COLISTIMETHATE SODIUM 1 Million I.U. Powder for solution for injection Ref.[6750] Active ingredients: Colistimethate

Consideration should be given to co-administering intravenous colistimethate sodium with another antibacterial agent whenever this is possible, taking into account the remaining susceptibilities of the pathogen(s) under treatment. As the development of resistance to intravenous colistin has been reported in particular when it is used as a monotherapy, co-administration with other antibacterial should also be considered in order to prevent the emergence of resistance.

There are limited clinical data on the efficacy and safety of intravenous colistimethate sodium. The recommended doses in all subpopulations are equally based on limited data (clinical and pharmacokinetic/pharmacodynamics data). In particular there are limited safety data for the use of high doses (>6MIU/day) and the use of a loading dose, and for special populations (patients with renal impairment and the paediatric population). Colistimethate sodium should only be used when other, more commonly prescribed antibiotics are not effective or not appropriate.

Renal function monitoring should be performed at the start of treatment and regularly during treatment in all patients. The dose of colistimethate sodium should be adjusted according to creatinine clearance (see section 4.2). Patients who are hypovolaemic or those receiving other potentially nephrotoxic drugs are at increased risk of nephrotoxicity from colistin (see sections 4.5 and 4.8).

Nephrotoxicity has been reported to be associated with cumulative dose and treatment duration in some studies. The benefit of prolonged treatment duration should be balanced against the potentially increased risk of renal toxicity.

Caution is advised when administering colistimethate sodium to infants <1 year of age as renal function is not fully mature in this age group. Further, the effect of immature renal and metabolic function on the conversion of colistimethate sodium to colistin is not known.

In case of an allergic reaction, treatment with colistimethate sodium must be discontinued and appropriate measures implemented.

High serum concentrations of colistimethate sodium, which may be associated with overdosage or failure to reduce the dosage in patients with renal impairment, have been reported to lead to neurotoxic effects such as facial paraesthesia, muscle weakness, vertigo, slurred speech, vasomotor instability, visual disturbances, confusion, psychosis and apnoea. Monitoring should be performed for perioral paraesthesia and paraesthesia in the extremities, which are signs of overdose (see section 4.9).

Colistimethate sodium is known to reduce the presynaptic release of acetyl-choline at the neuromuscular junction and should be used in patients with myasthenia gravis with the greatest caution and only if clearly needed.

Respiratory arrest has been reported following intramuscular administration of colistimethate sodium. Impaired renal function increases the possibility of apnoea and neuromuscular blockade following administration of colistimethate sodium.

Colistimethate sodium should be used with extreme caution in patients with porphyria.

Antibiotic-associated colitis and pseudomembranous colitis have been reported with nearly all antibacterial agents and may occur with colistimethate sodium. They may range from mild to lifethreatening in severity. It is important to consider this diagnosis in patients who develop diarrhoea during or after the use of colistimethate sodium (see section 4.8). Discontinuation of therapy and the administration of specific treatment for Clostridium difficile should be considered. Medicinal products that inhibit peristalsis should not be given.

Intravenous colistimethate sodium does not cross the blood brain barrier to a clinically relevant extent. The use of intrathecal or intraventricular administration of colistimethate sodium in the treatment of meningitis was not systematically investigated in clinical trials and is supported by case reports only. Data supporting the posology are very limited. The most commonly observed adverse effect of CMS administration was aseptic meningitis (see section 4.8).

Concomitant use of intravenous colistimethate sodium with other medications that are potentially nephrotoxic or neurotoxic should be undertaken with great caution.

Caution should be taken with concomitant use with other formulations of colistimethate sodium as there is little experience and there is a possibility of summative toxicity.

No in vivo interaction studies have been performed. The mechanism of conversion of Colistimethate sodium to the active substance, colistin, is not characterised. The mechanism of colistin clearance, including renal handling, is equally unknown. Colistimethate sodium or colistin did not induce the activity of any P 450 (CYP) enzyme tested (CYP1A2, 2B6, 2C8, 2C9, 2C19 and 3A4/5) in in vitro studies in human hepatocytes.

The potential for drug-drug interactions should be borne in mind when Colistimethate Sodium is coadministered with drugs known to inhibit or induce drug metabolising enzymes or drugs known to be substrates for renal carrier mechanisms.

Due to the effects of colistin on the release of acetylcholine, non-depolarising muscle relaxants should be used with caution in patients receiving colistimethate sodium as their effects could be prolonged (see section 4.4).

Co-treatment with colistimethate sodium and macrolides such as azithromycin and clarithromycin, or fluoroquinolones such as norfloxacin and ciprofloxacin should be undertaken with caution in patients with myasthenia gravis (see section 4.4).

There are no adequate data from the use of Colistimethate sodium in pregnant women. Animal studies in rats and mice do not indicate teratogenic properties. However, single dose studies in human pregnancy show that Colistimethate crosses the placental barrier and there may be a risk of foetal toxicity if repeated doses are given to pregnant patients.

Colistimethate should be used in pregnancy only if the benefit to the mother outweighs the potential risk to the foetus.

Colistimethate is secreted in breast milk, and should be administered to breastfeeding women only when clearly needed.

During parenteral treatment with Colistimethate sodium neurotoxicity may occur with the possibility of dizziness, confusion or visual disturbance. Patients should be warned not to drive or operate machinery if these effects occur.

The likelihood of adverse events may be related to the age, renal function and condition of the patient.

In cystic fibrosis patients neurological events have been reported in up to 27% of patients. These are generally mild and resolve during or shortly after treatment.

Adverse effects on renal function have been reported, usually following use of higher than recommended doses in patients with normal renal function, or failure to reduce the dose in patients with renal impairment or during concomitant use of other nephrotoxic antibiotics. The effects are usually reversible on discontinuation of therapy.

In cystic fibrosis patients treated within the recommended dosage limits, nephrotoxicity appears to be rare (less than 1%). In seriously ill hospitalised non-CF patients, signs of nephrotoxicity have been reported in approximately 20% of patients.

Neurotoxicity has been reported often in association with overdose, failure to reduce dose in patients with renal insufficiency and concomitant use of either neuromuscular blocking drugs or other drugs with similar neurological effects. Reducing the dose may alleviate symptoms.

Effects may include apnoea, transient sensory disturbances (such as facial paraesthesia and vertigo) and, rarely, vasomotor instability, slurred speech, visual disturbances, confusion or psychosis.

Hypersensitivity reactions including skin rash have been reported. If these occur treatment should be withdrawn.

Local irritation at the site of injection may occur.

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. Website: www.mhra.gov.uk/yellowcard.

In the absence of compatibility studies, reconstituted Colistimethate sodium must not be mixed with other medicinal products.