Actoplus Met XR

Name: Actoplus Met XR

What is Actoplus Met XR (metformin and pioglitazone)?

Metformin and pioglitazone is a combination of two oral diabetes medicines that help control blood sugar levels.

Metformin and pioglitazone is for people with type 2 diabetes who do not use daily insulin injections. This medication is not for treating type 1 diabetes.

Metformin and pioglitazone may also be used for purposes not listed in this medication guide.

What other drugs will affect Actoplus Met XR (metformin and pioglitazone)?

Tell your doctor if you use insulin. Taking metformin and pioglitazone while you are using insulin may increase your risk of serious heart problems.

Tell your doctor about all your current medicines and any you start or stop using, especially:

  • gemfibrozil;

  • morphine;

  • ranitidine;

  • an antibiotic--rifampin, trimethoprim, vancomycin; or

  • heart or blood pressure medication--digoxin, nifedipine, procainamide, quinidine.

You may be more likely to have hyperglycemia (high blood sugar) if you also take other drugs that can raise blood sugar, such as:

  • isoniazid;

  • diuretics (water pills);

  • steroids (prednisone and others);

  • niacin (Advicor, Niaspan, Niacor, Simcor, Slo-Niacin, and others);

  • phenothiazines (Compazine and others);

  • thyroid medicine (Synthroid and others);

  • birth control pills and other hormones; and

  • diet pills or medicines to treat asthma, colds or allergies.

These lists are not complete and many other medicines can increase or decrease the effects of metformin and pioglitazone on lowering your blood sugar. This includes prescription and over-the-counter medicines, vitamins, and herbal products. Not all possible drug interactions are listed here. Give a list of all your medicines to any healthcare provider who treats you.

Proper Use of pioglitazone and metformin

This section provides information on the proper use of a number of products that contain pioglitazone and metformin. It may not be specific to Actoplus Met XR. Please read with care.

Carefully follow the special diet your doctor gave you. This is the most important part of controlling your diabetes and will help the medicine work properly. Exercise regularly and test for sugar in your blood or urine as directed.

This medicine should come with a Medication Guide. Read and follow these instructions carefully. Ask your doctor if you have any questions.

This medicine should be taken with meals to help reduce the unwanted stomach effects that may occur during the first few weeks.

Swallow the medicine whole. Do not crush, break, or chew it.

Part of the extended-release tablet may pass into your stool (bowel movement). This is normal and nothing to worry about.

Dosing

The dose of this medicine will be different for different patients. Follow your doctor's orders or the directions on the label. The following information includes only the average doses of this medicine. If your dose is different, do not change it unless your doctor tells you to do so.

The amount of medicine that you take depends on the strength of the medicine. Also, the number of doses you take each day, the time allowed between doses, and the length of time you take the medicine depend on the medical problem for which you are using the medicine.

  • For type 2 diabetes:
    • For oral dosage form (extended-release tablets):
      • Adults—At first, 1 tablet once or two times a day with food. Your doctor may adjust your dose as needed and tolerated. However, the dose is usually not more than 45 milligrams (mg) of pioglitazone and 2000 mg of metformin per day.
      • Children—Use and dose must be determined by your doctor.
    • For oral dosage form (tablets):
      • Adults—At first, 1 tablet once or two times a day with food. Your doctor may adjust your dose as needed and tolerated. However, the dose is usually not more than 45 milligrams (mg) of pioglitazone and 2550 mg of metformin per day.
      • Children—Use and dose must be determined by your doctor.

Missed Dose

If you miss a dose of this medicine, take it as soon as possible. However, if it is almost time for your next dose, skip the missed dose and go back to your regular dosing schedule. Do not double doses.

Storage

Store the medicine in a closed container at room temperature, away from heat, moisture, and direct light. Keep from freezing.

Keep out of the reach of children.

Do not keep outdated medicine or medicine no longer needed.

Ask your healthcare professional how you should dispose of any medicine you do not use.

Actoplus Met XR Side Effects

Along with its needed effects, a medicine may cause some unwanted effects. Although not all of these side effects may occur, if they do occur they may need medical attention.

Check with your doctor immediately if any of the following side effects occur:

More common
  • Bladder pain
  • bloody or cloudy urine
  • difficult, burning, or painful urination
  • frequent urge to urinate
  • lower back or side pain
  • swelling of the face, fingers, feet, or lower legs
  • weight gain
Less common
  • Pain or swelling in the arms or legs without any injury
  • pale skin
  • troubled breathing with exertion
  • unusual bleeding or bruising
  • unusual tiredness or weakness
Rare
  • Abdominal or stomach discomfort
  • anxiety
  • blurred vision
  • chills
  • cold sweats
  • coma
  • confusion
  • cool, pale skin
  • decreased appetite
  • depression
  • diarrhea
  • dizziness
  • fast heartbeat
  • fast, shallow breathing
  • general feeling of discomfort
  • headache
  • increased hunger
  • muscle pain or cramping
  • nausea
  • nightmares
  • seizures
  • shakiness
  • sleepiness
  • slurred speech

Some side effects may occur that usually do not need medical attention. These side effects may go away during treatment as your body adjusts to the medicine. Also, your health care professional may be able to tell you about ways to prevent or reduce some of these side effects. Check with your health care professional if any of the following side effects continue or are bothersome or if you have any questions about them:

More common
  • Body aches or pain
  • cough
  • ear congestion
  • fever, sneezing, or sore throat
  • loss of voice
  • runny nose
  • stuffy nose

Other side effects not listed may also occur in some patients. If you notice any other effects, check with your healthcare professional.

Call your doctor for medical advice about side effects. You may report side effects to the FDA at 1-800-FDA-1088.

What are some things I need to know or do while I take Actoplus Met XR?

  • Do not drive if your blood sugar has been low. There is a greater chance of you having a crash.
  • The chance of getting bladder cancer may be raised when taking this medicine. Talk with the doctor.
  • Check your blood sugar as you have been told by your doctor.
  • Have blood work checked as you have been told by the doctor. Talk with the doctor.
  • Follow the diet and workout plan that your doctor told you about.
  • It may be harder to control your blood sugar during times of stress like when you have a fever, an infection, an injury, or surgery. A change in level of physical activity or exercise and a change in diet may also affect your blood sugar. Talk with your doctor.
  • Be careful in hot weather or while being active. Drink lots of fluids to stop fluid loss.
  • This medicine may raise the chance of broken bones. The chance may be higher in women. Broken bones were seen after people took Actoplus Met XR for 1 year. Most of the broken bones happened in the upper arm, hand, or foot. Talk with your doctor about how to keep your bones healthy or if you have any questions.
  • If you have been taking this medicine for a long time or at high doses, it may not work as well and you may need higher doses to get the same effect. This is known as tolerance. Call your doctor if Actoplus Met XR stops working well. Do not take more than ordered.
  • If you are 65 or older, use this medicine with care. You could have more side effects.
  • Do not give to a child. Talk with your doctor.
  • There is a chance of pregnancy in women of childbearing age who have not been ovulating. If you want to avoid pregnancy, use birth control that you can trust while taking Actoplus Met XR.
  • Use birth control that you can trust to prevent pregnancy while taking this medicine.
  • You may see something that looks like the tablet in your stool. This is normal and not a cause for concern. If you have questions, talk with your doctor.
  • Tell your doctor if you are pregnant or plan on getting pregnant. You will need to talk about the benefits and risks of using Actoplus Met XR (pioglitazone and metformin extended-release tablets) while you are pregnant.

How is this medicine (Actoplus Met XR) best taken?

Use this medicine as ordered by your doctor. Read all information given to you. Follow all instructions closely.

  • Take with meals.
  • To gain the most benefit, do not miss doses.
  • Take Actoplus Met XR at the same time of day.
  • Keep taking this medicine as you have been told by your doctor or other health care provider, even if you feel well.
  • Swallow whole. Do not chew, break, or crush.

What do I do if I miss a dose?

  • Take a missed dose as soon as you think about it.
  • If it is close to the time for your next dose, skip the missed dose and go back to your normal time.
  • Do not take 2 doses at the same time or extra doses.

Use in specific populations

Pregnancy

Risk Summary

Limited data with Actoplus Met XR 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 XR. The following data are based on studies conducted with the individual components of Actoplus Met XR.

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 XR 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 XR and any potential adverse effects on the breastfed infant from Actoplus Met XR 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 XR may result in ovulation in some premenopausal anovulatory women.

Pediatric Use

Safety and effectiveness of Actoplus Met XR in pediatric patients have not been established.

Actoplus Met XR 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, 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 XR is contraindicated in severe renal impairment, patients with an estimated glomerular filtration rate (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 XR is not recommended in patients with hepatic impairment [see Warnings and Precautions (5.2)].

Clinical Studies

There have been no clinical efficacy studies conducted with Actoplus Met XR. However, the efficacy and safety of the separate components have been previously established and the coadministration of the separate components has been evaluated for efficacy and safety in two clinical studies. These clinical studies established an added benefit of pioglitazone in patients with inadequately controlled type 2 diabetes while on metformin therapy. Bioequivalence of Actoplus Met XR with coadministered pioglitazone and extended-release metformin tablets was demonstrated for both tablet strengths of Actoplus Met XR [see Clinical Pharmacology (12.3)].

Two clinical trials were conducted with pioglitazone in combination with metformin. Both trials included patients with type 2 diabetes on any dose of metformin, either alone or in combination with another antidiabetic agent. All other antidiabetic agents were withdrawn at least 3 weeks prior to starting study treatment.

In the first trial, 328 patients were randomized to receive either 30 mg of pioglitazone or placebo once daily for 16 weeks in addition to their current metformin regimen. Treatment with pioglitazone as add-on to metformin produced statistically significant improvements in HbA1c and FPG at endpoint compared to placebo add-on to metformin (see Table 19).

Table 19. Glycemic Parameters in a 16 Week Placebo-Controlled, Add-on to Metformin Trial

Placebo
+ Metformin

Pioglitazone 30 mg
+ Metformin

Total Population

HbA1c (%)

N=153

N=161

Baseline (mean)

9.8

9.9

Change from baseline (adjusted mean*)

0.2

-0.6

Difference from placebo + metformin (adjusted mean*)
95% Confidence Interval

-0.8†
(-1.2, -0.5)

Fasting Plasma Glucose (mg/dL)

N=157

N=165

Baseline (mean)

260

254

Change from baseline (adjusted mean*)

-5

-43

Difference from placebo + metformin (adjusted mean*)
95% Confidence Interval

-38†
(-49, -26)

*Adjusted for baseline, pooled center, and pooled center by treatment interaction
†p≤0.05 versus placebo + metformin

In the second trial, 827 patients were randomized to receive either 30 mg or 45 mg of pioglitazone once daily for 24 weeks in addition to their current metformin regimen. The mean reduction from baseline at Week 24 in HbA1c was 0.8% for the 30 mg dose and 1.0% for the 45 mg dose (see Table 20). The mean reduction from baseline at Week 24 in FPG was 38 mg/dL for the 30 mg dose and 51 mg/dL for the 45 mg dose.

Table 20. Glycemic Parameters in a 24 Week Add-on to Metformin Study

Pioglitazone 30 mg +
Metformin

Pioglitazone 45 mg +
Metformin

Total Population

HbA1c (%)

N=400

N=398

Baseline (mean)

9.9

9.8

Change from baseline (adjusted mean*)

-0.8

-1.0

Difference from 30 mg daily Pioglitazone
+ Metformin (adjusted mean*) (95% CI)

-0.2
(-0.5, 0.1)

Fasting Plasma Glucose (mg/dL)

N=398

N=399

Baseline (mean)

233

232

Change from baseline (adjusted mean*)

-38

-51

Difference from 30 mg daily Pioglitazone
+ Metformin (adjusted mean*) (95% CI)

-12†
(-21, -4)

95% CI = 95% confidence interval
*Adjusted for baseline, pooled center, and pooled center by treatment interaction
†p ≤0.05 versus 30 mg daily pioglitazone + metformin

The therapeutic effect of pioglitazone in combination with metformin was observed in patients regardless of the metformin dose.

How Supplied/Storage and Handling

Actoplus Met XR is available in 15 mg pioglitazone (as the base)/1000 mg metformin hydrochloride extended-release and 30 mg pioglitazone (as the base)/1000 mg metformin hydrochloride extended-release tablets as follows:

15 mg/1000 mg tablet: white to off-white, round, film-coated tablets imprinted with "4833X" and "15/1000" in red on one side, available in:

NDC 64764-510-30 Bottles of 30

NDC 64764-510-60 Bottles of 60

NDC 64764-510-90 Bottles of 90

30 mg/1000 mg tablet: white to off-white round, film-coated tablets imprinted with "4833X" and "30/1000" in light blue on one side, available in:

NDC 64764-310-30 Bottles of 30

NDC 64764-310-60 Bottles of 60

NDC 64764-310-90 Bottles of 90

Storage

Store at 25°C (77°F); excursions permitted to 15° to 30°C (59° to 86°F) [see USP Controlled Room Temperature]. Keep container tightly closed, and protect from moisture and humidity.

Actoplus Met XR Dosage

Take this medication exactly as prescribed by your doctor. Follow the directions on your prescription label carefully.

The dose your doctor recommends may be based on the following:

  • the condition being treated
  • other medical conditions you have
  • other medications you are taking
  • how you respond to this medication

The recommended starting dose of Actoplus Met XR for the treatment of type 2 diabetes is 15 mg pioglitazone/1000 mg metformin or 30 mg pioglitazone/1000 mg metformin once daily. The dose should be gradually adjusted based on patient response, blood glucose levels, and other medications the patient is taking. The maximum dose of Actoplus Met XR is 45 mg pioglitazone/2000 mg metformin.

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