Adverse reactions : תופעות לוואי

6     ADVERSE REACTIONS
The following adverse reactions are also discussed elsewhere in the labeling: •    Lactic Acidosis [see Warnings and Precautions (5.1)]
•    Pancreatitis [see Warnings and Precautions (5.2)]
•    Heart Failure [see Warnings and Precautions (5.3)]
•    Acute Renal Failure [see Warnings and Precautions (5.4)]
•    Vitamin B12 Deficiency [see Warnings and Precautions (5.5)]
•    Hypoglycemia with Concomitant Use with Insulin or Insulin Secretagogues [see Warnings and Precautions (5.6)]
•    Hypersensitivity Reactions [see Warnings and Precautions (5.7)] •    Severe and Disabling Arthralgia [see Warnings and Precautions (5.8)] •    Bullous Pemphigoid [see Warnings and Precautions (5.9)]

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.



Sitagliptin and Metformin Immediate-Release Coadministration 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 coadministered to patients with type 2 diabetes inadequately controlled on diet and exercise.
Table 1: Sitagliptin and Metformin Immediate-Release Coadministered 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 (%)
Sitagliptin
Placebo        Sitagliptin          Metformin HCl                  50 mg twice daily + 100 mg once        Immediate-Release 500          Metformin HCl Immediate- daily           mg or 1000 mg twice            Release 500 mg or 1000 daily †                     mg twice daily †
N = 176         N = 179                N = 364†                        N = 372† Diarrhea                    7 (4.0)        5 (2.8)                28 (7.7)                         28 (7.5) Upper Respiratory           9 (5.1)        8 (4.5)                19 (5.2)                         23 (6.2) Tract 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.

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                 Study of Sitagliptin Add-on in Inadequately Controlled on Diet and Exercise                         Patients Inadequately Controlled on Metformin Immediate-Release
Alone
Placebo and Sitagliptin 100 mg
Placebo     Sitagliptin      Metformin HCl          Sitagliptin 50 mg bid +        Metformin        once daily and 100 mg        Immediate-Release            Metformin HCl                 HCl           Metformin HCl once daily     500 mg or 1000 mg         Immediate-Release            Immediate-          Immediate- twice daily *        500 mg or 1000 mg twice          Release             Release daily *               ≥1500 mg         ≥1500 mg daily 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         4 (2.3)       6 (3.4)          14 (3.8)                   11 (3.0)                    9 (3.8)       10 (2.2) Pain†
* 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 the above studies (N=5), 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 coadministered 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 coadministered 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 Coadministered with Glimepiride or Insulin

Sitagliptin 100 mg                      Placebo
Add-On to Glimepiride +                  + Metformin Immediate-Release       + Metformin Immediate-Release Metformin Immediate-Release (24                 + Glimepiride                      + Glimepiride weeks)
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) Sitagliptin 100 mg                      Placebo
Add-On to Insulin                        + Metformin Immediate-Release       + Metformin Immediate-Release + Metformin Immediate-Release (24                  + Insulin                          + Insulin weeks)
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.
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.
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).
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
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.



6.2    Postmarketing Experience
Additional adverse reactions have been identified during postapproval use of sitagliptin with metformin, sitagliptin, or metformin. 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; upper respiratory tract infection; 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; pruritus; mouth ulceration; stomatitis; cholestatic, hepatocellular, and mixed hepatocellular liver injury; 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