Farxiga (dapagliflozin)

Dosage of dapagliflozin propanediol is expressed in terms of dapagliflozin.

Dapagliflozin is administered orally once daily. Dapagliflozin is commercially available as single-entity tablets that may be administered with or without food. Dapagliflozin is also available in fixed combination with saxagliptin (Qtern(R)) or extended-release metformin hydrochloride (Xigduo(R) XR); the fixed-combination dapagliflozin/saxagliptin tablets should be administered orally once daily in the morning, with or without food, and the fixed combination dapagliflozin/metformin tablets should be administered once daily in the morning with food to reduce the adverse GI effects of the metformin component. See the full prescribing information for additional administration instructions for the combination products.

If a dose of dapagliflozin is missed, the missed dose should be taken as soon as it is remembered followed by resumption of the regular schedule. If the missed dose is not remembered until it is almost time for the next dose, the missed dose should be skipped and the regular schedule resumed; the dose should not be doubled to replace a missed dose.

Store dapagliflozin tablets at 20 to 25oC (excursions permitted between 15 and 30oC).

The metabolism of dapagliflozin is primarily mediated by uridine diphosphate-glucuronosyltransferase (UGT) isoenzyme 1A9; cytochrome P450 (CYP)-mediated metabolism is a minor clearance pathway.

There are no contraindication interactions for this drug.

There are no severe interactions for this drug.

Moderate Interaction: Assess the risk to the patient and take action as needed.

Antidiabetic Agents/Gymnema

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: Gymnema has been shown to increase the number of insulin-secreting beta cells in animals. It has also been shown to increase the activity of enzymes responsible for glucose uptake and utilization and inhibit peripheral utilization of glucose.(1)

CLINICAL EFFECTS: Use of gymnema may result in decreased requirements of antidiabetic agents.(2-4)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: Diabetic patients should be carefully monitored if gymnema is initiated or discontinued from concurrent therapy. The dosage of the patient's antidiabetic agent(s) may need to be adjusted.(2)

DISCUSSION: In a study in 22 non-insulin-dependent patients, patients had decreased blood glucose, glycosylated hemoglobin, and glycosylated plasma proteins during gymnema therapy. Patients were able to decrease the dosage of their conventional antidiabetic therapy and five patients were able to discontinue their conventional antidiabetic therapy.(3) In a study in 27 insulin-dependent patients, patients had decreased insulin requirements, fasting blood glucose, glycosylated hemoglobin, and glycosylated plasma protein levels.(4)

Sglt2 Inhibitors/Loop Diuretics

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: SGLT2 inhibitors cause intravascular volume contraction through osmotic diuresis, which can result in hypotension in patients who are volume depleted from loop diuretic use.(1-7)

CLINICAL EFFECTS: Concurrent use of SGLT2 inhibitors with loop diuretics may result in dehydration, hypotension, and acute renal failure.(1-8)

PREDISPOSING FACTORS: This interaction may be more severe in patients who have a eGFR of less than 60 ml/min/1.73m2, are also taking ACE inhibitors or ARBs and/or NSAIDs, are on a low sodium diet, have low systolic blood pressure prior to initiating SGLT2 inhibitors, and/or are 65 years of age or older.(1-7)

PATIENT MANAGEMENT: Before initiating SGLT2 inhibitors in patients maintained on loop diuretics, assess volume status and correct if needed and also assess renal function. Patients receiving concurrent therapy should be monitored for hypotension and acute renal failure.(1-8)

DISCUSSION: In clinical trials of canagliflozin, volume depletion-related adverse effects were associated with the use of loop diuretics, moderate renal impairment (eGFR 30 ml/min/1.73m2 to less than 60 ml/min/1.73m2), and age 75 years and older. In a pool of eight Phase 3 clinical trials, 2.3% of all patients taking 100 mg of canagliflozin experienced at least one volume depletion-related event, compared to 3.2% of patients taking 100 mg of canagliflozin with a loop diuretic. 3.4% of all patients taking 300 mg of canagliflozin experienced at least one volume depletion-related event, compared to 8.8% of patients taking 300 mg of canagliflozin with a loop diuretic.(1,2) Cases of acute renal failure, most requiring hospitalization, have been reported in patients receiving canagliflozin and dapagliflozin. Twenty-six of 101 cases involved concurrent use of diuretics.(7) In a post-hoc analysis of the EMPEROR-Preserve trial, the combination of empagliflozin and diuretics was associated with a higher incidence of volume depletion events (HR 1.34; 95% CI, 1.13-1.59). The most commonly reported events were hypotension, syncope, and dehydration. Coadministration of diuretics and empagliflozin did not result in a difference in the incidence of acute renal failure, hyperkalemia, or adverse events leading to trial discontinuation (including fatal events) compared to empagliflozin alone. There was also no change in the benefit of empagliflozin for the primary end point of first hospitalization for heart failure or cardiovascular death.(8)

Sodium-Glucose Co-Transporter 2 (Sglt2) Inhibitors/Lithium

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: Sodium-glucose cotransporter 2 (SGLT2) inhibitors may increase the renal excretion of lithium by impairing the proximal tubular reabsorption of lithium.(1,2)

CLINICAL EFFECTS: Concurrent use of SGLT2 inhibitors may result in decreased levels and clinical effectiveness of lithium.(1-6)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: Lithium levels should be monitored more frequently when starting or changing the dose of SGLT2 inhibitors. The dose of lithium may need to be adjusted.(3-6)

DISCUSSION: A 29 year old patient stabilized on lithium with good therapeutic response was started on empagliflozin on day 10 of lithium therapy. Three days later, lithium level was subtherapeutic. Empagliflozin was stopped. After 1 week, lithium levels returned to therapeutic range. Two days later, the patient had another trial of empagliflozin and again developed subtherapeutic lithium levels.(1) A post hoc analysis of 2 dapagliflozin trials (IMPROVE and DapKid) examined the effects of dapagliflozin on volume status in diabetic patients with albuminuric kidney disease. Lithium excretion, which served as a marker of proximal tubular sodium excretion, was found to increase by 19.6% (p < 0.01).(2)

*History of serious hypersensitivity reaction to dapagliflozin or any ingredient in the formulation. Serious hypersensitivity reactions, including anaphylaxis and angioedema, have been reported in patients receiving the drug.

There are no contraindication contraindications for this drug.

• Chronic kidney disease stage 4 (severe) GFR 15-29 ml/min
• Chronic kidney disease stage 5 (failure) GFr<15 ml/min
• Hypoglycemic disorder
• Hypovolemia
• Invasive surgical procedure
• Necrotizing fasciitis of perineum or genital area
• Pregnancy
• Type 1 diabetes mellitus

There are no moderate contraindications for this drug.

The most common adverse effects of dapagliflozin monotherapy (>=5% of patients) reported in clinical studies include female genital mycotic infections, nasopharyngitis, and urinary tract infections.

The most common adverse effects of dapagliflozin in combination with extended-release metformin hydrochloride (>5% of patients) reported in clinical trials include female genital mycotic infections, nasopharyngitis, urinary tract infection, diarrhea, and headache.

The most common adverse effects of dapagliflozin in combination with saxagliptin (>=5% of patients) reported in clinical trials include upper respiratory tract infection, urinary tract infection, and dyslipidemia.

More Frequent

• Urinary tract infection

Less Frequent

• Dehydration
• Hypotension

Rare or Very Rare

• Acquired phimosis
• Acute kidney injury
• Angioedema
• Bacterial sepsis
• Diabetic ketoacidosis
• Fracture
• Hypersensitivity drug reaction
• Ketoacidosis
• Malignant tumor of urinary bladder
• Metabolic acidosis
• Necrotizing fasciitis of perineum or genital area
• Pancreatitis
• Pyelonephritis
• Urosepsis

More Frequent

• Pharyngitis
• Vulvovaginal candidiasis

Less Frequent

• Back pain
• Candidal balanitis
• Constipation
• Dysuria
• Genital organ pruritus
• Genitourinary tract infections
• Hypercholesterolemia
• Hyperphosphatemia
• Hypoglycemic disorder
• Hypovolemia
• Increased hemoglobin
• Increased urinary frequency
• Influenza
• Nausea
• Orthostatic hypotension

Rare or Very Rare

• Skin rash
• Urticaria

No enhanced messaging available.

The safety and effectiveness of dapagliflozin as an adjunct to diet and exercise to improve glycemic control in type 2 diabetes mellitus have been established in pediatric patients 10 years of age and older. Use of dapagliflozin for this indication is supported by a 26-week, placebo-controlled trial with a 26-week extension in 157 pediatric patients 10 to 17 years of age with type 2 diabetes mellitus, pediatric pharmacokinetic data, and trials in adults with type 2 diabetes mellitus. The safety profile observed in the placebo-controlled trial in pediatric patients with type 2 diabetes mellitus was similar to that observed in adults. Safety and efficacy of dapagliflozin have not been established in pediatric patients younger than 10 years of age for glycemic control in type 2 diabetes mellitus.

Safety and efficacy of dapagliflozin have not been established in pediatric patients for other indications.

There is insufficient evidence with dapagliflozin in pregnant women to evaluate a drug-associated risk of major birth defects or miscarriage. Based on the results of reproductive and developmental toxicity studies in animals, dapagliflozin use during pregnancy may affect renal development and maturation. 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 dosage.

Poorly controlled diabetes mellitus and untreated heart failure also are associated with risks to the mother and fetus, including DKA, preeclampsia, spontaneous abortions, preterm delivery, delivery complications, major birth defects, stillbirth, and macrosomia-related morbidity. The manufacturer states that dapagliflozin therapy is not recommended in pregnant women during the second and third trimesters of pregnancy.

There are no data on the presence of dapagliflozin in human milk, the effects on the breast-fed child, or the effects on milk production. Dapagliflozin is distributed into milk in rats. 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. Use of dapagliflozin in women who are breast-feeding is not recommended.

No adjustment of dapagliflozin dosage is necessary based solely on age.

Among patients with type 2 diabetes mellitus in 21 clinical trials, 1424 (24%) were 65 years of age or older and 207 (3.5%) were 75 years of age or older. Efficacy of dapagliflozin was similar for patients younger than 65 years of age and those 65 years of age or older after controlling for renal function (eGFR). Geriatric patients receiving dapagliflozin for glycemic control were more likely to experience hypotension compared with patients treated with placebo.

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 years of age. In the DAPA-CKD study, 42% of patients were older than 65 years of age. In the DAPA-HF study, 57% of patients were older than 65 years. In the DELIVER study, 76% of patients were older than 65 years.