Adverse reactions : תופעות לוואי

6 ADVERSE REACTIONS
The following adverse reactions are also discussed elsewhere in the labeling: •   Pancreatitis [see Warnings and Precautions (5.1)]
•   Heart Failure [see Warnings and Precautions (5.2)]
•   Acute Renal Failure [see Warnings and Precautions (5.3)]
•   Hypoglycemia with Concomitant Use with Insulin or Insulin Secretagogues [see Warnings and Precautions (5.4)]
•   Hypersensitivity Reactions [see Warnings and Precautions (5.5)] •   Severe and Disabling Arthralgia [see Warnings and Precautions (5.6)] •   Bullous Pemphigoid [see Warnings and Precautions (5.7)]

6.1 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, pioglitazone, or rosiglitazone and metformin, 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 3); 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. Five placebo- controlled add-on combination therapy studies were also conducted: one with metformin; one with pioglitazone; one with metformin and rosiglitazone; one with glimepiride (with or without metformin); and one with insulin (with or without metformin). In these trials, patients with inadequate glycemic control on a stable dose of the background therapy were randomized to add-on therapy with JANUVIA 100 mg daily or placebo. The adverse reactions, excluding hypoglycemia, reported regardless of investigator assessment of causality in ≥5% of patients treated with JANUVIA 100 mg daily and more commonly than in patients treated with placebo, are shown in Table 1 for the clinical trials of at least 18 weeks duration. Incidences of hypoglycemia are shown in Table 3.
Table 1:
Placebo-Controlled Clinical Studies of JANUVIA Monotherapy or Add-on
Combination Therapy with Pioglitazone, Metformin + Rosiglitazone, or Glimepiride +/- Metformin: Adverse Reactions (Excluding Hypoglycemia) Reported in ≥5% of Patients and More Commonly than in Patients Given Placebo, Regardless of Investigator Assessment of Causality*
Number of Patients (%)
Monotherapy (18 or 24 weeks)      JANUVIA 100 mg                    Placebo N = 443                       N = 363
Nasopharyngitis                     23 (5.2)                      12 (3.3) JANUVIA 100 mg +                  Placebo +
Combination with Pioglitazone
Pioglitazone                  Pioglitazone
(24 weeks)
N = 175                       N = 178
Upper Respiratory Tract             11 (6.3)                      6 (3.4) Infection
Headache                              9 (5.1)                      7 (3.9) JANUVIA 100 mg                    Placebo
Combination with Metformin +         + Metformin                  + Metformin Rosiglitazone (18 weeks)          + Rosiglitazone              + Rosiglitazone N = 181                       N = 97
Upper Respiratory Tract
10 (5.5)                     5 (5.2)
Infection
Nasopharyngitis                       11 (6.1)                      4 (4.1) JANUVIA 100 mg                    Placebo
Combination with Glimepiride
+ Glimepiride                + Glimepiride
(+/- Metformin) (24 weeks)
(+/- Metformin)              (+/- Metformin)
N = 222                      N = 219
Nasopharyngitis                      14 (6.3)                     10 (4.6) Headache                             13 (5.9)                      5 (2.3) * Intent-to-treat population



In the 24-week 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 24-week study of patients receiving JANUVIA as add-on therapy to insulin (with or without 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, except for hypoglycemia (see Table 3).
In the study of JANUVIA as add-on combination therapy with metformin and rosiglitazone (Table 1), through Week 54 the adverse reactions reported regardless of investigator assessment of causality in ≥5% of patients treated with JANUVIA and more commonly than in patients treated with placebo were: upper respiratory tract infection (JANUVIA, 15.5%; placebo, 6.2%), nasopharyngitis (11.0%, 9.3%), peripheral edema (8.3%, 5.2%), and headache (5.5%, 4.1%).
In a pooled analysis of the two monotherapy studies, the add-on to metformin study, and the add-on to pioglitazone study, 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.
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 (%)
Sitagliptin                               Sitagliptin
Placebo     (JANUVIA)       Metformin HCl            50 mg bid +
100 mg QD      500 or 1000 mg          Metformin HCl
bid†           500 or 1000 mg bid†
N = 176     N = 179          N = 364†                N = 372†
Upper Respiratory            9 (5.1)     8 (4.5)           19 (5.2)               23 (6.2) Infection
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.


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).
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
JANUVIA 100 mg                      Placebo
Add-On to Glimepiride
+ Glimepiride                  + Glimepiride
(+/- Metformin) (24 weeks)
(+/- Metformin)                (+/- Metformin)
N = 222                        N = 219
Overall (%)                                   27 (12.2)                        4 (1.8) Rate (episodes/patient-year)†                    0.59                           0.24 Severe (%)‡                                    0 (0.0)                         0 (0.0) Add-On to Insulin                          JANUVIA 100 mg                      Placebo (+/- Metformin) (24 weeks)                    + Insulin                      + Insulin (+/- Metformin)                (+/- Metformin)
N = 322                        N = 319
Overall (%)                                   50 (15.5)                       25 (7.8) Rate (episodes/patient-year)†                    1.06                           0.51 Severe (%)‡                                    2 (0.6)                         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 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.
6.2 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; hepatic enzyme elevations; acute pancreatitis, including fatal and non-fatal hemorrhagic and necrotizing pancreatitis [see Indications and Usage (1)]; worsening renal function, including acute renal failure (sometimes requiring dialysis), and tubulointerstitial nephritis; severe and disabling arthralgia; bullous pemphigoid; constipation; vomiting; headache; myalgia; pain in extremity; back pain; interstitial lung disease; pruritus; mouth ulceration; stomatitis; rhabdomyolysis.
Reporting of suspected adverse reactions
Reporting suspected adverse reactions after authorisation of the medicinal product is important.
It allows continued monitoring of the benefit/risk balance of the medicinal product.
Any suspected adverse events should be reported to the Ministry of Health according to the National Regulation by using an online form
/https://sideeffects.health.gov.il.