Profile Pharma Limited

SUMMARY OF CHANGES

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

1.       Name of the Medicinal Product 

AMENDED FROM:

Promixin, 1 million International Units (IU), Powder for Solution for Injection

TO

Promixin, 1 million International Units (IU), Powder for Solution for Infusion

4.1.  Therapeutic Indications

AMENDED FROM:

Promixin is indicated for intravenous use in the treatment of serious infections where sensitivity testing indicate that they are caused by susceptible Gram-negative bacteria.

These include infections of the lower respiratory tract and urinary tract, where routine antibiotics may be contraindicated or ineffective because of resistance. 

Consideration should be given to official guidance on the appropriate use of antibacterial agents.

TO:

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

ADDED:

It is recommended that Promixin should be administered under the supervision of physicians with appropriate experience in its use.

The text contained within section 4.2 has been divided up under new sub-headings of “Method of Administration”, “Posology”, “Paediatric population”, “Renal impairment”, and “Hepatic impairment”

Under the sub-heading of “Posology” the following changes have been made:

AMENDED FROM:

The dose of Promixin is dependent upon the sensitivity of the causative bacteria, the severity and type of infection, the weight and renal function of the patient.

TO:

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.

AMENDED FROM:

Up to 60 kg:  50,000 IU/Kg (4 mg/Kg) bodyweight, to a maximum of 75,000 IU/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 dose is 6 million IU (480 mg) in 24 hours.

TO:

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, 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.

DELETED:

A minimum of 5 days treatment is recommended.

ADDED:

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).

Under the sub-heading “Paediatric populations” the following text has been ADDED:

Dose recommendations are the same in adults and all paediatric sub groups.

Under the sub-heading of “Renal impairment” the following changes have been made:

DELETED:

Serum concentration estimations are recommended, especially in patients with renal impairment or cystic fibrosis and in neonates.  Peak serum concentrations of 10-15 mg/L (approximately 0.125-0.2 million IU/L) should be adequate, for the treatment of most infections.

Dosage may be increased up to a maximum of 6 million IU per 24 hours according to the patient’s condition, if clinical or bacteriological response is slow.

ADDED:

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).

DELETED:

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

Table 1: Suggested modification of dosage of Promixin for adults with impaired renal function has been amended to delete creatinine values, as shown below:

Under the sub-heading “Hepatic  impairment”, the following text has been ADDED:

It is not known whether the dose of Promixin requires adjustment in patients with hepatic impairment and therefore caution is advised.

4.3 Contraindications

AMENDED FROM:

Promixin is contraindicated in patients with known hypersensitivity to colistimethate sodium.

TO:

Hypersensitivity to the active substance colistimethate sodium or other polymyxins.

4.4 Special warnings and precautions for use

ADDED:

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.

Under the statement “Nephrotoxicity or neurotoxicity may occur especially if the recommended dose is exceeded (see also Section 4.5)” the following text has been ADDED:

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.

ADDED:

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.

4.5 Interaction with other medicinal products and other forms of interaction

ADDED:

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 Fertility, Pregnancy and Lactation

ADDED:

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.

Sub-headings have been added for Pregnancy and Lactation.

The paragraph structure regarding use in pregnancy has been AMENDED FROM:

Safety in human pregnancy has not been established.  There is evidence that colistimethate sodium crosses the placenta and consequently there is potential for foetal toxicity in administered during pregnancy.  Animal studies are insufficient with respect to effects on reproduction.  Promixin should only be given during pregnancy if the benefits outweigh any potential risk

TO:

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.

4.8 Undesirable effects

ADDED:

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.

Angioedema has also been ADDED to the adverse reactions tabulation (see below)

5.1 Pharmacodynamic Properties

The first two paragraphs under “General properties” has been grouped under a new sub-heading of “Mode of action” and the following text from this section has been DELETED:

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.

A subheading of “PK/PD relationship”, with the following text, has been ADDED:

PK/PD relationship

Polymyxins have been reported to have a concentration-dependent bactericidal effect on susceptible bacteria

Under the previous sub-heading “Breakpoints”, the following has been AMENDED:

Breakpoints

Susceptible (S) < 4 mg/L Resistant (R) > 8 mg/L

TO:

EUCAST Breakpoints

                                                                                Susceptible (S) Resistant (R) ^a

                Acinetobacter                                                    S≤2  R>2 mg/L

Enterobacteriaceae                                         S≤2  R>2 mg/L 

                Pseudomonas Spp                                          S≤4  R>4 mg/L   

^a Breakpoints apply to dosage of 2-3 million IU x 3. A loading dose (9 million IU) may be needed.

A sub-heading of “Mechanisms of resistance”, with the following text, has been ADDED:

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.

The text and table under the sub-heading “Susceptibility” has been AMENDED FROM:

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.

TO:

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

ADDED:

Absorption

Absorption of colistimethate sodium from the gastrointestinal tract does not occur to any appreciable extent in the normal individual.

Under the sub-heading “Distribution” the previous text has been replaced as shown below:

DELETED:

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

In a study where cystic fibrosis patients received 5 to 7 mg/ Kg/day in divided doses given as a 30 minute intravenous infusion, Cmax was 21.4 ± 5 mg/L and the Cmin at 8 hours was 2.8 ± 1.8 mg/L. Steady state Cmax was 23 ± 6 mg/L and Cmin at 8 hours was 4.5 ± 4 mg/L.

In another study where cystic fibrosis patients received 2 million IU every 8 hours for 12 days, Cmax was 12.9 mg/L (5.7 – 29.6 mg/L) and Cmin was 2.76 mg/L (1.0 – 6.2 mg/L).

In healthy volunteers given 150 mg (2 million IU approximately) intravenously, peak serum levels of 18 mg/L were observed after 10 minutes.

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

ADDED :

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.

Under the sub-heading “Biotransformation” the following text has been AMENDED FROM:

Colistimethate sodium undergoes conversion to its base in vivo. Approximately 80% of the dose is recoverable unchanged in the urine. There is no biliary excretion and any remaining drug is believed to be inactivated in the tissues.

TO:

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.

Under the sub-heading “Elimination” the previous text has been replaced as shown below.

DELETED:

Following intravenous administration excretion is primarily renal with 40% of a dose recovered in the urine within 8 hours and around 80% in 24 hours. It follows that doses should be reduced in the renally impaired in order to prevent accumulation (see section 4.2).

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

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

ADDED:

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.

6.2 Incompatibilities

The previous text has been replaced as shown below.

DELETED:

Mixing drugs in solutions of Promixin should be avoided. The addition of other antibiotics such as erythromycin, tetracycline or cephalothin sodium to solutions of Promixin may lead to precipitation

ADDED:

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

6.3 Shelf life

DELETED:

Once reconstituted: Use immediately.

ADDED:

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 8ºC, unless reconstitution/dilution has taken place in controlled and validated aseptic conditions.

6.4 Special precautions for storage

ADDED:

For storage conditions of the reconstituted/diluted product see section 6.3.

6.5 Nature and contents of container

AMENDED FROM:

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 10 vials.

TO:

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

AMENDED FROM:

Promixin may be reconstituted with 0.9% saline or Water for Injections (WFI) 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. Suitable diluents are 0.9% saline, 5% dextrose, 5% fructose and Ringer’s Solution. Solutions should be used immediately after reconstitution (see section 4.2)

Any unused medicinal product or waste material should be disposed of in accordance with local requirements.

TO:

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.

10 DATE OF REVISION OF THE TEXT

DELETED:

28 January 2010

ADDED:

30^th August 2011

6.2              Incompatibilities

 

Mixing drugs in infusions or injections solutions of Promixin should be avoided. The addition of other antibiotics such as erythromycin, tetracycline or cephalothin sodium to solutions of Promixin may lead to precipitation. 

5.2       Pharmacokinetic properties

 

Promixin is presented as a sterile powder for reconstitution with Water for Injections or saline for administration by intravenous injection. 1 mg of colistimethate sodium is approximately equal to 12,500IU.

Distribution

 

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

 

In a study where CF cystic fibrosis patients received 5 to 7 mg/ kKg/day in divided doses given as a 30 minute i.v. intravenous infusion, Cmax was 21.4 ± 5 mg/L and the Cmin at 8 hours was 2.8 ± 1.8 mg/L. Steady state Cmax was 23 ± 6 mg/L and Cmin at 8 hours was 4.5 ± 4 mg/L.

 

In another study where CF cystic fibrosis patients received 2 MIU every 8 hours for 12 days, Cmax was 12.9 mg/L (5.7 – 29.6 mg/L) and Cmin was 2.76 mg/L (1.0 – 6.2 mg/L).

 

In healthy volunteers given 150 mg (2 MIU approximately) by bolus injection intravenously, peak serum levels of 18 mg/L were observed after 10 minutes.

 

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

Biotransformation

Colistimethate sodium undergoes conversion to its base in vivo. Approximately 80% of the dose is recoverable unchanged in the urine. There is no biliary excretion and any remaining drug is believed to be inactivated in the tissues.

Elimination

Following i.v. intravenous administration excretion is primarily renal with 40% of a parenteral dose recovered in the urine within 8 hours and around 80% in 24 hours. It follows that doses should be reduced in the renally impaired in order to prevent accumulation (Refer to see section 4.2.).

 

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

 

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

4.2       Posology and method of administration

 

Administration is by intravenous infusion or injection. 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 MIU 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 Ssee Ssection 6.6.

 

The dose of Promixin is dependent upon the sensitivity of the causative bacteria, the severity and type of infection, and the ageweight and renal function of the patient.

 

Up to 60 kKg: 50,000 IU/kKg (4 mg/kKg) bodyweight, to a maximum of 75,000 IU/kKg (6 mg/kKg), in 24 hours. The total daily dose should be administered as three equal doses at 8 hourly intervals.

 

Over 60 kKg(including the elderly): 1-2 MIU every 8 hours. The maximum dose is 6 MIU (480 mg) in 24 hours.

 

For each intravenous infusion each dose of Promixin can be diluted in 5.0 mL and administered by i.v. infusion over 30 minutes. Patients fitted with a totally implantavle venous access device (TIVAD) may tolerate a bolus injection of up to 2 MIU in 10 mL given over a minimum of 5 minutes. For reconstitution use 0.9% sodium chloride or Water for Injections. Higher doses may be required in Cystic Fibrosis (CF) patients in order to maintain therapeutic serum concentrations. A minimum of 5 days treatment is recommended.

 

Serum concentration estimations are recommended, especially in patients with renal impairment or cystic fibrosis and in neonates. Peak serum concentrations of 10–15 mg/L (approximately 0.125-0.2 MIU/L) should be adequate, for the treatment of most infections.

 

Dosage may be increased up to a maximum of 6 MIU per 24 hours according to the patient's condition, if clinical or bacteriological response is slow.

.

Dosages may be increased according to the patient's condistion if clinical or bacterialogical response is slow. A minimum of 5 days treatment is recommended. Where there is renal impairment, excretion is delayed and the daily dosage (magnitude of dose and dose interval) must be adjusted in relation to renal function as indicated in the table, to prevent accumulation of colistimethate sodium. The table below is a guide to dosage asjustment in order to prevent accumulation. Further dose adjustment may be required according to the needs of an individual patient.

Serum concentration estimations are recommended. Suggested modification of dosage of Promixin for adults with impaired renal function

	Degree of Renal Impairment
	Normal	Mild	Moderate	Severe
Creatinine (mmol/L)	60 - 105	106 - 129	130 - 214	215 - 340
Creatinine Clearance (% of normal)	76 to 100	40 to 75	25 to 40	Less than 25
Dose
Unit dose (MIU)	1.3 to 2	1 to 1.5	1(0.8 to 2)	1 to 1.5
Frequency (Times per day)	3	2	1 or 2	Every 36 hours
Total Daily Dose (MIU)	4 to 6	2 to 3	(0.5)1 to 2	0.6 to 1

 

6.3       Shelf life

Before openingUnopened: Two years.  

After reconstitution chemical and physical in-use stability has been demonstrated for up to 8 hours at room temperature.

Once reconstituted: From a microbiological point of view solutions should be Used immediately after reconsitution.  

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 oc unless reconstition/dilution has taken place in controlled and validated aseptic conditions.

6.6              Special precautions for disposal and other handling

Solutions of Promixin  for parenteral administration should be freshly prepared and used within 8 hours of reconstitution. Compatible infusion solutions are normally saline; 5% dextrose; 5% fructose; Ringer's solution. Mixing drugs in infusions or injections of Promixin should be avoided. The addition of other antibiotics such as erythromycin, tetracycline, cephalothin to solutions of Promixin may lead to precipitation.

Promixin may be reconstituted with 0.9% saline or Water for Injections (WFI) to produce a clear solution.  Following reconstitution, the solution should be diluted to a suitable volume for infusion over 30 minutes. Suitable diluents are 0.9% saline, 5% dextrose, 5% fructose and Ringer’s Solution.  Solutions should be used immediately after reconstitution (see section 4.2).

 

Any unused medicinal product or waste materials should be disposed of in accordance with local requirements.