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Pioglitazone/metformin 15-500mg Tb

Manufacturer MACLEODS Active Ingredient Pioglitazone and Metformin(pye oh GLI ta zone & met FOR min) Pronunciation pye oh GLI ta zone & met FOR min
WARNING: This drug may cause or make heart failure worse. Tell your doctor if you have had heart failure. This drug may need to be avoided with some types of heart failure. You will be watched closely while starting this drug and if your dose is raised. Call your doctor right away if you have swelling in the arms or legs, shortness of breath or trouble breathing (especially when lying down), sudden weight gain, or you feel very tired.Rarely, metformin may cause too much lactic acid in the blood (lactic acidosis). The risk is higher in people who have kidney problems, liver problems, heart failure, use alcohol, or take certain other drugs, including topiramate. The risk is also higher in people who are 65 or older and in people who are having surgery, an exam or test with contrast, or other procedures. If lactic acidosis happens, it can lead to other health problems and can be deadly. Kidney tests may be done while taking this drug.Do not take this drug if you have a very bad infection, low oxygen, or a lot of fluid loss (dehydration).Call your doctor right away if you have signs of too much lactic acid in the blood (lactic acidosis) like confusion; fast breathing; fast or slow heartbeat; a heartbeat that does not feel normal; very bad stomach pain, upset stomach, or throwing up; feeling very sleepy; shortness of breath; feeling very tired or weak; very bad dizziness; feeling cold; or muscle pain or cramps. @ COMMON USES: It is used to lower blood sugar in patients with high blood sugar (diabetes).
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Drug Class
Antidiabetic, Oral Combination
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Pharmacologic Class
Thiazolidinedione (TZD) / Biguanide
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Pregnancy Category
Category C
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FDA Approved
Aug 2005
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DEA Schedule
Not Controlled

Overview

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What is this medicine?

This medication is a combination of two drugs, pioglitazone and metformin, used to help control high blood sugar in people with type 2 diabetes. Pioglitazone helps your body use insulin better, and metformin helps reduce the amount of sugar your liver makes and your intestines absorb.
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How to Use This Medicine

Taking Your Medication Correctly

To get the most benefit from your medication, follow your doctor's instructions carefully. Read all the information provided with your prescription and follow the instructions closely. Take your medication with meals to help your body absorb it properly. Establish a routine by taking your medication at the same time every day. Continue taking your medication as directed by your doctor or healthcare provider, even if you start to feel better.

Storing and Disposing of Your Medication

To maintain the quality and effectiveness of your medication, store the tablets in their original container at room temperature. Keep the container tightly closed to protect the medication from moisture and light. Store the container in a dry place, away from direct sunlight and heat sources. Avoid storing your medication in a bathroom, as the humidity and temperature fluctuations can affect its potency.

What to Do If You Miss a Dose

If you forget to take a dose, take it as soon as you remember. However, if it's close to the time for your next scheduled dose, skip the missed dose and resume your regular dosing schedule. Do not take two doses at the same time or take extra doses to make up for the missed one.
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Lifestyle & Tips

  • Follow a healthy diet plan as recommended by your doctor or dietitian.
  • Engage in regular physical activity as advised by your healthcare provider.
  • Monitor your blood sugar levels regularly as instructed.
  • Limit alcohol intake, as it can increase the risk of a serious side effect called lactic acidosis with metformin.
  • Maintain good hydration, especially when exercising or in hot weather.
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Available Forms & Alternatives

Available Strengths:

Dosing & Administration

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Adult Dosing

Standard Dose: Initial: Pioglitazone 15 mg/Metformin 500 mg once or twice daily, with meals. Titrate gradually.
Dose Range: 15 - 45 mg

Condition-Specific Dosing:

maximumDailyDose: Pioglitazone 45 mg / Metformin 2550 mg (or 2000 mg for XR)
renalImpairment: See renal impairment section
hepaticImpairment: See hepatic impairment section
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Pediatric Dosing

Neonatal: Not established
Infant: Not established
Child: Not established
Adolescent: Not established
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Dose Adjustments

Renal Impairment:

Mild: eGFR 60-89 mL/min/1.73m²: No dose adjustment for pioglitazone. Metformin: Monitor renal function, consider dose reduction if eGFR approaches 60.
Moderate: eGFR 45-59 mL/min/1.73m²: Pioglitazone: No dose adjustment. Metformin: Max dose 1000 mg/day. eGFR 30-44 mL/min/1.73m²: Pioglitazone: No dose adjustment. Metformin: Max dose 500 mg/day.
Severe: eGFR < 30 mL/min/1.73m²: Contraindicated (due to metformin component).
Dialysis: Contraindicated (due to metformin component).
Confidence: High

Hepatic Impairment:

Mild: Pioglitazone: Use with caution. Metformin: No specific adjustment, but caution.
Moderate: Pioglitazone: Not recommended. Metformin: Caution.
Severe: Pioglitazone: Contraindicated in active liver disease. Metformin: Contraindicated.
Confidence: High

Pharmacology

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Mechanism of Action

Pioglitazone is a thiazolidinedione that acts as a potent and highly selective agonist for peroxisome proliferator-activated receptor-gamma (PPARγ). PPARγ receptors are found in 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, thereby improving insulin sensitivity in target tissues. Metformin is a biguanide that decreases hepatic glucose production, decreases intestinal absorption of glucose, and improves insulin sensitivity by increasing peripheral glucose uptake and utilization. It does not stimulate insulin secretion and, therefore, does not cause hypoglycemia.
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Pharmacokinetics

Absorption:

Bioavailability: Pioglitazone: >80%; Metformin: 50-60% (oral)
Tmax: Pioglitazone: 1.5-2 hours; Metformin: 2-3 hours (immediate release)
FoodEffect: Pioglitazone: Food has no effect on absorption; Metformin: Food decreases and slightly delays absorption, but clinical significance is minimal.

Distribution:

Vd: Pioglitazone: 0.63 L/kg; Metformin: 654 ± 358 L
ProteinBinding: Pioglitazone: >99% (to albumin); Metformin: Negligible
CnssPenetration: Pioglitazone: Limited; Metformin: Limited

Elimination:

HalfLife: Pioglitazone: 3-7 hours (parent drug), 16-24 hours (total active metabolites); Metformin: 6.2 hours (plasma), 17.6 hours (blood)
Clearance: Pioglitazone: Not available; Metformin: Renal clearance is approximately 3.5 times greater than creatinine clearance
ExcretionRoute: Pioglitazone: Primarily urine (15-30%) and feces (55-80%); Metformin: Renal (unchanged)
Unchanged: Pioglitazone: <2% (urine); Metformin: ~90% (urine)
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Pharmacodynamics

OnsetOfAction: Pioglitazone: Gradual, weeks to months for full effect; Metformin: Within days, full effect within 2 weeks
PeakEffect: Pioglitazone: 2-3 months; Metformin: 2-3 weeks
DurationOfAction: Pioglitazone: Prolonged; Metformin: 12-24 hours (immediate release)

Safety & Warnings

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BLACK BOX WARNING

CONGESTIVE HEART FAILURE: Thiazolidinediones, including pioglitazone, cause or exacerbate congestive heart failure in some patients. After initiation of pioglitazone, and during dose titration, observe patients carefully for signs and symptoms of heart failure (e.g., excessive, rapid weight gain, dyspnea, and/or edema). If these signs and symptoms develop, the heart failure should be managed according to current standards of care. Furthermore, discontinuation or dose reduction of pioglitazone must be considered. Pioglitazone is contraindicated in patients with established New York Heart Association (NYHA) Class III or IV heart failure. LACTIC ACIDOSIS: Postmarketing cases of metformin-associated lactic acidosis have resulted in death, hypothermia, hypotension, and resistant bradyarrhythmias. The onset of metformin-associated lactic acidosis is often subtle, accompanied only by nonspecific symptoms such as malaise, myalgias, respiratory distress, somnolence, and abdominal pain. Metformin-associated lactic acidosis was characterized by elevated blood lactate levels (>5 mmol/L), anion gap acidosis (without evidence of ketonuria or ketonemia), and an increased lactate/pyruvate ratio; metformin plasma levels generally >5 mcg/mL. If acidosis is suspected, discontinue metformin and institute general supportive measures in a hospital setting along with prompt hemodialysis. Risk factors include renal impairment, concomitant use of certain drugs, age 65 years or greater, radiological studies with contrast, surgery and other procedures, hypoxic states, excessive alcohol intake, and hepatic impairment.
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Side Effects

Urgent Side Effects: Seek Medical Attention Immediately

Although rare, some people may experience severe and potentially life-threatening side effects while taking this medication. If you notice any of the following symptoms, contact your doctor or seek medical help right away:

Signs of an allergic reaction, such as:
+ Rash
+ Hives
+ Itching
+ Red, swollen, blistered, or peeling skin with or without fever
+ Wheezing
+ Tightness in the chest or throat
+ Trouble breathing, swallowing, or talking
+ Unusual hoarseness
+ Swelling of the mouth, face, lips, tongue, or throat
 Bone pain
Changes in eyesight
 Pain when passing urine or blood in urine
Increased frequency of urination
 Swelling

Common Stomach Problems and Potential Complications

When starting this medication, it's common to experience stomach problems like upset stomach, vomiting, or diarrhea. However, if you develop stomach problems later during treatment, contact your doctor right away, as this may be a sign of a serious condition called lactic acidosis.

Low Blood Sugar and Other Potential Complications

Low blood sugar can occur, especially when this medication is used with other diabetes medications. If you experience any of the following symptoms, contact your doctor right away:

Dizziness
 Headache
Feeling sleepy or weak
 Shaking
Fast heartbeat
 Confusion
Hunger
 Sweating

Follow your doctor's instructions for managing low blood sugar, which may include taking glucose tablets, liquid glucose, or some fruit juices.

Severe Liver Problems

In rare cases, this medication can cause severe and potentially life-threatening liver problems. If you notice any of the following symptoms, contact your doctor right away:

Dark urine
 Tiredness
Decreased appetite
 Upset stomach or stomach pain
Light-colored stools
 Vomiting
Yellow skin or eyes

Other Possible Side Effects

Like all medications, this drug can cause side effects. Many people may not experience any side effects or only minor ones. However, if you're bothered by any of the following side effects or if they don't go away, contact your doctor or seek medical help:

 Diarrhea
Upset stomach
 Vomiting
Gas
 Headache
Signs of a common cold
 Weight gain
* Feeling tired or weak

Reporting Side Effects

If you have questions about side effects or want to report any, contact your doctor. You can also report side effects to the FDA at 1-800-332-1088 or online at https://www.fda.gov/medwatch.
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Seek Immediate Medical Attention If You Experience:

  • Signs of heart failure: unusual weight gain, swelling in your ankles or feet, shortness of breath, especially when lying down.
  • Signs of lactic acidosis (a serious side effect of metformin): unusual muscle pain, trouble breathing, stomach pain, feeling cold, dizziness, lightheadedness, or a very slow or irregular heartbeat.
  • Signs of low blood sugar (hypoglycemia): sweating, shaking, fast heartbeat, hunger, blurred vision, dizziness, or tingling in your hands or feet.
  • Signs of liver problems: nausea, vomiting, stomach pain, unusual tiredness, dark urine, or yellowing of your skin or eyes.
  • Signs of bladder cancer: blood in your urine, painful urination, or frequent urination.
  • Signs of bone fractures: new or unusual pain in your bones, especially in your arms or legs.
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Before Using This Medicine

Before Taking This Medication: Important Information to Share with Your Doctor

It is essential to inform your doctor about the following:

Any allergies you have, including allergies to this medication, its components, or other substances, such as foods or drugs. Describe the allergic reaction you experienced, including the symptoms that occurred.
 Certain health conditions, including:
+ Acidic blood problems
+ Bladder cancer
+ Type 1 diabetes (note: this medication is not intended to treat type 1 diabetes)
+ Kidney disease
+ Liver disease
+ Recent heart attack or stroke
If you have any difficulties with eating or drinking, such as before undergoing a procedure or surgery
 If you have had or are scheduled to have an exam or test that uses contrast media within the past 48 hours
If you are a child, as this medication is not suitable for pediatric use

Additionally, it is crucial to discuss all your medications, including:

 Prescription and over-the-counter (OTC) drugs
Natural products
 Vitamins

with your doctor and pharmacist to ensure safe use. Do not initiate, discontinue, or modify the dosage of any medication without first consulting your doctor. This will help verify that it is safe to take this medication in conjunction with your other medications and health conditions.
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Precautions & Cautions

It is essential to inform all your healthcare providers, including doctors, nurses, pharmacists, and dentists, that you are taking this medication. Before consuming alcohol, discuss the potential risks with your doctor.

If you experience low blood sugar, avoid driving, as it increases the risk of accidents. Monitor your blood sugar levels as instructed by your doctor. Additionally, follow your doctor's recommendations for regular blood work and other laboratory tests.

Adhere to the diet and exercise plan prescribed by your doctor. Be aware that stress, such as fever, infection, injury, or surgery, can affect blood sugar control. Changes in physical activity, exercise, or diet can also impact blood sugar levels.

Long-term treatment with metformin may lead to decreased vitamin B-12 levels. If you have a history of low vitamin B-12 levels, consult your doctor.

In hot weather or during physical activity, be cautious and drink plenty of fluids to prevent dehydration.

There is a potential increased risk of bladder cancer associated with this medication. Discuss this risk with your doctor.

This medication may also increase the risk of fractures, particularly in females. Most fractures occurred in the upper arm, hand, or foot after one year of treatment. Consult your doctor about maintaining bone health and addressing any concerns.

If you are 65 or older, use this medication with caution, as you may be more susceptible to side effects.

For individuals of childbearing age who have not been ovulating, there is a potential risk of pregnancy. To avoid pregnancy, use birth control while taking this medication.

If you are pregnant, plan to become pregnant, or are breastfeeding, inform your doctor. You will need to discuss the benefits and risks of this medication to both you and your baby.
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Overdose Information

Overdose Symptoms:

  • Hypoglycemia (if taken with insulin or sulfonylurea)
  • Lactic acidosis (severe and potentially fatal, symptoms include severe nausea/vomiting, diarrhea, abdominal pain, rapid/shallow breathing, muscle pain, unusual tiredness, dizziness, lightheadedness, decreased consciousness)
  • Fluid retention, heart failure symptoms

What to Do:

Seek immediate medical attention. Call 911 or your local emergency number. For suspected overdose, call a poison control center at 1-800-222-1222. Management includes supportive care, correction of hypoglycemia if present, and hemodialysis for lactic acidosis.

Drug Interactions

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Contraindicated Interactions

  • Iodinated contrast agents (for metformin, temporarily discontinue)
  • Alcohol (excessive acute or chronic intake, due to metformin's lactic acidosis risk)
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Major Interactions

  • Gemfibrozil (increases pioglitazone exposure)
  • Rifampin (decreases pioglitazone exposure)
  • Carbonic anhydrase inhibitors (e.g., topiramate, zonisamide, acetazolamide, dichlorphenamide - may increase lactic acidosis risk with metformin)
  • Drugs that affect renal function (e.g., NSAIDs, ACE inhibitors, ARBs - may increase metformin levels)
  • Cationic drugs eliminated by renal tubular secretion (e.g., amiloride, digoxin, morphine, procainamide, quinidine, quinine, ranitidine, triamterene, trimethoprim, vancomycin - may increase metformin levels)
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Moderate Interactions

  • Nifedipine (increases metformin absorption)
  • Cimetidine (increases metformin AUC)
  • Corticosteroids (may increase blood glucose, requiring dose adjustment of antidiabetic)
  • Thiazide diuretics (may increase blood glucose, requiring dose adjustment of antidiabetic)
  • Sympathomimetics (may increase blood glucose, requiring dose adjustment of antidiabetic)
  • Phenothiazines (may increase blood glucose, requiring dose adjustment of antidiabetic)
  • Thyroid products (may increase blood glucose, requiring dose adjustment of antidiabetic)
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Minor Interactions

  • Not specifically identified as minor for this combination, but general caution with drugs affecting glucose levels.

Monitoring

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Baseline Monitoring

HbA1c

Rationale: To establish baseline glycemic control and guide initial therapy.

Timing: Prior to initiation

Renal function (eGFR)

Rationale: Metformin is renally eliminated; risk of lactic acidosis increases with impaired renal function.

Timing: Prior to initiation

Liver function tests (ALT, AST, bilirubin)

Rationale: Pioglitazone is metabolized by the liver; contraindicated in active liver disease.

Timing: Prior to initiation

Complete Blood Count (CBC)

Rationale: Metformin can rarely cause vitamin B12 deficiency, leading to megaloblastic anemia.

Timing: Prior to initiation

Cardiac status (signs/symptoms of heart failure)

Rationale: Pioglitazone can cause or exacerbate congestive heart failure.

Timing: Prior to initiation

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Routine Monitoring

HbA1c

Frequency: Every 3-6 months

Target: Individualized, typically <7%

Action Threshold: >7% (or individualized target) may require dose adjustment or additional therapy

Renal function (eGFR)

Frequency: At least annually; more frequently (2-4 times/year) in elderly or those with risk factors for renal impairment

Target: >60 mL/min/1.73m² (for full dose metformin)

Action Threshold: <60 mL/min/1.73m² requires dose adjustment; <30 mL/min/1.73m² requires discontinuation

Liver function tests (ALT)

Frequency: Periodically, or if symptoms of liver dysfunction occur

Target: Within normal limits

Action Threshold: >3x ULN requires discontinuation of pioglitazone

Vitamin B12 levels

Frequency: Annually or every 2-3 years, especially in patients with risk factors for deficiency (e.g., malabsorption, prolonged use)

Target: Within normal limits

Action Threshold: Low levels require supplementation

Signs/symptoms of heart failure (e.g., edema, dyspnea, weight gain)

Frequency: At each visit

Target: Absence of symptoms

Action Threshold: New or worsening symptoms require immediate evaluation and potential discontinuation of pioglitazone

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Symptom Monitoring

  • Symptoms of lactic acidosis (e.g., malaise, myalgia, respiratory distress, increasing somnolence, abdominal distress)
  • Symptoms of hypoglycemia (e.g., sweating, tremor, dizziness, confusion, hunger)
  • Symptoms of heart failure (e.g., unusual weight gain, edema, shortness of breath)
  • Symptoms of bladder cancer (e.g., hematuria, dysuria, urinary urgency)
  • Symptoms of bone fractures (e.g., pain, swelling, deformity)
  • Symptoms of liver dysfunction (e.g., nausea, vomiting, abdominal pain, fatigue, dark urine, jaundice)

Special Patient Groups

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Pregnancy

Category C. Limited data on pioglitazone use in pregnant women to inform a drug-associated risk for major birth defects or miscarriage. Metformin has been studied more extensively and is often considered for gestational diabetes or type 2 diabetes in pregnancy, but the combination is generally not recommended unless benefits outweigh risks. Poorly controlled diabetes in pregnancy increases risk of birth defects, perinatal mortality, and other complications.

Trimester-Specific Risks:

First Trimester: Potential for increased risk of major birth defects with uncontrolled diabetes. Pioglitazone animal studies showed some developmental toxicity at high doses.
Second Trimester: Risk of fetal macrosomia and other complications from uncontrolled maternal diabetes.
Third Trimester: Risk of neonatal hypoglycemia and respiratory distress from uncontrolled maternal diabetes.
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Lactation

Metformin is excreted into breast milk in small amounts and is generally considered compatible with breastfeeding (L2). Pioglitazone is excreted into breast milk in rats, but human data are lacking. Due to potential for serious adverse reactions in the breastfed infant, including fluid retention and heart failure, breastfeeding is generally not recommended while taking pioglitazone/metformin (L3).

Infant Risk: Metformin: Low risk. Pioglitazone: Potential for fluid retention, weight gain, and other adverse effects; unknown long-term effects. Monitor infant for adverse effects.
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Pediatric Use

Safety and effectiveness have not been established in pediatric patients. Not recommended for use in children.

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Geriatric Use

Use with caution due to increased risk of renal impairment (metformin), heart failure (pioglitazone), and bone fractures (pioglitazone). Renal function should be assessed more frequently in elderly patients. Start with lower doses and titrate slowly. Avoid in patients ≥80 years unless renal function is normal.

Clinical Information

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Clinical Pearls

  • This combination is particularly useful for patients with type 2 diabetes who have insulin resistance and are not adequately controlled on metformin alone.
  • Pioglitazone has a delayed onset of action (weeks to months for full effect), so glycemic control should be assessed after sufficient time.
  • Patients should be educated on the signs and symptoms of heart failure and lactic acidosis, and instructed to seek immediate medical attention if they occur.
  • Regular monitoring of renal function is crucial due to the metformin component, especially before starting, annually, and more frequently in at-risk patients.
  • Liver function tests should be performed at baseline and periodically, or if symptoms of liver injury develop, due to the pioglitazone component.
  • Consider vitamin B12 monitoring in patients on long-term metformin therapy, especially if they develop symptoms of neuropathy or anemia.
  • Advise patients about the increased risk of bone fractures (especially in women) and bladder cancer with pioglitazone, though the absolute risk is small.
  • Temporarily discontinue this medication before any radiological procedure involving iodinated contrast agents or any surgical procedure requiring restricted food/fluid intake.
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Alternative Therapies

  • Metformin monotherapy
  • Pioglitazone monotherapy
  • Sulfonylureas (e.g., glipizide, glyburide)
  • DPP-4 inhibitors (e.g., sitagliptin, saxagliptin)
  • SGLT2 inhibitors (e.g., empagliflozin, canagliflozin)
  • GLP-1 receptor agonists (e.g., liraglutide, semaglutide)
  • Insulin therapy
  • Alpha-glucosidase inhibitors (e.g., acarbose)
  • Meglitinides (e.g., repaglinide)
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Cost & Coverage

Average Cost: $30 - $150 per 30 tablets (generic)
Generic Available: Yes
Insurance Coverage: Tier 1 or Tier 2 (for generic)
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General Drug Facts

If your symptoms or health issues persist or worsen, it is essential to contact your doctor promptly. To ensure safe use, never share your medication with others or take someone else's medication. This medication is accompanied by a Medication Guide, which is a valuable patient fact sheet. Please read this guide carefully and review it again whenever your prescription is refilled. If you have any questions or concerns about this medication, we encourage you to discuss them with your doctor, pharmacist, or other healthcare provider. In the event of a suspected overdose, immediately call your local poison control center or seek emergency medical attention. When seeking help, be prepared to provide information about the medication taken, the amount, and the time it occurred.