Source: Health Products Regulatory Authority (ZA) Revision Year: 2024 Publisher: Innovata Pharmaceuticals (Pty) LTD, 100 Northern Parkway Rd, Crownwood Office, Block D, Ground Floor, Ormonde, 2091
A high incident of side-effects occurs in immunocompromised patients such as those suffering from AIDS or patients receiving immunosuppressive therapy. The adverse effects include skin rash, recurrent fever, neutropenia, thrombocytopenia and raised liver enzyme values.
DUROBAC may cause the occurrence of erythema multiforme, toxic dermal necrolysis and allergic vasculitis. Treatment should be discontinued immediately when a rash appears because the danger of severe allergic reactions.
DUROBAC should be given with caution to patients with actual or possible folate deficiency because of possible interference with human folate metabolism by trimethoprim as in DUROBAC. Administration of folinic acid could be considered
Cross-sensitivity has been observed between sulfamethoxazole as in DUROBAC and chemically related compounds such as some diuretics, particularly acetazolamide and thiazides, and the sulfonylurea hypoglycaemic medicines.
All patients receiving prolonged treatment with DUROBAC should be given regular blood examinations.
Adverse effects on the blood may be more severe in malnourished or elderly patients: there also appears to be an increased risk of thrombocytopenia in elderly patients concurrently receiving diuretics, mainly thiazides.
DUROBAC should be used cautiously and in reduced dosage in patients with impaired renal function (see section 4.2).
Because of the risk of crystalluria, an adequate fluid intake should be maintained and the administration of alkalis may be necessary if very large doses are used.
DUROBAC and DUROBAC D/S contains:
DUROBAC contains Nipastat, a mixture of parahydroxybenzoate esters. It may cause allergic reactions (possibly delayed).
Sulfamethoxazole as in DUROBAC may potentiate the effects of some medicines such as oral anticoagulants, methotrexate, phenytoin; this may be due to displacement of the compound from plasma protein binding sites or to inhibition of metabolism.
Trimethoprim as in DUROBAC may potentiate the anticoagulant effect of warfarin. It also prolongs the half-life of phenytoin.
High doses of sulfamethoxazole as in DUROBAC may have a hypoglycaemic effect. The antidiabetic effect of the sulfonylurea compounds may be enhanced by the concomitant administration of sulfamethoxazole.
The action of sulfamethoxazole as in DUROBAC may be antagonised by paraaminobenzoic acid and compounds derived from it, particularly the procaine group of local anaesthetics.
Paraldehyde has been reported to increase the acetylation of sulfamethoxazole with subsequent increased risk of crystalluria.
Trimethoprim as in DUROBAC has been reported to interact with a number of other medicines by interfering with their clearance; such medicines include digoxin, procainamide, and tolbutamide.
Reversible deterioration in renal function has been reported in patients given trimethoprim as in DUROBAC and cyclosporine following renal transplantation.
Patients receiving pyrimethamine may develop megaloblastic anaemia due to the trimethoprim component as in DUROBAC.
Concomitant treatment with zidovudine may increase the risk of haematological adverse reactions to DUROBAC. If concomitant treatment is necessary, consideration should be given to monitoring of haematological parameters.
Administration of trimethoprim/sulfamethoxazole 160 mg/800 mg as in DUROBAC causes a 40% increase in lamivudine exposure because of the trimethoprim component. Lamivudine has no effect on the pharmacokinetics of trimethoprim or sulfamethoxazole.
Trimethoprim as in DUROBAC may increase the exposure of repaglinide which may result in hypoglycaemia.
Folinic acid supplementation has been shown to interfere with the antimicrobial efficacy of trimethoprim sulfamethoxazole as in DUROBAC. This has been observed in Pneumocystis jirovecii pneumonia prophylaxis and treatment.
Oral contraceptive failures have been reported with antibiotics such as, DUROBAC. The mechanism of this effect has not been elucidated. Women on DUROBAC treatment should temporarily use a barrier method in addition to the oral contraceptive or choose another method of contraception.
There are conflicting clinical reports of interactions between azathioprine and trimethoprim sulfamethoxazole as in DUROBAC, resulting in serious haematological abnormalities.
Caution should be exercised in patients taking any other medicines that can cause hyperkalaemia, for example ACE inhibitors, angiotensin receptor blockers and potassium-sparing diuretics such as spironolactone. Concomitant use of trimethoprim-sulfamethoxazole (co-trimoxazole) may result in clinically relevant hyperkalaemia.
Sulfamethoxazole may interfere with some diagnostic tests including those for urea, creatinine, and urinary glucose and urobilinogen.
Trimethoprim may interfere with some diagnostic tests including serum methotrexate assay where dihydrofolate reductase is used, and the Jaffe reaction for creatinine.
Trimethoprim and sulfamethoxazole as in DUROBAC cross the placenta and their safety in pregnant women has not been established. DUROBAC should not be used during pregnancy (see section 4.3).
The components of DUROBAC (trimethoprim and sulfamethoxazole) are excreted in breast milk. Administration of DUROBAC should be avoided in late pregnancy and in lactating mothers where the mother or infant has, or is at particular risk of developing, hyperbilirubinemia. DUROBAC should not be given to the new-born infant during the first weeks of life (see section 4.3).
It is not always possible to predict to what extent DUROBAC may interfere with the daily activities of a patient. DUROBAC can cause hallucinations, headache, dizziness and vertigo (see section 4.8). Patients should ensure that they do not engage in the above activities until they are aware of the measure to which DUROBAC affects them.
Hypersensitivity reactions particularly involving the skin are among the most common adverse effects of DUROBAC and are usually due to the sulfamethoxazole component. The Stevens-Johnson and Lyell’s syndromes have been reported.
Adverse effects on the gastro-intestinal tract may also occur fairly frequently.
Sulfamethoxazole:
| System Organ Class | Frequency | Adverse reactions |
|---|---|---|
| Infections and infestations | Frequent | Overgrowth fungal |
| Less frequent | Pseudomembranous colitis | |
| Blood and lymphatic system disorders | Less frequent | Agranulocytosis, aplastic anaemia, thrombocytopenia, leukopenia, hypoprothrombinaemia, eosinophilia, methaemoglobinaemia, acute haemolytic anaemia often associated with glucose-6- phosphate dehydrogenase deficiency, neutropenia |
| Immune system disorders | Less frequent | Anaphylaxis, serum sickness, allergic myocarditis, hypersensitivity vasculitis resembling Henoch-Schoenlein purpura, periarteritis nodosa, systemic lupus erythematosus, severe hypersensitivity reactions associated with PJP* |
| Endocrine disorders | Frequency unknown | Hypothyroidism |
| Metabolism and nutrition disorders | Frequent | Hyperkalaemia |
| Less frequent | Hypoglycaemia, hyponatraemia, decreased appetite, metabolic acidosis | |
| Psychiatric disorders | Less frequent | Depression, hallucination |
| Frequency unknown | Psychotic disorder | |
| Nervous system disorders | Frequent | Headache |
| Less frequent | Ataxia, dizziness, fatigue, insomnia, peripheral neuritis, seizure | |
| Eye disorders | Less frequent | Optic neuropathy, transient myopia, uveitis |
| Ear and labyrinth disorders | Less frequent | Vertigo, tinnitus |
| Respiratory, thoracic and mediastinal disorders | Less frequent | Cough*, dyspnoea*, lung infiltration* |
| Frequency unknown | Cyanosis due to methaemoglobinaemia or sulphaemoglobinaemia | |
| Gastrointestinal disorders | Frequent | Nausea, diarrhoea |
| Less frequent | Vomiting, glossitis, stomatitis, pancreatitis | |
| Hepato-biliary disorders | Frequent | Rash |
| Less frequent | Jaundice cholestatic*, hepatic necrosis*. increased transaminases, increased blood bilirubin | |
| Skin and subcutaneous tissue disorders | Less frequent | Photosensitivity reactions, exfoliative dermatitis, toxic epidermal necrolysis (Lyell’s syndrome), erythema nodosum, erythema multiforme, Steven- Johnson syndrome, systemic lupus erythematosus, fixed drug eruptions* |
| Frequency unknown | Acute febrile neutrophilic dermatosis (Sweet’s syndrome), drug reaction with eosinophilia and systemic symptoms (DRESS)* | |
| Musculoskeletal, connective tissue and bone disorders | Less frequent | Arthralgia, myalgia |
| Renal and urinary disorders | Less frequent | Renal failure, lumbar pain, haematuria, oliguria, and anuria may also occur due to crystallisation in the urine, tubulointerstitial nephritis and uveitis syndrome, renal tubular acidosis |
* See below Description of selected adverse reactions
Trimethoprim:
| System Organ Class | Frequency | Adverse reactions |
|---|---|---|
| Nervous system disorders | Frequent | Headache |
| Less frequent | Aseptic meningitis* | |
| Skin and subcutaneous tissue disorders | Frequent | Pruritus, skin rash, fever, nausea, vomiting and sore mouth, fixed drug eruptions* |
* See below Description of selected adverse reactions
Aseptic meningitis was rapidly reversible on withdrawal of the medicine, but recurred in a number of cases on re-exposure to either DUROBAC or to trimethoprim alone.
Cough, dyspnoea and lung infiltration may be early indicators of respiratory hypersensitivity which, while very rare, has been fatal.
Jaundice cholestatic and hepatic necrosis may be fatal.
Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN) and medicine reaction with eosinophilia and systemic symptoms (DRESS) have been reported to be life-threatening (see section 4.4).
Allergic reactions such as an itchy rash and hives may occur in patients with hypersensitivity to the components of DUROBAC. Very rare cases of acute generalised exanthematous pustulosis (AGEP) have been observed (see section 4.4).
Severe hypersensitivity reactions, rash, pyrexia, neutropenia, thrombocytopenia, hepatic enzyme increased, hyperkalaemia, hyponatraemia, rhabdomyolysis.
At the high dosages used for PJP management severe hypersensitivity reactions have been reported, necessitating cessation of therapy. Severe hypersensitivity reactions have been reported in PJP patients on re-exposure to co-trimoxazole, sometimes after a dosage interval of a few days. Rhabdomyolysis has been reported in HIV positive patients receiving co-trimoxazole for prophylaxis or treatment of PJP.
Dermatological manifestations of medicine reactions that often occur in the same location upon re-exposure to a medicine such as co-trimoxazole. They usually appear as erythematous-violaceous, circular patches, but several different variants have been described. They can often present without any associated symptoms, but in some cases, patients may complain of pain and pruritus.
Reporting suspected adverse reactions after authorisation of the medicine is important. It allows continued monitoring of the benefit/risk balance of the medicine. Healthcare professionals are asked to report any suspected adverse reactions to SAHPRA via the “6.04 Adverse Drug Reaction Reporting Form”, found online under SAHPRA’s publications: https://www.sahpra.org.za/Publications/Index/8
Not applicable.
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