ACTOPLUS MET- pioglitazone and metformin hydrochloride tablet, film coated

Country: United States

Language: English

Source: NLM (National Library of Medicine)

Active ingredient:

PIOGLITAZONE HYDROCHLORIDE (UNII: JQT35NPK6C) (pioglitazone - UNII:X4OV71U42S), metformin hydrochloride (UNII: 786Z46389E) (metformin - UNII:9100L32L2N)

Available from:

Takeda Pharmaceuticals America, Inc.

INN (International Name):

PIOGLITAZONE HYDROCHLORIDE

Composition:

pioglitazone 15 mg

Administration route:

ORAL

Prescription type:

PRESCRIPTION DRUG

Therapeutic indications:

ACTOPLUS MET is indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus when treatment with both pioglitazone and metformin is appropriate [see Clinical Studies (14)] . Important Limitations of Use Pioglitazone exerts its antihyperglycemic effect only in the presence of endogenous insulin. ACTOPLUS MET should not be used to treat type 1 diabetes or diabetic ketoacidosis, as it would not be effective in these settings. Use caution in patients with liver disease [see Warnings and Precautions (5.5)] . Risk Summary Limited data with ACTOPLUS MET 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 to 10% in women with pre-gestational diabetes with a HbA1c >7 and has been reported to be as high as 20 to 25% in women with a HbA1c >10. The estimated background risk of miscarriage for the indicated population is unknown. In the US general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 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 postmarketing studies have not reported a clear association with metformin and major birth defects, miscarriage, or adverse maternal or fetal outcomes when metformin 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 Pioglitazone and Metformin Hydrochloride Animal reproduction studies were not conducted with the combined products in ACTOPLUS MET. The following data are based on studies conducted with the individual components of ACTOPLUS MET. Pioglitazone Pioglitazone administered to pregnant rats during organogenesis did not cause adverse developmental effects at a dose of 20 mg/kg (~5 times the 45 mg clinical dose), but delayed parturition and reduced embryo-fetal viability at 40 and 80 mg/kg, or ≥9 times the 45 mg clinical dose, by body surface area. In pregnant rabbits administered pioglitazone during organogenesis, no adverse developmental effects were observed at 80 mg/kg (~35 times the 45 mg clinical dose), but reduced embryo-fetal viability at 160 mg/kg, or ~69 times the 45 mg clinical dose, by body surface area. When pregnant rats received pioglitazone during late gestation and lactation, delayed postnatal development, attributed to decreased body weight, occurred in offspring at maternal doses of 10 mg/kg and above or ≥2 times the 45 mg clinical dose, by body surface area. Metformin Hydrochloride Metformin hydrochloride 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 to 6 times a 2000 mg clinical dose based on body surface area (mg/m2 ) for rats and rabbits, respectively. Risk Summary There is no information regarding the presence of ACTOPLUS MET or pioglitazone in human milk, the effects on the breastfed infant, or the effects on milk production. Pioglitazone is present in rat milk; however, due to species-specific differences in lactation physiology, animal data may not reliably predict drug levels in human milk. Limited published studies report that metformin is present in human milk (see Data) . However, there is insufficient information on the effects of metformin on the breastfed infant and no available information on the effects of metformin on milk production. The developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for ACTOPLUS MET and any potential adverse effects on the breastfed infant from ACTOPLUS MET or from the underlying maternal condition. 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 during lactation because of small sample size and limited adverse event data collected in infants. Discuss the potential for unintended pregnancy with premenopausal women as therapy with ACTOPLUS MET, may result in ovulation in some anovulatory women. Safety and effectiveness of ACTOPLUS MET in pediatric patients have not been established. ACTOPLUS MET is not recommended for use in pediatric patients based on adverse effects observed in adults, including fluid retention and congestive heart failure, fractures, and urinary bladder tumors [see Warnings and Precautions (5.1, 5.3, 5.6, 5.7)]. Pioglitazone A total of 92 patients (15.2%) treated with pioglitazone in the three pooled 16 to 26 week double-blind, placebo-controlled, monotherapy trials were ≥65 years old and two patients (0.3%) were ≥75 years old. In the two pooled 16 to 24 week add-on to sulfonylurea trials, 201 patients (18.7%) treated with pioglitazone were ≥65 years old and 19 (1.8%) were ≥75 years old. In the two pooled 16 to 24 week add-on to metformin trials, 155 patients (15.5%) treated with pioglitazone were ≥65 years old and 19 (1.9%) were ≥75 years old. In the two pooled 16 to 24 week add-on to insulin trials, 272 patients (25.4%) treated with pioglitazone were ≥65 years old and 22 (2.1%) were ≥75 years old. In PROactive Trial, 1068 patients (41.0%) treated with pioglitazone were ≥65 years old and 42 (1.6%) were ≥75 years old. In pharmacokinetic studies with pioglitazone, no significant differences were observed in pharmacokinetic parameters between elderly and younger patients [see Clinical Pharmacology (12.3)] . Although clinical experiences have not identified differences in effectiveness and safety between the elderly (≥65 years) and younger patients, these conclusions are limited by small sample sizes for patients ≥75 years old. Metformin Hydrochloride Controlled clinical studies of metformin 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 young patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy and the higher risk of lactic acidosis. Assess renal function more frequently in elderly patients [see Warnings and Precautions (5.2), Dosage and Administration (2.2)]. Metformin is substantially excreted by the kidney, and the risk of metformin accumulation and lactic acidosis increases with the degree of renal impairment. ACTOPLUS MET is contraindicated in severe renal impairment, patients with an eGFR below 30 mL/min/1.73 m2 [see Dosage and Administration (2.2), Contraindications (4), Warnings and Precautions (5.2), Clinical Pharmacology (12.3)]. Use of metformin in patients with hepatic impairment has been associated with some cases of lactic acidosis. ACTOPLUS MET is not recommended in patients with hepatic impairment [see Warnings and Precautions (5.2)] .

Product summary:

ACTOPLUS MET is available in 15 mg pioglitazone (as the base)/850 mg metformin hydrochloride tablets as follows: 15 mg/850 mg tablet: white to off-white, oblong, film-coated tablet with "4833M" on one side and "15/850" on the other, available in: Bottles of 60 NDC 64764-158-60 Bottles of 180 NDC 64764-158-18 Storage Store at 25°C (77°F); excursions permitted to 15°-30°C (59°-86°F) [see USP Controlled Room Temperature]. Keep container tightly closed, and protect from moisture and humidity.

Authorization status:

New Drug Application

Patient Information leaflet

ACTOPLUS MET- PIOGLITAZONE AND METFORMIN HYDROCHLORIDE TABLET, FILM
COATED
Takeda Pharmaceuticals America, Inc.
----------
MEDICATION GUIDE
ACTOPLUS MET (ak-TŌ-plus-met)
(pioglitazone and metformin hydrochloride) tablets
Read this Medication Guide carefully before you start taking ACTOPLUS
MET and each time you get a
refill. There may be new information. This information does not take
the place of talking with your doctor
about your medical condition or your treatment. If you have any
questions about ACTOPLUS MET, ask
your doctor or pharmacist.
What is the most important information I should know about ACTOPLUS
MET?
ACTOPLUS MET can cause serious side effects, including:
•
new or worse heart failure. Pioglitazone, one of the medicines in
ACTOPLUS MET, can cause your
body to keep extra fluid (fluid retention), which leads to swelling
(edema) and weight gain. Extra
body fluid can make some heart problems worse or lead to heart
failure. Heart failure means your
heart does not pump blood well enough.
∘
Do not take ACTOPLUS MET if you have severe heart failure
∘
If you have heart failure with symptoms (such as shortness of breath
or swelling), even if
these symptoms are not severe, ACTOPLUS MET may not be right for you.
Call your doctor right away if you have any of the following:
∘
swelling or fluid retention, especially in the ankles or legs
∘
shortness of breath or trouble breathing, especially when you lie down
∘
an unusually fast increase in weight
∘
unusual tiredness
•
lactic acidosis. Metformin, one of the medicines in ACTOPLUS MET, can
cause a rare but serious
condition called lactic acidosis (a buildup of an acid in the blood)
that can cause death. Lactic
acidosis is a medical emergency and must be treated in the hospital.
Call your doctor right away if you have any of the following symptoms,
which could be signs of lactic
acidosis:
∘
you feel cold in your hands or feet
∘
you feel dizzy or lightheaded
∘
you have a slow or irregular heartbeat
∘
you feel very weak or tired
∘
you have

Summary of Product characteristics

ACTOPLUS MET- PIOGLITAZONE AND METFORMIN HYDROCHLORIDE TABLET, FILM
COATED
TAKEDA PHARMACEUTICALS AMERICA, INC.
----------
HIGHLIGHTS OF PRESCRIBING INFORMATION
THESE HIGHLIGHTS DO NOT INCLUDE ALL THE INFORMATION NEEDED TO USE
ACTOPLUS MET SAFELY
AND EFFECTIVELY. SEE FULL PRESCRIBING INFORMATION FOR ACTOPLUS MET.
ACTOPLUS MET (PIOGLITAZONE AND METFORMIN HYDROCHLORIDE) TABLETS, FOR
ORAL USE
INITIAL U.S. APPROVAL: 2005
WARNING: CONGESTIVE HEART FAILURE AND LACTIC ACIDOSIS
SEE FULL PRESCRIBING INFORMATION FOR COMPLETE BOXED WARNING.
CONGESTIVE HEART FAILURE
•
•
•
•
LACTIC ACIDOSIS
•
•
•
INDICATIONS AND USAGE
ACTOPLUS MET is a thiazolidinedione and biguanide combination product
indicated as an adjunct to diet
and exercise to improve glycemic control in adults with type 2
diabetes mellitus when treatment with both
pioglitazone and metformin is appropriate. (1, 14)
Important Limitations of Use:
•
DOSAGE AND ADMINISTRATION
•
•
THIAZOLIDINEDIONES, INCLUDING PIOGLITAZONE, WHICH IS A COMPONENT OF
ACTOPLUS
MET, CAUSE OR EXACERBATE CONGESTIVE HEART FAILURE IN SOME PATIENTS.
(5.1)
AFTER INITIATION OF ACTOPLUS MET, 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 HEART FAILURE DEVELOPS, IT SHOULD BE
MANAGED
ACCORDING TO CURRENT STANDARDS OF CARE AND DISCONTINUATION OR DOSE
REDUCTION OF
ACTOPLUS MET MUST BE CONSIDERED. (5.1)
ACTOPLUS MET IS NOT RECOMMENDED IN PATIENTS WITH SYMPTOMATIC HEART
FAILURE.
(5.1)
INITIATION OF ACTOPLUS MET IN PATIENTS WITH ESTABLISHED NEW YORK HEART
ASSOCIATION (NYHA) CLASS III OR IV HEART FAILURE IS CONTRAINDICATED.
(4, 5.1)
POST-MARKETING 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