Farxiga (Dapagliflozin Propanediol) - Warnings and Precautions

WARNINGS AND PRECAUTIONS

Hypotension

FARXIGA causes intravascular volume contraction. Symptomatic hypotension can occur after initiating FARXIGA [see Adverse Reactions ] particularly in patients with impaired renal function (eGFR less than 60 mL/min/1.73 m²), elderly patients, or patients on loop diuretics. Before initiating FARXIGA in patients with one or more of these characteristics, volume status should be assessed and corrected. Monitor for signs and symptoms of hypotension after initiating therapy.

Impairment in Renal Function

FARXIGA increases serum creatinine and decreases eGFR. Elderly patients and patients with impaired renal function may be more susceptible to these changes. Adverse reactions related to renal function can occur after initiating FARXIGA [see Adverse Reactions ]. Renal function should be evaluated prior to initiation of FARXIGA and monitored periodically thereafter.

Hypoglycemia with Concomitant Use with Insulin and Insulin Secretagogues

Insulin and insulin secretagogues are known to cause hypoglycemia. FARXIGA can increase the risk of hypoglycemia when combined with insulin or an insulin secretagogue [see Adverse Reactions ]. Therefore, a lower dose of insulin or insulin secretagogue may be required to minimize the risk of hypoglycemia when these agents are used in combination with FARXIGA.

Genital Mycotic Infections

FARXIGA 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 ]. Monitor and treat appropriately.

Increases in Low-Density Lipoprotein Cholesterol (LDL-C)

Increases in LDL‑C occur with FARXIGA [see Adverse Reactions ]. Monitor LDL‑C and treat per standard of care after initiating FARXIGA.

Bladder Cancer

Across 22 clinical studies, newly diagnosed cases of bladder cancer were reported in 10/6045 patients (0.17%) treated with FARXIGA and 1/3512 patient (0.03%) treated with placebo/comparator. After excluding patients in whom exposure to study drug was less than one year at the time of diagnosis of bladder cancer, there were 4 cases with FARXIGA and no cases with placebo/comparator. Bladder cancer risk factors and hematuria (a potential indicator of pre-existing tumors) were balanced between treatment arms at baseline. There were too few cases to determine whether the emergence of these events is related to FARXIGA.

There are insufficient data to determine whether FARXIGA has an effect on pre-existing bladder tumors. Consequently, FARXIGA should not be used in patients with active bladder cancer. In patients with prior history of bladder cancer, the benefits of glycemic control versus unknown risks for cancer recurrence with FARXIGA should be considered.

Macrovascular Outcomes

There have been no clinical studies establishing conclusive evidence of macrovascular risk reduction with FARXIGA or any other antidiabetic drug.

USE IN SPECIFIC POPULATIONS

Pregnancy

Pregnancy Category C

There are no adequate and well-controlled studies of FARXIGA in pregnant women. Based on results of reproductive and developmental toxicity studies in animals, dapagliflozin may affect renal development and maturation. In a juvenile rat study, increased incidence and/or severity of renal pelvic and tubular dilatations were evident at the lowest tested dose which was approximately 15 times clinical exposure from a 10 mg dose.

These outcomes occurred with drug exposures during periods of animal development that correlate with the late second and third trimesters of human pregnancy. During pregnancy, consider appropriate alternative therapies, especially during the second and third trimesters. FARXIGA should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

In a juvenile toxicity study, when dapagliflozin was dosed directly to young rats from postnatal day (PND) 21 until PND 90 at doses of 1, 15, or 75 mg/kg/day, increased kidney weights and renal pelvic and tubular dilatations were reported at all levels. Exposure at the lowest tested dose was 15 times the maximum clinical dose, based on AUC. The renal pelvic and tubular dilatations observed in juvenile animals did not fully reverse within the approximate 1-month recovery period.

In a prenatal and postnatal development study, maternal rats were dosed from gestation day 6 through lactation day 21 at doses of 1, 15, or 75 mg/kg/day, and pups were indirectly exposed in utero and throughout lactation. Increased incidence or severity of renal pelvic dilatation was observed in adult offspring of treated dams at 75 mg/kg/day (maternal and pup dapagliflozin exposures were 1415 times and 137 times, respectively, the human values at the clinical dose). Dose-related reductions in pup body weights were observed at doses ≥1 mg/kg/day (approximately ≥19 times the clinical dose). No adverse effects on developmental endpoints were noted at 1 mg/kg/day, or approximately 19 times the clinical dose.

In embryo-fetal development studies in rats and rabbits, dapagliflozin was administered for intervals coinciding with the first trimester period of organogenesis in humans. No developmental toxicities were observed in rabbits at any dose tested. In rats, dapagliflozin was neither embryolethal nor teratogenic at doses up to 75 mg/kg/day or 1441 times the maximum clinical dose of 10 mg. At higher doses in rats, malformations of blood vessels, ribs, vertebra, manubria, and skeletal variations in fetuses at ≥150 mg/kg or 2344 times the 10 mg clinical dose were observed.

Nursing Mothers

It is not known whether FARXIGA is excreted in human milk. Dapagliflozin is excreted in rat milk reaching levels 0.49 times that found in maternal plasma. Data in juvenile rats directly exposed to dapagliflozin showed risk to the developing kidney (renal pelvic and tubular dilatations) during maturation. 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 many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from FARXIGA, a decision should be made whether to discontinue nursing or to discontinue FARXIGA, taking into account the importance of the drug to the mother.

Pediatric Use

Safety and effectiveness of FARXIGA in pediatric patients under 18 years of age have not been established.

Geriatric Use

No FARXIGA dosage change is recommended based on age. A total of 1424 (24%) of the 5936 FARXIGA-treated patients were 65 years and older and 207 (3.5%) patients were 75 years and older in a pool of 21 double-blind, controlled, clinical safety and efficacy studies of FARXIGA. After controlling for level of renal function (eGFR), efficacy was similar for patients under age 65 years and those 65 years and older. In patients ≥65 years of age, a higher proportion of patients treated with FARXIGA had adverse reactions related to volume depletion and renal impairment or failure compared to patients treated with placebo [see Warnings and Precautions and Adverse Reactions ].

Renal Impairment

The safety and efficacy of FARXIGA were evaluated in a study that included patients with moderate renal impairment (eGFR 30 to less than 60 mL/min/1.73 m²). Compared to placebo-treated patients, patients with moderate renal impairment treated with FARXIGA did not have improvement in glycemic control [see Clinical Studies ] and had more renal-related adverse reactions and more bone fractures [see Dosage and Administration , Warnings and Precautions , and Adverse Reactions ]; therefore, FARXIGA should not be initiated in this population.

Based on its mechanism of action, FARXIGA is not expected to be effective in patients with severe renal impairment (eGFR less than 30 mL/min/1.73 m²) or ESRD [see Contraindications (4) ].

Hepatic Impairment

No dose adjustment is recommended for patients with mild, moderate, or severe hepatic impairment. However, the benefit-risk for the use of dapagliflozin in patients with severe hepatic impairment should be individually assessed since the safety and efficacy of dapagliflozin have not been specifically studied in this population [see Clinical Pharmacology ].