Rifampicin/ Isoniazid/ Pyrazinamide

Registered South African indications

• Pulmonary tuberculosis in children

Registered South African contraindications

• History of hypersensitivity to rifamycins, isoniazid, pyrazinamide, other chemically related medicines, or any of the excipients
• Presence of jaundice
• Hepatic impairment
• Pregnancy
• Lactation
• Moderate to severe renal impairment
• Diabetes mellitus
• Chronic alcoholism
• History of gout
• Convulsive disorders
• Porphyria
• Concomitant use with nevirapine, saquinavir, ritonavir

South African recommendations

Caution in the following patient group

• Mild renal impairment

Rifampicin

Liver function

• Patients with impaired liver function should not be given with this combination product
• Careful monitoring of liver function, especially ALT and AST, is required
• If signs of hepatocellular damage occur, treatment should be withdrawn
• If other serious complications arise, e.g. renal failure or haemolytic anaemia, rifampicin/ isoniazid/ pyrazinamide should be stopped and never restarted

Other rifampicin precautions

• Discolouration of bodily fluids and potential staining of soft contact lenses may occur
• Enhances metabolism of endogenous substrates including adrenal hormones, thyroid hormones, and vitamin D

Isoniazid

Liver function and hepatitis risk

• Contraindicated in patients with chronic liver disease or renal dysfunction
• Monitor for prodromal symptoms of hepatitis; discontinue treatment if hepatic damage is detected

Other isoniazid precautions

• Periodic eye examinations and Vitamin B₆ supplementation recommended
• Monitor use in patients with slow acetylators status, history of psychosis, peripheral neuropathy, and HIV infection

Pyrazinamide

Gout and liver function

• Use with caution in patients with a history of gout
• If hyperuricaemia accompanied by an acute gouty arthritis occurs, the patient should be transferred to a regimen not containing pyrazinamide
• Liver function should be assessed regularly
• Monitor patients with impaired renal function
• Diabetes mellitus management may be affected

General precautions

Effects on driving and machine operation

• May cause dizziness, impaired concentration, and/or drowsiness
• Advise patients to avoid driving or operating machinery if affected

Phenylketonurics

• Contains phenylalanine, a component of aspartame

Not indicated for use in adults

Paed. forms avail. in SA and covered in this monograph: dsp

South African registered indications and dosages

Pulmonary tuberculosis in children
- Initial intensive phase of the short course treatment of pulmonary tuberculosis

Rifampicin/ Isoniazid/ Pyrazinamide
75/50/150 (mg)

• Oral (dsp): Admin. daily for 5 days/week (as defined by the South African TB control programme); Rifampicin: 15mg/kg (10-20mg/kg); Max: 600mg/24hrs; Isoniazid: 10mg/kg (7-15mg/kg); Max: 300mg/24hrs; Pyrazinamide: 35mg/kg (30-40mg/kg); Max 2g/24hrs; Treatment duration: 2 months intensive phase

Dosage calculation, based on the patient's body mass (see table below)

For infants/children with body mass (kg)	Once daily dose
4-7	1 tab
8-11	2 tab
12-15	3 tab
16-24	4 tab
25 +	Adult dosages recommended with suitable formulation

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When indicated, other antituberculosis medicines such as streptomycin may be added

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Method of administration: The 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. The dose should be taken at least 1 hour before aluminium containing antacids are used

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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 for a period of 3 months. Routine chemoprophylaxis of those older than 5 years is not recommended

Pregnancy 

South African recommendations

• Contraindicated
• Safety during pregnancy has not been established. Rifampicin, isoniazid and pyrazinamide cross the placenta

Breastfeeding

South African recommendations

• Contraindicated
• Safety during lactation has not been established. Rifampicin, isoniazid and pyrazinamide are excreted in breastmilk

Fertility

South African recommendations

• No information available

South African recommendations

• Mild: Caution; no dose adjustment recommended
• Moderate to severe: Contraindicated

South African recommendations

• Contraindicated

South African recommendations

• Not indicated for use in geriatric patients

Rifampicin

Blood and Lymphatic System Disorders

Less frequent

• Blood dyscrasias
• Unusual bleeding or bruising
• Thrombocytopenia
• Purpura
• Haemolysis
• Eosinophilia
• Leucopenia
• Haemolytic anaemia

Immune System Disorders

Frequency not known

• Anaphylaxis and shock

Nervous System Disorders

Less frequent

• Confusion
• Drowsiness
• Headache
• Ataxia
• Dizziness
• Peripheral neuropathy and generalized numbness

Eye Disorders

Less frequent

• Blurred vision
• Eye irritation

Ear and Labyrinth Disorders

Less frequent

• Transient hearing loss

Respiratory, Thoracic, and Mediastinal Disorders

Frequency not known

• Pulmonary fibrosis
• Pneumonitis
• Shortness of breath and wheezing

Gastrointestinal Disorders

Frequent

• Nausea
• Vomiting
• Anorexia
• Diarrhoea
• Epigastric distress

Less frequent

• Pseudomembranous colitis

Frequency not known

• Ulcerative colitis
• Gastrointestinal bleeding

Hepato-biliary Disorders

Less frequent

• Hepatitis (which may be fatal)
• Hepatitis prodromal symptoms
  • Loss of appetite
  • Nausea or vomiting
  • Unusual tiredness or weakness

• Rise in serum transaminase levels

Skin and Subcutaneous Tissue Disorders

Frequent

• Cutaneous reactions (flushing and itching, with or without a rash)

Less frequent

• More serious hypersensitivity cutaneous reactions
  • Toxic epidermal necrolysis
  • Exfoliative dermatitis
  • Erythema multiforme including Stevens-Johnson syndrome
  • Drug reaction with eosinophilia system symptoms (DRESS)

Musculoskeletal and Connective Tissue Disorders

Frequent

• Muscle weakness
• Myopathy

Renal and Urinary Disorders

Less frequent

• Interstitial nephritis
• Renal failure

Reproductive System and Breast Disorders

Less frequent

• Disturbances of the menstrual cycle
• Reduction of effectiveness of oral contraceptives

General Disorders and Administrative Site Conditions

Frequent

• Reddish-orange to reddish-brown discolouration of the urine, faeces, saliva, sputum, sweat, and tears (soft contact lenses may be permanently stained)

Less frequent

• Flu syndrome (febrile reaction with influenza-like symptoms)
• Fungal overgrowth (sore mouth or tongue)

Isoniazid

Blood and Lymphatic System Disorders

Less frequent

• Various haematological disturbances including
  • Eosinophilia
  • Agranulocytosis
  • Thrombocytopenia
  • Various anaemias

Immune System Disorders

Less frequent

• Hypersensitivity reactions including
  • Various skin eruptions
  • Fever
  • Lymphadenopathy
  • Vasculitis
  • Lupus-like reactions

Metabolism and Nutrition Disorders

Less frequent

• Hyperglycaemia
• Metabolic acidosis

Psychiatric Disorders

Less frequent

• Psychotic reactions (characterised by delusions, hallucinations, and confusion)
• Memory impairment

Nervous System Disorders

Frequent

• Peripheral neuropathy

Less frequent

• Polyneuritis associated with paraesthesia, muscle weakness, loss of tendon reflexes, convulsions, increase in frequency of fits in epileptic patients, ataxia

Eye Disorders

Less frequent

• Optic neuritis (blurred vision or loss of vision, with or without eye pain)

Ear and Labyrinth Disorders

Less frequent

• Vertigo

Gastrointestinal Disorders

Frequent

• Diarrhoea
• Nausea and vomiting
• Stomach pain
• Constipation
• Dry mouth
• Pancreatitis

Hepato-biliary Disorders

Frequent

• Hepatitis (sometimes fatal)
• Hepatitis prodromal symptoms (loss of appetite, nausea or vomiting, unusual tiredness or weakness)
• Transient increase in liver enzymes

Skin and Subcutaneous Tissue Disorders

Less frequent

• Skin reactions
• Pellagra
• Acne
• Steven-Johnsons syndrome
• Exfoliative dermatitis

Frequency not known

• Alopecia
• Urticaria

Musculoskeletal and Connective Tissue Disorders

Frequency unknown

• A rheumatic syndrome
• Hyperreflexia

Renal and Urinary Disorders

Less frequent

• Urinary retention

Reproductive System and Breast Disorders

Less frequent

• Gynaecomastia

Pyrazinamide

Blood and Lymphatic Disorders

Less frequent

• Sideroblastic anaemia
• Thrombocytopenia

Immune System Disorders

Less frequent

• Hypersensitivity reaction

Metabolism and Nutrition Disorders

Less frequent

• Pellagra

Gastrointestinal Disorders

Less frequent

• Anorexia
• Nausea
• Vomiting
• Aggravation of peptic ulcer

Hepato-biliary Disorders

Frequent

• Hepatotoxicity (frequency appears to be dose-related)

Skin and Subcutaneous Tissue Disorders

Less frequent

• Photosensitivity
• Skin rash
• Pruritus

Musculoskeletal, Connective Tissue, and Bone Disorders

Frequent

• Arthralgia (related to hyperuricaemia)

Less frequent

• Gouty arthritis

Renal and Urinary Disorders

Less frequent

• Dysuria

General Disorders and Administrative Site Conditions

Less frequent

• Malaise
• Fever

Rifampicin

• Nevirapine
• Saquinavir/ritonavir
• Halogenated inhalation anaesthetics
• Ketoconazole
• Azathioprine
• Chloramphenicol
• Cimetidine
• Clofibrate
• Corticosteroids
• Coumarin anticoagulants
• Ciclosporin
• Dapsone
• Diazepam
• Doxycycline
• Fluconazole
• Haloperidol
• Hexobarbitone
• Itraconazole
• Methadone
• Oral hypoglycaemic medicines
• Phenytoin
• Quinine
• Sulphasalazine
• Thyroid hormones
• Theophylline
• Zidovudine
• Beta-adrenoceptor blocking medicines
• Digoxin
• Disopyramide
• Lorcainide
• Mexiletine
• Propafenone
• Quinidine
• Tocainide
• Verapamil and other calcium channel blockers
• Oral contraceptives
• Narcotics
• Analgesics
• Barbiturates
• Magnesium trisilicate
• Aluminium hydroxide
• Sodium bicarbonate
• Alcohol
• Delavirdine
• Efavirenz
• HIV-protease inhibitors

Isoniazid

• Cytochrome P-450 enzymes
• Phenytoin
• Primidone
• Carbamazepine
• Ethosuximide
• Benzodiazepines
• Diazepam
• Triazolam
• Warfarin
• Theophylline
• Cycloserine
• Disulfiram
• Alcohol
• Alfentanil
• Aminosalicylic acid
• Corticosteroids
• Ketoconazole
• Propranolol
• Large doses of pyridoxine
• Aluminium-containing antacids
• Paracetamol
• Hepatotoxic medicines
• Zalcitabine
• Stavudine

Other interactions

• Tyramine-containing foods
• Cheese
• Red wine
• Histamine-containing foods
• Skipjack
• Tuna
• Other tropical fish

Pyrazinamide

• Sulfinpyrazone
• Allopurinol
• Colchicine
• Probenecid
• Ciclosporin

• Liver function tests (AST, ALT) (baseline and periodic)
• Serum uric acid
• Serum bilirubin
• Serum creatinine
• Full blood count
• Chest x-ray

Specific cases may require

• Liver function tests (every 2 to 4 weeks in those at higher risk for hepatitis)
• Coagulation tests (in those at risk of vitamin K deficiency)

Additional observations

• Prodromal signs of hepatitis
• Symptoms of interstitial lung disease/pneumonitis and thrombotic microangiopathy, including thrombotic thrombocytopenic purpura and hemolytic uremia syndrome

Rifampicin/ isoniazid/ pyrazinamide is a combination of three medicines used in the treatment of tuberculosis. Rifampicin and pyrazinamide are bactericidal anti-tuberculosis medicines. Isoniazid is bactericidal for rapidly dividing micro-organisms and bacteriostatic for resting bacilli.

Rifampicin
Rifampicin inhibits the growth of Mycobacterium tuberculosis. Rifampicin binds to the β subunit of DNA-dependent RNA polymerase (rpoB) to form a stable medicine-enzyme complex. Rifampicin binding suppresses chain formation in RNA synthesis.

Isoniazid
Isoniazid is bactericidal and the mechanism of action is by entering the bacilli through passive diffusion. Isoniazid then inhibits the biosynthesis of mycolic acids which are essential components of the cell wall of Mycobacterium tuberculosis, leading to bacterial cell death.

Pyrazinamide
Pyrazinamide is the pyrazine analogue of nicotinamide. The mechanism of action is unknown, however, three mechanisms have been proposed
- Inhibition of fatty acid synthase type I leading to interference with mycolic acid synthesis
- Reduction of intracellular pH
- Disruption of membrane transport by HPOA (protonated pyrazinoic acid).