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 6.6 - Special precautions for disposal and other handling
  • 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 for Infusion is indicated in children aged 12 years and under (>6 weeks to <12 years old); children over 12 years old (>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):.

 

•           Acute uncomplicated urinary tract infection: It is recommended that initial episodes of uncomplicated urinary tract infections be treated with a single effective antibacterial agent rather than a combination such as Co-Trimoxazole for Infusion.

 

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

 

•           Treatment and prophylaxis of toxoplasmosis.

 

•           Treatment of nocardiosis.

 

•           In general, the indications for the use of Co-Trimoxazole for Infusion are the same as those for oral presentations.

 

           

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

 

 

 

 

4.2       Posology and method of administration

 

Adults (>18 years old)and children over 12 years:

 

STANDARD DOSAGE

Age      Solution for Infusion

>12 to <>18 years old    2 ampoules (10 ml) every 12 hours

 

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 tables below:

 

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

 

STANDARD DOSAGE

Age      Solution for Infusion

>12 to <18 years old      2 ampoules (10 ml) every 12 hours

Adults and paediatric patients over 12 years:

 

2 ampoules (10 ml) every 12 hours.

 

Children aged 12 years and under (>6 weeks to <12 years old):

Paediatric patients aged 12 years and under:

 

The recommended dosage is approximately 6 mg trimethoprim and 30 mg sulfamethoxazole per kg bodyweight per 24 hours, given in two equally divided doses. As a guide the following schedules may be used diluted as described above.

 

 

 

 

4.3       Contraindications

 

-•         Hypersensitivity to the active substance(s) sulphonamides, trimethoprim, co-trimoxazole or to any of the excipients listed in section 6.1Co-Trimoxazole 16 mg/80 mg per ml for Infusion should not be given to patients with a history of hypersensitivity to sulphonamides, trimethoprim, co-trimoxazole or any excipients of Co-Trimoxazole.

-•         Co-Trimoxazole 16 mg/80 mg per ml for Infusion is contra-indicated in patients with severe hepatic parenchymal damage. 

•           Co-Trimoxazole 16 mg/80 mg per ml for Infusion is contra-indicated in severe renal insufficiency where repeated measurements of the plasma concentration cannot be performed.

-          

-•         Co-Trimoxazole 16 mg/80 mg should not be given to patients with a history of drug-induced immune thrombocytopenia with use of trimethoprim and/or sulphonamides.

•           Co-Trimoxazole 16 mg/80 mg should not be given to patients with acute porphyria.

-          

•           Co-Trimoxazole 16 mg/80 mg should not be given to infants during the first 6 weeks of life.

 

            Co-Trimoxazole 16 mg/80 mg per ml for Infusion should not be given to premature babies nor to full-term infants during the first six 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).

 

6.6       Special precautions for disposal and other handling

The pH of the solution is in the range 9.5 to 11.0.

 

 

10        DATE OF REVISION OF THE TEXT

 

 

June 2017 08/12/2017 December 2016

Reasons for adding or updating:

  • 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 4.7 - Effects on ability to drive and use machines
  • Change to section 4.8 - Undesirable effects - how to report a side effect
  • Change to section 4.9 - Overdose
  • 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

 

 

 

4.2      Posology and method of administration

 

Method of administration:

 

Co-Trimoxazole for Infusion is for administration only by the intravenous route and must be diluted before administration.

 

It is intended that Co-Trimoxazole for Infusion should be used only during such a period as the patient is unable to accept oral therapy, where initiation of treatment is particularly urgent or for convenience if the patient is already receiving intravenous fluids. Although Co-Trimoxazole for Infusion is useful in critically ill patients, there may be no therapeutic advantage over the oral preparation.

 

For instructions on dilution of the product before administration, see section 6.6.

 

 

4.3         Contraindications

 

-              Co-Trimoxazole 16 mg/80 mg per ml for Infusion should not be given to patients with a history of hypersensitivity to sulphonamides, trimethoprim, co-trimoxazole or any excipients of Co-Trimoxazole.

-              Co-Trimoxazole 16 mg/80 mg per ml for Infusion is contra-indicated in patients with severe hepatic parenchymal damage.  

-              Co-Trimoxazole 16 mg/80 mg per ml for Infusion is contra-indicated in severe renal insufficiency where repeated measurements of the plasma concentration cannot be performed.

-              Co-Trimoxazole 16 mg/80 mg should not be given to patients with a history of drug-induced immune thrombocytopenia with use of trimethoprim and/or sulphonamides.

-              Co-Trimoxazole 16 mg/80 mg should not be given to patients with acute porphyria.

-              Co-Trimoxazole 16 mg/80 mg per ml for Infusion should not be given to premature babies nor to full-term infants during the first six 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.

 

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. These changes may be reversed by administration of folinic acid (5 to 10 mg/day) without interfering with the antibacterial activity.

 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 ciclosporin 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.

 

When trimethoprim 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.

 

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 as malarial prophylaxis 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 the prescriber should be alert for excessive phenytoin effect. Close monitoring of the patient's condition and serum phenytoin levels is 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.

 

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

 

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 Co-Trimoxazolein pregnant women has not been established. Case-control studies have shown that there may be an association between exposure to folate antagonists and birth defects in humans.

 

4.7       Effects on ability to drive and use machines

 

There have been no studies to investigate the effect of Co-Trimoxazole 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 Co-Trimoxazole should be borne in mind when considering the patients ability to operate machinery.

 

4.8         Undesirable effects

 

For the management of the hypersensitivity reactions associated with Co-Trimoxazole therapy concomitant administration of intravenous diphenhydramine may permit continued infusion when Co-Trimoxazole is used for the treatment of PJP.

 

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.

 

4.9       Overdose

 

Symptoms and Signs

 

The maximum tolerated dose in humans is unknown.

 

Nausea, vomiting, dizziness and confusion are likely symptoms of overdosage. Bone marrow depression has been reported in acute trimethoprim overdosage.

 

Treatment

 

Dependent on the status of renal function, administration of fluids is recommended if urine output is low. Both trimethoprim and active sulfamethoxazole are dialysable by renal dialysis. Peritoneal dialysis is not effective.

 

In cases of known, suspected or accidental overdosage, stop therapy.

Acidification of the urine will increase the elimination of trimethoprim. Inducing diuresis plus alkalinisation of urine will enhance the elimination of sulfamethoxazole. Alkalinisation will reduce the rate of elimination of trimethoprim. Calcium folinate will reverse any folate deficiency effect of trimethoprim on the bone marrow should this occur. General supportive measures are recommended.

 

5.1         Pharmacodynamic properties

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.

 

is an antibacterial drug composed of two active principles, sulfamethoxazole and trimethoprim. Sulfamethoxazole is a competitive inhibitor of dihydropteroate synthetase enzyme. Sulfamethoxazole competitively inhibits the utilisation 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 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.

 

 

Susceptibility testing breakpoints

 

EUCAST (European Committee on Antimicrobial Susceptibility Testing) limits

 

5.2       Pharmacokinetic properties

 

Absorption

 

Peak plasma levels of trimethoprim and sulfamethoxazole are higher and achieved more rapidly after one hour of intravenous infusion of Co-Trimoxazole 16 mg/80 mg per ml for Infusion than after oral administration of an equivalent dose of a Co-Trimoxazole oral presentation. Plasma concentrations, elimination half-life and urinary excretion rates show no significant differences following either the oral or intravenous route of administration.

 

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, sputum, and vaginal secretions. Levels in the aqueous humour, breast milk, cerebrospinal fluid, middle ear fluid, synovial fluid and tissue (interstitial) fluid are adequate for antibacterial activity. Trimethoprim passes into amniotic fluid and foetal tissues reaching concentrations approximating those of maternal serum.

  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.

 

 Approximately 66% of sulfamethoxazole in the plasma is protein bound.Sulfamethoxazole is a weak acid with a pKa of 6.0. 

 

 

The concentration of active sulfamethoxazole in amniotic fluid, aqueous humour, 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.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 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.

 

Biotransformation

 

Trimethoprim does not induce its own metabolism and therefore no dose modification is required on this account during long-term treatment.

 

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 sulfamethoxazol 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

 

 

The pH of the solution is in the range 9.5 to 11.0.

10. DATE OF REVISION OF THE TEXT

 

December 2016  Aug 2014

Reasons for adding or updating:

  • Change to section 1 - Name of the medicinal product
  • Change to section 2 - Qualitative and quantitative composition
  • 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

Date of revision of text on the SPC:28-10-2015

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

Septrin

 

 

1.         Name of the Medicinal Product

 

Co-Trimoxazole  Septrin 16 mg/80 mg per ml for Infusion

 

 

2.         Qualitative and Quantitative Composition

 

Each 5 ml of Co-Trimoxazole  Septrin 16 mg/80 mg per ml for Infusion contains 80 mg Trimethoprim and 400 mg Sulfamethoxazole. This is equivalent to 16 mg Trimethoprim and 80 mg Sulfamethoxazole per 1 ml.

4.1       Therapeutic Indications

 

Co-TrimoxazoleSeptrin for Infusion is indicated for the treatment of the following infections when owing to sensitive organisms (see section 5.1):

 

Acute uncomplicated urinary tract infection.

 

It is recommended that initial episodes of uncomplicated urinary tract infections be treated with a single effective antibacterial agent rather than a combination such as Co-TrimoxazoleSeptrin for Infusion.

 

Treatment and prevention of Pneumocystis jiroveci pneumonitis (previously known as Pneumocystis carinii pneumonia orPCP”)

 

Treatment and prophylaxis of toxoplasmosis.

 

Treatment of nocardiosis.

 

In general, the indications for the use of Co-TrimoxazoleSeptrin for Infusion are the same as those for oral presentations.


4.2       Posology and Method of Administration

 

Method of Administration: Co-TrimoxazoleSeptrin for Infusion is for administration only by the intravenous route and must be diluted before administration.

 

It is intended that Co-TrimoxazoleSeptrin for Infusion should be used only during such a period as the patient is unable to accept oral therapy, where initiation of treatment is particularly urgent or for convenience if the patient is already receiving intravenous fluids. Although Co-TrimoxazoleSeptrin for Infusion is useful in critically ill patients, there may be no therapeutic advantage over the oral preparation.

Measurements of plasma concentrations of sulfamethoxazole at intervals of 2 to 3 days are recommended in samples obtained 12 hours after administration of Co-TrimoxazoleSeptrin 16 mg/80 mg per ml for Infusion. If the concentration of total sulfamethoxazole exceeds 150 micrograms/ml then treatment should be interrupted until the value falls below 120 micrograms/ml.

 

Pneumocystis jiroveci (P. carinii) pneumonitis:

 

Treatment

20 mg trimethoprim and 100 mg sulfamethoxazole per kg of bodyweight per day in two or more divided doses. Therapy should be changed to the oral route as soon as possible and continued for a total treatment period of two weeks. The aim is to obtain peak plasma or serum levels of trimethoprim of greater than or equal to 5 microgram/ml (verified in patients receiving 1-hour infusions of intravenous SeptrinCo-Trimoxazole) (See 4.8 Undesirable Effects).


4.3       Contraindications

 

Co-TrimoxazoleSeptrin 16 mg/80 mg per  ml for Infusion should not be given to patients with a history of hypersensitivity to sulphonamides, trimethoprim, co-trimoxazole or any excipients of Co-TrimoxazoleSeptrin.

 

Co-TrimoxazoleSeptrin 16 mg/80 mg per ml for Infusion is contra-indicated in patients showing marked liver parenchymal damage.

 

Co-TrimoxazoleSeptrin 16 mg/80 mg per ml for Infusion is contra-indicated in severe renal insufficiency where repeated measurements of the plasma concentration cannot be performed.

 

Co-TrimoxazoleSeptrin 16 mg/80 mg per ml for Infusion should not be given to premature babies nor to full-term infants during the first six weeks of life except for the treatment/prophylaxis of PCP in infants 4 weeks of age or greater.

4.4         Special Warnings and Precautions for Use

 

• Life-threatening cutaneous reactions Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) have been reported with the use of Co-Trimoxazole. Septrin

• Patients should be advised of the signs and symptoms and monitored closely for skin reactions. The highest risk for occurrence of SJS or TEN is within the first weeks of treatment.
• If symptoms or signs of SJS or TEN (e.g. progressive skin rash often with blisters or mucosal lesions) are present, Co-Trimoxazole  Septrim treatment should be discontinued (see 4.8 Undesirable Effects).
• The best results in managing SJS and TEN come from early diagnosis and immediate discontinuation of any suspect drug. Early withdrawal is associated with a better prognosis.
• If the patient has developed SJS or TEN with the use of Co-Trimoxazole, Septrim Co-Trimoxazole Septrim must not be re-started in this patient at any time.

Regular monthly blood counts are advisable when Co-TrimoxazoleSeptrin is given for long periods, or to folate deficient patients or to the elderly since there exists a possibility

Co-TrimoxazoleSeptrin should be given with caution to patients with severe allergy or bronchial asthma.

Co-TrimoxazoleSeptrin should not be used in the treatment of streptococcal pharyngitis due to Group A beta-haemolytic streptococci. Eradication of these organisms from the oropharynx is less effective than with penicillin.

 

The administration of Co-TrimoxazoleSeptrin to patients known or suspected to be at risk of acute porphyria should be avoided. Both trimethoprim and sulphonamides (although not specifically sulfamethoxazole) have been associated with clinical exacerbation of porphyria.

Except under careful supervision Co-TrimoxazoleSeptrin for Infusion should not be given to patients with serious haematological disorders (see 4.8 Undesirable Effects). Co-TrimoxazoleSeptrin has been given to patients receiving cytotoxic therapy with little or no additional effect on the bone marrow or peripheral blood.

The combination of the antibiotics in Co-TrimoxazoleSeptrin for Infusion should only be used where, in the judgement of the physician, the benefits of treatment outweigh any possible risks; consideration should be given to the use of a single effective antibacterial agent

4.5       Interaction with other medicinal products and other forms of interaction
Concurrent use of rifampicin and Co-TrimoxazoleSeptrin 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

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-TrimoxazoleSeptrin is advisable

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

4.6.      Fertility, Pregnancy and Lactation

 

Pregnancy

 

There are not any adequate data from the use of Co-TrimoxazoleSeptrin for Infusion 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 (see 5.3 Preclinical Safety Data).

 

Co-TrimoxazoleSeptrin for Infusion should not be used in pregnancy, particularly in the first trimester, unless clearly necessary. Folate supplementation should be considered if Co-TrimoxazoleSeptrin for Infusion is used in pregnancy.

 

Sulfamethoxazole 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 hyperbilirubinaemia, with an associated theoretical risk of kernicterus, when Co-TrimoxazoleSeptrin for Infusion is administered to the mother near the time of delivery. This theoretical risk is particularly relevant in infants at increased risk of hyperbilirubinaemia, such as those who are preterm and those with glucose-6-phosphate dehydrogenase deficiency.

 

Lactation

 

The components of Co-TrimoxazoleSeptrin for Infusion (trimethoprim and sulfamethoxazole) are excreted in breast milk. Administration of Co-TrimoxazoleSeptrin for Infusion 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 Co-TrimoxazoleSeptrin for Infusion should be avoided in infants younger than eight weeks in view of the predisposition of young infants to hyperbilirubinaemia.

4.7       Effects on Ability to Drive and Use Machines

 

5.1       Pharmacodynamic Properties

 

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

 

Mode of Action

 

Co-TrimoxazoleSeptrin is an antibacterial drug composed of two active principles, sulfamethoxazole and trimethoprim. Sulfamethoxazole is a competitive inhibitor of dihydropteroate synthetase enzyme. Sulfamethoxazole competitively inhibits the utilisation 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 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.

5.2       Pharmacokinetic Properties

 

Peak plasma levels of trimethoprim and sulfamethoxazole are higher and achieved more rapidly after one hour of intravenous infusion of Co-TrimoxazoleSeptrin 16 mg/80 mg per ml for Infusion than after oral administration of an equivalent dose of a Co-TrimoxazoleSeptrin oral presentation. Plasma concentrations, elimination half-life and urinary excretion rates show no significant differences following either the oral or intravenous route of administration

 

6.6       Instructions for use and handling (and disposal)

 

Septrin Co-Trimoxazole for Infusion must be diluted before administration.

 

Dilution should be carried out immediately before use. After adding Co-TrimoxazoleSeptrin 16 mg/80 mg per ml for Infusion to the infusion solution, shake thoroughly to ensure complete mixing. If visible turbidity or crystallisation appears at any time before or during an infusion, the mixture should be discarded.

 

It is recommended that SeptrinCo-Trimoxazole 16 mg/80 mg per ml for Infusion is diluted according to the following schedules:

 

One ampoule (5 ml) to 125 ml infusion solution.

Two ampoules (10 ml) to 250 ml infusion solution.

Three ampoules (15 ml) to 500 ml infusion solution.

 

Co-TrimoxazoleSeptrin 16 mg/80 mg per ml for Infusion is known to be compatible, when diluted as recommended above, with the following fluids:

 

 

When fluid restriction is necessary, Co-TrimoxazoleSeptrin 16 mg/80 mg per ml for Infusion may be administered at a higher concentration, 5 ml diluted with 75 ml of glucose 5% w/v in water. The resultant solution, whilst being clear to the naked eye, may on occasion exceed the BP limits set for particulate matter in large volume parenterals. The solution should be infused over a period not exceeding one hour. Discard any unused solution.

10.       Date of Revision of Text

28/10/2015 August 2014


Reasons for adding or updating:

  • Change to section 7 - Marketing authorisation holder
  • Change to section 10 - Date of revision of the text

Date of revision of text on the SPC:01-08-2014

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



7.         Marketing Authorisation Holder

Aspen Pharma Trading Limited

3016 Lake Drive,

Citywest Business Campus,

Dublin 24,

Ireland

12/13 Exchange Place

I.F.S.C, Dublin 1

Ireland 

  

 

10.       Date of Revision of Text

 

            August 2014 May 2013

Reasons for adding or updating:

  • Change to section 4.4 - Special warnings and precautions for use
  • Change to section 4.8 - Undesirable effects
  • Change to section 10 - Date of revision of the text

Date of revision of text on the SPC:17-05-2013

Legal Category:P

Black Triangle (CHM): NO

Free-text change information supplied by the pharmaceutical company:




Text added highlighted in green, text scored through has been deleted. Updates to 4.4, 4.8 and 10

4.4         Special Warnings and Precautions for Use

 

Fatalities, although very rare, have occurred due to severe reactions including

Stevens-Johnson syndrome, Lyells syndrome (toxic epidermal necrolysis), fulminant hepatic necrosis, agranulocytosis, aplastic anaemia, other blood dyscrasias and hypersensitivity of the respiratory tract.

 

•   Life-threatening cutaneous  reactions  Stevens-Johnson  syndrome  (SJS)  and toxic epidermal necrolysis (TEN) have been reported with the use of Septrin.

•   Patients should be advised of the signs and symptoms and monitored closely for skin reactions. The highest risk for occurrence of SJS or TEN is within the first weeks of treatment.

•   If symptoms or signs of SJS or TEN (e.g. progressive skin rash often with blisters or mucosal lesions) are present, Septrin treatment should be discontinued (see 4.8 Undesirable Effects).

 The best results in managing SJS and TEN come from early diagnosis and immediate discontinuation of any suspect drug. Early withdrawal is associated with a better prognosis.

•   If the patient has developed SJS or TEN with the use of Septrin, Septrin must not be re-started in this patient at any time.

 

 

 

Septrin 16 mg/80 mg per ml for Infusion should be discontinued at the first appearance of a skin rash (see 4.8 Undesirable Effects).

 

4.8       Undesirable Effects

Very rare:       Photosensitivity exfoliativ dermatitis fixed    drug    eruption, erythema multiforme, severe cutaneous adverse reactions (SCARs): Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) have been reported (see section 4.4)

 

Stevens-Johnson syndrome, Lyells syndrome (toxic epidermal necrolysis)

 

Lyells syndrome carries a high mortality.

10.       Date of (Partial) Revision of Text

 

May 2012

Reasons for adding or updating:

  • Change to section 7 - Marketing Authorisation Holder
  • Change to section 8 - MARKETING AUTHORISATION NUMBER(S)
  • Change to section 10 date of revision of the text

Date of revision of text on the SPC:01-05-2012

Legal Category:P

Black Triangle (CHM): NO

Free-text change information supplied by the pharmaceutical company:



7. Marketing Authorisation Holder changed from Laboratoires Genopharm, ZI de l’Esplanade 2, rue Niels Bohr 77400 Saint-Thibault-des-Vignes, France to Aspen Pharma Trading Limited, 12/13 Exchange Place, I.F.S.C, Dublin 1, Ireland

  

8.         Marketing Authorisation Number changed from PL 26946/0009 to PL 39699/ 0044

 

10.       Date of (Partial) Revision of Text  changed from 16 September 2010 to May 2012

 

 

Reasons for adding or updating:

  • New SPC for eMC ie an SPC for an existing product, but one that is new for the eMC
  • New individual SPC (was previously included in combined SPC)

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

Legal Category:P

Black Triangle (CHM): NO