Special Warning : אזהרת שימוש

5 WARNINGS AND PRECAUTIONS
5.1 Lactic Acidosis
There have been post-marketing cases of metformin-associated lactic acidosis, including fatal cases. These cases had a subtle onset and were accompanied by nonspecific symptoms such as malaise, myalgias, abdominal pain, respiratory distress, or increased somnolence, ; however, hypothermia, hypotension, and resistant bradyarrhythmias have occurred with severe acidosis Metformin-associated lactic acidosis was characterized by elevated blood lactate concentrations (>5mmol/L), anion gap acidosis (without evidence of (ketonuria or ketonemia).
), and an increased lactate: pyruvate ratio; metformin plasma levels generally >5 mcg/mL. Metformin decreases liver uptake of lactate increasing lactate blood levels which may increase the risk of lactic acidosis especially in patients at risk.
If metformin-associated lactic acidosis is suspected, general supportive measures should be instituted.
promptly in a hospital setting, along with immediate discontinuation of XIGDUO XR.
In XIGDUO XR-treated patients with a diagnosis or strong suspicion of lactic acidosis, prompt hemodialysis is recommended to correct the acidosis and remove accumulated metformin. (metformin hydrochloride is dialyzable, with a clearance of up to 170 mL/min under good hemodynamic conditions).
Hemodialysis has often resulted in reversal of symptoms and recovery

Educate patients and their families about the symptoms of lactic acidosis and if these symptoms occur instruct them to discontinue XIGDUO XR and report these symptoms to their healthcare provider.
For each of the known and possible risk factors for metformin-associated lactic acidosis, recommendations to reduce the risk of and manage metformin-associated lactic acidosis are provided below:
Renal Impairment: The postmarketing metformin-associated lactic acidosis cases primarily occurred in patients with significant renal impairment. The risk of metformin accumulation and metformin-associated lactic acidosis increases with the severity of renal impairment because metformin is substantially excreted by the kidney. Clinical recommendations based upon the patient’s renal function include [see Dosage and Administration (2.1 and 2.4) and Clinical Pharmacology (12.3)]:
•       Before initiating XIGDUO XR, obtain an estimated glomerular filtration rate (eGFR).
•       XIGDUO XR is contraindicated in patients with an eGFR less than 30 mL/min/1.73 m2 [see Contraindications (4)].
•       Obtain an eGFR at least annually in all patients taking XIGDUO XR. In patients at increased risk for the development of renal impairment (e.g., the elderly), renal function should be assessed more frequently.

Drug Interactions: The concomitant use of XIGDUO XR with specific drugs may increase the risk of metformin-associated lactic acidosis: those that impair renal function, result in significant hemodynamic change, interfere with acid-base balance or increase metformin accumulation (e.g., cationic drugs) [see Drug Interactions (7)]. Therefore, consider more frequent monitoring of patients.
Age 65 or Greater: The risk of metformin-associated lactic acidosis increases with the patient’s age because elderly patients have a greater likelihood of having hepatic, renal, or cardiac impairment than younger patients. Assess renal function more frequently in elderly patients [see Use in Specific Populations (8.5)].
Radiological Studies with Contrast: Administration of intravascular iodinated contrast agents in metformin-treated patients has led to an acute decrease in renal function and the occurrence of lactic acidosis. Stop XIGDUO XR at the time of, or prior to, an iodinated contrast imaging procedure in patients with a history of hepatic impairment, alcoholism, or heart failure; or in patients who will be administered intra-arterial iodinated contrast. Re-evaluate eGFR 48 hours after the imaging procedure, and restart XIGDUO XR if renal function is stable.
Surgery and Other Procedures: Withholding of food and fluids during surgical or other procedures may increase the risk for volume depletion, hypotension and renal impairment. XIGDUO XR should be temporarily discontinued while patients have restricted food and fluid intake.
Hypoxic States : Several of the postmarketing cases of metformin-associated lactic acidosis occurred in the setting of acute congestive heart failure (particularly when accompanied by hypoperfusion and hypoxemia). Cardiovascular collapse (shock), acute myocardial infarction, sepsis, and other conditions associated with hypoxemia have been associated with lactic acidosis and may also cause prerenal azotemia. When such events occur , discontinue XIGDUO XR.
Excessive Alcohol Intake: Alcohol potentiates the effect of metformin on lactate metabolism, and this may increase the risk of metformin-associated lactic acidosis. Warn patients against excessive alcohol intake while receiving XIGDUO XR.
Hepatic Impairment: Patients with hepatic impairment have developed with cases of metformin- associated lactic acidosis. This may be due to impaired lactate clearance resulting in higher lactate blood levels. Therefore, avoid use of XIGDUO XR in patients with clinical or laboratory evidence of hepatic disease.

5.2 Diabetic Ketoacidosis in Patients with Type 1 Diabetes Mellitus and Other Ketoacidosis In patients with type 1 diabetes mellitus, dapagliflozin, a component of XIGDUO XR, significantly increases the risk of diabetic ketoacidosis, a life-threatening event, beyond the background rate. In placebo-controlled trials of patients with type 1 diabetes mellitus, the risk of ketoacidosis was markedly increased in patients who received sodium-glucose cotransporter 2 (SGLT2) inhibitors compared to patients who received placebo. XIGDUO XR is not indicated for glycemic control in patients with type 1 diabetes mellitus.
Type 2 diabetes mellitus and pancreatic disorders (e.g., history of pancreatitis or pancreatic surgery) are also risk factors for ketoacidosis. There have been postmarketing reports of fatal events of ketoacidosis in patients with type 2 diabetes mellitus using SGLT2 inhibitors, including dapagliflozin.
Precipitating conditions for diabetic ketoacidosis or other ketoacidosis include under-insulinization due to insulin dose reduction or missed insulin doses, acute febrile illness, reduced caloric intake, ketogenic diet, surgery, volume depletion, and alcohol abuse.
Signs and symptoms are consistent with dehydration and severe metabolic acidosis and include nausea, vomiting, abdominal pain, generalized malaise, and shortness of breath. Blood glucose levels at presentation may be below those typically expected for diabetic ketoacidosis (e.g., less than 250 mg/dL(.
Ketoacidosis and glucosuria may persist longer than typically expected. Urinary glucose excretion persists for 3 days after discontinuing XIGDUO XR [see Clinical Pharmacology (12.2)]; however, there have been postmarketing reports of ketoacidosis and/or glucosuria lasting greater than 6 days and some up to 2 weeks after discontinuation of SGLT2 inhibitors.
Consider ketone monitoring in patients at risk for ketoacidosis if indicated by the clinical situation.
Assess for ketoacidosis regardless of presenting blood glucose levels in patients who present with signs and symptoms consistent with severe metabolic acidosis. If ketoacidosis is suspected, discontinue XIGDUO XR, promptly evaluate, and treat ketoacidosis, if confirmed. Monitor patients for resolution of ketoacidosis before restarting XIGDUO XR.
Withhold XIGDUO XR, if possible, in temporary clinical situations that could predispose patients to ketoacidosis. Resume XIGDUO XR when the patient is clinically stable and has resumed oral intake [see Dosage and Administration (2.6)].
Educate all patients on the signs and symptoms of ketoacidosis and instruct patients to discontinue XIGDUO XR and seek medical attention immediately if signs and symptoms occur.

5.3 Volume Depletion
Dapagliflozin can cause intravascular volume depletion which may sometimes manifest as symptomatic hypotension or acute transient changes in creatinine. There have been post-marketing reports of acute kidney injury, some requiring hospitalization and dialysis, in patients with type 2 diabetes mellitus receiving SGLT2 inhibitors, including dapagliflozin. Patients with impaired renal function (eGFR less than 60 mL/min/1.73 m2), elderly patients, or patients on loop diuretics may be at increased risk for volume depletion or hypotension. Before initiating XIGDUO XR in patients with one or more of these characteristics, assess volume status and renal function. Monitor for signs and symptoms of hypotension and renal function after initiating therapy.

5.4 Urosepsis and Pyelonephritis
Serious urinary tract infections including urosepsis and pyelonephritis requiring hospitalization have been reported in patients receiving SGLT2 inhibitors, including dapagliflozin. Treatment with SGLT2 inhibitors increases the risk for urinary tract infections. Evaluate patients for signs and symptoms of urinary tract infections and treat promptly, if indicated. [see Adverse Reactions (6.2)].
5.5 Hypoglycemia with Concomitant Use with Insulin and Insulin Secretagogues Insulin and insulin secretagogues (e.g., sulfonylurea) are known to cause hypoglycemia. XIGDUO XR may increase the risk of hypoglycemia when combined with insulin and/or an insulin secretagogue [see Adverse Reactions (6.1)]. Therefore, a lower dose of insulin or insulin secretagogue may be required to minimize the risk of hypoglycemia when used in combination with XIGDUO XR [see Drug Interactions (7)].

5.6 Necrotizing Fasciitis of the Perineum (Fournier’s Gangrene)

Reports of necrotizing fasciitis of the perineum (Fournier’s Gangrene), a rare but serious and life- threatening necrotizing infection requiring urgent surgical intervention, have been identified in postmarketing surveillance in patients with diabetes mellitus receiving SGLT2 inhibitors, including dapagliflozin. Cases have been reported in both females and males. Serious outcomes have included hospitalization, multiple surgeries, and death.
Patients treated with XIGDUO XR presenting with pain or tenderness, erythema, or swelling in the genital or perineal area, along with fever or malaise, should be assessed for necrotizing fasciitis. If suspected, start treatment immediately with broad-spectrum antibiotics and, if necessary, surgical debridement. Discontinue XIGDUO XR, closely monitor blood glucose levels, and provide appropriate alternative therapy for glycemic control.

5.7 Vitamin B12 Concentrations
In controlled clinical trials of metformin of 29-week 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, may be associated with anemia but appears to be rapidly reversible with discontinuation of metformin or vitamin B12 supplementation.
Certain individuals (those with inadequate vitamin B12 or calcium intake or absorption) appear to be predisposed to developing subnormal vitamin B12 levels. Measure hematologic parameters on an annual basis and vitamin B12 at 2- to 3-year intervals in patients on XIGDUO XR and manage any abnormalities [see Adverse Reactions (6.1)].

5.8 Genital Mycotic Infections
Dapagliflozin increases the risk of genital mycotic infections. Patients with a history of genital mycotic infections were more likely to develop genital mycotic infections [see Adverse Reactions (6.1)]. Monitor and treat appropriately.

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

Effects on Driving