Pioglitazone + metformin

Oral
Type 2 diabetes mellitus
Adult: Each immediate-release tab contains pioglitazone 15 mg and metformin 500 mg or pioglitazone 15 mg and metformin 850 mg: Initially, 15 mg/500 mg bid or 15 mg/850 mg once daily. Patients inadequately controlled on metformin monotherapy: Initially, 15 mg/500 mg bid or 15 mg/850 mg 1-2 times daily, depending on current metformin dose. Patients inadequately controlled on pioglitazone monotherapy: Initially, 15 mg/500 mg bid or 15 mg/850 mg once daily. Max: Pioglitazone 45 mg and metformin 2,550 mg daily. Each extended-release tab contains pioglitazone 15 mg and metformin 1,000 mg or pioglitazone 30 mg and metformin 1,000 mg: Initially, 15 mg/1,000 mg or 30 mg/1,000 mg once daily. Patients inadequately controlled on metformin or pioglitazone monotherapy: 15 mg/1,000 mg bid or 30 mg/1,000 mg once daily. Max: Pioglitazone 45 mg and metformin 2,000 mg daily. Doses may be titrated gradually according to response.
Renal impairment:

CrCl (ml/min)	Dosage Recommendation
<60	Contraindicated.

Hepatic impairment: Contraindicated.

Special Populations: Patient taking pioglitazone and metformin w/ an insulin secretagogue (e.g. sulfonylurea): Decrease insulin secretagogue dose. Patient taking pioglitazone and metformin w/ insulin: Decrease insulin dose by 10-25%. Patient taking pioglitazone and metformin w/ strong CYP2C8 inhibitors: Max: 15 mg/850 mg daily (immediate-release tab) or 15 mg/1,000 mg daily (extended-release tab).

Current or history of cardiac failure (New York Heart Association stage I to IV), active or history of bladder cancer, uninvestigated macroscopic haematuria; type 1 DM, diabetic ketoacidosis or diabetic pre-coma; acute or chronic disease which may cause tissue hypoxia (e.g. cardiac or resp failure, recent MI, shock); conditions which may alter renal function (e.g. dehydration, severe infection, shock). Acute alcohol intoxication. Hepatic or renal impairment (CrCl <60 mL/min). Lactation. Intravascular admin of iodinated contrast agents.

Patient w/ oedema, anaemia. Premenopausal, anovulatory women. Pregnancy. Patient Counselling This drug may cause visual disturbance, if affected, do not drive or operate machinery. Monitoring Parameters Monitor HbA_1c, serum glucose; signs and symptoms of oedema or heart failure, bladder cancer; liver enzymes, haematologic parameters, renal function; vit B12 and folate if anaemia is present. Routine ophth examination.

Oedema, wt gain, hypoglycaemia, macular oedema, bone fractures, anaemia, upper resp infection, headache, diarrhoea, nausea, UTI, sinusitis.
Potentially Fatal: Lactic acidosis, CHF, bladder cancer, hepatic failure.

May impair vit B12 absorption. Increased plasma levels w/ strong CYP2C8 inhibitors (e.g. gemfibrozil). Decreased plasma levels w/ CYP2C8 inducers (e.g. rifampicin). Reduced metabolism w/ cationic drugs eliminated by renal tubular secretion.

Alcohol may increase the risk of lactic acidosis, avoid use.

Pioglitazone reduces hepatic glucose output and increases peripheral glucose disposal by increasing insulin sensitivity thru activation of specific nuclear receptors peroxisome proliferator activated receptor-γ (PPAR-γ). Metformin decreases hepatic glucose production by inhibiting gluconeogenesis and glycogenolysis, delays intestinal glucose absorption and improves insulin sensitivity by increasing peripheral glucose uptake and utilisation.
Absorption: Pioglitazone: Rapidly absorbed from the GI tract. Bioavailability: >80%. Time to peak plasma concentration: W/in 2 hr. Metformin: Slowly and incompletely absorbed from the GI tract. Bioavailability: Approx 50-60%.
Distribution: Pioglitazone: Plasma protein binding: >99%. Metformin: Crosses the placenta and enters breast milk.
Metabolism: Pioglitazone: Extensively metabolised by CYP2C8 isoenzyme to both active and inactive metabolites. Metformin: Not metabolised in the liver.
Excretion: Pioglitazone: Via urine and faeces. Plasma half-life: Up to 7 hr. Metformin: Via urine. Elimination half-life: Approx 2-6 hr.

Oral: Store at 25°C. Protect from light and humidity.

Antidiabetic Agents

A10BG03 - pioglitazone ; Belongs to the class of thiazolidinediones. Used in the treatment of diabetes.
A10BA02 - metformin ; Belongs to the class of biguanides. Used in the treatment of diabetes.