Actoplus Met

Name: Actoplus Met

What should I discuss with my healthcare provider before taking metformin and pioglitazone?

You should not use this medicine if you are allergic to metformin or pioglitazone, or if you have:

  • severe or uncontrolled heart failure;

  • kidney problems;

  • active bladder cancer;

  • metabolic acidosis; or

  • diabetic ketoacidosis (call your doctor for treatment with insulin).

If you need to have any type of x-ray or CT scan using a dye that is injected into your veins, you will need to temporarily stop taking metformin and pioglitazone. Be sure your caregivers know ahead of time that you are using this medication.

Some people taking metformin develop a serious condition called lactic acidosis. This may be more likely if you have liver or kidney disease, congestive heart failure, a severe infection, if you are dehydrated, or if you drink large amounts of alcohol. Talk with your doctor about your risk.

To make sure metformin and pioglitazone is safe for you, tell your doctor if you have:

  • congestive heart failure or heart disease;

  • fluid retention;

  • a history of bladder cancer;

  • a history of heart attack or stroke;

  • liver disease; or

  • if you are 80 years or older.

This medication may increase your risk of developing bladder cancer. Talk with your doctor about your specific risk.

Taking metformin and pioglitazone may increase your risk of serious heart problems. However, not treating your diabetes can damage your heart and other organs. Talk to your doctor about the risks and benefits of treating your diabetes with this medicine.

Follow your doctor's instructions about using this medicine if you are pregnant. Blood sugar control is very important during pregnancy, and your dose needs may be different during each trimester of pregnancy.

Some women using metformin and pioglitazone have started having menstrual periods, even after not having a period for a long time due to a medical condition. You may be able to get pregnant if your periods restart. Talk with your doctor about the need for birth control.

Women may be more likely than men to have bone fractures in the upper arm, hand, or foot while taking medicine that contains pioglitazone. Talk with your doctor if you are concerned about this possibility.

It is not known whether metformin and pioglitazone passes into breast milk or if it could harm a nursing baby. You should not breast-feed while using this medicine.

Metformin and pioglitazone should not be given to a child.

What should I avoid while taking metformin and pioglitazone?

Avoid drinking alcohol. It can lower your blood sugar and may increase your risk of lactic acidosis.

Uses For Actoplus Met

Pioglitazone and metformin combination is used with proper diet and exercise to treat high blood sugar levels caused by type 2 diabetes. Pioglitazone works by helping your body use insulin better. Metformin reduces the absorption of sugar from the stomach, reduces the release of stored sugar from the liver, and helps your body use sugar better. This medicine does not help patients who have insulin-dependent or type 1 diabetes.

This medicine is available only with your doctor's prescription.

Uses of Actoplus Met

  • It is used to lower blood sugar in patients with high blood sugar (diabetes).

Use in specific populations

Pregnancy

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 6-10% 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 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 embryofetal 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 embryofetal 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.

Lactation

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.

Females and Males of Reproductive Potential

Discuss the potential for unintended pregnancy with premenopausal women as therapy with Actoplus Met, may result in ovulation in some anovulatory women.

Pediatric Use

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)].

Geriatric Use

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) and Dosage and Administration (2.2)].

Renal Impairment

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) and Clinical Pharmacology (12.3)].

Hepatic Impairment

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)].

Actoplus Met Overview

Actoplus Met is a prescription medication used to treat type 2 diabetes.

It is a single product containing 2 medications: pioglitazone and metformin.

Pioglitazone belongs to a group of drugs called thiazolidinediones. These work by increasing the body’s sensitivity to insulin. Metformin belongs to a group of drugs called biguanides. These work by decreasing the amount of glucose absorbed from food and decreasing the amount of glucose that is produced by the liver.

This medication comes in tablet form and is taken one or two times a day, with food.

Common side effects of Actoplus Met include upper respiratory tract infection, edema, diarrhea, headache, muscle pain, and weight gain.

In combination with other medications to treat diabetes, Actoplus Met can also cause hypoglycemia (low blood sugar), which can cause blurred vision and dizziness. Do not drive or operate heavy machinery until you know how Actoplus Met affects you.

Actoplus Met Interactions

Tell your doctor about all the medicines you take, including prescription and non-prescription medicines, vitamins, and herbal supplements. Especially tell your doctor if you take:

  • acetazolamide (Diamox)
  • amiloride (Midamor, in Moduretic)
  • angiotensin-converting enzyme (ACE) inhibitors such as benazepril (Lotensin), captopril (Capoten), enalapril (Vasotec), fosinopril (Monopril), lisinopril (Prinivil, Zestril), moexipril (Univasc), perindopril (Aceon), quinapril (Accupril), ramipril (Altace), and trandolapril (Mavik)
  • atorvastatin (Lipitor)
  • beta-blockers such as atenolol (Tenormin), labetalol (Normodyne), metoprolol (Lopressor, Toprol XL), nadolol (Corgard), and propranolol (Inderal)
  • calcium channel blockers such as amlodipine (Norvasc), diltiazem (Cardizem, Dilacor, Tiazac, others), felodipine (Plendil), isradipine (DynaCirc), nicardipine (Cardene), nifedipine (Adalat, Procardia), nimodipine (Nimotop), nisoldipine (Sular), and verapamil (Calan, Isoptin, Verelan)
  • cimetidine (Tagamet)
  • digoxin (Lanoxin)
  • diuretics ('water pills')
  • furosemide (Lasix)
  • gemfibrozil (Lopid)
  • hormonal contraceptives (birth control pills, patches, rings, implants, and injections) or hormone replacement therapy
  • insulin or other medications to treat diabetes
  • isoniazid
  • ketoconazole (Nizoral)
  • medications for asthma and colds
  • medications for mental illness and nausea
  • medications for thyroid disease
  • midazolam (Versed)
  • morphine (MS Contin, others)
  • nifedipine (Procardia)
  • oral steroids such as dexamethasone (Decadron, Dexone), methylprednisolone (Medrol), and prednisone (Deltasone)
  • phenytoin (Dilantin, Phenytek)
  • procainamide (Procanbid)
  • quinidine
  • quinine
  • ranitidine (Zantac)
  • rifampin (Rifadin, Rifater, in Rifamate)
  • topiramate (Topamax)
  • triamterene (Dyazide, Maxzide, others)
  • trimethoprim (Primsol)
  • vancomycin (Vancocin)
  • zonisamide (Zonegran)

This is not a complete list of Actoplus Met drug interactions. Ask your doctor or pharmacist for more information.

Other Requirements

  • Store Actoplus Met at room temperature.
  • Keep this and all medicines out of the reach of children.

Actoplus Met side effects

Some people develop lactic acidosis while taking metformin. Early symptoms may get worse over time and this condition can be fatal. Get emergency medical help if you have even mild symptoms such as: muscle pain or weakness, numb or cold feeling in your arms and legs, trouble breathing, stomach pain, nausea with vomiting, fast or uneven heart rate, dizziness, or feeling very weak or tired.

Get emergency medical help if you have any of these signs of an allergic reaction to Actoplus Met: hives; difficulty breathing; swelling of your face, lips, tongue, or throat.

Call your doctor at once if you have:

  • shortness of breath (even with mild exertion), swelling, rapid weight gain;

  • pink or red urine, painful or difficult urination, new or worsening urge to urinate;

  • pale skin, easy bruising or bleeding;

  • nausea, upper stomach pain, itching, loss of appetite, dark urine, clay-colored stools, jaundice (yellowing of the skin or eyes); or

  • changes in your vision.

Common Actoplus Met side effects may include:

  • headache;

  • diarrhea; or

  • cold symptoms such as stuffy nose, sinus pain, sneezing, sore throat.

This is not a complete list of side effects and others may occur. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

Metformin / pioglitazone Breastfeeding Warnings

UK: Use is contraindicated. US: A decision should be made to discontinue breastfeeding or discontinue the drug, taking into account the importance of the drug to the mother. Excreted into human milk: Yes, in small amounts (metformin); Unknown (pioglitazone) Excreted into animal milk: Yes (metformin); Yes (pioglitazone) Comments: The effects in the nursing infant are unknown.

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