Last Updated on eMC 14-12-2017 View medicine  | Aspen Contact details

When a pharmaceutical company changes an SPC or PIL, a new version is published on the eMC.  For each version, we show the dates it was published on the eMC and the reasons for change.

Reasons for adding or updating:

  • Change to section 4.1 - Therapeutic indications
  • Change to section 4.2 - Posology and method of administration
  • Change to section 4.3 - Contraindications
  • Change to section 5.2 - Pharmacokinetic properties
  • Change to section 10 - Date of revision of the text
  • Improved presentation of SPC

Date of revision of text on the SPC:08-12-2017

Legal Category:POM

Black Triangle (CHM): NO

Free-text change information supplied by the pharmaceutical company:

Text in red = new text
Text strikethrough = deleted text


4 CLINICAL PARTICULARS

4.1 Therapeutic indications

Co-Trimoxazole tablets are indicated in adolescent children (>12 to <18 years old) and adults (>18 years old) for the treatment of the following infections when owing to sensitive organisms (see section 5.1):

• Treatment and prevention of Pneumocystis jirovecii pneumonitis or “PJP”. (previously known as Pneumocystis carinii pneumonia or “PCP”).


4.2 Posology and method of administration


Standard dosage recommendations for acute infections

Adults (>18 years old):

STANDARD DOSAGE
Age Tablets
>18 years old 2 tablets every 12 hours


This dosage approximates to 6 mg trimethoprim and 30 mg sulfamethoxazole per kilogram body weight per 24 hours.

Children over 12 years old (>12 to <18 years old):

The standard dosage for children is equivalent to approximately 6 mg trimethoprim and 30 mg sulfamethoxazole per kg body weight per day, given in two equally divided doses. The schedules for children are according to the child’s age and provided in the table below:

Age Tablets
>12 to <18 years old 2 tablets every 12 hours

Special Dosage Recommendations
(Standard dosage applies unless otherwise specified)

Where dosage is expressed as "tablets" this refers to the adult tablet, i.e. 80 mg Trimethoprim BP and 400 mg Sulfamethoxazole BP. If other formulations are to be used appropriate adjustment should be made.

Dosage recommendation:

Children (>12 to <18 years old) and adults (>18 years old)Adults and paediatric patients over 12 years (no information is available for paediatric patients under 12 years of age):

Creatinine Clearance (ml/min) Recommended Dosage
>30 2 tablets every 12 hoursSTANDARD DOSAGE
15 to 30 1 tablets every 12 hoursHalf the STANDARD DOSAGE
<15 Not recommended

No information available for children aged 12 years and under with renal failure. See section 5.2 for the pharmacokinetics in the paediatric population with normal renal function of both components of Co-Trimoxazole, TMP and SMZ.

Prevention - Paediatric patients (Children (>12 to <18 years old):
The standard dosage for children is equivalent to approximately 6 mg trimethoprim and 30 mg sulfamethoxazole per kg body weight per day, given in two equally divided doses. The following dose schedules may be used for the duration of the period at risk (see Standard dosage recommendations for acute infections subsection of 4.2):


Age Tablets
>12 to <18 years old 2 tablets every 12 hours, seven days per week
>12 to <18 years old 2 tablets every 12 hours, three times per week on alternative days
>12 to <18 years old 2 tablets every 12 hours, three times per week on consecutive days
>12 to <18 years old 4 tablets once a day, three times per week on consecutive days


• Standard dosage taken in two divided doses, seven days per week.
• Standard dosage taken in two divided doses, three times per week on alternate 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.


4.3 Contraindications

• Hypersensitivity to the active substance(s) sulphonamides, trimethoprim, co-trimoxazole or to any of the excipients listed in section 6.1.
 Co-Trimoxazole should not be given to patients with a history of hypersensitivity to sulphonamides, trimethoprim, co-trimoxazole or any excipients of Co-Trimoxazole.
• sSevere hepatic parenchymal damage. Contra-indicated in severe renal insufficiency where repeated measurements of the plasma concentration cannot be performed.
• Co-trimoxazole should not be given to infants (children <6 weeks of age) during the first 6 weeks of lifeCo-Trimoxazole should not be given to premature babies nor to full-term infants during the first 6 weeks of life except for the treatment /prophylaxis of PJP in infants 4 weeks of age or greater.


5.2 Pharmacokinetic properties

The pharmacokinetics in the paediatric population with normal renal function of both components of Co-Trimoxazole, TMP and SMZ are age dependent. Elimination of TMP-SMZ is reduced in neonates, during the first two months of life, thereafter both TMP and SMZ show a higher elimination with a higher body clearance and a shorter elimination half-life. The differences are most prominent in young infants (> 1.7 months up to 24 months) and decrease with increasing age, as compared to young children (1 year up to 3.6 years), children (7.5 years and < 10 years) and adults (see section 4.2).


10 DATE OF REVISION OF THE TEXT

June 2017 08/12/2017 December 2016

Reasons for adding or updating:

  • Change to section 3 - Pharmaceutical form
  • Change to section 4.1 - Therapeutic indications
  • Change to section 4.2 - Posology and method of administration
  • Change to section 4.3 - Contraindications
  • Change to section 4.4 - Special warnings and precautions for use
  • Change to section 4.5 - Interaction with other medicinal products and other forms of interaction
  • Change to section 4.6 - Fertility, pregnancy and lactation
  • Change to section 5.1 - Pharmacodynamic properties
  • Change to section 5.2 - Pharmacokinetic properties
  • Change to section 6.6 - Special precautions for disposal and other handling
  • Change to section 10 - Date of revision of the text
  • Correction of spelling/typing errors
  • Improved presentation of SPC

Date of revision of text on the SPC:30-12-2016

Legal Category:POM

Black Triangle (CHM): NO

Free-text change information supplied by the pharmaceutical company:



Text in red = new text
Text strikethrough = deleted text

 

3.   PHARMACEUTICAL form

 

Tablet

 

White, elongated tablet marked “S3” on one side and a scoreline on the other side.

 

The scoreline is only to facilitate breaking for ease of swallowing and not to divide into equal doses

4.       Clinical particulars

 

4.1       Therapeutic indications

Treatment and prevention of Pneumocystis jiroveci pneumonitis or “PJP” (previously known as Pneumocystis carinii pneumonia or “PCP”).

 

4.2       Posology and method of administration

 

Method of administration

 

Oral

 

It may be preferable to take Co-Trimoxazole with some food or drink to minimise the possibility of gastrointestinal disturbances.

 

4.3       Contraindications

 

Co-Trimoxazole should not be given to patients with a history of hypersensitivity to sulphonamides, trimethoprim, co-trimoxazole or any excipients of Co-Trimoxazole.

Severe hepatic parenchymal damage.

-              Contra-indicated in severe renal insufficiency where repeated measurements of the plasma concentration cannot be performed.

-              Co-Trimoxazole should not be given to patients with a history of drug-induced immune thrombocytopenia with use of trimethoprim and/or sulphonamides.

-              Co-Trimoxazole should not be given to patients with acute porphyria.

-              Co-Trimoxazole should not be given to premature babies nor to full-term infants during the first 6 weeks of life except for the treatment/prophylaxis of PJP in infants 4 weeks of age or greater.

 

4.4     Special warnings and precautions for use

 

Fatalities, although very rare, have occurred due to severe reactions including Stevens-Johnson syndrome, toxic epidermal necrolysis, fulminant hepatic necrosis, agranulocytosis, aplastic anaemia, other blood dyscrasias and hypersensitivity of the respiratory tract.

 

 

For patients with known renal impairment special measures should be adopted (see section 4.2).

 

 

Regular monthly blood counts are advisable when Co-Trimoxazole 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. Supplementation with folinic acid may be considered during treatment but this should be initiated with caution due to possible interference with antimicrobial efficacy (see section 4.5).

 

 

Co-Trimoxazole has been associated with metabolic acidosis when other possible underlying causes have been excluded. Close monitoring is always advisable when metabolic acidosis is suspected.

 

 

4.5       Interaction with other medicinal products and other forms of interaction

 

Interaction with laboratory tests: 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.

 

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

 

Cyclosporin: reversible deterioration in renal function has been observed in patients treated with co-trimoxazole and cyclosporin following renal transplantation.

 

Rifampicin: concurrent use of rifampicin and Co-Trimoxazole 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.

 

Diuretics (thiazides): in elderly patients concurrently receiving diuretics, mainly thiazides, there appears to be an increased risk of thrombocytopenia with or without purpura.

 

Pyrimethamine: occasional reports suggest that patients receiving pyrimethamine at doses in excess of 25 mg weekly may develop megaloblastic anaemia should co- trimoxazole be prescribed concurrently.

 

Warfarin: co-trimoxazole 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 Co-Trimoxazole is advisable.

 

Phenytoin: co-trimoxazole prolongs the half-life of phenytoin and if co-administered could result in excessive phenytoin effect. Close monitoring of the patient's condition and serum phenytoin levels are advisable.

 

Digoxin: concomitant use of trimethoprim with digoxin has been shown to increase plasma digoxin levels in a proportion of elderly patients.

 

Methotrexate: co-trimoxazole may increase the free plasma levels of methotrexate. If Co-Trimoxazole is considered appropriate therapy in patients receiving other anti- folate drugs such as methotrexate, a folate supplement should be considered (see section 4.4).

 

Lamivudine: administration of trimethoprim/sulfamethoxazole 160 mg/800 mg (co- trimoxazole) causes a 40% increase in lamivudine exposure because of the trimethoprim component. Lamivudine has no effect on the pharmacokinetics of trimethoprim or sulfamethoxazole.

 

Hyperkalaemia: caution should be exercised in patients taking any other drugs that can cause hyperkalaemia.

 

Repaglinide: trimethoprim may increase the exposure of repaglinide which may result in hypoglycaemia.

 

Folinic acid: folinic acid supplementation has been shown to interfere with the antimicrobial efficacy of trimethoprim-sulfamethoxazole. This has been observed in Pneumocystis jiroveci pneumonia prophylaxis and treatment.

 

Contraceptives: oral contraceptive failures have been reported with antibiotics. The mechanism of this effect has not been elucidated. Women on treatment with antibiotics should temporarily use a barrier method in addition to the oral contraceptive, or choose another method of contraception.

 

Co-Trimoxazole

 

 

4.6       Fertility, pregnancy and lactation

 

Pregnancy

 

Trimethoprim and sulfamethoxazole cross the placenta and their safety in pregnant women has not been established.Co-TrimoxazoleCase

 

 

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the Yellow Card Scheme at www.mhra.gov.uk/yellowcard.

 

5.       PHARMACOLOGICAL PROPERTIES

 

5.1       Pharmacodynamic properties

 

Pharmacotherapeutic group: Combinations of sulphonamides and trimethoprim, incl. derivatives, ATC code: J01EE01.

 

Mechanism of Action

 

Sulfamethoxazole competitively inhibits the utilisation of para-aminobenzoic acid in the synthesis of dihydrofolate by the bacterial cell resulting in bacteriostasis. Trimethoprim reversibly inhibits bacterial dihydrofolate reductase (DHFR), an enzyme active in the folate metabolic pathway converting dihydrofolate to tetrahydrofolate. Depending on the conditions the effect may be bactericidal. Thus trimethoprim and sulfamethoxazole block two consecutive steps in the biosynthesis of purines and therefore nucleic acids essential to many bacteria. This action produces marked potentiation of activity in vitro between the two agents.

Trimethoprim binds to plasmodial DHFR but less tightly than to the bacterial enzyme. Its affinity for mammalian DHFR is some 50,000 times less than for the corresponding bacterial enzyme.

 

5.2       Pharmacokinetic properties

 

Distribution

 

Approximately 50% of trimethoprim in the plasma is protein bound. 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 66% of sulfamethoxazole in the plasma is protein bound. The concentration of active sulfamethoxazole in amniotic fluid, aqueous humour, bile, cerebrospinal fluid, middle ear fluid, sputum, synovial fluid and tissue (interstitial)  fluids is of the order of 20 to 50% of the plasma concentration.

 

Biotransformation

Renal excretion of intact sulfamethoxazole accounts for 15-30% of the dose. This drug is more extensively metabolised than trimethoprim, via acetylation, oxidation or glucuronidation. Over a 72 hour period, approximately 85% of the dose can be accounted for in the urine as unchanged drug plus the major (N4-acetylated) metabolite.

 

Elimination

 

The half-life of trimethoprim 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 elderly patients 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.

 

The half-life of sulfamethoxazole 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 is prolongation of the half-life of the major, acetylated metabolite when the creatinine clearance is below 25 ml/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.

 

Special patient population

 

Renal impairment

 

The elimination half-life of trimethoprim is increased by a factor of 1.5-3.0 when the creatinine clearance is less than 10 mL/minute. When the creatinine clearance falls below 30 mL/min the dosage of Co-Trimoxazole should be reduced (see section 4.2).

 

Hepatic impairment

 

Caution should be exercised when treating patients with severe hepatic parenchymal damage as there may be changes in the absorption and biotransformation of trimethoprim and sulfamethoxazole.

 

Elderly patients

 

In elderly patients, a slight reduction in renal clearance of sulfamethoxazole but not trimethoprim has been observed.

 

Paediatric population

 

See special dosage regimen (see section 4.2).

 

 

6.6       Special precautions for disposal and other handling

 

 

10.     DATE OF REVISION OF THE TEXT

 

December 2016 Feb 2015

 

 

 

 

 

 

 

 

Reasons for adding or updating:

  • New SPC for new product

Date of revision of text on the SPC:01-01-0001

Legal Category:POM

Black Triangle (CHM): NO