Dosage & Administration
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Invokamet Prescribing Information
- 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, and hepatic impairment [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)] .
INVOKAMET
INVOKAMET is a combination of canagliflozin and metformin HCl immediate-release indicated as an adjunct to diet and exercise to improve glycemic control in adults and pediatric patients aged 10 years and older with type 2 diabetes mellitus.
INVOKAMET XR
INVOKAMET XR is a combination of canagliflozin and metformin HCl extended-release indicated as an adjunct to diet and exercise to improve glycemic control in adults and pediatric patients aged 10 years and older with type 2 diabetes mellitus.
Canagliflozin
Canagliflozin, when used as a component of INVOKAMET or INVOKAMET XR, is indicated in adults with type 2 diabetes mellitus to reduce the risk of:
- Major adverse cardiovascular events (cardiovascular death, nonfatal myocardial infarction and nonfatal stroke) in adults with type 2 diabetes mellitus and established cardiovascular disease (CVD).
- End-stage kidney disease (ESKD), doubling of serum creatinine, cardiovascular (CV) death, and hospitalization for heart failure in adults with type 2 diabetes mellitus and diabetic nephropathy with albuminuria greater than 300 mg/day.
Limitations of Use
INVOKAMET or INVOKAMET XR are not recommended for use to improve glycemic control in patients with type 1 diabetes mellitus [see Warnings and Precautions (5.2)] .
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 (2.3), Contraindications (4), 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 (5.4)and Use in Specific Populations (8.5, 8.6)] .
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 (3).
- 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 (2.3] .
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.
| Current Regimen | INVOKAMET Recommended Dosage | INVOKAMET XR Recommended Dosage |
|---|---|---|
| ||
| Not treated with either canagliflozin or metformin HCl | Total daily dosage is canagliflozin 100 mg and metformin HCl 1,000 mg | |
| Metformin HCl * | Total daily dosage is canagliflozin 100 mg and the nearest appropriate total daily dosage of metformin HCl | |
| 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 (6.1)].
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 (6.1)].
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 (8.6)and Clinical Studies (14.4)].
| Estimated Glomerular Filtration Rate [eGFR (mL/min/1.73 m 2)] | Recommended Dosage of INVOKAMET or INVOKAMET XR * |
|---|---|
| |
| 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)] . |
Concomitant Use with UDP-Glucuronosyltransferase (UGT) Enzyme Inducers
When co-administering INVOKAMET or INVOKAMET XR with an inducer of UGT (e.g., rifampin, phenytoin, phenobarbital, ritonavir), increase the total daily dosage of canagliflozin based on renal function [see Drug Interactions (7)] :
- In patients with eGFR 60 mL/min/1.73 m 2or greater, increase the total daily dosage of canagliflozin to 200 mg in patients currently tolerating a total daily dosage of canagliflozin 100 mg. The maximum total daily dosage of canagliflozin is 300 mg.
- In patients with eGFR less than 60 mL/min/1.73 m 2, increase the total daily dosage of canagliflozin to a maximum of 200 mg in patients currently tolerating a total daily dosage of canagliflozin 100 mg.
Discontinuation for Iodinated Contrast Imaging Procedures
Discontinue INVOKAMET or INVOKAMET XR at the time of, or prior to, an iodinated contrast imaging procedure in patients with an eGFR of less than 60 mL/min/1.73 m 2; in patients with a history of liver disease, alcoholism or heart failure; or in patients who will be administered intra-arterial iodinated contrast. Re-evaluate eGFR 48 hours after the imaging procedure; restart INVOKAMET or INVOKAMET XR if renal function is stable [see Warnings and Precautions (5.1)] .
Temporary Interruption for Surgery
Withhold INVOKAMET or INVOKAMET XR at least 3 days, if possible, prior to surgery or procedures associated with prolonged fasting. Resume INVOKAMET or INVOKAMET XR when the patient is clinically stable and has resumed oral intake [see Warnings and Precautions (5.2)and Clinical Pharmacology (12.2)].
INVOKAMET (canagliflozin and metformin HCl) tablets are available as follows:
| Canagliflozin Strength | Metformin HCl Strength | Color/Shape | Tablet Identifiers * |
|---|---|---|---|
| |||
| 50 mg | 500 mg | white/capsule-shaped | CM 155 |
| 50 mg | 1,000 mg | beige/capsule-shaped | CM 551 |
| 150 mg | 500 mg | yellow/capsule-shaped | CM 215 |
| 150 mg | 1,000 mg | purple/capsule-shaped | CM 611 |
INVOKAMET XR (canagliflozin and metformin HCl) extended-release tablets are available as follows:
| Canagliflozin Strength | Metformin HCl Strength | Color/Shape | Tablet Identifiers * |
|---|---|---|---|
| |||
| 50 mg | 500 mg | almost white to light orange/oblong, biconvex | CM1 |
| 50 mg | 1,000 mg | pink/oblong, biconvex | CM3 |
| 150 mg | 500 mg | orange/oblong, biconvex | CM2 |
| 150 mg | 1,000 mg | reddish brown/oblong, biconvex | CM4 |
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 directly to juvenile rats from postnatal day (PND) 21 until PND 90 at doses of 4, 20, 65, or 100 mg/kg increased kidney weights and dose dependently increased the incidence and severity of renal pelvic and tubular dilatation at all doses tested. Exposure at the lowest dose was greater than or equal to 0.5-times the 300 mg clinical dose, based on AUC. These outcomes occurred with drug exposure during periods of renal development in rats that correspond to the late second and third trimester of human renal development. The renal pelvic dilatations observed in juvenile animals did not fully reverse within a 1-month recovery period.
In embryo-fetal development studies in rats and rabbits, canagliflozin was administered for intervals coinciding with the first trimester period of organogenesis in humans. No developmental toxicities independent of maternal toxicity were observed when canagliflozin was administered at doses up to 100 mg/kg in pregnant rats and 160 mg/kg in pregnant rabbits during embryonic organogenesis or during a study in which maternal rats were dosed from gestation day (GD) 6 through PND 21, yielding exposures up to approximately 19-times the 300 mg clinical dose, based on AUC.
Metformin HCl
Metformin HCl did not cause adverse developmental effects when administered to pregnant Sprague Dawley rats and rabbits up to 600 mg/kg/day during the period of organogenesis. This represents an exposure of about 2- and 6-times a 2,000 mg clinical dose based on body surface area (mg/m 2) for rats and rabbits, respectively.
Canagliflozin and Metformin HCl
No adverse developmental effects were observed when canagliflozin and metformin HCl were co-administered to pregnant rats during the period of organogenesis at exposures up to 11 and 13 times, respectively, the 300 mg and 2,000 mg clinical doses of canagliflozin and metformin HCl based on AUC.
Lactation
Risk Summary
There is no information regarding the presence of INVOKAMET, INVOKAMET XR or canagliflozin in human milk, the effects on the breastfed infant, or the effects on milk production. Limited published studies report that metformin is present in human milk [see Data] . However, there is insufficient information on the effects of metformin HCl on the breastfed infant and no available information on the effects of metformin HCl on milk production. Canagliflozin is present in the milk of lactating rats [see Data] . Since human kidney maturation occurs in uteroand during the first 2 years of life when lactational exposure may occur, there may be risk to the developing human kidney.
Because of the potential for serious adverse reactions in a breastfed infant, advise women that use of INVOKAMET or INVOKAMET XR is not recommended while breastfeeding.
Data
Published clinical lactation studies report that metformin is present in human milk which resulted in infant doses approximately 0.11% to 1% of the maternal weight-adjusted dosage and a milk/plasma ratio ranging between 0.13 and 1. However, the studies were not designed to definitely establish the risk of use of metformin HCl during lactation because of small sample size and limited adverse event data collected in infants.
Radiolabeled canagliflozin administered to lactating rats on day 13 post-partum was present at a milk/plasma ratio of 1.40, indicating that canagliflozin and its metabolites are transferred into milk at a concentration comparable to that in plasma. Juvenile rats directly exposed to canagliflozin showed a risk to the developing kidney (renal pelvic and tubular dilatations) during maturation.
Females and Males of Reproductive Potential
Discuss the potential for unintended pregnancy with premenopausal women as therapy with metformin HCl may result in ovulation in some anovulatory women.
Pediatric Use
The safety and effectiveness of INVOKAMET and INVOKAMET XR as an adjunct to diet and exercise to improve glycemic control in type 2 diabetes mellitus have been established in pediatric patients aged 10 years and older.
Use of INVOKAMET and INVOKAMET XR for this indication is supported by evidence from a 52-week double-blind, placebo-controlled trial of canagliflozin in 171 pediatric patients aged 10 to 17 years with type 2 diabetes mellitus and in a pediatric pharmacokinetic study [see Clinical Pharmacology (12.3)and Clinical Studies (14.2)] . The safety profile of pediatric patients treated with canagliflozin was similar to that observed in adults with type 2 diabetes mellitus.
The use of INVOKAMET and INVOKAMET XR for this indication is also supported by evidence from adequate and well-controlled trials of metformin HCl immediate-release tablets in adults with additional data from a controlled clinical trial using metformin HCl immediate-release tablets in pediatric patients 10 to 16 years old with type 2 diabetes mellitus, and pharmacokinetic data with metformin HCl extended-release tablets in adults [see Clinical Pharmacology (12.3)and Clinical Studies (14.1, 14.2)]. In the clinical trial with pediatric patients receiving metformin HCl immediate-release tablets, adverse reactions with metformin HCl immediate-release tablets were similar to those described in adults [see Adverse Reactions (6.1)].
The safety and effectiveness of INVOKAMET or INVOKAMET XR for glycemic control in patients with type 2 diabetes mellitus have not been established in pediatric patients under 10 years of age.
The safety and effectiveness of INVOKAMET or INVOKAMET XR have not been established in pediatric patients to reduce the risk of:
- major adverse cardiovascular events (cardiovascular death, nonfatal myocardial infarction and nonfatal stroke) in patients with type 2 diabetes mellitus and established cardiovascular disease (CVD).
- end-stage kidney disease (ESKD), doubling of serum creatinine, cardiovascular (CV) death, and hospitalization for heart failure in patients with type 2 diabetes mellitus and diabetic nephropathy with albuminuria greater than 300 mg/day.
Geriatric Use
INVOKAMET and INVOKAMET XR
Because renal function abnormalities can occur after initiating canagliflozin, metformin is substantially excreted by the kidney, and aging can be associated with reduced renal function, monitor renal function more frequently after initiating INVOKAMET or INVOKAMET XR in the elderly and then adjust dose based on renal function [see Dosage and Administration (2.4)and Warnings and Precautions (5.1, 5.4)] .
Canagliflozin
In 13 clinical trials of canagliflozin, 2,294 patients 65 years and older, and 351 patients 75 years and older were exposed to canagliflozin. Of these patients, 1,534 patients 65 years and older and 196 patients 75 years and older were exposed to the combination of canagliflozin and metformin HCl [see Clinical Studies (14.1)] . Patients 65 years and older had a higher incidence of adverse reactions related to reduced intravascular volume with canagliflozin (such as hypotension, postural dizziness, orthostatic hypotension, syncope, and dehydration), particularly with the 300 mg daily dose, compared to younger patients; a more prominent increase in the incidence was seen in patients who were 75 years and older [see Dosage and Administration (2.1)and Adverse Reactions (6.1)]. Smaller reductions in HbA 1Cwith canagliflozin relative to placebo were seen in older (65 years and older; -0.61% with canagliflozin 100 mg and -0.74% with canagliflozin 300 mg relative to placebo) compared to younger patients (-0.72% with canagliflozin 100 mg and -0.87% with canagliflozin 300 mg relative to placebo).
Metformin HCl
Controlled clinical trials of metformin HCl did not include sufficient numbers of elderly patients to determine whether they respond differently from younger patients, although other reported clinical experience has not identified differences in responses between the elderly and younger patients. The initial and maintenance dosing of metformin HCl should be conservative in patients with advanced age due to the potential for decreased renal function in this population. Any dose adjustment should be based on a careful assessment of renal function [see Contraindications (4), Warnings and Precautions (5.4), and Clinical Pharmacology (12.3)] .
Renal Impairment
Canagliflozin
The efficacy and safety of canagliflozin for glycemic control were evaluated in a trial that included adult patients with moderate renal impairment (eGFR 30 to less than 50 mL/min/1.73 m 2). These patients had less overall glycemic efficacy, and patients treated with canagliflozin 300 mg per day had increases in serum potassium, which were transient and similar by the end of the trial. Patients with renal impairment using canagliflozin for glycemic control may also be more likely to experience hypotension and may be at higher risk for acute kidney injury [see Warnings and Precautions (5.4)] .
Efficacy and safety trials with canagliflozin did not enroll adult patients with ESKD on dialysis or patients with an eGFR less than 30 mL/min/1.73 m 2[see Clinical Pharmacology (12.3)] .
Metformin HCl
Metformin is substantially excreted by the kidney, and the risk of metformin accumulation and lactic acidosis increases with the degree of renal impairment. INVOKAMET or INVOKAMET XR is contraindicated in severe renal impairment (eGFR less than 30 mL/min/1.73 m 2) or in patients on dialysis [see Dosage and Administration (2.4), Contraindications (4), Warnings and Precautions (5.1), and Clinical Pharmacology (12.3)].
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 (5.1)].
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 (5.9)and Adverse Reactions (6)] .