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 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 were coadministered to patients with type 2 diabetes inadequately controlled on diet and exercise.

Table 1: Sitagliptin and Metformin 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 500 mg/            50 mg twice daily + 100 mg once        Metformin HCl 1000 mg           Metformin HCl 500 mg/ daily               twice daily†               Metformin HCl 1000 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 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              Study of Sitagliptin Add-on in on Diet and Exercise                                      Patients Inadequately Controlled on Metformin Alone

Sitagliptin 50 mg twice         Placebo and   Sitagliptin 100 mg
Placebo    Sitagliptin      Metformin HCl daily +                 Metformin     once daily and
100 mg             500 mg/
Metformin HCl 500 mg/               HCl         Metformin HCl once daily       Metformin HCl
Metformin HCl 1000 mg            1500 mg       1500 mg daily
1000 mg twice daily*                 daily twice 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 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 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 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 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 Coadministered with Glimepiride or Insulin

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

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, no clinically meaningful changes in vital signs or in ECG (including in 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

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

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 B 12 absorption from the B 12-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 JANUET, 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.