 (organogenesis) was not teratogenic at oral doses up to 250 mg/kg (rats) and 125 mg/kg (rabbits), or approximately 30-and 20-times human exposure at the maximum recommended human dose (MRHD) of 100 mg/day based on AUC comparisons. Higher doses increased the incidence of rib malformations in offspring at 1000 mg/kg, or approximately 100 times human exposure at the MRHD.
Sitagliptin administered to female rats from gestation day 6 to lactation day 21 decreased body weight in male and female offspring at 1000 mg/kg. No functional or behavioral toxicity was observed in offspring of rats.
Placental transfer of sitagliptin administered to pregnant rats was approximately 45% at 2 hours and 80% at 24 hours postdose. Placental transfer of sitagliptin administered to pregnant rabbits was approximately 66% at 2 hours and 30% at 24 hours.
Sitagliptin is secreted in the milk of lactating rats at a milk to plasma ratio of 4:1. It is not known whether sitagliptin is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when JANUVIA is administered to a nursing woman.
Safety and effectiveness of JANUVIA in pediatric patients under 18 years of age have not been established.
Of the total number of subjects (N=3884) in pre-approval clinical safety and efficacy studies of JANUVIA, 725 patients were 65 years and over, while 61 patients were 75 years and over. No overall differences in safety or effectiveness were observed between subjects 65 years and over and younger subjects. While this and other reported clinical experience have not identified differences in responses between the elderly and younger patients, greater sensitivity of some older individuals cannot be ruled out.
This drug is known to be substantially excreted by the kidney. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection in the elderly, and it may be useful to assess renal function in these patients prior to initiating dosing and periodically thereafter [see DOSAGE AND ADMINISTRATION; CLINICAL PHARMACOLOGY].This monograph has been modified to include the generic and brand name in many instances.
Last reviewed on RxList: 3/27/2015
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