Chitrim Sulphamethoxazole Trimethoprim Caplets and Tablets

CHITRIM® 480 TABLETS

CHITRIM® 960 CAPLETS

 

COMPOSITION

Each Tablet contains 400 mg Sulphamethoxazole and 80 mg Trimethoprim BP

Each Caplet contains 800 mg Sulphamethoxazole and 160 mg Trimethoprim BP

 

PHARMACEUTICAL FORM

CHITRIM 480 tablet: is presented as white, circular, biconvex uncoated tablet with imprint letter CHITRIM, 480 and break-line embossed on one side and Letter CHI on other side.

CHITRIM 960 Caplet: is presented as white, capsule shaped uncoated tablet with imprint Letter CHITRIM 960 embossed on one side and Letter CHI and break-line on other side.

 

INDICATIONS

CHITRIM Tablet is indicated for the treatment of the following infections when owing to sensitive organisms:

Treatment and prevention of Pneumocystis jiroveci (P carinii) pneumonitis

Treatment and prophylaxis of toxoplasmosis.

Treatment of nocardiosis.

The following infections may be treated with Chitrim where there is bacterial evidence of sensitivity to Chitrim and good reason to prefer the combination of antibiotics in Chitrim to a Single antibiotic:

Acute uncomplicated urinary tract infection.

Acute otitis media.

Acute exacerbation of chronic bronchitis.

Consideration should be given to official guidance on the appropriate use of antibacterial agents.

 

DOSAGE AND METHOD OF ADMINISTRATION

Method of administration: For oral administration.

It may be preferable to take Chitrim with some food or drink to minimize the possibility of gastrointestinal disturbances.

Treatment should be continued until the patient 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.

The standard dose for Adults and children 12 years and over: 2 tablets twice daily.

Children: A more appropriate dosage formulation should be used.

6 weeks -5 months; 120mg twice daily.

6 months -5 years old; 240mg twice daily.

6 years – 11 years; 480mg twice daily.

Elderly: Adult dosage Care must be taken since the elderly 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.

Treatment of Pneumocytosis jiroveci (P carinii) infection- the usual dosage is 20mg.

Trimethoprim and 100mg Sulfamethoxazole per kg body weight per day in 2 or more doses.

Prophylaxis of Pneumocytosis jiroveci (P carinii) infection- the following regimens has been used:

Two tablets daily for seven days or

Two tablets daily three times a week on alternate days or

Two tablets twice a day three times a week on alternate days.

Treatment of Nocardiosis: Six to eight tablets daily for up to 3 months.

Treatment and prophylrails of toxoplasmosis: as prophylaxis of  Pneumocytosis jiroveci (P. carinii).

 

The following regimens are recommended in patients’ age 12 years or over with renal impairment:

Creatinine Clearance (ml/min) Recommended Dosage
>30 Standard Dosage
15 to 30 Half the Standard Dosage
<15 Not recommended

Measurements of plasma concentrations of Sulfamethoxazole at intervals of two to three days are recommended in samples obtained 12 hours after administration. If the concentration of total Sulfamethoxazole exceeds 150µg/ml, then treatment should be interrupted until the value falls below 120µg/ml.

It may be preferable to take Co-trimoxezole with food or drink to minimize the possibility of gastrointestinal disturbances.

 

CONTRAINDICATIONS

Chitrim should not be given to patients with a history of hypersensitivity to Sulphonamides, Trimethoprim, co-trimoxazole, or any excipients of Chitrim. Contra-indicated in patients showing marked liver parenchyma damage. Contra-indicated in severe renal insufficiency where repeated measurements of the plasma concentration cannot be performed.

Chitrim should not be given to premature babies or to full-term infants during the first 6 weeks of life except for the treatment/prophylaxis of PCP in infants 4 weeks of age or greater.

 

WARNINGS AND PRECAUTIONS FOR USE

Fatalities, although very rare, have occurred due to severe reactions including Stevens-Johnson syndrome, Lyell’s syndrome (toxic epidermal necrolysis) fulminant hepatic necrosis, agranulocytosis, aplastic anaemia, other blood dyscrasias and hypersensitivity of the respiratory tract. Chitrim should be discontinued at the first appearance of skin rash. (See Undesirable Effects). Particular care 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.

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.

Regular monthly blood counts are advisable when Chitrim is given for long periods, or to foliate deficient patients or to the elderly, since there exists a possibility of asymptomatic changes in hematological laboratory indices due to lack of available foliate. These changes may be reversed by administration of folinic acid (5 to 10 mg/day) without interfering with the-antibacterial activity.

In glucose-6-phosphate dehydrogenase (G-6-PD) deficient patients’ haemolysis may occur.

Chitrim should be given with caution to patients with severe allergy or bronchial asthma.

Chitrim should not be used in the treatment of strepococcal pharyngitis due to Group A beta-hemolytic 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 phenylketonuric patients on appropriate dietary restriction. The administration of Chitrim to patients known or suspected to be at risk of acute porphyria should be avoided. Both Trimethoprim and sulphonamides (although not specifically Sulphamethoxazole) have been associated with clinical exacerbation of porphyria. Close monitoring of serum potassium and sodium is warranted in patients at risk of hyperkalaemia and hyopnatraemia. Except under careful supervision Chitrim should not be given to patients with serious hematological disorders (see Undesirable Effects).

Chitrim has been given to patients receiving cytotoxic therapy with little or no additional effect on the bone marrow or peripheral blood.

The combination of antibiotics in Chitrim 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.

Patients with rare hereditary problems of fructose intolerance should not take this medicine.

This medicinal product contains methyl hydroxybenzoate, which may cause allergic reactions (possibly delayed).

 

DRUG INTERACTIONS AND OTHER FORMS OF INTERACTIONS

Trimethoprim 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%. The creatinine clearance is reduced: the renal tubular secretion of creatinine is decreased from 23% to 9% whilst the glomerular filtration remains unchanged.

In some situations, concomitant treatment with zidovudine may increase the risk of hematological adverse reactions to co-trimoxazole. If concomitant treatment is necessary, consideration should be given to monitoring of hematological parameters.

Reversible deterioration in renal function has been observed in patients treated with co-trimoxazole and cyctosponne following renal transplantation. Concurrent use of Rifampicin and Chitrim 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 clinical Significance.

In elderly patients concurrently receiving diuretics, mainly thiazides, there appears to be an increased risk of thrombocytopenia with or without purpura. Occasional reports suggest that patients receiving pyrimethamine at doses in excess of 25 mg weekly may develop megaloblastic anaemia should cotrimoxazole be prescribed concurrently.

Co-trimoxazole may increase the free plasma levels of methotrexate. Trimethoprim interferes with assays for serum methotrexate when dihydrofolate reductase from Lactobacilius casei is used in the assay. No interference occurs if methotrexate is measured by radioimmunology assay. Administration of Trimethoprim/ Sulphamethoxazole 160mg/800mg (cotrimoxazole) causes a 40% increase in lamivudine exposure because of the Trimethoprim component. Lamivudine has no effect on the pharmacokinetics of Trimethoprim or Sulphamethoxazole.

Interaction with sulphonylurea hypoglycaemic agents is uncommon but potentiation has been reported.

If Chitrim is considered appropriate therapy in patients receiving other anti- foliate drugs such as methotrexate, a foliate supplement should be considered.

 

PREGNANCY AND LACTATION

Pregnancy

There are not any adequate data from the use of Chitrim in pregnant women. Case-control studies have shown that there may be an association between exposure to folate antagonists and birth defects in humans. Trimethoprim is a folate antagonist and, in animal studies, both agents have been shown to cause foetal abnormalities.

Chitrim should not be used in pregnancy, particularly in the first trimester, unless clearly necessary. Folate supplementation should be considered if Chitrim is used in pregnancy.

Sulphamethoxazole competes with bilirubin for binding to plasma albumin. As significantly maternally derived drug levels persist for several days in the newborn, there may be a risk of precipitating or exacerbating neonatal hyperbitirubinaemia with an associated theoretical risk of kemicterus, when Chitrim is administered to the mother near the time of delivery. This theoretical risk is particularly relevant in infants at hyperbilirubinaemia, such as those who are preterm and those with glucose-6-phosphate dehydrogenase deficiency.

 

Lactation

The components of Chitrim (Trimethoprim and Sulphamethoxazole) are excreted in breast milk. Administration of Chitrim should be avoided in late pregnancy and in lactating mothers where the mother or infant has, or is at particular risk of developing hyperbilirubinaemia. Additionally, administration of Chitrim should be avoided in infants younger than eight weeks in view of the predisposition of young infants to hyperbilirubinaemia.

 

EFFECTS ON ABILITY TO DRIVE AND USE MACHINES

There have been no studies to investigate the effect of Chitrim on driving performance or the ability to operate machinery. Further a detrimental effect on such activities cannot be predicted from the pharmacology of the drug.

Nevertheless the clinical status of the patient and the adverse events profile of Chitrim should be borne in mind when considering the patients ability to operate machinery.

 

UNDESIRABLE EFFECTS

The following convention has been used for the classification of adverse effects in terms of frequency: Very common

Infections and Infestations

Common: Monilial overgrowth

 

Blood and lymphatic system disorders

Very rare: Leucopenia, neutropenia, thrombocytopenia, agranulocytosis, megaloblastic 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, and drug fever, allergic vasculitis resembling Henoch-Schoenlein purpura, periarteritis nodosa, and systemic lupus erythematosus.

 

Metabolism and nutrition disorders

Very common: Hyperkalaemia

Very rare: Hypoglycemia, hyopnatraemia, 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 in 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.

 

Gastrointestinal disorders

Common: Nausea, diarrhoea.

Uncommon: Vomiting.

 

Hepato-biliary 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, Lyelis syndrome (toxic epidermal necrolysis).

Lyell’s syndrome carries a high mortality.

 

Musculoskeletal and connective tissue disorders

Very rare: Arthralgia, myalgia.

 

Renal and urinary disorders

Very rare: Impaired renal function (sometimes reported as renal failure), interstitial nephritis.

 

Effects associated with Pheumocystis jiroveci (P. carinii Pneumonitis (PCP) management

Very rare: Severe hypersensitivity reactions, rash, fever, neutropenia,
thrombocytopenia, raised liver enzymes, hyperkataemia, hyponatraemia, rhabdomyolysis.

At the high dosages used for PCP management severe hypersensitivity reactions have been reported, necessitating cessation of therapy. It signs of bone marrow depression occur, the patient should be given calcium folinate supplementation (5-10 mg/day).

Severe hypersensitivity reactions have been reported in PCP 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 PCP.

 

CLINICAL PHARMACOLOGY

Pharmacotherapeutic group: Combinations of sulfonamides and Trimethoprim.

Mode of Action
Chitrim is an antibacterial drug composed of two active principles,
Sulphamethoxazole and Trimethoprim. Sulphamethoxazole is a competitive inhibitor of dihydropteroate synthetase enzyme. Sulphamethoxazole competitively inhibits the utilization of para-aminobenzoic acid (PABA) in the synthesis of dihydrofolate by the bacterial cell resulting in bacteriostasis. Trimethoprim binds to and reversibly inhibits bacterial dihydrofolate reductase (DHFR) and blocks the production of tetrahydrofolate. Depending on the conditions the effect may be bactericidal. Thus Trimethoprim and
Sulphamethoxazole block two consecutive steps in the biosynthesis of purines and therefore nucleic acids essential to many bacteria. This action produces marked potentiatiori of activity in vitro between the two agents.

 

Antibacterial Spectrum

The prevalence of resistance may vary geographically and with time for selected species and local information on resistance is desirable, particularly when treating severe infections. As necessary, expert advice should be sought when the local prevalence of resistance is such that the utility of the agent in at least some types of infections is questionable. This information gives only an approximate guidance on probabilities whether microorganisms will be susceptible to Trimethoprim and Sulphamethoxazote or not.

Trimethoprim/Sulphamethoxazote susceptibility against a number of bacteria are shown in the table below:

Commonly susceptible species

Gram-positive aerobes

Staphylococcus aureus

Staphylococcus saprophyticus

Streptococcus pyogenes

 

Gram-negative aerobes

Enterobacter cloacae

Haemophilus influenzae

Klebsiella oxytoca

Moraxella catarrhalis

Salmonella spp.

Stenotrophomonas maitophilia

Yersinia spp.

 

Species for which acquired resistance may be a problem

Gram-positive aerobes

Enterococcus faecalis

Enterococcus faecium

Nocardia spp.

Staphylococcus epidermidis

Streptococcus pneumoniae

 

Gram-negative aerobes

Citrobacter spp.

Enterobacter aerogenes

Escherchia coli

Klebsiella pneumoniae

Klebsiella pneumonia

Proteus mirabilis

Proteus vulgaris

Providencia spp.

Serrafia marcesans

 

Inherently resistant organisms

Gram-negative aerobes

Pseudomonas aeruginosa

Shigella spp.

Vibro cholera

 

After oral administration, Trimethoprim and Sulphamethoxazole are rapidly and nearly 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 2-3 days.

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 lipophilic. Tissue levels of Trimethoprim are generally higher than corresponding plasma levels, the lungs and kidneys showing especially high concentrations. Trimethoprim 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 fluid, middle ear fluid, synovial fluid and tissue (intestinal) fluid are adequate for antibacterial activity. Trimethoprim passes into amniotic fluid and foetal 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 8.6 to 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 Trimethoprim 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.

Sulphamethoxazole is a weak acid with a pKa of 6.0. The concentration of active Sulphamethoxazole in a variety of body fluids is of the order of 20 to 50% of the plasma concentration.

Approximately 66% of Sulphamethoxazole in the plasma is protein bound and the principal route of excretion of Sulphamothoxazole is renal. The half-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 Sulphamethoxazole with a reduction in renal function but there is prolongation of the half-life of the major, acetylated metabolite when the creatinine clearance is below 25 ml/minute. The principle route of excretion of Sulphamethoxazole 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 Sulphamethoxazole.

 

STORAGE CONDITIONS

Store in a cool and dry place.

Keep out of reach of children.

 

NATURE AND CONTENTS OF CONTAINER

CHITRIM 480 Tablet is supplied in 10 blister strips of 10 tablets in a pack.

CHITRIM 960 Caplet is supplied in 10 blister strips of 10 Caplets in a pack.

NAFDAC Reg. No: 04-7575

NAFDAC Reg. No: 04-7096

 

Manufactured By

Chi Pharmaceuticals Ltd.

14, Chivita Avenue, Ajao Estate, Isolo, Lagos, Nigeria.

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