canagliflozin/metformin (Invokamet, Invokamet-XR)

Dosing and uses of Invokamet (canagliflozin/metformin)

• Adult
• Pediatric

 

Adult dosage forms and strengths

canagliflozin/metformin

tablet

• 50mg/500mg
• 50mg/1000mg
• 150mg/500mg
• 150mg/1000mg

film-coated tablet Xr

• 50mg/500mg
• 50mg/1000mg
• 150mg/500mg
• 150mg/1000mg

 

Type 2 Diabetes Mellitus

Indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus who are not adequately controlled on a regimen containing metformin or canagliflozin or in patients already being treated with both canagliflozin and metformin, individualize dose based on the patient’s current regimen

Take BID daily with meals, with gradual dose escalation to reduce the adverse GI effects due to metformin

Patients on metformin: Switch to tablet containing canagliflozin 50 mg with a similar total daily dose of metformin

Patients on canagliflozin: Switch to tablet containing metformin 500 mg with a similar total daily dose of canagliflozin

Patients already treated with canagliflozin and metformin: Switch to combination products containing the same total daily doses of each component

Adjust dose based on effectiveness and tolerability; not to exceed daily dose of 300 mg/2000 mg

Extended Release Formulation

• Individualize based on the patient’s current regimen
• Take two tablets once daily with the morning meal
• Patients currently not treated with either canagliflozin or metformin: Initiate therapy with two tablets, each tablet containing canagliflozin 50 mg and metformin 500 mg
• Patients already treated with canagliflozin and metformin: Switch to two tablets containing the same total daily dose of canagliflozin and the same, or nearest appropriate, total daily dose of metformin
• Patients that require additional glycemic control taking a total daily dose of canagliflozin 100 mg: May increase dose to canagliflozin 300 mg once daily; not to exceed 300 mg total daily dose
• Gradually escalate metformin dose to reduce gastrointestinal side effects while not exceeding a total daily dose of 2000 mg

 

Dosage modifications

UDP-glucuronosyl transferase (UGT) enzyme inducers

• Coadministration with UGT inducers (eg, rifampin, phenytoin, phenobarbital, ritonavir): Consider increasing canagliflozin dose to 150 mg BID in patients currently tolerating 50 mg BID if eGFR ≥60 mL/min/1.73 m² and additional glycemic control is required
• Consider another antihyperglycemic agent if eGFR is 45 to <60 mL/min/1.73 m²

Renal impairment

• Obtain eGFR before starting metformin and periodically thereafter
• Mild renal impairment (eGFR ≥ 60 mL/min/1.73 m²): No dosage adjustment required
• eGFR 45 to <60 mL/min/1.73 m²: Not to exceed canagliflozin 50 mg BID; for extended release formulation, administer 2 tablets once daily
• eGFR <45 mL/min/1.73 m²: Contraindicated

 

Dosing Considerations

Assess renal function before initiating and periodically thereafter

Correct volume depletion before initiating in patients not previously treated with canagliflozin

Not for treatment of type 1 diabetes or diabetic ketoacidosis

Therapy may need to be discontinued at time of, or prior to, iodinated contrast imaging procedures

Extended Release Formulation

• Swallow whole; never crush, cut, or chew

 

Pediatric dosage forms and strengths

Safety and efficacy not established

 

Invokamet (canagliflozin/metformin) adverse (side) effects

>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

 

Warnings

Black box warnings

Metformin

• Lactic acidosis caused by metformin accumulation (plasma concentration >5 mcg/mL) is a rare but potentially severe consequence; if it occurs, mortality is ~50%
• Risk increases with certain conditions (eg, renal impairment, sepsis, dehydration, excess alcohol intake, hepatic impairment, and acute CHF)
• Onset is subtle, accompanied only by nonspecific symptoms (eg, malaise, myalgias, respiratory distress, increasing somnolence, and nonspecific abdominal distress)
• Laboratory abnormalities include low pH, increased anion gap, and elevated blood lactate
• If lactic acidosis is suspected, discontinue drug and immediately hospitalize the patient
• Risk factors include renal impairment, concomitant use of certain drugs, age >65 years old, radiological studies with contrast, surgery and other procedures, hypoxic states, excessive alcohol intake, and hepatic impairment
• 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

 

Contraindications

Moderate renal impairment (eGFR <45 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

Hypersensitivity

 

Cautions

Lactic acidosis; risk increases with degree of renal dysfunction and age (see Black box warnings)

Metformin use in patients with impaired hepatic function has been associated with some cases of lactic acidosis

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

Renal impairment; canagliflozin increases serum creatinine and decreases eGFR; metformin is known to be substantially excreted by the kidney and risk of metformin accumulation and lactic acidosis increases with the degree of renal impairment; ensure normal renal function before initiating and at least annually thereafter

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

Dose-related increases in LDL‑C reported with canagliflozin; monitor LDL-C and treat as indicated

Canagliflozin increases risk for genital mycotic infections; treat if indicated

If hypersensitivity occurs, discontinue therapy and monitor until signs and symptoms resolve

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

Ketoacidosis associated with SGLT2 inhibitors reported; 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

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

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 and lactation

Pregnancy category: C

Canagliflozin: Based on studies in rats, may affect renal development

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

Lactation: Unknown if canagliflozin is distributed in human breast milk; metformin is 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.

 

Pharmacology of Invokamet (canagliflozin/metformin)

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