Summary

More frequently reported 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.

Serious side effects

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

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]