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Logo DUROBAC TABLETS
DUROBAC DOUBLE STRENGTH TABLETS

SCHEDULING STATUS:
S4

PROPRIETARY NAME
(and dosage form):

DUROBAC TABLETS
DUROBAC DOUBLE STRENGTH TABLETS

COMPOSITION:
Each Durobac Tablet contains:
        80 mg
Trimethoprim and 400 mg Sulphamethoxazole

Each Durobac Double Strength Tablet contains:
        160 mg Trimethoprim and 800 mg Sulphamethoxazole

PHARMACOLOGICAL CLASSIFICATION:
20.2 Antimicrobial agents other than antibiotics

PHARMACOLOGICAL ACTION:
The antimicrobial activity of the combination of trimethoprim and sulphamethoxazole results from its action on two steps of the enzymatic pathway for the synthesis of tetrahydrofolic acid. Sulphonamide inhibits the incorporation of PABA into folic acid, and trimethoprim prevents the reduction of dihydrofolate to tetrahydrofolate. The latter is the form of folate essential for one-carbon transfer reactions, for example, the synthesis of thymidylate from deoxyuridylate. Selective toxicity for micro-organisms is achieved in two ways. Mammalian cells utilise preformed folates from the diet and do not synthesise the compound. Furthermore, trimethoprim is a highly selective inhibitor of dihydrofolate reductase of lower organisms. This is vitally important, since this enzymatic function is e crucial one in all species. The synergistic interaction between sulphonamides and trimethoprim is thus predictable from their respective mechanisms. There is an optimal ratio of concentrations of the two agents for synergism, and this is equal to the ratio of the minimal inhibitory concentrations of the drugs acting independently. The pharmacokinetic properties of the sulphonamide chosen to be in combination with trimethoprim are thus important, since relative concentrations of the two compounds in the body is desired.

Bacterial resistance: The frequency of development of bacterial resistance to trimethoprim-sulphamethoxazole is lower than it is to either of the agents alone. Resistance in Gram-negative bacteria is associated with the presence of R factor, which can be transferred to susceptible micro-organisms by conjugation.

Absorption, Distribution and Excretion: After a single oral dose of the combined preparation trimethoprim is absorbed more rapidly than sulphamethoxazole. The co-administration of the drugs appears to slow the absorptionr of sulphamethoxazole. Peak blood concentrations of trimethoprim usually occur by 2 hours in most patients, while peak concentrations of sulphamethoxazole are seen by 4 hours after a single oral dose. 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 minimal steady-state concentrations of the drugs are approximately 20 and 1 µg/mL, respectively. 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. 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 sulphamethoxazole are excreted in the urine in 24 hours. Two-thirds of the sulphonamide is unconjugated. Metabolites of trimethoprim are also excreted. The rates of excretion and urine concentrations of both compounds are significantly reduced in patients with uremia.

INDICATIONS:
Urinary tract infections:
The management of uncomplicated infections of the lower urinary tract. Acute and chronic cystitis, chronic infections of the upper urinary tract, and asymptomatic bacilluria.

Genital infections: Acute gonococcal urethritis in both men and women.

Respiratory tract infections: Pulmonary infections with various types of H. influenzae, and Strep. pneumoniae.

There is some difference of opinion concerning the therapeutic value of trimethoprim-sulphamethoxazole in typhoid fever. The experience of Scragg and Rubidge (1971) suggests that, in children, this drug is not as effective as chloramphenicol. In adults with this disease, trimethoprim-sulphamethoxazole appears to be as effective as chloramphenicol when the dose is 2 tablets every 12 hours for 15 days.

The combination has been used in the treatment of cholera; it appears to be an effective alternative to tetracycline.

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

DOSAGE AND DIRECTIONS FOR USE:
Adults and children over 12 years:
Standard dosage: 2 Durobac tablets or 1 Durobac Double Strength tablet twice daily, morning and evening after meals.

Minimum dosage and dosage for long term treatment (more than 14 days): 1 Durobac Tablet twice daily or ½ Durobac Double Strength twice daily.

Maximum dosage (for particularly severe cases): 3 Durobac tablets or 1½ Durobac Double Strength tablets twice daily.

In acute infections, Durobac should be given for at least 5 days or until the patient has been symptom free for 2 days.

SIDE-EFFECTS AND SPECIAL PRECAUTIONS:
Durobac may cause or precipitate megaloblastosis, leucopenia or thrombocytopenia. About 75% of the side-effects involve the skin. Exfoliative dermatitis, Stevens-Johnson syndrome, toxic epidermal necrolysis (Lyell’s syndrome), erythema multiforme and allergic vasculitis may occur. Skin reactions have developed in from 1,6 to 8% of individuals in different series of patients. Nausea and vomiting constitute the bulk of gastro-intestinal reactions; diarrhoea may occur. Glossitis and stomatitis may occur. Transient jaundice has been noted and appears to have the histological features of allergic cholestatic hepatitis. Most patients who have developed icterus have had a history of prior infectious hepatitis, central nervous system reactions consist of headache, depression and hallucinations. Haematological reactions in addition to those mentioned above, are various types of anaemia (including aplastic, haemolytic and macrocytic), coagulation disorders, granulocytopenia, agranulocytosis, purpura, Henoch-Schönlein purpura, and sulph-haemoglobinemia. Previous or simultaneous administration of diuretics with trimethoprim-sulphamethoxazole may carry an increased risk of thrombocytopenia, especially in elderly patients with heart failure; death may occur. Blood counts should be made frequently, particularly in patients undergoing prolonged treatment.

KNOWN SYMPTOMS OF OVERDOSAGE AND PARTICULARS OF ITS TREATMENT:
High doses may cause diarrhoea, nausea and vomiting. 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. Treatment is symptomatic.

IDENTIFICATION:
Durobac: White bisected tablets
Durobac Double Strength: White oblong, biconvex, bisected tablets

PRESENTATION:
Durobac        30 tablets
Durobac Double Strength        10 tablets

STORAGE INSTRUCTIONS:
Store in a cool, dry place below 25°C.
KEEP OUT OF REACH OF CHILDREN.

REGISTRATION NUMBER:
Durobac Tablets        J/20.2/279
Durobac Double Strength Tablets        P/20.2/55

NAME AND BUSINESS ADDRESS OF APPLICANT:
Pharmaceutical Enterprises (Pty) Ltd,
Howard Studios, Howard Drive, Pinelands 7405.

DATE OF PUBLICATION OF THIS PACKAGE INSERT:
06 July 1993

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