Glimepiride and pioglitazone

Pioglitazone/glimepiride is a prescription medication used to treat Type 2 Diabetes. It is used in combination with diet and exercise. It is available as a single product containing 2 medications—pioglitazone and glimepiride. 

Pioglitazone belongs to a class of drugs called thiazolidinediones. It helps the body control blood sugar levels by making the body more sensitive to insulin. Glimepiride is in a different class of drugs called sulfonylureas. It causes the pancreas to make more insulin and helps the body to use insulin more efficiently. This helps to control blood sugar. 

Pioglitazone/glimepiride is available as a tablet and is taken once daily, with the first meal of the day.

Common side effects of pioglitazone combined with a medication like glimepiride include hypoglycemia, upper respiratory tract infection, increased weight, and lower limb swelling. 

Pioglitazone/glimepiride may cause low blood sugar, also known as hypoglycemia. This can reduce your ability to concentrate or react. Do not drive or operate heavy machinery until you know how pioglitazone/glimepiride affects you, or if you are having any signs or symptoms of hypoglycemia.

Pioglitazone/glimepiride is a prescription medication used to treat Type 2 Diabetes. It is used in combination with diet and exercise. This medication may be prescribed for other uses. Ask your doctor or pharmacist for more information.

Before taking pioglitazone/glimepiride, tell your doctor about all of your medical conditions. Especially tell your doctor if you:

• Are allergic to pioglitazone, glimepiride, any ingredients of pioglitazone or glimepiride, or sulfa drugs
• Nave heart failure
• Have kidney problems
• Have Type I Diabetes or have had ketoacidosis
• Have a vision problem called macular degeneration
• Have liver problems
• Have, or have had, bladder cancer
• Are pregnant, or are planning to become pregnant
• Are breastfeeding
• Are premenopausal and have no periods, or irregular periods
• Have a genetic condition known as G6PD deficiency

Tell your doctor about all the medicines you take including prescription and non-prescription medicines, vitamins, and herbal supplements.

Tell your doctor if you are pregnant or plan to become pregnant.

The FDA categorizes medications based on safety for use during pregnancy. Five categories—A, B, C, D, and X—are used to classify the possible risks to an unborn baby when a medication is taken during pregnancy.

Pioglitazone/glimepiride falls into category C. In animal studies, pregnant animals were given this medication and had some babies born with problems. No well–controlled studies have been done in humans. Therefore, this medication may be used if the potential benefits to the mother outweigh the potential risks to the unborn child.

Seek emergency medical attention or call the Poison Help line at 1-800-222-1222. A glimepiride and pioglitazone overdose can cause life-threatening hypoglycemia. Symptoms of severe hypoglycemia include extreme weakness, blurred vision, sweating, trouble speaking, tremors, stomach pain, confusion, and seizure (convulsions).

Applies to glimepiride / pioglitazone: oral tablet

Along with its needed effects, glimepiride / 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 glimepiride / pioglitazone:

• Anxiety
• bladder pain
• bloody or cloudy urine
• blurred vision
• chills
• cold sweats
• coma
• confusion
• cool, pale skin
• depression
• difficult, burning, or painful urination
• fast heartbeat
• frequent urge to urinate
• headache
• increased hunger
• increased weight
• lower back or side pain
• nausea
• nightmares
• seizures
• shakiness
• slurred speech
• swelling of the feet or lower legs
• unusual tiredness or weakness

• Accidental injury
• loss of appetite
• pain or swelling in the arms or legs without any injury
• pale skin
• stomach pain
• troubled breathing with exertion
• unusual bleeding or bruising
• vomiting
• weight loss
• yellow eyes or skin

Some side effects of glimepiride / 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:

• Body aches or pain
• cough
• diarrhea
• difficulty with moving
• dryness or soreness of the throat
• ear congestion
• fever
• hoarseness
• joint pain
• loss of voice
• muscle aching or cramping
• muscle pains or stiffness
• runny nose
• sneezing
• stuffy nose
• swollen joints
• tender, swollen glands in the neck
• tooth disorder
• trouble swallowing
• voice changes

• Dizziness
• itching skin or rash
• lack or loss of strength

Applies to glimepiride / pioglitazone: oral tablet

General

The most common adverse reactions included upper respiratory tract infections, accidental injury, and combined edema/peripheral edema.[Ref]

Cardiovascular

Pioglitazone-Sulfonylurea
Very common (10% or more): Lower leg edema (up to 12.3%)

Pioglitazone:
Very common (10% or more): Edema (up to 26.7%)
Common (1% to 10%): Cardiac failure, chest pain[Ref]

Pioglitazone is associated with edema (peripheral, generalized, and pitting edema and fluid retention) when used alone or when used in combination therapy. In pioglitazone monotherapy trials, edema occurred in 2.5% (n=81), 4.7% (n=275), and 6.5% (n=169) of patients receiving 15 mg, 30 mg, and 45 mg of pioglitazone daily for 16 to 26 weeks. Pioglitazone in combination with a sulfonylurea for 16 to 24 weeks resulted in edema in 1.6% (n=184), 11.3% (n=540), and 23.1% (n=351) of patients receiving 15 mg, 30 mg, and 45 mg of pioglitazone daily, respectively. In a study in patients with NYHA class II or III heart failure the percentage of patients experiencing CHF progression during the study was 13.4% and 8.2% in patients receiving pioglitazone (n=262) and glyburide (n=256), respectively.

In the PROactive trial, a study in 5238 patients with type 2 diabetes and a history of macrovascular disease who were force-uptitrated to pioglitazone 45 mg once a day or received placebo in addition to standard of care, edema occurred in 27.3% of patients treated with pioglitazone (n=2605) compared with 15.9% of placebo (n=2633) patients. Treatment-emergent adverse events leading to at least 1 hospitalized congestive heart failure event occurred in 5.7% of patients receiving pioglitazone and 4.1% of patients receiving placebo.

The primary objective of the 3-year PROactive trial was to examine the effect of pioglitazone on mortality and macrovascular morbidity in high-risk patients. No statistically significant difference between pioglitazone and placebo/standard care were observed for time to the first occurrence of their first event (all-cause mortality, nonfatal myocardial infarction (MI) including silent MI, stroke, acute coronary syndrome, cardiac intervention including coronary artery bypass grafting or percutaneous intervention, major leg amputation above the ankle, and bypass surgery or revascularization in the leg). A total of 514 patients receiving pioglitazone experienced at least 1 event compared with 572 patients receiving placebo/standard care.

Postmarketing reports of congestive heart failure have been received in patients treated with pioglitazone. Reports have been received from patients both with and without a history of a known history of heart disease and both with and without concomitant insulin use.[Ref]

Hepatic

Pioglitazone:
Uncommon (0.1% to 1%): ALT values greater than 3 times upper limit of normal (3 x ULN)
Postmarketing reports: Hepatic failure

Glimepiride:
Common (1% to 10%): Elevated ALT to greater than 2 x ULN
Postmarketing reports: Liver function impairment (e.g. with cholestasis and jaundice), as well as hepatitis, which may progress to liver failure, hepatic porphyria reactions and disulfiram-like reactions[Ref]

Hypersensitivity

There have been postmarketing reports of serious allergic reactions in patients receiving glimepiride such as anaphylaxis, angioedema, Stevens-Johnson syndrome, dyspnea, hypotension, and shock. In clinical trials allergic reactions such as pruritus, erythema, urticaria, and morbilliform or maculopapular eruptions, occurred in less than 1% of patients receiving glimepiride, and some resolved despite continued treatment.

Glimepiride:
Uncommon (0.1% to 1%): Allergic reactions
Postmarketing reports: Serious allergic reactions

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]

Pioglitazone:
Uncommon (0.1% to 1%): Bladder cancer[Ref]

Endocrine

Pioglitazone:
Frequency not reported: Resumption of ovulation in premenopausal, anovulatory women, hormonal imbalance

Glimepiride:
Postmarketing reports: Hyponatremia, syndrome of inappropriate antidiuretic hormone secretion (SIADH)[Ref]

SIADH has been reported postmarketing in patients receiving glimepiride, most often in patients who are on other medications or who have medical conditions known to cause hyponatremia or increase release of antidiuretic hormone.[Ref]

Ocular

Pioglitazone:
Postmarketing reports: New or worsening diabetic macular edema with decreased visual acuity[Ref]

Macular edema has been reported in postmarketing experience in diabetic patients who were taking pioglitazone or another thiazolidinedione. Some patients presented with blurred vision or decreased visual acuity, but some patients appear to have been diagnosed on routine ophthalmologic examination. Some patients had peripheral edema at the time macular edema was diagnosed. Some patients had improvement in their macular edema after discontinuation of their thiazolidinedione. It is unknown whether or not there is a causal relationship between pioglitazone and macular edema.[Ref]

Metabolic

Pioglitazone is associated with dose-related weight gain when used alone or when used in combination therapy. The mechanism of weight gain is unclear, but probably involves a combination of fluid retention and fat accumulation. In pioglitazone monotherapy trials, weight increases of 0.9 kg, 1 kg, and 2.6 kg occurred in patients receiving 15 mg, 30 mg, and 45 mg of pioglitazone daily for 16 to 26 weeks. Pioglitazone in combination with a sulfonylurea for 16 to 24 weeks resulted in weight increases of 2 kg, 3.1 kg, and 4.1 kg, for patients receiving 15 mg, 30 mg, and 45 mg of pioglitazone daily respectively. In the PROactive (Prospective Pioglitazone Clinical Trial in Macrovascular Events) trial, the median change in body weight in patients treated with pioglitazone (n=2560) compared with placebo (n=2581) was -0.5 kg compared to +3.6 kg. The median exposure to drug was 2.7 years.[Ref]

Pioglitazone-Sulfonylurea
Very common (10% or more): Hypoglycemia (up to 15.7%), weight increase (up to 13.4%)[Ref]

Respiratory

Pioglitazone-Sulfonylurea
Very common (10% or more): Upper respiratory tract infection (up to 14.8%)
Common (1% to 10%): Sinusitis, pharyngitis

Pioglitazone:
Very common (10% or more): Upper respiratory tract infection (up to 13.2%)[Ref]

Hematologic

Pioglitazone-Sulfonylurea
Frequency not reported: Anemia

Pioglitazone:
Frequency not reported: Decreases in hemoglobin and hematocrit

Glimepiride:
Postmarketing reports: Hemolytic Anemia, leukopenia, agranulocytosis, aplastic anemia, pancytopenia, thrombocytopenia, thrombocytopenia purpura[Ref]

Laboratory findings have shown decreases in hemoglobin and hematocrit with pioglitazone therapy; mean hemoglobin values declined by 2% to 4% in pioglitazone treated patients compared to -1% to 1% in placebo-treated patients. These changes primarily occurred during the first 3 months. Changes may be related to increased plasma volume and not likely to be associated with any clinically significant hematologic effects.[Ref]

Gastrointestinal

Pioglitazone-Sulfonylurea
Common (1% to 10%): Diarrhea, nausea[Ref]

Nervous system

Pioglitazone-Sulfonylurea
Common (1% to 10%): Headache, dizziness[Ref]

Musculoskeletal

Pioglitazone-Sulfonylurea
Common (1% to 10%): Limb pain

Pioglitazone:
Common (1% to 10%): Myalgia, pain in extremity, back pain
Frequency not reported: Elevated creatine phosphokinase (CPK)[Ref]

Elevations in CPK were observed during protocol-specified measurement of CPK in pioglitazone clinical trials. Isolated elevation to 10 times the upper limit of normal was observed in 9 patients (0.2%). Elevations resolved without any clinical sequelae and the relationship to drug therapy is unknown.[Ref]

Dermatologic

Glimepiride:
Postmarketing reports: Porphyria cutanea tarda, photosensitivity reactions and allergic vasculitis[Ref]

Genitourinary

Pioglitazone-Sulfonylurea
Common (1% to 10%): Urinary tract infection[Ref]

Some side effects of glimepiride / pioglitazone may not be reported. Always consult your doctor or healthcare specialist for medical advice. You may also report side effects to the FDA.

Use with caution: Initial dosing, dose increments, and maintenance dosage should be conservative to minimize the risk of hypoglycemia.

US BOXED WARNING: Congestive Heart Failure
-Thiazolidinediones, including pioglitazone, may cause or exacerbate congestive heart failure in some patients.
-After initiation of therapy and with any dosage increases, observe patients carefully for signs and symptoms of heart failure including excessive, rapid weight gain, dyspnea, and/or edema; if signs and symptoms of heart failure develop, manage in accordance to current standards of care.
-Drug discontinuation or dosage reduction should be considered in patients showing signs and symptoms of heart failure; this drug is not recommended in patients with symptomatic heart failure.
-Initiation in patients with established NYHA Class III or IV heart failure is contraindicated.

Safety and efficacy have not been established in patients younger than 18 years.

Consult WARNINGS section for additional precautions.