Actoplus Met XR

Name: Actoplus Met XR

Actoplus Met XR (metformin and pioglitazone) 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: 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 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.

Uses of Actoplus Met XR

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

What are some side effects that I need to call my doctor about right away?

WARNING/CAUTION: Even though it may be rare, some people may have very bad and sometimes deadly side effects when taking a drug. Tell your doctor or get medical help right away if you have any of the following signs or symptoms that may be related to a very bad side effect:

  • Signs of an allergic reaction, like rash; hives; itching; red, swollen, blistered, or peeling skin with or without fever; wheezing; tightness in the chest or throat; trouble breathing or talking; unusual hoarseness; or swelling of the mouth, face, lips, tongue, or throat.
  • Bone pain.
  • Feeling very tired or weak.
  • Change in eyesight.
  • Pain when passing urine or blood in urine.
  • Passing urine more often.
  • Swelling.
  • It is common to have stomach problems like upset stomach, throwing up, or loose stools (diarrhea) when you start taking Actoplus Met XR. If you have stomach problems later during care, call your doctor right away. This may be a sign of an acid health problem in the blood (lactic acidosis).
  • Low blood sugar can happen. The chance of low blood sugar may be raised when this medicine is used with other drugs for high blood sugar (diabetes). Signs may be dizziness, headache, feeling sleepy, feeling weak, shaking, a fast heartbeat, confusion, hunger, or sweating. Call your doctor right away if you have any of these signs. Follow what you have been told to do if you get low blood sugar. This may include taking glucose tablets, liquid glucose, or some fruit juices.
  • Very bad and sometimes deadly liver problems have happened with Actoplus Met XR. Call your doctor right away if you have signs of liver problems like dark urine, feeling tired, not hungry, upset stomach or stomach pain, light-colored stools, throwing up, or yellow skin or eyes.

Dosage Forms and Strengths

  • 15 mg/1000 mg tablets: White to off-white, round, film-coated tablets imprinted with "4833X" and "15/1000" in red on one side
  • 30 mg/1000 mg tablets: White to off-white, round, film-coated tablets imprinted with "4833X" and "30/1000" in light blue on one side

Actoplus Met XR - Clinical Pharmacology

Mechanism of Action

Actoplus Met XR

Actoplus Met XR combines two anti-diabetic medications with different mechanisms of action to improve glycemic control in adults with type 2 diabetes: pioglitazone, a thiazolidinedione, and metformin hydrochloride, a biguanide. Thiazolidinediones are insulin-sensitizing agents that act primarily by enhancing peripheral glucose utilization, whereas biguanides act primarily by decreasing endogenous hepatic glucose production.

Pioglitazone

Pioglitazone is a thiazolidinedione that depends on the presence of insulin for its mechanism of action. Pioglitazone decreases insulin resistance in the periphery and in the liver resulting in increased insulin-dependent glucose disposal and decreased hepatic glucose output. Pioglitazone is not an insulin secretagogue. Pioglitazone is an agonist for peroxisome proliferator-activated receptor-gamma (PPARγ). PPAR receptors are found in tissues important for insulin action such as adipose tissue, skeletal muscle, and liver. Activation of PPARγ nuclear receptors modulates the transcription of a number of insulin responsive genes involved in the control of glucose and lipid metabolism.

In animal models of diabetes, pioglitazone reduces the hyperglycemia, hyperinsulinemia, and hypertriglyceridemia characteristic of insulin-resistant states such as type 2 diabetes. The metabolic changes produced by pioglitazone result in increased responsiveness of insulin-dependent tissues and are observed in numerous animal models of insulin resistance.

Because pioglitazone enhances the effects of circulating insulin (by decreasing insulin resistance), it does not lower blood glucose in animal models that lack endogenous insulin.

Metformin hydrochloride

Metformin hydrochloride improves glucose tolerance in patients with type 2 diabetes, lowering both basal and postprandial plasma glucose. Metformin decreases hepatic glucose production, decreases intestinal absorption of glucose and improves insulin sensitivity by increasing peripheral glucose uptake and utilization. Metformin does not produce hypoglycemia in either patients with type 2 diabetes or healthy subjects [except in specific circumstances, see Warnings and Precautions (5.4)] and does not cause hyperinsulinemia. With metformin therapy, insulin secretion remains unchanged while fasting insulin levels and day-long plasma insulin response may actually decrease.

Pharmacodynamics

Pioglitazone

Clinical studies demonstrate that pioglitazone improves insulin sensitivity in insulin-resistant patients. Pioglitazone enhances cellular responsiveness to insulin, increases insulin-dependent glucose disposal and improves hepatic sensitivity to insulin. In patients with type 2 diabetes, the decreased insulin resistance produced by pioglitazone results in lower plasma glucose concentrations, lower plasma insulin concentrations, and lower HbA1c values. In controlled clinical trials, pioglitazone had an additive effect on glycemic control when used in combination with a sulfonylurea, metformin, or insulin [see Clinical Studies (14)].

Patients with lipid abnormalities were included in clinical trials with pioglitazone. Overall, patients treated with pioglitazone had mean decreases in serum triglycerides, mean increases in HDL cholesterol, and no consistent mean changes in LDL and total cholesterol. There is no conclusive evidence of macrovascular benefit with pioglitazone or any other antidiabetic medication [see Warnings and Precautions (5.10) and Adverse Reactions (6.1)].

In a 26-week, placebo-controlled, dose-ranging monotherapy study, mean serum triglycerides decreased in the 15 mg, 30 mg, and 45 mg pioglitazone dose groups compared to a mean increase in the placebo group. Mean HDL cholesterol increased to a greater extent in patients treated with pioglitazone than in the patients treated with placebo. There were no consistent differences for LDL and total cholesterol in patients treated with pioglitazone compared to placebo (Table 14).

Table 14. Lipids in a 26-Week Placebo-Controlled Monotherapy Dose-Ranging Study

Placebo

Pioglitazone
15 mg
Once
Daily

Pioglitazone
30 mg
Once
Daily

Pioglitazone
45 mg
Once
Daily

Triglycerides (mg/dL)

N=79

N=79

N=84

N=77

Baseline (mean)

263

284

261

260

Percent change from baseline (adjusted mean*)

4.8%

-9.0%†

-9.6%†

-9.3%†

HDL Cholesterol (mg/dL)

N=79

N=79

N=83

N=77

Baseline (mean)

42

40

41

41

Percent change from baseline (adjusted mean*)

8.1%

14.1%†

12.2%

19.1%†

LDL Cholesterol (mg/dL)

N=65

N=63

N=74

N=62

Baseline (mean)

139

132

136

127

Percent change from baseline (adjusted mean*)

4.8%

7.2%

5.2%

6.0%

Total Cholesterol (mg/dL)

N=79

N=79

N=84

N=77

Baseline (mean)

225

220

223

214

Percent change from baseline (adjusted mean*)

4.4%

4.6%

3.3%

6.4%

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

In the two other monotherapy studies (16 weeks and 24 weeks) and in combination therapy studies with metformin (16 weeks and 24 weeks), the results were generally consistent with the data above.

Pharmacokinetics

Absorption

Actoplus Met XR

In bioequivalence studies of Actoplus Met XR 15 mg/1000 mg and 30 mg/1000 mg, the AUC and maximum concentration (Cmax) of both the pioglitazone and the extended-release metformin components following a single dose of the combination tablet were bioequivalent to ACTOS 15 mg and 30 mg concomitantly administered with extended-release metformin hydrochloride (FORTAMET) 1000 mg tablets under fed conditions in healthy subjects.

Administration of Actoplus Met XR 30 mg/1000 mg with food resulted in no change in total (AUC) exposure of pioglitazone; however, a decrease in Cmax by approximately 18% was observed. With the extended-release metformin component, there was an increase in Cmax by approximately 98% and AUC exposure by approximately 85% when administered with food. These levels are comparable to exposures obtained with extended release metformin when administered with food. Time to peak serum concentration (Tmax) was prolonged by approximately three and two hours for pioglitazone and extended-release metformin respectively, under fed conditions.

Pioglitazone

Following once daily administration of pioglitazone, steady-state serum concentrations of both pioglitazone and its major active metabolites, M-III (keto derivative of pioglitazone) and M-IV (hydroxyl derivative of pioglitazone), are achieved within 7 days. At steady-state, M-III and M-IV reach serum concentrations equal to or greater than that of pioglitazone. At steady-state, in both healthy volunteers and patients with type 2 diabetes, pioglitazone comprises approximately 30% to 50% of the peak total pioglitazone serum concentrations (pioglitazone plus active metabolites) and 20% to 25% of the total AUC.

Cmax, AUC, and trough serum concentrations (Cmin) for pioglitazone and M-III and M-IV, increased proportionally with administered doses of 15 mg and 30 mg per day.

Following oral administration of pioglitazone, Tmax of pioglitazone was within two hours. Food delays the Tmax to three to four hours, but does not alter the extent of absorption (AUC).

Metformin hydrochloride

The absolute bioavailability of a 500 mg metformin tablet given under fasting conditions is approximately 50% - 60%. Studies using single oral doses of metformin tablets of 500 mg to 1500 mg, and 850 mg to 2550 mg, indicate that there is a lack of dose proportionality with increasing doses, which is due to decreased absorption rather than an alteration in elimination. At usual clinical doses and dosing schedules of metformin, steady-state plasma concentrations of metformin are reached within 24 - 48 hours and are generally <1 mcg/mL. During controlled clinical trials, maximum metformin plasma levels did not exceed 5 mcg/mL, even at maximum doses.

Food decreases the rate and extent of metformin absorption, as shown by approximately a 40% lower mean Cmax, a 25% lower AUC, and a 35-minute prolongation of Tmax following administration of a single 850 mg tablet of metformin with food, compared to the same tablet strength administered fasting. The clinical relevance of these decreases is unknown.

Distribution

Pioglitazone

The mean apparent volume of distribution (Vd/F) of pioglitazone following single-dose administration is 0.63 ± 0.41 (mean ± SD) L/kg of body weight. Pioglitazone is extensively protein bound (>99%) in human serum, principally to serum albumin. Pioglitazone also binds to other serum proteins, but with lower affinity. M-III and M-IV are also extensively bound (>98%) to serum albumin.

Metformin hydrochloride

The Vd/F of metformin following single oral doses of 850 mg immediate-release metformin averaged 654 ± 358 L. Metformin is negligibly bound to plasma proteins. Metformin partitions into erythrocytes, most likely as a function of time.

Metabolism

Pioglitazone

Pioglitazone is extensively metabolized by hydroxylation and oxidation; the metabolites also partly convert to glucuronide or sulfate conjugates. Metabolites M‑III and M‑IV are the major circulating active metabolites in humans.

In vitro data demonstrate that multiple CYP isoforms are involved in the metabolism of pioglitazone which include CYP2C8 and, to a lesser degree, CYP3A4 with additional contributions from a variety of other isoforms including the mainly extrahepatic CYP1A1. In vivo study of pioglitazone in combination with gemfibrozil, a strong CYP2C8 inhibitor, showed that pioglitazone is a CYP2C8 substrate [see Dosage and Administration (2.3) and Drug Interactions (7.1)]. Urinary 6ß-hydroxycortisol/cortisol ratios measured in patients treated with pioglitazone showed that pioglitazone is not a strong CYP3A4 enzyme inducer.

Metformin hydrochloride

Intravenous single-dose studies in healthy subjects demonstrate that metformin is excreted unchanged in the urine and does not undergo hepatic metabolism (no metabolites have been identified in humans) nor biliary excretion.

Excretion and Elimination

Pioglitazone

Following oral administration, approximately 15% to 30% of the pioglitazone dose is recovered in the urine. Renal elimination of pioglitazone is negligible and the drug is excreted primarily as metabolites and their conjugates. It is presumed that most of the oral dose is excreted into the bile either unchanged or as metabolites and eliminated in the feces.

The mean serum half-life (t1/2) of pioglitazone and its metabolites (M-III and M-IV) range from three to seven hours and 16 to 24 hours, respectively. Pioglitazone has an apparent clearance (CL/F) calculated to be five to seven L/hr.

Metformin hydrochloride

Renal clearance is approximately 3.5 times greater than creatinine clearance (CLcr) which indicates that tubular secretion is the major route of metformin elimination. Following oral administration, approximately 90% of the absorbed drug is eliminated via the renal route within the first 24 hours, with a plasma t1/2 of approximately 6.2 hours. In blood, the t1/2 is approximately 17.6 hours, suggesting that the erythrocyte mass may be a compartment of distribution.

Specific Populations

Renal Impairment

Pioglitazone

The serum t1/2 of pioglitazone, M-III and M-IV remains unchanged in patients with moderate (CLcr 30 to 50 mL/min) and severe (CLcr <30 mL/min) renal impairment when compared to subjects with normal renal function. Therefore, no dose adjustment in patients with renal impairment is required.

Metformin hydrochloride

In patients with decreased renal function (based on eGFR), the plasma and blood t1/2 of metformin is prolonged and the renal clearance is decreased in proportion to the decrease in eGFR [see Dosage and Administration (2.2), Contraindications (4) and Warnings and Precautions (5.2)].

Hepatic Impairment

Pioglitazone

Compared with healthy controls, subjects with impaired hepatic function (Child-Turcotte-Pugh Grade B/C) have an approximate 45% reduction in pioglitazone and total pioglitazone (pioglitazone, M-III and M-IV) mean Cmax but no change in the mean AUC values. Therefore, no dose adjustment in patients with hepatic impairment is required.

There are postmarketing reports of liver failure with pioglitazone and clinical trials have generally excluded patients with serum ALT >2.5 times the upper limit of the reference range. Use Actoplus Met XR with caution in patients with liver disease [see Warnings and Precautions (5.5)].

Metformin hydrochloride

No pharmacokinetic studies of metformin have been conducted in subjects with hepatic impairment [see Warnings and Precautions (5.5)].

Geriatric Patients

Pioglitazone

In healthy elderly subjects, Cmax of pioglitazone was not significantly different, but AUC values were approximately 21% higher than those achieved in younger subjects. The mean t1/2 of pioglitazone was also prolonged in elderly subjects (about ten hours) as compared to younger subjects (about seven hours). These changes were not of a magnitude that would be considered clinically relevant.

Metformin hydrochloride

Limited data from controlled pharmacokinetic studies of metformin in healthy elderly subjects suggest that total plasma CL/F is decreased, the t1/2 is prolonged, and Cmax is increased, compared to healthy young subjects. From these data, it appears that the change in metformin pharmacokinetics with aging is primarily accounted for by a change in renal function.

Pediatrics

Pioglitazone

Safety and efficacy of pioglitazone in pediatric patients have not been established. Actoplus Met XR is not recommended for use in pediatric patients [see Use in Specific Populations (8.4)].

Metformin hydrochloride

After administration of a single oral metformin 500 mg tablet with food, geometric mean metformin Cmax and AUC differed less than 5% between pediatric type 2 diabetic patients (12 to 16 years of age) and gender- and weight-matched healthy adults (20 to 45 years of age), all with normal renal function.

Gender

Pioglitazone

The mean Cmax and AUC values of pioglitazone were increased 20% to 60% in women compared to men. In controlled clinical trials, HbA1c decreases from baseline were generally greater for females than for males (average mean difference in HbA1c 0.5%). Because therapy should be individualized for each patient to achieve glycemic control, no dose adjustment is recommended based on gender alone.

Metformin hydrochloride

Metformin pharmacokinetic parameters did not differ significantly between normal subjects and patients with type 2 diabetes when analyzed according to gender (males=19, females=16). Similarly, in controlled clinical studies in patients with type 2 diabetes, the antihyperglycemic effect of metformin was comparable in males and females.

Ethnicity

Pioglitazone

Pharmacokinetic data among various ethnic groups are not available.

Metformin hydrochloride

No studies of metformin pharmacokinetic parameters according to race have been performed. In controlled clinical studies of metformin in patients with type 2 diabetes, the antihyperglycemic effect was comparable in whites (n=249), blacks (n=51), and Hispanics (n=24).

Drug-Drug Interactions

Specific pharmacokinetic drug interaction studies with Actoplus Met XR have not been performed, although such studies have been conducted with the individual pioglitazone and metformin components.

Pioglitazone

Table 15. Effect of Pioglitazone Coadministration on Systemic Exposure of Other Drugs

Coadministered Drug

Pioglitazone
Dosage
Regimen (mg)*

Name and Dose Regimens

Change
in AUC†

Change
in Cmax†

45 mg
(N = 12)

Warfarin‡

Daily loading then maintenance doses
based PT and INR values
Quick's Value = 35 ± 5%

R-Warfarin   ↓3%

R-Warfarin

↓2%

S-Warfarin

↓1%

S-Warfarin

↑1%

45 mg
(N = 12)

Digoxin

0.200 mg twice daily (loading dose) then
0.250 mg daily (maintenance dose, 7 days)

↑15%

↑17%

45 mg daily
for 21 days
(N = 35)

Oral Contraceptive

[Ethinyl Estradiol (EE) 0.035 mg plus
Norethindrone (NE) 1 mg] for 21 days

EE

↓11%

EE

↓13%

NE

↑3%

NE

↓7%

45 mg
(N = 23)

Fexofenadine

60 mg twice daily for 7 days

↑30%

↑37%

45 mg
(N = 14)

Glipizide

5 mg daily for 7 days

↓3%

↓8%

45 mg daily
for 8 days
(N = 16)

Metformin

1000 mg single dose on Day 8

↓3%

↓5%

45 mg
(N = 21)

Midazolam

7.5 mg single dose on Day 15

↓26%

↓26%

45 mg
(N = 24)

Ranitidine

150 mg twice daily for 7 days

↑1%

↓1%

45 mg daily
for 4 days
(N = 24)

Nifedipine ER

30 mg daily for 4 days

↓13%

↓17%

45 mg
(N = 25)

Atorvastatin Ca

80 mg daily for 7 days

↓14%

↓23%

45 mg
(N = 22)

Theophylline

400 mg twice daily for 7 days

↑2%

↑5%

*Daily for 7 days unless otherwise noted
†% change (with/without coadministered drug and no change = 0%); symbols of ↑ and ↓ indicate the exposure increase and decrease, respectively
‡Pioglitazone had no clinically significant effect on prothrombin time

  Table 16. Effect of Coadministered Drugs on Pioglitazone Systemic Exposure

Coadministered Drug and
Dosage Regimen

Pioglitazone

Dose
Regimen
(mg)*

Change
in AUC†

Change
in Cmax†

Gemfibrozil 600 mg
twice daily for 2 days
(N = 12)

15 mg
single dose

↑3.2-fold‡

↑6%

Ketoconazole 200 mg
twice daily for 7 days
(N = 28)

45 mg

↑34%

↑14%

Rifampin 600 mg
daily for 5 days
(N = 10)

30 mg
single dose

↓54%

↓5%

Fexofenadine 60 mg
twice daily for 7 days
(N = 23)

45 mg

↑1%

0%

Ranitidine 150 mg
twice daily for 4 days
(N = 23)

45 mg

↓13%

↓16%

Nifedipine ER 30 mg
daily for 7 days
(N = 23)

45 mg

↑5%

↑4%

Atorvastatin Ca 80 mg
daily for 7 days
(N = 24)

45 mg

↓24%

↓31%

Theophylline 400 mg
twice daily for 7 days
(N = 22)

45 mg

↓4%

↓2%

*Daily for 7 days unless otherwise noted
†Mean ratio (with/without coadministered drug and no change = 1-fold) % change (with/without coadministered drug and no change = 0%); symbols of ↑ and ↓ indicate the exposure increase and decrease, respectively.
‡The half-life of pioglitazone increased from 8.3 hours to 22.7 hours in the presence of gemfibrozil [see Dosage and Administration (2.3) and Drug Interactions (7.1)]

Metformin hydrochloride

Table 17. Effect of Coadministered Drug on Plasma Metformin Systemic Exposure

Coadministered
Drug

Dose of
Coadministered
Drug*

Dose of
Metformin*

Geometric Mean Ratio (ratio with/without
coadministered drug) No effect = 1.00

AUC†

Cmax

No dosing adjustments required for the following:

Glyburide

5 mg

500 mg§

0.98‡

0.99‡

Furosemide

40 mg

850 mg

1.09‡

1.22‡

Nifedipine

10 mg

850 mg

1.16

1.21

Propranolol

40 mg

850 mg

0.90

0.94

Ibuprofen

400 mg

850 mg

1.05‡

1.07‡

Drugs that are eliminated by renal tubular secretion may increase the accumulation of metformin [see Warnings and Precautions (5) and Drug Interactions (7)].

Cimetidine

400 mg

850 mg

1.40

1.61

Carbonic anhydrase inhibitors may cause metabolic acidosis [see Warnings and Precautions (5) and Drug Interactions (7)].

Topiramate

100 mg¶

500 mg¶

1.25¶

1.17

*All metformin and coadministered drugs were given as single doses
†AUC = AUC0–∞
‡Ratio of arithmetic means
§Metformin hydrochloride extended-release tablets, 500 mg
¶At steady state with topiramate 100 mg every 12 hours and metformin 500 mg every 12 hours; AUC = AUC0-12h

Table 18. Effect of Metformin on Coadministered Drug Systemic Exposure

Coadministered
Drug

Dose of
Coadministered
Drug*

Dose of
Metformin*

Geometric Mean Ratio (ratio with/without
coadministered drug) No effect = 1.00

AUC†

Cmax

No dosing adjustments required for the following:

Glyburide

5 mg

500 mg§

0.78‡

0.63‡

Furosemide

40 mg

850 mg

0.87‡

0.69‡

Nifedipine

10 mg

850 mg

1.10§

1.08

Propranolol

40 mg

850 mg

1.01§

0.94

Ibuprofen

400 mg

850 mg

0.97¶

1.01¶

Cimetidine

400 mg

850 mg

0.95§

1.01

*All metformin and coadministered drugs were given as single doses
†AUC = AUC0–∞
‡Ratio of arithmetic means, p-value of difference <0.05
§AUC0-24 hr reported
¶Ratio of arithmetic means

Actoplus Met XR Overview

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

It is a single product containing 2 medications: immediate-release pioglitazone and extended-release 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 XR include upper respiratory tract infection, edema, diarrhea, headache, muscle pain, and weight gain.

In combination with other medications to treat diabetes, Actoplus Met XR 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 XR affects you.

Manufacturer

  • Takeda Pharmaceuticals America, Inc.

Actoplus Met XR Drug Class

Actoplus Met XR is part of the drug class:

  • Combinations of oral blood glucose lowering drugs

Actoplus Met XR FDA Warning

WARNING: CONGESTIVE HEART FAILURE AND LACTIC ACIDOSIS

Congestive Heart Failure

Thiazolidinediones, including pioglitazone, which is a component of ACTOPLUS MET XR, cause or exacerbate congestive heart failure in some patients.After initiation of ACTOPLUS MET XR, 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 XR must be considered.ACTOPLUS MET XR is not recommended in patients with symptomatic heart failure.Initiation of ACTOPLUS MET XR in patients with established New York Heart Association (NYHA) Class III or IV heart failure is contraindicated.

Lactic Acidosis

Lactic acidosis is a rare, but serious complication that can occur due to metformin accumulation. The risk increases with conditions such as sepsis, dehydration, excess alcohol intake, hepatic impairment, renal impairment, and acute congestive heart failure.The onset is often subtle, accompanied only by nonspecific symptoms such as malaise, myalgias, respiratory distress, increasing somnolence, and nonspecific abdominal distress. Laboratory abnormalities include low pH, increased anion gap and elevated blood lactate.If acidosis is suspected, ACTOPLUS MET XR should be discontinued and the patient hospitalized immediately.

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

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