Adverse reactions : תופעות לוואי

6 ADVERSE REACTIONS
The following important adverse reactions are described below and elsewhere in the labeling:
•   Lactic Acidosis [see Boxed Warning and Warnings and Precautions (5.1)]
•   Diabetic Ketoacidosis in Patients with Type 1 Diabetes Mellitus and Other Ketoacidosis [see Warnings and Precautions (5.2)]
•   Volume Depletion [see Warnings and Precautions (5.3)]
•   Urosepsis and Pyelonephritis [see Warnings and Precautions (5.4)]
•   Use with Medications Known to Cause Hypoglycemia [see Warnings and Precautions (5.5)] •   Necrotizing Fasciitis of the Perineum (Fournier’s Gangrene) [see Warnings and Precautions (5.6)]
•   Vitamin B12 Concentrations [see Warnings and Precautions (5.7)]
•   Genital Mycotic Infections [see Warnings and Precautions (5.8)] 
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 clinical practice.

Dapagliflozin and Metformin hydrochloride
Data from a prespecified pool of patients from 8 short-term, placebo-controlled studies of dapagliflozin coadministered with metformin immediate- or extended-release was used to evaluate safety. This pool included several add-on studies (metformin alone and in combination with a dipeptidyl peptidase-4 [DPP4] inhibitor and metformin, or insulin and metformin, 2 initial combination with metformin studies, and 2 studies of patients with CVD and type 2 diabetes mellitus who received their usual treatment [with metformin as background therapy]). For studies that included background therapy with and without metformin, only patients who received metformin were included in the 8-study placebo-controlled pool.
Across these 8 studies 983 patients were treated once daily with dapagliflozin 10 mg and metformin and 1185 were treated with placebo and metformin. These 8 studies provide a mean duration of exposure of 23 weeks. The mean age of the population was 57 years and 2% were older than 75 years. Fifty-four percent (54%) of the population was male; 88% White, 6% Asian, and 3% Black or African American. At baseline, the population had diabetes for an average of 8 years, mean hemoglobin A1c (HbA1c) was 8.4%, and renal function was normal or mildly impaired in 90% of patients and moderately impaired in 10% of patients.
The overall incidence of adverse events for the 8-study, short-term, placebo-controlled pool in patients treated with dapagliflozin 10 mg and metformin was 60.3% compared to 58.2% for the placebo and metformin group. Discontinuation of therapy due to adverse events in patients who received dapagliflozin 10 mg and metformin was 4% compared to 3.3% for the placebo and metformin group. The most commonly reported events leading to discontinuation and reported in at least 3 patients treated with dapagliflozin 10 mg and metformin were renal impairment (0.7%), increased blood creatinine (0.2%), decreased renal creatinine clearance (0.2%), and urinary tract infection (0.2%).
Table 2 shows common adverse reactions associated with the use of dapagliflozin and metformin. These adverse reactions were not present at baseline, occurred more commonly on dapagliflozin and metformin than on placebo, and occurred in at least 2% of patients treated with either dapagliflozin 5 mg or dapagliflozin 10 mg.
Table 2: Adverse Reactions in Placebo-Controlled Studies Reported in ≥2% of Patients Treated with Dapagliflozin and Metformin
Adverse Reaction                                                                                        % of Patients Pool of 8 Placebo-Controlled Studies
Placebo and     Dapagliflozin    Dapagliflozin
Metformin         5 mg and        10 mg and
Metformin        Metformin
N=1185            N=410            N=983
Female genital mycotic infections1                                                    1.5              9.4              9.3 Nasopharyngitis                                                                         5.9                  6.3                   5.2 Urinary tract infections2                                                               3.6                 6.1                    5.5 Diarrhea                                                                                5.6                  5.9                   4.2 Headache                                                                                2.8                  5.4                   3.3 3                                                    0                  4.3                    3.6 Male genital mycotic infections
Influenza                                                                               2.4                  4.1                   2.6 Nausea                                                                                  2.0                  3.9                   2.6 Back pain                                                                               3.2                  3.4                   2.5 Dizziness                                                                               2.2                  3.2                   1.8 Cough                                                                                   1.9                  3.2                   1.4 Constipation                                                                            1.6                  2.9                   1.9 Dyslipidemia                                                                            1.4                  2.7                   1.5 Pharyngitis                                                                             1.1                  2.7                   1.5 4                                                                 1.4                  2.4                   2.6 Increased urination
Discomfort with urination                                                               1.1                  2.2                   1.6 1.     Genital mycotic infections include the following adverse reactions, listed in order of frequency reported for females: vulvovaginal mycotic infection, vaginal infection, genital infection, vulvovaginitis, fungal genital infection, vulvovaginal candidiasis, vulval abscess, genital candidiasis, and vaginitis bacterial. (N for females: Placebo and metformin=534, dapagliflozin 5 mg and metformin=223, dapagliflozin 10 mg and metformin=430).
2.     Urinary tract infections include the following adverse reactions, listed in order of frequency reported: urinary tract infection, cystitis,
pyelonephritis, urethritis, and prostatitis.
3.     Genital mycotic infections include the following adverse reactions, listed in order of frequency reported for males: balanitis, fungal genital infection, balanitis candida, genital candidiasis, genital infection, posthitis, balanoposthitis. (N for males: Placebo and metformin=651, dapagliflozin 5 mg and metformin=187, dapagliflozin 10 mg and metformin=553).
4.     Increased urination includes the following adverse reactions, listed in order of frequency reported: pollakiuria, polyuria, and urine output increased.


Metformin hydrochloride
In placebo-controlled monotherapy trials of metformin extended-release, diarrhea and nausea/vomiting were reported in >5% of metformin-treated patients and more commonly than in placebo-treated patients (9.6% versus 2.6% for diarrhea and 6.5% versus 1.5% for nausea/vomiting). Diarrhea led to discontinuation of study medication in 0.6% of the patients treated with metformin extended-release.
Pool of 12 Placebo-Controlled Studies for Dapagliflozin 5 and 10 mg for Glycemic ControlDapagliflozin

The data in Table 3 are derived from 12 glycemic control placebo-controlled studies ranging from 12 to 24 weeks. In 4 studies dapagliflozin was used as monotherapy, and in 8 studies dapagliflozin was used as add-on to background antidiabetic therapy or as combination therapy with metformin [see Clinical Studies (14.1)].
These data reflect exposure of 2338 patients to dapagliflozin with a mean exposure duration of 21 weeks.
Patients received placebo (N=1393), dapagliflozin 5 mg (N=1145), or dapagliflozin 10 mg (N=1193) once daily. The mean age of the population was 55 years and 2% were older than 75 years of age. Fifty percent (50%) of the population were male; 81% were White, 14% were Asian, and 3% were Black or African American. At baseline, the population had diabetes for an average of 6 years, had a mean HbA1c of 8.3%, and 21% had established microvascular complications of diabetes. Baseline renal function was normal or mildly impaired in 92% of patients and moderately impaired in 8% of patients (mean eGFR 86 mL/min/1.73 m2).

Table 3 shows common adverse reactions associated with the use of dapagliflozin. These adverse reactions were not present at baseline, occurred more commonly on dapagliflozin than on placebo, and occurred in at least 2% of patients treated with either dapagliflozin 5 mg or dapagliflozin 10 mg.


Table3: Adverse Reactions in Placebo-Controlled Studies of Glycemic Control Reported in ≥2% of Patients Treated with Dapagliflozin
Adverse Reaction                                                                               % of Patients Pool of 12 Placebo-Controlled Studies
Placebo         Dapagliflozin        Dapagliflozin
5 mg               10 mg
N=1393             N=1145              N=1193
Female genital mycotic infections1                                         1.5                 8.4                 6.9 Nasopharyngitis                                                             6.2                    6.6                       6.3 2
Urinary tract infections                                                    3.7                    5.7                       4.3 Back pain                                                                   3.2                    3.1                       4.2 3
Increased urination                                                         1.7                    2.9                       3.8 Male genital mycotic infections4                                            0.3                    2.8                       2.7 Nausea                                                                      2.4                    2.8                       2.5 Influenza                                                                   2.3                    2.7                       2.3 Dyslipidemia                                                                1.5                    2.1                       2.5 Constipation                                                                1.5                    2.2                       1.9 Discomfort with urination                                                   0.7                    1.6                       2.1 Pain in extremity                                                           1.4                    2.0                       1.7 1. Genital mycotic infections include the following adverse reactions, listed in order of frequency reported for females: vulvovaginal mycotic infection, vaginal infection, vulvovaginal candidiasis, vulvovaginitis, genital infection, genital candidiasis, fungal genital infection, vulvitis, genitourinary tract infection, vulval abscess, and vaginitis bacterial. (N for females: Placebo=677, dapagliflozin 5 mg=581, dapagliflozin 10 mg=598).
2. Urinary tract infections include the following adverse reactions, listed in order of frequency reported: urinary tract infection,
cystitis, Escherichia urinary tract infection, genitourinary tract infection, pyelonephritis, trigonitis, urethritis, kidney infection, and prostatitis.
3. Increased urination includes the following adverse reactions, listed in order of frequency reported: pollakiuria, polyuria, and urine output increased.
4. Genital mycotic infections include the following adverse reactions, listed in order of frequency reported for males: balanitis, fungal genital infection, balanitis candida, genital candidiasis, genital infection male, penile infection, balanoposthitis, balanoposthitis infective, genital infection, posthitis. (N for males: Placebo=716, dapagliflozin 5 mg=564, dapagliflozin 10 mg=595).

Pool of 13 Placebo-Controlled Studies for Dapagliflozin 10 mg for Glycemic Conrol Dapagliflozin 10 mg was also evaluated in a larger glycemic control placebo-controlled study pool. This pool combined 13 placebo-controlled studies, including 3 monotherapy studies, 9 add-on to background antidiabetic therapy studies, and an initial combination with metformin study. Across these 13 studies, 2360 patients were treated once daily with dapagliflozin 10 mg for a mean duration of exposure of 22 weeks. The mean age of the population was 59 years and 4% were older than 75 years. Fifty-eight percent (58%) of the population were male; 84% were White, 9% were Asian, and 3% were Black or African American. At baseline, the population had diabetes for an average of 9 years, had a mean HbA1c of 8.2%, and 30% had established microvascular disease. Baseline renal function was normal or mildly impaired in 88% of patients and moderately impaired in 11% of patients (mean eGFR 82 mL/min/1.73 m2).

Volume Depletion
Dapagliflozin causes an osmotic diuresis, which may lead to a reduction in intravascular volume. Adverse reactions related to volume depletion (including reports of dehydration, hypovolemia, orthostatic hypotension, or hypotension) for the 12-study and 13-study, short-term, placebo-controlled pools and for the DECLARE study are shown in Table 4 [see Warnings and Precautions (5.3)].


Table 4: Adverse Reactions Related to Volume Depletion1 in Clinical Studies with Dapagliflozin Pool of 12 Placebo-Controlled                     Pool of 13 Placebo-               DECLARE Study Studies                               Controlled Studies

Placebo      Dapagliflozin      Dapagliflozin        Placebo      Dapagliflozin       Placebo      Dapagliflozin 5 mg               10 mg                             10 mg                            10 mg 
Overall           N=1393          N=1145              N=1193           N=2295           N=2360          N=8569           N=8574 population            5               7                   9               17               27              207              213 N (%)              (0.4%)          (0.6%)              (0.8%)           (0.7%)           (1.1%)          (2.4%)           (2.5%) 
Patient Subgroup n (%)

Patients on         n=55            n=40                n=31            n=267            n=236            n=934           n=866 loop                  1               0                   3                4                6               57              57 diuretics          (1.8%)                              (9.7%)           (1.5%)           (2.5%)           (6.1%)          (6.6%) 
Patients           n=107           n=107                n=89            n=268            n=265            n=658           n=604 with                  2               1                   1                4                5               30              35 moderate           (1.9%)          (0.9%)              (1.1%)           (1.5%)           (1.9%)           (4.6%)          (5.8%) renal impairment with eGFR
30 and <60
mL/min/1.7
3 m2

Patients 65      n=276          n=216              n=204          n=711           n=665           n=3950        n=3948 years of age         1              1                  3              6              11               121           117 (0.4%)         (0.5%)             (1.5%)         (0.8%)          (1.7%)           (3.1%)        (3.0%) 
1    Volume depletion includes reports of dehydration, hypovolemia, orthostatic hypotension, or hypotension.

Hypoglycemia
The frequency of hypoglycemia by study [see Clinical Studies (14.1)] is shown in Table 5.
Hypoglycemia was more frequent when dapagliflozin was added to sulfonylurea or insulin [see Warnings and Precautions (5.5)].

Table 5: Incidence of severe Hypoglycemia* and Hypoglycemia with Glucose < 54 mg/dL† in Controlled Glycemic Control Clinical Studies
Placebo       Dapagliflozin 5        Dapagliflozin mg                   10 mg
Add-on to Metformin1 (24 weeks)                                          N=137              N=137               N=135 Severe [n (%)]                                                              0                  0                   0 Glucose < 54 mg/dL [n (%)]                                                  0                  0                   0 Add-on to DPP4 inhibitor (with or without Metformin) (24                N=226                 –                 N=225 weeks)
Severe [n (%)]                                                              0                 –                 1 (0.4) Glucose < 54 mg/dL [n (%)]                                              1 (0.4)               –                 4 (1.8) Add-on to Insulin with or without other OADs‡ (24 weeks)                N=197               N=212               N=196 

Severe [n (%)]                                                          1 (0.5)             2 (0.9)            2 (1.0) Glucose < 54 mg/dL [n (%)]                                             43 (21.8)         55 (25.9)            45 (23.0) *       Severe episodes of hypoglycemia were defined as episodes of severe impairment in consciousness or behavior, requiring external (third party) assistance, and with prompt recovery after intervention regardless of glucose level.
†       Episodes of hypoglycemia with glucose < 54 mg/dL (3 mmol/L) were defined as reported episodes of hypoglycemia meeting the glucose criteria that did not also qualify as a severe episode.
‡        OAD = oral antidiabetic therapy.


In the DECLARE study [see Clinical Studies (14.2)], severe events of hypoglycemia were reported in 58 (0.7%) out of 8574 patients treated with dapagliflozin 10 mg and 83 (1.0%) out of 8569 patients treated with placebo.

Genital Mycotic Infections
In the glycemic control studies, genital mycotic infections were more frequent with dapagliflozin treatment.
Genital mycotic infections were reported in 0.9% of patients on placebo, 5.7% on dapagliflozin 5 mg, and 4.8% on dapagliflozin 10 mg, in the 12-study placebo-controlled pool. Discontinuation from study due to genital infection occurred in 0% of placebo-treated patients and 0.2% of patients treated with dapagliflozin 10 mg. Infections were more frequently reported in females than in males (see Table 3). The most frequently reported genital mycotic infections were vulvovaginal mycotic infections in females and balanitis in males.
Patients with a history of genital mycotic infections were more likely to have a genital mycotic infection during the study than those with no prior history (10.0%, 23.1%, and 25.0% versus 0.8%, 5.9%, and 5.0% on placebo, dapagliflozin 5 mg, and dapagliflozin 10 mg, respectively). In the DECLARE study [see Clinical Studies (14.2)], serious genital mycotic infections were reported in <0.1% of patients treated with dapagliflozin 10 mg and <0.1% of patients treated with placebo. Genital mycotic infections that caused study drug discontinuation were reported in 0.9% of patients treated with dapagliflozin 10 mg and <0.1% of patients treated with placebo.

Hypersensitivity Reactions
Hypersensitivity reactions (e.g., angioedema, urticaria, hypersensitivity) were reported with dapagliflozin treatment. In glycemic control studies, serious anaphylactic reactions and severe cutaneous adverse reactions and angioedema were reported in 0.2% of comparator-treated patients and 0.3% of dapagliflozin- treated patients. If hypersensitivity reactions occur, discontinue use of dapagliflozin; treat per standard of care and monitor until signs and symptoms resolve.

Ketoacidosis
In the DECLARE study [see Clinical Studies (14.2)], events of diabetic ketoacidosis (DKA) were reported in 27 out of 8574 patients in the dapagliflozin-treated group and in 12 out of 8569 patients in the placebo group. The events were evenly distributed over the study period.


Laboratory Tests
Increases in Serum Creatinine and Decreases in eGFR
Dapagliflozin

Initiation of SGLT2 inhibitors, including dapagliflozin, causes a small increase in serum creatinine and decrease in eGFR. These changes in serum creatinine and eGFR generally occur within two weeks of starting therapy and then stabilize regardless of baseline kidney function. Changes that do not fit this pattern should prompt further evaluation to exclude the possibility of acute kidney injury [see Warnings and Precautions (5.3)]. In two studies that included patients with type 2 diabetes mellitus with moderate renal impairment, the acute effect on eGFR reversed after treatment discontinuation, suggesting acute hemodynamic changes may play a role in the renal function changes observed with dapagliflozin.

Increase in Hematocrit
Dapagliflozin

In the pool of 13 placebo-controlled studies of glycemic control, increases from baseline in mean hematocrit values were observed in dapagliflozin-treated patients starting at Week 1 and continuing up to Week 16, when the maximum mean difference from baseline was observed. At Week 24, the mean changes from baseline in hematocrit were -0.33% in the placebo group and 2.30% in the dapagliflozin 10 mg group. By Week 24, hematocrit values >55% were reported in 0.4% of placebo-treated patients and 1.3% of dapagliflozin 10 mg–treated patients.

Increase in Low-Density Lipoprotein Cholesterol
Dapagliflozin
In the pool of 13 placebo-controlled studies of glycemic control, changes from baseline in mean lipid values were reported in dapaglifloz-treated patients compared to placebo-treated patients. Mean percent change from baseline at Week 24 were 0.0% versus 2.5% for total cholesterol and −1.0% versus 2.9% for LDL cholesterol in the placebo and dapagliflozin 10 mg groups, respectively. In the DECLARE study [see Clinical Studies (14.2)], mean changes from baseline after 4 years were 0.4 mg/dL versus -4.1 mg/dL for total cholesterol, and -2.5 mg/dL versus -4.4 mg/dL for LDL cholesterol, in dapagliflozin 10 mg-treated and the placebo groups, respectively.

Vitamin B12 Concentrations
Metformin hydrochloride

In metformin clinical trials of 29-week duration, a decrease to subnormal levels of previously normal serum vitamin B12 levels was observed in approximately 7% of patients.

6.2 Postmarketing Experience
Dapagliflozin
Additional adverse reactions have been identified during post approval use of dapagliflozin. 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.
Infections: Necrotizing fasciitis of the perineum (Fournier’s Gangrene), urosepsis and pyelonephritis Metabolism and Nutrition Disorders: Ketoacidosis
Renal and Urinary Disorders: Acute kidney injury
Skin and Subcutaneous Tissue Disorders: Rash

Metformin hydrochloride
Hepatobiliary Disorders: Cholestatic, hepatocellular, and mixed hepatocellular liver injury.

Reporting of suspected adverse reactions
Reporting suspected adverse reactions after authorization 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