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:

  • Combination therapy is used to improve glycemic control in adults with type 2 diabetes mellitus in addition to diet and exercise.

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  per oral b.i.d daily or pioglitazone 15 mg/metformin 850 mg tablets once daily

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

    • Pioglitazone 15 mg/metformin 500 mg per oral once daily or pioglitazone 15 mg/metformin 850 mg once daily.
    • Note: Pioglitazone is avoided in patients with symptomatic HF and contraindicated with stage III or IV HF.

  • Inadequately controlled on metformin monotherapy:

    • Pioglitazone 15mg/metformin 500 mg per oral b.i.d daily or pioglitazone 15 mg/metformin 850 mg once or b.i.d daily (depending on the dose of metformin already being taken).

  • Inadequately controlled on pioglitazone monotherapy:

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

  • Dose titration:

    • Careful monitoring of adverse effects such as weight gain, edema, signs/symptoms of heart failure is required while titrating the dose.
    • Maximum daily dose:
      • Pioglitazone 45 mg/metformin 2.55 g;
      • consider limiting pioglitazone dose to ≤30 mg/day if there is a worsening of heart failure.
    • Note: Metformin daily doses >2 g may be better tolerated if given thrice daily.

• Extended-release tablet:

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

  • Inadequately controlled on metformin or pioglitazone monotherapy:

    • Pioglitazone 15 mg/metformin 1 g per oral b.i.d daily or pioglitazone 30 mg/metformin 1 g once daily.

  • Dose titration: 

    • Maximum daily dose: Pioglitazone 45 mg/metformin 2 g; consider limiting pioglitazone dose to ≤30 mg/day if worsening of heart failure occurs.

  • Dosage adjustment for hypoglycemia with combination therapy:

    • The Dose reduction of sulphonylurea is required if given in combination with pioglitazone metformin tablets.
    • With insulin:
      • Reduce Insulin dose by 10% to 25%.

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

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

Pioglitazone Metformin dose in Childrens

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 adjustment necessary; monitor renal function at least annually.
  • More frequent monitoring (every 3 to 6 months) and a maximum metformin dose of 2 g/day has been recommended for patients with eGFR >45 to <60 mL/minute/1.73 m (ADA [Lipska 2011]; Inzucchi 2014).
• eGFR 30 to 45 mL/minute/1.73 m :
  • Preexisting impairment: Use is not recommended for initiation of therapy; refer also to individual agents.
• If eGFR falls between 30 and <45 mL/minute/1.73 m during therapy:
  • Consider benefits/risks of continuing therapy.
  • If continuing therapy, a metformin dosage reduction of 50% (maximum: 1 g/day) and monitoring of renal function every 3 months is recommended (ADA [Lipska 2011]; Inzucchi 2014).
• eGFR <30 mL/minute/1.73 m :
  • Use is contraindicated.

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. 
  • If the benefits outweigh the risks, it can be used with caution in patients who are at high risk of lactic acidosis. 
  • 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 pioglitazone, metformin or any other component of the formulation
• Diabetes ketoacidosis/ Metabolic acidosis
• NYHA class III and IV heart failure
• Grave renal impairment (eGFR 30mL/minute).

Warnings and precautions

• Bladder cancer

  • Pioglitazone should not be used in patients with active bladder carcinoma.
  • Patients with a history or bladder cancer should consider the risks and benefits of using pioglitazone before beginning therapy.

• 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

  • Pioglitazone can cause an exacerbation or worsening of heart disease.
  • This could manifest as rapid weight gain, dyspnea and edema.In the event of heart failure, you will need to reduce or stop taking pioglitazone.
  • Patients with NYHA Class III or IV heart disease are not recommended for therapy. Therapy should be avoided in hospitalized or unstable patients with heart disease..
  • 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:

  • Long-term metformin therapy can lead to vitamin B12 deficiency.
  • 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.
    • After gastric bypass or sleeve-gastrectomy, absorption can be altered.
    • Extended-release tablets have a reduced effect due to direct bypass of the stomach, proximal bowel and small intestine with gastric bypass.
    • 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:

  • If the patient is subject to extreme stress, such as trauma, fever, or surgery, it is best to discontinue metformin administration and insulin administration.

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: