Farxiga
(dapagliflozin)Dosage & Administration
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Farxiga Prescribing Information
FARXIGA (dapagliflozin) is indicated:
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- To reduce the risk of sustained eGFR decline, end-stage kidney disease, cardiovascular death, and hospitalization for heart failure in adults with chronic kidney disease at risk of progression.
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- To reduce the risk of cardiovascular death, hospitalization for heart failure, and urgent heart failure visit in adults with heart failure.
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- To reduce the risk of hospitalization for heart failure in adults with type 2 diabetes mellitus and either established cardiovascular disease or multiple cardiovascular risk factors.
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- As an adjunct to diet and exercise to improve glycemic control in adults and pediatric patients aged 10 years and older with type 2 diabetes mellitus.
Limitations of Use
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- FARXIGA is not recommended for use to improve glycemic control in patients with type 1 diabetes mellitus [see Warnings and Precautions (5.1)].
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- FARXIGA is not recommended for use to improve glycemic control in patients with type 2 diabetes mellitus with an eGFR less than 45 mL/min/1.73 m2. FARXIGA is likely to be ineffective in this setting based upon its mechanism of action.
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- FARXIGA is not recommended for the treatment of chronic kidney disease in patients with polycystic kidney disease or patients requiring or with a recent history of immunosuppressive therapy for kidney disease. FARXIGA is not expected to be effective in these populations.
Prior to Initiation of FARXIGA
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- Assess renal function prior to initiation of FARXIGA therapy and then as clinically indicated [see Warnings and Precautions (5.2)].
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- Assess volume status. In patients with volume depletion, correct this condition before initiating FARXIGA [see Warnings and Precautions (5.2) and Use in Specific Populations (8.5, 8.6)].
2.2 Recommended Dosage for Glycemic Control in Adults and Pediatric Patients Aged 10 Years and Older with Type 2 Diabetes Mellitus
In adults and pediatric patients aged 10 years and older with type 2 diabetes mellitus, the recommended starting dosage of FARXIGA is 5 mg orally once daily to improve glycemic control. For additional glycemic control, the dosage can be increased to 10 mg orally once daily.
For Adult and Pediatric Patients with Type 2 Diabetes Mellitus and Renal Impairment:
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- The recommended dosage for FARXIGA in patients with an eGFR greater than or equal to 45 mL/min/1.73 m2 is the same as the recommended dosage in patients with normal renal function.
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- FARXIGA is not recommended for use to improve glycemic control in patients with type 2 diabetes mellitus with an eGFR less than 45 mL/min/1.73 m2. FARXIGA is likely to be ineffective to improve glycemic control in this setting based upon its mechanism of action.
Recommended Dosage for Other Indications in Adults
The recommended dosage of FARXIGA is 10 mg orally once daily in adults for the following indications:
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- To reduce the risk of sustained eGFR decline, end stage kidney disease (ESKD), cardiovascular (CV) death, and hospitalization for heart failure (hHF) in patients with chronic kidney disease at risk of progression.
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- To reduce the risk of CV death, hHF, and urgent heart failure visit in patients with heart failure.
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- To reduce the risk of hHF in patients with type 2 diabetes mellitus and either established CV disease or multiple CV risk factors.
For Adults with Renal Impairment Receiving FARXIGA for Indications Other than Glycemic Control:
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- The recommended dosage of FARXIGA in patients with an eGFR greater than or equal to 25 mL/min/1.73 m2 is the same as the recommended dosage in patients with normal renal function.
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- Initiation with FARXIGA is not recommended in patients with an eGFR less than 25 mL/min/1.73 m2.
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- If the eGFR falls below 25 mL/min/1.73 m2 while receiving treatment with FARXIGA, patients may continue FARXIGA 10 mg orally once daily to reduce the risk of eGFR decline, ESKD, CV death and hHF.
Temporary Interruption for Surgery
- Withhold FARXIGA for at least 3 days, if possible, prior to major surgery or procedures associated with prolonged fasting. Resume FARXIGA when the patient is clinically stable and has resumed oral intake [see Warnings and Precautions (5.1) and Clinical Pharmacology (12.2)].
3 DOSAGE FORMS AND STRENGTHS
Tablets:
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- 5 mg yellow, biconvex, round, film-coated tablets with “5” engraved on one side and “1427” engraved on the other side.
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- 10 mg yellow, biconvex, diamond-shaped, film-coated tablets with “10” engraved on one side and “1428” engraved on the other side.
Pregnancy
Risk Summary
Based on animal data showing adverse renal effects, FARXIGA is not recommended during the second and third trimesters of pregnancy.
Limited data with FARXIGA in pregnant women are not sufficient to determine drug-associated risk for major birth defects or miscarriage. There are risks to the mother and fetus associated with poorly controlled diabetes and untreated heart failure in pregnancy (see Clinical Considerations).
In animal studies, adverse renal pelvic and tubule dilatations, that were not fully reversible, were observed in rats when dapagliflozin was administered during a period of renal development corresponding to the late second and third trimesters of human pregnancy, at all doses tested; the lowest of which provided an exposure 15-times the 10 mg clinical dose (see Data).
The estimated background risk of major birth defects is 6 to 10% in women with pre-gestational diabetes with a HbA1c greater than 7% and has been reported to be as high as 20 to 25% in women with HbA1c greater than 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 embryofetal risk
Poorly controlled diabetes in pregnancy increases the maternal risk for diabetic ketoacidosis, preeclampsia, 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
Dapagliflozin dosed directly to juvenile rats from postnatal day (PND) 21 until PND 90 at doses of 1, 15, or 75 mg/kg/day, increased kidney weights and increased the incidence of renal pelvic and tubular dilatations at all dose levels. Exposure at the lowest dose tested was 15-times the 10 mg clinical dose (based on AUC). The renal pelvic and tubular dilatations observed in juvenile animals did not fully reverse within a 1-month recovery period.
In a prenatal and postnatal development study, dapagliflozin was administered to maternal rats 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 21-day-old pups 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 10 mg clinical dose, based on AUC). Dose-related reductions in pup body weights were observed at greater or equal to 29-times the 10 mg clinical dose (based on AUC). No adverse effects on developmental endpoints were noted at 1 mg/kg/day (19-times the 10 mg clinical dose, based on AUC). These outcomes occurred with drug exposure during periods of renal development in rats that corresponds to the late second and third trimester of human development.
In embryofetal development studies in rats and rabbits, dapagliflozin was administered throughout organogenesis, corresponding to the first trimester of human pregnancy. In rats, dapagliflozin was neither embryolethal nor teratogenic at doses up to 75 mg/kg/day (1441-times the 10 mg clinical dose, based on AUC). Dose-related effects on the rat fetus (structural abnormalities and reduced body weight) occurred only at higher dosages, equal to or greater than 150 mg/kg (more than 2344-times the 10 mg clinical dose, based on AUC), which were associated with maternal toxicity. No developmental toxicities were observed in rabbits at doses up to 180 mg/kg/day (1191-times the 10 mg clinical dose, based on AUC).
Lactation
Risk Summary
There is no information regarding the presence of dapagliflozin in human milk, the effects on the breastfed infant, or the effects on milk production. Dapagliflozin is present in the milk of lactating rats (see Data). However, due to species-specific differences in lactation physiology, the clinical relevance of these data is not clear. 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 breastfed infants, advise women that use of FARXIGA is not recommended while breastfeeding.
Data
Dapagliflozin was present in rat milk at a milk/plasma ratio of 0.49, indicating that dapagliflozin and its metabolites are transferred into milk at a concentration that is approximately 50% of that in maternal plasma. Juvenile rats directly exposed to dapagliflozin showed risk to the developing kidney (renal pelvic and tubular dilatations) during maturation.
Pediatric Use
The safety and effectiveness of FARXIGA as an adjunct to diet and exercise to improve glycemic control in type 2 diabetes mellitus have been established in pediatric patients aged 10 years and older. Use of FARXIGA for this indication is supported by a 26-week placebo-controlled trial with a 26-week extension in 157 pediatric patients aged 10 to 17 years with type 2 diabetes mellitus, pediatric pharmacokinetic data, and trials in adults with type 2 diabetes mellitus [see Clinical Pharmacology (12.3) and Clinical Studies (14.1 , 14.2)]. The safety profile observed in the placebo-controlled trial in pediatric patients with type 2 diabetes mellitus was similar to that observed in adults [see Adverse Reactions (6.1)].
The safety and effectiveness of FARXIGA for glycemic control in type 2 diabetes mellitus have not been established in pediatric patients less than 10 years of age.
The safety and effectiveness of FARXIGA have not been established in pediatric patients to reduce the risk of [see Indications and Usage (1)].
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- sustained eGFR decline, end stage kidney disease, cardiovascular death, and hospitalization for heart failure in patients with chronic kidney disease at risk of progression.
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- cardiovascular death, hospitalization for heart failure, and urgent heart failure visit in patients with heart failure.
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- hospitalization for heart failure in patients with type 2 diabetes mellitus and either established cardiovascular disease or multiple cardiovascular risk factors.
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 trials assessing the efficacy of FARXIGA in improving glycemic control in type 2 diabetes mellitus. 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 for glycemic control had adverse reactions of hypotension [see Warnings and Precautions (5.2) and Adverse Reactions (6.1)].
In the DAPA-CKD, DAPA-HF and DELIVER trials, safety and efficacy were similar for patients aged 65 years and younger and those older than 65. In the DAPA-HF study, 2714 (57%) out of 4744 patients with HFrEF were older than 65 years. In the DELIVER study, 4759 (76%) out of 6263 patients with heart failure (LVEF >40%) were older than 65 years. In the DAPA-CKD study, 1818 (42%) out of 4304 patients with CKD were older than 65 years.
Renal Impairment
FARXIGA was evaluated in 4304 adult patients with chronic kidney disease (eGFR 25 to 75 mL/min/1.73 m2) in the DAPA-CKD trial. FARXIGA was also evaluated in 1926 adult patients with an eGFR of 30 to 60 mL/min/1.73 m2 in the DAPA-HF trial. The safety profile of FARXIGA across eGFR subgroups in these studies was consistent with the known safety profile [see Adverse Reactions (6.1) and Clinical Studies (14.4, 14.5)].
FARXIGA was evaluated in two glycemic control adult trials that included patients with type 2 diabetes mellitus with moderate renal impairment (an eGFR of 45 to less than 60 mL/min/1.73 m2[see Clinical Studies (14.1)], and an eGFR of 30 to less than 60 mL/min/1.73 m2, respectively). Patients with diabetes and renal impairment using FARXIGA may be more likely to experience hypotension and may be at higher risk for acute kidney injury secondary to volume depletion. In the trial of adult patients with an eGFR 30 to less than 60 mL/min/1.73 m2, 13 patients receiving FARXIGA experienced bone fractures compared to none receiving placebo. Use of FARXIGA for glycemic control in patients without established CV disease or CV risk factors is not recommended when eGFR is less than 45 mL/min/1.73 m2[see Dosage and Administration (2.1)].
Efficacy and safety trials with FARXIGA did not enroll patients with an eGFR less than 25 mL/min/1.73 m2 or on dialysis. Once enrolled in the DAPA-CKD and DELIVER trials, adult patients were not required to discontinue therapy if eGFR fell below 25 mL/min/1.73 m2 or if dialysis was initiated. Once enrolled in the DAPA-HF trial, adult patients were not required to discontinue therapy if eGFR fell below 30 mL/min/1.73 m2 or if dialysis was initiated [see Dosage and Administration (2.3) and Clinical Studies (14.4, 14.5)].
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 (12.3)].
FARXIGA is contraindicated in patients with a history of a serious hypersensitivity reaction to dapagliflozin or any of the excipients in FARXIGA. Serious hypersensitivity reactions, including anaphylaxis and angioedema have been reported with FARXIGA [see Adverse Reactions (6.1)].
Diabetic Ketoacidosis in Patients with Type 1 Diabetes Mellitus and Other Ketoacidosis
In patients with type 1 diabetes mellitus, FARXIGA 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. FARXIGA 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 FARXIGA.
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 FARXIGA [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 with type 1 diabetes mellitus and consider ketone monitoring in others 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 FARXIGA, promptly evaluate, and treat ketoacidosis, if confirmed. Monitor patients for resolution of ketoacidosis before restarting FARXIGA.
Withhold FARXIGA, if possible, in temporary clinical situations that could predispose patients to ketoacidosis. Resume FARXIGA when the patient is clinically stable and has resumed oral intake [see Dosage and Administration (2.3)].
Educate all patients on the signs and symptoms of ketoacidosis and instruct patients to discontinue FARXIGA and seek medical attention immediately if signs and symptoms occur.
Volume Depletion
FARXIGA 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 FARXIGA. 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 FARXIGA 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.
Urosepsis and Pyelonephritis
Serious urinary tract infections including urosepsis and pyelonephritis requiring hospitalization have been reported in patients receiving SGLT2 inhibitors, including FARXIGA. 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)].
Hypoglycemia with Concomitant Use with Insulin and Insulin Secretagogues
Insulin and insulin secretagogues (e.g., sulfonylureas) are known to cause hypoglycemia. FARXIGA may increase the risk of hypoglycemia when combined with insulin 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 these agents are used in combination with FARXIGA [see Drug Interactions (7)].
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 FARXIGA. Cases have been reported in both females and males. Serious outcomes have included hospitalization, multiple surgeries, and death.
Patients treated with FARXIGA 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 FARXIGA, closely monitor blood glucose levels, and provide appropriate alternative therapy for glycemic control.
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 (6.1)]. Monitor and treat appropriately.