- 1. Name of the medicinal product
- 2. Qualitative and quantitative composition
- 3. Pharmaceutical form
- 4. Clinical particulars
- 4.1 Therapeutic indications
- 4.2 Posology and method of administration
- 4.3 Contraindications
- 4.4 Special warnings and precautions for use
- 4.5 Interaction with other medicinal products and other forms of interaction
- 4.6 Pregnancy and lactation
- 4.7 Effects on ability to drive and use machines
- 4.8 Undesirable effects
- 4.9 Overdose
- 5. Pharmacological properties
- 5.1 Pharmacodynamic properties
- 5.2 Pharmacokinetic properties
- 5.3 Preclinical safety data
- 6. Pharmaceutical particulars
- 6.1 List of excipients
- 6.2 Incompatibilities
- 6.3 Shelf life
- 6.4 Special precautions for storage
- 6.5 Nature and contents of container
- 6.6 Special precautions for disposal and other handling
- 7. Marketing authorisation holder
- 8. Marketing authorisation number(s)
- 9. Date of first authorisation/renewal of the authorisation
- 10. Date of revision of the text
- 11. Legal category
|1 million IU/vial:||Sterile white powder in a 10ml colourless glass vial with a red 'flip-off' cap.|
|2 million IU/vial:||Sterile white powder in a 10ml colourless glass vial with a lilac 'flip-off' cap.|
Children and adults (including the elderly):Up to 60kg: 50,000 units/kg/day to a maximum of 75,000 units/kg/day. The total daily dose should be divided into three doses given at approximately 8-hour intervals. Over 60kg: 1-2 million units three times a day. The maximum dose is 6 million units in 24 hours.Anomalous distribution in patients with cystic fibrosis may require higher doses in order to maintain therapeutic serum levels.Renal impairment: In moderate to severe renal impairment, excretion of colistimethate sodium is delayed. Therefore, the dose and dose interval should be adjusted in order to prevent accumulation. The table below is a guide to dose regimen modifications in patients of 60kg bodyweight or greater. It is emphasised that further adjustments may have to be made based on blood levels and evidence of toxicity.SUGGESTED DOSAGE ADJUSTMENT IN RENAL IMPAIRMENT
Creatinine clearance (ml/min)
Over 60kg bodyweight
1-2 million units every 8hr
1 million units every 12-18 hr
1 million units every 18-24 hr
|Children <2 years:||500,000-1 million units twice daily|
|Children >2 years and adults:||1-2 million units twice daily|
Mode of actionColistimethate sodium is a cyclic polypeptide antibiotic derived from Bacillus polymyxa var. colistinus and belongs to the polymyxin group. The polymyxin antibiotics are cationic agents that work by damaging the cell membrane. The resulting physiological affects are lethal to the bacterium. Polymyxins are selective for Gram-negative bacteria that have a hydrophobic outer membrane.
ResistanceResistant bacteria are characterised by modification of the phosphate groups of lipopolysaccharide that become substituted with ethanolamine or aminoarabinose. Naturally resistant Gram-negative bacteria, such as Proteus mirabilis and Burkholderia cepacia, show complete substitution of their lipid phosphate by ethanolamine or aminoarabinose.
Cross resistanceCross resistance between colistimethate sodium and polymyxin B would be expected. Since the mechanism of action of the polymyxins is different from that of other antibiotics, resistance to colistin and polymixin by the above mechanism alone would not be expected to result in resistance to other drug classes.
BreakpointsThe suggested general MIC breakpoint to identify bacteria susceptible to colistimethate sodium is < 4mg/l. Bacteria for which the MIC of colistimethate sodium is ≥ 8mg/l should be considered resistant.
SusceptibilityThe prevalence of acquired resistance may vary geographically and with time for selected species and local information on resistance is desirable, particularly when treating severe infections. As necessary, expert advice should be sought when the local prevalence of resistance is such that the utility of the agent in at least some types of infections is questionable.
Commonly susceptible species
Species for which acquired resistance may be a problem
Inherently resistant organisms
Burkholderia cepacia and related species.
All Gram positive organisms
AbsorptionAbsorption from the gastrointestinal tract does not occur to any appreciable extent in the normal individual. When given by nebulisation, variable absorption has been reported that may depend on the aerosol particle size, nebuliser system and lung status. Studies in healthy volunteers and patients with various infections have reported serum levels from nil to potentially therapeutic concentrations of 4mg/l or more. Therefore, the possibility of systemic absorption should always be borne in mind when treating patients by inhalation.
DistributionAfter the administration to patients with cystic fibrosis of 7.5 mg/kg/day in divided doses given as 30-min intravenous infusions to steady state the C max was determined to be 23+6 mg/l and C min at 8 h was 4.5+4 mg/l. In another study in similar patients given 2 million units every 8 hours for 12 days the C max was 12.9 mg/l (5.7 29.6 mg/l) and the C min was 2.76 mg/l (1.0 6.2 mg/l). In healthy volunteers given a bolus injection of 150mg (2 million units approx.) peak serum levels of 18 mg/l were observed 10 minutes after injection. Protein binding is low. Polymyxins persist in the liver, kidney, brain, heart and muscle. One study in cystic fibrosis patients gives the steady-state volume of distribution as 0.09 L/kg.
BiotransformationColistimethate sodium is converted to the base in vivo. As 80% of the dose can be recovered unchanged in the urine, and there is no biliary excretion, it can be assumed that the remaining drug is inactivated in the tissues. The mechanism is unknown.
EliminationThe main route of elimination after parenteral administration is by renal excretion with 40% of a parenteral dose recovered in the urine within 8 hours and around 80% in 24 hours. Because colistimethate sodium is largely excreted in the urine, dose reduction is required in renal impairment to prevent accumulation. Refer to the table in Section 4.2. After intravenous administration to healthy adults the elimination half-life is around 1.5 hrs. In a study in cystic fibrosis patients given a single 30-minute intravenous infusion the elimination half-life was 3.4 + 1.4 hrs. The elimination of colistimethate sodium following inhalation has not been studied. A study in cystic fibrosis patients failed to detect any colistimethate sodium in the urine after 1 million units were inhaled twice daily for 3 months. Colistimethate sodium kinetics appear to be similar in children and adults, including the elderly, provided renal function is normal. Limited data are available on use in neonates which suggest kinetics are similar to children and adults but the possibility of higher peak serum levels and prolonged half-life in these patients should be considered and serum levels monitored.
|Before opening:||3 years.|
|Reconstituted solutions:||Solutions for infusion or injection: Chemical and physical in-use stability for 28 days at 4oC has been demonstrated. From a microbiological point of view, solutions should be used immediately. If not used immediately in-use storage times and conditions prior to use are the responsibility of the user. They would normally be no longer than 24 hours at 2 to 8°C, unless reconstituted and diluted under controlled and validated aseptic conditions. Solutions for nebulisation: Solutions for nebulisation have similar in-use stability and should be treated as above. Patients self-treating with nebulised antibiotic should be advised to use solutions immediately after preparation. If this is not possible, solutions should not be stored for longer than 24hrs in a refrigerator.|
|1 million IU/vial:||Type I glass vial with red 'flip-off' cap supplied in cartons of ten vials.|
|2 million IU/vial:||Type I glass vial with lilac 'flip-off' cap supplied in cartons of ten vials.|
Parenteral administrationThe normal adult dose of 2 million units should be dissolved in 10-50ml of 0.9% sodium chloride intravenous infusion or water for injections to form a clear solution. The solution is for single use only and any remaining solution should be discarded.
InhalationThe required amount of powder is dissolved preferably in 2-4ml 0.9% sodium chloride solution and poured into the nebuliser. Alternatively, water for injections may be used. The solution will be slightly hazy and may froth if shaken. Usually jet or ultrasonic nebulisers are preferred for antibiotic delivery. These should produce the majority of their output in the respirable particle diameter range of 0.5-5.0 microns when used with a suitable compressor. The instructions of the manufacturers should be followed for the operation and care of the nebuliser and compressor.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.The solution is for single use only and any remaining solution should be discarded.
|1 million IU/vial:||PL 0108/5006R|
|2 million IU/vial:||PL 0108/0122|
|1 million IU/vial:||June 1986 / November 2006|
|2 million IU/vial:||June 2003 / November 2006|
Forest Laboratories UK Limited (a subsidiary of Actavis PLC)
Whiddon Valley, Barnstaple, Devon, EX32 8NS, UK
+44 (0)1271 346106
+44 (0)1271 311 200
+44(0)1271 385 257