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JANSSEN PHARM.
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Uses

Diabetes Mellitus

Canagliflozin is used as monotherapy as an adjunct to diet and exercise to improve glycemic control in patients with type 2 diabetes mellitus. Canagliflozin is also used in combination with other antidiabetic agents (e.g., metformin, a sulfonylurea, a peroxisome proliferator-activated receptorγ [PPARγ] agonist [thiazolidinedione]) or insulin as an adjunct to diet and exercise in patients with type 2 diabetes mellitus who have not achieved adequate glycemic control.

Canagliflozin should not be used in patients with type 1 diabetes mellitus or for the treatment of diabetic ketoacidosis.

Canagliflozin Monotherapy

When given as monotherapy for the management of type 2 diabetes mellitus, canagliflozin improves glycemic control compared with placebo as evidenced by reductions in glycosylated hemoglobin HbA1c and in fasting and 2-hour postprandial plasma glucose concentrations. Efficacy of canagliflozin as monotherapy for the management of type 2 diabetes mellitus has been established in a double-blind, placebo-controlled study of 26 weeks' duration. Canagliflozin (100 or 300 mg once daily) improved glycemic control as evidenced by reductions in HbA1c and fasting and 2-hour postprandial plasma glucose concentrations. HbA1c was reduced by 0.77 or 1% in patients receiving canagliflozin 100 or 300 mg once daily, respectively, compared with an increase of 0.1% in those receiving placebo. Patients receiving canagliflozin 100 or 300 mg once daily also lost substantially more body weight (2.8 or 3.9%, respectively) than those receiving placebo (0.6%).

Combination Therapy

When given in combination with one or more oral antidiabetic agents or insulin, canagliflozin improves glycemic control compared with monotherapy with these drugs and generally is associated with reductions in body weight. Canagliflozin generally is well tolerated, although genital mycotic infections appear to be more common with canagliflozin than with other antidiabetic agents.(See Genital Mycotic Infections under Cautions: Warnings/Precautions.)

Efficacy of canagliflozin in combination with metformin, a sulfonylurea, and/or a thiazolidinedione for the management of type 2 diabetes mellitus (in patients inadequately controlled with metformin, a sulfonylurea, and/or a thiazolidinedione monotherapy) is supported by results from several long-term, randomized, active- or placebo-controlled trials. In these trials, the addition of canagliflozin (100 or 300 mg once daily) to existing therapy improved glycemic control as evidenced by reductions in HbA1c, fasting plasma glucose, 2-hour postprandial plasma glucose concentrations, and/or body weight compared with placebo. In a 26-week study in patients receiving metformin hydrochloride therapy (dosage of at least 1.5 g daily), the addition of canagliflozin resulted in a reduction of 0.8-0.9% in HbA1c, while HbA1c was increased by 0.1% with add-on placebo. In a 52-week study in patients receiving metformin hydrochloride therapy (dosage of at least 1.5 g daily), canagliflozin 100 mg once daily was noninferior to glimepiride (titrated to 6 or 8 mg once daily), and canagliflozin 300 mg once daily was superior to glimepiride, in reducing HbA1c; patients achieved reductions of 0.8, 0.9, or 0.8% in HbA1c with canagliflozin 100 mg, canagliflozin 300 mg, or glimepiride, respectively. In an 18-week trial in patients receiving a sulfonylurea (generally glimepiride, glyburide [glibenclamide], or gliclazide [not commercially available in the US]), add-on therapy with canagliflozin 100 or 300 mg once daily resulted in a reduction in HbA1c of 0.74 or 0.83%, respectively, compared with placebo.

Efficacy and safety of the combination of canagliflozin and metformin as initial therapy in patients with type 2 diabetes mellitus inadequately controlled with diet and exercise is supported by results of a 26-week, randomized, double-blind trial. In this trial, concurrent therapy with canagliflozin (100 or 300 mg once daily) and metformin hydrochloride extended-release (dosage of at least 1.5 g daily; 90% of patients achieved a dosage of 2 g daily) substantially improved glycemic control (as evidenced by reductions in HbA1c) compared with canagliflozin or metformin hydrochloride monotherapy. Reductions in HbA1c were 1.77 or 1.78% with canagliflozin 100 or 300 mg once daily, respectively, plus metformin hydrochloride; 1.37 or 1.42% with canagliflozin 100 or 300 mg once daily, respectively; and 1.3% with metformin hydrochloride monotherapy. Additionally, a greater percentage of patients achieved an HbA1c of less than 7% with canagliflozin and metformin combination therapy compared with canagliflozin or metformin hydrochloride monotherapy.

In a 26-week trial in patients receiving metformin hydrochloride (dosage of at least 1.5 g daily) and a sulfonylurea (sulfonylurea not specified), addition of canagliflozin 100 or 300 mg once daily resulted in a reduction in HbA1c of 0.85 or 1.06%, respectively, compared with a 0.13% reduction in HbA1c with placebo. In a 52-week study in patients receiving metformin hydrochloride (dosage of at least 1.5 g daily) and a sulfonylurea (generally glipizide, glyburide [glibenclamide], or gliclazide [not commercially available in the US]), addition of canagliflozin 300 mg or sitagliptin 100 mg resulted in a reduction in HbA1c of 1 or 0.6%, respectively. Canagliflozin was noninferior to sitagliptin and demonstrated superiority to sitagliptin in reducing HbA1c in subsequent analyses. In a 26-week trial in patients inadequately controlled on metformin hydrochloride (dosage of at least 1.5 g daily) and sitagliptin (100 mg daily), the addition of canagliflozin (100 mg daily titrated to 300 mg daily) resulted in a substantial reduction in HbA1c from baseline at 26 weeks compared with the addition of placebo (reduction of 0.83 versus 0.03%, respectively).

In a 26-week trial in patients receiving metformin hydrochloride (dosage of at least 1.5 g daily) and pioglitazone (30 or 45 mg daily), addition of canagliflozin 100 or 300 mg once daily or placebo resulted in a reduction in HbA1c of approximately 0.9, 1, or 0.3%, respectively.

Efficacy of canagliflozin in combination with insulin in the management of type 2 diabetes mellitus in patients who have inadequate glycemic control with insulin is supported by results of an 18-week, randomized, placebo-controlled trial. In this trial, addition of canagliflozin (100 or 300 mg daily) to existing insulin therapy resulted in improvements in HbA1c, fasting plasma glucose, and body weight. In patients who received canagliflozin 100 or 300 mg as add-on therapy to insulin, 20 or 25%, respectively, had HbA1c reductions to less than 7%, compared with 8% of patients receiving add-on placebo.

Dosage and Administration

Administration

Canagliflozin should be administered orally once daily, before the first meal of the day.

If a dose 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 the time of 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.

Dosage

Dosage of canagliflozin is expressed in terms of anhydrous canagliflozin.

The recommended initial dosage of canagliflozin for the management of type 2 diabetes mellitus is 100 mg once daily, taken before the first meal of the day. If well tolerated, the dosage may be increased to 300 mg once daily in patients with an estimated glomerular filtration rate (eGFR) of at least 60 mL/minute per 1.73 m who require additional glycemic control.

Patients with volume depletion should have this condition corrected before initiation of canagliflozin therapy.

Special Populations

No dosage adjustment is necessary in patients with mild or moderate hepatic impairment. Data are lacking on use of canagliflozin in patients with severe hepatic impairment, and the manufacturer states that such use is not recommended.

No dosage adjustment is necessary in patients with mild renal impairment (eGFR of at least 60 mL/minute per 1.73 m). The recommended dosage in patients with moderate renal impairment (eGFR 45 to less than 60 mL/minute per 1.73 m) is 100 mg once daily. Initiation of canagliflozin is not recommended in patients with an eGFR of less than 45 mL/minute per 1.73 m. Continued use of canagliflozin is not recommended in patients with an eGFR persistently less than 45 mL/minute per 1.73 m. The drug is contraindicated in patients with an eGFR less than 30 mL/minute per 1.73 m.

The manufacturer makes no specific dosage recommendations for geriatric patients.

Cautions

Contraindications

History of serious hypersensitivity reactions (e.g., anaphylaxis, angioedema) to canagliflozin.

Severe renal impairment (estimated glomerular filtration rate [eGFR] less than 30 mL/minute per 1.73 m), end-stage renal disease, or on hemodialysis.

Warnings/Precautions

Warnings

Lower Limb Amputation

In 2 randomized, placebo-controlled studies (Canagliflozin Cardiovascular Assessment Study [CANVAS] and CANVAS-R) evaluating the effects of canagliflozin on the risk of cardiovascular disease and the overall safety and tolerability of the drug, canagliflozin-treated patients had a twofold increased risk of lower limb (leg and foot) amputations (mostly affecting the toes and midfoot) compared with placebo. In the CANVAS study, canagliflozin- or placebo-treated patients had 5.9 or 2.8 amputations per 1000 patients per year, respectively; the amputation rate in the CANVAS-R trial was 7.5 or 4.2 per 1000 patients per year with canagliflozin or placebo, respectively. Amputations below and above the knee also occurred, and some patients had more than one amputation (some involving both lower limbs). The increased risk of lower limb amputation was observed with both the 100- and 300-mg daily dosage regimens. Patients with a baseline history of prior amputation, peripheral vascular disease, or neuropathy were at greatest risk for amputation. The most common precipitating medical events leading to an amputation were lower limb infections, gangrene, diabetic foot ulcers, and ischemia.

Prior to initiating therapy with canagliflozin, clinicians should consider patient factors that may predispose them to the need for amputation, such as a history of amputation, peripheral vascular disease, neuropathy, or diabetic foot ulcers. Clinicians should monitor patients receiving canagliflozin for the presence of infection (including osteomyelitis), new pain or tenderness, and sores or ulcers involving the lower limbs; canagliflozin should be discontinued if such complications occur. Patients should also be counseled on the importance of routine preventative foot care.

Sensitivity Reactions

Hypersensitivity reactions (e.g., generalized urticaria), some serious, have been reported with canagliflozin treatment. These reactions generally occurred within hours to days of canagliflozin initiation. If a hypersensitivity reaction occurs, the drug should be discontinued, appropriate treatment instituted, and the patient monitored until signs and symptoms resolve.

Other Warnings/Precautions

Use of Fixed Combinations

When canagliflozin is used in fixed combination with other drugs (e.g., metformin), cautions, precautions, contraindications, and interactions associated with the concomitant agent(s) should be considered in addition to those associated with canagliflozin.

Ketoacidosis

Use of sodium glucose cotransporter 2 (SGLT2) inhibitors (canagliflozin, dapagliflozin, empagliflozin) in patients with type 2 diabetes mellitus may lead to ketoacidosis requiring hospitalization. Ketoacidosis associated with use of SGLT2 inhibitors may be present without markedly elevated blood glucose concentrations (e.g., less than 250 mg/dL).

FDA identified 73 cases of acidosis (reported as diabetic ketoacidosis [DKA], ketoacidosis, or ketosis) associated with SGLT2 inhibitor use in the FDA Adverse Event Reporting System (FAERS) between March 2013 and May 2015. DKA had an atypical presentation in most of the reported cases in that type 2 diabetes mellitus was noted as the indication for the drug, and glucose concentrations were only slightly elevated (median: 211 mg/dL); type 1 diabetes mellitus was named as the indication in a few cases, and in some reports the indication was not specified. The median time to onset of symptoms of acidosis following initiation or increase in dosage of the SGLT2 inhibitor was 43 days (range: 1-365 days). No trend demonstrating a relationship between the dosage of an SGLT2 inhibitor and the risk of ketoacidosis was identified. In all reported episodes, a diagnosis of DKA or ketoacidosis was made by the clinician and hospitalization or treatment in an emergency department was warranted. In most cases, at least 1 diagnostic laboratory criterion suggestive of ketoacidosis (e.g., high anion gap metabolic acidosis, ketonemia, reduced serum bicarbonate) was reported. Most cases of ketoacidosis were associated with a concurrent event, most commonly dehydration, infection, or change in insulin dosage. Potential factors for development of ketoacidosis with SGLT2 inhibitor therapy identified in the 73 cases included infection, low carbohydrate diet or reduced caloric intake (due to illness or surgery), pancreatic disorders suggesting insulin deficiency (e.g., type 1 diabetes mellitus, history of pancreatitis, pancreatic surgery), reduced dosage or discontinuance of insulin, discontinuance of an oral insulin secretagogue, and alcohol use.

Prior to initiating therapy with an SGLT2 inhibitor, clinicians should consider patient factors that may predispose the patient to ketoacidosis, such as pancreatic insulin deficiency from any cause, reduced caloric intake, and alcohol abuse. Clinicians should evaluate for the presence of acidosis, including ketoacidosis, in patients experiencing signs or symptoms of acidosis while receiving SGLT2 inhibitors, regardless of the patient's blood glucose concentration. Additionally, clinicians should consider monitoring for ketoacidosis and temporarily discontinuing therapy with an SGLT2 inhibitor in clinical situations known to predispose individuals to ketoacidosis (e.g., prolonged fasting due to acute illness or surgery). If acidosis is confirmed, the SGLT2 inhibitor should be discontinued and appropriate treatment initiated to correct the acidosis; glucose concentrations should be monitored appropriately. In addition, supportive medical treatment should be instituted to treat and correct factors that may have precipitated or contributed to the metabolic acidosis. Euglycemic DKA associated with SGLT2 inhibitors may be detected and potentially prevented by having patients monitor urine and/or plasma ketone levels if they feel unwell, regardless of ambient glucose concentrations. Clinicians should inform patients and caregivers of the signs and symptoms of ketoacidosis (e.g., tachypnea or hyperventilation, anorexia, abdominal pain, nausea, vomiting, lethargy, mental status changes) and instruct patients to discontinue the SGLT2 inhibitor and immediately seek medical attention should they experience such signs or symptoms.

Hypotension

Canagliflozin may cause intravascular volume contraction. Following initiation of canagliflozin, symptomatic hypotension can occur, particularly in patients with impaired renal function (eGFR less than 60 mL/minute per 1.73 m), geriatric patients, patients receiving diuretics or drugs that interfere with the renin-angiotensin-aldosterone system (e.g., angiotensin-converting enzyme [ACE] inhibitors, angiotensin II receptor antagonists), or patients with low systolic blood pressure. (See Drug Interactions: Drugs Affecting the Renin-Angiotensin System, and also see Drug Interactions: Diuretics.) Prior to initiating canagliflozin in such patients, intravascular volume should be assessed and corrected. Patients should be monitored for signs and symptoms of hypotension after initiating canagliflozin therapy.

Renal Effects

Canagliflozin causes intravascular volume contraction and can cause renal impairment. Canagliflozin may increase serum creatinine concentration and decrease eGFR; patients with hypovolemia may be more susceptible to these changes. Abnormalities in renal function can occur following initiation of the drug. Patients should be monitored for acute kidney injury, and more frequent monitoring is recommended for patients with an eGFR less than 60 mL/minute per 1.73 m. If acute kidney injury occurs during canagliflozin therapy, the drug should be discontinued and appropriate treatment initiated.

FDA identified 101 cases of acute kidney injury associated with canagliflozin or dapagliflozin therapy in FAERS between March 2013 and October 2015. Hospitalization for evaluation and management of kidney injury was warranted in most cases, and some cases required admission to an intensive care unit and initiation of dialysis. In approximately half of the cases, onset of acute kidney injury occurred within 1 month or less of initiating canagliflozin or dapagliflozin therapy, and most patients' kidney function improved after stopping the drug. However, kidney injury may not be fully reversible in some situations and has led to death in some patients.

Prior to initiating canagliflozin therapy, clinicians should consider patient factors that may predispose the patient to acute kidney injury, including hypovolemia, chronic renal insufficiency, heart failure, and concomitant drug therapy (e.g., diuretics, angiotensin converting enzyme [ACE] inhibitors, angiotensin II receptor antagonists, nonsteroidal anti-inflammatory agents [NSAIAs]). Clinicians should consider temporarily discontinuing canagliflozin in any setting of reduced oral intake (e.g., acute illness, fasting) or fluid losses (e.g., GI illness, excessive heat exposure).

Hyperkalemia

Use of canagliflozin may cause hyperkalemia, particularly in patients with moderate renal impairment who are taking drugs that interfere with potassium excretion (e.g., potassium-sparing diuretics) or drugs that interfere with the renin-angiotensin-aldosterone system. (See Drug Interactions: Drugs Affecting the Renin-Angiotensin System, and also see Drug Interactions: Diuretics.) Serum potassium concentrations should be monitored periodically following initiation of canagliflozin in patients with impaired renal function and in those predisposed to hyperkalemia due to drug therapy or other medical conditions.

Concomitant Therapy with Hypoglycemic Agents

When canagliflozin is added to therapy with an insulin secretagogue (e.g., a sulfonylurea) or insulin, the risk of hypoglycemia is increased compared with sulfonylurea or insulin monotherapy. Therefore, patients receiving canagliflozin may require a reduced dosage of the concomitant insulin secretagogue or insulin to reduce the risk of hypoglycemia.(See Drug Interactions: Antidiabetic Agents.)

Genital Mycotic Infections

Canagliflozin may increase the risk of genital mycotic infections in males (e.g., balanoposthitis, candidal balanitis) and females (e.g., vulvovaginal candidiasis, vulvovaginal mycotic infection, vulvovaginitis). In clinical trials, patients with a history of genital mycotic infections and uncircumcised males were more likely to develop such infections. Patients should be monitored for genital mycotic infections and appropriate treatment should be instituted if these infections occur.

Urosepsis and Pyelonephritis

Canagliflozin may increase the risk of serious urinary tract infections.

FDA identified 19 cases of urosepsis and pyelonephritis, which began as urinary tract infections associated with SGLT2 inhibitor use, in FAERS between March 2013 and October 2014. In all cases reported, hospitalization was warranted and some patients required admission to an intensive care unit or dialysis for treatment. The median time to onset of infection following initiation of the SGLT2 inhibitor was 45 days (range: 2-270 days).

Prior to initiating therapy with an SGLT2 inhibitor, clinicians should consider patient factors that may predispose them to serious urinary tract infections, such as a history of difficulty urinating or infections of the bladder, kidneys, or urinary tract. Patients should be monitored for urinary tract infections and treatment instituted if indicated.

Risk of Bone Fracture

Pooled data from 9 clinical trials representing a mean canagliflozin exposure of 85 weeks indicate an increased risk of bone fracture in patients receiving the drug. Fractures were observed as early as 12 weeks after initiation of treatment and were more likely to affect the upper extremities and be associated with minor trauma (e.g., falls from no greater than standing height). Dose-related decreases in bone mineral density (e.g., hip and lumbar spine) also have been observed in older adults (mean age: 64 years) receiving canagliflozin therapy over a period of 2 years. Clinicians should consider factors that contribute to fracture risk and counsel patients about such factors prior to initiating canagliflozin therapy.(See Advice to Patients.)

Effects on Lipoproteins

Dose-related increases in low-density lipoprotein (LDL)-cholesterol have been observed during canagliflozin therapy. Serum LDL-cholesterol concentrations should be monitored during treatment with canagliflozin and such lipid elevations treated if appropriate.

Macrovascular Outcomes

Evidence of macrovascular risk reduction with canagliflozin or any other antidiabetic agent has not been conclusively demonstrated in clinical trials.

Laboratory Test Interferences

SGLT2 inhibitors such as canagliflozin increase urinary glucose excretion and will result in false-positive urine glucose tests. In addition, the manufacturer states that the 1,5-anhydroglucitol assay is unreliable for monitoring glycemic control in patients taking SGLT2 inhibitors. Alternative methods of monitoring glycemic control should be used in patients receiving SGLT2 inhibitors.

Specific Populations

Pregnancy

Based on the results of reproductive and developmental toxicity studies in animals, canagliflozin use during pregnancy may affect renal development and maturation, especially during the second and third trimesters of pregnancy. Limited data with canagliflozin in pregnant women are not sufficient to determine a drug-associated risk for major birth defects or miscarriage, and poorly controlled diabetes mellitus during pregnancy carries risks to the mother and fetus; however, canagliflozin therapy is not recommended in pregnant women during the second and third trimesters of pregnancy.

Lactation

Canagliflozin is distributed into milk in rats; it is not known whether the drug is distributed into human milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from canagliflozin, use of the drug is not recommended while breastfeeding.

Pediatric Use

Safety and efficacy of canagliflozin have not been established in pediatric patients younger than 18 years of age.

Geriatric Use

Among patients in 9 randomized trials, 2034 were 65 years of age or older and 345 were 75 years of age or older, including one trial in patients 55 to 80 years of age. Geriatric patients experienced reduced efficacy of canagliflozin compared with younger patients, which may be related to decreased renal function in geriatric patients. Geriatric patients also were more likely to experience certain adverse effects related to reduced intravascular volume (e.g., hypotension, postural dizziness, orthostatic hypotension, syncope, dehydration) with canagliflozin, particularly those receiving 300 mg daily.

Hepatic Impairment

Compared with values in individuals with normal hepatic function, canagliflozin area under the concentration-time curve (AUC) and peak plasma concentrations were increased by 10 and 7%, respectively (based on geometric mean ratios), in patients with mild hepatic impairment (Child-Pugh class A) following a single 300-mg dose of the drug; canagliflozin AUC was increased by 11% and peak plasma concentration was decreased by 4% in patients with moderate hepatic impairment (Child-Pugh class B). These differences were not considered clinically important.

Data are lacking on the use of canagliflozin in patients with severe hepatic impairment (Child-Pugh class C), and such use is not recommended.

Renal Impairment

Safety and efficacy of canagliflozin were evaluated in a study that included 269 patients with moderate renal impairment (eGFR 30 to less than 50 mL/minute per 1.73 m) and type 2 diabetes mellitus. These patients experienced less overall improvement in glycemic control and had higher rates of adverse reactions related to reduced intravascular volume, renal-related adverse reactions, and decreases in eGFR compared with those who had mild renal impairment or normal renal function. Patients receiving canagliflozin 300 mg were more likely to experience increases in serum potassium concentrations.

Renal impairment did not affect peak plasma concentrations of canagliflozin. In patients with mild (eGFR 60 to less than 90 mL/minute per 1.73 m), moderate (eGFR 30 to less than 60 mL/minute per 1.73 m), or severe renal impairment (eGFR less than 30 mL/minute per 1.73 m), canagliflozin AUC was increased by 15, 29, or 53%, respectively, compared with that in healthy individuals following a single 200-mg dose of the drug.

Renal function should be assessed prior to initiation of therapy and periodically thereafter.

Common Adverse Effects

Adverse effects reported in at least 2% of patients receiving canagliflozin in clinical trials and more frequently than with placebo include female genital mycotic infections, urinary tract infection, increased urination, male genital mycotic infections, vulvovaginal pruritus, thirst, constipation, and nausea.

Drug Interactions

The major metabolic elimination pathway for canagliflozin is O-glucuronidation; the drug is mainly glucuronidated by uridine diphosphate-glucuronosyltransferase (UGT) isoenzymes UGT1A9 and UGT2B4.

Canagliflozin is a P-glycoprotein substrate and weakly inhibits P-glycoprotein. Canagliflozin also is a substrate of MRP2.

Drugs Affecting or Metabolized by Hepatic Microsomal Enzymes

Canagliflozin did not induce cytochrome P-450 (CYP) isoenzymes 3A4, 2C9, 2C19, 2B6, or 1A2 in cultured human hepatocytes. Canagliflozin also does not inhibit CYP isoenzymes 1A2, 2A6, 2C19, 2D6, or 2E1 but weakly inhibits CYP2B6, 2C8, 2C9, and 3A4 in human hepatic microsomes.

Drugs Affecting the Renin-Angiotensin System

Concomitant use of canagliflozin with drugs that interfere with the renin-angiotensin-aldosterone system, including angiotensin-converting enzyme (ACE) inhibitors or angiotensin II receptor antagonists, may increase the incidence of symptomatic hypotension. Prior to initiating canagliflozin in such patients, intravascular volume should be assessed and corrected; patients should be monitored for signs and symptoms of hypotension after initiating therapy.(See Hypotension under Cautions: Warnings/Precautions.) These drugs also may cause hyperkalemia in patients with moderate renal impairment. Serum potassium concentrations should be monitored periodically following initiation of canagliflozin in patients predisposed to hyperkalemia due to drug therapy.(See Hyperkalemia under Cautions: Warnings/Precautions.)

Uridine Diphosphate-glucuronosyltransferase Enzyme Inducers

Concomitant use of canagliflozin with an inducer of UGT enzymes may decrease the efficacy of canagliflozin. When a single dose of canagliflozin (300 mg) was administered to patients receiving rifampin (600 mg once daily for 8 days), a nonselective inducer of UGT isoenzymes 1A9 and 2B4, canagliflozin area under the concentration-time curve (AUC) was decreased by 51% and peak plasma concentration was reduced by 28% (based on geometric mean ratios). If concomitant use of a UGT enzyme inducer (e.g., rifampin, phenytoin, phenobarbital, ritonavir) and canagliflozin cannot be avoided, increasing the daily dosage of canagliflozin to 300 mg once daily should be considered in patients with an estimated glomerular filtration rate (eGFR) exceeding 60 mL/minute per 1.73 m who are currently tolerating canagliflozin 100 mg once daily and require additional glycemic control. In patients with an eGFR of 45 to less than 60 mL/minute per 1.73 m who are receiving concomitant therapy with a UGT enzyme inducer and require additional glycemic control, an alternative antidiabetic agent should be considered.

Acetaminophen

Administration of a single dose of acetaminophen (1 g) to individuals receiving canagliflozin (300 mg twice daily for 25 days) had no effect on peak plasma acetaminophen concentration; acetaminophen AUC increased by 6% (based on geometric mean ratios). No adjustment of concomitant acetaminophen dosage is necessary.

Antidiabetic Agents

When canagliflozin is added to therapy with an insulin secretagogue (e.g., a sulfonylurea) or insulin, the incidence of hypoglycemia is increased compared with sulfonylurea or insulin monotherapy. Patients receiving canagliflozin may require a reduced dosage of the concomitant insulin secretagogue or insulin to reduce the risk of hypoglycemia.

Administration of a single dose of glyburide (1.25 mg) to individuals receiving canagliflozin (200 mg once daily for 6 days) increased glyburide AUC by 2% (based on geometric mean ratios) and decreased peak plasma concentrations by 7% (based on geometric mean ratios). No adjustment of glyburide dosage is necessary with concomitant canagliflozin.

Cyclosporine

Administration of a single dose of cyclosporine (400 mg) to individuals receiving canagliflozin (300 mg once daily for 8 days) increased canagliflozin AUC and peak plasma concentrations by 23 and 1%, respectively (based on geometric mean ratios). No adjustment of canagliflozin dosage is necessary with concomitant cyclosporine.

Digoxin

Concomitant use of canagliflozin (300 mg once daily for 7 days) and digoxin (0.5 mg once daily for one day, then 0.25 mg once daily for 6 days) increased AUC and mean peak plasma concentration of digoxin by 20 and 36%, respectively (based on geometric mean ratios). Patients should be monitored appropriately when receiving canagliflozin and digoxin concomitantly.

Diuretics

Concomitant use of canagliflozin with diuretics may increase the incidence of symptomatic hypotension. Prior to initiation of canagliflozin, volume status should be assessed and corrected in patients receiving diuretics. Patients should be monitored for signs and symptoms of symptomatic hypotension following initiation of canagliflozin therapy.

Patients with moderate renal impairment receiving potassium-sparing diuretics are more likely to develop hyperkalemia. Serum potassium concentrations should be monitored periodically following initiation of canagliflozin in patients predisposed to hyperkalemia due to drug therapy.

Hormonal Contraceptives

Administration of a single dose of ethinyl estradiol (0.03 mg) and levonorgestrel (0.15 mg) to individuals receiving canagliflozin (200 mg once daily for 6 days) increased ethinyl estradiol and levonorgestrel AUC (7 and 6%, respectively, based on geometric mean ratios) and peak plasma concentration (22% for both drugs, based on geometric mean ratios) and decreased canagliflozin AUC and peak plasma concentration (9 and 8%, respectively, based on geometric mean ratios). No dosage adjustment is necessary for any of the drugs.

Hydrochlorothiazide

Concurrent use of hydrochlorothiazide (25 mg once daily for 35 days) and canagliflozin (300 mg once daily for 7 days) increased canagliflozin AUC and peak plasma concentrations (12 and 15%, respectively, based on geometric mean ratios) and decreased hydrochlorothiazide AUC and peak plasma concentrations (1 and 6%, respectively, based on geometric mean ratios). No dosage adjustment is necessary for either drug.(See also Drug Interactions: Diuretics.)

Metformin

In individuals receiving canagliflozin (300 mg once daily for 8 days), a single dose of metformin hydrochloride (2 g) increased canagliflozin and metformin AUCs (10 and 20%, respectively, based on geometric mean ratios) and peak plasma concentrations (5 and 6%, respectively, based on geometric mean ratios). No dosage adjustment is necessary for either drug.

Probenecid

Concomitant use of probenecid (500 mg twice daily for 3 days) and canagliflozin (300 mg once daily for 17 days) increased canagliflozin AUC and peak plasma concentration by 21 and 13%, respectively (based on geometric mean ratios). No adjustment of canagliflozin dosage is necessary.

Simvastatin

Administration of a single dose of simvastatin (40 mg) in individuals receiving canagliflozin (300 mg once daily for 7 days) increased simvastatin AUC and peak plasma concentration by 12 and 9%, respectively (based on geometric mean ratios). No simvastatin dosage adjustment is necessary.

Warfarin

Administration of a single dose of warfarin (30 mg) in individuals receiving canagliflozin (300 mg once daily for 12 days) slightly increased R- and S-warfarin AUC (1 and 6%, respectively, based on geometric mean ratios) and peak plasma concentrations (3 and 1%, respectively, based on geometric mean ratios). No warfarin dosage adjustment is necessary.

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