Adult: Pioglitazone 15 mg and glimepiride 2 mg tab Pioglitazone 30 mg and glimepiride 2 mg tab Pioglitazone 30 mg and glimepiride 4 mg tab
As an adjunct to diet and exercise to improve glycaemic control: Initial dose must be based on patient's current regimen of pioglitazone and/or sulfonylurea. For patients inadequately controlled on pioglitazone monotherapy; patients on sulfonylurea monotherapy (other than glimepiride) or switching from combination therapy of pioglitazone and sulfonylurea (other than glimepiride): Initially, 15 mg/2 mg once daily. Alternatively, 30 mg/2 mg once daily. For patients inadequately controlled on glimepiride monotherapy: Initially, 15 mg/2 mg once daily. Alternatively, 30 mg/2 mg or 30 mg/4 mg once daily. Doses may be gradually titrated according to therapeutic response and tolerability. Max: 45 mg pioglitazone/8 mg glimepiride once daily. Dosage recommendations may vary among countries and individual products (refer to specific product guidelines). Elderly: Start with glimepiride 1 mg daily before initiating pioglitazone + glimepiride therapy; initial dose and dose adjustments of pioglitazone + glimepiride must be conservative.
Special Patient Group
Patients taking strong CYP2C8 inhibitors (e.g. gemfibrozil): Max dose of pioglitazone: 15 mg daily.
Patients with systolic dysfunction: Use the lowest approved dose only after titration from 15 mg to 30 mg pioglitazone has been safely tolerated; monitor closely.
Debilitated or malnourished patients: Start with glimepiride 1 mg daily before initiating pioglitazone + glimepiride therapy; initial dose and dose adjustments of pioglitazone + glimepiride must be conservative.
Renal Impairment
Start with glimepiride 1 mg daily before initiating pioglitazone + glimepiride therapy; initial dose and dose adjustments of pioglitazone + glimepiride must be conservative.
Administration
Should be taken with food. Take w/ 1st main meal of the day.
Contraindications
History of hypersensitivity reaction to sulfonamide derivatives. Established heart failure (NYHA class III or IV); active bladder cancer.
Special Precautions
Patient with systolic dysfunction, oedema, risk factors for CHF; predisposition to hypoglycaemia (e.g. adrenal or pituitary insufficiency, deficient caloric intake; those who have undergone severe or prolonged exercise); history of bladder cancer; G6PD deficiency. Patient exposed to stress-related states (e.g. fever, trauma, infection, surgery). Patient taking strong CYP2C8 inhibitors (e.g. gemfibrozil). Debilitated or malnourished patient. Not intended for the treatment of type 1 diabetes mellitus or diabetic ketoacidosis. Not recommended in patients with symptomatic heart failure. Treatment initiation in patients with clinical evidence of active liver disease or increased ALT >2.5 times ULN at baseline is not recommended. Renal and hepatic impairment. Elderly. Pregnancy and lactation.
Adverse Reactions
Significant: Hypoglycaemia, may cause or exacerbate CHF; oedema (including peripheral oedema); hypersensitivity reactions (e.g. anaphylaxis, angioedema, cutaneous eruptions, Stevens-Johnson syndrome), increased risk of urinary bladder cancer; weight gain; haemolytic anaemia (particularly in patients with G6PD deficiency); increased incidence of bone fractures (especially in women); decreased Hb/haematocrit. Rarely, new-onset or worsening macular oedema with decreased visual acuity. Blood and lymphatic system disorders: Anaemia, leucopenia, agranulocytosis, aplastic anaemia, pancytopenia, thrombocytopenia. Gastrointestinal disorders: Nausea, diarrhoea. Hepatobiliary disorders: Cholestasis, jaundice, hepatitis, hepatic porphyria. Metabolism and nutrition disorders: Hyponatraemia and SIADH. Musculoskeletal and connective tissue disorders: Limb pain. Nervous system disorders: Headache. Renal and urinary disorders: UTI. Respiratory, thoracic and mediastinal disorders: URTI. Skin and subcutaneous tissue disorders: Photosensitivity reactions, porphyria cutanea tarda. Potentially Fatal: Increased CV mortality; severe hypoglycaemia; hepatic failure.
This drug may cause impaired concentration or ability to react due to hypoglycaemia or low blood sugar, if affected, do not drive or operate machinery.
Monitoring Parameters
Obtain LFTs (e.g. ALT, AST, alkaline phosphatase, total bilirubin) before treatment initiation. Measure LFTs immediately in patients who have symptoms that may indicate liver injury (e.g. jaundice, dark urine, right upper abdominal discomfort, fatigue, anorexia). Monitor serum glucose, HbA1c (at least twice yearly in patients with stable glycaemic control and are meeting treatment goals; quarterly in patients with change in therapy and whom treatment goals have not been met); monitor for weight gain. Perform regular ophthalmologic examinations. Assess for signs and symptoms of hypoglycaemia, heart failure (e.g. dyspnoea, oedema, rapid weight gain) and bladder cancer (e.g. urinary urgency, macroscopic haematuria, dysuria).
Overdosage
Glimepiride: Symptoms: Severe hypoglycaemia. Management: For severe cases of hypoglycaemia with seizure, neurological impairment, or coma, administer glucagon or IV glucose. Monitor patient continuously and additional carbohydrate intake may be needed as hypoglycaemia may recur after apparent recovery.
Drug Interactions
Pioglitazone: Increased exposure with strong CYP2C8 inhibitors (e.g. gemfibrozil). Decreased exposure with CYP2C8 inducers (e.g. rifampicin) and topiramate.
Glimepiride: May increase hypoglycaemic effect with other oral antidiabetic agents, insulin, pramlintide, ACE inhibitors, disopyramide, quinolones, tetracyclines, clarithromycin, fibrates, H2-receptor antagonists, propoxyphene, pentoxifylline, somatostatin analogues, anabolic steroids and androgens, fluconazole, miconazole, and drugs that are highly protein-bound (e.g. probenecid, fluoxetine, NSAIDs, salicylates, MAOIs, sulfonamides, coumarins, chloramphenicol). May decrease hypoglycaemic effect with atypical antipsychotic agents (e.g. olanzapine, clozapine), corticosteroids, danazol, glucagon, isoniazid, rifampicin, nicotinic acid, phenothiazines, protease inhibitors, somatropin, barbiturates, phenytoin, laxatives, diazoxide, thiazides and other diuretics, sympathomimetic agents (e.g. salbutamol, epinephrine, terbutaline), thyroid hormones, estrogens and oral contraceptives. May increase or decrease hypoglycaemic effect with clonidine, reserpine, and β-adrenergic blocking agents; signs of hypoglycaemia may be reduced or absent in patients receiving sympatholytic agents. Concurrent use with colesevelam may decrease the serum concentration of glimepiride.
Food Interaction
Increased risk of hypoglycaemia with alcohol.
Action
Description: Mechanism of Action: Pioglitazone, a thiazolidinedione antidiabetic agent, acts mainly by enhancing insulin sensitivity in target tissues, as well as decreasing hepatic gluconeogenesis. It is a selective and potent agonist for peroxisome proliferator-activated receptor-γ (PPARγ) that increases transcription of certain insulin-responsive genes. Its mechanism of action is dependent on the presence of insulin for activity.
Glimepiride, a sulfonylurea antidiabetic agent, stimulates insulin release from the pancreatic β-cells. It reduces glucose output from the liver and enhances insulin sensitivity at peripheral target sites. Duration: Glimepiride: 24 hours. Pharmacokinetics: Absorption: Pioglitazone: Rapidly absorbed. Bioavailability: >80%. Time to peak plasma concentration: Approx 2 hours; delayed with food.
Glimepiride: Completely absorbed from the gastrointestinal tract. Time to peak plasma concentration: 2-3 hours. Distribution: Pioglitazone: Plasma protein binding: >99%, primarily to albumin.
Glimepiride: Plasma protein binding: >99.5%. Metabolism: Pioglitazone: Extensively metabolised in the liver via hydroxylation and oxidation mainly by CYP2C8 and, to a lesser extent, CYP3A4 into active (M-III and M-IV) and inactive metabolites.
Glimepiride: Extensively metabolised in the liver via oxidation by CYP2C9 into cyclohexyl hydroxy methyl derivative (M1) metabolite, which is further metabolised by one or several cytosolic enzymes into inactive metabolite, carboxyl derivative (M2). Excretion: Pioglitazone: Via urine (approx 15-30%); faeces (as metabolites). Elimination half-life: 3-7 hours (pioglitazone); 16-24 hours (M-III and M-IV).
Glimepiride: Via urine (approx 60%, 80-90% as M1 and M2); faeces (40%, 70% as M1 and M2). Elimination half-life: 5-9 hours.
Chemical Structure
Pioglitazone Source: National Center for Biotechnology Information. PubChem Compound Summary for CID 4829, Pioglitazone. https://pubchem.ncbi.nlm.nih.gov/compound/Pioglitazone. Accessed Nov. 23, 2023.
Glimepiride Source: National Center for Biotechnology Information. PubChem Compound Summary for CID 3476, Glimepiride. https://pubchem.ncbi.nlm.nih.gov/compound/Glimepiride. Accessed Nov. 23, 2023.
Storage
Store 15-30°C. Protect from humidity and moisture.
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