Canagliflozin And Metformin Hydrochloride

⛔ FDA Black Box 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, 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) ] . 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

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 (5.9) 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 & Breastfeeding

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 contro