ActoMeg

• Type 2 Diabetes Mellitus (T2DM):
  Indicated as an adjunct to diet and exercise to improve glycemic control in adults with T2DM:
• In patients inadequately controlled on metformin alone or pioglitazone alone
• As initial combination therapy for patients with high baseline HbA1c requiring multiple mechanisms of action for control
• Can be used in combination with other oral antidiabetic agents or insulin when dual therapy is insufficient
• Off-label Uses:
  Limited; primarily focused on T2DM management.

• Route: Oral
• Dosage Forms: Fixed-dose combination tablets with varying strengths, commonly:
• Pioglitazone 15 mg + Metformin 500 mg
• Pioglitazone 15 mg + Metformin 850 mg
• Pioglitazone 30 mg + Metformin 500 mg
• Pioglitazone 30 mg + Metformin 1000 mg
• Adult Dosing:
• Start with pioglitazone 15 mg + metformin 500 mg once or twice daily with meals to minimize GI side effects.
• Dose may be titrated gradually every 1 to 2 weeks based on glycemic response and tolerability.
• Maximum dose depends on individual components, generally pioglitazone up to 45 mg/day and metformin up to 2550 mg/day.
• Elderly:
• Initiate at lower doses to reduce risk of lactic acidosis and hypoglycemia; monitor renal function closely.
• Renal Impairment:
• Contraindicated in severe renal impairment (eGFR <30 mL/min/1.73m²).
• Dose adjustment and caution advised for mild to moderate impairment.
• Hepatic Impairment:
• Contraindicated in active liver disease or dysfunction.

Pioglitazone activates PPAR-γ nuclear receptors, enhancing insulin sensitivity in adipose tissue, muscle, and liver, promoting glucose uptake and reducing hepatic gluconeogenesis. Metformin primarily decreases hepatic glucose production (gluconeogenesis), improves peripheral glucose uptake and utilization, and enhances insulin sensitivity. Together, these agents provide complementary effects by improving insulin action (pioglitazone) and reducing glucose production (metformin), resulting in improved glycemic control.

• Pioglitazone:
• Oral bioavailability ~83%, peak plasma levels in ~2 hours
• Metabolized mainly via CYP2C8 and CYP3A4 to active metabolites
• Half-life of parent compound 3–7 hours; active metabolites 16–24 hours
• Eliminated primarily in feces (55%) and urine (15%)
• Metformin:
• Bioavailability 50–60%, peak plasma levels 2–3 hours post-dose
• Not metabolized, excreted unchanged via kidneys
• Half-life ~4–8.7 hours depending on renal function
• Renal clearance accounts for elimination

• Pregnancy:
• FDA category B for pioglitazone, category B for metformin.
• Use only if clearly needed; insulin is preferred during pregnancy.
• Lactation:
• Both drugs are excreted in small amounts in breast milk.
• Use caution during breastfeeding; monitor infant for hypoglycemia or other adverse effects.

• Antidiabetic Agents (Oral):
• Pioglitazone: Thiazolidinedione (PPAR-γ agonist)
• Metformin: Biguanide (insulin sensitizer, decreases hepatic glucose production)

• Known hypersensitivity to pioglitazone, metformin, or excipients
• Severe renal impairment (eGFR <30 mL/min/1.73 m²)
• Acute or chronic metabolic acidosis, including diabetic ketoacidosis
• Hepatic impairment or liver disease
• Conditions predisposing to hypoxia (e.g., severe cardiac or respiratory disease)
• Congestive heart failure (NYHA Class III or IV)
• History of lactic acidosis
• Pregnancy and breastfeeding (unless benefits outweigh risks)

• Lactic acidosis: Rare but serious risk from metformin; monitor renal function regularly.
• Heart failure: Pioglitazone can cause or exacerbate congestive heart failure due to fluid retention.
• Hepatic monitoring: Required before and during treatment.
• Bone fractures: Increased risk reported with pioglitazone, especially in women.
• Bladder cancer risk: Monitor for hematuria or urinary symptoms with pioglitazone.
• Hypoglycemia: Risk increases when combined with other antidiabetic drugs, although metformin alone rarely causes hypoglycemia.

• Common:
• Gastrointestinal upset (nausea, diarrhea, abdominal discomfort)
• Edema and weight gain (pioglitazone)
• Hypoglycemia (especially when combined with other hypoglycemics)
• Upper respiratory infections
• Headache
• Serious:
• Lactic acidosis
• Heart failure exacerbation
• Hepatotoxicity
• Bladder cancer (rare)
• Bone fractures
• Severe hypoglycemia

• CYP450 interactions: Pioglitazone metabolized by CYP2C8 and CYP3A4; inhibitors (e.g., gemfibrozil) increase levels.
• Drugs increasing lactic acidosis risk: Alcohol, iodinated contrast agents, cimetidine.
• Drugs altering glycemic control: Diuretics, corticosteroids, beta-blockers may reduce efficacy.
• Medications increasing hypoglycemia risk: Other sulfonylureas, insulin, meglitinides.
• Rifampin: Induces CYP2C8, may decrease pioglitazone efficacy.

• Current ADA and EASD guidelines support use of pioglitazone plus metformin as an effective combination therapy for T2DM, especially where insulin resistance predominates.
• Emphasis on monitoring for heart failure and bladder cancer risk with pioglitazone.
• Updated warnings on lactic acidosis risk with metformin use in renal impairment.

• Store at 20°C to 25°C (68°F to 77°F).
• Protect from moisture, heat, and direct light.
• Keep in tightly closed container.
• Do not freeze.
• Keep out of reach of children.