Ethambutol / Isoniazid / Pyrazinamide / Rifampicin

DAE Class; Rx

Common Brand Names; MYRIN-P, MYRIN-P FORTE, VORACTIV

• Tuberculosis

Tablets containing 150mg rifampicin, 75mg isoniazid, 400mg pyrazinamide and 275mg ethambutol

Uses for the initial treatment of tuberculosis according to World Health Organisation (WHO) guidelines. Consideration should also be given to other official guidance on the appropriate use of antituberculosis agents.

Leucopenia
Eosinophilia
Haemolysis
Haemolytic anaemia
Menstrual disturbances
Confusion
Tiredness
Drowsiness
Headache
Lightheadedness
Dizziness
Ataxia
Muscle weakness
Reddening of eyes
Possible staining of soft contact lenses
Visual disturbances
Anorexia
Nausea
Abdominal pain
Bloating
Vomiting
Diarrhoea
Gastritis
Pseudomembranous colitis
Flushing
Itching
Rash
Urticaria
Skin reactions
Hypersensitivity reactions
Elevation of liver enzymes
Hepatitis
Jaundice
Porphyria
Increase in blood urea nitrogen
Increased uric acid level
Acute renal failure
Reddish discolouration of body fluids
Collapse
Shock
Oedema
Thrombocytopenia
Agranulocytosis
Gynaecomastia
Cushing’s syndrome
Hyperglycaemia
Decreased glycaemic control in diabetes
Metabolic acidosis
Psychoses
Hyperactivity
Euphoria
Insomnia
Peripheral neuropathy
Paraesthesia
Optic nerve damage
Convulsions
Encephalopathy
Pancreatitis
Malaise
Allergic reaction
Exanthema
Drug fever
Dry mouth
Heartburn
Micturition disorders
Lupus erythematosus-like syndrome
Pellagra
Vasculitis
Lymphadenopathy
Acne
Splenomegaly
Hepatotoxicity
Hepatomegaly
Hyperuricaemia
Gout
Interstitial nephritis
Dysuria
Arthralgia
Myalgia
Photosensitivity
Pruritus
Hallucinations
Peripheral neuritis
Optic neuritis
Disturbances of appetite
Anaphylactic reaction
Exfoliative dermatitis
Lyell’s syndrome
Pemphigoid reaction
Influenza-like syndrome
Thrombocytopenic purpura
Epigastric distress
Chills
Cerebral haemorrhage

Treatment should be given under close supervision of a physician trained in the management of tuberculosis.

Consideration should be given to official guidance on the appropriate use of antituberculosis agents.

Pregnancy – see Pregnancy section
Breastfeeding – see Breastfeeding section

Patients with hepatic impairment see Dosage; Hepatic impairment.
Patients with renal impairment see Dosage; Renal impairment.

Rifampicin with isoniazid and pyrazinamide and ethambutol should be used with caution in patients with:
History of psychosis
HIV infection

Patients with extremely fast or extremely slow acetylating capability should receive the four components (rifampicin, isoniazid, pyrazinamide and ethambutol) separately in order to facilitate the dose adjustment of isoniazid.

Rifampicin with isoniazid, pyrazinamide and ethambutol tablets should be withdrawn immediately if severe acute hypersensitivity reactions, such as thrombocytopenia, purpura, haemolytic anaemia, dyspnoea and asthma-like attacks, shock or renal failure occur. Patients developing such reactions must never be treated with rifampicin again.

Rifampicin with isoniazid, pyrazinamide and ethambutol tablets should be used with care in patients with visual defects. 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 use if a visual disturbance arises pending clinical evaluation.

For undernourished or elderly patients supplementation of pyridoxine (vitamin B6) may be useful, because isoniazid in high doses can lead to pyridoxine (vitamin B6) deficiency.

Use with caution in patients with a history of gout. Regular monitoring of serum uric acid should be undertaken. Treatment should be stopped in gouty arthritis.

Full blood count should be monitored during prolonged treatment and in patients with hepatic disorders. Rifampicin should be withdrawn permanently if thrombocytopenia or purpura occurs. The possibility of pyrazinamide having an undesirable effect on blood clotting time or vascular integrity should be borne in mind in patients with haemoptysis.

Use with caution in patients with diabetes mellitus. Increased difficulty has been reported in controlling diabetes mellitus when such patients are given isoniazid.

Patients suffering from convulsive disorders must be kept under special observation during treatment because of the neurotoxic effects of isoniazid and ethambutol hydrochloride.

Caution should be exercised in subjects with peripheral or optic neuritis. Regular neurological examination is necessary with special care in patients with a history of alcohol abuse. Use of pyridoxine (vitamin B6) may prevent or diminish neuropathy due to isoniazid treatment especially in elderly and in malnourished patients. Pyridoxine should be given in line with official guidelines.

Advise patients of importance of full compliance. If initial intensive phase treatment with rifampicin with isoniazid, pyrazinamide and ethambutol tablets is interrupted for any reason, including non-compliance, this fixed drug combination product 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. Reference should be made to official guidance on the appropriate resumption of treatment with anti-tuberculosis agents.

Patients should abstain from alcohol while receiving treatment.

Isoniazid may increase the formation of toxic metabolites of paracetamol if paracetamol is taken during isoniazid treatment. Advise patients that they should limit the use of paracetamol-containing products during treatment with isoniazid and, preferably, seek medical advice before taking paracetamol-containing products.

Food with a high content of tyramine or histamine should be avoided. Isoniazid may inhibit monoamine oxidase and diamine oxidase. Intake of food containing tyramine (e.g. cheese, red wine) or histamine (e.g. tuna fish) may lead to headache, palpitations, flushing.

Warn patient that red discolouration of body fluids may occur.

Discolours soft contact lenses.

Additional non-hormonal means of contraception must be employed to prevent the possibility of pregnancy during treatment.

Ability to drive or operate machinery may be affected by side effects.

May cause vitamin K dependent coagulopathy and severe bleeding. Consider vitamin K supplementation, risk of vitamin K dependent coagulopathy.

Use rifampicin with isoniazid, pyrazinamide and ethambutol tablets with caution during pregnancy.

Use rifampicin with isoniazid, pyrazinamide and ethambutol tablets with caution during breastfeeding.

Adults:

Patients with body weight less than 30kg

Contraindicated in patients weighing less than 30kg

Dosage should be calculated according to patient weight based on the ratio 8-12mg/kg rifampicin, 4-6mg/kg isoniazid, 20-30mg/kg pyrazinamide and 15-20mg/kg ethambutol as follows:

30 – 39kg bodyweight: 2 tablets daily for 2 months
40 – 54kg bodyweight: 3 tablets daily for 2 months
55 – 70kg bodyweight: 4 tablets daily for 2 months
over 70kg bodyweight: 5 tablets daily for 2 months

Elderly

See Dosage; Adults.

Supplementation of pyridoxine (vitamin B6) may be useful in elderly patients.

Children

Patients with body weight less than 30kg

Contraindicated in patients weighing less than 30kg

Children under 8 years

Contraindicated in children under 8 years old because of risk of aspiration and difficulties in evaluation of changes of visual acuity.

Ethambutol / Isoniazid / Pyrazinamide / Rifampicin