Note: This document contains side effect information about metformin / pioglitazone. Some dosage forms listed on this page may not apply to the brand name ActoPlus Met XR.
Summary
More frequent side effects include: dental disease, edema, myalgia, pharyngitis, weight gain, and decreased vitamin b12 serum concentrate. Continue reading for a comprehensive list of adverse effects.
Applies to metformin / pioglitazone: oral tablet.
Warning
Oral route (Tablet; Tablet, Extended Release)
May cause or worsen congestive heart failure, is not recommended in patients with symptomatic heart failure, and is contraindicated in patients with established NYHA Class III or IV heart failure. Monitor patients for signs and symptoms of heart failure after initiation or dose increases and if heart failure occurs, consider dose reduction or discontinuing metformin/pioglitazone (immediate and extended-release formulations) and manage according to current standards of care. Lactic acidosis can occur due to metformin accumulation during treatment with metformin / pioglitazone (immediate and extended-release formulations) and may result in death, hypothermia, hypotension, and resistant bradyarrhythmias; risk factors include renal impairment, concomitant carbonic anhydrase inhibitor use (eg, topiramate), age 65 years or greater, having a radiological study with contrast, surgery and other procedures, hypoxic states (eg, acute congestive heart failure), excessive alcohol intake, and hepatic impairment. Onset is often subtle with nonspecific symptoms such as malaise, myalgias, respiratory distress, somnolence, and abdominal pain; laboratory abnormalities include elevated blood lactate (greater than 5 mmol/L), anion gap acidosis (without ketonuria or ketonemia), increased lactate:pyruvate ratio, and metformin levels generally greater than 5 mcg/mL. If acidosis is suspected, discontinue treatment, hospitalize the patient immediately, and promptly initiate hemodialysis.
Serious side effects of ActoPlus Met XR
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
- Anxiety
- blurred vision
- chills
- cold sweats
- confusion
- cool, pale skin
- decreased appetite
- depression
- diarrhea
- dizziness
- fast heartbeat
- fast, shallow breathing
- general feeling of discomfort
- headache
- increased hunger
- loss of consciousness
- muscle pain or cramping
- nausea
- nightmares
- seizures
- shakiness
- sleepiness
- slurred speech
- stomach discomfort
Other side effects of ActoPlus Met XR
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
- loss of voice
- runny or stuffy nose
- sneezing
- sore throat
For Healthcare Professionals
Applies to metformin / pioglitazone: oral tablet, oral tablet extended release.
Cardiovascular
Thiazolidinediones, including pioglitazone can cause dose-related fluid retention which can cause or exacerbate congestive heart failure in some patients. Combination with insulin and use in patients with NYHA Class I and II congestive heart failure may increase risk.[Ref]
Metformin-pioglitazone:
Common (1% to 10%): Edema
Pioglitazone:
Very common (10% or more): Edema (26.7%)
Common (1% to 10%): Cardiac failure, chest pain[Ref]
Gastrointestinal
Metformin-pioglitazone:
Very common (10% or more): Abdominal pain, diarrhea, loss of appetite, nausea, vomiting
Uncommon (0.1% to 1%): Flatulence
Metformin:
Very common (10% or more): Abdominal pain, diarrhea, loss of appetite, nausea, vomiting[Ref]
Gastrointestinal events occur most frequently during initiation of therapy and resolve spontaneously in most cases.[Ref]
Hematologic
Metformin-pioglitazone
Common (1% to 10%): Anemia
Very rare (less than 0.01%): Vitamin B12 absorption decreased, lactic acidosis
Metformin:
Very rare (less than 0.01%): Vitamin B12 absorption decreased, lactic acidosis[Ref]
Metabolic
Metformin-pioglitazone:
Common (1% to 10%): Weight increased
Pioglitazone:
Very common (10% or more): Hypoglycemia (27.3%)
Common (1% to 10%): Weight gain[Ref]
Mean weight increase in patients receiving pioglitazone monotherapy for 1 year was 2 to 3 kg. In combination with metformin, mean weight increase over 1 year was 1.5 kg. The mechanism of weight gain is unclear, but probably involves a combination of fluid retention and fat accumulation.[Ref]
Respiratory
Metformin-pioglitazone
Common (1% to 10%): Upper respiratory infection
Uncommon (0.1% to 1%): Sinusitis
Pioglitazone:
Common (1% to 10%): Upper respiratory infection, pharyngitis
Uncommon (0.1% to 1%): Sinusitis[Ref]
Nervous system
Metformin-pioglitazone:
Common (1% to 10%): Hypoesthesia, headache, taste disturbance
Uncommon (0.1% to 1%): Insomnia
Metformin:
Common (1% to 10%): Taste disturbance
Pioglitazone:
Common (1% to 10%): Hypoesthesia, headache[Ref]
Ocular
Visual disturbances have been reported early in treatment and may be related to changes in blood glucose due to temporary alteration in the turgidity and refractive index of the lens. Macular edema has been reported postmarketing in patients taking pioglitazone or another thiazolidinedione. Some patients presented with blurred vision or decreased visual acuity, although some were diagnosed on routine ophthalmologic examination. Most patients had peripheral edema at time of diagnosis. Some patients improved with drug discontinuation.[Ref]
Metformin-pioglitazone:
Common (1% to 10%): Visual disturbances
Postmarketing reports: Macular edema
Pioglitazone:
Common (1% to 10%): Visual disturbances
Frequency not reported: Macular edema[Ref]
Dermatologic
Metformin-pioglitazone:
Very rare (less than 0.01%): Erythema, pruritus, urticaria
Metformin:
Very rare (less than 0.01%): Erythema, pruritus, urticaria[Ref]
Endocrine
Common (1% to 10%): Erectile dysfunction[Ref]
General
The most commonly reported adverse events included upper respiratory tract infection, edema, diarrhea, headache, and weight gain.[Ref]
Hepatic
There have been postmarketing reports of hepatic failure, including fatalities, in patients taking pioglitazone. The reports contain insufficient information to establish causality.[Ref]
Metformin-pioglitazone:
Frequency not reported: Hepatitis, alanine aminotransferase increased, abnormal liver function tests
Metformin:
Frequency not reported: Hepatitis, abnormal liver function tests
Pioglitazone:
Frequency not reported: Alanine aminotransferase increased
Postmarketing reports: Hepatic failure[Ref]
Musculoskeletal
In pooled analysis of bone fractures in 8100 patients receiving pioglitazone and 7400 receiving comparator treatment; a higher rate of fractures was observed in women receiving pioglitazone (2.6% versus 1.7%). Some epidemiologic studies have suggested a similarly increased risk of fracture in men.[Ref]
Metformin-pioglitazone:
Common (1% to 10%): Bone fracture, arthralgia
Pioglitazone:
Common (1% to 10%): Bone fracture, myalgia, extremity pain, back pain
Uncommon (0.1% to 1%): Serum creatine phosphokinase elevations[Ref]
Oncologic
The US FDA has released results of its review of pioglitazone and bladder cancer and concluded that the data suggests use of this drug may be linked to an increase risk of bladder cancer. A 10-year prospective cohort study in diabetic patients performed by the manufacturer (n=158,918 never users; n=34,181 ever users) identified 1075 newly diagnosed cases of bladder cancer in never users and 186 cases in ever users. The fully adjusted hazard ratio (HR) showed pioglitazone use was not associated with an increased risk (HR 1.06 (95% confidence interval 0.89 to 1.26). And while a modest trend towards higher risk with increasing duration was observed, this trend was not statistically significant. Compared to the interim 5-year results, the 10-year results found weaker associations that were not statistically significant. However, there are studies that have shown a statistically significant association between exposure to this drug and bladder cancer and an association between cumulative dose or cumulative duration of exposure and bladder cancer. Overall, this drug may be associated with an increase in the risk of urinary bladder tumors, however there is insufficient data to determine whether this drug is a tumor promoter for urinary bladder tumors.[Ref]
Metformin-pioglitazone
Uncommon (0.1% to 1%): Bladder cancer
Pioglitazone:
Uncommon (0.1% to 1%): Bladder cancer[Ref]
Renal
Common (1% to 10%): Hematuria[Ref]
Hypersensitivity
Metformin-pioglitazone:
Postmarketing reports: Hypersensitivity and allergic reactions (anaphylaxis, angioedema, and urticaria)
Pioglitazone:
Postmarketing reports: Hypersensitivity and allergic reactions (anaphylaxis, angioedema, and urticaria)[Ref]
