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Antitubercular fixed-dose combination (4FDC) Pregnancy: UK SPC section 4.6: 'Treatment should be considered on a case by case basis after benefit of medicinal product combination has been assessed. Consequently, Rimstar could be given during pregnancy if the potential benefit for the mother is judged to outweigh the potential risk to the foetus.' Component notes: rifampicin is teratogenic in animals at very high doses, crosses the placenta, and 'administration of rifampicin during the last few weeks of pregnancy can cause postnatal haemorrhage in the mother and newborn infant'; isoniazid crosses the placenta and 'might exert neurotoxic effects on the child'; no reproductive studies exist for pyrazinamide; ethambutol crosses the placenta and is teratogenic in animals. Two explicit actions are stated: 'In case of third trimester exposure, maternal administration of oral phytomenadione (vitamin K) during the last month of pregnancy and neonatal administration at delivery are recommended' and 'Supplementation of pyridoxine (vitamin B6) is recommended during pregnancy'. Breast-feeding: all four drugs pass into breast milk and although 'no undesirable effects on breast-fed infants have been observed', breast-feeding 'is not recommended in view of the theoretical possibility of neurotoxic effects due to isoniazid and ethambutol'.

Rifampicin with ethambutol, isoniazid and pyrazinamide

Brand names: Voractiv

A four-drug oral fixed-dose combination providing the standard intensive (initial) phase of treatment for active tuberculosis, combining rifampicin, ethambutol, isoniazid and pyrazinamide in one tablet to aid adherence.

Adult dose

Dose: Initial intensive phase of anti-tuberculous treatment, adults — the four-drug fixed-dose combination tablet in the ratio rifampicin 150 mg + isoniazid 75 mg + pyrazinamide 400 mg + ethambutol hydrochloride 275 mg (HRZE), dosed by bodyweight as a single daily dose: 30 to 39 kg = 2 tablets; 40 to 54 kg = 3 tablets; 55 to 70 kg = 4 tablets; over 70 kg = 5 tablets. SCOPE: this is the INITIAL INTENSIVE PHASE only — the SPC states the product 'is a fixed combination product intended for use in the initial intensive phase of anti-tuberculous treatment' and 'should be administered on a daily basis throughout the 2 month initial phase of treatment'. Continuation-phase regimens in the same table use DIFFERENT products (rifampicin with isoniazid, or separate drugs) and are not this page's product.
Route: Oral. 'The tablets should be given as a single dose (number of tablets depending on the patient's bodyweight...), in a fasting state at least 1 hour before a meal.'
Frequency: Once daily, every day throughout the 2 month initial phase
Max: Maximum 5 tablets once daily — the highest banded dose in the SPC weight table, for patients over 70 kg. No higher tablet count is given for any bodyweight, and the product 'should only be used when the fixed ratio... will permit treatment of an individual patient in line with official recommendations and practice'.
Verbatim source wording (UK SPC section 4.2, Table 2 'WHO-recommended number of tablets with fixed-dose combinations of anti-TB drugs in adults'), initial phase, daily, HRZE (75 mg+150 mg+400 mg+275 mg) for 2 months, by patient bodyweight 30-39 / 40-54 / 55-70 / >70 kg: '2 3 4 5' tablets. SUPERVISION: 'Rimstar should be administered under the supervision of a physician trained in the management of tuberculosis.' 'The recommended dose and dosage schedules... are based on WHO guidelines' and 'may differ from recommendations on the use of anti-tuberculosis agents given in other official guidance.' EXTENDED INTENSIVE PHASE: the same table carries a further HRZE row of '2 3 4 5' tablets for 1 additional month, footnoted as applying to 'patients with previously treated sputum smear-positive pulmonary tuberculosis: relapse, treatment after interruption, treatment failure, according to the category II of WHO recommendations'. ADDITIONAL DRUGS: 'When indicated, other anti-tuberculous medicinal products such as streptomycin may be added in the initial phase of treatment.' PER-COMPONENT WHO RANGES (Table 1, mg/kg daily, quoted for cross-checking the tablet count against the patient's weight — these are ranges for the individual drugs, NOT a dose for the combination tablet): isoniazid 5 (4-6); rifampicin 10 (8-12); pyrazinamide 25 (20-30); streptomycin 15 (12-18); ethambutol 15 (15-20). ⚠️ INTERRUPTION RULE (section 4.2): 'If initial intensive phase treatment with Rimstar is interrupted for any reason including non-compliance, a fixed drug combination product such as Rimstar is contraindicated for the resumption of treatment. Rifampicin, isoniazid, pyrazinamide and ethambutol hydrochloride must be administered separately for the resumption of treatment, because rifampicin needs to be reintroduced at a lower dose.' ⚠️ ACETYLATOR STATUS (section 4.4): 'In cases of known acetylation phenotypes, patients with extremely fast or extremely slow acetylating capability should receive the four components separately in order to facilitate dose adjustment of isoniazid.' ELDERLY: 'No special dosage regimen is necessary, but concurrent hepatic and/or renal insufficiency should be taken into account. Supplementation of pyridoxine (vitamin B6) may be useful.' Some sections of the product information we used were incomplete — check the full SPC.

Paediatric dose

Route: Oral
Frequency: Not applicable — no paediatric regimen for this fixed-dose combination is given
Max: Not applicable — the product is not a suitable dosage form below 30 kg
NO PAEDIATRIC DOSE IS PUBLISHED, and none has been derived. Verbatim source wording (UK SPC section 4.2, Paediatric population): 'Rimstar is not a suitable dosage form for use in the treatment of children with a body weight of less than 30 kg. Rimstar is not recommended in children under 8 years of age because of risk of aspiration and possible difficulties in evaluation of changes of visual acuity.' The same restriction is repeated for adults: 'Rimstar is not a suitable dosage form for use in the treatment of patients with a body weight of less than 30 kg.' Section 4.4 adds that visual disturbances caused by the ethambutol component 'may be difficult to diagnose in young children', and that in children 'the presentation of a rash can be mistaken for the underlying infection'. A child of 8 years or older weighing 30 kg or more falls inside the adult weight-band table above. For any child outside that, use single-agent anti-tuberculous products and verify doses against a children's formulary and current national TB guidance.

Dose adjustments

Renal

'Rimstar should be used with caution in patients with moderate renal impairment (creatinine clearance 30 - 60 ml/min).' 'Rimstar is contra-indicated in patients with severe renal impairment (creatinine clearance < 30 ml/min).' No adjusted tablet count is given. (UK SPC section 4.2 and section 4.3)

Hepatic

'Rimstar should be used with caution and under strict medical supervision in impaired liver function.' 'Rimstar is contraindicated in patients with a history of drug induced hepatitis and in patients with acute liver diseases.' No adjusted tablet count is given. (UK SPC section 4.2 and section 4.3)

Dose independently re-sourced from UK Summary of Product Characteristics (SPC) via the eMC; US FDA prescribing information (openFDA / DailyMed) — cross-check; US labelling may differ from UK — clinician-reviewed. Always confirm against the product SmPC and your local formulary before prescribing.

Contraindications

  • Hypersensitivity to rifamycins, isoniazid, pyrazinamide, ethambutol hydrochloride and/or to any of the excipients (UK SPC section 4.3)
  • A history of drug induced hepatitis, and acute liver diseases regardless of origin (section 4.3)
  • Porphyria (section 4.3)
  • Acute gouty arthritis (section 4.3)
  • Severe renal impairment (creatinine clearance below 30 ml/min) (section 4.3)
  • Concomitant use with voriconazole and protease inhibitors, except ritonavir when given at full dose or 600 mg twice daily (section 4.3)
  • Concomitant medicines strongly affected by rifampicin's induction of drug metabolising enzymes and transporters, such as lurasidone, sofosbuvir and the antiretrovirals cabotegravir, fostemsavir and lenacapavir (section 4.3)
  • Resumption of treatment after an interrupted intensive phase — 'a fixed drug combination product such as Rimstar is contraindicated for the resumption of treatment' (section 4.2)
  • Not a suitable dosage form below 30 kg bodyweight; not recommended in children under 8 years (sections 4.2 and 4.4)

Side effects

  • Rifampicin component, common (section 4.8): tiredness, drowsiness, headache, light-headedness, dizziness; reddening of the eyes and permanent discolouration of soft contact lenses; anorexia, nausea, abdominal pain, bloatedness; flushing, itching with or without skin rash, urticaria; asymptomatic increase in liver enzymes; reddish discolouration of body fluids and secretions (urine, sputum, lacrimal fluid, faeces, saliva and sweat); paradoxical drug reaction
  • Rifampicin component, rare: transient leucopenia, eosinophilia, agranulocytosis; thrombocytopenia and thrombocytopenic purpura (more frequent with intermittent than continuous daily therapy — 'When rifampicin administration has been continued after the occurrence of purpura, cerebral haemorrhage and fatalities have been reported'); haemolysis, haemolytic anaemia; disseminated intravascular coagulation; menstrual disturbances including amenorrhoea; induction of crisis in Addison patients; mental confusion, psychosis; ataxia, muscular weakness, myopathy; visual disturbances, exudative conjunctivitis; vomiting or diarrhoea, erosive gastritis, pseudomembranous colitis, pancreatitis; hepatitis or jaundice, induction of porphyria; raised blood urea nitrogen and serum uric acid; acute renal failure due to haemoglobinuria, haematuria, interstitial nephritis, glomerulonephritis and tubular necrosis; collapse, shock, oedema
  • Severe skin reactions — Stevens-Johnson syndrome, toxic epidermal necrolysis, DRESS and acute generalised exanthematous pustulosis 'which can be life-threatening or fatal, have been reported'; also exfoliative dermatitis, Lyell's syndrome and pemphigoid reactions (sections 4.4 and 4.8)
  • Hypersensitivity reactions that require immediate withdrawal: thrombocytopenia, purpura, haemolytic anaemia, dyspnoea and asthma-like attacks, shock or renal failure — 'Patients developing such reactions must never again be treated with rifampicin' (section 4.4)
  • ⚠️ Section 4.8 is truncated at the source-fetch limit and the retrieved text covers the RIFAMPICIN component only — the isoniazid, pyrazinamide and ethambutol adverse-reaction tables were not retrieved and this list is therefore incomplete

Interactions

  • Rifampicin is a potent inducer of drug metabolising enzymes and transporters — co-administration is CONTRAINDICATED with voriconazole, with protease inhibitors (except ritonavir at full dose or 600 mg twice daily), and with lurasidone, sofosbuvir, cabotegravir, fostemsavir and lenacapavir (section 4.3)
  • ⚠️ Section 4.5 was NOT retrieved in this bundle — the interactions listed here are only those stated in section 4.3. Check the full interaction section of the SPC and a current formulary appendix before co-prescribing anything with this combination

Monitoring

  • Vision — 'Ocular examinations including acuity, colour discrimination and visual field are recommended before starting treatment and periodically during treatment, especially if high doses are used. Patients should be questioned at every visit about their vision and advised to discontinue Rimstar if a visual disturbance arises pending clinical evaluation' (section 4.4)
  • Skin — 'At the time of prescription patients should be advised of the signs and symptoms and monitored closely for skin reactions'; withdraw immediately and never restart if SJS, TEN, DRESS or AGEP occurs (section 4.4)
  • Liver function — the product is contraindicated in drug-induced hepatitis and acute liver disease and must be 'used with caution and under strict medical supervision in impaired liver function'; asymptomatic rises in liver enzymes are a common reaction (sections 4.2, 4.3, 4.4 and 4.8)
  • Renal function — contraindicated below a creatinine clearance of 30 ml/min and used with caution between 30 and 60 ml/min (section 4.2)
  • Bodyweight, because the number of tablets is set by weight band (section 4.2)
  • Watch for paradoxical worsening after initial improvement — 'After initial improvement of tuberculosis under therapy... the symptoms may worsen again' (section 4.4; this passage is cut off by the source-fetch limit)

Clinical monograph

How it works

Rifampicin inhibits bacterial RNA polymerase, isoniazid blocks mycolic acid synthesis, pyrazinamide is active against semi-dormant bacilli in acidic environments, and ethambutol inhibits arabinosyl transferase to impair cell-wall synthesis — together attacking different mycobacterial populations and reducing resistance.

Prescribing in practice

  • Rifampicin, isoniazid and pyrazinamide are all potentially hepatotoxic — check baseline liver function, monitor during treatment, and warn patients to report symptoms of hepatitis promptly.
  • Ethambutol can cause dose-related optic neuritis, so assess visual acuity and colour vision at baseline and advise patients to report any visual change; the combination is unsuitable when individual dose adjustment (for example in renal impairment) is required.
  • Rifampicin is a potent enzyme inducer that reduces the efficacy of many drugs including hormonal contraception, and pyridoxine is co-prescribed to prevent isoniazid-induced peripheral neuropathy.

Monitoring

Monitor liver function and clinical wellbeing during treatment, with baseline and ongoing assessment of visual function because of the ethambutol component and renal function to confirm the fixed combination is appropriate.

Counselling the patient

  • Take the tablets as a single daily dose, usually before food, and do not stop without advice — completing the full course is essential.
  • Rifampicin turns urine, tears and other body fluids orange-red and can permanently stain soft contact lenses.
  • Report promptly any yellowing of the skin or eyes, nausea, or any change in your vision or colour perception.

Evidence & guidelines

Fixed-dose combination therapy is recommended in NICE tuberculosis guidance to support adherence and reduce the risk of acquired drug resistance during the intensive phase.

Reference: NICE NG33; WHO; Drug verified in RxNorm (NLM); confirm dosing against the manufacturer SPC (eMC). Verify against your local formulary and current prescribing references before prescribing. The structured dose values shown have been reviewed by a clinician. Monograph status: clinician-reviewed (2026-07-04).

Related

Curated clinical cross-links plus same-class fallbacks.

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