SEPTRIN

SEPTRIN 

SEPTRIN TM
(Trimethoprim + Sulfamethoxazole)
ORAL PRESENTATIONS
CP223/05
QUALITATIVE AND QUANTITATIVE COMPOSITION
Formulation
Trimethoprim content
Sulfamethoxazole content
Adult Tablet
80 mq
400 mg
Dispersible
80 mq
400 mg
Double Strength (Forte) Tablets
160 mq
800 mg
Paediatric Tablets
20 mg
100 mq
Capsules
80 mq
400 mg
Adult Oral Suspension
80 mq per 5 ml
400 mq per 5 ml
Paediatric Oral Suspension
40 mg per 5 ml
200 mg per 5 ml
PHARMACEUTICAL FORM Tablets. Dispersible tablets. Capsules. Oral suspension. CLINICAL PARTICULARS Indications SEPTRIN should only be used where, in the judgment of the physician, the benefits of treatment outweigh any possible risks, consideration should be given to the use of a single effective antibacterial agent. The in vitro susceptibility of bacteria to antibiotics varies geographically and with time; the local situation should always be considered when selecting antibiotic therapy. Urinary tract Infections Treatment of acute uncomplicated urinary tract infections. It is recommended that initial episodes of uncomplicated urinary tract infections be treated with a single effective antibacterial agent rather than the combination. Respiratory tract infections Treatment of otitis media. SEPTRIN is not indicated for prophylactic or prolonged administration in otitis media. Treatment of acute exacerbations of chronic bronchitis. Treatment and prevention of Pneurnocystis jiroveci (P carinii) pneumonitis (see Dosage and Administration and Adverse Reactions). Genital tract infections Treatment of gonorrhoea, including oro-pharyngeal and ano-rectal infection (see Dosage and Administration). This regimen is less effective in some parts of the world due to disease caused by resistant organisms. Treatment of chancroid (see Dosage and Administration). This regimen may be less effective in some parts of the world due to disease caused by resistant organisms. Treatment of granuloma inguinale (venereum) (see Dosage and Administration). Gastrointestinal tract infections Clinicians should be aware that first line therapy in the management of all patients with dianhoeal disease is the maintenance of adequate hydration. Treatment of cholera, as an adjunct to fluid and electrolyte replacement, when the organism has been shown to be sensitive in vitro. Treatment of shigellosis, this regime may be less effective in some parts of the world due to resistant organisms. Treatment of travellers' diarrhoea (including gastroenteritis due to enterotoxigenic E. coli). Other bacterial infections caused by sensitive organisms There are a number of other bacterial infections caused by sensitive organisms for which treatment with SEPTRIN may be appropriate; the use of SEPTRIN in such conditions should be based on clinical experience and local in vitro data. Treatment of nocardiosis (see Dosage and Administration). SEPTRIN may be useful in: - toxoplasmosis - brucellosis (second-line therapy), when used in combination with gentamicin ar rifampicin - melioidosis, when used in combination with ceftazidime or cefoperazonelsulbactam. Dosage and Administration It may be preferable to take SEPTRIN with some food or drink to minimise the possibility of gastrointes nal disturbances.
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Unless otherwise specified STANDARD DOSAGE applies. Where dosage is expressed as 'tablets" this refers to the adult tablet, i.e. 80 mg trimethoprim and 400 mg sulfamethoxazole. If other formulations are to be used appropriate adjustment should be made. Acute Infections • Adults and children over 12 years
STANDARD DOSAGE
Tablets/Capsules
Double Strength Tablets
Adult Suspension
2 every 12 hours
1 every 12 hours
10 ml every 12 hours
Children aged 12 years and under
STANDARD DOSAGE
Age
6 to 12 years
6 months to 5 years
6 weeks to 5 months
 L
Paediatric Tablets
Paediatric Suspension
4 every 12 hours
10 ml every 12 hours
2 every 12 hours
5 ml every 12 hours
2.5 ml every 12 hours
This dosage approximates to 6 mg trimethop m and 30 mg sulfamethoxazole per kilogram body weight per 24 hours. Treatment should be continued until the patie t has been symptom free for two days; the majority will require treatment for at least 5 days. If clinical improvement is not evident after 7 days' therapy, the patient should be reassessed. As an alternative to STANDARD DOSAGE for acute uncomplicated lower urinary tract infections, short term therapy of 1 to 3 days' *ration has been shown to be effective. • Elderly See Wamings and Precautions. • Renal impairmeM Adults and children over 12 years (no information is available for children under 12 years of age). Creatinine Clearance (ml/min) Recommended Dosage >30 STANDARD DOSAGE 15 10 30 Half the STANDARD DOSAGE <15 Not recommended Measurements of plasma concentration of sulfamethoxazole at intervals of 2 to 3 days are recommended in samples obtained 12 hours after administration of SEPTRIN. If the concentration of total sulfamethoxazole exceeds 150 micrograms/ml then treatment should be interrupted until the value falls below 120 micrograms/ml. Pneumocystis jlrovecl (P. carinii) pneumonitis Treatment: A higher dosage is recommended, using 20 no trimethoprim and 100 mg sulfamethoxazole per kg of body weight per day in two or mom divided doses for two weeks. The aim is to obtain peak plasma or serum levels of himethophm of greater or equal to 5 micrograms/ml (verified in patients receiving 1 hour infusions of intravenous SEPTRIN)(see Adverse Reactions). Prevention: • Adults The following dose schedules may be used: - 160 mg trimethoprim 1800 mg sulfamethoxazole daily 7 days per week - 160 mg trimethophm / 800 mg sulfamethoxazole three times per week on altemate days - 320 mg trimethoprim / 1600 mg sulfamethoxazole per day in two divided doses three times per week on altemate days. Children The following dose schedules may be used for the duration of the period at risk (see Dosage and Administration, Acute Infections, Children): - standard dosage taken in two divided doses, seven days per week - standard dosage taken in two divided doses, three times per week on altemate days - standard dosage taken in two divided doses, three times per week on consecutive days - standard dosage taken as a single dose, three times per week on consecutive days. The daily dose given on a treatment day approximates to 150 mg trimethoprim/m'/day and 750 mg suffamethoxazole/meday. The total daily dose should not exceed 320 mg Trimethoprim and 1600 mg sulfamethoxazole. Gonorrhoea In uncomplicated cases 4 tablets every 12 hours for two days or 5 tablets followed by a further 5 tablets eight hours later or 10 tablets once daily for 3 days. If poor patient compliance is expected a single dose of 8 tablets taken under supervision may be employed. Oro-pharyngeal gonococcal infection: 2 tablets three times daily for seven days. Chancroid 2 tablets twice daily for 7 days. If no evidence of healing is apparent after 7 days a further 7 days treatment can be considered. However, physicians should be aware that failure to respond may indicate that the disease is caused by a resistant organism.
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Granulom inguinale 2 tablets hove daily for up to 2 weeks. Nocardiosis There is no consensus on th most appropriate dosage. Adult doses of 6 to 8 tablets daily for up to 3 months have been used. Brucellosi It may be advisable to use a igher than standard dosage initially. Treatment should continue for a period of at least four weeks and repeated courses may be be eficial. SEPTRIN should be given in combination with gentamicin or rifampidn. Melioidosi 8 mg/kg/da trimethoprim an 40 mg/kg/day sulfamethoxazole in divided doses, 3 or 4 limes per day for 6 months given in combinatio with ceftazidime or cefoperazotie/sulbactam. Contraindications SEPTRIN hould not be given to patients with a history of hypersensitivity to sulphonamides, trimethoprim, co-trimozazole or any excipients f SEPTRIN. SEPTRIN should not be given to premature babies or to full-term infants in the neonatal period. Warnings nd Precautions Fatalities, (though very rare, have occurred due to severe reactions including Stevens-Johnson syndrome, Lyell's syndrome (toxic epidermal ecrolysis), fulminant hepatic necrosis, agranulocylosis, aplastic anaemia, other blood dyscrasias and hypersensitivity of the respirat ry tract. SEPTRIN hould be discontinued at the first appearance of skin rash (see Adverse Reactions). Particular c re is always advisable when treating elderly patients because, as a group, they are more susceptible to adverse reactions and more likely to suffer serious effects as a result particularly when complicating conditions exist, e.g. impaired kidney and/or liver function and/or concomitant use of other drugs. For patients with known renal impairment special measures should be adopted (see Dosage and Administration). An adequate urinary output should be maintained at all times. Evidence of crystalluria in vivo is rare, although sulphonamide crystals have been noted in cooled urine from treated patients. In patients suffering from malnutrition the risk may be increased. Exercise caution when treating patients with severe hepatic parenchymal damage as changes may occur in the absorption and metabolism of trimethoprim and sulfamethoxazole. Regular monthly blood counts are advisable when SEPTRIN is given for long periods, or to folate deficient patients or to the elderly, since there exists a possibility of asymptomatic changes in haematological laboratory indices due to lack of available folate. These changes may be reversed by administration of folinic acid (5 to 10 mg/day) without interfering with the antibacterial activity A folate supplement should also be considered with prolonged high dosage of SEPTRIN (see Interactions). In glucose-6-phosphate dehydrogenase (G-6-PD) deficient patients haemolysis may occur. SEPTRIN should be given with caution to patients with severe allergy or bronchial asthma. SEPTRIN should not be used in the treatment of streptococcal pharyngitis due to Group A beta-haemotytic streptococci; eradication of these organisms from the oropharynx is less effective than with penicillin. Trimethoprim has been noted to impair phenylalanine metabolism but this is of no significance in phenylketonuhc patients on appropriate dietary restriction. The administration of SEPTRIN to patients known or suspected to be at risk of acute porphyda should be avoided. Both trimethoprim and sulphonamides (although not specifically sulfamethoxazole) have been associated with clinical exacerbation of porphyria. Close monitoring of serum potassium and sodium is warranted in patients at risk of hyperkalaemia and hyponatraemia. Except under careful supervision SEPTRIN should not be given to patients with serious haematological disorders (see Adverse Reactions). Trimethoprim-sulfamethoxazole has been given to patients receiving cytotoxic therapy with little or no additional effect on the bone marrow or peripheral blood. Interactions In elderly patients concurrently receiving diuretics, mainly thiazides, there appears to be an increased risk of thrombocytopenia. Occasional reports suggest that patients receiving pyrimethamine at doses in excess of 25 mg weekly may develop megaloblastic anaemia should SEPTRIN be prescribed concurrently. In some situations, concomitant treatment with zidovudine may increase the risk of haematological adverse reactions to SEPTRIN. If concomitant treatment is necessary, consideration should be given to monitoring of haematological parameters. Administration of trimethoprim /sulfamethoxazole 160 mg/800 mg (SEPTRIN) causes a 40% increase in lamivudine exposure because of the trimethoprim component. Lamivudine has no effect on the pharmacakinetics of trimethopdm or sulfamethoxazole. SEPTRIN has been shown to potentiate the anticoagulant activity of warfarin via stereo-selective inhibition of its metabolism. Sulfamethoxazole may displace warfarin from plasma-albumin protein-binding sites in vitro. Careful control of the anticoagulant therapy during treatment with SEPTRIN is advisable. SEPTRIN prolongs the half-life of phenytoin and if co-administered the prescriber should be alert for excessive phenytoin effect. Close monitoring of the patient's condition and serum phenytoin levels is advisable. Interaction with sulphonylurea hypoglycaemic agents is uncommon but potentiation has been reposed. Concurrent use of rifampicin and SEPTRIN results in a shortening of the plasma half-life of trimethoprim after a period of about one week. This is not thought to be of drainer significance. Reversible deterioration in renal function has been observed in patients Vented with SEPTRIN and cyclosporin following renal transplantation. When thmethophm is administered simultaneously with drugs that form cations at physiological pH, and are also partly excreted by active renal secretion (e.g. procainamide, amantadine), there is the possibility of competitive inhibition of this process which may lead to an increase in plasma concentration of one or both of the drugs.

SEPTRIN 

Concomitant use of thmethoprim with digoxin has been shown to increase plasma digoxin levels in a proportion of elderly patients. Caution should be exercised in patients taking any other drugs that can cause hyperkalaemia. SEPTRIN may increase the free plasma levels of methotrexate. If SEPTRIN is considered appropriate therapy in patients receiving other anti-folate drugs such as methotrexate, a folate supplement should be considered (see Warnings and Precautions). Laboratory tests interactions Tnmethoprim Interferes with assays for serum methotrexate when dihydrofolate reductase from Lactobacillus casei is used in the assay. No interference occurs if methotrexate is measured by radio-immune assay. Trimethophm may interfere with the estimation of serum/plasma creatinine when the alkaline picrate reaction is used. This may result in overestimation of serum/plasma creatinine of the order of 10% Functional inhibition of the renal tubular secretion of creatinine may produce a spurious fall in the estimated rate of creatinine clearance. SEPTRIN may affect the results of thyroid function tests but this is probably of little or no clinical significance. Pregnancy and Lactation Tnmethoprim and sulfamethoxazole cross the placenta and their safety in human pregnancy has not been established. Tnmethopnm is a folate antagonist and, in animal studies, both agents have been shown to cause foetal abnormalities (see Pre-clinical Safety Data). Case-control studies have shown that there may be an association between exposure to folate antagonists and birth defects in humans. Therefore SEPTRIN should be avoided in pregnancy. particularly in the first trimester, unless the potential benefit to the mother outweighs the potential nsk to the foetus; folate supplementation should be considered if SEPTRIN is used in pregnancy. Suffamethoxazole competes with bilinthin for binding to plasma albumin. As significant maternally derived drug levels persist for several days in the newborn, there may be a nsk of precipitating or exacerbating neonatal hyperbilirubinaemo, with an associated theoretical nsk of kemicterus, when SEPTRIN is administered to the mother near the time of delivery. This theoretical risk is particularly relevant in infants at increased nsk of hyperbilirobinaemia, such as those who are preterm and those with glucose-6-phosphate dehydrogenase deficiency. Trimethopdm and sulfamethoxazole are excreted in breast milk. Administration of SEPTRIN should be avoided in late pregnancy and in lactating mothers where the mother or infant has, or is at particular risk of developing, hyperbilinthinaemia. Additionally, administration of SEPTRIN should be avoided in infants younger than eight weeks in view of the predisposition of young infants to hyperbitirubinaemia. Effects on Ability to Drive and Use Machines No data Adverse Reactions As SEPTRIN contains tdmethoprim and a sulphonamide the type and frequency of adverse reactions associated with such compounds are expected to be consistent with extensive historical experience. Data from large published clinical trials were used to determine the frequency of very common to rare adverse events. Very rare adverse events were primarily determined from post-marketing experience data and therefore refer to reporting rate rather than a 'true" frequency. In addition, adverse reactions may vary in their incidence depending on the indication. The following convention has been used for the classification of adverse events in terms of frequency: very common 21/10, common z1/100 and <1/10, uncommon z1/1,000 and <1/100, rare z1/10,000 and <1/1,000, very rare <1/10,000. Infections and Infestations Common. Monilial overgrowth. Blood and lymphatic system disorders Very rare Leucopenia. neutropenia, thrombocytopenia, agranulocytosis, megaloblasfic anaemia, aplastic anaemia, haemolytic anaemia, methaemoglobinaemia, eosinophilia, purpura, haemolysis in certain susceptible G-6-PD deficient patients. Immune system disorders Very rare- Serum sickness, anaphylaxis, allergic myocarditis, angioedema, drug fever, allergic vasculitis resembling Henoch-Schoenlein purpura, periarteritis nodosa, systemic lupus erythematosus. Metabolism and nutrition disorders Very common: Hyperkalaemia Very rare: Hypoglycaemia, hyponatraemia, anorexia Psychiatric disorders Very rare Depression, hallucinations. Nervous system disorders Common: Headache. Very rare: Aseptic meningitis, convulsions, peripheral neuritis, ataxia, vertigo, tinnitus. dizziness. Aseptic meningitis was rapidly reversible on withdrawal of the drug, but recurred on a number of cases on re-exposure to either co- trimoxazole or to trimethoprim alone. Respiratory, thoracic and mediastinal disorders Very rare Cough, shortness of breath, pulmonary infiltrates. Cough, shortness of breath and pulmonary infiltrates may be early indicators of respiratory hypersensitivity which, while very rare, has been fatal. 

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Gastrointestinal disorders Common, Nausea, diarrhoea. Uncommon Vomiting. Very rare: Glossitis, stomatitis. pseudomembranous colitis, pancreatitis. Eye disorders Very ram: ()veil. Hepatobiliary disorders Very rare: Elevation of serum transaminases, elevation of bilirubin levels. cholestatic jaundice, hepatic necrosis. Cholestatic jaundice and hepatic necrosis may be fatal. Skin and subcutaneous tissue disorders Common: Skin rashes. Very rare: Photosensitivity, exfoliative dermatitis, fixed drug eruption, erythema multiforme, Stevens-Johnson syndrome, Lyell's syndrome (toxic epidermal necrolysis) Lyell's syndrome Games a high mortality. Musculoskeletal and connective tissue disorders Very rare: Arthralma, myalgia. Renal and urinary disorders Very rare. Impaired renal function (sometimes reported as renal failure), interstitial nephritis. Effects associated with Pneumocystis ironed (P. carinii) pneumonitis (PCP) management Very rare: Severe hypersensitivity reactions, rash, fever, neutropenia, thrombocytopenia, raised liver enzymes, rhabdomyolyms, hyperkalaemia, hyponatraemia. At the high dosages used for PCP management severe hypersensitivity reactions have been reported, necessitating cessation of therapy. If signs of bone marrow depression occur, the patient should be given calcium folinate supplementation (5 to 10 mg/day). Severe hypersensitivity reactions have been reported in PCP patients on re-exposure to SEPTRIN, sometimes after a dosage interval of a few days. Rhabdomyolysis has been reported in HIV positive patients receiving SEPTRIN for prophylaxis or treatment of PJP. Overdose Nausea, vomiting, dizziness and confusion are likely signs/symptoms of overdosage. Bone marrow depression has been reported in acute trimethopnm overdosage. If vomiting has not occurred induction of vomiting may be desirable. Gastric lavage may be useful, though absorption horn the gastrointestinal tract is normally very rapid and complete in approximately two hours. This may not be the case in gross overdosage. Dependent on the status of renal function, administration of fluids is recommended if urine output is low. Both thmethuprim and active sulfamethoxazole are diatysable by haemodialysis. Peritoneal dialysis is not effective, Phamiacodynamics In Vitro Activity Sulfamethoxazole competitively inhibits the utilisation of para-aminobenzoic acid in the synthesis of dihydrofolate by the bacterial cell resulting in bactermstasis. Trimethoprim reversibly inhibits bacterial dihydrofolate reductase (DHFR), an enzyme active in the folate metabolic pathway converting dihydrofolate to letrahydrofolate. Depending on the conditions the effect may be bactericidal. Thus trtmethoprim and,uffamethoxazole block Iwo consecutive steps in the biosynthesis of mines and therefore nucleic acids essential to many bacteria. This action produces marked potentiation of activity in rem between the two agents. The affinity of trimethoprim for mammalian DHFR is some 50,000 times less than for the corresponding bactenal enzyme. The majority of common pathogenic bacteria are sensitive in vitro to thmethophm and sulfamethoxazole at concentrations well belga, those reached in blood, tissue fluids and urine after the administration of recommended doses. In common with other antimicrobial'' agents in vitro activity does not necessarily imply that clinical efficacy has been demonstrated. These organisms include, Gram Negative Brucella spp. Citrobacter spp. Escherichia cola (including enterotoxigerfic strains) Haemophilus ducreyi Haernophllus influenzae (including arnocillin-resistant strains) Klebstella/Enterobacter spy. Legionella pneumophila Morganelia morganfi (previously Proteus morganfi) Neisseria spp. Proteus spy. Providencia spp. (including previously Proteus rettgeri) Certain Pseudomonas spp. except aeruginosa Salmonella spp. including S. fyphi and pamtyphi Serratia marcescens Shigella spp. Vibrio cholerae Yersinia spp. 

Gram Positive Lisferia monocylogenes Nocardia spp. Staphylococcus aureus 

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Staphylococcus pdennidis and saprophyticus Enterococcus la cabs Streptococcus p eumoniae Streptococcus vi dans. Many strains of Bacteroides Ira ills are sensitive. Some strains of Campylobacter fetus subsp.jeruMand Chtamydia are sensitive without evidence of synergy. S me varieties of non-tuberculous mycobacteria are sensitive to sulfamethoxazole but not trimethoprim. Mycoplasmas, Ureaplasma ure lyticum, Mycobacterium tuberculosis and Treponema pellidurn are insensitive. thSaytmis,fnaectory sensitivity testing is achieved only with recommended media free from inhibitory substances especially thymidine and Pharmacokinetics After oral administration trimethoprim and sulfamethoxazole are rapidly and ready completely absorbed. The presence of food does not appear to delay absorption. Peak levels in the blood occur between one and four hours after ingestion and the level attained is dose related. Effective levels persist in the blood for up to 24 hours after a therapeutic dose. Steady state levels in adults are reached after dosing for 2 to 3 day, Neither component has an appreciable effect on the concentrations achieved in the blood by the other. Trimethoprim is a weak base with a pKa of 7.4. It is lipophific. Tissue levels of trimethoprtm are generally higher than corresponding plasma levels. the lungs and kidneys showing especially high concentrations. TdmMhoprim concentrations exceed those in plasma in the case of bile, prostatic fluid and tissue, saliva, sputum and vaginal secretions. Levels in the aqueous humor, breast milk, cerebrospinal; middle ear fluid synovial fluid and tissue (interstitial) fluid are adequate for antibactenal activity. Trimethopnm passes into amniotic fluid and fetal tissues reaching concentrations approximating those of maternal serum. Approximately 50% of trimethoprim in the plasma is protein bound. The half-life in man is in the range 8.610 17 hours in the presence of normal renal function. It is increased by a factor of 1.5 to 3.0 when the creatinine clearance is less than 10 ml/minute. There appears to be no significant difference in the elderly compared with young patients. The principal route of excretion of trimethophm is renal and approximately 50% of the dose is excreted in the urine within 24 hours as unchanged drug. Several metabolites have been identified in the urine. Urinary concentrations of trimethoprim vary widely. Sulfamethoxazole is a weak acid with a pKa of 6.0. The concentration of active sulfamethoxazole in amniotic fluid, aqueous humor, bile, cerebrospinal fluid, middle ear fluid, sputum, synovial fluid and tissue (interstitial) fluid is of the order of 20 to 50% of the plasma concentration. Approximately 66% of sulfamethoxazole in the plasma is protein bound. The hart-life in man is approximately 9 to 11 hours in the presence of normal renal function. There is no change in the half-life of active sulfamethoxazole with a reduction in renal function but there in prolongation of the half-life of the major, acetylated metabolite when the creatinine clearance is below 25 nil/minute. The principal route of excretion of sulfamethoxazole is renal; between 15% and 30% of the dose recovered in the urine is in the active form. In elderly patients there is a reduced renal clearance of sulfamethoxazole. Pre-clinical Safety Data Reproductive toxicology: At doses in excess of the recommended human therapeutic dose, trimethoprim and sulfamethoxazole have been reported to cause cleft palate and other foetal abnormalities in rats, findings typical of a folate antagonist. Effects with trimethoprim were preventable by co-administration of dietary folate. In rabbits, foetal loss was seen at doses of trimethopnm in excess of human therapeutic doses. Special Precautions for Storage Protect all SEPTRIN products from fight Keep SEPTRIN dispersible tablets and capsules dry. Instructions for Use/Handling SEPTRIN Adult and Paediatric Suspensions may be diluted with Syrup BP. Although they may show some sedimentation such dilutions remain stable for at least a month. Shake thoroughly before use. Not all presentations are available in every country. Version number: GDS20/IP104 Date of issue: 20 November 2007 

CP223/05 

KEEP ALL MEDICAMENTS OUT OF THE REACH OF CHILDREN 

SEPTRIN is a trademark of the GlaxoSmithKline group of companies Manufactured by GlaxoSmithKline S.A.E., El Salem City, Cairo, k Under license from the GlaxoSmithKline group of companies 

CPGIaxoSmithKline