Invokana (canagliflozin)

Dosage of canagliflozin is expressed in terms of anhydrous canagliflozin.

Canagliflozin is administered orally once daily. Canagliflozin is commercially available as single-entity tablets that should be administered before the first meal of the day. Canagliflozin is also available in fixed combination with immediate- or extended-release metformin hydrochloride (Invokamet(R), Invokamet XR(R)). The fixed combination of canagliflozin and immediate-release metformin hydrochloride should be administered twice daily with meals. The fixed combination of canagliflozin and extended-release metformin hydrochloride should be administered once daily with the morning meal; the tablet should be swallowed whole and should not be crushed, chewed, or cut. See the full prescribing information for additional administration instructions for the combination products.

If a dose of canagliflozin 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.

Store canagliflozin tablets (single-entity and fixed combinations with metformin hydrochloride) at 20degreesC to 25degreesC; excursions permitted between 15degreesC and 30degreesC. Fixed combination tablets with immediate- or extended-release metformin hydrochloride should be stored and dispensed in the original container; however, the tablets may be stored in a pill box or pill organizer for <=30 days.

No dosing information is available for this tab.

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 multidrug resistance-associated protein 2 (MRP2).

There are no contraindication interactions for this drug.

Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

Canagliflozin/Ugt Inducers

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: UGT inducers may induce the metabolism of canagliflozin, which is glucuronidated by UGT1A9 and UGT2B4.(1)

CLINICAL EFFECTS: Concurrent use of an inducer of UGT may result in decreased levels and effectiveness of canagliflozin.(1)

PREDISPOSING FACTORS: This interaction may be more severe in patients who have a eGFR of less than 60 ml/min/1.73m2.(1)

PATIENT MANAGEMENT: In patients with a eGFR of 60 ml/min/1.73m2 or more who are currently tolerating canagliflozin 100 mg daily and require therapy with an inducer of UGT, the manufacturer of canagliflozin recommends increasing the dose of canagliflozin to 200 mg daily. Patients currently tolerating canagliflozin 200 mg daily and require additional glycemic control may have their dose increased to 300 mg daily.(1) In patients with a eGFR of less than 60 ml/min/1.73m2 who are currently tolerating canagliflozin 100 mg daily and receiving therapy with a UGT inducer, increase the dose of canagliflozin to 200 mg daily. Consider other antihyperglycemic agents in patients who require additional glycemic control.(1)

DISCUSSION: Pretreatment with rifampin (600 mg daily for 8 days) decreased the area-under-curve (AUC) and maximum concentration (Cmax) of a single dose of canagliflozin (300 mg) by 51% and 28%, respectively.(1) Inducers of UGT include: carbamazepine, efavirenz, fosphenytoin, lorlatinib, phenobarbital, phenytoin, primidone, rifampin, and ritonavir.(1)

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 reactions (e.g., anaphylaxis, angioedema) to canagliflozin.

• History of diabetes-related lower-extremity amputation

• Chronic kidney disease stage 3A (moderate) GFR 45-59 ml/min
• Chronic kidney disease stage 3B (moderate) GFR 30-44 ml/min
• Chronic kidney disease stage 4 (severe) GFR 15-29 ml/min
• Chronic kidney disease stage 5 (failure) GFr<15 ml/min
• Diabetic foot infection
• Hyperkalemia
• Hypoglycemic disorder
• Hypovolemia
• Invasive surgical procedure
• Necrotizing fasciitis of perineum or genital area
• Peripheral vascular disease
• Pregnancy
• Type 1 diabetes mellitus

• Diabetic peripheral neuropathy
• Osteopenia

The most common adverse effects of canagliflozin (>=5% of patients) include female genital mycotic infections, urinary tract infection, and increased urination.

More Frequent

• Hypoglycemic disorder

Less Frequent

• Dehydration
• Hypermagnesemia
• Hypersensitivity drug reaction
• Hypotension
• Syncope

Rare or Very Rare

• Accidental fall
• Acute kidney injury
• Anaphylaxis
• Angioedema
• Bacterial sepsis
• Depression
• Diabetic ketoacidosis
• Fracture
• Genitourinary tract infections
• Hyperkalemia
• Ketoacidosis
• Kidney disease with reduction in glomerular filtration rate (GFr)
• Metabolic acidosis
• Necrotizing fasciitis of perineum or genital area
• Osteopenia
• Pancreatitis
• Pyelonephritis
• Renal cell carcinoma
• Urosepsis

More Frequent

• Increased urinary frequency
• Urinary tract infection
• Vulvovaginal candidiasis

Less Frequent

• Candidal balanitis
• Constipation
• Dental abscess
• Fatigue
• General weakness
• Genital organ pruritus
• Hypercholesterolemia
• Hyperlipidemia
• Hyperphosphatemia
• Increased hemoglobin
• Nausea
• Orthostatic hypotension
• Polydipsia
• Xerostomia

Rare or Very Rare

• Acute abdominal pain
• Skin photosensitivity
• Urticaria

No enhanced messaging available.

The safety and effectiveness of canagliflozin 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 canagliflozin for this indication is supported by a 52-week, placebo-controlled trial in 171 patients 10--17 years of age with type 2 diabetes mellitus and a pediatric pharmacokinetic study. The safety, exposure, and response of canagliflozin in pediatric patients was similar to that observed in adults. Safety and efficacy of canagliflozin have not been established in pediatric patients younger than 10 years of age. Safety and efficacy of canagliflozin for other indications have not been established.

There is insufficient evidence with canagliflozin in pregnant women to evaluate a drug-associated risk for major birth defects or miscarriage. 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. In juvenile animal studies, adverse renal pelvic and tubule dilatations that were not reversible were observed in rats when canagliflozin was administered during a period of renal development corresponding to the late second and third trimesters of human pregnancy, at an exposure 0.5 times the 300-mg clinical dosage, based on area under the concentration-time curve (AUC).

Poorly controlled diabetes mellitus during pregnancy carries risks to the mother and fetus, including DKA, pre-eclampsia, spontaneous abortions, preterm delivery, delivery complications, major birth defects, stillbirth, and macrosomia-related morbidity. The manufacturer states that canagliflozin therapy is not recommended in pregnant women during the second and third trimesters of pregnancy.

There is no information regarding the presence of canagliflozin in human milk, the effects on the breast-fed infant, or the effects on milk production. Canagliflozin is distributed into milk in rats. Juvenile rats directly exposed to canagliflozin showed a 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 a risk to the developing human kidney. Because of the potential for serious adverse reactions in nursing infants from canagliflozin, use of the drug is not recommended while breastfeeding.

Among patients in 13 clinical trials, 2294 were 65 years of age or older and 351 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 as evidenced by smaller reductions in glycosylated hemoglobin (hemoglobin A1c; HbA1c). Patients 65 years of age and older 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; a prominent increase in the incidence of volume depletion-related adverse effects in these trials was seen in patients who were 75 years of age and older.