INVOKAMET- canagliflozin and metformin hydrochloride tablet, film coated INVOKAMET XR- canagliflozin and metformin hydrochloride tablet, film coated, extended release

Country: United States

Language: English

Source: NLM (National Library of Medicine)

Active ingredient:

CANAGLIFLOZIN (UNII: 0SAC974Z85) (CANAGLIFLOZIN ANHYDROUS - UNII:6S49DGR869), METFORMIN HYDROCHLORIDE (UNII: 786Z46389E) (METFORMIN - UNII:9100L32L2N)

Available from:

Janssen Pharmaceuticals, Inc.

INN (International Name):

canagliflozin

Composition:

canagliflozin anhydrous 50 mg

Administration route:

ORAL

Prescription type:

PRESCRIPTION DRUG

Therapeutic indications:

INVOKAMET and INVOKAMET XR are a combination of canagliflozin and metformin HCl indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus. Canagliflozin is indicated 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). Canagliflozin is indicated to reduce the risk of 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 is not recommended for use to improve glycemic control in patients with type 1 diabetes mellitus [see Warnings and Precautions (5.2)] . 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)] . - With acute or chronic metabolic acidosis, including diabetic ketoacidosis [see Warnings and Precautions (5.2)] . - With serious hypersensitivity reaction to canagliflozin or metformin HCl, such as anaphylaxis or angioedema [see Warnings and Precautions (5.9)and Adverse Reactions (6)] . Risk Summary Based on 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 animal studies, adverse renal pelvic and tubule dilatations that were not reversible were observed in rats when canagliflozin was administered at an exposure 0.5-times the 300 mg clinical dose, based on AUC during a period of renal development corresponding to the late second and third trimesters of human pregnancy. 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 2000 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 an 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 2000 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 2000 mg clinical doses of canagliflozin and metformin HCl based on AUC. 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 utero and 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. Discuss the potential for unintended pregnancy with premenopausal women as therapy with metformin HCl may result in ovulation in some anovulatory women. Safety and effectiveness of INVOKAMET or INVOKAMET XR in pediatric patients under 18 years of age have not been established. 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)] . 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 1C with 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)] . Canagliflozin The efficacy and safety of canagliflozin for glycemic control were evaluated in a trial that included 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 study. 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 studies with canagliflozin did not enroll 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)]. 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)].

Product summary:

INVOKAMET ® tablets are available in bottles of 60 in the strengths listed below: INVOKAMET ® XR tablets are available in bottles of 60 in the strengths listed below: Storage and Handling Keep out of reach of children. Store at 20°C to 25°C (68°F to 77°F); excursions permitted between 15°C to 30°C (59°F to 86°F) [see USP Controlled Room Temperature] . Store and dispense in the original container. Storage in a pill box or pill organizer is allowed for up to 30 days.

Authorization status:

New Drug Application

Patient Information leaflet

INVOKAMET XR- CANAGLIFLOZIN AND METFORMIN HYDROCHLORIDE TABLET, FILM
COATED, EXTENDED
RELEASE
Janssen Pharmaceuticals, Inc.
----------
MEDICATION GUIDE
INVOKAMET ®(IN VOK' A MET)
(CANAGLIFLOZIN AND METFORMIN HYDROCHLORIDE (HCL)) TABLETS, FOR ORAL
USE
AND
INVOKAMET ®(IN VOK' A MET) XR
(CANAGLIFLOZIN AND METFORMIN HCL) EXTENDED-RELEASE TABLETS, FOR ORAL
USE
This Medication Guide has been approved by the U.S. Food and Drug
Administration.
Revised 01/2024
What is the most important information I should know about INVOKAMET
or INVOKAMET XR?
INVOKAMET and INVOKAMET XR can cause serious side effects, including:
•
Lactic Acidosis.Metformin, one of the medicines in INVOKAMET and
INVOKAMET XR, can
cause a rare but serious condition called lactic acidosis (a build-up
of lactic acid in the blood) that
can cause death. Lactic acidosis is a medical emergency and must be
treated in the hospital.
Stop taking INVOKAMET or INVOKAMET XR and call your doctor right away
if you have any
of the following symptoms of lactic acidosis:
•
feel cold in your hands or feet
•
feel very weak or tired
•
have trouble breathing
•
have stomach pains, nausea, or vomiting
•
have a slow or irregular heartbeat
•
have unusual (not normal) muscle
pain
•
have unusual sleepiness or sleep
longer than usual
•
feel dizzy or lightheaded
Most people who have had lactic acidosis had other conditions that, in
combination with metformin use,
led to the lactic acidosis. Tell your doctor if you have any of the
following, because you have a higher
chance for getting lactic acidosis with INVOKAMET or INVOKAMET XR if
you:
•
have severe kidney problems or your kidneys are affected by certain
x-ray tests that use
injectable dye.
•
have liver problems.
•
drink alcohol very often or drink a lot of alcohol in short-term
"binge" drinking.
•
get dehydrated (lose a large amount of body fluids). This can happen
if you are sick with a
fever, vomiting, or diarrhea. Dehydration can also happen when you
sweat a lot with activity or
exercise and do not dr

Summary of Product characteristics

INVOKAMET- CANAGLIFLOZIN AND METFORMIN HYDROCHLORIDE TABLET, FILM
COATED
INVOKAMET XR- CANAGLIFLOZIN AND METFORMIN HYDROCHLORIDE TABLET, FILM
COATED,
EXTENDED RELEASE
JANSSEN PHARMACEUTICALS, INC.
----------
HIGHLIGHTS OF PRESCRIBING INFORMATION
THESE HIGHLIGHTS DO NOT INCLUDE ALL THE INFORMATION NEEDED TO USE
INVOKAMET OR
INVOKAMET XR SAFELY AND EFFECTIVELY. SEE FULL PRESCRIBING INFORMATION
FOR INVOKAMET OR
INVOKAMET XR.
INVOKAMET
(CANAGLIFLOZIN AND METFORMIN HYDROCHLORIDE (HCL) TABLETS), FOR ORAL
USE
INVOKAMET
XR (CANAGLIFLOZIN AND METFORMIN HCL EXTENDED-RELEASE TABLETS), FOR
ORAL USE
INITIAL U.S. APPROVAL: 2014
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, AND HEPATIC IMPAIRMENT. 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, DISCONTINUE INVOKAMET OR INVOKAMET XR
AND
INSTITUTE GENERAL SUPPORTIVE MEASURES IN A HOSPITAL SETTING. PROMPT
HEMODIALYSIS IS
RECOMMENDED. ( 5.1)
RECENT MAJOR CHANGES
Indications and Usage ( 1)
07/2023
Dosage and Administration ( 2.2, 2.3, 2.4, 2.5, 2.7)
07/2023
Contraindications ( 4)
07/2023
Warnings and Precautions ( 5.2)
07/2023
Warnings and Precautions ( 5.3)
01/2024
INDICATIONS AND USAGE
INVOKAMET and INVOKAMET XR are a combination of canagliflozin, a
sodium-glucose co-transporter 2
(SGLT2) inhibitor, an