1. Name Of The Medicinal Product
Promixin, 1 million International Units (IU) Powder for Nebuliser Solution
2. Qualitative And Quantitative Composition
Each vial contains 1 million International Units (IU) which is approximately equivalent to 80 mg of colistimethate sodium.
3. Pharmaceutical Form
Powder for nebuliser solution. The powder is white to off-white
4. Clinical Particulars
4.1 Therapeutic Indications
Promixin is indicated for the treatment by nebulisation of colonisation and infections of the lung due to susceptible Pseudomonas aeruginosa in patients with cystic fibrosis.
Consideration should be given to official guidance on the appropriate use of antibacterial agents.
4.2 Posology And Method Of Administration
Sputum cultures should be obtained to confirm colonisation with Pseudomonas aeruginosa sensitive to colistimethate sodium prior to initiating treatment with Promixin.
The following information provides guidance on recommended doses and the dose should be adjusted according to clinical response.
Recommended doses are:
Children >2 years and adults: 1-2 million IU two or three times daily
Children < 2 years: The safety and efficacy of Promixin has not been demonstrated in patients less than 2 years of age.
The dosage is determined by the severity and type of infection.
The dose may be varied across this range depending on the condition being treated.
Initial colonisation with Pseudomonas aeruginosa sensitive to colistimethate sodium may be treated with a 3-week course of 2 million IU twice daily in conjunction with other parenteral or oral antibiotics.
For frequent, recurrent infections (Less than three positive cultures of Pseudomonas aeruginosa sensitive to colistimethate sodium in a six month period) the dose may be increased up to a maximum of 2 million IU three times daily for up to 3 months, in conjunction with other parenteral or oral antibiotics.
Chronic colonisation (Three or more positive cultures of Pseudomonas aeruginosa sensitive to colistimethate sodium in a six month period) may require long-term therapy with 1 to 2 million IU twice daily. Additional parenteral or oral antibiotics may need to be administered to treat acute exacerbations of pulmonary infection.
Nebulised Promixin should be administered after physiotherapy and other inhaled treatments, where used. Other inhaled therapies may include agents to reduce the viscoelasticity of sputum and bronchodilators (see Section 4.4).
Mode of administration
Promixin for nebulisation is intended for administration by nebulisation using a suitable nebuliser.
Drug delivery characteristics from in vitro studies with different nebuliser systems are detailed below;
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For special precautions for disposal and handling of reconstituted solutions, see Section 6.6
4.3 Contraindications
Promixin is contraindicated in patients with known hypersensitivity to colistimethate sodium or other polymyxins.
Colistimethate sodium is known to reduce the amount of acetylcholine released from the pre-synaptic neuromuscular junction and therefore should not be used in patients with myasthenia gravis.
4.4 Special Warnings And Precautions For Use
Bronchospasm
Nebulisation of colistimethate sodium may induce coughing or bronchospasm. It is advisable to administer the first dose under medical supervision. Pre-dosing with a bronchodilator is recommended and should be routine, especially if this is part of the patient's current therapeutic regimen. FEV1 should be evaluated pre and post dosing. If there is evidence of colistimethate sodium induced bronchial hyperreactivity in a patient not receiving pre-treatment bronchodilators the test should be repeated on a separate occasion using a bronchodilator. Evidence of bronchial hyperreactivity in the presence of a bronchodilator may indicate an allergic response and Promixin should be discontinued. Bronchospasm that occurs should be treated as medically indicated.
Bronchial hyperreactivity in response to colistimethate sodium may develop with continued use over time and it is recommended that pre and post treatment FEV1s are evaluated at regular clinic visits.
Renal impairment
Colistimethate sodium is renally excreted and is nephrotoxic if high serum concentrations are achieved. Whilst this is unlikely during inhalation therapy, serum concentration estimations are recommended especially in patients with renal impairment.
Nephrotoxicity
Impairment of renal function has been reported, usually following use of higher than recommended intravenous or intramuscular doses in patients with normal renal function, or failure to reduce the intravenous or intramuscular dosage in patients with renal impairment or when used concomitantly with other nephrotoxic drugs. The effect is usually reversible on discontinuation of therapy.
Neurotoxicity
High serum concentrations of colistimethate sodium after intravenous or intramuscular administration may be associated with overdosage or failure to reduce the dosage in patients with renal impairment, and this may lead to neurotoxicity. Concomitant use with either non-depolarising muscle relaxants or antibiotics with similar neurotoxic effects can also lead to neurotoxicity. Dose reduction of colistimethate sodium may relieve symptoms. Neurotoxic effects that have been reported include: vertigo, transient facial paraesthesia, slurred speech, vasomotor instability, visual disturbances, confusion, psychosis and apnoea. (see also Section 4.5)
Porphyria
Use with extreme caution in patients with porphyria.
Microbial Resistance
Colistimethate sodium acquired resistance in mucoid Pseudomonas aeruginosa during clinical use has been reported. Susceptibility testing should be performed on patients who are treated on a long term basis, at regular clinic visits, and whenever a patient experiences an exacerbation (see Section 5.1).
4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction
Due to the effects of colistimethate sodium on the release of acetylcholine, non-depolarising muscle relaxants should be used with extreme caution in patients receiving Promixin as their effects could be prolonged (see Section 4.4).
Concomitant use of inhaled colistimethate sodium with other medications that are nephrotoxic or neurotoxic (e.g. cephalothin sodium, aminoglycosides, non-depolarising muscle relaxants) including those which are administered by the i.v. or i.m. routes should only be undertaken with the greatest caution (see Section 4.4).
4.6 Pregnancy And Lactation
Safety in human pregnancy has not been established. Animal studies do not indicate a teratogenic potential. However there is evidence that colistimethate sodium crosses the placenta and consequently there is potential for foetal toxicity if administered during pregnancy. Promixin should only be given during pregnancy if the benefits outweigh any potential risk.
Colistimethate sodium is excreted in breast milk; breast feeding is not recommended during therapy.
4.7 Effects On Ability To Drive And Use Machines
Neurotoxicity, characterised by dizziness, confusion or visual disturbances have been reported following parenteral administration of colistimethate sodium. If these effects occur patients should be warned against driving or operating machinery.
4.8 Undesirable Effects
The commonest undesirable effects following nebulisation of colistimethate sodium are coughing and bronchospasm (indicated by chest tightness which may be detected by a decrease in FEV1) in approximately 10% of patients. (See also Section 4.4)
Adverse reactions are tabulated below by system organ class and frequency. Frequencies are defined as Very common (
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Should hypersensitivity reactions such as skin rash occur treatment with colistimethate sodium should be withdrawn.
Cases of sore throat or sore mouth may be due to hypersensitivity or superinfection with Candida species.
4.9 Overdose
Overdosage may cause apnoea, muscle weakness, vertigo, transient facial paraesthesia, slurred speech, vasomotor instability, visual disturbances, confusion, psychosis and renal insufficiency.
No antidote is available. Management of overdose is by means of supportive treatment and measures designed to increase clearance of colistimethate sodium such as inducing an osmotic diuresis with mannitol, peritoneal dialysis or prolonged haemodialysis.
5. Pharmacological Properties
5.1 Pharmacodynamic Properties
Pharmacotherapeutic group: other antibacterials, Polymyxins.
ATC code: J01XB01
General properties
Mode of action
Colistimethate sodium is a prodrug of colistin, a polymyxin antibiotic , (belonging to the polymyxin E group). It is a polypeptide structure and is derived from Bacillus polymyxa var. colistinus.
The polymyxin antibiotics are surface active agents and act by binding to and changing the permeability of the bacterial cell membrane causing bacterial cell death. Polymyxins are bactericidal against Gram-negative bacteria with a hydrophobic outer membrane.
PK/PD relationship
Polymyxins have been reported to have a concentration-dependent bactericidal effect on susceptible bacteria.
Mechanisms of resistance
Resistance develops due to modifications of lipopolysaccharide (LPS) or other components in the bacterial cell membrane.
Susceptibility
The 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
Acinetobacter species
Haemophilus influenzae
Klebsiella species
Pseudomonas aeruginosa
Species for which acquired resistance may be a problem
Stenotrophomonas maltophilia
Achromobacter xylosoxidans (formerly Alcaligenes xylosoxidans)
Inherently resistant organisms
Burkholderia cepacia and related species
Proteus spp
Providencia spp
Serratia spp
Resistance
Colistimethate sodium acquired resistance in mucoid Pseudomonas aeruginosa has been reported to be approximately 3%. However, local rates of resistance may vary including higher rates (see Section 4.4).
Cross resistance
The resistance to polymyxins is not crossed with other antibiotic families.
5.2 Pharmacokinetic Properties
Absorption
Gastrointestinal absorption is negligible hence the swallowing of colistimethate sodium deposited in the nasopharynx is unlikely to add to the systemic exposure.
Absorption following lung administration is influenced by the nebuliser system, aerosol droplet size and disease state of the lungs.
Pharmacokinetics
A study in healthy volunteers, who inhaled colistimethate sodium, demonstrated the Cmax of polymyxin E1 (the active moiety) varied between 40.0 and 69.9 ng/mL and the AUC varied between 350 and 668 ng/mL/h depending on the nebuliser and the fill volume and concentration, which varied the dose from 0.3 million IU to 2 million IU. The half-life was approximately 5.2 hours. The absolute bioavailability was calculated to vary between 5% and 18% depending on the nebuliser. The AUC following an intravenous dose of 0.5 million IU was 3,352 ng/ml/h and the Cmax was 1,232 ng/mL.
Biotransformation
Colistimethate sodium undergoes conversion to its base in vivo.
Elimination
There is no information on the elimination of colistimethate sodium following nebulisation.
Following i.v. administration excretion is primarily renal with 62% of a parenteral dose recovered in the urine within 8 hours and around 80% in 24 hours.
5.3 Preclinical Safety Data
Animal studies with colistimethate do not indicate adverse effects on fertility or embryo-foetal development. Peri-postnatal studies have not been conducted.
Data on potential genotoxicity and carcinogenicity for colistimethate sodium are lacking. Colistin has been shown to induce chromosomal aberrations in human lymphocytes in vitro an effect that might be related to a reduction in mitotic index, which was also observed. Colistin was not mutagenic in a set of other tests.
6. Pharmaceutical Particulars
6.1 List Of Excipients
None
6.2 Incompatibilities
The addition of other antibiotics to solutions of Promixin may lead to precipitation. This medicinal product should not be mixed with other medicinal products except those mentioned in section 6.6.
6.3 Shelf Life
Unopened: 2 years.
Once reconstituted: Use immediately.
6.4 Special Precautions For Storage
No special precautions for storage
6.5 Nature And Contents Of Container
The product is supplied in clear type I glass vials sealed with a siliconised chlorobutyl type I rubber stopper and protected by a 20 mm aluminium tear-off cap incorporating a red flip-up central plastic top. The product is supplied in packs of 30 vials. Each pack contains a Promixin Disc to enable use with the I-neb AAD System.
6.6 Special Precautions For Disposal And Other Handling
Promixin may be reconstituted with Water for Injections (WFI) to produce a clear colourless to pale yellow hypotonic solution or a 50:50 mixture of WFI and 0.9% saline to produce a clear colourless to pale yellow isotonic solution. When reconstituted, Promixin may be used with any conventional nebuliser suitable for delivery of antibiotic solutions.
Solutions should be used immediately after reconstitution. Any unused solution remaining in the nebuliser must be discarded following treatment. Promixin is supplied with a Promixin Disc, for use with the I-neb AAD System. For instructions on the use of Promixin with the I-neb AAD System, please refer to detailed instructions provided with the device.
Conventional nebulisers operate on a continuous flow basis and it is likely that some nebulised drug will be released into the local environment. When used with a conventional nebuliser, Promixin should be administered in a well-ventilated room, particularly in hospitals where several patients may be using nebulisers at the same time. Tubing or filters may be used to prevent waste aerosol from entering the environment.
7. Marketing Authorisation Holder
Profile Pharma Limited
Chichester Business Park
City Fields Way
Tangmere
Chichester
West Sussex
PO20 2FT
United Kingdom
8. Marketing Authorisation Number(S)
PL 19419/0001
9. Date Of First Authorisation/Renewal Of The Authorisation
20 February 2003/13th August 2008
10. Date Of Revision Of The Text
15/06/2011
11. LEGAL CATEGORY
POM
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