Rifampicin/ Isoniazid

Registered South African indications:

• Continuation phase treatment of pulmonary and extra-pulmonary tuberculosis

Registered South African contraindications

300/150 (mg) tablets
150/75 (mg) tablets

• History of hypersensitivity to rifamycins, isoniazid or any of the components
• Jaundice
• Acute porphyria
• Rifampicin can cause thrombocytopenia and purpura usually with intermittent tuberculosis regimens; further administration is contraindicated
• Coadministration with saquinavir/ritonavir

75/50 (mg) dispersible tablets

• Hypersensitivity or a history of hypersensitivity to rifampicin, other rifampicins, isoniazid, or to any of the ingredients
• Jaundice
• Hepatic impairment
• Moderate to severe renal impairment
• Diabetes mellitus
• Chronic alcoholism
• History of gout
• Patients suffering from convulsive disorders
• Porphyria
• Concomitant use with nevirapine
• Coadministration with saquinavir/ritonavir
• Pregnancy
• Lactation

60/60 (mg) tablets

• Known or suspected hypersensitivity to rifamycins, isoniazid or any of the excipients
• Jaundice
• Hepatic impairment
• Acute porphyria
• Renal impairment
• Diabetes mellitus
• Chronic alcoholism
• History of gout
• Patients suffering from convulsive disorders
• Coadministration with saquinavir/ritonavir
• Pregnancy
• Lactation
• Rifampicin can cause thrombocytopenia and purpura usually with intermittent tuberculosis regimens; further administration is contraindicated

Contraindications registered in other jurisdictions

• Hypersensitivity to rifamycins or isoniazid or any of the excipients
• Presence of jaundice
• Coadministration with saquinavir/ritonavir

• Pregnancy (South African recommendations for 300/150 (mg) and 150/75 (mg) tablets)
• Pregnancy (Recommendations in other jurisdictions)
• Breastfeeding (South African recommendations for 300/150 (mg) and 150/75 (mg) tablets)
• Breastfeeding (Recommendations in other jurisdictions)
• Mild renal impairment (South African recommendations for 75/50 (mg))
• Severe renal impairment (South African recommendations for 300/150 (mg) and 150/75 (mg) tablets)
• Severe renal impairment (Recommendations in other jurisdictions)
• Hepatic impairment (South African recommendations for 300/150 (mg) and 150/75 (mg) tablets)
• Hepatic impairment (Recommendations in other jurisdictions)
• Elderly 
• Malnourished 
• Children below two years 
• Slow acetylator status
• Epilepsy
• History of psychosis
• History of peripheral neuropathy
• Diabetes 
• Alcohol dependence
• HIV infection 
• Porphyria
• Fructose intolerance
• Glucose-galactose malabsorption 
• Sucrase-isomaltase insufficiency

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

South African registered indications and dosages

Continuation phase treatment of pulmonary and extra-pulmonary tuberculosis
-  In newly diagnosed patients and re-treatment of adult cases

Rifampicin/ Isoniazid
300/150 (mg)
150/75 (mg)

South African National Tuberculosis Control Programme dosage recommendation

• Oral (fct, tab): New, smear positive patients, new smear negative patients and extra-pulmonary TB: Admin. daily for 5 consecutive days/week; Rifampicin dose: 10mg/kg (8-12mg/kg); Max: 600mg/24hrs; Isoniazid: 5mg/kg (4-6mg/kg); Max: 300mg/24hrs; Treatment duration: 4 months

WHO dosage recommendation

• Oral (fct, tab): Admin. on a continuous daily basis; Rifampicin dose: 10mg/kg (8-12mg/kg); Max: 600mg/24hrs; Isoniazid: 5mg/kg (4-6mg/kg); Max: 300mg/24hrs; Treatment duration: 4 months

Table: Number of tablets based on patient body mass

Patient body mass (kg)	Rifampicin/ Isoniazid 150/75 (mg) Number of tablets daily	Rifampicin/Isoniazid  300 /150 (mg) Number of tablets daily
30-37	2	--
38-54	3	--
55 or more	--	2

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

South African registered indications and dosages

Continuation phase treatment of pulmonary and extra-pulmonary tuberculosis
-  In newly diagnosed patients

Rifampicin/ Isoniazid
300/150 (mg)
150/75 (mg)

• Younger than 12 years: Not suitable
• 12 years and older: See adult dosage

Continuation phase of pulmonary tuberculosis

Rifampicin/ Isoniazid
75/50 (mg)

• Oral (odt): Admin. on a continuous daily basis; Rifampicin dose: 15mg/kg (10-20mg/kg); Max: 600mg/24hrs; Isoniazid: 10mg/kg (7-15mg/kg); Max: 300mg/24hrs

Table 1: Number of tablets based on patient body mass

Number of dispersible tablets	For infants/children with body mass (kg)
1	4-7
2	8-11
3	12-15
4	16-24
Adult dosages recommended	25 +

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Method of administration
The dispersible tablets can either be dispersed in as little as 5ml of water, or chewed and should preferably be taken on an empty stomach as a single dosage, orally. Rifampicin/ isoniazid 75/50 (mg) dispersible tablets should be taken at least 1 hour before using aluminium containing antacids

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For missed doses, the missing dose can be taken as soon as possible, and then take the next dose at its regular time. However, if the next dose is due within 6 hours, do not take the missed dose. Wait and take the next dose at the regular time. A double dose should not be taken to make up for a forgotten tablet

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Continuation phase of pulmonary tuberculosis

Rifampicin/ Isoniazid
60/60 (mg)

• Oral (tab): Admin. on an intermittent basis; Rifampicin dose: 10mg/kg (8-12mg/kg), 3 times a week; Isoniazid: 10mg/kg (8-12mg/kg); Max: 6 tabs/24hrs

Table 2: Number of tablets based on patient body mass

Number of tablets	For infants/children with body mass
½	3kg < 5kg
1	5kg < 7.5kg
1½	7.5kg < 10kg
2	10kg < 15kg
3	15kg < 20kg
4	20kg < 25kg
5	25kg < 30kg
6	30kg < 35kg

Each rifampicin/ isoniazid 60/60 (mg) tablet contains rifampicin (RMP) and isoniazid (INH) in such a ratio that the administration of 10mg/kg RMP and 10mg/kg INH can be achieved by giving 1 tablet per 5kg body mass, i.e. 1 tablet to children of 5kg, 2 tablets to children of 10kg, 3 tablets to children of 15kg, 4 tablets to children of 20kg, 5 tablets to children of 25kg body mass per day. No child should take more than 6 rifampicin/ isoniazid 60/60 (mg) tablets per day

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The daily dosage is calculated from the recommended daily requirement given above and the tablets can be halved to more closely regulate dosage according to body mass

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The tablets can either be dispersed in as little as 5ml water or chewed and should preferably be taken on an empty stomach, as a single dosage

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Chemoprophylaxis:
Children less than 5 years of age in close household contact with a smear positive case of pulmonary TB should be treated with rifampicin/ isoniazid (RMP/INH) for a period of 3 months. Routine chemoprophylaxis of those older than 5 years is not recommended

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

300/150 (mg) tablets
150/75 (mg) tablets

• Caution
• The safety of rifampicin/ isoniazid tablets in pregnant women has not been established
• When administered during the last few weeks of pregnancy, rifampicin can cause post-natal haemorrhages in the mother and infant, for which treatment with Vitamin K may be indicated

75/50 (mg) dispersible tablets

• Contraindicated
• Safety during pregnancy has not been established

60/60 (mg) tablets

• Contraindicated
• The safety of rifampicin/ isoniazid during pregnancy has not been established
• When administered during the last few weeks of pregnancy, rifampicin can cause post-natal haemorrhages in the mother and infant, for which treatment with Vitamin K may be indicated
• Rifampicin/ isoniazid should be used in pregnant women or in women of childbearing potential only if the potential benefit justifies the potential risk to the foetus. Disturbance of menstrual cycle have been reported in women receiving long term antitubercular therapy with regimens containing rifampicin. The effectiveness of oral contraceptives may also be reduced

Recommendations in other jurisdictions

• Caution
• Rifampicin has been shown to be teratogenic in rodents when given in large doses. There are no well-controlled studies with rifampicin/ isoniazid combination tablets 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
• When administered during the last few weeks of pregnancy, rifampicin can cause postnatal haemorrhages in the mother and infant, for which treatment with Vitamin K1 may be indicated
• It has been reported that in both rats and rabbits, isoniazid may exert an embryocardial effect when administered orally during pregnancy, although no isoniazid-related congenital anomalies have been found in reproduction studies in mammalian species (mice, rats, rabbits)
• Therefore, rifampicin/ isoniazid combination tablets should be used in pregnant women or in women of childbearing potential only if the potential benefit justifies the potential risk to the foetus

Breastfeeding

South African recommendations

300/150 (mg) tablets
150/75 (mg) tablets

• Caution
• The safety of rifampicin/ isoniazid tablets in lactating women has not been established
• Rifampicin and isoniazid are known to pass into maternal breast milk

75/50 (mg) dispersible tablets

• Contraindicated
• Safety during lactation has not been established. Rifampicin and isoniazid cross the placenta, and both are excreted in breastmilk

60/60 (mg) tablets

• Contraindicated
• The safety of rifampicin/ isoniazid during lactation has not been established
• Rifampicin and isoniazid are excreted in maternal breast milk. Therefore, mothers on rifampicin/ isoniazid should not breastfeed their babies unless in the physician's judgement the potential benefit to the patient outweighs the potential risk to the infant
• In breastfed infants whose mothers are taking isoniazid, there is a theoretical risk of convulsions and neuropathy (associated with vitamin B₆ deficiency), therefore they should be monitored for early signs of these effects and consideration should be given to treating both mother and infant prophylactically with pyridoxine

Recommendations in other jurisdictions

• Caution; not recommended
• Rifampicin and isoniazid are excreted in breast milk and infants should not be breastfed by a patient receiving rifampicin and isoniazid unless the potential benefit to the patient outweighs the potential risk to the infant
• In breastfed infants whose mothers are taking isoniazid, there is a theoretical risk of convulsions and neuropathy (associated with vitamin B₆ deficiency), therefore they should be monitored for early signs of these effects and consideration should be given to treating both mother and infant prophylactically with pyridoxine

Fertility

Recommendations below are applicable to South Africa and other jurisdictions

• No information available

South African recommendations

300/150 (mg) tablets
150/75 (mg) tablets

• Mild to moderate: No dose adjustment recommended
• Severe: Caution; no dose adjustment recommended
  Use of isoniazid should be carefully monitored in patients with current severe renal dysfunction

75/50 (mg) dispersible tablets

• Mild: Caution; no dose adjustment recommended
  Patients with renal impairment, particularly those who are slow acetylators may be at increased risk for isoniazid adverse effects such as peripheral neuropathy and should be monitored accordingly
• Moderate to severe: Contraindicated

60/60 (mg) tablets

• Contraindicated

Recommendations in other jurisdictions

• Mild to moderate: No dose adjustment recommended
• Severe: Caution; no dose adjustment recommended
  Use of isoniazid should be carefully monitored in patients with current severe renal dysfunction

South African recommendations

300/150 (mg) tablets
150/75 (mg) tablets

• Caution; no dose adjustment recommended
• Patients with impaired liver function should only be given rifampicin in cases of necessity and then with caution and under strict medical supervision
• Use of isoniazid should be carefully monitored in patients with current chronic liver disease

75/50 (mg) dispersible tablets
60/60 (mg) tablets

• Contraindicated
• Patients with impaired liver function should not be given rifampicin/ isoniazid
• Rifampicin should also be withdrawn if clinically significant changes in hepatic function occur

• Use of isoniazid should be carefully monitored in patients with current chronic liver disease

Recommendations in other jurisdictions

• Caution; no dose adjustment recommended
• Patients with impaired liver function should only be given rifampicin in cases of necessity and then with caution and under strict medical supervision
• Use of isoniazid should be carefully monitored in patients with current chronic liver disease

Recommendations below are applicable to South Africa and other jurisdictions

• Caution; no dose adjustment recommended

Central Nervous System Disorders

• Psychotic disorder
• Cerebral haemorrhage 
• Vertigo
• Polyneuritis
• Convulsions
• Toxic encephalopathy
• Optic neuritis and atrophy
• Memory impairment 
• Toxic psychosis

Cardiovascular Disorders

• Shock
• Flushing
• Vasculitis

Respiratory Disorders

• Dyspnoea
• Wheezing
• Sputum discoloured

Gastrointestinal Disorders

• Nausea and vomiting
• Diarrhoea
• Gastrointestinal disorder
• Abdominal discomfort
• Constipation
• Dry mouth
• Pancreatitis

Hepatobiliary Disorders

• Hepatitis
• Hyperbilirubinaemia 

Genitourinary Disorders

• Acute kidney injury 
• Renal tubular necrosis 
• Tubulointerstitial nephritis
• Chromaturia
• Post-partum haemorrhage
• Fetal-maternal haemorrhage
• Menstrual disorder
• Gynaecomastia

Endocrine and Metabolic Disorders

• Adrenal insufficiency 
• Decreased appetite
• Hyperglycaemia

Musculoskeletal Disorders

• Muscle weakness
• Myopathy
• Bone pain

Skin and Subcutaneous Tissue Disorders

• Erythema multiforme 
• Stevens-Johnson syndrome 
• Toxic epidermal necrolysis
• Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) syndrome 
• Skin reaction
• Pruritus
• Rash pruritic
• Urticaria
• Dermatitis allergic
• Pemphigoid
• Sweat discolouration
• Acne
• Exfoliative dermatitis 

Immune, Blood and Lymphatic System Disorders

• Thrombocytopenia with or without purpura
• Leukopenia
• Disseminated intravascular coagulation
• Eosinophilia
• Agranulocytosis
• Hemolytic anaemia
• Anaphylactic reaction
• Porphyria
• Anaemia
• Aplastic anaemia
• Haemolytic anaemia

Sensory Disorders

• Tear discolouration

Others

• Oedema
• Pseudomembranous colitis
• Influenza consisting of episodes of pyrexia, chills, headache, dizziness
• Pellagra
• Systemic lupus erythematosus-like syndrome

• Saquinavir/ritonavir
• Nevirapine
• Tyramine- and histamine-containing foods
• CYP450 substrates
• Antacids
• Alcohol
• Analgesics 
• Antiarrhythmics 
• Antibacterials 
• Anticoagulants
• Antidiabetics
• Antiepileptics 
• Antifungals 
• Antipsychotics 
• Antivirals 
• Anxiolytics and hypnotics 
• Atovaquone
• Barbiturates 
• Beta blockers 
• Calcium channel blockers
• Corticosteroids
• Cardiac glycosides 
• Clofibrate
• Cytotoxics
• Diuretics 
• Oestrogen
• Progestogens
• Hormone antagonists 
• Immunosuppressive agents
• Irinotecan
• Losartan
• Enalapril
• Praziquantel
• Quinine
• Riluzole
• Selective 5-HT3 receptor antagonists 
• Systemic hormonal contraceptives
• Theophylline
• Thyroid hormones
• Halothane
• General anaesthetics
• Para-aminosalicylic acid
• Cycloserine

None routine. Specific cases may require

• Hepatic function
• Renal function

Rifampicin
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
Isoniazid is bacteriostatic against semi-dormant bacilli and bactericidal against rapidly dividing Mycobacterium. It inhibits the synthesis of mycoloic acids, an essential component of the bacterial cell wall.

COMBINATION PREPARATIONS

Rifampicin/ Isoniazid

Tablet 60mg/30mg

• Rimactazid Paed 60/30 (Sandoz) 

Tablet 60mg/60mg

• Afaris Paed ODT 60/60 (Mylan)
• Rimactazid Paed 60/60 (Sandoz) 

Tablet 150mg/75mg

• Afaris FS (Mylan)
• Rifinah 150+75mg (Sanofi)
• Rimactazid Paed 150/75 (Sandoz) 

Tablet 150mg/100mg

• Rifinah-150 (Sanofi) 

Tablet 300mg/150mg

• Afaris FC (Mylan)
• Ebsar-2 Ds (Dezzo)
• Rifinah-300 (Sanofi) 
• Rimactazid 300/150 (Sandoz)