Adverse reactions : תופעות לוואי

Adverse Reactions
Placebo (%)              JARDIANCE 10 mg(%)             JARDIANCE 25 mg(%) N=995                           N=999                          N=977
Urinary tract infectiona                                     7.6                             9.3                            7.6 Female genital mycotic infectionsb                           1.5                             5.4                            6.4 Upper respiratory tract infection                            3.8                             3.1                            4.0 Increased urinationc                                         1.0                             3.4                            3.2 Dyslipidemia                                                 3.4                             3.9                            2.9 Arthralgia                                                   2.2                             2.4                            2.3 Male genital mycotic infectionsd                             0.4                             3.1                            1.6 Nausea                                                       1.4                             2.3                            1.1 a
Predefined adverse event grouping, including, but not limited to, urinary tract infection, asymptomatic bacteriuria, cystitis b
Female genital mycotic infections include the following adverse reactions: vulvovaginal mycotic infection, vaginal infection, vulvitis, vulvovaginal candidiasis, genital infection, genital candidiasis, genital infection fungal, genitourinary tract infection, vulvovaginitis, cervicitis, urogenital infection fungal, vaginitis bacterial. Percentages calculated with the number of female subjects in each group as denominator: placebo (N=481), JARDIANCE 10 mg (N=443), JARDIANCE       25 mg (N=420).
c
Predefined adverse event grouping, including, but not limited to, polyuria, pollakiuria, and nocturia d
Male genital mycotic infections include the following adverse reactions: balanoposthitis, balanitis, genital infections fungal, genitourinary tract infection, balanitis candida, scrotal abscess, penile infection. Percentages calculated with the number of male subjects in each group as denominator: placebo (N=514), JARDIANCE 10 mg (N=556), JARDIANCE       25 mg (N=557).

Thirst (including polydipsia) was reported in 0%, 1.7%, and 1.5% for placebo, JARDIANCE 10 mg, and JARDIANCE 25 mg, respectively.

Volume Depletion
JARDIANCE causes an osmotic diuresis, which may lead to intravascular volume contraction and adverse reactions related to volume depletion. In the pool of five placebo-controlled clinical trials, adverse reactions related to volume depletion (e.g., blood pressure (ambulatory) decreased, blood pressure systolic decreased, dehydration, hypotension, hypovolemia, orthostatic hypotension, and syncope) were reported by 0.3%, 0.5%, and 0.3% of patients treated with placebo, JARDIANCE 10 mg, and JARDIANCE 25 mg respectively. JARDIANCE may increase the risk of hypotension in patients at risk for volume contraction [see Use in Specific Populations (11.5, 11.6)].
Increased Urination
In the pool of five placebo-controlled clinical trials, adverse reactions of increased urination (e.g., polyuria, pollakiuria, and nocturia) occurred more frequently on JARDIANCE than on placebo (see Table 1). Specifically, nocturia was reported by 0.4%, 0.3%, and 0.8% of patients treated with placebo, JARDIANCE 10 mg, and JARDIANCE 25 mg, respectively.
Hypoglycemia
The incidence of hypoglycemia by study is shown in Table 2. The incidence of hypoglycemia increased when JARDIANCE was administered with insulin or sulfonylurea


Boehringer Ingelheim Israel                                                                         Page 6 of 41 Jardiance                                                                  Updated Prescribing Information 10 mg, 25 mg                                                                                     Nov 2022 Table 2 Incidence of Overalla and Severeb Hypoglycemic Events in Placebo-Controlled Clinical Studiesc
Monotherapy                                         Placebo                JARDIANCE 10 mg            JARDIANCE 25 mg (24 weeks)                                          (n=229)                      (n=224)                    (n=223) Overall (%)                                            0.4                          0.4                        0.4 Severe (%)                                              0                            0                          0 In Combination with                           Placebo + Metformin         JARDIANCE 10 mg +          JARDIANCE 25 mg + Metformin                                           (n=206)                    Metformin                  Metformin (24 weeks)                                                                       (n=217)                    (n=214) Overall (%)                                            0.5                          1.8                        1.4 Severe (%)                                              0                            0                          0 In Combination with                                  Placebo              JARDIANCE 10 mg +          JARDIANCE 25 mg + Metformin + Sulfonylurea                             (n=225)                  Metformin +                Metformin + (24 weeks)                                                                    Sulfonylurea               Sulfonylurea (n=224)                    (n=217)
Overall (%)                                            8.4                         16.1                       11.5 Severe (%)                                              0                            0                          0 In Combination with                                  Placebo              JARDIANCE 10 mg +          JARDIANCE 25 mg + Pioglitazone +/- Metformin                           (n=165)                 Pioglitazone +/-           Pioglitazone +/- (24 weeks)                                                                     Metformin                  Metformin (n=165)                    (n=168)
Overall (%)                                                  1.8                    1.2                        2.4 Severe (%)                                                    0                      0                          0 In Combination with Basal Insulin +/-                     Placebo          JARDIANCE 10 mg            JARDIANCE 25 mg Metformin                                                 (n=170)                (n=169)                    (n=155) (18 weeksd)
Overall (%)                                                 20.6                        19.5                28.4 Severe (%)                                                    0                           0                 1.3 In Combination with MDI Insulin +/-                       Placebo               JARDIANCE 10 mg       JARDIANCE 25 mg Metformin                                                 (n=188)                     (n=186)             (n=189) (18 weeksd)
Overall (%)                                                 37.2                        39.8                    41.3 Severe (%)                                                   0.5                         0.5                    0.5 a
Overall hypoglycemic events: plasma or capillary glucose of less than or equal to 70 mg/dL b
Severe hypoglycemic events: requiring assistance regardless of blood glucose c
Treated set (patients who had received at least one dose of study drug) d
Insulin dose could not be adjusted during the initial 18 week treatment period 

Genital Mycotic Infections
In the pool of five placebo-controlled clinical trials, the incidence of genital mycotic infections (e.g., vaginal mycotic infection, vaginal infection, genital infection fungal, vulvovaginal candidiasis, and vulvitis) was increased in patients treated with JARDIANCE compared to placebo, occurring in 0.9%,     4.1%, and 3.7% of patients randomized to placebo, JARDIANCE 10 mg, and JARDIANCE 25 mg,
respectively. Discontinuation from study due to genital infection occurred in 0% of placebo-treated patients and 0.2% of patients treated with either JARDIANCE 10 mg or 25 mg.
Genital mycotic infections occurred more frequently in female than male patients (see Table 1).
Phimosis occurred more frequently in male patients treated with JARDIANCE 10 mg (less than 0.1%) and JARDIANCE 25 mg (0.1%) than placebo (0%).

Urinary Tract Infections
In the pool of five placebo-controlled clinical trials, the incidence of urinary tract infections (e.g., urinary tract infection, asymptomatic bacteriuria, and cystitis) was increased in patients treated with JARDIANCE compared to placebo (see Table 1). Patients with a history of chronic or recurrent urinary Boehringer Ingelheim Israel                                                                   Page 7 of 41 Jardiance                                                           Updated Prescribing Information 10 mg, 25 mg                                                                              Nov 2022 tract infections were more likely to experience a urinary tract infection. The rate of treatment discontinuation due to urinary tract infections was 0.1%, 0.2%, and 0.1% for placebo, JARDIANCE 10 mg, and JARDIANCE 25 mg, respectively.


Urinary tract infections occurred more frequently in female patients. The incidence of urinary tract infections in female patients randomized to placebo, JARDIANCE 10 mg, and JARDIANCE 25 mg was 16.6%, 18.4%, and 17.0%, respectively. The incidence of urinary tract infections in male patients randomized to placebo, JARDIANCE 10 mg, and JARDIANCE 25 mg was 3.2%, 3.6%, and 4.1%, respectively [see Use in Specific Populations (11.5)].

Clinical Trials in Patients with Heart Failure
The EMPEROR-Reduced study included 3730 patients with heart failure and left ventricular ejection fraction (LVEF) ≤40% followed for a median of 16 months, and EMPEROR-Preserved included 5988 patients with heart failure and LVEF >40% followed for a median of 26 months. In both studies, patients were randomized to JARDIANCE 10 mg or placebo. The safety profile in patients with heart failure was generally consistent with that observed in patients with type 2 diabetes mellitus.

Laboratory Tests
Increases in Serum Creatinine and Decreases in eGFR
Initiation of JARDIANCE causes an increase in serum creatinine and decrease in eGFR within weeks of starting therapy and then these changes stabilize. In a study of patients with moderate renal impairment, larger mean changes were observed. In a long-term cardiovascular outcomes trial, the increase in serum creatinine and decrease in eGFR generally did not exceed 0.1 mg/dL and -9.0 mL/min/1.73 m2, respectively, at Week 4, and reversed after treatment discontinuation, suggesting acute hemodynamic changes may play a role in the renal function changes observed with JARDIANCE.

Increase in Low-Density Lipoprotein Cholesterol (LDL-C)
Dose-related increases in low-density lipoprotein cholesterol (LDL-C) were observed in patients treated with JARDIANCE. LDL-C increased by 2.3%, 4.6%, and 6.5% in patients treated with placebo, JARDIANCE 10 mg, and JARDIANCE 25 mg, respectively. The range of mean baseline LDL-C levels was 90.3 to 90.6 mg/dL across treatment groups.


Increase in Hematocrit
In a pool of four placebo-controlled studies, median hematocrit decreased by 1.3% in placebo and increased by 2.8% in JARDIANCE 10 mg and 2.8% in JARDIANCE 25 mg treated patients. At the end of treatment, 0.6%, 2.7%, and 3.5% of patients with hematocrits initially within the reference range had values above the upper limit of the reference range with placebo, JARDIANCE 10 mg, and JARDIANCE 25 mg, respectively.
9.2 Postmarketing Experience
Additional adverse reactions have been identified during postapproval use of JARDIANCE. 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.
Gastrointestinal Disorders: Constipation
Infections: Necrotizing fasciitis of the perineum (Fournier’s gangrene), urosepsis and pyelonephritis Metabolism and Nutrition Disorders: Ketoacidosis
Boehringer Ingelheim Israel                                                             Page 8 of 41 Jardiance                                                                      Updated Prescribing Information 10 mg, 25 mg                                                                                         Nov 2022 Renal and Urinary Disorders: Acute kidney injury
Skin and Subcutaneous Tissue Disorders: Angioedema, skin reactions (e.g., rash, urticaria) Reporting of suspected adverse reactions
You can report side effects to the Ministry of Health by following the link ‘Reporting Side Effects of Drug Treatment' on the Ministry of Health home page (www.health.gov.il) which links to an online form for reporting side effects. You can also use this link: https://sideeffects.health.gov.il
10 DRUG INTERACTIONS
Table 3  Clinically Relevant Interactions with JARDIANCE
Diuretics
Clinical Impact             Coadministration of empagliflozin with diuretics resulted in increased urine volume and frequency of voids, which might enhance the potential for volume depletion.
Intervention                Before initiating JARDIANCE, assess volume status and renal function. In patients with volume depletion, correct this condition before initiating JARDIANCE. Monitor for signs and symptoms of volume depletion, and renal function after initiating therapy.
Insulin or Insulin Secretagogues
Clinical Impact             The risk of hypoglycemia is increased when JARDIANCE is used in combination with insulin secretagogues (e.g., sulfonylurea) or insulin.
Intervention                Coadministration of JARDIANCE with an insulin secretagogue (e.g., sulfonylurea) or insulin may require lower doses of the insulin secretagogue or insulin to reduce the risk of hypoglycemia.
Lithium

Clinical Impact                    Concomitant use of an SGLT2 inhibitor with lithium may decrease serum lithium concentrations.

Intervention                       Monitor serum lithium concentration more frequently during JARDIANCE initiation and dosage changes.

Positive Urine Glucose Test
Clinical Impact             SGLT2 inhibitors increase urinary glucose excretion and will lead to positive urine glucose tests.
Intervention                Monitoring glycemic control with urine glucose tests is not recommended in patients taking SGLT2 inhibitors. Use alternative methods to monitor glycemic control.
Interference with 1,5-anhydroglucitol (1,5-AG) Assay
Clinical Impact             Measurements of 1,5-AG are unreliable in assessing glycemic control in patients taking SGLT2 inhibitors.
Intervention                Monitoring glycemic control with 1,5-AG assay is not recommended. Use alternative methods to monitor glycemic control.



11 USE IN SPECIFIC POPULATIONS
11.1 Pregnancy

Risk Summary

Boehringer Ingelheim Israel                                                                         Page 9 of 41 Jardiance                                                            Updated Prescribing Information 10 mg, 25 mg                                                                               Nov 2022 Based on animal data showing adverse renal effects, JARDIANCE is not recommended during the second and third trimesters of pregnancy.

The limited available data with JARDIANCE in pregnant women are not sufficient to determine a drug- associated risk for major birth defects and miscarriage. There are risks to the mother and fetus associated with poorly controlled diabetes in pregnancy [see Clinical Considerations].
In animal studies, adverse renal changes were observed in rats when empagliflozin was administered during a period of renal development corresponding to the late second and third trimesters of human pregnancy. Doses approximately 13-times the maximum clinical dose caused renal pelvic and tubule dilatations that were reversible [see Data].
The estimated background risk of major birth defects is 6% to 10% in women with pre-gestational diabetes with a HbA1c >7 and has been reported to be as high as 20 % to 25% in women with HbA1c >10. The estimated background risk of miscarriage for the indicated population is unknown. In the U.S.
general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to-4% and 15% to 20%, respectively.

Clinical Considerations
Disease-associated maternal and/or embryo/fetal risk: Poorly controlled diabetes in pregnancy increases the maternal risk for diabetic ketoacidosis, pre-eclampsia, spontaneous abortions, preterm delivery, and delivery complications. Poorly controlled diabetes increases the fetal risk for major birth defects, stillbirth, and macrosomia related morbidity.


Data
Animal Data
Empagliflozin dosed directly to juvenile rats from postnatal day (PND) 21 until PND 90 at doses of 1, 10, 30, and 100 mg/kg/day caused increased kidney weights and renal tubular and pelvic dilatation at 100 mg/kg/day, which approximates 13-times the maximum clinical dose of 25 mg, based on AUC.
These findings were not observed after a 13 week, drug-free recovery period. These outcomes occurred with drug exposure during periods of renal development in rats that correspond to the late second and third trimester of human renal development.


In embryo-fetal development studies in rats and rabbits, empagliflozin was administered for intervals coinciding with the first trimester period of organogenesis in humans. Doses up to 300 mg/kg/day, which approximates 48- times (rats) and 128-times (rabbits) the maximum clinical dose of 25 mg (based on AUC), did not result in adverse developmental effects. In rats, at higher doses of empagliflozin causing maternal toxicity, malformations of limb bones increased in fetuses at 700 mg/kg/day or 154 times the 25 mg maximum clinical dose. Empagliflozin crosses the placenta and reaches fetal tissues in rats. In the rabbit, higher doses of empagliflozin resulted in maternal and fetal toxicity at 700 mg/kg/day, or 139 times the 25 mg maximum clinical dose.


In pre- and postnatal development studies in pregnant rats, empagliflozin was administered from gestation day 6 through to lactation day 20 (weaning) at up to 100 mg/kg/day (approximately 16 times the 25 mg maximum clinical dose) without maternal toxicity. Reduced body weight was observed in the offspring at greater than or equal to 30 mg/kg/day (approximately 4 times the 25 mg maximum clinical dose).
Boehringer Ingelheim Israel                                                           Page 10 of 41 Jardiance                                                            Updated Prescribing Information 10 mg, 25 mg                                                                               Nov 2022 11.2 Lactation
Risk Summary
There is limited information regarding the presence of JARDIANCE in human milk, the effects of JARDIANCE on the breastfed infant or the effects on milk production. Empagliflozin is present in the milk of lactating rats [see Data]. Since human kidney maturation occurs in utero and during the first 2 years of life when lactational exposure may occur, there may be risk to the developing human kidney.
Because of the potential for serious adverse reactions in a breastfed infant, including the potential for empagliflozin to affect postnatal renal development, advise patients that use of JARDIANCE is not recommended while breastfeeding.

Data
Empagliflozin was present at a low level in rat fetal tissues after a single oral dose to the dams at gestation day 18. In rat milk, the mean milk to plasma ratio ranged from 0.634 to 5, and was greater than one from 2 to 24 hours post-dose. The mean maximal milk to plasma ratio of 5 occurred at 8 hours post-dose, suggesting accumulation of empagliflozin in the milk. Juvenile rats directly exposed to empagliflozin showed a risk to the developing kidney (renal pelvic and tubular dilatations) during maturation.

11.4 Pediatric Use
The safety and effectiveness of JARDIANCE have not been established in pediatric patients .

11.5 Geriatric Use
In glycemic control studies in patients with type 2 diabetes mellitus, a total of 2721 (32%) patients treated with JARDIANCE were 65 years of age and older, and 491 (6%) were 75 years of age and older. JARDIANCE is expected to have diminished glycemic efficacy in elderly patients with renal impairment [see Use in Specific Populations (11.6)]. The risk of volume depletion-related adverse reactions increased in patients who were 75 years of age and older to 2.1%, 2.3%, and 4.4% for placebo, JARDIANCE 10 mg, and JARDIANCE 25 mg. The risk of urinary tract infections increased in patients who were 75 years of age and older to 10.5%, 15.7%, and 15.1% in patients randomized to placebo, JARDIANCE 10 mg, and JARDIANCE 25 mg, respectively [see Warnings and Precautions (8.2) and Adverse Reactions (9.1)].

In heart failure studies, EMPEROR-Reduced included 1188 (64%) patients treated with JARDIANCE 65 years of age and older, and 503 (27%) patients 75 years of age and older. EMPEROR-Preserved included 2402 (80%) patients treated with JARDIANCE 65 years of age and older, and 1281 (43%) patients 75 years of age and older. Safety and efficacy were similar for patients 65 years and younger and those older than 65 years.
11.6 Renal Impairment
The efficacy and safety of JARDIANCE for glycemic control were evaluated in a study of patients with type 2 diabetes mellitus with mild and moderate renal impairment (eGFR 30 to less than 90 mL/min/1.73 m2) [see Clinical Studies (16)]. In this study, 195 patients exposed to JARDIANCE had an eGFR between 60 and 90 mL/min/1.73 m2, 91 patients exposed to JARDIANCE had an eGFR between 45 and 60 mL/min/1.73 m2, and 97 patients exposed to JARDIANCE had an eGFR between 30 and 45 mL/min/1.73 m2. The glucose lowering benefit of JARDIANCE 25 mg decreased in patients with worsening renal function. The risks of renal impairment, volume depletion adverse reactions and urinary tract infection-related adverse reactions increased with worsening renal function [see Warnings and Precautions (8.2)]. Use of JARDIANCE for glycemic control in patients without 
Boehringer Ingelheim Israel                                                             Page 11 of 41 Jardiance                                                          Updated Prescribing Information 10 mg, 25 mg                                                                             Nov 2022 established cardiovascular disease or cardiovascular risk factors is not recommended when eGFR is less than 30 mL/min/1.73 m2.

In a large cardiovascular outcomes study of patients with type 2 diabetes and established cardiovascular disease, there were 1819 patients with eGFR below 60 mL/min/1.73 m2. The cardiovascular death findings in this subgroup were consistent with the overall findings [see Clinical Studies (16)].

Studies of patients with heart failure [see Clinical Studies (16)] enrolled patients with eGFR equal to or above 20 mL/min/1.73 m2.. There are insufficient data to support a dosing recommendation in patients with eGFR below 30 mL/min/1.73 m2.

Efficacy and safety studies with JARDIANCE did not enroll patients with an eGFR less than 20 mL/min/1.73 m2. JARDIANCE is contraindicated in patients on dialysis [see Contraindications (7)].

11.7 Hepatic Impairment
JARDIANCE may be used in patients with hepatic impairment [see Clinical Pharmacology (14.3)].