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Aspen

3016 Lake Drive, Citywest Business Campus, Dublin 24, Ireland
Telephone: 003531 630 8400
Medical Information Direct Line: 0080000404142 - Freephone
Medical Information e-mail: aspenmedinfo@professionalinformation.co.uk
Summary of Product Characteristics last updated on medicines.ie: 14/11/2017
SPC Septrin Forte 160mg/800mg Tablets

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

Updated on 14/11/2017 and displayed until Current
Reasons for adding or updating:
  • 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 5.1 - Pharmacodynamic properties
  • Change to section 5.2 - Pharmacokinetic properties
  • Change to section 6.4 - Special precautions for storage
  • 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:   31-Oct-2017
Legal Category:   Product subject to medical prescription which may be renewed (B)

Free-text change information supplied by the pharmaceutical company



Text in red = new text

Text strikethrough = deleted text

 

3.     PHARMACEUTICAL FORM

 

Tablet

 

White, round, biconvex tablets, debossed with “S2” on one side and scored on the other side.

 

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

 

4.4   Special warnings and precautions for use

 

4.4   Special warnings and precautions for use

 

Life threatening adverse reaction

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.

 

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 section 4.8).

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.

 

Elderly patients

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.

Patients with renal impairment

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

Urinary output

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 hypoalbuminaemia the risk may be increased.

 

Folate

 

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. 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).

 

Patients with glucose-6-phosphate dehydrogenase deficiency

 

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

 

Patients with severe atopy or bronchial asthma

Septrin should be given with caution to patients with severe atopy or bronchial asthma.

Treatment of streptococcal pharyngitis due to Group A beta-haemolytic streptococci

Septrin should not be used in the treatment of streptococcal pharyngitis due to Group A β-haemolytic streptococci, eradication of these organisms from the oropharynx is less effective than with penicillin.

 

Phenylalanine metabolism

Trimethoprim has been noted to impair phenylalanine metabolism but this is of no significance in phenylketonuric patients on appropriate dietary restriction.

 

Patients with or at risk of porphyria

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

 

Patients with hyperkalaemia and hyponatraemia

Close monitoring of serum potassium and sodium is warranted in patients at risk of hyperkalaemia and hyponatraemia.

 

 

Patients with serious haematological disorders

Except under careful supervision Septrin should not be given to patients with serious haematological disorders (see section 4.8). Septrin has been given to patients receiving cytotoxic therapy with little or no additional effect on the bone marrow or peripheral blood.

 

4.5   Interaction with other medicinal products and other forms of interaction

 

Diuretics (thiazides): in elderly patients concurrently receiving diuretics, mainly thiazides, there appears to be an increased risk of thrombocytopenia.

 

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

 

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.

 

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.

 

Warfarin: co-trimoxazole has been shown to poteniate 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.

 

Phenytoin: co-trimoxazole prolongs the half-life of phenytoin and if co-administered the prescriber should be alert for excessive phenytoin effects. Close monitoring of the patients conditions and serum phenytoin levels is advisable.

 

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

 

Rifampicin: 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 clinical significance.

 

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

 

When trimethoprim is administered simultaneously with drugs that form cautions 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.

 

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

 

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

Azathioprine: There are conflicting clinical reports of interactions, resulting in serious haematological abnormalities, between azathioprine and co-trimoxazole.

Methotrexate: co-trimoxazole 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 section 4.4).

 

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.

 

 

 

 

5.1   Pharmacodynamic properties

 

Resistance

 

In vitro studies have shown that bacterial resistance can develop more slowly with both sulfamethoxazole and trimethoprim in combination that with either sulfamethoxazole or trimethoprim alone.

 

Resistance to sulfamethoxazole may occur by different mechanisms. Bacterial mutations cause an increase the concentration of PABA and thereby out-compete with sulfamethoxazole resulting in a reduction of the inhibitory effect on dihydropteroate synthetase enzyme. Another resistance mechanism is plasmid-mediated and results from production of an altered dihydropteroate synthetase enzyme, with reduced affinity for sulfamethoxazole compared to the wild-type enzyme.

 

Resistance to trimethoprim occurs through a plasmid-mediated mutation which results in production of an altered dihydrofolate reductase enzyme having a reduced affinity for trimethoprim compared to the wild-type enzyme.

 

Susceptibility testing breakpoints

Testing of trimethoprim  sulfamethoxazole was performed using the common dilution series to assess the Minimum Inhibitory Concentration (MIC). The MIC breakpoints for resistance are those recommended by CLSI (Clinical and Laboratory Standards Institute – formerly the National Committee for Clinical Laboratory Standards (NCCLS) and EUCAST guidelines.

 

Pharmacodynamic effects

 

 

5.2   Pharmacokinetic properties

 

 

Absorption

 

After oral administration trimethoprim and sulfamethoxazole 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 in the concentrations achieved in the blood by the other.

 

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, salvia, sputum and vaginal secretions. Levels in the aqueous humour, breast milk, cerebrospinal; middle ear fluid synovial fluid and tissue (interstitial) fluid are adequate for antibacterial activity.

 

Trimethoprim passes into amniotic fluid and foetal tissue reaching concentrations approximately 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) fluid is of the order of 20-50% of the plasma concentration.

 

Biotransformation

 

Renal excretion of intact SMX accounts for 15-30% of the dose. This drug is more extensively metabolised than TMP, 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. There appears to be no significant difference in the elderly compared with young patients.

 

The principle 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 9-11 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 25ml/minute. The principle 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.

 

 

6.4     Special precautions for storage

 

Do not store above 25°C.

Store in the original package in order to protect from light.

 

 

6.6     Special precautions for disposal of a used medicinal product or waste materials derived from such medicinal product and other handling of the product

 

 

 

10.   DATE OF REVISION OF THE TEXT

 

April 2014FebruaryAugust 2015 October 2017

Updated on 16/03/2015 and displayed until 14/11/2017
Reasons for adding or updating:
  • Change to section 3 - Pharmaceutical form
  • Change to section 10 - Date of revision of the text
Date of revision of text on the SPC:   01-Feb-2015
Legal Category:   Product subject to medical prescription which may be renewed (B)

Free-text change information supplied by the pharmaceutical company

Text in red new text
Text in cross thru red - old text


3 PHARMACEUTICAL FORM


Tablet. White, biconvex, elongated tablets, scored along the shorter axis and coded S3 on one side. 'GX 02C'.

 



10 DATE OF REVISION OF THE TEXT

February 2015 April 2014

Updated on 11/04/2014 and displayed until 16/03/2015
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-Apr-2014
Legal Category:   Product subject to medical prescription which may be renewed (B)

Free-text change information supplied by the pharmaceutical company



Text in red = new text
Text strikethrough = deleted text



 

7 MARKETING AUTHORISATION HOLDER

12/13 Exchange Place

I.F.S.C Dublin 1

3016 Lake Drive,

Citywest Business Campus

Dublin 24

10 DATE OF REVISION OF THE TEXT

july April 20143

Updated on 24/07/2013 and displayed until 11/04/2014
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
  • Correction of spelling/typing errors
Date of revision of text on the SPC:   16-Jul-2013
Legal Category:   Product subject to medical prescription which may be renewed (B)

Free-text change information supplied by the pharmaceutical company



Text added: Blue
Text deleted: Strike through

Spelling error for
trimethoprim and sulfamethoxazole corrected.

4.4 Special warnings and precautions for use

 

Fatalities, although very rare, have occurred due to severe reactions including fulminant Stevens-Johnson syndrome, Lyell’s syndrome (toxic epidermal necrolysis), 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.

4.8 Undesirable effects

 

Skin and subcutaneous tissue disorders

Common:          Skin rashes

Very rare:          Photosensitivity, exfoliative 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, Lyell’s syndrome (toxic epidermal necrolysis),

Lyell’s syndrome carries a high mortality.

 

10 DATE OF REVISION OF THE  TEXT

 

February 2011 July 2013

 

Updated on 23/01/2013 and displayed until 24/07/2013
Reasons for adding or updating:
  • Improved electronic presentation
Date of revision of text on the SPC:   01-Feb-2011
Legal Category:   Product subject to medical prescription which may be renewed (B)

Free-text change information supplied by the pharmaceutical company

Improved electronic presentation
Updated on 05/05/2011 and displayed until 23/01/2013
Reasons for adding or updating:
  • Change to section 7 - Marketing authorisation holder
  • Change to section 8 - MA number
  • Change to section 10 - Date of revision of the text
  • SPC retired pending re-submission
Date of revision of text on the SPC:   01-Jan-2011
Legal Category:   Product subject to medical prescription which may be renewed (B)

Free-text change information supplied by the pharmaceutical company



Product ownership changed from GSK to Aspen

Updated on 28/10/2008 and displayed until 05/05/2011
Reasons for adding or updating:
  • Correction of spelling/typing errors
Updated on 11/09/2008 and displayed until 28/10/2008
Reasons for adding or updating:
  • Change to section 4.8 - Undesirable effects
Date of revision of text on the SPC:   09/2008
Legal Category:   prescription only

Free-text change information supplied by the pharmaceutical company

 

The following text has been added to section 4.8 of the SPC’s:

 

Eye disorders:

Very rare: Uveitis

Updated on 04/04/2008 and displayed until 11/09/2008
Reasons for adding or updating:
  • Change to section 4.5 - Interaction with other medicinal products and other forms of interaction
  • Change to section 5.1 - Pharmacodynamic properties
Date of revision of text on the SPC:   03/2008
Legal Category:   prescription only

Free-text change information supplied by the pharmaceutical company

4.5       Interaction with other medicaments and other forms of interaction

5.1       Pharmacodynamic Properties

Updated on 12/06/2007 and displayed until 04/04/2008
Reasons for adding or updating:
  • Change to section 4.3 - Contraindications
  • Change to section 4.4 - Special warnings and precautions for use
  • Change to section 4.8 - Undesirable effects
Date of revision of text on the SPC:   05/2007
Legal Category:   prescription only

Free-text change information supplied by the pharmaceutical company

4.3       Contraindications

 

Septrin presentations should not be given to patients with a history of hypersensitivity to sulphonamides, trimethoprim or co-trimoxazole or any excipients of the presentations.
 
4.4       Special Warnings and Special Precautions for Use
 

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.

 

In glucose-6-phosphate dehydrogenase deficient (G-6-PD) 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-haemolytic 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 Septrin 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.

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

4.8       Undesirable Effects

 

As Septrin contains trimethoprim 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 events 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 1/10, 

common 1/100 and <1/10, 

uncommon 1/1000 and <1/100, 

rare 1/10,000 and <1/1000, 

very rare <1/10,000.

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, 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 in a number of cases on re-exposure to either Septrin 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

Very rare:

Glossitis, stomatitis, pseudomembranous colitis, pancreatitis

 

Hepatobiliary disorders

Very rare:

Cholestatic jaundice, hepatic necrosis

Cholestatic jaundice and hepatic necrosis may be fatal.

Oral:

Very rare: 

Elevation of serum transaminases, elevation of bilirubin levels

 

Skin and subcutaneous tissue disorders

Common: 

Skin rashes

Very rare:

Photosensitivity, exfoliative dermatitis, fixed drug eruption, erythema multiforme, Stevens-Johnson syndrome, Lyells syndrome (toxic epidermal necrolysis)

Lyells 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 Pneumocystis jiroveci (carinii) pneumonitis (PJP) management

Very rare:

Severe hypersensitivity reactions, rash, fever, neutropenia, thrombocytopenia, raised liver enzymes, rhabdomyolysis

 

At the high dosages used for PJP 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 PJP patients on re-exposure to trimethoprim-sulfamethoxazole, sometimes after a dosage interval of a few days. Rhabdomyolysis has been reported in HIV positive patients receiving Septrinfor prophylaxis or treatment of PJP.

 

Very rare:

Hyperkalaemia, hyponatraemia

 

Updated on 23/05/2006 and displayed until 12/06/2007
Reasons for adding or updating:
  • Change to section 1 - Name of medicinal product
  • Change to section 4.8 - Undesirable effects
  • Change to section 5.1 - Pharmacodynamic properties
  • Change to section 5.3 - Preclinical safety data
  • Change to section 6.4 - Special precautions for storage
  • Change to section 6.5 - Nature and contents of container
  • Change to section 9 - Date of renewal of authorisation
Updated on 01/07/2003 and displayed until 23/05/2006
Reasons for adding or updating:
  • New SPC for medicines.ie

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Active Ingredients

 
   Trimethoprim
   Sulfamethoxazole