Pioglitazole And Metformin Hydrochloride

⛔ FDA Black Box Warning

WARNING: CONGESTIVE HEART FAILURE AND LACTIC ACIDOSIS FULL PRESCRIBING INFORMATION WARNING: CONGESTIVE HEART FAILURE and LACTIC ACIDOSIS Congestive Heart Failure • Thiazolidinediones, including pioglitazone, which is a component of pioglitazone and metformin hydrochloride, cause or exacerbate congestive heart failure in some patients [see Warnings and Precautions ( 5.1 )]. • After initiation of pioglitazone and metformin hydrochloride, and after dose increases, monitor patients carefully for signs and symptoms of heart failure (e.g., excessive, rapid weight gain, dyspnea, and/or edema). If congestive heart failure develops while taking pioglitazone and metformin hydrochloride, consider discontinuation of pioglitazone and metformin hydrochloride or dosage reduction of pioglitazone in pioglitazone and metformin hydrochloride [see Warnings and Precautions ( 5.1 )]. • Pioglitazone and metformin hydrochloride is not recommended in patients with symptomatic heart failure [ see Warnings and Precautions ( 5.1 ) ]. • Initiation of pioglitazone and metformin hydrochloride in patients with established New York Heart Association (NYHA) Class III or IV heart failure is contraindicated [see Contraindications ( 4 ) and Warnings and Precautions ( 5.1 )]. Lactic Acidosis • Postmarketing 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 (greater than 5 mmol/L), anion gap acidosis (without evidence of ketonuria or ketonemia), an increased lactate:pyruvate ratio; and metformin plasma levels generally greater than 5 mcg/mL [see Warnings and Precautions ( 5.2 )]. • Risk factors for metformin-associated lactic acidosis include renal impairm

Contraindications

4 CONTRAINDICATIONS Pioglitazone and metformin hydrochloride tablets are contraindicated in patients with: • Established NYHA Class III or IV heart failure at the time of pioglitazone and metformin hydrochloride tablets initiation [see Boxed Warning]. • Severe renal impairment (eGFR below 30 mL/min) [see Warnings and Precautions (5.2)]. • A history of serious hypersensitivity to pioglitazone, metformin HCl, or any of the excipients in pioglitazone and metformin hydrochloride tablets. • Acute or chronic metabolic acidosis, including diabetic ketoacidosis [see Warnings and Precautions (5.2)]. Pioglitazone and metformin hydrochloride tablets is contraindicated in patients with: • Established NYHA Class III or IV heart failure at the time of pioglitazone and metformin hydrochloride tablets initiation [see Boxed Warning]. • Severe renal impairment (eGFR below 30 mL/min) [see Warnings and Precautions ( 5.2 )]. • A history of serious hypersensitivity to pioglitazone, metformin HCl, or any of the excipients in pioglitazone and metformin hydrochloride tablets. • Acute or chronic metabolic acidosis, including diabetic ketoacidosis [see Warnings and Precautions ( 5.2 )].

Pregnancy & Breastfeeding

8.1 Pregnancy Risk Summary Limited data with pioglitazone and metformin hydrochloride or pioglitazone in pregnant women are not sufficient to determine a drug-associated risk for major birth defects or miscarriage. Published studies with metformin use during pregnancy have not reported a clear association with metformin 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 reproduction studies, no adverse developmental effects were observed when pioglitazone was administered to pregnant rats and rabbits during organogenesis at exposures up to 5- and 35-times the 45 mg clinical dose, respectively, based on body surface area. No adverse developmental effects were observed when metformin was administered to pregnant Sprague Dawley rats and rabbits during the period of organogenesis at doses up to 2- to 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 a HbA1c >7 and has been reported to be as high as 20-25% in women with a HbA1c >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, still birth and delivery complications. Poorly controlled diabetes increases the fetal risk for major birth defects, still birth, and macrosomia related morbidity. Data Human Data Published data from post-marketing studies have not reported a clear association with metformin and ma