1. Name Of The Medicinal Product
Promixin, 1 million International Units (IU), Powder for Solution for Infusion.
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 solution for infusion
The powder is white to off white
4. Clinical Particulars
4.1 Therapeutic Indications
Promixin is indicated for treatment of the following infections caused by susceptible aerobic Gram-negative bacteria (see section 5.1):
- Hospital acquired pneumonia (HAP)
- Complicated urinary tract infections
It is recommended that Promixin should be selected when antibacterial agents that are commonly used to treat these infections are not considered to be appropriate for the individual patient and/or the causative pathogen(s) (see sections 4.4 and 5.1).
Consideration should be given to official guidance on the appropriate use of antibacterial agents.
4.2 Posology And Method Of Administration
It is recommended that Promixin should be administered under the supervision of physicians with appropriate experience in its use.
Method of Administration
Administration is by intravenous infusion. Each dose of Promixin can be diluted in 50 mL and administered by intravenous infusion over 30 minutes. Patients fitted with a totally implantable venous access device (TIVAD) may tolerate an injection of up to 2 million IU in 10 mL given over a minimum of 5 minutes.
Solutions should be used immediately after reconstitution. For instructions on dilution of the product before administration see section 6.6.
Posology
The dose regimen of Promixin that is selected should take into account factors such as the susceptibility of the pathogen(s), the severity and type of infection, and the ideal body weight and renal function of the patient. The duration of treatment is usually at least 5 days.
Standard dose recommendations are as follows:
Up to 60 Kg: 50,000 IU/Kg (4 mg/Kg) bodyweight, to a maximum of 75,000 IU/Kg (6 mg/Kg), in 24 hours. The total daily dose should be administered as three equal doses at 8 hourly intervals.
Over 60 Kg: 1-2 million IU every 8 hours. The maximum standard dose is 6 million IU (480 mg) in 24 hours.
Limited pharmacokinetic data from critically ill patients suggest that use of a loading dose and higher than standard doses may be appropriate (see Section 5.2). For severe infections and in critically ill patients doses up to 9 million IU per day in divided doses, have been reported in the literature. Clinical efficacy and safety data with these regimens are very limited and caution is advised (see sections 4.4 and 5.2).
Paediatric population
Dose recommendations are the same in adults and all paediatric sub groups.
Renal impairment
The suggested dose recommendations in Table 1 for patients with renal impairment are based on the standard total daily dose of 3-6 million IU/day. For patients with renal impairment in whom higher doses (e.g. up to 9 million IU/day) would be considered if their renal function was normal, corresponding proportional adjustments should be considered when calculating the dose. Caution is advised when administering Promixin to any patient with renal impairment due to the limited information available on safety and appropriate dose regimens (see section 4.4).
Table 1: Suggested modification of dosage of Promixin for adults with impaired renal function
| ||||
|
|
|
| |
|
|
|
|
|
| ||||
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
Hepatic impairment
It is not known whether the dose of Promixin requires adjustment in patients with hepatic impairment and therefore caution is advised.
4.3 Contraindications
Hypersensitivity to the active substance colistimethate sodium or other polymyxins.
4.4 Special Warnings And Precautions For Use
Use with caution in patients with renal impairment as colistimethate sodium is renally excreted.
Nephrotoxicity or neurotoxicity may occur especially if the recommended dose is exceeded (see also Section 4.5). There are limited safety data when colistimethate sodium is used in doses exceeding 6 million IU/day.
Monitoring of renal function should be performed before initiating treatment with Promixin. Monitoring of serum creatinine must continue at regular intervals (at least daily) during therapy. Particular caution should be exercised when administering doses greater than 6 million IU/day. The dose of Promixin may have to be reduced if serum creatinine concentrations rise or exceed the upper limit of normal.
There is evidence that it is the total cumulative dose (not the daily dose) of colistimethate sodium that may be associated with risk of nephrotoxicity.
Do not use concomitantly with other medications with nephrotoxic or neurotoxic effects except with the greatest caution.
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, unless in life-threatening situations.
Clostridium difficile associated diarrhoea (CDAD) has been reported with use of nearly all antibacterial agents, and may range in severity from mild diarrhoea to fatal colitis. Treatment with antibacterial agents alters the normal flora of the colon leading to overgrowth of C. difficile. Therefore, it is important to consider this diagnosis in patients who present with diarrhoea during or subsequent to the administration of colistimethate sodium. Discontinuation of therapy with colistimethate sodium and the administration of specific treatment for Clostridium difficile should be considered. Medicinal products that inhibit peristalsis should not be given.
Use with extreme caution in patients with porphyria.
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.
Concomitant use of colistimethate sodium with other medications that are nephrotoxic or neurotoxic (eg. cephalothin sodium, aminoglycosides, non-depolarising muscle relaxants) should only be undertaken with the greatest caution.
The potential of colistimethate sodium to affect the pharmacokinetics of other medicinal products has not been evaluated. Caution is recommended if colistimethate sodium is combined with medicinal products with a narrow therapeutic index.
4.6 Pregnancy And Lactation
Fertility
There are no data on the effects of colistimethate sodium on human fertility. Effects on male and female fertility have not been evaluated in animal studies.
Pregnancy
Safety in human pregnancy has not been established. Animal studies are insufficient with respect to effects on reproduction. There is evidence that colistimethate sodium crosses the placenta and consequently there is potential for foetal toxicity if administered during pregnancy. Hence, Promixin should only be given during pregnancy if the benefits outweigh any potential risk.
Lactation
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 most commonly reported adverse reaction is renal function impairment, and more rarely renal failure, usually following use of higher than recommended doses in patients with normal renal function, or failure to reduce the dosage in patients with renal impairment or when used concomitantly with other nephrotoxic antibiotics. The effect is usually reversible on discontinuation of therapy, but rarely intervention (renal replacement therapy) may be required.
High serum concentrations of colistimethate sodium, which may be associated with overdosage or failure to reduce the dosage in patients with renal impairment, have been reported to lead to neurotoxic effects such as facial paraesthesia, muscle weakness, vertigo, slurred speech, vasomotor instability, visual disturbances, confusion, psychosis and apnoea. 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.
Hypersensitivity reactions such as skin rash and angioedema have been known to occur. In the event such reactions occur, treatment with colistimethate sodium should be withdrawn.
Adverse reactions are tabulated below by system organ class and frequency. Frequencies are defined as Very common (
|
|
|
|
|
|
|
|
|
|
| |
|
|
|
|
|
|
|
| |
|
|
|
4.9 Overdose
Overdosage may cause renal insufficiency, renal failure, apnoea, muscle weakness, vertigo, slurred speech, vasomotor instability, visual disturbances, confusion and psychosis.
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
The polymyxin antibiotics are surface active agents and act by binding to and changing the permeability of 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.
EUCAST Breakpoints
|
|
|
|
|
|
|
|
aBreakpoints apply to dosage of 2-3 million IU x 3. A loading dose (9 million IU) may be needed.
Mechanisms of resistance
Acquired resistance to Colistimethate sodium in Pseudomonas aeruginosa appears to be related to alterations in the bacterial outer membrane. In-vitro studies with Salmonella and E. coli have shown that resistance may occur due to modification of the cell wall lipopolysaccharide phosphate groups. Modification is achieved by substitution of the phosphate groups with ethanolamine or aminoarabinose. Proteus mirabilis, Burkholderia cepacia and other naturally resistant Gram-negative bacteria, show complete substitution of their lipopolysaccharide groups.
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. There is no co- resistance between polymyxins and other groups of antibiotics.
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. 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
Klebsiella species
Pseudomonas aeruginosa
Species for which acquired resistance may be a problem
Stenotrophomonas maltophilia
Achromobacter xylosoxidans
Inherently resistant organisms
Burkholderia cepacia and related species
Proteus spp
Providencia spp
Serratia spp
5.2 Pharmacokinetic Properties
Absorption
Absorption of colistimethate sodium from the gastrointestinal tract does not occur to any appreciable extent in the normal individual.
Distribution
The volume of distribution of colistin following administration of colistimethate sodium in healthy volunteers and in patients with cystic fibrosis has been reported to be 12.4L and 20.4L respectively. In comparison the volume of distribution for colistin following administration of colistimethate sodium has been shown to be between 90.6 L and 139.9 L in critically ill patients. The increase in the volume of distribution in critically ill patients, may lead to a delay in reaching effective plasma concentrations. Therefore the use of an initial loading dose of up to 9 million IU has been suggested, especially in critically ill patients.
In critically ill patients given colistimethate sodium 2 million IU and 3 million IU three times a day intravenously, peak colistin plasma concentrations of 2.21 and 2.93 mg/L, respectively, were observed.
Biotransformation
Colistimethate sodium undergoes conversion to polymyxin E1 and polymyxin E2 (colistin) in vivo. It has been estimated that approximately 30% of the colistimethate sodium is converted to colistin.
Elimination
Colistimethate sodium is primarily excreted unchanged in the urine where the hydrolysis to the active moiety continues. Following intravenous administration 62% of a dose is recovered in the urine within 8 hours.
Colistin is excreted by the non-renal route.
The half-life of colistin following administration of colistimethate sodium in healthy volunteers and in patients with cystic fibrosis has been reported to be 3 hours and 4.2 hours respectively. The half-life of colistin following administration of colistimethate sodium has been reported to increase when administered to critically ill patients compared to healthy volunteers and mean half life is estimated to range from approximately 5.9 hours to 7.4 hours following intravenous administration to critically ill patients.
In patients with renal impairment, colistimethate sodium excretion is reduced and a higher proportion may be converted to colistin, leading to increased plasma colistin concentrations.
5.3 Preclinical Safety Data
Animal studies are insufficient with respect to effects on reproduction.
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.
6. Pharmaceutical Particulars
6.1 List Of Excipients
None
6.2 Incompatibilities
This medicinal product must not be mixed with other medicinal products except those mentioned in section 6.6.
6.3 Shelf Life
Unopened:
Two years
After reconstitution:
Chemical and physical in-use stability has been demonstrated for up to 8 hours at room temperature.
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 and would normally not be longer than 24 hours at 2 to 8°C, unless reconstitution/dilution has taken place in controlled and validated aseptic conditions.
6.4 Special Precautions For Storage
No special precautions for storage.
For storage conditions of the reconstituted/diluted product see section 6.3.
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 pack sizes of 10 vials.
6.6 Special Precautions For Disposal And Other Handling
For single use only.
Promixin must be reconstituted, under aseptic conditions, with sodium chloride solution 9 mg/mL (0.9%) to produce a clear colourless to pale yellow solution. Following reconstitution, the solution should be diluted to a suitable volume for infusion over 30 minutes with sodium chloride solution 9 mg/mL (0.9%) for infusion. The solution should be inspected visually for particulate matter and discoloration prior to administration. The solution should only be used if the solution is clear and free from particles.
Solutions should be used immediately after reconstitution (see section 4.2).
Discard any unused solution. Waste material should be disposed of in accordance with local requirements.
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 19419/0002
9. Date Of First Authorisation/Renewal Of The Authorisation
Date of first authorisation: 24th June 2003
Date of latest renewal: 13th March 2009
10. Date Of Revision Of The Text
30th August 2011
No comments:
Post a Comment