Source: Medicines & Healthcare Products Regulatory Agency (GB) Revision Year: 2021 Publisher: Teva UK Limited, Brampton Road, Hampden Park, Eastbourne, East Sussex, BN22 9AG, United Kingdom
Colomycin by intravenous administration 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).
Colomycin by inhalation is also indicated for the management of adult and paediatric chronic pulmonary infections due to Pseudomonas aeruginosa in patients with cystic fibrosis (see section 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 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 9 million IU/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.
Haemodialysis:
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.
CVVHF / CVVHDF:
As in patients with normal renal function. Three times daily dosing is recommended.
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:
Intraventricular route:
125,000 IU/day.
Intrathecally administered doses should not exceed those recommended for intraventricular use.
No specific dosing recommendation can be made in children for intrathecal and intraventricular routes of administration.
Colomycin is administered intravenously as a slow infusion over 30 – 60 minutes.
Patients with a totally implantable venous access device (TIVAD) in place may tolerate a bolus injection of up to 2 million units in 10ml given over a minimum of 5 minutes (see section 6.6).
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 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
It is recommended that colistimethate sodium (CMS) should be administered under the supervision of physicians with appropriate experience in its use.
The dosage can be adjusted depending on the severity of the condition and clinical response.
Adults, adolescents and children ≥2 years:
1-2 MIU two to three times per day (max 6 MIU/day).
Children <2 years:
0.5-1 MIU twice daily (max 2 MIU/day).
Relevant clinical guidance on treatment regimens, including duration of treatment, periodicity and co-administration of other antibacterial agents should be adhered to.
Dose adjustment is not considered necessary
Dose adjustment is not considered necessary, however caution is advised in patients with renal impairment (see sections 4.4 and 5.2).
Dose adjustment is not considered necessary
For inhalation use.
Suitable nebulisers are the reusable jet nebulisers including the PARI LC PLUS or the PARI LC SPRINT, which are used with a suitable compressor, or the membrane nebuliser namely eFlow rapid.
Colomycin 1 Million IU is intended for administration by nebulisation using a suitable nebuliser as mentioned above.
Drug delivery characteristics from in vitro studies with the different nebuliser systems are detailed in the table below:
| Nebuliser System | |||
|---|---|---|---|
| Parameter | PARI LC Plus | PARI LC Sprint | eFlow rapid |
| Total Drug Delivered from Nebuliser mouthpiece (Million IU) | 0.611 | 0.682 | 0.544 |
| Drug delivery rate (Million IU/minute) | 0.078 | 0.092 | 0.159 |
| Fine Particle Fraction (% <5%) | 51.8 | 57.9 | 48.2 |
| Droplet Size Distribution.Mass Median Aerodynamic Diameter (MMAD) (µm) | 4.7 | 4.0 | 5.1 |
| Geometric Standard Deviation (GSD) | 2.2 | 2.3 | 2.0 |
| Measured using Colomycin 1 MIU reconstituted with 3 ml of 0.9% sodium chloride solution | |||
Colistimethate sodium is very soluble in the reconstitution medium. The recommended technique for dissolving the medicinal product is the addition of 3 ml isotonic sodium chloride solution (0.9% w/w), to the vial containing Colomycin 1 million IU by gentle shaking.
Due to potential foaming, vigorous shaking should be avoided. The resulting solution for nebulisation should be clear and carefully transferred into the medication reservoir of the nebuliser.
The solution is for single use only and any remaining solution should be discarded.
The nebuliser must be kept according to the instructions of the corresponding nebuliser during operation.
The patient should sit in an upright position and breathing normally during inhalation. Inhalation should be performed without any interruption to normal breathing.
The nebuliser must be cleaned and disinfected after use as described in the ‘instruction of use’ of the corresponding nebuliser.
Colistimethate sodium undergoes hydrolysis to the active substance colistin in aqueous solution. For special precautions for disposal and handling of reconstituted solutions, see section 6.6.
If other treatments are being taken, they should be taken in the order recommended by the physician.
See above for the Dose conversion table.
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. Measures to increase the rate of elimination of colistin e.g. mannitol diuresis, prolonged haemodialysis or peritoneal dialysis may be tried, but effectiveness is unknown.
Before opening:
3 years.
Reconstituted solutions:
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 or nebulisation, 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.
For solutions for intrathecal and intraventricular administration, the reconstituted product should be used immediately.
Do not store above 25°C.
Keep the vials in the outer carton in order to protect from light.
For storage of solutions following reconstitution refer to 6.3.
Type I, 10 ml nominal capacity glass vial with red ‘flip-off’ cap supplied in cartons of 10, 56 or 60 vials.
Not all pack sizes may be marketed.
For bolus injection:
Reconstitute the contents of the vial with not more than 10ml water for injection or 0.9% sodium chloride.
For infusion:
The contents of the reconstituted vial may be diluted, usually with 50ml 0.9% sodium chloride.
When the intrathecal and intraventricular routes of administration are used, the volume administered should not exceed 1 ml (reconstituted concentration 125,000 IU/ml).
For inhalation by nebuliser:
Reconstitute the contents of the vial with either water for injections or with sodium chloride 9 mg/ml (0.9% solution).
Colistimethate sodium is very soluble in the reconstitution medium. The recommended technique for dissolving the medicinal product is the addition of 3 ml isotonic sodium chloride solution (0.9% w/w), to the vial containing Colomycin 1 million IU by gentle shaking.
The output from the nebuliser may be vented to the open air or a filter may be fitted. Nebulisation should take place in a well ventilated room.
Solutions are for single use only and any remaining solution should be discarded.
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