Schedule H

Oral

• Tablets: 7.5 mg, 15 mg, 30 mg, 45 mg

INDICATIONS + DOSING — FOR CLINICIAN USE ONLY

Primary Indications (Approved / Standard in India)

Type 2 Diabetes Mellitus (Monotherapy or Combination Therapy)

Parameter Details

Starting dose 15 mg once daily (with or without food)

Titration Increase to 30 mg once daily after 4–8 weeks if glycaemic response inadequate

Usual maintenance dose 15–30 mg once daily

Maximum dose 45 mg once daily

Clinical Notes:

• May be used as monotherapy when metformin is contraindicated or not tolerated

• Commonly combined with metformin, sulfonylureas, DPP-4 inhibitors, or insulin

• Onset of action is gradual; full glycaemic effect may take 8–12 weeks

• Preferred in patients with insulin resistance phenotype (central obesity, NAFLD, PCOS features)

• Not indicated for Type 1 diabetes or diabetic ketoacidosis

Secondary Indications – Adults Only (Off-label)

Indication Dose Duration Notes

Non-alcoholic Steatohepatitis (NASH) 30–45 mg once daily Minimum 6 months; long-term if benefit sustained OFF-LABEL; Specialist only (Hepatologist/Endocrinologist); Evidence: PIVENS trial and meta-analyses show histological improvement in biopsy-proven NASH with fibrosis

Polycystic Ovary Syndrome (PCOS) with insulin resistance 15–30 mg once daily 3–6 months initially OFF-LABEL; Specialist only (Endocrinologist/Gynaecologist); Evidence: Limited Indian data; used in PCOS patients who cannot tolerate metformin

Lipodystrophy syndromes 30–45 mg once daily Long-term OFF-LABEL; Specialist only; Evidence: Case series and specialist practice

PAEDIATRIC DOSING (Specialist Only)

Primary Indications

Not applicable — Pioglitazone is NOT APPROVED for use in patients below 18 years of age. Safety and efficacy have not been established in the paediatric population.

Secondary Indications – Paediatrics (Off-label)

Not applicable — No evidence-based paediatric indication exists. Use in children or adolescents is not recommended.

Age Restriction: NOT RECOMMENDED below 18 years except in exceptional circumstances under paediatric endocrinologist supervision in clinical trial settings only.

Mandatory: Baseline liver function tests (ALT, AST) required before initiation. Do not initiate if ALT >2.5× upper limit of normal (ULN).

• Hypersensitivity to pioglitazone or any excipient

• Active liver disease or ALT >2.5× ULN at baseline

• History of drug-induced hepatotoxicity

• Heart failure (NYHA Class III or IV)

• Active bladder cancer or history of bladder cancer

• Uninvestigated macroscopic haematuria

• Diabetic ketoacidosis

• Pregnancy

• Lactation

• Severe hepatic impairment (Child-Pugh C)

• History of heart failure (NYHA Class I–II) — monitor closely for fluid retention; consider dose reduction or discontinuation if symptoms worsen

• Concurrent use with insulin — significantly increased risk of oedema and heart failure exacerbation

• Postmenopausal women — increased fracture risk (distal limbs, spine)

• Elderly patients — higher susceptibility to fluid retention and fractures

• Pre-existing macular oedema or diabetic retinopathy — monitor visual symptoms

• Patients with risk factors for bladder cancer (smoking, prior pelvic radiation, chronic UTIs)

• Anaemia — pioglitazone may cause haemodilution

• Weight gain — dose-related; use lowest effective dose

• Women using oral contraceptives — may reduce contraceptive efficacy

Aspect Details

Overall safety Contraindicated; limited human data; animal studies show embryotoxicity

Preferred alternatives Insulin (first-line); metformin may be continued under specialist guidance

When it may be used Should not be used during pregnancy

Pre-conception advice Discontinue pioglitazone before planned conception; switch to insulin

Monitoring if exposed Fetal growth monitoring; maternal glycaemic control with alternative agents

Aspect Details

Compatibility Not compatible with breastfeeding

Expected levels in milk Unknown; excreted in animal milk

Preferred alternatives Insulin (first-line); metformin (compatible with breastfeeding)

If use unavoidable Advise against breastfeeding during therapy

Infant monitoring Not applicable — drug should not be used during lactation

Aspect Recommendation

Starting dose 15 mg once daily

Titration Slower than younger adults; reassess after 8–12 weeks

Maximum dose Limit to 30 mg once daily; avoid 45 mg in elderly

Additional risks Fluid retention, heart failure exacerbation, bone fractures (especially in women), weight gain, falls

Pre-initiation assessment Cardiac function (clinical exam, consider echocardiography if history of CVD), bone health assessment, renal function

Monitoring Regular weight checks, peripheral oedema assessment, fracture risk review annually

Interacting Drug Effect Recommendation

Insulin Markedly increased risk of heart failure exacerbation and peripheral oedema Avoid combination if possible; if essential, use lowest doses of both and monitor closely for fluid retention

Gemfibrozil Strong CYP2C8 inhibitor; increases pioglitazone AUC by ~3-fold Limit pioglitazone to maximum 15 mg once daily; monitor for adverse effects

Rifampicin Strong CYP2C8 inducer; reduces pioglitazone levels significantly May reduce glycaemic efficacy; consider alternative antidiabetic or dose adjustment with close monitoring

Interacting Drug Effect Recommendation

Sulfonylureas Additive hypoglycaemic effect Monitor blood glucose closely; consider reducing sulfonylurea dose

Metformin Additive glucose-lowering effect Generally safe combination; monitor for hypoglycaemia

NSAIDs May exacerbate fluid retention Monitor for oedema; avoid prolonged concurrent use

Loop diuretics (furosemide, torasemide) Competing effects on fluid status Monitor fluid balance carefully

Ketoconazole, Fluconazole Moderate CYP2C8/3A4 inhibitors; may increase pioglitazone exposure Monitor for adverse effects

Oral contraceptives (ethinylestradiol-containing) Pioglitazone may reduce contraceptive hormone levels Counsel regarding potential reduced contraceptive efficacy; consider additional barrier method

Trimethoprim Weak CYP2C8 inhibitor; may increase pioglitazone levels Monitor; usually clinically insignificant

• Weight gain (dose-related; typically 2–4 kg)

• Peripheral oedema

• Upper respiratory tract infection

• Headache

• Myalgia

• Sinusitis

• Pharyngitis

• Hypoglycaemia (when combined with insulin or sulfonylureas)

• Mild anaemia (haemodilution effect)

Adverse Effect Action Required

Congestive heart failure (new onset or exacerbation) Discontinue immediately; diuretic therapy and cardiology referral

Hepatotoxicity (ALT >3× ULN with symptoms) Discontinue immediately; hepatology evaluation; do not rechallenge

Bladder cancer Rare association with prolonged use; discontinue if diagnosed; urological evaluation

Bone fractures (distal limb, vertebral) Increased risk in women; consider discontinuation if recurrent fractures; bone health evaluation

Macular oedema Rare; discontinue and refer to ophthalmology if visual symptoms (blurred vision, decreased acuity) develop

Severe hypoglycaemia When combined with insulin/sulfonylureas; adjust concomitant drug doses

Anaphylaxis/Angioedema Rare; immediate discontinuation and emergency management

Baseline LFTs (ALT, AST), FPG/HbA1c, weight, clinical cardiac assessment, peripheral oedema check, renal function Before initiation

After initiation LFTs, weight, oedema assessment, symptoms of heart failure Every 3 months for first year

After initiation HbA1c 3 months after starting or dose change

Stable long-term therapy LFTs Every 6–12 months

Stable long-term therapy HbA1c Every 3–6 months

Stable long-term therapy Weight, oedema, cardiac symptoms At each visit

Special monitoring Bone health assessment (DEXA) Annually in postmenopausal women and elderly on long-term therapy

As needed Ophthalmic evaluation If visual symptoms develop

As needed Urinalysis If haematuria or bladder symptoms

Single-ingredient formulations:

• Pioz (USV)

• Piozone (Cipla)

• Pioglit (Sun Pharma)

• Actos (Takeda/Abbott)

• Piosafe (Glenmark)

• Pioglar (Torrent)

Fixed-Dose Combinations:

Note: Pioglitazone 15 mg and 30 mg are included in NLEM 2022; NPPA price-controlled formulations available.

1. Patient selection: Best suited for patients with insulin resistance phenotype — central obesity, features of metabolic syndrome, NAFLD, or PCOS. Avoid in patients with heart failure risk or fragility fracture history.

1. Slow onset: Full glycaemic effect takes 8–12 weeks; counsel patients about delayed response and avoid premature dose escalation.

1. Weight and oedema management: Weight gain is dose-related and largely due to fluid retention and subcutaneous fat redistribution. Use lowest effective dose; consider combining with metformin to offset weight gain.

1. Fracture risk: Counsel postmenopausal women and elderly patients about increased fracture risk. Consider baseline DEXA and annual bone health assessment in long-term users.

1. Heart failure vigilance: Do not use in NYHA Class III–IV heart failure. In Class I–II, monitor closely and discontinue at first sign of worsening symptoms (dyspnoea, oedema, weight gain >2–3 kg in a week).

1. Bladder cancer screening: Avoid in patients with active or past bladder cancer. Investigate unexplained haematuria before and during therapy. Long-term use (>2 years) may carry slightly increased bladder cancer risk.

Type 2 diabetes; thiazolidinedione; insulin sensitizer; NASH; heart failure caution; bladder cancer; bone fracture risk; NLEM India; hepatic monitoring; weight gain

RxIndia v1.0 — 25 Jan 2025

• CDSCO Product Database

• Indian Pharmacopoeia (latest edition)

• National List of Essential Medicines (NLEM) 2022

• API Textbook of Medicine (11th edition)

• ICMR Guidelines for Management of Type 2 Diabetes (2023)

• AIIMS Pharmacology Internal Prescribing Manual

• Goodman & Gilman's The Pharmacological Basis of Therapeutics

• PIVENS Trial (for NASH off-label evidence)

• PROactive Trial (cardiovascular outcomes data)