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Logo PURBAC INJECTION 5 mL

SCHEDULING STATUS:
S4

PROPRIETARY NAME
(and dosage form):

PURBAC INJECTION 5 mL

COMPOSITION:
Each 5 mL contains: Trimethoprim 80 mg
  Sulphamethoxazole 400 mg
  Ethyl alcohol (100%) 10% v/v
PHARMACOLOGICAL CLASSIFICATION:
A 20.2 Anti-microbial agents other than antibiotics.

PHARMACOLOGICAL ACTION:
The introduction of Trimethoprim in combination with Sulphamethoxazole represents the practical application of a theoretical consideration, that is, if two drugs act on sequential steps in the pathway of an obligate enzymatic reaction in bacteria, the result of their combination will be supra-additive.
Mechanism of action: Sulphamethoxazole inhibits the incorporation of PABA into folic acid and Trimethoprim is a highly selective inhibitor of dihydrofolate reductase. Therefore by using Trimethoprim and Sulphamethoxazole in combination, the maximum synergistic effect is achieved and the risk of bacterial resistance developing is reduced to a minimum.
Antibacterial spectrum: All strains of Strep. pneumoniae, C. diphtheriae, and N. meningitidis are sensitive to Purbac (Co-trimoxazole). From 50 to 95% of strains of Staph. aureus, Epidermidis, Strep. pyogenes, the Viridans group of Streptococci, Strep. faecalis, E. coli, Pr. mirabilis, Pr. morganii, Pr. rettgeri, Enterobacter (Aerobacter) species, Salmonella, Shigella, Pseud. pseudomallei, Serratia and Alcaligenes species are inhibited. Also sensitive are Klebsiella species, Brucella abortus, Pasteurella haemolytica, Yersinia pseudotuberculosis, Y. enterocolitica and Nocardia asteroides. Very few strains of Pseud. aeruginosa are sensitive. Methicillin-resistant strains of Staph. aureus, although also resistant to Trimethoprim or Sulphamethoxazole alone, are susceptible to the combination. A synergistic interaction between the components of the preparation is apparent even when micro-organisms are resistant to Sulphonamide or resistant to Sulphonamide and moderately resistant to Trimethoprim. However a maximal degree of synergism occurs when microorganisms are sensitive to both components.
Bacterial resistance: The frequency of development of bacterial resistance to Co-trimoxazole is lower than it is to either of the components alone. Resistance in gram-negative bacteria is associated with the presence of R-factors, which can be transferred to susceptible micro-organisms by conjugation. Resistance to high concentrations of Sulphonamides and to moderate concentrations of Trimethoprim has been demonstrated to be transferred in this manner. Resistance to Trimethoprim in Staph. aureus appears to be determined by a chromosomal gene rather than by a plasmid. The development of resistance to the combination also occurs in vivo. E. coli resistant to Trimethoprim and H. influenzae resistant to Co-trimoxazole have been isolated from patients treated with the combination.
Absorption, distribution and excretion: The co-administration of the drugs appears to slow the absorption of Sulphamethoxazole. The half-lives of Trimethoprim and Sulphamethoxazole are 16 and 10 hours, respectively. When 400 mg of Sulphamethoxazole is given with 80 mg of Trimethoprim (the conventional 5:1 ratio), three times daily, the mean minimal steady-state concentrations of the drugs are approximately 20 and 1 µg/mL, respectively –the optimal ratio that is sought. Trimethoprim is rapidly distributed and concentrated in tissues, and relatively small quantities are bound to plasma protein in the presence of Sulphamethoxazole. The drug enters the cerebrospinal fluid and sputum readily. High concentrations of each component of the mixture are also found in bile. About 65% of Sulphamethoxazole is bound to plasma protein. Up to 60% of administered Trimethoprim and from 25% to 50% of Sulphonamide are excreted in the urine in 24 hours. The rates of excretion and the urine concentrations of both compounds are significantly reduced in patients with uremia.

INDICATIONS:
Purbac (Co-trimoxazole) Injection is indicated for infections, caused by sensitive micro-organisms, requiring parenteral treatment.

CONTRA-INDICATIONS:
The use of Purbac (Co-trimoxazole) is contra-indicated in persons with jaundice, porphyria and in persons who have shown hypersensitivity to sulphonamides. It is also generally considered to be contra-indicated in patients with impaired renal or liver function. The effects of sulphonamides may be enhanced by displacement from plasma binding sites by more highly bound acidic substances. Purbac (Co-trimoxazole) should not be given to infants within at least 2 weeks of birth and to pregnant women. Repeated haematological investigations are required during prolonged therapy.

DOSAGE AND DIRECTIONS FOR USE:
TO BE GIVEN BY INTRAVENOUS INFUSION ONLY.
Adults and children over 12 years:
Standard dosage: 10 mL twice daily, morning and evening.
Minimum dosage: For long term treatment (more than 14 days): 5 mL twice daily, morning and evening
Maximum dosage: For particularly severe cases: 15 mL twice daily, morning and evening.
Dosage for children up to 12 years:
6 weeks to 5 months: 1,25 mL twice daily, morning and evening.
6 months to 5 years: 2,5 mL twice daily, morning and evening.
6 to 12 years: 5,0 mL twice daily, morning and evening.
Typhoid fever:
Adult dosage: 5 mL twice daily, morning and evening for 15 days.
The recommended dosage is approximately 6 mg Trimethoprim and 30 mg Sulphamethoxazole per kg body mass per day, divided into two equal doses, morning and evening.
In acute infections, Purbac (Co-trimoxazole) should be given for at least 5 days or until the patient has been symptom free for 2 days. As soon as oral treatment becomes possible, the intravenous administration must be discontinued.

Purbac (Co-trimoxazole) Injection must not be injected intravenously in the undiluted state, but must be added to infusions such as Dextrose 5%, Dextrose 10%, Inverted Sugar 10%, Laevulose 5%, Ringer-lactate solution, Sodium Chloride 0,9% solution and Sodium Chloride 0,45% + Dextrose 2,5% solution in the ratio of 1 to 30 mL of infusion.

Purbac (Co-trimoxazole) must not be injected intramuscularly or subcutaneously.
Infusion solutions must be used within 6 hours of preparation and must be administered slowly over a period of approximately one and a half hours.

SIDE-EFFECTS AND SPECIAL PRECAUTIONS:
The margin between therapeutic and toxic blood levels, in man, is relatively narrow, especially in patients deficient in folates. In such cases, Purbac (Co-trimoxazole) may cause or precipitate megaloblastosis, leucopoenia or thrombocytopoenia, erythema multiforme, toxic dermal necrolysis and allergic vasculitis. In routine use, the combination appears to exert little toxicity. About 75% of the side-effects involve the skin. These are typical of those known to be produced by Sulphonamides. Exfoliative dermatitis, Stevens-Johnson syndrome, and toxic dermal necrolysis (Lyell's syndrome) occur primarily in older individuals. Nausea and vomiting and diarrhoea constitute the bulk of gastro-intestinal reactions. Glossitis and stomatitis occur. Transient jaundice has been noted and appears to have the histological features of allergic cholestatic hepatitis. Most patients who have developed icterus have a history of prior infectious hepatitis. Central nervous system reactions consist of headache, depression and hallucinations. Haematological reactions, in addition to those mentioned above, include various types of anaemia (including aplastic, haemolytic and macrocytic), coagulation disorders, granulocytopoenia, agranulocytosis, purpura, Henoch-Schonlein purpura, and sulph-globinaemia. Prior or simultaneous administration of diuretics with Purbac (Co-trimoxazole) may carry an increased risk of thrombocytopoenia, especially in elderly patients with heart failure. Death may occur. It should be remembered that Purbac (Co-trimoxazole) has the toxic potential equal at least to that of the sulphonamides. In all decisions, the results of microbial sensitivity testing must be considered.

Purbac (Co-trimoxazole) Injection must not be injected intramuscularly or subcutaneously.

KNOWN SYMPTOMS OF OVERDOSAGE AND PARTICULARS OF ITS TREATMENT:
See "Side effects and special precautions". High doses may cause diarrhoea, nausea and vomiting, skin rashes and other allergic reactions. It may cause a depression of haemopoiesis due to interference of the drug in the metabolism of folic acid. Injections of calcium folinate may be given to counteract this interference. Blood counts should be performed frequently particularly in patients undergoing prolonged treatment. Supportive measures i.e. cortisone, intravenous infusion, adrenaline etc. can be used if anaphylaxis occurs.

IDENTIFICATION:
A clear colourless and slight straw-coloured solution in 5 mL clear ampoules.

PRESENTATION:
5 mL ampoules in containers of 10.

STORAGE INSTRUCTIONS:
Store below 25°C. Do not refrigerate. Protect from light.
KEEP ALL MEDICINE OUT OF REACH OF CHILDREN.

REGISTRATION NUMBER:
L/20.2/336

NAME AND BUSINESS ADDRESS OF APPLICANT:
Intramed (Pty) Ltd
6 Gibaud Road
PORT ELIZABETH
6001

DATE OF PUBLICATION OF THIS PACKAGE INSERT:
July 1979 12-058/7-94

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