Pioglitazone Metformin Tablets is a combination of two drugs - Pioglitazone and metformin. It is available as 15/500 mg, 15/850 mg, 15/1000, and 30/1000 mg tablets.

Indications of Pioglitazone and Metformin:

• Type II Diabetes mellitus:

  • In addition to diet and exercise, combination therapy is used to enhance glycemic control in persons with type 2 diabetes mellitus.

Pioglitazone Metformin dose in Adults

Pioglitazone Metformin dose in the treatment of type 2 Diabetes mellitus:

• Immediate-release tablet:

  • Initial: Pioglitazone 15 mg/Metformin 500 mg or Pioglitazone 15 mg/Metformin 850 mg tablets once day are two options for treatment.

  • Patients with asymptomatic NYHA class I or II heart failure (HF):

    • Either pioglitazone 15 mg/metformin 850 mg or pioglitazone 15 mg/metformin 500 mg per oral once daily.
    • Note: Pioglitazone should be avoided and is contraindicated in those with stage III or IV heart failure.

  • Inadequately controlled on metformin monotherapy:

    • Pioglitazone 15 mg/850 mg of metformin or pioglitazone 15 mg/500 mg of metformin orally once or twice daily (depending on the dose of metformin already being taken).

  • Inadequately controlled on pioglitazone monotherapy:

    • Either pioglitazone 15 mg/metformin 850 mg or pioglitazone 15 mg/metformin 500 per oral b.i.d. daily.

  • Dose titration:

    • While adjusting the dose, it's important to keep a close eye out for any negative side effects, including weight gain, edoema, and heart failure signs and symptoms.
    • Maximum daily dose:
      • Pioglitazone 45 mg/metformin 2.55 g;
      • If heart failure worsens, think about lowering the dose of pioglitazone to less than 30 mg per day.
    • Note: If administered three times per day, metformin daily doses >2 g might be tolerated better.

• Extended-release tablet:

  • Initial: Pioglitazone 15 to 30 mg/metformin 1 g per oral once daily.

  • Inadequately controlled on metformin or pioglitazone monotherapy:

    • Alternatively, pioglitazone 30 mg/metformin 1 g once day, or pioglitazone 15 mg/metformin 1 g per oral b.i.d.

  • Dose titration: 

    • Pioglitazone 45 mg/metformin 2 g is the maximum recommended daily dose; if heart failure worsens, you may want to reduce this to 30 mg/day.

  • Dosage adjustment for hypoglycemia with combination therapy:

    • Sulphonylurea dosage must be reduced if pioglitazone metformin pills are also administered.
    • With insulin: Metformin 850 mg and pioglitazone 15 mg each
      • Reduce Insulin dose by 10% to 25%.

• Dosage adjustment with strong CYP2C8 inhibitors (eg, gemfibrozil):

  • Maximum recommended dose: Pioglitazone 15 mg/metformin 1 g daily or pioglitazone 15 mg/metformin 850 mg daily (immediate-release) (extended-release).

Pioglitazone Metformin dose in Children

Not recommended for use in children.

Pregnancy Risk Category: C

• Metformin can cross the placenta. Refer to individual drugs

Use while breastfeeding

• Metformin is secreted in breast milk, while pioglitazone secretion is unknown.
• According to the manufacturer of the product, when deciding whether to continue breastfeeding or stop breastfeeding during therapy, it should consider the risks and benefits to the infant as well as the benefits to the mother.
• Refer to individual drugs.

Dose adjutment in renal disease:

• eGFR >45 mL/minute/1.73 m :
  • No dosage adjustments are required; renal function should be checked at least once a year.
  • For individuals with eGFR >45 to 60 mL/minute/1.73 m, more regular monitoring (every 3 to 6 months) and a maximum metformin dose of 2 g/day have been advised (ADA [Lipska 2011]; Inzucchi 2014).
• eGFR 30 to 45 mL/minute/1.73 m :
  • Preexisting impairment: Use is not advised for therapy start; consult also with specific agents.
• If eGFR falls between 30 and <45 mL/minute/1.73 m during therapy:
  • Think about the pros and cons of continuing treatment.
  • The dosage of metformin should be reduced by 50% (to a maximum of 1 g/day) if medication is continued, and kidney function should be checked every three months (ADA [Lipska 2011]; Inzucchi 2014).
• eGFR <30 mL/minute/1.73 m :
  • Use is not advised.

Dose adjustment in liver disease:

• Tablets with immediate-release and extended-release:

  • Metformin should never be administered to patients with liver disease, as it can cause lactic acidosis. 
  • In individuals who have a high risk of developing lactic acidosis, it can be taken with caution if the advantages outweigh the dangers.
  • Pioglitazone should be used with caution. You can also see individual agents (metformin and pioglitazone).

Common Side Effects of Pioglitazone metformin tablets:

• Cardiovascular:

  • Lower Extremity Edema

• Respiratory:

  • Upper Respiratory Tract Infection

Rare Side Effects Of Actoplus met:

• Central Nervous System:

  • Headache
  • Dizziness

• Endocrine & Metabolic:

  • Weight Gain

• Gastrointestinal:

  • Diarrhea
  • Nausea

• Genitourinary:

  • Urinary Tract Infection

• Hematologic & Oncologic:

  • Anemia

• Respiratory:

  • Sinusitis

Contraindications to Pioglitazone and metformin:

• Hypersensitivity to metformin, pioglitazone, or any other formulation ingredient
• Diabetes ketoacidosis/ Metabolic acidosis
• NYHA class III and IV heart failure
• Grave renal impairment (eGFR 30mL/minute).

Warnings and precautions

• Bladder cancer

  • Patients with active bladder cancer should not use pioglitazone.
  • Before starting treatment, patients with a history of bladder cancer should weigh the advantages and disadvantages of using pioglitazone.

• Edema

  • Pioglitazone can cause new-onset or worsening of existing edema. Patients with edema should be careful and monitor their condition.

• Fractures

  • Females who have been treated with pioglitazone, especially the lower limbs and upper limbs, are at greater risk of breaking bones.

• [US Boxed Warning] Heart Failure/cardiac effects

  • Heart disease may worsen or become more severe as a result of pioglitazone.
  • This could show up as edoema, dyspnea, and rapid weight gain.
  • You must cut back on or stop taking pioglitazone if you get heart failure.
  • Therapy is not advised for patients with NYHA Class III or IV heart disease. In hospitalised or unstable cardiac disease patients, therapy should be avoided.
  • Hypoperfusion can increase the risk for lactic acidosis.
  • The American Heart Association states that metformin can worsen underlying myocardial dysfunction.

• Hematologic effects

  • Pioglitazone can increase plasma volume, which may cause hemoglobin/hematocrit to drop.

• Hepatic effects

  • Pioglitazone has been linked to life-threatening hepatic impairment. Therefore, it is important to monitor closely.

• Hypoglycemia

  • Combining pioglitazone with insulin or other diabetes medications can increase the risk of hypoglycemia.

• [US Boxed Warning] Lactic acidosis

  • Metformin can cause lactic acidosis. It manifests as malaise, myalgias and respiratory distress.
  • Patients with elderly, alcoholics and contrast Xrays are all risk factors for lactic acidsis.
  • In the event of lactic acidosis, it is important to immediately stop using the drug and get urgent hemodialysis.Patients with hypoperfusion, hypoperfusion, sepsis, and dehydration should not take the drug.
  • Metformin can cause fatal lactic acidosis, which can result in hypotension, hypothermia and resistant bradyarrhythmias, or even death.

• Macular edema

  • Pioglitazone can cause macular edema, which is characterized by blurred vision and decreased visual acuity. This condition requires urgent medical attention.

• Concentrations of Vitamin B:

  • Inadequate levels of vitamin B12 can result with prolonged metformin medication.
  • Patients with anemia and peripheral neuropathy who have taken metformin must be monitored for B serum levels.

• Weight loss

  • Pioglitazone can cause weight gain and fluid retention.

• Bariatric surgery

  • Absorption altered:
    • After surgery, immediate-release tablets are recommended.
    • Absorption may change after a gastric bypass or sleeve gastrectomy.
    • Due to the direct bypass of the stomach, proximal colon, and small intestine during gastric bypass, the action of extended-release pills is decreased.
    • Following gastric bypass (Rouxen-Y gastric bypass), immediate-release tablets were administered to increase absorption (AUC rose by 21%), and bioavailability (increased 50%).
    • Regardless of whether metformin is used, lactate levels drop after gastric bypass (RYGB).
    • Normal renal status does not require lowering the metformin dose following gastric bypass.
  • Weight loss
    • Weight gain can be caused by the therapy after gastric bypass, gastric banding, or sleeve gastricectomy.

• Hepatic impairment

  • Metformin may be recommended for certain patients suffering from diabetes and liver dysfunction (cirrhosis)
  • All patients should have serum liver function tests done before pioglitazone is ingested.
  • If you experience symptoms such as anorexia or fatigue, jaundice and dark urine, or right upper abdominal discomfort, it is important to stop therapy immediately.
  • Do not resume treatment if serum ALT exceeds ULN by more than three times without any known cause.
  • The risk of severe drug-induced liver injury is increased if serum ALT is greater than 3 times the ULN and serum totalbilirubin is more than 2 times the ULN.

• Renal impairment

  • Metformin is excreted through the kidneys so it is important to test your renal function before and during treatment.
  • Patients with an eGFR of 30 to 45 mL/minute or less should reduce their doses of metformin. However, patients with an eGFR below 30 mL/minute are advised not to use it.
  • Metformin may also be affected by drugs that affect tubular secretion.
  • Patients with prerenal azotemia or dehydration should not take metformin.

• Stress-related disorders:

  • It is preferable to stop giving metformin and insulin to a patient if they are experiencing significant stress, such as trauma, fever, or surgery.

Monitoring parameters:

• Hemoglobin, hematocrit, red blood cell indices
• Blood glucose
• Liver function tests
• Renal function tests
• Hemoglobin A
• Vitamin B serum concentrations periodically
• weight gain
• ophthalmic exam
• Signs and symptoms of edema or heart failure
• signs/symptoms of bladder malignancy (dysuria, macroscopic hematuria, dysuria, urinary urgency).

How to administer?

• It should be taken orally with meals.
• The extended-release tablets should be swallowed whole without crushing, splitting or chewing.

Mechanism of action:

• Pioglitazone, a thiazolidinedione anti-hyperglycemic agent, is also known as Pioglitazone. 
• It works by increasing insulin response in target cells, decreasing blood glucose levels and increasing insulin secretion. 
• For its action, it requires insulin. Metformin improves insulin sensitivity. 
• Metformin reduces the absorption of glucose in the intestine and increases glucose production in liver.

International Brands of Pioglitazone and metformin:

• Actoplus Met
• Actoplus Met XR
• Actos M
• Actos Met
• Actosmet
• Averofage
• Cereluc Met
• Competact
• Diavista-M
• Furuitong
• Glubrava
• Metact
• Nilgar M 15
• Nilgar M-30
• Pioglit-MF15
• Pioglite Plus
• Pionix-M
• Pioplus
• Politor
• Prialta-Met
• Suganorm
• Zolid Plus
• Zonaform

Pioglitazone and Metformin Brands in Pakistan: