SUMMARY OF CHANGES

Text that has been added is displayed in red text. Text that has been removed is shown in blue.

4.2      Posology and method of administration

Added:

Children < 2 years: The safety and efficacy of Promixin has not been demonstrated in patients less than 2 years of age.

Amended from:

Promixin is administered by nebulisation using a suitable nebuliser.  For instructions on reconstitution of the product before administration see section 6.6.  Once reconstituted use immediately.

to:

Mode of administration

Promixin for nebulisation is intended for administration by nebulisation using a suitable nebuliser.

For special precautions for disposal and handling of reconstituted solutions, see Section 6.6.

Deleted: ‘and renal function of the patient’ from the sentence starting ‘The dosage is determined by the severity and type of infection.’

Deleted:

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.

Where there is renal impairment, excretion may be delayed and the daily dosage (magnitude of dose and dose interval) must be adjusted in relation to renal function to prevent accumulation of colistimethate sodium as indicated in the table.

Suggested modification of dosage of Promixin for patients with impaired renal function

4.3      Contraindications

Added: ‘or other polymyxins’ to the sentence ‘Promixin is contraindicated in patients with known hypersensitivity to colistimethate sodium.’

4.4      Special warnings and precautions for use

New paragraphs added with the subheadings: ‘Renal impairment’ and ‘Microbial Resistance’.

Subheadings given to existing paragraphs: ‘Bronchospasm’, ‘Nephrotoxicity’, ‘Neurotoxicity’ and ‘Porphyria’.

Deleted:

Use with caution in renal impairment as colistimethate sodium is renally excreted.

Moved from Section 4.2:

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.

Added:

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).

In subsection Nephrotoxicity:

At the end of the first sentence, the word ‘antibiotics’ has been replaced with ‘drugs’ broadening the warning of nephrotoxicity when used concomitantly with other medications.

4.5      Interaction with other medicinal products and other forms of interaction

Both paragraphs have had a cross-reference to section 4.4 added.

4.6      Pregnancy and lactation

Added: Animal studies do not indicate a teratogenic potential.

Deleted: Animal studies are insufficient with respect to effects on reproduction.

5.1      Pharmacodynamic properties

New subheadings of ‘Mode of action’, ‘PK/PD relationship’, ‘Mechanisms of resistance’, ‘Commonly susceptible species’, ‘Inherently resistant organisms’, ‘Species for which acquired resistance may be a problem’ have been added.

Added:

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.

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

Under the subheading Mode of action, the following sentences:

Colistimethate sodium is a polymyxin antibiotic and is derived from Bacillus polymyxa var. colistinus. It is a polypeptide and is active against a number of aerobic, Gram-negative bacteria.

have been replaced with:

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.

Under the subheading Resistance the text ‘Susceptibility testing should be performed on patients who are treated on a long term basis.’ has been removed and ‘However, local rates of resistance may vary including higher rates (see Section 4.4).’ has been added.

Under the subheading Susceptibility following text and table has been deleted:

The table below lists bacterial species which are regarded as susceptible to colistimethate sodium. Bacterial resistance may vary according to region and information on resistant species in a specific area is desirable, particularly when treating severe infections. Only bacteria likely to be relevant to the clinical indication are listed.

and the text below added:

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.

Deleted:

Breakpoints

Susceptible (S) ≤ 4 mg/L    Resistant (R) ≥ 8 mg/L

Under the subheading Cross resistance the first sentence ‘Polymyxins including colistimethate sodium differ in their mechanism of action compared with other antibiotics and there is evidence to show that Gram-negative bacteria resistant to other antibiotics may be susceptible to colistimethate sodium.’ has been deleted.

5.2      Pharmacokinetic properties

Deleted from Absorption:

Absorption following lung administration appears to be variable and clinical work has shown that resultant serum concentrations may range from undetectable to rarely exceeding 4 mg/L (50,000 IU/L) compared to serum concentrations of 10–20 mg/L (approx. 125,000-250,000 IU/L) following intravenous use.

A study in cystic fibrosis patients showed that colistimethate sodium was undetectable in the urine after 1 million IU were inhaled twice daily for 3 months. This is despite the fact that excretion is known to be primarily via the urine.

Deleted:

Distribution

Colistimethate sodium shows a low level of protein binding. Polymyxin antibiotics are known to persist in muscle tissue, liver, kidney, heart and brain.

Added to 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.

Deleted from Pharmacokinetics:

Serum concentrations and pharmacokinetics in 5 patients receiving inhaled colistimethate sodium

Volume of distribution has been calculated to be 0.09 L/Kg in a single study in patients with cystic fibrosis (CF).

Deleted from Biotransformation:

Approximately 80% of the parenteral dose is recoverable unchanged in the urine. There is no biliary excretion.

Deleted from Elimination:

It follows that dose should be reduced in the renally impaired in order to prevent accumulation. Refer to Section 4.2.

The elimination half-life is approximately 1.5 hours following i.v. administration to healthy adults. This compares with an elimination half-life of 3.4 ± 1.4 hours when CF patients were given a single 30 minute i.v. infusion.

Colistimethate sodium kinetics appear to be similar in all patient groups provided renal function is normal.

Amended in Elimination:

40% amended to 62% to read ‘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

Added: Animal studies with colistimethate do not indicate adverse effects on fertility or embryo-foetal development. Peri-postnatal studies have not been conducted.

Deleted: Animal studies are insufficient with respect to effects on reproduction.

The paragraph:

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.

now reads:

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.

6.2      Incompatibilities

Added: This medicinal product should not be mixed with other medicinal products except those mentioned in section 6.6.

6.6      Instructions for use, handling and disposal

Cross reference to section 4.2 removed.

10.      Date of revision of the text

          Date amended from 09/01/2009 to 11/11/2010.

4.4     Special warnings and precautions for use

changed to

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 antibiotics. The effect is usually reversible on discontinuation of therapy.

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)

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 (³1/10): common (³1/100 to <1/10): uncommon (³1/1,000 to <1/100): rare (³1/10,000 to <1/1,000) and very rare (<1/10,000), not known (cannot be estimated from the available data)

Cases of sore throat or sore mouth have been reported. This may be due to hypersensitivity or superinfection with Candida species.

Should hHypersensitivity reactions such as skin rash have been known to occur.  In the event that such reactions occur, treatment with colistimethate sodium should be withdrawn.

Impairment of renal function has been reported, usually following use of higher than recommended i.v. or i.m. doses in patients with normal renal function, or failure to reduce the i.v. or i.m dosage in patients with renal impairment or when used concomitantly with other nephrotoxic antibiotics. The effect is usually reversible on discontinuation of therapy.

4.9     Overdose

Overdosage may cause apnoea, muscle weakness, vertigo, transient facial paraesthesia, slurred speech, vasomotor instability, visual disturbances, confusion, psychosis  and renal insufficiency.

10.   Date of revision of the text

November 2006

September 2008