Schedule H

Oral

• Tablets: 250 mg, 500 mg, 750 mg, 1000 mg, 1500 mg

• Dispersible tablets: 150 mg (paediatric, under NTEP)

• Oral suspension: 250 mg/5 mL (limited availability)

• Fixed-dose combinations (FDCs): Multiple adult and paediatric formulations with rifampicin (R), isoniazid (H), and ethambutol (E) under NTEP

INDICATIONS + DOSING — FOR CLINICIAN USE ONLY

Primary Indications (Approved / Standard in India)

Pulmonary and Extrapulmonary Tuberculosis — Intensive Phase

Pyrazinamide is an essential component of the standard first-line 4-drug regimen (HRZE) during the initial 2-month intensive phase of TB treatment. It provides potent sterilising activity against semi-dormant bacilli in acidic environments.

Adult Dosing (per NTEP/Index TB Guidelines):

Weight-band Based Daily Dosing:

Body Weight Daily Dose Formulation

30–39 kg 1000 mg once daily 2 × 500 mg tablets

40–54 kg 1500 mg once daily 3 × 500 mg tablets

55–69 kg 1500 mg once daily 3 × 500 mg tablets

≥70 kg 2000 mg once daily 4 × 500 mg tablets

Alternative mg/kg Dosing:

Parameter Recommendation

Starting dose 20–25 mg/kg/day once daily (round to nearest weight band)

Titration Not applicable

Usual maintenance dose 20–25 mg/kg/day once daily

Maximum dose 2000 mg/day (2 g/day)

Duration: 2 months (intensive phase only); NOT used in continuation phase

Clinical Notes:

• Always use as part of combination therapy (never as monotherapy)

• Preferably use fixed-dose combinations (FDCs) for better compliance and reduced resistance development

• Administer once daily, preferably in the morning on empty stomach or with light meal

• Daily regimen preferred over intermittent regimen per current NTEP guidelines

• Monitor for hepatotoxicity especially during first 2 months

Secondary Indications — Adults (Off-label)

Not applicable — Pyrazinamide is not routinely used off-label in Indian TB practice. Its use is restricted to tuberculosis treatment as part of standard regimens.

PAEDIATRIC DOSING (Specialist Only)

Primary Indications (Approved / Standard in India)

Pulmonary and Extrapulmonary Tuberculosis — Intensive Phase

Used as part of HRZ(E) combination during intensive phase (2 months) per IAP and NTEP paediatric TB guidelines.

Weight-band Based Dosing (per NTEP Paediatric Guidelines):

Body Weight Daily Dose Pyrazinamide Component

4–7 kg 150 mg once daily 1 dispersible tablet (150 mg)

8–11 kg 300 mg once daily 2 dispersible tablets

12–15 kg 450 mg once daily 3 dispersible tablets

16–24 kg 600 mg once daily 4 dispersible tablets

25–29 kg 750 mg once daily 5 dispersible tablets OR tablet formulation

30–39 kg 1000 mg once daily Adult tablet formulation

≥40 kg Use adult weight-band dosing Adult tablet formulation

Alternative mg/kg Dosing:

Parameter Recommendation

Starting dose 30–40 mg/kg/day once daily

Titration Not applicable

Usual maintenance dose 35 mg/kg/day once daily (optimal)

Maximum dose 2000 mg/day

Duration: 2 months (intensive phase)

Clinical Notes:

• Use paediatric dispersible FDC tablets (available under NTEP) whenever possible

• Dispersible tablets should be dissolved in small amount of water before administration

• Higher mg/kg dosing in children compared to adults due to faster metabolism

• Weight should be measured at each visit and dose adjusted accordingly

Minimum Age Statement: May be used from birth in neonates with TB (congenital or acquired) under specialist supervision. Generally recommended from 3 months of age as part of standard paediatric TB regimen.

Safety Monitoring:

• Baseline and monthly LFTs in high-risk children (HIV co-infection, malnutrition, hepatic disease)

• Monitor for symptoms of hepatotoxicity (anorexia, jaundice, vomiting, abdominal pain)

• Monitor for arthralgia (less common in children than adults)

• Clinical assessment at each visit

Secondary Indications — Paediatrics (Off-label)

Not applicable — No established off-label paediatric indications.

30 No dose adjustment required; use standard weight-band dosing

<30 (not on dialysis) Reduce frequency: 25–35 mg/kg three times weekly (e.g., Monday, Wednesday, Friday)

Haemodialysis 25–35 mg/kg three times weekly; administer after dialysis session

Peritoneal dialysis 25–35 mg/kg three times weekly

Notes:

• Pyrazinamide is significantly removed by haemodialysis

• Monitor serum uric acid more frequently in renal impairment (accumulation of pyrazinoic acid)

• Monitor for hepatotoxicity signs

• Coordinate with nephrologist for optimal dialysis-day dosing

Notes:

• Pyrazinamide is the most hepatotoxic of the first-line TB drugs

• Pre-existing liver disease significantly increases hepatotoxicity risk

• If transaminases rise >3× ULN with symptoms OR >5× ULN without symptoms, discontinue all hepatotoxic TB drugs (H, R, Z)

• Rechallenge protocols available under NTEP for drug-induced hepatotoxicity

• Known hypersensitivity to pyrazinamide

• Acute hepatic disease (acute hepatitis, jaundice, significantly elevated transaminases)

• Severe hepatic impairment (Child-Pugh C) or decompensated liver disease

• Acute gout attack (current flare)

• Severe hyperuricaemia with gouty arthritis

• Pre-existing chronic liver disease (even compensated) — increased hepatotoxicity risk; close monitoring required

• History of gout or asymptomatic hyperuricaemia — may precipitate acute gouty arthritis

• HIV/AIDS co-infection — increased hepatotoxicity risk; monitor LFTs frequently

• Chronic alcohol use — additive hepatotoxicity

• Malnutrition — reduced hepatic reserve; increased toxicity risk

• Concurrent use of other hepatotoxic drugs (including other ATT drugs, antiretrovirals, antiepileptics)

• Diabetes mellitus — pyrazinamide may worsen glycaemic control; monitor glucose

• Porphyria — may exacerbate

• Renal impairment — dose reduction required; increased uric acid accumulation

• Elderly patients — increased susceptibility to hepatotoxicity

Parameter Recommendation

Safety Category Generally considered safe in pregnancy; used routinely as part of standard HRZE regimen per Indian TB guidelines; limited human data but extensive clinical experience without documented teratogenicity

Preferred Alternatives No alternative required; pyrazinamide is included in standard pregnancy TB regimen in India

When to Use Throughout intensive phase (2 months) as part of first-line regimen; benefits of adequate TB treatment outweigh theoretical risks

Monitoring Baseline and monthly LFTs; standard antenatal monitoring; fetal growth surveillance

Notes:

• WHO and Indian NTEP guidelines recommend pyrazinamide in pregnancy

• Untreated TB in pregnancy carries significant maternal and fetal risks

• Ensure adequate pyridoxine supplementation (along with isoniazid)

Parameter Recommendation

Breastfeeding Compatibility Compatible with breastfeeding; continue breastfeeding during TB treatment

Drug Levels in Milk Low (small amounts excreted; insufficient to provide therapeutic or prophylactic effect in infant)

Preferred Alternatives Not required; pyrazinamide is acceptable during lactation

Infant Monitoring Monitor for jaundice, feeding difficulties, irritability (unlikely); infant should receive isoniazid preventive therapy (IPT) if mother is smear-positive

Parameter Recommendation

Starting dose Use lower end of weight-band dosing (20 mg/kg/day rather than 25 mg/kg/day)

Titration Not applicable

Maximum dose 1500 mg/day preferred (rather than 2000 mg) unless body weight clearly warrants higher dose

Additional Risks Increased hepatotoxicity risk; higher incidence of hyperuricaemia and gout; age-related renal impairment affecting drug clearance; polypharmacy increasing interaction risk

Monitoring Baseline and biweekly LFTs during intensive phase; serum uric acid if symptomatic; renal function assessment

Interacting Drug Mechanism/Effect Management

Isoniazid + Rifampicin (concurrent) All three drugs (H, R, Z) have hepatotoxic potential; additive/synergistic hepatotoxicity when used together Standard combination in TB treatment; monitor LFTs at baseline and regularly; educate patient about hepatotoxicity symptoms; discontinue all three if significant hepatotoxicity develops

Probenecid Inhibits renal tubular secretion of pyrazinamide metabolites; increased pyrazinamide levels and toxicity risk; also antagonises uricosuric effect of probenecid Avoid combination if possible; if essential, monitor for pyrazinamide toxicity

Zidovudine (AZT) Additive hepatotoxicity; bone marrow suppression Monitor LFTs and FBC frequently in HIV-TB co-infected patients; consider alternative ART if possible

Live vaccines (BCG) Pyrazinamide (as part of ATT) may reduce immune response Avoid BCG during active TB treatment; vaccination not typically required in patients with active TB

Interacting Drug Effect Management

Allopurinol Pyrazinamide causes hyperuricaemia; allopurinol may be needed for symptomatic gout; some antagonism of uric acid-lowering effect May use allopurinol if symptomatic gout develops; asymptomatic hyperuricaemia usually does not require treatment

Other hepatotoxic drugs (methotrexate, valproate, azole antifungals, statins) Additive hepatotoxicity Monitor LFTs more frequently; avoid non-essential hepatotoxic medications during intensive phase

Oral hypoglycaemic agents Pyrazinamide may worsen glycaemic control Monitor blood glucose more frequently in diabetic patients; adjust antidiabetic dose if needed

Ciclosporin Possible decreased ciclosporin levels (uncertain mechanism) Monitor ciclosporin levels in transplant patients on TB treatment

Anticoagulants (warfarin) Possible alteration of INR (limited data) Monitor INR more frequently during ATT initiation

Ethionamide Additive hepatotoxicity Use together only when essential (MDR-TB regimens); close LFT monitoring

• Hyperuricaemia (very common; usually asymptomatic; dose-related)

• Arthralgia (non-gouty joint pain)

• Nausea

• Vomiting

• Anorexia

• Malaise

• Hepatotoxicity (elevated transaminases — usually mild and reversible)

• Flushing

• Dysuria

Adverse Effect Clinical Significance

Severe hepatotoxicity / Hepatic failure Most concerning adverse effect; may be fatal; typically occurs in first 2 months; presents with jaundice, hepatomegaly, coagulopathy; discontinue pyrazinamide (and other hepatotoxic ATT) immediately if ALT >3× ULN with symptoms or >5× ULN without symptoms

Acute gouty arthritis Painful monoarthritis (typically great toe); occurs due to hyperuricaemia; treat with NSAIDs or colchicine; pyrazinamide can usually be continued if gout controlled

Severe polyarthralgia Non-gouty; may require discontinuation if debilitating

Hypersensitivity reactions Rash, fever, eosinophilia; discontinue if severe

Sideroblastic anaemia Rare; pyridoxine may help

Photosensitivity Rare; advise sun protection

Interstitial nephritis Rare

Baseline:

• Liver function tests (AST, ALT, bilirubin, ALP)

• Serum uric acid (optional; useful if history of gout)

• Renal function (serum creatinine, eGFR)

• Complete blood count

• Blood glucose (in diabetic patients)

• Clinical assessment for pre-existing liver disease, gout, renal impairment

After Initiation/During Intensive Phase:

• LFTs: At 2 weeks, then monthly during intensive phase for standard-risk patients

• LFTs: Weekly or biweekly in high-risk patients (HIV, elderly, pre-existing liver disease, alcohol use)

• Clinical assessment for hepatotoxicity symptoms (anorexia, nausea, vomiting, jaundice, abdominal pain, unexplained fatigue) at each visit

• Uric acid: Only if symptoms of gout develop (routine monitoring not required for asymptomatic hyperuricaemia)

• Joint examination if arthralgia reported

When to Discontinue:

• AST/ALT >5× ULN (without symptoms)

• AST/ALT >3× ULN with hepatotoxicity symptoms (nausea, vomiting, jaundice)

• Total bilirubin >2× ULN

• Signs of hepatic failure

Long-term:

• Not applicable — pyrazinamide used only during 2-month intensive phase

Single-drug Formulations:

• Zinamide® (Lupin)

• Pyzina® (Svizera)

• P-Zide® (Macleods)

• Tebrazid® (Cadila)

• Rifazone-Z® (various)

Fixed-Dose Combinations (FDCs) — extensively used under NTEP:

• AKT-4® (Lupin) — HRZE combination

• Forecox® (Lupin) — HRZE combination

• R-Cinex Z® (Lupin) — HRZ combination

• Mycobutol Plus® (Cadila)

• Risorine® (various)

• Paediatric dispersible FDCs (under NTEP supply)

Note: FDCs preferred over individual drugs for better compliance and reduced resistance development.

Paediatric dispersible FDC Supplied free under NTEP

• Included in NLEM 2022

• NPPA price-controlled

• Provided FREE under National Tuberculosis Elimination Programme (NTEP) through government health facilities

• Available in private market with significant price variation between brands

• FDCs preferred: Always use fixed-dose combinations rather than individual drugs whenever possible — improves compliance, reduces dosing errors, and prevents resistance development

• Intensive phase only: Pyrazinamide is used ONLY during the 2-month intensive phase; it is NOT continued in the continuation phase — a common prescribing error

• Hepatotoxicity vigilance: Most hepatotoxicity occurs in the first 2 months (when pyrazinamide is used); high-risk patients (elderly, HIV, alcohol use, pre-existing liver disease) require more frequent LFT monitoring

• Hyperuricaemia is expected: Asymptomatic uric acid elevation is very common (occurs in majority of patients) and does NOT require treatment; only treat if symptomatic gout develops

• Rechallenge protocol: If hepatotoxicity occurs, pyrazinamide can often be successfully reintroduced using the NTEP rechallenge protocol; however, if severe hepatotoxicity occurred, pyrazinamide may need to be permanently omitted from the regimen

• Renal dosing: In ESRD/dialysis, use thrice-weekly dosing post-dialysis — daily dosing leads to drug accumulation

pyrazinamide; tuberculosis; first-line ATT; antitubercular; hepatotoxicity; hyperuricaemia; intensive phase; NTEP; NLEM; pregnancy-safe; paediatric-TB

RxIndia v1.0 — 10 Jan 2025

• CDSCO approved prescribing information

• Indian Pharmacopoeia (IP)

• National Formulary of India (NFI)

• National List of Essential Medicines (NLEM 2022)

• Index TB Guidelines (NTEP India)

• ICMR Guidelines for Tuberculosis

• AIIMS TB Management Protocol

• Indian Academy of Pediatrics (IAP) Guidelines on Childhood TB

• API Textbook of Medicine

• Goodman & Gilman's The Pharmacological Basis of Therapeutics

• WHO Consolidated Guidelines on Tuberculosis