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Janumet (Sitagliptin / Metformin Hydrochloride) - Side Effects and Adverse Reactions

 
 



ADVERSE REACTIONS

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 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 were co-administered to patients with type 2 diabetes inadequately controlled on diet and exercise.

 

Table 1: Sitagliptin and Metformin 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) 1
Number of Patients (%)

Placebo

Sitagliptin

100 mg QD

Metformin 500 mg/

Metformin 1000 mg bid 2

Sitagliptin

50 mg bid +

Metformin 500 mg/

Metformin 1000 mg bid

N = 176 N = 179 N = 364 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)

1 Intent-to-treat population.
2 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 Alone

In a 24-week placebo-controlled trial of sitagliptin 100 mg administered once daily added to a twice daily metformin 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, 1.9%; placebo and metformin, 2.5%).

Gastrointestinal Adverse Reactions

The incidences of pre-selected gastrointestinal adverse experiences in patients treated with sitagliptin and metformin were similar to those reported for patients treated with metformin 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
Number of Patients (%)
Study of Sitagliptin and Metformin in Patients Inadequately Controlled on Diet and Exercise Study of Sitagliptin Add-on in Patients Inadequately Controlled on Metformin Alone

Placebo

Sitagliptin

100 mg QD

Metformin 500 mg/

Metformin 1000 mg bid 1

Sitagliptin

50 mg bid +

Metformin 500 mg/

Metformin 1000 mg bid

Placebo and Metformin

≥1500 mg daily

Sitagliptin 100 mg QD and Metformin

≥1500 mg daily

N = 176 N = 179 N = 364 N = 372 N = 237 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 2 4 (2.3) 6 (3.4) 14 (3.8) 11 (3.0) 9 (3.8) 10 (2.2)

1 Data pooled for the patients given the lower and higher doses of metformin.
2 Abdominal discomfort was included in the analysis of abdominal pain in the study of initial therapy.

Sitagliptin in Combination with Metformin 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 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 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 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 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 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 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 co-administered with a sulfonylurea or with insulin (Table 3).

Table 3: Incidence and Rate of Hypoglycemia 1 (Regardless of Investigator Assessment of Causality) in Placebo-Controlled Clinical Studies of Sitagliptin in Combination with Metformin Co-administered with Glimepiride or Insulin
Add-On to Glimepiride +
    Metformin
(24 weeks)

Sitagliptin 100 mg

+ Metformin

+ Glimepiride

Placebo

+ Metformin

+ Glimepiride

N = 116 N = 113
    Overall (%) 19 (16.4) 1 (0.9)
    Rate (episodes/patient-year) 2 0.82 0.02
    Severe (%) 3 0 (0.0) 0 (0.0)
Add-On to Insulin
    + Metformin
(24 weeks)

Sitagliptin 100 mg

+ Metformin

+ Insulin

Placebo

+ Metformin

+ 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)

1 Adverse reactions of hypoglycemia were based on all reports of symptomatic hypoglycemia; a concurrent glucose measurement was not required: Intent-to-treat population.
2 Based on total number of events (i.e., a single patient may have had multiple events).
3 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 alone, and 1.6% in patients given sitagliptin in combination with metformin. In patients with type 2 diabetes inadequately controlled on metformin 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 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.

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

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.]

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.

The most common (>5%) established adverse reactions due to initiation of metformin therapy are diarrhea, nausea/vomiting, flatulence, abdominal discomfort, indigestion, asthenia, and headache.

Laboratory Tests

Sitagliptin

The incidence of laboratory adverse reactions was similar in patients treated with sitagliptin and metformin (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 JANUMET or sitagliptin, one of the components of JANUMET. These reactions have been reported when JANUMET or sitagliptin have been used alone 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]; 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.



REPORTS OF SUSPECTED JANUMET SIDE EFFECTS / ADVERSE REACTIONS

Below is a sample of reports where side effects / adverse reactions may be related to Janumet. The information is not vetted and should not be considered as verified clinical evidence.

Possible Janumet side effects / adverse reactions in 76 year old male

Reported by a physician from France on 2011-08-02

Patient: 76 year old male weighing 90.0 kg (198.0 pounds)

Reactions: Dehydration, Renal Failure Acute

Adverse event resulted in: hospitalization

Suspect drug(s):
Amlodipine Besylate and Perindopril Arginine
    Administration route: Oral
    Indication: Hypertension
    Start date: 2010-03-02
    End date: 2011-07-04

Janumet
    Administration route: Oral
    Indication: Type 2 Diabetes Mellitus
    Start date: 2010-01-14



Possible Janumet side effects / adverse reactions in 69 year old female

Reported by a health professional (non-physician/pharmacist) from United States on 2011-10-10

Patient: 69 year old female

Reactions: Polymyalgia Rheumatica, Weight Decreased, Vitamin B12 Decreased, Blood Magnesium Decreased, Blood Calcium Decreased, Malaise, Dizziness, Decreased Appetite, White Blood Cell Count Increased, Vomiting, Nausea, Cystitis, Tremor, Blood Potassium Decreased, Vitamin D Decreased, Dehydration

Adverse event resulted in: hospitalization

Suspect drug(s):
Janumet

Other drugs received by patient: Metformin



Possible Janumet side effects / adverse reactions in 84 year old female

Reported by a physician from France on 2011-10-11

Patient: 84 year old female

Reactions: Drug Ineffective, Femoral Neck Fracture, Fall

Adverse event resulted in: hospitalization

Suspect drug(s):
Janumet



See index of all Janumet side effect reports >>

Drug label data at the top of this Page last updated: 2012-03-09

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