Rifampicin/ Isoniazid/ Pyrazinamide/ Ethambutol

Registered South African indications:

• Initial phase treatment of pulmonary and extrapulmonary tuberculosis
  - In new adult patients and re-treatment of adult cases

Registered South African contraindications

• Hypersensitivity to the active ingredients or any of the excipients in this combination product
• Hypersensitivity to other chemically related medication
• Presence of jaundice or active hepatic disease
• Optic neuritis
• Porphyria
• Children under 13 years
• Coadministration with saquinavir/ritonavir

Contraindications registered in other jurisdictions

• Hypersensitivity to rifamycins, isoniazid, pyrazinamide, ethambutol hydrochloride and/or to any of the excipients
• History of drug induced hepatitis and acute liver diseases regardless of its origin
• Porphyria
• Acute gouty arthritis
• Severe renal impairment (CrCl<30ml/min)
• Coadministration with voriconazole and protease inhibitors, except ritonavir when given at full dose or 600mg twice daily

• Pregnancy
• Breastfeeding
• Renal impairment (South African recommendations)
• Moderate renal impairment (CrCl 30-60ml/min) (Recommendations in other jurisdictions)
• Hepatic impairment (Recommendations in other jurisdictions) 
• Elderly
• Patients with extremely fast or extremely slow acetylating capability should receive the four components separately in order to facilitate dose adjustment of isoniazid
• Diabetes mellitus
• Epilepsy
• Alcohol abuse
• Malnutrition

Forms avail. in SA and covered in this monograph: fct, tab

South African registered indications and dosages

Initial phase treatment of pulmonary and extrapulmonary tuberculosis
- In new adult patients and re-treatment of adult cases

Rifampicin/ Isoniazid/ Pyrazinamide/ Ethambutol
150/75/400/275 (mg)

• Oral (fct, tab): Recommended treatment dosage, based on the patient's body weight (see table below), given daily; Treatment duration: Initial phase: 2 months

Take 1 hour before or 2 hours after meals. However, if gastrointestinal irritation occurs, the tablets may be taken with food. If aluminium–containing antacids are taken, administer 1 hour after the tablet dose

Paed. forms avail. in SA and covered in this monograph: fct, tab

South African registered indications and dosages

Initial phase treatment of pulmonary and extrapulmonary tuberculosis

Rifampicin/ Isoniazid/ Pyrazinamide/ Ethambutol
150/75/400/275 (mg)

Younger than 13  years

• Contraindicated

Older than 13 years

• See adult dosage

Decisions related to dose adjustment/discontinuing TB regimen must be discussed in advance with Pulmonologists/Infectious Disease specialists, and cases must be dealt with individually

Pregnancy

South African recommendations

• Caution
• Safety in pregnancy has not been established
• Rifampicin has been reported to cross the placental barrier. When administered during the last weeks of pregnancy, rifampicin can cause post-natal haemorrhages in the mother and infant, for which treatment with vitamin K may be indicated

Recommendations in other jurisdictions

• Caution
• Treatment should be considered on a case by case basis after benefit of medicinal product combination has been assessed. Consequently, rifampicin/ isoniazid/ pyrazinamide/ ethambutol could be given during pregnancy if the potential benefit for the mother is judged to outweigh the potential risk to the foetus
• Rifampicin: At very high doses in animals rifampicin has been shown to have teratogenic effects. There are no well-controlled studies with rifampicin in pregnant women. Although rifampicin has been reported to cross the placental barrier and appear in cord blood, the effect of rifampicin, alone or in combination with other antituberculosis drugs, on the human foetus is not known. Therefore, rifampicin should be used in pregnant women or in women of childbearing potential only if the potential benefit justifies the potential risk to the foetus. Administration of rifampicin during the last few weeks of pregnancy can cause postnatal haemorrhage in the mother and newborn infant
• Isoniazid: On limited data, congenital malformations have not been observed to be any more frequent than what may be expected in a normal population. Isoniazid crosses the placenta. Isoniazid might exert neurotoxic effects on the child. Animal studies have shown reproductive toxicity
• Pyrazinamide: No animal reproductive studies have been conducted with pyrazinamide. Nor is it known whether pyrazinamide can cause foetal damage when administered to a pregnant woman
• Ethambutol: Ethambutol crosses the placenta, and may result in foetal plasma concentrations that are approximately 30% of maternal plasma concentrations. Limited clinical data on exposed pregnancies suggest no increase in the rate of foetal malformations in humans. Animal studies have shown a teratogenic potential
• 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, because rifampicin can lead to maternal or neonatal haemorrhage. Supplementation of pyridoxine (vitamin B6) is recommended during pregnancy because isoniazid might exert neurotoxic effects on the child

Breastfeeding

South African recommendations

• Caution
• All substances of rifampicin/ isoniazid/ pyrazinamide/ ethambutol tablets are excreted in breast milk
• Safety during lactation has not been established

Recommendations in other jurisdictions

• Caution; not recommended
• Rifampicin, isoniazid, pyrazinamide, ethambutol pass into the breast milk, but no undesirable effects on breastfed infants have been observed. Breastfeeding is, however, not recommended in view of the theoretical possibility of neurotoxic effects due to isoniazid and ethambutol

Fertility

Recommendations below are applicable to South Africa and other jurisdictions

• No information available

South African recommendations

• Caution; dose adjustment recommended
  Use of isoniazid should be carefully monitored in patients with severe renal dysfunction
  Treatment should be discontinued permanently should thrombocytopenia, purpura, shock or renal failure occur
  Caution should be observed with the use of rifampicin/ isoniazid/ pyrazinamide/ ethambutol tablets in patients with impaired kidney function, dosage adjustment may be required according to the serum concentration of ethambutol

Recommendations in other jurisdictions

• Mild to moderate (CrCl>60ml/min): No dose adjustment recommended
• Moderate (CrCl 30-60ml/min): Caution; no dose adjustment recommended
• Severe (CrCl<30ml/min): Contraindicated

South African recommendations

• Jaundice or active hepatic disease: Contraindicated
  If liver damage is confirmed, the medicine should not be recommenced
  Use of isoniazid should be carefully monitored in patients with current chronic liver disease

Recommendations in other jurisdictions

• Caution; no dose adjustment recommended
  The combination product rifampicin/ isoniazid/ pyrazinamide/ ethambutol should be used with caution and under strict medical supervision in impaired liver function
  The combination product is contraindicated in patients with a history of drug induced hepatitis and in patients with acute liver diseases

Recommendations below are applicable to South Africa and other jurisdictions

• Caution; no dose adjustment recommended

Central Nervous System Disorders

• Mental confusion
• Psychosis
• Tiredness
• Drowsiness
• Headache
• Light-headedness
• Dizziness
• Ataxia
• Muscular weakness
• Myopathy

Gastrointestinal Disorders

• Anorexia
• Nausea and vomiting
• Abdominal pain
• Bloatedness
• Diarrhoea
• Erosive gastritis 
• Pseudomembranous colitis
• Pancreatitis

Hepatobiliary Disorders

• Asymptomatic increase in liver enzymes 
• Hepatitis
• Jaundice
• Induction of porphyria 

Genitourinary Disorders

• Elevations of blood urea nitrogen 
• Elevations of serum uric acid 
• Acute renal failure
• Haemoglobinuria
• Haematuria
• Interstitial nephritis
• Glomerulonephritis 
• Tubular necrosis 

Endocrine and Metabolic Disorders

• Menstrual disturbances 
• Induction of crisis in Addison patients 

Skin and Subcutaneous Tissue Disorders

• Flushing
• Itching with or without skin rash 
• Urticaria
• Stevens-Johnson syndrome 
• Exfoliative dermatitis
• Lyell's syndrome
• Pemphigoid reactions

Immune, Blood and Lymphatic System

• Transient leucopenia
• Eosinophilia
• Agranulocytosis
• Thrombocytopenia
• Thrombocytopenic purpura 
• Haemolysis
• Haemolytic anaemia
• Disseminated intravascular coagulation 

Sensory Disorders

• Reddening of the eyes
• Permanent discolouration of soft contact lenses
• Visual disturbances
• Exudative conjunctivitis

Others

• Reddish discoloration of body fluids and secretions such a
• Collapse
• Shock
• Oedema

• Nevirapine
• Saquinavir/ritonavir
• Ketoconazole
• Voriconazole
• Protease inhibitors (except ritonavir when given at full dose or 600mg twice daily)
• CYP3A substrates
• CYP2C substrates
• Antacids
• Ritonavir 
• Analgesics 
• Antiarrhythmics 
• Antibacterials 
• Anticoagulants
• Antidiabetics
• Antiepileptics 
• Antifungals 
• Antipsychotics 
• Antivirals 
• Anxiolytics and hypnotics 
• Atovaquone
• Barbiturates 
• Beta-blockers 
• Calcium channel blockers
• Corticosteroids
• Cardiac glycosides
• Cimetidine
• Clofibrate
• Cytotoxics
• Diuretics 
• Oestrogen
• Progestogens
• Fexofenadine
• Hormone antagonists 
• Immunosuppressive agents
• Losartan
• Imidapril
• Enalapril
• Praziquantel
• Quinine
• Selective 5-HT3 receptor antagonists 
• Statins metabolised by CYP 3A4
• Fluvastatin
• Systemic hormonal contraceptives
• Theophylline
• Thyroid hormones
• Tricyclic antidepressants 
• Halogenated volatile anaesthetics
• Pyrazinamide
• Theophylline
• Probenecid
• Sulfinpyrazon
• Oral contraceptives
• Oral typhoid vaccine
• Food with a high content of tyramine or histamines

None routine. Specific cases may require

• Hepatic function
• Serum uric acid
• Full blood count

Rifampicin is a broad-spectrum bactericidal antibiotic. It acts on Mycobacterium tuberculosis and variable activity against other atypical species of Mycobacterium. It inhibits DNA-dependent RNA polymerase, leading to a suppression of RNA synthesis and cell death.
Isoniazid is bacteriostatic against semi-dromant bacilli and bactericidal against rapidly dividing Mycobacterium. It inhibits the synthesis of mycoloic acids, an essential component of the bacterial cell wall.
Pyrazinamide may be bactericidal or bacteriostatic. It gets activated to pyrazinoic acid in the bacilli where it interferes with fatty acid synthase FAS I, which prevents the bacteriums ability to synthesize new fatty acids, required for growth and replication.
Ethambutol is a bacteriostatic anti-tubercular agent. It diffuses into mycobacteria and suppresses multiplication by interfering with RNA synthesis. It is effective only against mycobacteria that are actively dividing. It inhibits arabinosyl transferases which is involved in cell wall biosynthesis, leading to an increase in cell wall permeability.

COMBINATION PREPARATIONS

Rifampicin/ Isoniazid/ Pyrazinamide/ Ethambutol

Tablet 150mg/75mg/400mg/275mg

• Rifafour e-275 (Sanofi)
• Rimstar 4-Fdc (Sandoz SA)
• Rimtib (Mylan)