Table 2. Initial Therapy with Combination of Sitagliptin and Metformin: Adverse Reactions Reported (Regardless of Investigator Assessment of Causality) in ≥5% of Patients Receiving Combination Therapy (and Greater than in Patients Receiving Metformin alone, Sitagliptin alone, and Placebo)*


Number of Patients (%) Placebo N = 176 Upper


Respiratory Infection


Headache 9 (5.1) 5 (2.8)


*Intent-to-treat population. †


8 (4.5) 2 (1.1) 19 (5.2) 14 (3.8) Data pooled for the patients given the lower and higher doses of metformin.


In a 24-week study of initial therapy with JANUVIA in combination with pioglitazone, there were no adverse reactions reported (regardless of investigator assessment of causality) in ≥5% of patients and more commonly than in patients given pioglitazone alone.


No clinically meaningful changes in vital signs or in ECG (including in QTc interval) were observed in patients treated with JANUVIA.


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). [See Warnings and Precautions.]


Hypoglycemia. In the above studies (N=9), adverse reactions of hypoglycemia were based on all reports of symptomatic hypoglycemia. A concurrent blood glucose measurement was not required although most (74%) reports of hypoglycemia were accompanied by a blood glucose measurement ≤70 mg/dL. When JANUVIA was coadministered with a sulfonylurea or with insulin, the percentage of patients with at least one adverse reaction of hypoglycemia was higher than in the corresponding placebo group (Table 3).


Table 3. Incidence and Rate of Hypoglycemia* in Placebo-Controlled Clinical Studies when JANUVIA was used as Add-On Therapy to Glimepiride (with or without Metformin) or Insulin (with or without Metformin), Regardless of Investigator Assessment of Causality


Add-On to Glimepiride (+/- Metformin) (24 weeks)


Overall (%)


Rate (episodes/patient-year)† Severe (%)‡


Add-On to Insulin (+/- Metformin) (24 weeks)


Overall (%)


Rate (episodes/patient-year)† Severe (%)‡


JANUVIA 100 mg + Glimepiride (+/- Metformin)


N = 222 27 (12.2) 0.59


0 (0.0)


JANUVIA 100 mg + Insulin


(+/- Metformin) N = 322 50 (15.5) 1.06


2 (0.6) Placebo


+ Glimepiride (+/- Metformin)


N = 219 4 (1.8) 0.24


0 (0.0)


Placebo + Insulin


(+/- Metformin) N = 319 25 (7.8) 0.51


1 (0.3)


* Adverse reactions of hypoglycemia were based on all reports of symptomatic hypoglycemia; a concurrent glucose measurement was not required; intent-to-treat population. † Based on total number of events (i.e., a single patient may have had multiple events).


‡


Severe events of hypoglycemia were defined as those events requiring medical assistance or exhibiting depressed level/loss of consciousness or seizure.


In a pooled analysis of the two monotherapy studies, the add-on to metformin study, and the add-on to pioglitazone study, the overall incidence of adverse reactions of hypoglycemia was 1.2% in patients treated with JANUVIA 100 mg and 0.9% in patients treated with placebo.


In the study of JANUVIA as add-on combination therapy with metformin and rosiglitazone, the overall incidence of hypoglycemia was 2.2% in patients given add-on JANUVIA 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 JANUVIA and 1.0% in patients given add-on placebo.


In the 24-week, placebo-controlled factorial study of initial therapy with JANUVIA in combination with metformin, the incidence of hypoglycemia was 0.6% in patients given placebo, 0.6% in patients given JANUVIA alone, 0.8% in patients given metformin alone, and 1.6% in patients given JANUVIA in combination with metformin.


In the study of JANUVIA as initial therapy with pioglitazone, one patient taking JANUVIA experienced a severe episode of hypoglycemia. There were no severe hypoglycemia episodes reported in other studies except in the study involving coadministration with insulin.


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.


Laboratory Tests. Across clinical studies, the incidence of laboratory adverse reactions was similar in patients treated with JANUVIA 100 mg compared to patients treated with placebo. A small increase in white blood cell count (WBC) was observed due to an increase in neutrophils. This increase in WBC (of approximately 200 cells/microL vs placebo, in four pooled placebo- controlled clinical studies, with a mean baseline WBC count of approximately 6600 cells/microL) is not considered to be clinically relevant. In a 12-week study of 91 patients with chronic renal


23 (6.2) 22 (5.9) (JANUVIA®


Sitagliptin 100 mg QD


N = 179 [sitagliptin])


Metformin 500 or 1000 mg bid†


N = 364†


Sitagliptin 50 mg bid + Metformin


500 or 1000 mg bid† N = 372†


insufficiency, 37 patients with moderate renal insufficiency were randomized to JANUVIA 50 mg daily, while 14 patients with the same magnitude of renal impairment were randomized to placebo. Mean (SE) increases in serum creatinine were observed in patients treated with JANUVIA [0.12 mg/ dL (0.04)] and in patients treated with placebo [0.07 mg/dL (0.07)]. The clinical significance of this added increase in serum creatinine relative to placebo is not known.


Postmarketing Experience. Additional adverse reactions have been identified during postapproval use of JANUVIA as monotherapy and/or in combination with other antihyperglycemic agents. 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 [see Warnings and Precautions]; hepatic enzyme elevations; acute pancreatitis, including fatal and non-fatal hemorrhagic and necrotizing pancreatitis [see Indications and Usage; Warnings and Precautions]; worsening renal function, including acute renal failure (sometimes requiring dialysis) [see Warnings and Precautions]; severe and disabling arthralgia [see Warnings and Precautions]; bullous pemphigoid [see Warnings and Precautions]; constipation; vomiting; headache; myalgia; pain in extremity; back pain; pruritus; mouth ulceration; stomatitis; rhabdomyolysis.


DRUG INTERACTIONS


Digoxin. There was a slight increase in the area under the curve (AUC, 11%) and mean peak drug concentration (Cmax


, 18%) of digoxin with the coadministration of 100 mg sitagliptin for 10 days.


Patients receiving digoxin should be monitored appropriately. No dosage adjustment of digoxin or JANUVIA is recommended.


Insulin Secretagogues or Insulin. Coadministration of JANUVIA with an insulin secretagogue (e.g., sulfonylurea) or insulin may require lower doses of the insulin secretagogue or insulin to reduce the risk of hypoglycemia. [See Warnings and Precautions.]


USE IN SPECIFIC POPULATIONS


Pregnancy. Pregnancy Exposure Registry There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to JANUVIA during pregnancy. Health care providers are encouraged to report any prenatal exposure to JANUVIA by calling the Pregnancy Registry at 1-800-986-8999.


Risk Summary The limited available data with JANUVIA in pregnant women are not sufficient to inform a drug-associated risk for major birth defects and miscarriage. There are risks to the mother and fetus associated with poorly controlled diabetes in pregnancy [see Clinical Considerations]. 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 [see Data].


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 Animal Data 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.


Lactation. Risk Summary There is no information regarding the presence of JANUVIA in human milk, the effects on the breastfed infant, or the effects on milk production. Sitagliptin is present in rat milk and therefore possibly present in human milk [see Data]. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for JANUVIA and any potential adverse effects on the breastfed infant from JANUVIA or from the underlying maternal condition.


Data Sitagliptin is secreted in the milk of lactating rats at a milk to plasma ratio of 4:1.


Pediatric Use. Safety and effectiveness of JANUVIA in pediatric patients under 18 years of age have not been established.


Geriatric Use. 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.


Because sitagliptin is substantially excreted by the kidney, and because aging can be associated with reduced renal function, renal function should be assessed more frequently in elderly patients. [see Warnings and Precautions.]


Renal Impairment. Sitagliptin is excreted by the kidney, and sitagliptin exposure is increased in patients with renal impairment. Lower dosages are recommended in patients with eGFR less than 45 mL/min/1.73 m2


(moderate and severe renal impairment, as well as in ESRD patients requiring dialysis). [See Dosage and Administration.]


For more detailed information, please read the Prescribing Information. uspi-mk0431-t-1908r024 Revised: 08/2019


Copyright © 2020 Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc. All rights reserved.


US-DIA-01754 08/20


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