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Janumet XR

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Janumet XR

Janumet XR

Janumet XR Side Effects Center

Medical Editor: Charles Patrick Davis, MD, PhD

Janumet XR (sitagliptin and metformin HCl extended-release) is a combination of two drugs indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus when treatment with both sitagliptin and metformin extended release is appropriate. Janumet XR is not available as a generic drug. Most common adverse reactions associated with Janumet XR are diarrhea, upper respiratory tract infection, and headache.

Janumet XR has three strengths that come in tablets: 50/500, 50/1000 and 100/1000mg of sitagliptin/metformin HCl, respectively. The starting dose of Janumet XR should be individualized based on the patient's current regimen. Dosing may be adjusted based on effectiveness and tolerability while not exceeding the maximum recommended daily dose of 100 mg sitagliptin and 2000 mg metformin extended-release. Janumet XR should be taken once daily, preferably in the evening, with a gradual escalation in doses to reduce the gastrointestinal side effects due to metformin. Janumet XR should be swallowed whole, and should never be split, crushed, or chewed. Serious side effects include lactic acidosis, hypoglycemia, pancreatitis and impaired hepatic function. There are no adequate and well-controlled studies in pregnant women with Janumet XR or its individual components; therefore, the safety of Janumet XR in pregnant women is not known. Janumet XR should be used during pregnancy only if clearly needed. Women should alert their doctors if they are breastfeeding or plan to breastfeed. It is not known if Janumet XR will pass into breast milk. Safety and effectiveness of Janumet XR in the pediatric population has not been established.

Our Janumet XR to Side Effects Drug Center provides a comprehensive view of available drug information on the potential side effects when taking this medication.

This is not a complete list of side effects and others may occur. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

What is Prescribing information?

The FDA package insert formatted in easy-to-find categories for health professionals and clinicians.

Janumet XR FDA Prescribing Information: Side Effects
(Adverse Reactions)

SIDE EFFECTS

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.

Sitagliptin and Metformin Immediate-Release Co-administration in Patients with Type 2 Diabetes Inadequately Controlled on Diet and Exercise

Table 1 summarizes the most common ( ≥ 5% of patients) adverse reactions reported (regardless of investigator assessment of causality) in a 24-week placebo-controlled factorial study in which sitagliptin and metformin immediate-release were co-administered to patients with type 2 diabetes inadequately controlled on diet and exercise.

Table 1: Sitagliptin and Metformin Immediate-Release Co-administered to Patients with Type 2 Diabetes Inadequately Controlled on Diet and Exercise: Adverse Reactions Reported (Regardless of Investigator Assessment of Causality) in ≥ 5% of Patients Receiving Combination Therapy (and Greater than in Patients Receiving Placebo) *

  Number of Patients (%)
Placebo
N = 176
Sitagliptin 100 mg once daily
N = 179
Metformin Immediate-Release 500 mg or 1000 mg twice daily †
N = 364†
Sitagliptin 50 mg twice daily + Metformin Immediate-Release 500 mg or 1000 mg twice daily †
N = 372†
Diarrhea 7 (4.0) 5 (2.8) 28 (7.7) 28 (7.5)
Upper Respiratory Tract Infection 9 (5.1) 8 (4.5) 19 (5.2) 23 (6.2)
Headache 5 (2.8) 2 (1.1) 14 (3.8) 22 (5.9)
* Intent-to-treat population.
† Data pooled for the patients given the lower and higher doses of metformin.

Sitagliptin Add-on Therapy in Patients with Type 2 Diabetes Inadequately Controlled on Metformin Immediate-Release Alone

In a 24-week placebo-controlled trial of sitagliptin 100 mg administered once daily added to a twice daily metformin immediate-release regimen, there were no adverse reactions reported regardless of investigator assessment of causality in ≥ 5% of patients and more commonly than in patients given placebo. Discontinuation of therapy due to clinical adverse reactions was similar to the placebo treatment group (sitagliptin and metformin immediate-release, 1.9%; placebo and metformin immediate-release, 2.5%).

Gastrointestinal Adverse Reactions

The incidences of pre-selected gastrointestinal adverse experiences in patients treated with sitagliptin and metformin immediate-release were similar to those reported for patients treated with metformin immediate-release alone. See Table 2.

Table 2: Pre-selected Gastrointestinal Adverse Reactions (Regardless of Investigator Assessment of Causality) Reported in Patients with Type 2 Diabetes Receiving Sitagliptin and Metformin Immediate-Release

  Number of Patients (%)
Study of Sitagliptin and Metformin Immediate-Release in Patients Inadequately Controlled on Diet and Exercise Study of Sitagliptin Add-on in Patients Inadequately Controlled on Metformin Immediate-Release Alone
Placebo
N = 176
Sitagliptin 100 mg once daily
N = 179
Metformin Immediate-Release 500 mg or 1000 mg twice daily *
N = 364
Sitagliptin 50 mg bid + Metformin Immediate-Release 500 mg or 1000 mg twice daily *
N = 372
Placebo and Metformin Immediate-Release ≥ 1500 mg daily
N = 237
Sitagliptin 100 mg once daily and Metformin Immediate-Release ≥ 1500 mg daily
N = 464
Diarrhea 7 (4.0) 5 (2.8) 28 (7.7) 28 (7.5) 6 (2.5) 11 (2.4)
Nausea 2 (1.1) 2 (1.1) 20 (5.5) 18 (4.8) 2 (0.8) 6 (1.3)
Vomiting 1 (0.6) 0 (0.0) 2 (0.5) 8 (2.2) 2 (0.8) 5 (1.1)
Abdominal Pain† 4 (2.3) 6 (3.4) 14 (3.8) 11 (3.0) 9 (3.8) 10 (2.2)
* Data pooled for the patients given the lower and higher doses of metformin.
† Abdominal discomfort was included in the analysis of abdominal pain in the study of initial therapy.

Sitagliptin in Combination with Metformin Immediate-Release and Glimepiride

In a 24-week placebo-controlled study of sitagliptin 100 mg as add-on therapy in patients with type 2 diabetes inadequately controlled on metformin immediate-release and glimepiride (sitagliptin, N=116; placebo, N=113), the adverse reactions reported regardless of investigator assessment of causality in ≥ 5% of patients treated with sitagliptin and more commonly than in patients treated with placebo were: hypoglycemia (Table 3) and headache (6.9%, 2.7%).

Sitagliptin in Combination with Metformin Immediate-Release and Rosiglitazone

In a placebo-controlled study of sitagliptin 100 mg as add-on therapy in patients with type 2 diabetes inadequately controlled on metformin immediate-release and rosiglitazone (sitagliptin, N=181; placebo, N=97), the adverse reactions reported regardless of investigator assessment of causality through Week 18 in ≥ 5% of patients treated with sitagliptin and more commonly than in patients treated with placebo were: upper respiratory tract infection (sitagliptin, 5.5%; placebo, 5.2%) and nasopharyngitis (6.1%, 4.1%). Through Week 54, the adverse reactions reported regardless of investigator assessment of causality in ≥ 5% of patients treated with sitagliptin and more commonly than in patients treated with placebo were: upper respiratory tract infection (sitagliptin, 15.5%; placebo, 6.2%), nasopharyngitis (11.0%, 9.3%), peripheral edema (8.3%, 5.2%), and headache (5.5%, 4.1%).

Sitagliptin in Combination with Metformin Immediate-Release and Insulin

In a 24-week placebo-controlled study of sitagliptin 100 mg as add-on therapy in patients with type 2 diabetes inadequately controlled on metformin immediate-release and insulin (sitagliptin, N=229; placebo, N=233), the only adverse reaction reported regardless of investigator assessment of causality in ≥ 5% of patients treated with sitagliptin and more commonly than in patients treated with placebo was hypoglycemia (Table 3).

Hypoglycemia

In all (N=5) studies, adverse reactions of hypoglycemia were based on all reports of symptomatic hypoglycemia; a concurrent glucose measurement was not required although most (77%) reports of hypoglycemia were accompanied by a blood glucose measurement ≤ 70 mg/dL. When the combination of sitagliptin and metformin immediate-release was co-administered with a sulfonylurea or with insulin, the percentage of patients reporting at least one adverse reaction of hypoglycemia was higher than that observed with placebo and metformin immediate-release co-administered with a sulfonylurea or with insulin (Table 3).

Table 3: Incidence and Rate of Hypoglycemia* (Regardless of Investigator Assessment of Causality) in Placebo-Controlled Clinical Studies of Sitagliptin in Combination with Metformin Immediate-Release Co-administered with Glimepiride or Insulin

Add-On to Glimepiride + Metformin Immediate-Release (24 weeks) Sitagliptin 100 mg + Metformin Immediate-Release + Glimepiride Placebo + Metformin Immediate-Release + Glimepiride
  N = 116 N = 113
  Overall (%) 19 (16.4) 1 (0.9)
  Rate (episodes/patient-year) † 0.82 0.02
  Severe (%)‡ 0 (0.0) 0 (0.0)
Add-On to Insulin + Metformin Immediate-Release (24 weeks) Sitagliptin 100 mg + Metformin Immediate-Release + Insulin Placebo + Metformin Immediate-Release + Insulin
  N = 229 N = 233
  Overall (%) 35 (15.3) 19 (8.2)
  Rate (episodes/patient-year) † 0.98 0.61
  Severe (%)‡ 1 (0.4) 1 (0.4)
* 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.

The overall incidence of reported adverse reactions of hypoglycemia in patients with type 2 diabetes inadequately controlled on diet and exercise was 0.6% in patients given placebo, 0.6% in patients given sitagliptin alone, 0.8% in patients given metformin immediate-release alone, and 1.6% in patients given sitagliptin in combination with metformin immediate-release. In patients with type 2 diabetes inadequately controlled on metformin immediate-release alone, the overall incidence of adverse reactions of hypoglycemia was 1.3% in patients given add-on sitagliptin and 2.1% in patients given add-on placebo.

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

Vital Signs and Electrocardiograms

With the combination of sitagliptin and metformin immediate-release, no clinically meaningful changes in vital signs or in electrocardiogram parameters (including the QTc interval) were observed.

Pancreatitis

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]

Sitagliptin

The most common adverse experience in sitagliptin monotherapy reported regardless of investigator assessment of causality in ≥ 5% of patients and more commonly than in patients given placebo was nasopharyngitis.

Metformin Extended-Release

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%).

Laboratory Tests

Sitagliptin

The incidence of laboratory adverse reactions was similar in patients treated with sitagliptin and metformin immediate-release (7.6%) compared to patients treated with placebo and metformin (8.7%). In most but not all studies, a small increase in white blood cell count (approximately 200 cells/microL difference in WBC vs. placebo; mean baseline WBC approximately 6600 cells/microL) was observed due to a small increase in neutrophils. This change in laboratory parameters is not considered to be clinically relevant.

Metformin hydrochloride

In controlled clinical trials of metformin of 29 weeks duration, a decrease to subnormal levels of previously normal serum Vitamin B12 levels, without clinical manifestations, was observed in approximately 7% of patients. Such decrease, possibly due to interference with B12 absorption from the B12-intrinsic factor complex, is, however, very rarely associated with anemia and appears to be rapidly reversible with discontinuation of metformin or Vitamin B12 supplementation. [See WARNINGS AND PRECAUTIONS]

Postmarketing Experience

Additional adverse reactions have been identified during postapproval use of sitagliptin with or without metformin, and/or in combination with other antidiabetic medications. 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]; upper respiratory tract infection; 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]; constipation; vomiting; headache; arthralgia; myalgia; pain in extremity; back pain.

Read the entire FDA prescribing information for Janumet XR (Sitagliptin and Metformin HCl) »

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