Source: Medicines & Healthcare Products Regulatory Agency (GB) Revision Year: 2018 Publisher: Beacon Pharmaceuticals Limited, DCC Vital, Westminster Industrial Estate, Repton Road, Measham, DE12 7DT, England
Colistimethate Sodium is indicated in adults and children including neonates for the treatment of serious infections due to selected aerobic Gram-negative pathogens in patients with limited treatment options (see sections 4.2, 4.4, 4.8 and 5.1).
Consideration should be given to official guidance on the appropriate use of antibacterial agents.
The dose to be administered and the treatment duration should take into account the severity of the infection as well as the clinical response. Therapeutic guidelines should be adhered to.
The dose is expressed in international units (IU) of colistimethate sodium (CMS). A conversion table from CMS in IU to mg of CMS as well as to mg of colistin base activity (CBA) is included at the end of this section.
The following dose recommendations are made based on limited population-pharmacokinetic data in critically ill patients (see section 4.4):
Maintenance dose 9MIU/day in 2-3 divided doses.
In patients who are critically ill, a loading dose of 9 MIU should be administered.
The most appropriate time interval to the first maintenance dose has not been established.
Modelling suggests that loading and maintenance doses of up to 12 MIU may be required in patients with good renal function in some cases. Clinical experience with such doses is however extremely limited and safety has not been established.
The loading dose applies to patients with normal and impaired renal functions including those on renal replacement therapy.
Dose adjustments in renal impairment are necessary, but pharmacokinetic data available for patients with impaired renal function is very limited.
The following dose adjustments are suggested as guidance.
Dose reductions are recommended for patients with creatinine clearance <50 ml/min: Twice daily dosing is recommended.
| Creatinine clearance (ml/min) | Daily dose |
|---|---|
| <50-30 | 5.5-7.5 MIU |
| <30-10 | 4.5-5.5 MIU |
| <10 | 3.5 MIU |
MIU = million IU
Colistin appears to be dialyzable through conventional haemodialysis and continuous venovenous haemo(dia)filtration (CVVHF, CVVHDF). There are extremely limited data from population PK studies from very small numbers of patients on renal replacement therapy. Firm dose recommendations cannot be made. The following regimes could be considered.
No-HD days: 2.25 MIU/day (2.2-2.3 MIU/day).
HD days: 3 MIU/day on haemodialysis days, to be given after the HD session. Twice daily dosing is recommended.
As in patients with normal renal function. Three times daily dosing is recommended. Hepatic impairment
There are no data in patients with hepatic impairment. Caution is advised when administering colistimethate sodium in these patients.
No dose adjustments in older patients with normal renal function are considered necessary.
The data supporting the dose regimen in paediatric patients are very limited. Renal maturity should be taken into consideration when selecting the dose. The dose should be based on lean body weight.
75,000-150,000 IU/kg/day divided into 3 doses.
For children with a body weight above 40 kg, use of the dosing recommendation for adults should be considered.
The use of doses >150,000 IU/kg/day has been reported in children with cystic fibrosis.
There are no data regarding the use or magnitude of a loading dose in critically ill children.
No dose recommendations have been established in children with impaired renal function.
Based on limited data, the following dose is recommended in adults:
Colistimethate Sodium is administered intravenously as a slow infusion over 30–60 minutes. Colistimethate sodium undergoes hydrolysis to the active substance colistin in aqueous solution. For dose preparation, particularly where combination of multiple vials is needed, reconstitution of the required dose must be performed using strict aseptic technique (see section 6.6).
In the EU, the dose of colistimethate sodium (CMS) must be prescribed and administered only as International Units (IU). The product label states the number of IU per vial.
Confusion and medication errors have occurred because of the different expressions of dose in terms of potency. The dose is expressed in the US, and other parts of the world, as milligrams of colistin base activity (mg CBA).
The following conversion table is prepared for information and the values must be considered nominal and approximate only.
CMS conversion table:
| Potency | ≈ mass of CMS (mg)* | |
|---|---|---|
| IU | ≈ mg CBA | |
| 12.500 | 0.4 | 1 |
| 150.000 | 5 | 12 |
| 1.000.000 | 34 | 80 |
| 4.500.000 | 150 | 360 |
| 9.000.000 | 300 | 720 |
* Nominal potency of the drug substance = 12.500 IU/mg
Overdose can result in neuromuscular blockade that can lead to muscular weakness, apnoea and possible respiratory arrest. Overdose can also cause acute renal failure characterised by decreased urine output and increased serum concentrations of BUN and creatinine.
There is no specific antidote. Manage by supportive treatment and measures to increase the rate of elimination of colistimethate e.g. mannitol diuresis, prolonged haemodialysis or peritoneal dialysis.
Shelf life: 3 years.
Hydrolysis of colistimethate is significantly increased when reconstituted and diluted below its critical micelle concentration of about 80,000 IU per ml.
Solutions below this concentration should be used immediately
For solutions for bolus injection, the chemical and physical in-use stability of reconstituted solution in the original vial, with a concentration ≥80,000 IU/mL, has been demonstrated for 24 hours at 2 to 8°C.
From a microbiological point of view, unless the method of opening/reconstitution/dilution precludes the risk of microbial contamination, the product should be used immediately.
If not used immediately, in-use storage times and conditions are the responsibility of user.
Solutions for infusion, which have been diluted beyond the original vial volume and/or with a concentration <80,000 IU/mL, should be used immediately.
Do not store above 25°C. Store the vial in the outer carton in order to protect from light
Do not freeze. Reconstituted Colistimethate sodium solution may be kept for up to 8 hours when not stored above 25°C or for up to 24 hours stored in a refrigerator.
7 ml Type I glass vial with a rubber stopper and an aluminium cap. Each carton contains 1 or 10 vials.
Reconstitute the contents of the vial with not more than 7ml water for injection or 0.9% sodium chloride.
The contents of the reconstituted vial may be diluted, usually with 50ml 0.9% sodium chloride
During reconstitution swirl gently to avoid frothing. The reconstituted Colistimethate sodium is a clear solution.
The outer surface of the primary container is non-sterile. For single use only. Any unused solution should be disposed of in accordance with local requirements.
Does not contain preservatives.
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