INDICATIONS     CONTRA-INDICATIONS     DOSAGE     SIDE-EFFECTS     PREGNANCY     OVERDOSE     IDENTIFICATION     PATIENT INFORMATION
BEECHAM CHLORAMPHENICOL Capsules

SCHEDULING STATUS:
S4

PROPRIETARY NAME
(and dosage form):

BEECHAM CHLORAMPHENICOL Capsules

COMPOSITION:
Gelatin capsules containing 250 mg chloramphenicol.

PHARMACOLOGICAL CLASSIFICATION:
A. 20.1.1 Broad and medium spectrum antibiotics.

PHARMACOLOGICAL ACTION:
Chloramphenicol is a broad spectrum antibiotic effective against a wide range of Gram-negative and Gram-positive bacteria, rickettsias, and chlamydias. It acts by interfering with bacterial protein synthesis and is mainly bacteriostatic.

Chloramphenicol is active when given orally and diffuses into the cerebrospinal fluid even when the meninges are not inflamed. The majority of a dose is inactivated in the liver, only a small proportion appearing unchanged in the urine.

INDICATIONS:

1.	Typhoid fever and other types of systemic salmonella infections. The carrier state will not be eliminated.
2.	Bacterial meningitis due to Haemophilus influenzae.
3.	Anaerobic infections originating from foci in the bowel or pelvis.
4.	Rickettsial diseases such as epidemic, murine, scrub and recrudescent typhus, Rocky Mountain spotted fever and Q. fever when tetracyclines are not indicated.
5.	Brucellosis when tetracyclines are contra-indicated.

The use of chloramphenicol should be limited to serious infections where positive bacteriological evidence and clinical judgement indicates that chloramphenicol is an appropriate antibiotic.

CONTRA-INDICATIONS:
Chloramphenicol is contra-indicated in the following conditions:

1.	patients with a history of hypersensitivity or toxic reactions.
2.	for minor infections or for prophylaxis.
3.	aplastic anaemia.
4.	during active immunisation.

WARNINGS:
The risk of aplastic anaemia does not restrict the use of chloramphenicol in situations in which it is necessary; however, it emphasizes that the drug should never be employed in diseases readily, safely and effectively treatable with other antimicrobial agents or in undefined cases.
Because of the risk of the “grey”syndrome, neonates should only be given chloramphenicol when it may be life-saving and no alternative treatment is available.
The use of chloramphenicol during pregnancy is best avoided.
Repeated courses and prolonged treatment should be avoided.
Concomitant administration of chloramphenicol with other drugs liable to depress bone-marrow function should be avoided.
Chloramphenicol enhances the effects of coumarin anticoagulants, some hypoglycaemic agents (chlorpropamide and tolbutamide) and phenytoin.

DOSAGE AND DIRECTIONS FOR USE:
Adults: –500 mg every 6 hours or 50 mg/kg body mass daily in divided doses every 6 hours.

The dose of chloramphenicol should be reduced in the presence of hepatic disease or in patients with renal insufficiency.

Children: –25 to 50 mg/kg body mass daily, given in divided doses at intervals of 6 hours.

SIDE-EFFECTS AND SPECIAL PRECAUTIONS:
Hypersensitivity reactions: Macular or vesicular skin rashes occur as a result of hypersensitization to chloramphenicol. Fever may appear simultaneously or be the sole manifestation. Angioedema is a rare complication. Herxheimer reactions have been observed. Erythema multiforme has been reported.

Hematological Toxicity: The most important adverse effect of chloramphenicol is on the bone-marrow.

Changes in peripheral blood include leukopenia, thrombocytopenia, and aplasia of the marrow with fatal pancytopenia. The incidence is not dose-related. The fatality rate is high when bone-marrow aplasia is complete, and there is a high incidence of acute leukemia in those who recover.

A second haematological effect of chloramphenicol is a predictable but reversible erythroid suppression of the bone marrow. The clinical picture is featured initially by reticulopenia, which occurs 5 to 7 days after the initiation of therapy, followed by a decrease in haemoglobin, an increase in plasma iron, cytoplasmic vacuolation of early erythroid forms and granulocyte precursors, and normoblastosis with a shift to early erythrocyte forms. Severe leukopenia and thrombocytopenia may also occur. The incidence and severity of this syndrome are dose-related. It occurs regularly when plasma concentrations are 25µg/mL or higher and is observed during the use of large doses of chloramphenicol, prolonged treatment, or both. Haemolytic anaemia has occurred in persons with a genetic deficiency of glucose-6-phosphate dehydrogenase activity.

Other Effects: Gastrointestinal symptoms including nausea, vomiting, unpleasant taste, diarrhoea and perineal irritation may follow oral administration of chloramphenicol. Disturbances of the oral and intestinal flora may cause stomatitis, glossitis, and rectal or vaginal irritation.

Prolonged oral administration of chloramphenicol may induce bleeding either by bone-marrow depression or by reducing the intestinal flora with consequent inhibition of vitamin K synthesis and greatly increased prothrombin time.

Among the toxic effects produced by chloramphenicol are blurring of vision and digital paresthesias. Peripheral as well as optic neuritis has been reported in patients receiving chloramphenicol, usually over prolonged periods.

A toxic manifestation –“the grey syndrome”– has occurred in premature and other newborn infants receiving large doses of chloramphenicol. A similar syndrome has been reported in adults and children given high doses. Chloramphenicol should never be given for minor infections or for prophylaxis and repeated courses and prolonged treatment should be avoided.

Reduced doses should be given to patients with impaired liver function. Uraemic patients may be more susceptible to the depressant effect of chloramphenicol on bone-marrow but reducing the dose may result in inadequate plasma concentrations. Routine periodic blood examinations are advisable in all patients including infants; these examinations will not warn of aplastic anaemia.

Because of the risk of the “grey” syndrome newborn infants should not be given chloramphenicol, unless it may be lifesaving and there is no alternative treatment. The use of chloramphenicol is best avoided during pregnancy; nursing infants should be observed with care since chloramphenicol given to the mother is excreted in the milk.

KNOWN SYMPTOMS OF OVERDOSAGE AND PARTICULARS OF ITS TREATMENT:
The “grey”syndrome-characterised by vomiting, abdominal distension, ashen colour, hypothermia, irregular respiration, progressive pallid cyanosis, and shock, followed by death in a few hours or days.

Other toxic manifestations include aplastic anaemia, blurring of vision, digital paresthesias, optic neuritis, allergic skin rashes, and gastro-intestinal haemorrhage.

Chloramphenicol should be discontinued immediately on the appearance of toxic symptoms.

Treatment is symptomatic and supportive.

IDENTIFICATION:
Opaque white/white capsules.

PRESENTATION:
Containers containing 100, 500 or 1000 capsules.

STORAGE INSTRUCTIONS:
Store below 25°C and protect from light.
Keep out of reach of children.

REGISTRATION NUMBER:
V/20.1.1/317

NAME AND BUSINESS ADDRESS OF THE APPLICANT:
SmithKline Beecham Pharmaceuticals (Pty) Limited
6 Carey Street, Wynberg Ext. 6, Johannesburg 2090.

DATE OF PUBLICATION OF THIS PACKAGE INSERT:
13 October 1988..
P0602
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