INDICATIONS     CONTRA-INDICATIONS     DOSAGE     SIDE-EFFECTS     PREGNANCY     OVERDOSE     IDENTIFICATION     PATIENT INFORMATION
RIFAFOUR e-200® TABLETS

SCHEDULING STATUS:
S4

PROPRIETARY NAME
(and dosage form):

RIFAFOUR e-200^® TABLETS

COMPOSITION:
Each tablet contains:
Rifampicin 120 mg
Isoniazid 60 mg
Pyrazinamide 300 mg
Ethambutol 200 mg

PHARMACOLOGICAL CLASSIFICATION:
A 20.2.3 Tuberculostatic combinations

PHARMACOLOGICAL ACTION:
Rifafour e-200^® tablets is a combination of four first line agents used in the treatment of tuberculosis. Rifampicin and pyrazinamide are bactericidal antituberculosis agents. Isoniazid is bacteriostatic for semi-dormant bacilli and bactericidal for rapidly dividing micro-organisms. Ethambutol is bacteriostatic.

INDICATIONS:
Initial phase treatment of pulmonary and extrapulmonary tuberculosis in adults and reof adult cases.

CONTRA-INDICATIONS:
Rifafour e-200^® tablets are contra-indicated in patients with hypersensitivity to rifamycins, isoniazid, pyrazinamide, ethambutol or any of the other components of this medicine.
Contra-indicated in the presence of jaundice or any other pre-existing liver disorders.
Contra-indicated in patients with optic neuritis.
Not to be used in children under the age of thirteen.
Safely in pregnancy has not been established.
All agents of Rifafour e-200^® tablets are excreted in breast milk. Safety during lactation has not been established.

WARNINGS:
Caution should be observed with the use of Rifafour e-200^® tablets in the following patients:

•	impaired kidney function: dosage adjustment may be required according to the serum concentrations of ethambutol
•	patients with impaired hepatic function (see "Special Precautions")
•	elderly patients
•	patients with visual defects: should visual disturbances occur during treatment, these must be reported immediately and the medicine discontinued pending visual evaluation
•	patients at risk of neuropathy or pyridoxine deficiency, including those who are diabetic, alcoholic, malnourished, uraemic or pregnant: pyridoxine supplementation (in a 10 mg to 50 mg daily dose) is usually required in these instances
•	patients with a history of gout
•	Rifampicin may decrease the effect of oral contraceptives and patients are advised to change to non-hormonal methods of birth control
•	epileptic patients: isoniazid may precipitate seizures

DOSAGE AND DIRECTIONS FOR USE:
Take Rifafour e-200^® tablets with a full glass of water one hour before or 2 hours after a meal.
However, if gastrointestinal irritation occurs, the tablets may be taken with food. If aluminium containing antacids are taken, administer one hour after the tablet dose.
The recommended treatment dosages (given 5 days a week) for the 2 month initial phase:
Adults and children over 13 years between 30 to 50 kg: 4 tablets daily 5 days a week
                Over 50 kg: 5 tablets daily 5 days a week

SIDE EFFECTS AND SPECIAL PRECAUTIONS:
Gastrointestinal: Nausea, vomiting, anorexia, diarrhoea, abdominal pain.
Hypersensitivity reactions: Fever, pruritis, skin eruptions, soreness of the mouth and tongue, lymphadenopathy, vasculitis.
Neurological effects: Headache, drowsiness, dizziness, visual disturbances, peripheral neuritis, muscular weakness, psychotic reactions, convulsions (usually in patients with prior history of seizures); optic neuritis and atrophy.
Rifampicin:
Some patients experience cutaneous reactions such as facial flushing, itching, rash, or less frequently, eye irritation 2 to 3 hours after a daily dose. A 12-hour "flu" syndrome of fever, chills and malaise has been associated with intermittent administration.
Pseudomembranous colitis has been reported. Hepatitis occurs less frequently. Alterations in kidney and liver function have occurred.
Thrombocytopenia, eosinophilia, transient leucopenia and haemolytic anaemia have been reported to occur.
Rifafour e-200^® tablets may cause an orange-red discoloration of faeces, saliva, sputum, tears, urine and other body fluids. Patients are warned that soft contact lenses may be permanently discoloured.
Isoniazid:
Patients that are slow inactivators of isoniazid have a higher incidence of certain side effects.
Peripheral neuropathy is a common side effect, especially in patients with poor nutrition, as is rash, fever and jaundice.
Haematological effects: various anaemias; agranulocytosis; thrombocytopenia; eosinophilia
Other side effects: hyperglycaemia; metabolic acidosis; lupus-like syndrome; rheumatoid syndrome; urinary retention; methaemoglobinaemia; tinnitus; gynaecomastia; pellagra.
The prophylactic administration of pyridoxine prevents the development of peripheral neuritis as well as most other nervous system dysfunctions.
Pyrazinamide:
The most serious side effect is hepatotoxicity and its frequency appears to be dose-related.
Hyperuricaemia commonly occurs (occasionally accompanied by arthralgia) and may lead to attacks of gout.
Other side effects: arthralgia; malaise; fever; sideroblastic anaemia; dysuria.
Photosensitivity and skin rash have been reported less frequently.
Ethambutol:
The most important adverse effect is retrobulbar neuritis with a reduction in visual acuity, which appears to be dose-related; constriction of visual field; central or peripheral scotoma and green-red colour blindness affecting one or both eyes.
Renal clearance of urate may be reduced and acute gout may be precipitated.
Other side effects. leucopenia; disorientation; hallucinations; jaundice; transient liver dysfunction; peripheral neuritis; metallic taste.
SPECIAL PRECAUTIONS:
In the following cases. treatment with Rifafour e-200^® tablets should be stopped immediately and the patient evaluated:
•        Jaundice (associated with isoniazid, rifampicin and pyrazinamide)
•        Elevated liver enzymes associated with the clinical signs of hepatitis such as nausea and vomiting or fatigue
Hepatic function determinations are based on ALT (SGPT) and AST (SGOT) concentrations ie. serum alanine and aspartate aminotransferase concentrations. These tests may be required monthly during treatment, especially in the elderly, pregnant women and those with preliver damage.
Severe and sometimes fatal hepatitis has been reported.
•        Rash and fever (associated with isoniazid and rifampicin)
•        Bleeding tendency; shock; renal failure (associated with rifampicin): Treatment to be discontinued permanently should this occur.
•        Visual impairment (associated with ethambutol)
INTERACTIONS:
Rifampicin induces microsomal enzymes and may therefore accelerate clearance of medicines metabolised in the liver eg. methadone; oral anticoagulants (coumarin derivatives); glucocorticoids. oestrogens; oral hypoglycaemic agents; digitoxin; antiarrythmics (quinidine, verapamil mexiletine); theophylline; anticonvulsants; beta-blockers; azole antifungals (ketoconazole, fluconazole); cyclosporin.
Isoniazid inhibits the hepatic drug metabolism of the following agents: Antiepileptics (eg. phenytoin primidone, carbamazepine, ethosuxemide); benzodiazepines (eg. diazepam); warfarin; theophylline.
Isoniazid may also increase the metabolism of some medicines eg. enflurane.
Other interactions: Alcohol (metabolism of isoniazid may be increased in chronic alcoholics); aminosalicylic acid; aluminium containing antacids (reduces oral absorption of isoniazid); corticosteroids; ketoconazole; propranolol; cheese; red wine; some types of fish.
Pyrazinamide may decrease the efficacy of gout therapy (eg. allopurinol, colchicine, probenecid or sulphinpyrazone) and dosage adjustments of this medication may be necessary.
Concurrent administration of neurotoxic medication with ethambutol may potentiate neurotoxic effects such as optic and peripheral neuritis.

KNOWN SYMPTOMS OF OVERDOSAGE AND PARTICULARS OF ITS TREATMENT:
Symptoms of isoniazid overdose include slurred speech metabolic acidosis, hyperglycaemia, hallucinations, respiratory and CNS depression, convulsions and coma. Treatment of overdosage consists of gastric lavage symptomatic and supportive therapy. Haemodialysis may be of value in reducing serum concentrations of isoniazid and ethambutol.

IDENTIFICATION:
Purple, film coated, biconvex tablets scored on one side.

PRESENTATION:
Securitainers of 80, 100 and 500 tablets.

STORAGE INSTRUCTIONS:
Store in a cool place (below 25°C) in tightly closed containers, protected from light.
KEEP OUT OF REACH OF CHILDREN.

REGISTRATION NUMBER:
33/20.2.3/0125

NAME AND BUSINESS ADDRESS OF THE APPLICANT:
Hoechst Marion Roussel Limited
16th Road, Midrand.

DATE OF PUBLICATION OF THIS PACKAGE INSERT:
24 July 1998

Hoechst Marion Roussel Ltd.
16th Road
Midrand

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