Colistimethate sodium is a prodrug that undergoes hydrolysis in vivo to form primarily the active drug, colistin, which is a mixture of the 2 active components colistin A (polymyxin E1) and colistin B (polymyxin E2).2734; 3152; 3153; 3154 Colistimethate sodium is available as a lyophilized cake of a complex mixture, containing colistimethate sodium or pentasodium colistinmethanesulfonate, in vials containing the equivalent of 150 mg of colistin base activity.3150; 3151; 3154
Each 150-mg vial should be reconstituted with 2 mL of sterile water for injection to yield a solution containing 75 mg/mL of colistin base activity.3150; 3151 During reconstitution, the contents of the vials should be gently swirled to avoid frothing.3150; 3151 Reconstituted solutions should be visually inspected for particulate matter and discoloration prior to administration; if particulate matter is present or discoloration occurs, the solution should not be used.3150; 3151
Units
The strength of colistimethate for injection products is expressed in terms of equivalent colistin base activity, not in terms of the prodrug.3150; 3151; 3153 In the US, it has been recommended that all prescribing of the drug consistently be in terms of colistin base activity to avoid dosing errors that could result from confusion between the 2 forms.3153 The manufacturers provide dosage recommendations in terms of colistin base activity.3150; 3151; 3153 If the drug is ordered as colistimethate or colistimethate sodium, the dosage should be clarified in terms of colistin base activity.3153
Sodium Content
Colistimethate sodium (Perrigo) contains approximately 0.099 mg (0.0043 mEq) of sodium per mg of colistin.3151
Trade Name(s)
Coly-Mycin M Parenteral
Colistimethate sodium may be administered intravenously or intramuscularly.3150; 3151
For intravenous administration, half of the total daily dose should be administered as an intermittent direct intravenous injection over 3 to 5 minutes every 12 hours.3150; 3151 Alternatively, half of the total daily dose should be administered as a direct intravenous injection over 3 to 5 minutes and the remaining half of the total daily dose should be diluted in a compatible infusion solution and administered by slow intravenous infusion over 22 to 23 hours beginning 1 to 2 hours after administration of the direct intravenous injection.3150; 3151 Slower rates of infusion may be warranted in specific populations (e.g., those with renal impairment).3150; 3151
The reconstituted solution also may be administrated by deep intramuscular injection into a large muscle mass (e.g., gluteal muscles, lateral part of the thigh).3150; 3151
Colistimethate sodium is a white to slightly yellow lyophilized cake.3150; 3151 Intact vials should be stored at controlled room temperature.3150; 3151
In addition to undergoing hydrolysis in vivo, colistimethate sodium also may undergo spontaneous hydrolysis to colistin in aqueous solution prior to administration.2734; 3152; 3154 In 2007, FDA warned healthcare professionals that prolonged storage (longer than 24 hours) of the reconstituted drug resulted in increased concentrations of colistin in solution.2734 The FDA warning followed the death of a cystic fibrosis patient who received the injectable colistimethate sodium product prepared in advance and administered by inhalation via nebulization; the drug is not FDA-labeled for such use.2734; 3150; 3151 It was not known how far in advance of administration the drug was prepared or whether it was prepared with saline or water;3154 however, some studies have indicated that hydrolysis of colistimethate sodium to colistin is both temperature and concentration dependent3152 and that the drug is substantially less stable when diluted in saline.3154 The FDA recommends that colistimethate sodium be administered promptly after mixing.2734
The manufacturers state that the reconstituted solution may be stored at 2 to 8°C or between 20 and 25°C and used within 7 days.3150; 3151 Solutions diluted for intravenous infusion should be used after preparation or within 24 hours.3150; 3151
One study found that the reconstituted solution of 75 mg/mL of colistin base activity (APP) prepared with sterile water for injection and stored at -70, -20, 4, and 21°C for 24 hours exhibited formation of less than 1% colistin A and B combined.3154; 3231 A single freeze-thaw cycle did not appear to substantially affect hydrolysis.3154
In another study, less than 0.1% of the initial colistimethate sodium concentration was present as colistin after storage of the reconstituted solution of 75 mg/mL of colistin base activity (Pfizer) prepared with sterile water for injection at 4 or 25°C for 7 days in the dark.3155
Diluted solutions of 0.333 mg/mL of colistin base activity (Foster) were prepared using sodium chloride 0.9% and stored at 4°C in an elastomeric pump (Braun Easypump).3152 Degradation of colistimethate sodium to colistin was not detected within the first 3 days of storage at 4°C; however, after 7 days of storage at 4°C and a subsequent 24 hours of storage at 20 to 25°C, the drug was rapidly hydrolyzed to colistin (more than 30%).3152
In a diluted solution of 1.5 mg/mL of colistin base activity (Pfizer) prepared using sodium chloride 0.9% or dextrose 5% and stored at 4 or 25°C for 48 hours in the dark, colistin formation was 0.3% of the initial colistimethate sodium concentration at 4°C and 4% at 25°C in both diluents.3155
Filtration
Colistimethate sodium (R. Bellon) 0.16 mg/mL in dextrose 5% and sodium chloride 0.9% was filtered through a 0.22-µm cellulose ester member filter (Ivex-HP, Millipore) over 6 hours. No significant drug loss due to binding to the filter was noted.1034
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