canagliflozin/metformin (Rx)

>10%

canagliflozin

• Female genital mycotic infections (10.4-11.4%)

metformin

• Diarrhea (53.2%)
• Nausea/vomiting (25.5%)
• Flatulence (12.1%)

1-10%

canagliflozin

• Increased urination (4.6-5.3%)
• Male genital mycotic infections (3.7-4.2%)
• Vulvovaginal pruritus (1.6-3%)
• Thirst (2.3-2.8%)
• Falls (1.3-2.1%)
• Constipation (1.8-2.3%)
• Bone fractures (1.1-1.5%)
• Nausea (2.2-2.3%)
• Abdominal pain (1.7-1.8%)

• volume depletion

  • Overall population (2.3-3.4%)
  • Age >75 yr (4.9-8.7%)
  • eGFR <60/mL/min/1.73 mL² (4.7-8.1%)
  • Use of loop diuretic (3.2-8.8%)

metformin

• Asthenia (9.2%)
• Indigestion (7.1%)
• Abdominal discomfort (6.4%)
• Headache (5.7%)

Postmarketing Reports

Angioedema

Acute kidney injury and impairment of renal function

canagliflozin

• Acute kidney injury and impairment in renal function

metformin

• Cholestatic, hepatocellular, and mixed hepatocellular liver injury
• Anaphylaxis
• Urosepsis and Pyelonephritis

Contraindications

Moderate renal impairment (eGFR <30 mL/min/1.73 m²), which may also result from conditions such as shock, acute MI, and septicemia; ESRD, or patients on dialysis

Acute or chronic metabolic acidosis, including diabetic ketoacidosis (see Black Box Warnings)

History of a serious hypersensitivity reaction to canagliflozin or metformin, such as anaphylaxis or angioedema

Cautions

Alcohol is known to potentiate the effect of metformin on lactate metabolism

Shock from various causes (eg, acute CHF, acute MI, and other conditions characterized by hypoxemia) has been associated with lactic acidosis and may also cause prerenal azotemia

Withholding of food and fluids during surgical or other procedures may increase risk for volume depletion, hypotension and renal impairment

Before initiating therapy, obtain an estimated glomerular filtration rate and obtain an eGFR at least annually; assess more frequently in patients at increased risk for development of renal impairment

Consider temporarily discontinuing in settings of reduced oral intake or fluid losses; if acute kidney injury occurs, discontinue and promptly treat; monitor renal function during therapy

Hyperkalemia reported with canagliflozin; monitor potassium levels in patients with impaired renal function and in patients predisposed to hyperkalemia

Canagliflozin increases risk for genital mycotic infections; treat if indicated

Increases risk of urinary tract infections (UTIs), including life-threatening urosepsis and pyelonephritis that started as UTIs; evaluate patients for signs and symptoms of urinary tract infections and treat promptly, if indicated

Metformin may lower vitamin B12 levels without manifestations; monitor hematologic parameters annually

Increased risk of bone fracture, occurring as early as 12 weeks after treatment initiation, reported; consider factors that contribute to fracture risk prior to initiating therapy

Hypersensitivity reactions, including angioedema and anaphylaxis reported with canagliflozin; these reactions generally occurred within hours to days after initiating canagliflozin; if hypersensitivity reactions occur, discontinue therapy; treat and monitor until signs and symptoms resolve

Lower limb amputation

• Increased risk of lower limb amputations associated with canagliflozin use was observed in 2 large, randomized, placebo-controlled trials (CANVAS AND CANVAS-R) 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 (eg, history of prior amputation, peripheral vascular disease, neuropathy, diabetic foot ulcers)
• Monitor for infection, new pain or tenderness, and sores or ulcers involving the lower limbs; discontinue if these complications occur

Ketoacidosis

• Fatal ketoacidosis associated with SGLT2 inhibitors
• Monitor for signs of ketoacidosis and advise patients to seek immediate medical attention for symptoms (eg, difficulty breathing, nausea, vomiting, abdominal pain, confusion, unusual fatigue or sleepiness)
• Assess patients who present with signs and symptoms of metabolic acidosis for ketoacidosis, regardless of blood glucose level
• Consider risk factors for ketoacidosis prior to initiating therapy; patients may require temporary discontinuation of therapy in clinical situations that may predispose to ketoacidosis

Necrotizing fascitis

• Necrotizing fasciitis of the perineum (Fournier gangrene) reported with SGLT2 inhibitors
• Signs and symptoms include tenderness, redness, or swelling of the genitals or the area from the genitals back to the rectum, and have a fever above 100.4 F or a general feeling of being unwell
• If suspected, discontinue SGLT2 inhibitor and start treatment immediately with broad-spectrum antibiotics and surgical debridement if necessary

Renal impairment

• Therapy causes intravascular volume contraction and can cause renal impairment; acute kidney injury, some requiring hospitalization and dialysis reported
• Before initiating therapy, consider factors that may predispose patients to acute kidney injury including hypovolemia, chronic renal insufficiency, congestive heart failure, and concomitant medications (diuretics, ACE inhibitors, ARBs, NSAIDs)
• Consider temporarily discontinuing therapy in any setting of reduced oral intake (such as acute illness or fasting) or fluid losses (such as gastrointestinal illness or excessive heat exposure)
• Canagliflozin increases serum creatinine and decreases eGFR; ensure normal renal function before initiating and at least annually thereafter

Lactic acidosis

• Risk increases with degree of renal dysfunction and age (see Black Box Warnings)
• Metformin-associated lactic acidosis cases associated primarily with significant renal impairment; risk of metformin accumulation and metformin-associated lactic acidosis increases with severity of renal impairment; metformin substantially excreted by kidney
• Metformin-associated lactic acidosis have resulted in death, hypothermia, hypotension, and resistant bradyarrhythmias
• Onset is often subtle, accompanied only by nonspecific symptoms such as malaise, myalgias, respiratory distress, somnolence, and abdominal pain
• If suspected, discontinue therapy immediately and institute general supportive measures in hospital setting; prompt hemodialysis recommended
• Metformin use in patients with impaired hepatic function has been associated with cases of lactic acidosis

Iodinated contrast imaging procedures

• Discontinue metformin at the time of or before an iodinated contrast imaging procedure in patients with an eGFR between 45-60 mL/minute/1.73 m²; in patients with a history of liver disease, alcoholism, or heart failure; or in patients who will be administered intra-arterial iodinate contrast
• Reevaluate eGFR 48 hr after the imaging procedure; restart metformin if renal function is stable

Hypoglycemia

• Canagliflozin can increase the risk of hypoglycemia when combined with insulin or an insulin secretagogue; a lower dose of insulin or insulin secretagogue may be required
• Metformin: Hypoglycemia does not occur in patients receiving metformin alone under usual circumstances of use, but could occur when caloric intake is deficient, when strenuous exercise is not compensated by caloric supplementation, or during concomitant use with other glucose-lowering agents (eg, sulfonylureas, insulin) or ethanol

Hypotension

• Canagliflozin causes intravascular volume contraction
• Symptomatic hypotension can occur after initiating, particularly with eGFR <60 mL/min/1.73 m², elderly patients, coadministration with diuretics or medications that interfere with the renin-angiotensin-aldosterone system (eg, ACE inhibitors, angiotensin receptor blockers), or patients with low systolic blood pressure
• Assess volume status and correct hypovolemia in patients with renal impairment, the elderly, in patients with low systolic blood pressure, or on diuretics, ACE inhibitors, or ARB; monitor for signs and symptoms during therapy

Pregnancy

Canagliflozin

• Based on animal data showing adverse renal effects, not recommended during the second and third trimesters of pregnancy
• Data are limited in pregnant women and are not sufficient to determine a drug associated risk for major birth defects or miscarriage

Metformin

• Metformin was not teratogenic in rats and rabbits at doses up to 600 mg/kg/day; determination of fetal concentrations demonstrated a partial placental barrier to metformin

Clinical considerations

• Poorly controlled diabetes in pregnancy increases maternal risk for diabetic ketoacidosis, preeclampsia, spontaneous abortions, preterm delivery, stillbirth, and delivery complications
• Poorly controlled diabetes increases fetal risk for major birth defects, stillbirth, and macrosomia related morbidity

Lactation

Breastfeeding not recommended

Canagliflozin

• No information regarding distribution in human milk or effects on the breastfed infant or milk production
• Present in milk of lactating rats
• Since human kidney maturation occurs in utero and during the first 2 yr of life when lactational exposure may occur, there may be risk to the developing human kidney

Metformin

• Excreted into milk in rats and reaches levels comparable to those in plasma; breastfeeding not recommended

Pregnancy Categories

A: Generally acceptable. Controlled studies in pregnant women show no evidence of fetal risk.

B: May be acceptable. Either animal studies show no risk but human studies not available or animal studies showed minor risks and human studies done and showed no risk.

C: Use with caution if benefits outweigh risks. Animal studies show risk and human studies not available or neither animal nor human studies done.

D: Use in LIFE-THREATENING emergencies when no safer drug available. Positive evidence of human fetal risk.

X: Do not use in pregnancy. Risks involved outweigh potential benefits. Safer alternatives exist.

NA: Information not available.

Mechanism of Action

Canagliflozin: Selective sodium-glucose transporter-2 (SGLT2) inhibitor; SGLT2 is expressed in the proximal renal tubules and is responsible for the majority of the reabsorption of filtered glucose from the tubular lumen; SGLT2 inhibitors reduce glucose reabsorption and lower the renal threshold for glucose, thereby increasing urinary glucose excretion

Metformin: Biguanide; acts by decreasing endogenous hepatic glucose production, decreases intestinal absorption of glucose, and improves insulin sensitivity by increasing peripheral glucose uptake and utilization; improves glucose tolerance and lowers both basal and postprandial plasma glucose

Absorption

Bioavailability: 65% (canagliflozin); 50-60% (metformin)

Distribution

Protein bound: 99% (canagliflozin); negligible (metformin)

Vd: 119 L (canagliflozin); 654 L (metformin)

Metabolism

Metformin: Excreted unchanged in the urine and does not undergo hepatic metabolism

Canagliflozin

• O-glucuronidation is the major metabolic elimination pathway, which is mainly glucuronidated by UGT1A9 and UGT2B4 to 2 inactive O-glucuronide metabolites
• CYP3A4-mediated (oxidative) metabolism of canagliflozin is minimal (~7%) in humans

Elimination

Half-life, metformin: 6.2 hr (plasma); 17.6 hr (blood); depicts erythrocyte compartmentalization

Clearance

• Canagliflozin: 192 mL/min (systemic); 1.3-1.55 mL/min (renal)
• Metformin (renal): 3.5 x CrCl, which indicates that tubular secretion is the major route of elimination

Excretion

• Canagliflozin: 33% urine, mainly as O-glucuronide metabolites
• Metformin: 90% urine

Oral Administration

Regular tablet: Take BID with morning and evening meals

Extended-release: Take once daily with morning meal

Extended-release: Swallow whole; do not crush, cut, or chew