DAPAGLIFLOZIN PROPANEDIOL Drug Interactions: What You Need to Know

INTERACTIONS Table 4: Clinically Relevant Interactions with DAPAGLIFLOZIN TABLETS Insulin or Insulin Secretagogues Clinical Impact The risk of hypoglycemia may be increased when DAPAGLIFLOZIN TABLETS are used concomitantly with insulin or insulin secretagogues (e.g., sulfonylurea) [see Warnings and Precautions (5.4) ] .

Intervention

Concomitant use may require lower doses of insulin or the insulin secretagogue 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 DAPAGLIFLOZIN TABLETS 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.

• See full prescribing information for information on drug interactions and interference of DAPAGLIFLOZIN TABLETS with laboratory tests. (7)

Drug Interactions In Vitro

Assessment of Drug Interactions In in vitro studies, dapagliflozin and dapagliflozin 3-O-glucuronide neither inhibited CYP 1A2, 2C9, 2C19, 2D6, or 3A4, nor induced CYP 1A2, 2B6, or 3A4. Dapagliflozin is a weak substrate of the P-glycoprotein (P-gp) active transporter, and dapagliflozin 3-O-glucuronide is a substrate for the OAT3 active transporter. Dapagliflozin or dapagliflozin 3-O-glucuronide did not meaningfully inhibit P-gp, OCT2, OAT1, or OAT3 active transporters. Overall, dapagliflozin is unlikely to affect the pharmacokinetics of concurrently administered medications that are P-gp, OCT2, OAT1, or OAT3 substrates. Effects of Other Drugs on Dapagliflozin Table 5 shows the effect of coadministered drugs on the pharmacokinetics of dapagliflozin in adults. No dose adjustments are recommended for dapagliflozin.

Table

5: Effects of Coadministered Drugs on Dapagliflozin Systemic Exposure Coadministered Drug (Dose Regimen) Single dose unless otherwise noted. Dapagliflozin (Dose Regimen) Effect on Dapagliflozin Exposure [% Change (90% CI)] C max AUC AUC = AUC(INF) for drugs given as single dose and AUC = AUC(TAU) for drugs given in multiple doses. No dosing adjustments required for the following: Oral Antidiabetic Agents Metformin (1000 mg) 20 mg ↔ ↔ Pioglitazone (45 mg) 50 mg ↔ ↔ Sitagliptin (100 mg) 20 mg ↔ ↔ Glimepiride (4 mg) 20 mg ↔ ↔ Voglibose (0.2 mg three times daily) 10 mg ↔ ↔ Other Medications Hydrochlorothiazide (25 mg) 50 mg ↔ ↔ Bumetanide (1 mg) 10 mg once daily for 7 days ↔ ↔ Valsartan (320 mg) 20 mg ↓12% [↓3%, ↓20%] ↔ Simvastatin (40 mg) 20 mg ↔ ↔ Anti-infective Agent Rifampin (600 mg once daily for 6 days) 10 mg ↓7% [↓22%, ↑11%] ↓22% [↓27%, ↓17%]

Nonsteroidal

Anti-inflammatory Agent Mefenamic Acid (loading dose of 500 mg followed by 14 doses of 250 mg every 6 hours) 10 mg ↑13% [↑3%, ↑24%] ↑51% [↑44%, ↑58%] ↔ = no change (geometric mean ratio of test: reference within 0.80 to 1.25); ↓ or ↑ = parameter was lower or higher, respectively, with coadministration compared to dapagliflozin administered alone (geometric mean ratio of test: reference was lower than 0.80 or higher than 1.25). Effects of Dapagliflozin on Other Drugs Table 6 shows the effect of dapagliflozin on other coadministered drugs in adults. Dapagliflozin did not meaningfully affect the pharmacokinetics of the coadministered drugs.

Table

6: Effects of Dapagliflozin on the Systemic Exposures of Coadministered Drugs Coadministered Drug (Dose Regimen) Single dose unless otherwise noted. Dapagliflozin (Dose Regimen) Effect on Coadministered Drug Exposure [% Change (90% CI)] C max AUC AUC = AUC(INF) for drugs given as single dose and AUC = AUC(TAU) for drugs given in multiple doses. No dosing adjustments required for the following: Oral Antidiabetic Agents Metformin (1000 mg) 20 mg ↔ ↔ Pioglitazone (45 mg) 50 mg ↓7% [↓25%, ↑15%] ↔ Sitagliptin (100 mg) 20 mg ↔ ↔ Glimepiride (4 mg) 20 mg ↔ ↑13% [0%, ↑29%]

Other Medications

Hydrochlorothiazide (25 mg) 50 mg ↔ ↔ Bumetanide (1 mg) 10 mg once daily for 7 days ↑13% [↓2%, ↑31%] ↑13% [↓1%, ↑30%] Valsartan (320 mg) 20 mg ↓6% [↓24%, ↑16%] ↑5% [↓15%, ↑29%] Simvastatin (40 mg) 20 mg ↔ ↑19% Digoxin (0.25 mg) 20 mg loading dose then 10 mg once daily for 7 days ↔ ↔ Warfarin (25 mg) 20 mg loading dose then 10 mg once daily for 7 days ↔ ↔ ↔ = no change (geometric mean ratio of test: reference within 0.80 to 1.25); ↓ or ↑ = parameter was lower or higher, respectively, with coadministration compared to the other medicine administered alone (geometric mean ratio of test: reference was lower than 0.80 or higher than 1.25).

Dapagliflozin and Metformin HCl extended-release tablets are contraindicated in patients with:

• Severe renal impairment (eGFR below 30 mL/min/1.73 m 2 ) or end-stage renal disease [see Warnings and Precautions (5.1) ] .
• History of a serious hypersensitivity reaction to dapagliflozin, metformin HCl, or any of the excipients in Dapagliflozin and Metformin HCl extended-release tablets. Serious hypersensitivity reactions, including anaphylaxis and angioedema have been reported with dapagliflozin [see Adverse Reactions (6.1) ] .
• Acute or chronic metabolic acidosis, including diabetic ketoacidosis, with or without coma. Diabetic ketoacidosis should be treated with insulin [see Warnings and Precautions (5.1) and Warnings and Precautions (5.2) ] .
• Severe renal impairment (eGFR below 30 mL/min/1.73 m 2 ) or end-stage renal disease. ( 4 )
• History of serious hypersensitivity to dapagliflozin, metformin HCl, or any of the excipients in Dapagliflozin and Metformin HCl extended-release tablets. ( 4 )
• Metabolic acidosis, including diabetic ketoacidosis. ( 4 )

AND PRECAUTIONS

• Lactic Acidosis : See boxed warning. ( 5.1 )
• Diabetic Ketoacidosis in Patients with Type 1 Diabetes Mellitus and Other Ketoacidosis: Consider ketone monitoring in patients at risk for ketoacidosis, as indicated. Assess for ketoacidosis regardless of presenting blood glucose levels and discontinue Dapagliflozin and Metformin HCl extended-release tablets if ketoacidosis is suspected. Monitor patients for resolution of ketoacidosis before restarting. (5.2)
• Volume Depletion: Before initiating Dapagliflozin and Metformin HCl extended-release tablets, assess and correct volume status in the elderly, patients with renal impairment or low systolic blood pressure, and in patients on diuretics. Monitor for signs and symptoms during therapy. (5.3 )
• Urosepsis and Pyelonephritis : Evaluate patients for signs and symptoms of urinary tract infections and treat promptly, if indicated. (5.4)
• Hypoglycemia : Consider a lower dosage of insulin or an insulin secretagogue to reduce the risk of hypoglycemia when used concomitantly with Dapagliflozin and Metformin HCl extended-release tablets. (5.5)
• Necrotizing Fasciitis of the Perineum (Fournier’s Gangrene): Serious, life-threatening cases have occurred in both females and males. Assess patients presenting with pain or tenderness, erythema, or swelling in the genital or perineal area, along with fever or malaise. If suspected, institute prompt treatment. (5.6)
• Vitamin B 12 Deficiency : Metformin may lower vitamin B 12 levels. Measure hematological parameters annually. ( 5.7 )
• Genital Mycotic Infections : Monitor and treat if indicated. (5.8)

5.1 Lactic Acidosis There have been post-marketing cases of metformin-associated lactic acidosis, including fatal cases. These cases had a subtle onset and were accompanied by non-specific symptoms such as malaise, myalgias, abdominal pain, respiratory distress, or increased somnolence; however, hypothermia, hypotension and resistant bradyarrhythmias have occurred with severe acidosis. Metformin-associated lactic acidosis was characterized by elevated blood lactate concentrations (>5 mmol/L), anion gap acidosis (without evidence of ketonuria or ketonemia), and an increased lactate: pyruvate ratio; metformin plasma levels generally >5 mcg/mL. Metformin decreases liver uptake of lactate increasing lactate blood levels which may increase the risk of lactic acidosis, especially in patients at risk. If metformin-associated lactic acidosis is suspected, general supportive measures should be instituted promptly in a hospital setting, along with immediate discontinuation of Dapagliflozin and Metformin HCl extended-release tablets.

In

Dapagliflozin and Metformin HCl extended-release tablets-treated patients with a diagnosis or strong suspicion of lactic acidosis, prompt hemodialysis is recommended to correct the acidosis and remove accumulated metformin (metformin HCl is dialyzable, with a clearance of up to 170 mL/min under good hemodynamic conditions). Hemodialysis has often resulted in reversal of symptoms and recovery. Educate patients and their families about the symptoms of lactic acidosis and if these symptoms occur, instruct them to discontinue Dapagliflozin and Metformin HCl extended-release tablets and report these symptoms to their healthcare provider. For each of the known and possible risk factors for metformin-associated lactic acidosis, recommendations to reduce the risk of and manage metformin-associated lactic acidosis are provided below: Renal Impairment : The postmarketing metformin-associated lactic acidosis cases primarily occurred in patients with significant renal impairment. The risk of metformin accumulation and metformin-associated lactic acidosis increases with the severity of renal impairment because metformin is substantially excreted by the kidney. Clinical recommendations based upon the patient’s renal function include [see Dosage and Administration (2.1 , 2.4 ) and Clinical Pharmacology (12.3) ] :

• Before initiating Dapagliflozin and Metformin HCl extended-release tablets, obtain an estimated glomerular filtration rate (eGFR).
• Dapagliflozin and Metformin HCl extended-release tablets are contraindicated in patients with an eGFR less than 30 mL/min/1.73 m 2 [see Contraindications (4) ] .
• Obtain an eGFR at least annually in all patients taking Dapagliflozin and Metformin HCl extended-release tablets. In patients at increased risk for the development of renal impairment (e.g., the elderly), renal function should be assessed more frequently.

Drug

Interactions: The concomitant use of Dapagliflozin and Metformin HCl extended-release tablets with specific drugs may increase the risk of metformin-associated lactic acidosis: those that impair renal function, result in significant hemodynamic change, interfere with acid-base balance or increase metformin accumulation (e.g., cationic drugs) [see Drug Interactions (7) ] . Therefore, consider more frequent monitoring of patients.

Age

65 or Greater: The risk of metformin-associated lactic acidosis increases with the patient’s age because elderly patients have a greater likelihood of having hepatic, renal, or cardiac impairment than younger patients. Assess renal function more frequently in elderly patients [see Use in Specific Populations (8.5) ] .

Radiological

Studies with Contrast: Administration of intravascular iodinated contrast agents in metformin-treated patients has led to an acute decrease in renal function and the occurrence of lactic acidosis.

Stop

Dapagliflozin and Metformin HCl extended-release tablets at the time of, or prior to, an iodinated contrast imaging procedure in patients with a history of hepatic impairment, alcoholism, or heart failure; or in patients who will be administered intra-arterial iodinated contrast. Re-evaluate eGFR 48 hours after the imaging procedure, and restart Dapagliflozin and Metformin HCl extended-release tablets if renal function is stable. Surgery and Other Procedures: Withholding of food and fluids during surgical or other procedures may increase the risk for volume depletion, hypotension and renal impairment. Dapagliflozin and Metformin HCl extended-release tablets should be temporarily discontinued while patients have restricted food and fluid intake.

Hypoxic

States: Several of the postmarketing cases of metformin-associated lactic acidosis occurred in the setting of acute congestive heart failure (particularly when accompanied by hypoperfusion and hypoxemia). Cardiovascular collapse (shock), acute myocardial infarction, sepsis, and other conditions associated with hypoxemia have been associated with lactic acidosis and may also cause prerenal azotemia. When such events occur, discontinue Dapagliflozin and Metformin HCl extended-release tablets.

Excessive Alcohol

Intake: Alcohol potentiates the effect of metformin on lactate metabolism and this may increase the risk of metformin-associated lactic acidosis. Warn patients against excessive alcohol intake while receiving Dapagliflozin and Metformin HCl extended-release tablets.

Hepatic

Impairment: Patients with hepatic impairment have developed with cases of metformin-associated lactic acidosis. This may be due to impaired lactate clearance resulting in higher lactate blood levels. Therefore, avoid use of Dapagliflozin and Metformin HCl extended-release tablets in patients with clinical or laboratory evidence of hepatic disease.

5.2 Diabetic Ketoacidosis in Patients with Type 1 Diabetes Mellitus and Other Ketoacidosis In patients with type 1 diabetes mellitus, dapagliflozin, a component of Dapagliflozin and Metformin HCl extended-release tablets, 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. Dapagliflozin and Metformin HCl extended-release tablets are 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 dapagliflozin. 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 Dapagliflozin and Metformin HCl extended-release tablets [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 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 Dapagliflozin and Metformin HCl extended-release tablets, promptly evaluate, and treat ketoacidosis, if confirmed. Monitor patients for resolution of ketoacidosis before restarting Dapagliflozin and Metformin HCl extended-release tablets.

Withhold

Dapagliflozin and Metformin HCl extended-release tablets, if possible, in temporary clinical situations that could predispose patients to ketoacidosis.

Resume

Dapagliflozin and Metformin HCl extended-release tablets when the patient is clinically stable and has resumed oral intake [see Dosage and Administration (2.6) ] . Educate all patients on the signs and symptoms of ketoacidosis and instruct patients to discontinue Dapagliflozin and Metformin HCl extended-release tablets and seek medical attention immediately if signs and symptoms occur.

5.3 Volume Depletion Dapagliflozin 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 dapagliflozin. Patients with impaired renal function (eGFR less than 60 mL/min/1.73 m 2 ), elderly patients, or patients on loop diuretics may be at increased risk for volume depletion or hypotension. Before initiating Dapagliflozin and Metformin HCl extended-release tablets 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.

5.4 Urosepsis and Pyelonephritis Serious urinary tract infections including urosepsis and pyelonephritis requiring hospitalization have been reported in patients receiving SGLT2 inhibitors, including dapagliflozin. 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 <span class="opacity-50 text-xs">[see Adverse Reactions (6.2) ]</span> .

5.5 Hypoglycemia with Concomitant Use with Insulin or Insulin Secretagogues Insulin and insulin secretagogues (e.g., sulfonylureas) are known to cause hypoglycemia. Dapagliflozin and Metformin HCl extended-release tablets may increase the risk of hypoglycemia when combined with insulin and/or an insulin secretagogue <span class="opacity-50 text-xs">[see Adverse Reactions (6.1) ]</span> . The risk of hypoglycemia may be lowered by a reduction in the dose of sulfonylurea (or other concomitantly administered insulin secretagogues) or insulin. Inform patients using these concomitant medications of the risk of hypoglycemia and educate them on the signs and symptoms of hypoglycemia.

5.6 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 dapagliflozin. Cases have been reported in both females and males. Serious outcomes have included hospitalization, multiple surgeries, and death. Patients treated with Dapagliflozin and Metformin HCl extended-release tablets 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

Dapagliflozin and Metformin HCl extended-release tablets, closely monitor blood glucose levels, and provide appropriate alternative therapy for glycemic control.

5.7 Vitamin B 12 Concentrations In controlled clinical trials of metformin of 29-week duration, a decrease to subnormal levels of previously normal serum vitamin B 12 levels, without clinical manifestations, was observed in approximately 7% of patients. Such decrease, possibly due to interference with B 12 absorption from the B 12 -intrinsic factor complex, may be associated with anemia but appears to be rapidly reversible with discontinuation of metformin or vitamin B 12 supplementation. Certain individuals (those with inadequate vitamin B 12 or calcium intake or absorption) appear to be predisposed to developing subnormal vitamin B 12 levels. Measure hematologic parameters on an annual basis and vitamin B 12 at 2- to 3-year intervals in patients on Dapagliflozin and Metformin HCl extended-release tablets and manage any abnormalities <span class="opacity-50 text-xs">[see Adverse Reactions (6.1) ]</span> .

5.8 Genital Mycotic Infections Dapagliflozin increases the risk of genital mycotic infections. Patients with a history of genital mycotic infections were more likely to develop genital mycotic infections <span class="opacity-50 text-xs">[see Adverse Reactions (6.1) ]</span> . Monitor and treat appropriately.