SEPTRIN Concentrate for solution for infusion Ref.[108387] Active ingredients: Sulfamethoxazole Trimethoprim

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), toxic epidermal necrolysis (TEN) or drug reaction with eosinophilia and systemic symptoms (DRESS) 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 and for DRESS the risk of occurrence is in the first two to eight weeks after drug administration.
• If symptoms or signs of SJS, TEN (e.g. progressive skin rash often with blisters or mucosal lesions) or DRESS (e.g. fever, eosinophilia, rash, lymphadenopathy, abnormal blood/liver function test and/or visceral organ involvement) are present, Septrin treatment should be discontinued (see section 4.8).
• The best results in managing SJS, TEN and DRESS 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, TEN or DRESS with the use of Septrin, Septrin must not be re-started in this patient at any time.
• The occurrence of a generalised febrile erythema associated with pustules, should raise the suspicion of acute generalised exanthematous pustulosis (AGEP) (see section 4.8); it requires cessation of treatment and contraindicates any new administration of Co-Trimoxazole alone or in combination with other drugs.

Haemophagocytic lymphohistiocytosis (HLH)

Cases of HLH have been reported very rarely in patients treated with co-trimoxazole. HLH is a life-threatening syndrome of pathologic immune activation characterised by clinical signs and symptoms of an excessive systemic inflammation (e.g. fever, hepatosplenomegaly, hypertriglyceridaemia, hypofibrinogenaemia, high serum ferritin, cytopenias and haemophagocytosis). Patients who develop early manifestations of pathologic immune activation should be evaluated immediately. If diagnosis of HLH is established, co-trimoxazole treatment should be discontinued.

Respiratory toxicity

Very rare, severe cases of respiratory toxicity, sometimes progressing to Acute Respiratory Distress Syndrome (ARDS), have been reported during co-trimoxazole treatment. The onset of pulmonary signs such as cough, fever, and dyspnoea in association with radiological signs of pulmonary infiltrates, and deterioration in pulmonary function may be preliminary signs of ARDS. In such circumstances, co-trimoxazole should be discontinued and appropriate treatment given.

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 specifically 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.

Metabolic acidosis

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

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.

Sulphites

Septrin for infusion contains sulphite. This may cause allergic-type reactions including anaphylactic symptoms and life-threatening or less severe asthmatic episodes in susceptible individuals.

Fluid overload

Fluid overload is possible, especially when very high doses are being administered to patients with underlying cardio-pulmonary disease.

Excipients with known effects

• This medicinal product contains 38.25 mg of sodium per 5 ml ampoule, equivalent to 1.9% of the WHO recommended maximum daily intake of 2 g sodium for an adult.
• This medicinal product contains sodium metabisulphite (E 223), which may rarely cause severe hypersensitivity reactions and bronchospasm.
• This medicinal product contains 2.25 g of propylene glycol (E 1520) per 5 ml ampoule which is equivalent to 450 mg/ml. While propylene glycol has not been shown to cause reproductive or developmental toxicity in animals or humans, it may reach the foetus and was found in milk. As a consequence, administration of propylene glycol to pregnant or lactating patients should be considered on a case by case basis. Medical monitoring is required in patients with impaired renal or hepatic functions because various adverse events attributed to propylene glycol have been reported such as renal dysfunction (acute tubular necrosis), acute renal failure and liver dysfunction. Various adverse events, such as hyperosmolality, lactic acidosis; renal dysfunction (acute tubular necrosis), acute renal failure; cardiotoxicity (arrhythmia, hypotension); central nervous system disorders (depression, coma, seizures); respiratory depression, dyspnoea; liver dysfunction; haemolytic reaction (intravascular haemolysis) and haemoglobinuria; or multisystem organ dysfunction, have been reported with high doses or prolonged use of propylene glycolTherefore, doses higher than 500 mg/kg/day may be administered in children >5 years old but will have to be considered case by case. Adverse events usually reverse following weaning off of propylene glycol, and in more severe cases following hemodialysis. Medical monitoring is required. Co-administration with any substrate for alcohol dehydrogenase such as ethanol may induce adverse effects in children less than 5 years old. This medicine should not be used in children less than 5 years old if the calculated dose for any given indication exceeds a propylene glycol threshold of 500 mg/kg/day.
• This medicinal product contains 0.5 mg of ethanol in each 5 ml ampoule which is equivalent to 0.1 mg/ml. The amount in 5 ml of this medicinal product is equivalent to less than 1 ml beer or 1 ml wine. The small amount of alcohol in this medicine will not have any noticeable effects.

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

The product should be used with care in patients taking concomitant therapy with drugs which are strongly bound, including oral hypoglycaemics and anti-coagulants.

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

Methotrexate and Phenytoin: Sulphonamides may displace methotrexate from protein binding sites and compete with renal transport of methotrexate and may inhibit phenytoin metabolism in the liver increasing the toxicity of each. 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.

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).

Interaction with sulphonylurea hypoglycaemic agents is uncommon but potentiation has been reported. Septrin should be used with care in patients on concomitant therapy with these agents.

This product may precipitate folate deficiency in patients liable to folate deficiency such as those taking folate antagonists, or anticonvulsants, or pyrimethamine.

Cyclosporin: reversible deterioration in renal function has been observed in patients treated with trimethoprim-sulfamethoxazole and ciclosporin following renal transplantation.

Hyperkalaemia: caution should be exercised in patients taking any other drugs that can cause hyperkalaemia, for example ACE inhibitors, angiotensin receptor blockers and potassium-sparing diuretics such as spironolactone. Concomitant use of trimethoprim-sulfamethoxazole (co-trimoxazole) may result in clinically relevant hyperkalaemia.

Azathioprine: There are conflicting clinical reports of interactions, resulting in serious haematological abnormalities, between azathioprine and trimethoprim – sulfamethoxazole.

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

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.

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.

Warfarin: trimethoprim – sulfamethoxazole has been shown to potentiate the anticoagulant activity of warfarin via stereo-selective inhibition of its metabolism. Sulfamethoxazole may displace warfarin from plasma-albumin protein-binding sites in vitro. Careful control of the anticoagulant therapy during treatment with Septrin is advisable.

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

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 jirovecii 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.

Interaction with laboratory tests: Trimethoprim interferes with assays for serum methotrexate when dihydrofolate reductase from Lactobacilluscasei is used in the assay. No interference occurs if methotrexate is measured by radioimmuno assay.

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.

Pregnancy

Trimethoprim and sulfamethoxazole cross the placenta and their safety in human pregnancy has not been established. Trimethoprim is a folate antagonist and, in animal studies, both agents established have been shown to cause foetal abnormalities (see section 5.3).

Case-control studies have shown that there may be an association between exposure to folate antagonists and birth defects in humans. Therefore Septrin should be avoided in pregnancy, particularly in the first trimester, unless the potential benefit to the mother outweighs the potential risk to the foetus; folate supplementation should be considered if trimethoprim – sulfamethoxazole 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 new-born, there may be a risk of precipitating or exacerbating neonatal hyperbilirubinaemia, with an associated theoretical risk of kernicterus, when Septrin 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.

Breast Feeding

Trimethoprim and sulfamethoxazole are excreted in breast milk. Administration of trimethoprim-sulfamethoxazole 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 trimethoprim-sulfamethoxazole should be avoided in infants younger than eight weeks in view of the predisposition of young infants to hyperbilirubinaemia.

See also section 4.4 for more information about ethanol content in this formulation.

Effects on the ability to drive and operate machinery in patients taking this medicine have not been studied.

See also section 4.4 for more information about ethanol and propylene glycol (E1520) content in this formulation.

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, Not known: cannot be estimated from the available data.

^* see description of selected adverse reactions

Description of selected adverse reactions

Aseptic meningitis

Aseptic meningitis was rapidly reversible on withdrawal of the drug, but recurred in a number of cases on re-exposure to either trimethoprim-sulfamethoxazole or to trimethoprim alone.

Pulmonary hypersensitivity reactions

Cough, dyspnoea, and lung infiltration may be early indicators of respiratory hypersensitivity which, while very rare, has been fatal.

Severe cutaneous adverse reactions (SCARs)

Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN) and drug reaction with eosinophilia and systemic symptoms (DRESS) have been reported to be life threatening (see Section 4.4).

As with any other drug, allergic reactions such as an itchy rash and hives may occur in patients with hypersensitivity to the components of the drug. Very rare cases of acute generalised exanthematous pustulosis (AGEP) have been observed (see section 4.4).

Hepatobiliary disorders

Jaundice cholestatic and hepatic necrosis may be fatal.

Effects associated with Pneumocystis jirovecii (carinii) pneumonitis (PJP) management

At the high dosages used for PJP management severe hypersensitivity reactions have been reported, necessitating cessation of therapy. 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 Septrin for prophylaxis or treatment of PJP.

IV Infusion

Concomitant administration of intravenous diphenhydramine may permit continued infusion.

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: HPRA Pharmacovigilance, Website: www.hpra.ie.

Septrin for Infusion should only be mixed with the recommended diluent (see section 6.6).

NO OTHER SUBSTANCE SHOULD BE MIXED WITH THE INFUSION.