RIFAFOUR®e-275 TABLETS|利福平+吡嗪酰胺+乙胺丁醇和异烟肼 =结核病治疗药物复方制剂

SCHEDULING STATUS:
S4

PROPRIETARY NAME
(and dosage form):

RIFAFOUR^®e-275 TABLETS

COMPOSITION:
Each tablet contains:
Rifampicin 150 mg
Isoniazid 75 mg
Pyrazinamide 400 mg
Ethambutol 275 mg
Contains sodium ascorbate as anti-oxidant.
PHARMACOLOGICAL CLASSIFICATION:
A 20.2.3 Tuberculostatic combinations
PHARMACOLOGICAL ACTION:
Rifafour e-275 tablets is a combination of four first line agents used in the treatment of tuberculosis. Rifampicin is a semi-synthetic, broad-spectrum bactericidal antibiotic. Isoniazid is a synthetic, antitubercular agent which is bacteriostatic against semi-dormant bacilli and bactericidal against actively dividing mycobacteria. Pyrazinamide may be bactericidal or bacteriostatic, depending on its concentration and the susceptibility of the organism. Ethambutol is a synthetic, bacteriostatic antitubercular agent. All agents are readily absorbed following oral administration, with wide distribution to most tissues and fluids including cerebrospinal fluid.

INDICATIONS:
Initial phase treatment of pulmonary and extrapulmonary tuberculosis in new adult patients and re-treatment of adult cases.

CONTRA-INDICATIONS:
Rifafour e-275 tablets are contra-indicated in:

SIDE-EFFECTS AND SPECIAL PRECAUTIONS:
Side-effects associated with rifampicin:
Some patients may experience a cutaneous syndrome which presents 2 to 3 hours after a daily or intermittent dose i.e. facial flushing, itching, rash, eye irritation.
A 12 hour "flu" syndrome, usually occurring after 3 to 6 months of intermittent treatment and usually with doses of 20 mg/kg or more, may present as fever, chills, bone pain and malaise.
Gastrointestinal effects include nausea, vomiting, anorexia, diarrhoea and epigastric distress, which may be alleviated by administration with food.
There have been reports of pseudomembranous colitis.
Hepatitis and the prodromal symptoms of hepatitis may occur (nausea, vomiting, unusual tiredness/fatigue).
Rifampicin can cause thrombocytopenia and purpura usually with intermittent regimens. Other haematological adverse effects include eosinophilia, leucopenia and haemolytic anaemia.
Nervous system effects include headache, drowsiness, dizziness, ataxia, numbness, visual disturbances and muscular weakness.
Alterations in kidney function and renal failure have occurred.
Rifampicin may cause orange-red discoloration of urine and other body fluids.
Menstrual disturbances have been reported.
Side-effects associated with isoniazid:
Elevated liver enzymes associated with clinical signs of hepatitis such as nausea, vomiting or fatigue may indicate hepatic damage. The incidence of liver damage is highest in patients over 35 years of age, those who are slow acetylators and those who consume alcohol on a daily basis. Gastrointestinal effects (nausea, vomiting, pellagra) and hypersensitivity reactions (skin eruptions including erythema multiforme, fever, lymphadenopathy, vasculitis) may occur.
Haematological effects have been reported (sideroblastic anaemia, agranulocytosis, haemolytic anaemia, thrombocytopenia, neutropenia, eosinophiliaand less frequently, aplastic anaemia).
Neurological effects include psychotic reactions and convulsions.
Other effects: hyperglycaemia, metabolic acidosis, lupus-like syndrome, rheumatoid syndrome, urinary retention and gynaecomastia.
Optic neuritis has also been reported.
Peripheral neuropathy has also been associated with isoniazid administration. Pyridoxine supplementation prevents the development of peripheral neuritis, as well as most other nervous system dysfunctions.
Side-effects associated with 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. Photosensitivity and skin rash have been reported less frequently. Other side-effects that have been reported are anorexia, nausea and vomiting, malaise, fever, sideroblastic anaemia and dysuria.
Side-effects associated with ethambutol:
Retrobulbar neuritis with a reduction in visual acuity, constriction of visual field, central or peripheral scotoma, and green-red colour blindness may occur, affecting one or both eyes. The degree of visual impairment appears to depend on the dose and duration of therapy. Retinal haemorrhage has occurred less frequently. Renal clearance of urate may be reduced and acute gout has been precipitated. Hypersensitivity reactions include skin rash, pruritis, leucopenia, fever and joint pains. Gastrointestinal disturbances include metallic taste, nausea, vomiting, anorexia and abdominal pain. Other adverse effects: Confusion, disorientation, hallucinations, headache, dizziness, malaise, jaundice or transient liver dysfunction, peripheral neuritis.
SPECIAL PRECAUTIONS:
In the following cases, treatment with Rifafour e-275 tablets should be stopped immediately and the patient eva luated: jaundice, rash and fever, elevated liver enzymes associated with the clinical signs of hepatitis, visual impairment. If liver damage is confirmed, the medicine should not be recommenced.
Treatment should be discontinued permanently should thrombocytopenia, purpura, shock or renal failure occur. Periodic eye examinations during treatment is suggested.
INTERACTIONS:
Rifampicin:
Concurrent use of alcohol, acetaminophen, isoniazid and other hepatotoxic medication may increase the incidence of rifampicin-induced hepatotoxicity. The effectiveness of oestrogen-containing oral preparations is reduced. Rifampicin accelerates the metabolism of certain medicines by inducing microsomal enzymes. Medicines that are affected include: atorvaquone, azathioprine, chloramphenicol, cimetidine, clofibrate, corticosteroids, coumarin anticoagulants, cyclosporin, dapsone, diazepam and other benzodiazepines, doxycycline, azole antifungals (ketoconazole, itraconazole, fluconazole), haloperidol, hexobarbitone, methadone, oral hypoglycaemic agents, phenytoin, quinine, sulphasalazine, thyroxine, theophylline, zidovudine, beta-blockers, digitoxin, digoxin, antiarrhythmic agents (e.g. disopyramide, verapamil) and calcium channel blockers.
Isoniazid:
Chronic use of isoniazid may decrease the plasma clearance and prolong the duration of action of alfentanil, coumarin anticoagulants, benzodiazepines, carbamazepine, phenytoin, ethosuximide, chlorzoxazone, and theophylline. Appropriate adjustment of the anticonvulsant dose may be required. Concurrent use of paracetamol, alcohol, rifampicin and other hepatotoxic medication, may increase the potential for isoniazid-induced hepatotoxicity.
Aluminium-containing antacids may delay absorption and decrease serum concentrations of isoniazid. Ingestion of certain types of cheese e.g. Swiss or Cheshire, or fish e.g. tuna, may result in itching of the skin, rapid or pounding heart, chills or headache. Glucocorticoid corticosteroids may increase hepatic metabolism and/or excretion of isoniazid.
Concurrent use of cycloserine, disulfiram and other neurotoxic medicines may increase the potential for CNS toxicity. Isoniazid may increase the formation of potentially nephrotoxic inorganic fluoride metabolites when used concurrently with enflurane. Interactions with ketoconazole and miconazole have been reported. False positive reactions with copper sulphate urine glucose tests may occur.
Pyrazinamide:
Pyrazinamide may decrease the efficacy of gout therapy (e.g. allopurinol, colchicine, probenecid or sulphinpyrazone) and dosage adjustments of this medication may be necessary.
Ethambutol:
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:
For symptoms of overdosage, refer to "Side-Effects".
Treatment of overdosage consists of gastric lavage, symptomatic and supportive therapy.

IDENTIFICATION:
Purple, round, film coated tablets.

PRESENTATION:
Securitainers of 40, 60, 80, 100 and 500 tablets.

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

REGISTRATION NUMBER:
34/20.2.3/0187

NAME AND BUSINESS ADDRESS OF THE APPLICANT:
Aventis Pharma (Pty) Ltd
2 Bond Street, Midrand, 1685

DATE OF PUBLICATION OF THIS PACKAGE INSERT:
11 February 2002

Aventis Pharma (Pty) Ltd
2 Bond Street
Midrand
1685

        RO2-A0003
        Britepak