Canagliflozin

Tell your doctor about all prescription, non-prescription, illegal, recreational, herbal, nutritional, or dietary drugs you're taking before taking Invokana, especially:

• Angiotensin receptor blockers (ARBs) such as Edarbi (azilsartan), Atacand (candesartan), Teveten (eprosartan), Avapro (irbesartan), Cozaar (losartan), Benicar (olmesartan), Micardis (telmisartan), and Diovan (valsartan)
• Angiotensin-converting enzyme (ACE) inhibitors such as Lotensin (benazepril), Capoten (captopril), Vasotec (enalapril), Monopril (fosinopril), Univasc (moexipril), Aceon (perindopril), Accupril (quinapril), Altace (ramipril), Mavik (trandolapril), and Prinivil or Zestril (lisinopril)
• Dilantin or Phenytek (phenytoin)
• Diuretics (water pills)
• Lanoxin (digoxin)
• Other diabetes medicines
• Phenobarbital
• Rifampin (Rifadin, Rimactane, in Rifamate, in Rifater)
• Ritonavir (Norvir, in Kaletra)

Invokana and Alcohol

Consuming alcohol can cause changes in your blood sugar.

Talk to your doctor about how much alcohol is safe to consume while taking Invokana.

Invokana comes as a tablet to be taken orally.

It's typically taken once a day before breakfast or your first main meal of the day.

Your doctor might start you on a lower dose of Invokana and gradually increase it.

The recommended starting dose of Invokana is 100 milligrams (mg) once a day. The maximum dose is 300 mg a day.

Try to take this medicine around the same time each day.

Follow the directions on your prescription label carefully. Don't take more or less of the medicine than is prescribed.

Invokana Overdose

If you suspect an overdose, contact a poison control center or emergency room immediately.

You can get in touch with a poison control center at 800-222-1222.

Missed Dose of Invokana

If you miss a dose of Invokana, take it as soon as you remember.

However, if it's almost time for your next dose, skip the missed dose and continue on your regular medication schedule.

Don't take an extra dose to make up for a missed one.

: Canagliflozin may slightly increase the concentration of digoxin (Lanoxin) in the body when both drugs are being taken. Digoxin concentrations should be monitored appropriately.

Rifampin, phenytoin (Dilantin, Dilantin-125, phenobarbital, and ritonavir (Norvir) may reduce the effect of canagliflozin by increasing its elimination and reducing its concentration in the body. The dose of canagliflozin should be increased to 300 mg daily when combined with rifampin, phenytoin, phenobarbital, or ritonavir.

Monitoring glucose control with urine glucose tests is not recommended in patients taking canagliflozin and similar drugs. These drugs increase urinary glucose excretion and will lead to positive urine glucose tests. Use alternative methods to monitor glucose control.

Tablets: 100 and 300 mg

Tablets should be stored at room temperature, 15 C to 30 C (59 F to 86 F)

Dosage Forms & Strengths

tablet

• 100mg
• 300mg

Diabetes Mellitus Type 2

Selective sodium-glucose transporter-2 (SGLT2) inhibitor indicated as an adjunct to diet and exercise to improve glycemic control with type 2 diabetes mellitus

Initial: 100 mg PO qDay taken before the first meal of the day

May increase dose to 300 mg qDay in patients tolerating 100 mg/day who have an eGFR ≥60 mL/min/1.73 m² and require additional glycemic control

Dosage Modifications

Renal impairment

• eGFR ≥60 mL/min/1.73 m²: No dosage adjustment required
• eGFR 45 to <60 mL/min/1.73 m²: Do not exceed 100 mg/day
• eGFR <45 mL/min/1.73 m²: Do not initiate canagliflozin
• Not recommended with eGFR that declines persistently below 45 mL/min/1.73 m²
• eGFR <30 mL/min/1.73 m²: Contraindicated

UGT enzyme inducers

• Coadministration with UGT enzyme inducers (eg, rifampin, phenytoin, phenobarbital, ritonavir): Consider increasing dose to 300 mg qDay in patients tolerating 100 mg/day with eGFR ≥60 mL/min/1.73 m² and require additional glycemic control
• Consider another antihyperglycemic agents if eGFR is 45 to <60 mL/min/1.73 m² and receiving a UGT inducer

Dosing Considerations

Not recommended for treating type 1 diabetes mellitus or diabetic ketoacidosis

Correct volume depletion prior to initiating canagliflozin

Safety and efficacy not established

Canagliflozin may be found in some form under the following brand names:

• Invokamet

• Invokana

Canagliflozin is part of the drug class:

• Other blood glucose lowering drugs, excl. insulins

Medications can interact with certain foods. In some cases, this may be harmful and your doctor may advise you to avoid certain foods. In the case of canagliflozin, there are no specific foods that you must exclude from your diet when receiving this medication.

You should not use canagliflozin if you are allergic to it, or if you have:

• severe kidney disease (or if you are on dialysis).

To make sure canagliflozin is safe for you, tell your doctor if you have ever had:

• kidney disease;

• liver disease;

• bladder infections or other urination problems;

• blood circulation problems;

• nerve problems caused by diabetes;

• a diabetic foot ulcer or amputation;

• an electrolyte imbalance (such as high levels of potassium in your blood);

• high cholesterol levels;

• diabetic ketoacidosis (call your doctor for treatment with insulin);

• if you are on a low salt diet; or

• if you use insulin or other oral diabetes medicines.

It is not known whether canagliflozin will harm an unborn baby. Tell your doctor if you are pregnant or plan to become pregnant.

It is not known whether canagliflozin passes into breast milk or if it could harm a nursing baby. You should not breast-feed while using this medicine.

Canagliflozin is not approved for use by anyone younger than 18 years old.

Administration

Oral Administration

Administer once daily, before the first meal of the day.1

If a dose is missed, take missed dose as soon as it is remembered followed by resumption of regular schedule.1 If missed dose is not remembered until the time of the next dose, skip missed dose and resume regular schedule; do not double dose to replace a missed dose.1

Dosage

Pending revision, the material in this section should be considered in light of more recently available information in the MedWatch notification at the beginning of this monograph.

Dosage expressed in terms of anhydrous canagliflozin.1

Adults

Initially, 100 mg once daily, taken before first meal of day.1

If well tolerated, increase dosage to 300 mg once daily in patients with an eGFR ≥60 mL/minute per 1.73 m2 who require additional glycemic control.1

Correct volume depletion in patients with this condition before initiation of canagliflozin therapy.1

Special Populations

Hepatic Impairment

Mild or moderate hepatic impairment: No dosage adjustment necessary.1

Severe hepatic impairment: Data lacking; use not recommended.1

Renal Impairment

Mild renal impairment (eGFR ≥60 mL/minute per 1.73 m2): No dosage adjustment necessary.1

Moderate renal impairment (eGFR 45 to <60 mL/minute per 1.73 m2): 100 mg once daily.1 Initiation not recommended if eGFR <45 mL/minute per 1.73 m2.1 Continued use not recommended in patients with eGFR persistently <45 mL/minute per 1.73 m2.1

Severe renal impairment (eGFR <30 mL/minute per 1.73 m2): Contraindicated.1

Geriatric Patients

No specific dosage recommendations.1

Contraindications

Pending revision, the material in this section should be considered in light of more recently available information in the MedWatch notification at the beginning of this monograph.

• History of serious hypersensitivity reaction (e.g., anaphylaxis, angioedema) to canagliflozin.1

• Severe renal impairment (eGFR <30 mL/minute per 1.73 m2), end-stage renal disease, or on hemodialysis.1

Warnings/Precautions

Ketoacidosis

Ketoacidosis (e.g., diabetic ketoacidosis, ketoacidosis, ketosis) requiring hospitalization reported with SGLT2 inhibitors; may occur without markedly elevated blood glucose concentrations (e.g., <250 mg/dL).1 39 40 41 42 50

Evaluate for the presence of acidosis, including ketoacidosis, in patients experiencing signs or symptoms of acidosis regardless of the patient's blood glucose concentration; discontinue SGLT2 inhibitor and initiate appropriate treatment to correct acidosis if confirmed.1 39 40 50 (See Advice to Patients.)

Prior to initiating canagliflozin therapy, consider factors that may predispose patients to ketoacidosis (e.g., pancreatic insulin deficiency, reduced caloric intake, alcohol abuse).1 50

Consider temporarily discontinuing SGLT2 inhibitor in patients with clinical situations known to predispose patients to ketoacidosis (e.g., prolonged fasting due to acute illness or surgery).1 50

Advise patients to monitor urine and/or plasma ketone levels if patients feel unwell (see Advice to Patients).1 40 42 50

Hypotension

May cause intravascular volume contraction.1 Symptomatic hypotension can occur, particularly in patients with impaired renal function (eGFR <60 mL/minute per 1.73 m2), 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 BP.1 Assess and correct intravascular volume prior to initiating canagliflozin in such patients.1

Monitor patients for sign and symptoms of hypotension after initiating therapy.1

Renal Effects

Causes intravascular volume contraction and can cause renal impairment.1 51

May increase Scr concentration and decrease eGFR; hypovolemic patients may be more susceptible.1 Renal function abnormalities can occur following initiation of therapy.1

Consider factors that may predispose patients to acute kidney injury, such as hypovolemia, chronic renal insufficiency, heart failure, concomitant medications (e.g., diuretics, ACE inhibitors, angiotensin II receptor antagonists, NSAIAs), prior to initiating canagliflozin therapy.1 51

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).1 51

Monitor patients for acute kidney injury; monitor patients with an eGFR <60 mL/minute per 1.73 m2 more frequently.1 Discontinue canagliflozin and initiate appropriate treatment if such injury occurs.1 51

Hyperkalemia

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.1

Monitor serum potassium concentrations periodically following initiation in patients with impaired renal function and those predisposed to hyperkalemia due to drug therapy or other medical conditions.1

Concomitant Therapy with Hypoglycemic Agents

When adding canagliflozin to therapy with an insulin secretagogue (e.g., a sulfonylurea) or insulin, consider reducing dosage of the concomitant insulin secretagogue or insulin to reduce the risk of hypoglycemia.1 (See Specific Drugs under Interactions.)

Genital Mycotic Infections

Possible increased risk of genital mycotic infections in males (e.g., balanoposthitis, candidal balanitis) and females (e.g., vulvovaginal candidiasis, vulvovaginal mycotic infection, vulvovaginitis).1 Patients with a history of genital mycotic infections and uncircumcised males more likely to develop such infections.1

Monitor patients for genital mycotic infections and institute appropriate treatment if these infections occur.1

Urosepsis and Pyelonephritis

May increase the risk of serious urinary tract infections (e.g., urosepsis, pyelonephritis requiring hospitalization).1 50

Prior to initiating canagliflozin therapy, consider patient factors that may predispose to serious urinary tract infections (e.g., history of difficulty urinating; infection of the bladder, kidneys, or urinary tract).50

Monitor patients for urinary tract infections and initiate treatment if indicated.1 50

Risk of Bone Fracture

Increased risk of bone fracture.1 43 Fractures observed as early as 12 weeks after initiation of canagliflozin treatment; more likely to affect the upper extremities and be associated with minor trauma (e.g., falls from no greater than standing height).1 43

Dose-related decreases in bone mineral density also observed in older adults (mean age: 64 years) receiving canagliflozin.1 43

Consider factors that contribute to fracture risk and counsel patients about such factors prior to initiating canagliflozin therapy.1 43

Effects on Lipoproteins

Dose-related increases in LDL-cholesterol can occur.1 Monitor serum lipid concentrations and treat if appropriate.1

Macrovascular Outcomes

Evidence of macrovascular risk reduction with canagliflozin or any other antidiabetic agent has not been conclusively demonstrated in clinical trials.1

Risk of Amputation

Interim analysis of data from an ongoing clinical study evaluating canagliflozin (Canagliflozin Cardiovascular Assessment Study [CANVAS]) revealed an increase in leg and foot amputations, mostly affecting the toes, in patients receiving the drug.52 53 A similar ongoing study has revealed no such increase in amputation risk.

FDA has not reached any conclusions about whether canagliflozin increases the risk of leg and foot amputations and is continuing to evaluate this potential risk.52

Instruct patients to seek medical attention if they experience new pain or tenderness, sores or ulcers, or infections in their legs or feet.52 (See Advice to Patients.)

Sensitivity Reactions

Hypersensitivity reactions (e.g., generalized urticaria), some serious, reported.1 Discontinue the drug if hypersensitivity reaction occurs, institute appropriate treatment, and monitor patients until signs and symptoms resolve.1

Specific Populations

Studies in animals indicate that canagliflozin use during pregnancy may affect renal development and maturation.1

Not recommended for use in the second or third trimesters of pregnancy.1

Distributed into milk in rats; not known whether distributed into human milk.1 Discontinue nursing or the drug.1

Safety and efficacy not established in pediatric patients <18 years of age.1

Reduced efficacy compared with younger patients, which may be related to decreased renal function in geriatric patients.1 8 Such patients more likely to experience certain adverse effects related to reduced intravascular volume (e.g., hypotension, postural dizziness, orthostatic hypotension, syncope, dehydration), particularly with canagliflozin 300 mg daily.1 8

No dosage adjustment necessary in patients with mild or moderate hepatic impairment.1

Not studied in severe hepatic impairment (Child-Pugh class C); use not recommended.1

No dosage adjustment necessary in patients with mild renal impairment.1 Dosage adjustment recommended in patients with moderate renal impairment.1 (See Renal Impairment under Dosage and Administration.)

Contraindicated in patients with severe renal impairment, end-stage renal disease, or on hemodialysis.1

Assess renal function prior to initiation of therapy and periodically thereafter.1

Common Adverse Effects

Female genital mycotic infections,1 urinary tract infection,1 increased urination,1 male genital mycotic infections,1 vulvovaginal pruritus,1 thirst,1 constipation,1 nausea.1

Along with its needed effects, a medicine may cause some unwanted effects. Although not all of these side effects may occur, if they do occur they may need medical attention.

Check with your doctor immediately if any of the following side effects occur:

• Bladder pain
• bloody or cloudy urine
• decreased frequency or amount of urine
• difficult, burning, or painful urination
• discharge with a strong odor from the penis
• frequent urge to urinate
• increased thirst
• itching of the vagina or outside of the genitals
• loss of appetite
• lower back or side pain
• nausea
• pain during sexual intercourse
• pain in the skin around the penis
• redness, itching, or swelling of the penis
• swelling of the face, fingers, or lower legs
• troubled breathing
• unusual tiredness or weakness
• vaginal discharge without odor or with mild odor
• vomiting
• weight gain

• Anxiety
• blurred vision
• chills
• cold sweats
• confusion
• cool, pale skin
• depression
• dizziness
• dry mouth
• fast or irregular heartbeat
• headache
• hives or welts, itching skin, rash
• increased hunger
• large, hive-like swelling on the face, eyelids, lips, tongue, throat, hands, legs, feet, or sex organs
• nightmares
• redness of the skin
• seizures
• shakiness
• slurred speech
• unusual tiredness or weakness

• Abdominal or stomach pain
• blurred vision
• dizziness, faintness, or lightheadedness when getting up suddenly from a lying or sitting position
• flushed, dry skin
• frequent or painful urination
• frequent urge to urinate
• fruit-like breath odor
• increased urination
• loss of consciousness
• numbness or tingling in the hands, feet, or lips
• stomach pain
• sweating
• unexplained weight loss
• weakness or heaviness of the legs

Some side effects may occur that usually do not need medical attention. These side effects may go away during treatment as your body adjusts to the medicine. Also, your health care professional may be able to tell you about ways to prevent or reduce some of these side effects. Check with your health care professional if any of the following side effects continue or are bothersome or if you have any questions about them:

• Difficulty having a bowel movement (stool)
• lack or loss of strength
• pain or swelling in the arms or legs without an injury

• Increased sensitivity of the skin to sunlight
• redness or other discoloration of the skin
• severe sunburn

Other side effects not listed may also occur in some patients. If you notice any other effects, check with your healthcare professional.

Call your doctor for medical advice about side effects. You may report side effects to the FDA at 1-800-FDA-1088.

(kan a gli FLOE zin)

An approximately 2-fold increased risk of lower limb amputations associated with canagliflozin use was observed in CANVAS and CANVAS-R, 2 large, randomized, placebo-controlled trials in patients with type 2 diabetes who had established cardiovascular disease (CVD) or were at risk for CVD. Amputations of the toe and midfoot were most frequent; however, amputations involving the leg were also observed. Some patients had multiple amputations, some involving both limbs. Before initiating, consider factors that may increase the risk of amputation, such as a history of prior amputation, peripheral vascular disease, neuropathy, and diabetic foot ulcers. Monitor patients receiving canagliflozin for infection, new pain or tenderness, sores or ulcers involving the lower limbs, and discontinue if these complications occur.

Commonly reported side effects of canagliflozin include: vulvovaginal candidiasis, vaginal infection, vulvitis, vulvovaginitis, and mean glomerular filtration rate decreased. Other side effects include: balanitis, balanoposthitis, increased urine output, nocturia, polyuria, urinary urgency, and pollakiuria. See below for a comprehensive list of adverse effects.

Mild renal dysfunction (eGFR of 60 mL/min/1.73 m2 or greater): No adjustment recommended.
Moderate renal dysfunction (eGFR of 45 to less than 60 mL/min/1.73 m2): Limit to 100 mg orally once daily
Severe renal dysfunction (eGFR less than 45 mL/min/1.73 m2): Initiation of therapy is not recommended
Severe renal dysfunction (eGFR less than 30 mL/min/1.73 m2): Use is contraindicated

If during therapy, eGFR is persistently less than 45 mL/min/1.73 m2: Use is not recommended

Mild to moderate liver dysfunction: No adjustment recommended
Severe liver dysfunction: Not recommended