Actoplus Met

Name: Actoplus Met

What is the most important information I should know about metformin and pioglitazone?

You should not use this medicine 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). Metformin and pioglitazone is not for treating type 1 diabetes.

Metformin and pioglitazone can cause or worsen congestive heart failure. Call your doctor at once if you have shortness of breath (even with mild exertion), swelling, or rapid weight gain.

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.

Some people develop lactic acidosis while taking metformin. 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, slow or uneven heart rate, dizziness, or feeling very weak or tired.

How should I take metformin and pioglitazone?

Follow all directions on your prescription label. Do not take this medicine in larger or smaller amounts or for longer than recommended.

Take metformin and pioglitazone with meals. Take the extended-release (XR) tablet once daily with your evening meal.

Do not crush, chew, or break an extended-release tablet. Swallow it whole.

Your blood sugar will need to be checked often, and you may need other blood tests at your doctor's office.

Low blood sugar (hypoglycemia) can happen to everyone who has diabetes. Symptoms include headache, hunger, sweating, pale skin, irritability, dizziness, feeling shaky, or trouble concentrating. Always keep a source of sugar with you in case you have low blood sugar. Sugar sources include fruit juice, hard candy, crackers, raisins, and non-diet soda. Be sure your family and close friends know how to help you in an emergency.

If you have severe hypoglycemia and cannot eat or drink, use a glucagon injection. Your doctor can prescribe a glucagon emergency injection kit and tell you how to use it.

Check your blood sugar carefully during times of stress, travel, illness, surgery or medical emergency, vigorous exercise, or if you drink alcohol or skip meals. These things can affect your glucose levels and your dose needs may also change. Do not change your medication dose or schedule without your doctor's advice.

Use metformin and pioglitazone regularly to get the most benefit. Get your prescription refilled before you run out of medicine completely.

If you take extra vitamin B12 while you are taking metformin and pioglitazone, take only the amount of vitamin B12 that your doctor has prescribed.

Metformin and pioglitazone is only part of a treatment program that may also include diet, exercise, weight control, blood sugar testing, and special medical care. Follow your doctor's instructions very closely.

Store at room temperature away from moisture, heat, and light. Keep the bottle tightly closed when not in use.

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

  • 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 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 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.
  • Use birth control that you can trust to prevent pregnancy while taking this medicine.
  • 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 (pioglitazone and metformin tablets) while you are pregnant.
  • Tell your doctor if you are breast-feeding. You will need to talk about any risks to your baby.

If OVERDOSE is suspected

If you think there has been an overdose, call your poison control center or get medical care right away. Be ready to tell or show what was taken, how much, and when it happened.

Dosage Forms and Strengths

• 15 mg/500 mg tablets: White to off-white, oblong, film-coated tablets debossed with "4833M" on one side and "15/500" on the other • 15 mg/850 mg tablets: White to off-white, oblong, film-coated tablets debossed with "4833M" on one side and "15/850" on the other

Clinical Studies

Patients Who Have Inadequate Glycemic Control with Diet and Exercise Alone

In a 24-week, randomized, double-blind clinical trial, 600 patients with type 2 diabetes mellitus inadequately controlled with diet and exercise alone (mean baseline HbA1c 8.7%) were randomized to Actoplus Met 15/850 mg, pioglitazone 15 mg, or metformin 850 mg twice daily. Statistically significant improvements in HbA1c and fasting plasma glucose (FPG) were observed in patients treated with Actoplus Met compared to either pioglitazone or metformin alone (see Table 21).

* Adjusted for baseline † p ≤0.05 versus Actoplus Met

Table 21. Glycemic Parameters in 24-Week Study of Actoplus Met in Patients with Type 2 Diabetes Mellitus Inadequately Controlled with Diet and Exercise

Parameter

Treatment Group

Actoplus Met 15/850 mg
Twice Daily

Pioglitazone
15 mg
Twice Daily

Metformin
850 mg
Twice Daily

HbA1c (%)

N=188

N=162

N=193

  Baseline (mean)

8.9

8.7

8.7

  Change from Baseline (adjusted mean*)

-1.8

-1.0

-1.0

  Difference between Actoplus Met (adjusted mean*)
  95% Confidence Interval

0.9†
(0.5, 1.2)

0.8†
(0.5, 1.2)

  % of patients with HbA1c ≤7%

64

47

39

Fasting Plasma Glucose (mg/dL)

N=196

N=176

N=202

  Baseline (mean)

177

171

171

  Change from Baseline (adjusted mean*)

-40

-22

-25

  Difference between Actoplus Met (adjusted mean*)
  95% Confidence Interval

18†
(8, 28)

15†
(6, 25)

Patients Previously Treated with Metformin

The efficacy and safety of pioglitazone as add-on to metformin therapy have been established in two clinical studies. Bioequivalence of Actoplus Met with coadministered pioglitazone and metformin tablets was demonstrated for both Actoplus Met strengths [see Clinical Pharmacology (12.3)].

The two clinical trials testing pioglitazone as add-on to metformin therapy 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 three 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 22).

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

Table 22. 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)

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 23). 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.

* Adjusted for baseline, pooled center, and pooled center by treatment interaction † p ≤0.05 vs. 30 mg daily pioglitazone + metformin

Table 23. 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

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

Uses of Actoplus Met

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

This medication may be prescribed for other uses. Ask your doctor or pharmacist for more information.

 

Side Effects of Actoplus Met

Serious side effects have been reported with Actoplus Met. See the “Actoplus Met Precautions” section.

Common side effects of Actoplus Met include the following:

  • Upper respiratory tract infection
  • Headache
  • Sinusitis
  • Muscle pain
  • Sore throat
  • Weight gain
  • Diarrhea

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

Tell your doctor if you have any side effect that bothers you or that does not go away.

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

Before taking this medicine

You should not use Actoplus Met 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 Actoplus Met. 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 Actoplus Met 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.

Actoplus Met may increase your risk of developing bladder cancer. Talk with your doctor about your specific risk.

Taking Actoplus Met 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 Actoplus Met 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.

Actoplus Met should not be given to a child.

How should I take Actoplus Met?

Take Actoplus Met exactly as prescribed by your doctor. Follow all directions on your prescription label. Do not take this medicine in larger or smaller amounts or for longer than recommended.

Take Actoplus Met with meals. Take the extended-release (XR) tablet once daily with your evening meal.

Do not crush, chew, or break an extended-release tablet. Swallow it whole.

Your blood sugar will need to be checked often, and you may need other blood tests at your doctor's office.

Low blood sugar (hypoglycemia) can happen to everyone who has diabetes. Symptoms include headache, hunger, sweating, pale skin, irritability, dizziness, feeling shaky, or trouble concentrating. Always keep a source of sugar with you in case you have low blood sugar. Sugar sources include fruit juice, hard candy, crackers, raisins, and non-diet soda. Be sure your family and close friends know how to help you in an emergency.

If you have severe hypoglycemia and cannot eat or drink, use a glucagon injection. Your doctor can prescribe a glucagon emergency injection kit and tell you how to use it.

Check your blood sugar carefully during times of stress, travel, illness, surgery or medical emergency, vigorous exercise, or if you drink alcohol or skip meals. These things can affect your glucose levels and your dose needs may also change. Do not change your Actoplus Met dosage or dosing schedule without your doctor's advice.

Use Actoplus Met regularly to get the most benefit. Get your prescription refilled before you run out of medicine completely.

If you take extra vitamin B12 while you are taking Actoplus Met, take only the amount of vitamin B12 that your doctor has prescribed.

Actoplus Met is only part of a treatment program that may also include diet, exercise, weight control, blood sugar testing, and special medical care. Follow your doctor's instructions very closely.

Store at room temperature away from moisture, heat, and light. Keep the bottle tightly closed when not in use.

What happens if I miss a dose?

Take the missed dose as soon as you remember (be sure to take the medicine with food). Skip the missed dose if it is almost time for your next scheduled dose. Do not take extra medicine to make up the missed dose.

For the Consumer

Applies to metformin / pioglitazone: oral tablet, oral tablet extended release

Along with its needed effects, metformin / pioglitazone 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 while taking metformin / pioglitazone:

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 of metformin / pioglitazone 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

Metformin / pioglitazone Pregnancy Warnings

Benefit should outweigh risk US FDA pregnancy category: Not Assigned Risk summary: Abnormal blood glucose concentrations during pregnancy are associated with a higher incidence of congenital anomalies, increased neonatal morbidity, and mortality. Most experts recommend insulin use during pregnancy to maintain blood glucose concentrations as close to normal as possible. Comment: Premenopausal anovulatory women may be at risk for pregnancy with use of pioglitazone; these women should be informed of pregnancy risk.

Published studies with metformin use during pregnancy have not reported a risk of major birth defects or miscarriage risk. Animal studies using pioglitazone at 10 to 40 times the maximum recommended human dose have shown increased rates of postimplantation loss, delayed development, reduced fetal weights, and delayed parturition. There are no adequate and well-controlled studies in pregnant women. US FDA pregnancy category Not Assigned: The US FDA has amended the pregnancy labeling rule for prescription drug products to require labeling that includes a summary of risk, a discussion of the data supporting that summary, and relevant information to help health care providers make prescribing decisions and counsel women about the use of drugs during pregnancy. Pregnancy categories A, B, C, D, and X are being phased out.

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