Januvia (Sitagliptin) - 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.

In controlled clinical studies as both monotherapy and combination therapy with metformin or pioglitazone, the overall incidence of adverse reactions, hypoglycemia, and discontinuation of therapy due to clinical adverse reactions with JANUVIA were similar to placebo. In combination with glimepiride, with or without metformin, the overall incidence of clinical adverse reactions with JANUVIA was higher than with placebo, in part related to a higher incidence of hypoglycemia (see Table 1); the incidence of discontinuation due to clinical adverse reactions was similar to placebo.

Two placebo-controlled monotherapy studies, one of 18- and one of 24-week duration, included patients treated with JANUVIA 100 mg daily, JANUVIA 200 mg daily, and placebo. Three 24-week, placebo-controlled add-on combination therapy studies, one with metformin, one with pioglitazone, and one with glimepiride with or without metformin, were also conducted. In addition to a stable dose of metformin, pioglitazone, glimepiride, or glimepiride and metformin, patients whose diabetes was not adequately controlled were given either JANUVIA 100 mg daily or placebo. The adverse reactions, reported regardless of investigator assessment of causality in ≥5% of patients treated with JANUVIA 100 mg daily as monotherapy, JANUVIA in combination with pioglitazone, or JANUVIA in combination with glimepiride, with or without metformin, and more commonly than in patients treated with placebo, are shown in Table 1.

Table 1: Placebo-Controlled Clinical Studies of JANUVIA Monotherapy or Add-on Combination Therapy with Pioglitazone or Glimepiride +/- Metformin: Adverse Reactions Reported in ≥5% of Patients and More Commonly than in Patients Given Placebo, Regardless of Investigator Assessment of Causality ¹

	Number of Patients (%)
Monotherapy	JANUVIA 100 mg	Placebo
	N = 443	N = 363
Nasopharyngitis	23 (5.2)	12 (3.3)
Combination with Pioglitazone	JANUVIA 100 mg + Pioglitazone	Placebo + Pioglitazone
	N = 175	N = 178
Upper Respiratory Tract Infection	11 (6.3)	6 (3.4)
Headache	9 (5.1)	7 (3.9)
Combination with Glimepiride   (+/- metformin)	JANUVIA 100 mg + Glimepiride (+/- Metformin)	Placebo + Glimepiride (+/- Metformin)
	N = 222	N = 219
Hypoglycemia	27 (12.2)	4 (1.8)
Nasopharyngitis	14 (6.3)	10 (4.6)
Headache	13 (5.9)	5 (2.3)

In the study of patients receiving JANUVIA as add-on combination therapy with metformin, there were no adverse reactions reported regardless of investigator assessment of causality in ≥5% of patients and more commonly than in patients given placebo.

In the prespecified 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 in patients treated with JANUVIA 100 mg was similar to placebo (1.2% vs 0.9%). Adverse reactions of hypoglycemia were based on all reports of hypoglycemia; a concurrent glucose measurement was not required. The incidence of selected gastrointestinal adverse reactions in patients treated with JANUVIA was as follows: abdominal pain (JANUVIA 100 mg, 2.3%; placebo, 2.1%), nausea (1.4%, 0.6%), and diarrhea (3.0%, 2.3%).

In an additional, 24-week, placebo-controlled factorial study of initial therapy with sitagliptin in combination with metformin, the adverse reactions reported (regardless of investigator assessment of causality) in ≥5% of patients are shown in Table 2. The incidence of hypoglycemia 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.

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) ¹

	Number of Patients (%)
	Placebo	Sitagliptin   (JANUVIA) 100 mg QD	Metformin 500 or 1000 mg bid 2	Sitagliptin 50 mg bid + Metformin 500 or 1000 mg bid
	N = 176	N = 179	N = 364	N = 372
Upper Respiratory 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)

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

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 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] and in patients treated with placebo [0.07 mg/dL]. The clinical significance of this added increase in serum creatinine relative to placebo is not known.

Postmarketing Experience

The following additional adverse reactions have been identified during postapproval use of JANUVIA. 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 include anaphylaxis, angioedema, rash, urticaria, cutaneous vasculitis, and exfoliative skin conditions including Stevens-Johnson syndrome [see Warnings and Precautions]; hepatic enzyme elevations; pancreatitis.

REPORTS OF SUSPECTED JANUVIA SIDE EFFECTS / ADVERSE REACTIONS

Possible Januvia side effects / adverse reactions in 53 year old male

Reported by a physician from France on 2011-10-03

Patient: 53 year old male weighing 117.0 kg (257.4 pounds)

Reactions: Lower Limb Fracture, Lung Adenocarcinoma Metastatic

Adverse event resulted in: hospitalization

Suspect drug(s):
Januvia
    Administration route: Oral
    Indication: Type 2 Diabetes Mellitus
    Start date: 2010-02-09
    End date: 2011-05-04

Januvia
    Administration route: Oral
    Start date: 2011-07-01

Other drugs received by patient: Gliclazide; Metformin; Metformin; Janumet; Gliclazide; Metformin

Possible Januvia side effects / adverse reactions in 74 year old female

Reported by a health professional (non-physician/pharmacist) from Denmark on 2011-10-03

Patient: 74 year old female

Reactions: Dysphagia, Angioedema, Stridor, Swollen Tongue, Throat Tightness, Dysarthria, Sensation of Foreign Body, Pharyngeal Oedema, Respiratory Failure, Acute Coronary Syndrome

Adverse event resulted in: hospitalization

Suspect drug(s):
Januvia
    Administration route: Oral
    Indication: Type 2 Diabetes Mellitus
    Start date: 2011-06-01
    End date: 2011-09-02

Daxas
    Administration route: Oral
    Indication: Chronic Obstructive Pulmonary Disease
    Start date: 2010-11-01
    End date: 2011-09-02

Other drugs received by patient: Albuterol Sulfate; Acetaminophen; Pantoprazole; Amiloride Hydrochloride and Hydrochlorothiazide; Zocor; Tiotropium Bromide; Fluticasone Propionate and Salmeterol Xinafoate; Metformin; Vaseretic

Possible Januvia side effects / adverse reactions in 70 year old female

Reported by a physician from Japan on 2011-10-03

Patient: 70 year old female

Reactions: Pyrexia

Adverse event resulted in: hospitalization

Suspect drug(s):
Januvia