"The US Food and Drug Administration (FDA) has approved a new type 2 diabetes drug that combines the sodium glucose cotransporter 2 (SGLT2) inhibitor empagliflozin with metformin hydrochloride (Synjardy, Boehringer Ingelheim and Eli Lilly"...
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.
Reports of ketoacidosis, a serious life-threatening condition requiring urgent hospitalization have been identified in postmarketing surveillance in patients with type 1 and type 2 diabetes mellitus receiving sodium glucose co-transporter-2 (SGLT2) inhibitors, including FARXIGA. FARXIGA is not indicated for the treatment of patients with type 1 diabetes mellitus [see INDICATIONS AND USAGE].
Patients treated with FARXIGA who present with signs and symptoms consistent with severe metabolic acidosis should be assessed for ketoacidosis regardless of presenting blood glucose levels as ketoacidosis associated with FARXIGA may be present even if blood glucose levels are less than 250 mg/dL. If ketoacidosis is suspected, FARXIGA should be discontinued, the patient should be evaluated and prompt treatment should be instituted. Treatment of ketoacidosis may require insulin, fluid and carbohydrate replacement.
In many of the postmarketing reports, and particularly in patients with type 1 diabetes, the presence of ketoacidosis was not immediately recognized and the institution of treatment was delayed because the presenting blood glucose levels were below those typically expected for diabetic ketoacidosis (often less than 250 mg/dL). Signs and symptoms at presentation were consistent with dehydration and severe metabolic acidosis and included nausea, vomiting, abdominal pain, generalized malaise, and shortness of breath. In some but not all cases, factors predisposing to ketoacidosis such as insulin dose reduction, acute febrile illness, reduced caloric intake due to illness or surgery, pancreatic disorders suggesting insulin deficiency (e.g., type 1 diabetes, history of pancreatitis or pancreatic surgery), and alcohol abuse were identified.
Before initiating FARXIGA, consider factors in the patient history that may predispose to ketoacidosis including pancreatic insulin deficiency from any cause, caloric restriction and alcohol abuse. In patients treated with FARXIGA consider monitoring for ketoacidosis and temporarily discontinuing FARXIGA in clinical situations known to predispose to ketoacidosis (e.g., prolonged fasting due to acute illness or surgery).
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.
Urosepsis And Pyelonephritis
There have been postmarketing reports of serious urinary tract infections including urosepsis and pyelonephritis requiring hospitalization 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].
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.
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.
There have been no clinical studies establishing conclusive evidence of macrovascular risk reduction with FARXIGA or any other antidiabetic drug.
Patient Counseling Information
See FDA-approved patient labeling (Medication Guide).
Instruct patients to read the Medication Guide before starting treatment with FARXIGA and to reread it each time the prescription is renewed.
Inform patients of the potential risks and benefits of FARXIGA and of alternative modes of therapy. Also inform patients about the importance of adherence to dietary instructions, regular physical activity, periodic blood glucose monitoring and HbA1c testing, recognition and management of hypoglycemia and hyperglycemia, and assessment of diabetes complications. Advise patients to seek medical advice promptly during periods of stress such as fever, trauma, infection, or surgery, as medication requirements may change.
Instruct patients to take FARXIGA only as prescribed. If a dose is missed, advise patients to take it as soon as it is remembered unless it is almost time for the next dose, in which case patients should skip the missed dose and take the medicine at the next regularly scheduled time. Advise patients not to take two doses of FARXIGA at the same time.
Inform patients that the most common adverse reactions associated with use of FARXIGA are genital mycotic infections, nasopharyngitis, and urinary tract infections.
Instruct patient to immediately inform her healthcare provider if she is pregnant or plans to become pregnant. Based on animal data, FARXIGA may cause fetal harm in the second and third trimesters of pregnancy.
Instruct patient to immediately inform her healthcare provider if she is breastfeeding or planning to breastfeed. It is not known if FARXIGA is excreted in breast milk; however, based on animal data, FARXIGA may cause harm to nursing infants.
Inform patients that symptomatic hypotension may occur with FARXIGA and advise them to contact their healthcare provider if they experience such symptoms [see WARNINGS AND PRECAUTIONS]. Inform patients that dehydration may increase the risk for hypotension, and to have adequate fluid intake.
Genital Mycotic Infections in Females (e.g., Vulvovaginitis)
Inform female patients that vaginal yeast infections may occur and provide them with information on the signs and symptoms of vaginal yeast infections. Advise them of treatment options and when to seek medical advice [see WARNINGS AND PRECAUTIONS].
Inform patients that ketoacidosis has been reported during use of FARXIGA. Instruct patients to check ketones (when possible) if symptoms consistent with ketoacidosis occur even if blood glucose is not elevated. If symptoms of ketoacidosis (including nausea, vomiting, abdominal pain, tiredness and labored breathing) occur, instruct patients to discontinue FARXIGA and seek medical advice immediately [see WARNINGS AND PRECAUTIONS].
Serious Urinary Tract Infections
Inform patients of the potential for urinary tract infections, which may be serious. Provide them with information on the symptoms of urinary tract infections. Advise them to seek medical advice promptly if such symptoms occur [see WARNINGS AND PRECAUTIONS].
Genital Mycotic Infections in Males (e.g., Balanitis)
Inform male patients that yeast infections of the penis (e.g., balanitis or balanoposthitis) may occur, especially in patients with prior history. Provide them with information on the signs and symptoms of balanitis and balanoposthitis (rash or redness of the glans or foreskin of the penis). Advise them of treatment options and when to seek medical advice [see WARNINGS AND PRECAUTIONS].
Inform patients that serious hypersensitivity reactions (e.g., urticaria and angioedema) have been reported with FARXIGA. Advise patients to immediately report any signs or symptoms suggesting allergic reaction or angioedema, and to take no more of the drug until they have consulted prescribing physicians.
Inform patients to promptly report any signs of macroscopic hematuria or other symptoms potentially related to bladder cancer.
Due to its mechanism of action, patients taking FARXIGA will test positive for glucose in their urine.
Carcinogenesis, Mutagenesis, Impairment Of Fertility
Dapagliflozin did not induce tumors in either mice or rats at any of the doses evaluated in 2-year carcinogenicity studies. Oral doses in mice consisted of 5, 15, and 40 mg/kg/day in males and 2, 10, and 20 mg/kg/day in females, and oral doses in rats were 0.5, 2, and 10 mg/kg/day for both males and females. The highest doses evaluated in mice were approximately 72 times (males) and 105 times (females) the clinical dose of 10 mg per day based on AUC exposure. In rats, the highest dose was approximately 131 times (males) and 186 times (females) the clinical dose of 10 mg per day based on AUC exposure.
Dapagliflozin was negative in the Ames mutagenicity assay and was positive in a series of in vitro clastogenicity assays in the presence of S9 activation and at concentrations ≥ 100 μg/mL. Dapagliflozin was negative for clastogenicity in a series of in vivo studies evaluating micronuclei or DNA repair in rats at exposure multiples > 2100 times the clinical dose.
There was no carcinogenicity or mutagenicity signal in animal studies, suggesting that dapagliflozin does not represent a genotoxic risk to humans.
Dapagliflozin had no effects on mating, fertility, or early embryonic development in treated male or female rats at exposure multiples ≤ 1708 times and 998 times the maximum recommended human dose in males and females, respectively.
Use In Specific Populations
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.
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.
Safety and effectiveness of FARXIGA in pediatric patients under 18 years of age have not been established.
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].
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.
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].This monograph has been modified to include the generic and brand name in many instances.
Last reviewed on RxList: 12/18/2015
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