1. Name Of The Medicinal Product
Colistimethate Sodium 1 Million I.U. Powder for Solution for Injection
2. Qualitative And Quantitative Composition
Colistimethate Sodium 1 Million I.U. (International Units)
3. Pharmaceutical Form
Powder for Solution for Injection
White lyophilised powder in a glass vial.
4. Clinical Particulars
4.1 Therapeutic Indications
Colistimethate Sodium is indicated in the treatment of the following infections where sensitivity testing suggests that they are caused by susceptible bacteria:
• Intravenous administration for the treatment of some serious infections caused by Gram-negative bacteria, including those of the lower respiratory tract and urinary tract, when more commonly used systemic antibacterial agents may be contra-indicated or may be ineffective because of bacterial resistance.
Consideration should be given to official guidance on the appropriate use of antibacterial agents.
4.2 Posology And Method Of Administration
Posology
The dosage is determined by the severity and type of infection, the sensitivity of the causative bacteria and the age, weight and renal function of the patient. General guidance is given below.
Should clinical or bacteriological response be slow, the dose may be increased as indicated by the patient's condition. Anomalous distribution in CF patients may require higher doses in order to maintain therapeutic serum levels.
Estimation of serum levels is particularly recommended for patients with renal impairment, neonates and patients with cystic fibrosis. Serum levels of 10 - 15 mg/l (approximately 125-200 units/ml) should be adequate for most infections.
A minimum of 5 days treatment is generally recommended.
Children and adults (including the elderly):
Over 60kg: 1-2 million units three times a day. The maximum dose is 6 million units in 24 hours.
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.
Renal Impairment: In moderate or severe renal impairment, excretion of Colistimethate is delayed. Therefore, the dose and the 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 stressed that adjustments may still have to be made on evaluation of the individual patient based on blood levels and evidence of toxicity.
Suggested Dose Adjustment in Renal Impairment
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Method of Administration
Colistimethate Sodium can be given as a 50ml intravenous infusion over a period of 30 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
For instructions on dilution of the product before administration, see section 6.6.
4.3 Contraindications
Hypersensitivity to Colistimethate sodium (also known as colistin) or to polymyxin B.
Myasthenia gravis.
4.4 Special Warnings And Precautions For Use
Use with extreme caution in patients with porphyria.
Nephrotoxicity or neurotoxicity may occur if the recommended parenteral dose is exceeded.
Use with caution in renal impairment (see Section 4.2 - Posology and method of administration). It is advisable to assess baseline renal function and to monitor during treatment. Serum colistimethate concentrations should be monitored.
4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction
Neuromuscular blocking drugs and ether should be used with extreme caution in patients receiving colistimethate sodium.
Concomitant use of colistimethate sodium with other medicinal products of neurotoxic and/or nephrotoxic potential should be avoided. These include the aminoglycoside antibiotics such as gentamicin, amikacin, netilmicin and tobramycin. There may be an increased risk of nephrotoxicity if given concomitantly with cephalosporin antibiotics.
4.6 Pregnancy And Lactation
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.
4.7 Effects On Ability To Drive And Use Machines
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.
4.8 Undesirable Effects
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.
4.9 Overdose
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.
5. Pharmacological Properties
5.1 Pharmacodynamic Properties
Pharmacotherapeutic group: Antibacterials for systemic use.
ATC Code: J01X B01.
Mode of Action
Colistimethate (also known as colistin) 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.
Resistance
Resistant bacteria are characterised by modification of the phosphate groups of lipopolysaccharides due to substitution with ethanolamine or aminoarabinose. Naturally resistant Gram-negative bacteria, such as Proteus rnirabilis and Burkholderia cepacia, show complete substitution of their lipid phosphate by ethanolamine or aminoarabinose.
Cross-resistance between Colistimethate and polymyxin B would be expected. Since the mechanism of action of the polymyxins is different from that of other antibiotics, resistance to colistimethate and polymyxin by the above mechanism alone would not be expected to result in resistance to other drug classes.
Breakpoints
The BSAC-recommended general MIC breakpoint to identify bacteria susceptible to Colistimethate is < 4 mg/l.
Bacteria for which the MIC of Colistimethate is > 8 mg/I should be considered resistant.
Susceptibility
The prevalence of 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
Acinetobacter species*
Citrobacter species
Escherichia coli
Haemophilus influenzae
Pseudomonas aeruginosa
Species for which acquired resistance may be a problem
Enterobacter species
Klebsiella species
Inherently resistant organisms
Brucella species
Burkholderia cepacia and related species.
Neisseria species
Proteus species
Providencia species
Serratia species
Anaerobes
All Gram positive organisms
*Note that the in-vitro demonstration of susceptibility may not reliably predict clinical efficacy for Acinetobacter species.
5.2 Pharmacokinetic Properties
Absorption
Absorption from the gastrointestinal tract does not occur to any appreciable extent in the normal individual.
Distribution
After administration to cystic fibrosis (CF) patients of 7.5 mg/kg/day in divided doses given as 30 minute intravenous infusions to steady state the Cmax was determined to be 23 (+6) mg/l and Cmin at 8 hr was 4.5 (+4) mg/l. In another study in CF patients given 2 million units every 8 hours for 12 days the Cmax was 12.9 mg/l (5.7 – 29.6 mg/l) and the Cmin was 2.76 mg/l (1.0 – 6.2 mg/l). In healthy volunteers given a bolus injection of 150 mg (approximately 2 million units) peak serum levels of 18mg/l were observed 10 minutes after injection.
Protein binding is low. Polymyxins persist in the liver, kidney, brain, heart and muscle. One study in CF patients estimated the steady-state volume of distribution as 0.09 l/Kg.
Biotransformation
Colistimethate 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.
Elimination
The 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 is largely excreted in the urine, dosage 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 CF patients given a single intravenous infusion over 30 minutes the elimination half-life was 3.4 + 1.4 hrs.
Colistimethate pharmacokinetics appear to be similar in children and adults, including the elderly, provided renal function is normal. Limited data are available on use in neonates that suggest that pharmacokinetics 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.
5.3 Preclinical Safety Data
Data on potential genotoxicity are limited and carcinogenicity data for colistimethate sodium are lacking. Colistimethate sodium has been shown to induce chromosomal aberrations in human lymphocytes in vitro. This effect may be related to a reduction in mitotic index, which was also observed.
Reproductive toxicity studies in rats and mice do not indicate teratogenic properties. However, colistimethate sodium given intramuscularly during organogenesis to rabbits at 4.15 and 9.3 mg/kg resulted in talipes varus in 2.6 and 2.9% of foetuses respectively. These doses are 0.5 and 1.2 times the maximum daily human dose. In addition, increased reabsorption occurred at 9.3mg/kg.
There are no other preclinical safety data of relevance to the prescriber that are additional to safety data derived from patient exposure and already included in other sections of the SPC.
6. Pharmaceutical Particulars
6.1 List Of Excipients
None
6.2 Incompatibilities
In the absence of compatibility studies, reconstituted Colistimethate sodium must not be mixed with other medicinal products.
6.3 Shelf Life
2 years
From a microbiological point of view, the reconstituted product should be used immediately. If not used immediately, in-house storage times and conditions prior to use are the responsibility of the user and should not be longer than 24 hours in the refrigerator (2 to 8°C) or 8 hours when stored at temperatures not exceeding 25°C.
6.4 Special Precautions For Storage
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.
6.5 Nature And Contents Of Container
10 ml Type III glass vial with a rubber stopper and an aluminium cap. Each carton contains 1 or 10 vials.
6.6 Special Precautions For Disposal And Other Handling
For dilution use 0.9% sodium chloride intravenous infusion or water for injections.
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.
7. Marketing Authorisation Holder
Beacon Pharmaceuticals Ltd.
Tunbridge Wells
Kent TN1 1YG
8. Marketing Authorisation Number(S)
PL 18157/0009
9. Date Of First Authorisation/Renewal Of The Authorisation
28/09/2009
10. Date Of Revision Of The Text
22/03/2011
Beacon Pharmaceuticals Ltd.
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