Canagliflozin and metformin
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Boxed warning
WARNING: LACTIC ACIDOSIS Post-marketing cases of metformin-associated lactic acidosis have resulted in death, hypothermia, hypotension, and resistant bradyarrhythmias. The onset of metformin-associated lactic acidosis is often subtle, accompanied only by nonspecific symptoms such as malaise, myalgias, respiratory distress, somnolence, and abdominal pain. Metformin-associated lactic acidosis was characterized by elevated blood lactate levels (> 5 mmol/Liter), anion gap acidosis (without evidence of ketonuria or ketonemia), an increased lactate/pyruvate ratio; and metformin plasma levels generally >5 mcg/mL [see Warnings and Precautions (5.1) ] .
Risk factors for metformin-associated lactic acidosis include renal impairment, concomitant use of certain drugs (e.g., carbonic anhydrase inhibitors such as topiramate), age 65 years old or greater, having a radiological study with contrast, surgery and other procedures, hypoxic states (e.g., acute congestive heart failure), excessive alcohol intake, hepatic impairment, and mitochondrial diseases [see Warnings and Precautions (5.1) ] .
Steps to reduce the risk of and manage metformin-associated lactic acidosis in these high risk groups are provided in the full prescribing information [see Dosage and Administration (2.2 , 2.3) , Contraindications (4) , Warnings and Precautions (5.1) , Drug Interactions (7) , and Use in Specific Populations (8.6 , 8.7) ] . If metformin-associated lactic acidosis is suspected, immediately discontinue INVOKAMET or INVOKAMET XR and institute general supportive measures in a hospital setting. Prompt hemodialysis is recommended [see Warnings and Precautions (5.1) ] . WARNING: LACTIC ACIDOSIS See full prescribing information for complete boxed warning.
Postmarketing cases of metformin-associated lactic acidosis have resulted in death, hypothermia, hypotension, and resistant bradyarrhythmias. Symptoms included malaise, myalgias, respiratory distress, somnolence, and abdominal pain. Laboratory abnormalities included elevated blood lactate levels, anion gap acidosis, increased lactate/pyruvate ratio; and metformin plasma levels generally >5 mcg/mL. ( 5.1 ) 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, hepatic impairment, and mitochondrial diseases.
Steps to reduce the risk of and manage metformin-associated lactic acidosis in these high risk groups are provided in the Full Prescribing Information. ( 5.1 ) If lactic acidosis is suspected,…
Dosing in kidney impairment
Prior to Initiation of INVOKAMET or INVOKAMET XR Assess renal function before initiating INVOKAMET or INVOKAMET XR and as clinically indicated [see Dosage and Administration , Contraindications , and Warnings and Precautions (5.1 , 5.4) ]. In patients with volume depletion, correct this condition before initiating INVOKAMET or INVOKAMET XR [see Warnings and Precautions and Use in Specific Populations (8.5 , 8.6) ] .
Recommended Dosage in Adults and Pediatric Patients Aged 10 Years and Older with Renal Impairment Initiation of INVOKAMET or INVOKAMET XR is not recommended in adults or pediatric patients aged 10 years and older with an eGFR less than 45 mL/min/1.73 m 2 , due to the metformin component. Table 2 provides dosage recommendations for adults and pediatric patients aged 10 years and older with renal impairment, based on eGFR [see Use in Specific Populations and Clinical Studies ]. [See table below.]
| Estimated Glomerular Filtration Rate [eGFR (mL/min/1.73 m2)] | Recommended Dosage of INVOKAMET or INVOKAMET XRFor the dosing frequency of INVOKAMET and INVOKAMET XR, see Dosage and Administration (2.2). |
|---|---|
| eGFR 45 to less than 60 | The maximum total daily dosage of canagliflozin is 100 mg. |
| eGFR 30 to less than 45 | Assess the benefit risk of continuing INVOKAMET or INVOKAMET XR. The maximum total daily dosage of canagliflozin is 100 mg. |
| eGFR less than 30 | Contraindicated. If eGFR falls below 30 during treatment; discontinue INVOKAMET or INVOKAMET XR [see Contraindications (4)]. |
Dosing in liver impairment
Hepatic Impairment Use of metformin HCl in patients with hepatic impairment has been associated with some cases of lactic acidosis. INVOKAMET or INVOKAMET XR is not recommended in patients with hepatic impairment [see Warnings and Precautions ].
Preparation and administration
Recommended Dosage and Administration INVOKAMET and INVOKAMET XR INVOKAMET and INVOKAMET XR contain canagliflozin and metformin HCl. For the available strengths of the canagliflozin and metformin HCl components in INVOKAMET and INVOKAMET XR, [ see Dosage Forms and Strengths ] . Individualize the starting dosage of INVOKAMET or INVOKAMET XR based on the patient's current regimen as presented in Table 1 and based on renal function as presented in Table 2 [see Dosage and Administration ] .
INVOKAMET Take one tablet of INVOKAMET orally twice daily with meals. INVOKAMET XR Take two tablets of INVOKAMET XR orally once daily with the morning meal. Swallow each tablet whole and never crush, cut, or chew. Table 1 presents the recommended starting dosage of INVOKAMET and INVOKAMET XR based on the patient's current regimen. [See table below.] Canagliflozin The same total daily dosage of canagliflozin and a total daily dosage of metformin HCl 1,000 mg Canagliflozin and metformin HCl The same total daily dosage of canagliflozin and the nearest appropriate total daily dosage of metformin HCl Recommended Dosage for Additional Glycemic Control in Adults and Pediatric Patients Aged 10 Years and Older INVOKAMET The dosage of canagliflozin in INVOKAMET may be increased to the maximum total daily dosage of 300 mg (150 mg orally twice daily) in patients tolerating a dosage of 100 mg (50 mg twice daily) of canagliflozin.
The dosage of metformin HCl in INVOKAMET may be increased to the maximum total daily dosage of 2,000 mg (1,000 mg orally twice daily), with gradual escalation to reduce the risk of gastrointestinal adverse reactions with metformin HCl [see Adverse Reactions ]. INVOKAMET XR The dosage of canagliflozin in INVOKAMET XR may be increased to the maximum total daily dosage of 300 mg orally once daily in patients tolerating a 100 mg once daily dosage of canagliflozin.
The dosage of metformin HCl in INVOKAMET XR may be increased to the maximum total daily dosage of 2,000 mg once daily, with gradual escalation to reduce the risk of gastrointestinal adverse reactions with metformin HCl [see Adverse Reactions ].
Drug interactions
Check canagliflozin and metformin against a medication listLabel text (9 paragraphs)
Table 8: Clinically Significant Drug Interactions with INVOKAMET or INVOKAMET XR Carbonic Anhydrase Inhibitors Clinical Impact: Carbonic anhydrase inhibitors frequently cause a decrease in serum bicarbonate and induce non-anion gap, hyperchloremic metabolic acidosis. Concomitant use of these drugs with INVOKAMET or INVOKAMET XR may increase the risk for lactic acidosis. Intervention: Consider more frequent monitoring of these patients.
Examples: Topiramate or other carbonic anhydrase inhibitors (e.g., zonisamide, acetazolamide or dichlorphenamide) Drugs That Reduce Metformin Clearance Clinical Impact: Concomitant use of drugs that interfere with common renal tubular transport systems involved in the renal elimination of metformin (e.g., organic cationic transporter-2 [OCT2] / multidrug and toxin extrusion [MATE] inhibitors) could increase systemic exposure to metformin and may increase the risk for lactic acidosis [see Clinical Pharmacology (12.3) ]. Intervention: Consider the benefits and risks of concomitant use.
Examples: Ranolazine, vandetanib, dolutegravir, and cimetidine Alcohol Clinical Impact: Alcohol is known to potentiate the effect of metformin HCl on lactate metabolism. Intervention: Warn patients against excessive alcohol intake while receiving INVOKAMET or INVOKAMET XR. UGT Enzyme Inducers Clinical Impact: UGT enzyme inducers decrease canagliflozin exposure which may reduce the effectiveness of INVOKAMET or INVOKAMET XR.
Intervention: For patients with eGFR 60 mL/min/1.73 m 2 or greater, if an inducer of UGTs is co-administered with INVOKAMET or INVOKAMET XR, increase the total daily dose of canagliflozin to 200 mg in patients currently tolerating INVOKAMET or INVOKAMET XR with a total daily dose of canagliflozin 100 mg. The total daily dose of canagliflozin may be increased to 300 mg in patients currently tolerating canagliflozin 200 mg and who require additional glycemic control.
For patients with eGFR less than 60 mL/min/1.73 m 2 , if an inducer of UGTs is co-administered with INVOKAMET or INVOKAMET XR, increase the total daily dose of canagliflozin to 200 mg in patients currently tolerating canagliflozin 100 mg [see Dosage and Administration (2.4) and Clinical Pharmacology (12.3) ] . Examples: Rifampin, phenytoin, phenobarbital, ritonavir Insulin or Insulin Secretagogues Clinical Impact: The risk of hypoglycemia is increased when INVOKAMET or INVOKAMET XR is used concomitantly with insulin secretagogues (e.g., sulfonylurea) or insulin.
Intervention: Concomitant use may require a lower dosage of the insulin secretagogue or insulin to reduce the risk of hypoglycemia. Drugs Affecting Glycemic Control Clinical Impact: Certain drugs tend to produce hyperglycemia and may lead to loss of glycemic control. Intervention: When such drugs are administered to a patient receiving INVOKAMET or INVOKAMET XR, monitor for loss of blood glucose control. When such drugs are withdrawn from a patient receiving INVOKAMET or INVOKAMET XR, monitor for hypoglycemia.
Examples: Thiazides and other diuretics, corticosteroids, phenothiazines, thyroid products, estrogens, oral contraceptives, phenytoin, nicotinic acid, sympathomimetics, calcium channel blockers, and isoniazid. Digoxin Clinical Impact: Canagliflozin increases digoxin exposure [see Clinical Pharmacology (12.3) ] . Intervention: Monitor patients taking INVOKAMET or INVOKAMET XR with concomitant digoxin for a need to adjust the dosage of digoxin. Lithium Clinical Impact: Concomitant use of an SGLT2 inhibitor with lithium may decrease serum lithium concentrations. Intervention: Monitor serum lithium concentration more frequently during INVOKAMET or INVOKAMET XR initiation and dosage changes.
Drug/Laboratory Test Interference Positive Urine Glucose Test Clinical Impact: SGLT2 inhibitors increase urinary glucose excretion which will lead to positive urine glucose tests. Intervention: Monitoring glycemic control with urine glucose tests is not recommended in patients taking SGLT2 inhibitors. Use alternative methods to monitor glycemic control. Interference with 1,5-anhydroglucitol (1,5-AG) Assay Clinical Impact: Measurements of 1,5-AG are unreliable in assessing glycemic control in patients taking SGLT2 inhibitors. Intervention: Monitoring glycemic control with 1,5-AG assay is not recommended in patients taking SGLT2 inhibitors. Use alternative methods to monitor glycemic control.
Carbonic Anhydrase Inhibitors : May increase risk of lactic acidosis. Consider more frequent monitoring ( 7 ). Drugs that Reduce Metformin Clearance : May increase risk of lactic acidosis. Consider benefits and risks of concomitant use ( 7 ). See full prescribing information for additional drug interactions and information on interference of INVOKAMET and INVOKAMET XR with laboratory tests. ( 7 ).
Contraindications
4 CONTRAINDICATIONS INVOKAMET or INVOKAMET XR is contraindicated in patients with: Severe renal impairment (eGFR less than 30 mL/min/1.73 m 2 ) [see Warnings and Precautions (5.1) and Use in Specific Populations (8.6) ] . Acute or chronic metabolic acidosis, including diabetic ketoacidosis [see Warnings and Precautions (5.2) ] . Serious hypersensitivity reaction to canagliflozin or metformin HCl, such as anaphylaxis or angioedema [see Warnings and Precautions (5.7) and Adverse Reactions (6) ] . Severe renal impairment (eGFR less than 30 mL/min/1.73 m 2 ) ( 4 ) Metabolic acidosis, including diabetic ketoacidosis ( 4 ) Serious hypersensitivity reaction to canagliflozin or metformin HCl ( 4 )
Pregnancy and lactation
Pregnancy
8.1 Pregnancy Risk Summary Based on juvenile animal data showing adverse renal effects from canagliflozin, INVOKAMET or INVOKAMET XR is not recommended during the second and third trimesters of pregnancy. Limited data with INVOKAMET, INVOKAMET XR or canagliflozin in pregnant women are not sufficient to determine a drug-associated risk for major birth defects or miscarriage. Published studies with metformin HCl use during pregnancy have not reported a clear association with metformin HCl and major birth defect or miscarriage risk [see Data ]. There are risks to the mother and fetus associated with poorly controlled diabetes in pregnancy [see Clinical Considerations ].
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 dose, based on AUC. No adverse developmental effects were observed when metformin HCl was administered to pregnant Sprague Dawley rats and rabbits during the period of organogenesis at doses up to 2- and 6-times, respectively, a 2,000 mg clinical dose, based on body surface area [see Data ] .
The estimated background risk of major birth defects is 6–10% in women with pre-gestational diabetes with a HbA 1C >7 and has been reported to be as high as 20–25% in women with a HbA 1C >10. The estimated background risk of miscarriage for the indicated population is unknown. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2–4% and 15–20%, respectively.
Clinical Considerations Disease-Associated Maternal and/or Embryo/Fetal Risk Poorly controlled diabetes in pregnancy increases the maternal risk for diabetic ketoacidosis, pre-eclampsia, spontaneous abortions, preterm delivery, and delivery complications. Poorly controlled diabetes increases the fetal risk for major birth defects, stillbirth, and macrosomia related morbidity. Data Human Data Published data from post-marketing studies have not reported a clear association with metformin HCl and major birth defects, miscarriage, or adverse maternal or fetal outcomes when metformin HCl was used during pregnancy.
However, these studies cannot definitely establish the absence of any metformin-associated risk because of methodological limitations, including small sample size and inconsistent comparator groups. Animal Data Canagliflozin Canagliflozin dosed…
For breastfeeding, also see LactMed (National Library of Medicine), which summarizes milk levels and infant effects.
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