Informations for option: Kolject 2 Miu Powder For Solution For Infusion, show other option

Select option:

1. Kolject 2 Miu Powder For Solution For Infusion
2. Kolject 2 Miu Powder For Solution For Infusion

Document: document 1 change

• document 0
• document 1

---

SUMMARY OF PRODUCT CHARACTERISTICS

1 NAME OF THE MEDICINAL PRODUCT

Kolject 2 MIU, Powder for solution for infusion.

2 QUALITATIVE AND QUANTITATIVE COMPOSITION

Each vial contains 2 million International Units (MIU) colistimethate sodium.

For the full list of excipients, see section 6.1.

3 PHARMACEUTICAL FORM

Powder for solution for infusion.

Sterile white powder in a 10 ml colourless glass vial with a lilac ‘flip-off cap.

4    CLINICAL PARTICULARS

4.1    Therapeutic indications

Kolject 2 MIU is indicated in the treatment of the following infections caused by susceptible aerobic Gram-negative bacteria (see section 5.1):

-    Hospital acquired pneumonia (HAP)

-    Complicated urinary tract infections

Bacteraemia that occurs in association with, or is suspected to be associated with, any of the infections listed above.

It is recommended that Kolject 2 MIU 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 Kolject 2 MIU should be administered under the supervision of physicians with appropriate experience in its use.

Posology

The dose regimen of Kolject 2 MIU 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:

Children and adults:

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

Over 60kg: 1-2 million I. U. every 8 hours. The maximum standard dose is 6 million I. U. (480mg) 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 adult patients doses up to 9 million I. U. 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). Loading doses should be limited to 9 MIU.

Renal impairment:

The suggested dose recommendations in the following table for patients with renal impairment are based on the standard total daily dose of 3-6 million I. U. per day. For patients with renal impairment in whom higher doses (e. g. up to 9 million I. U. per 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 colistimethate sodium to any patient with renal impairment due to the limited information available on safety and appropriate dose regimens (see section 4.4).

Suggested dosage adjustment in renal impairment

Degree of Renal Impairment

_Normal_Mild_Moderate_Severe_

Creatinine clearance 76 to 100    40 to 75    25 to 40    Less than 25

(% of normal)

Dose

Unit dose (million I.U.)	1.3 to 2	1 to 1.5	1	1 to 1.5
Frequency (times per day)	3	2	1 or 2	Every 36 hours
Total daily dose (million I.U.)	4 to 6	2 to 3	1 to 2	0.6 to 1

Hepatic impairment

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

Method of administration

Administration is by intravenous infusion. Each dose of Kolject 2 MIU can be diluted with 50ml and administered by intravenous infusion over a period of 30 minutes. Patients fitted with a totally implantable venous access device (TIVAD) may tolerate an injection of up to 2 million I. U. in 10ml given over a minimum of 5 minutes.

For instructions on dilution of the medicinal product before administration, see section 6.6.

4.3 Contraindications

Hypersensitivity to colistimethate sodium, colistin sulphate or to other polymyxins.

4.4 Special warnings and precautions for use

Use with extreme caution in patients with porphyria.

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.

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 I. U. per day.

Monitoring of renal function should be performed before initiating treatment with colistimethate sodium. 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 I. U. per day. The dose of colistimethate sodium may have to be reduced if serum creatinine concentrations rise or exceed the upper limit of normal (see section 4.2).

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 (see also section 4.5).

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 C. 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

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 Kolject 2 MIU as their effects could be prolonged (see also section 4.4).

Concomitant use of colistimethate sodium with other medicinal products of neurotoxic and/or nephrotoxic potential should only be undertaken with greatest caution. These include the aminoglycoside antibiotics such as gentamicin, amikacin, netilmicin and tobramycin as well as cephalosporins and non-depolarising muscle relaxants.

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, in particular if they have a neurotoxic and/or nephrotoxic potential.

4.6 Fertility, Pregnancy and lactation

Data on the possible impact of colistimethate sodium on human fertility are not available.

Animal studies do not indicate effects with respect to fertility (see Section 5.3).

Pregnancy

There are no adequate data from the use of colistimethate sodium in pregnant women. However, single dose studies in human pregnancy show that colistimethate sodium crosses the placental barrier and there may be a risk of

foetal toxicity if repeated doses are given to pregnant patients. Animal studies are insufficient with respect to the effect of colistimethate sodium on reproduction and development (see section 5.3).

Colistimethate sodium should be used in pregnancy only if the benefit to the mother outweighs the potential risk to the foetus.

Breastfeeding

Colistimethate sodium is secreted in human milk. Colistimethate sodium should be administered to breastfeeding women only when clearly indicated and the benefit to the mother outweighs the potential risk to the child.

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 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 (>1/10);

Common (>1/100 to <1/10);

Uncommon (>1/1,000 to <1/100);

Rare (>1/10,000 to <1/1,000),

Very rare (<1/10,000),

Not known: Frequency cannot be estimated from the available data.

Body System	Frequency	Reported adverse reaction
Immune system disorders	Not known	Hypersensitivity reactions such as skin rash and angioedema
Nervous system disorders	Very common	Neurotoxicity such as facial, mouth and perioral paraesthesia, headache, and muscle weakness
	Not known	Dizziness Ataxia
Skin and subcutaneous tissue disorders	Very common	Pruritus
Renal and urinary disorders	Very common	Renal impairment demonstrated by increased blood creatinine and/or urea and/or decreased creatinine renal clearance
	Rare	Renal failure
General disorders and administration site conditions	Not known	Injection site reaction

Reporting of suspected adverse reactions

Reporting suspected adverse reactions is an important way to gather more information to continuously monitor the benefit/risk balance of the medicinal product. Any suspected adverse reactions should be reported via the Yellow Card Scheme (Website: www.mhra.gov.uk/yellowcard).

4.9 Overdose

Symptoms:

Overdose can result in neuromuscular blockade that can lead to muscular weakness, apnoea and possible respiratory arrest. Vertigo, transient facial paraesthesia, slurred speech, vasomotor instability, visual disturbances, confusion, and psychosis have been reported.

Overdose can also cause acute renal failure characterised by decreased urine output and increased serum concentrations of BUN and creatinine.

Treatment:

There is no specific antidote, manage by supportive treatment and measures to increase the rate of elimination of colistimethate sodium e.g. mannitol diuresis or prolonged haemodialysis.

5 PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties

Pharmacotherapeutic group: Other antibacterials, polymyxins, ATC Code: JO1X B01.

Mechanism of action

Colistimethate sodium (also known as colistin) is a cyclic polypeptide antibiotic derived from Paenibacillus polymyxa var. colistinus and belongs to the polymyxin group. The polymyxin antibiotics are cationic, surface active agents and act by binding to and damaging the cell membrane. The resulting physiological effects are lethal to the bacterium. Polymyxins are selective for Gram-negative bacteria that have a hydrophobic outer membrane.

PK/PD relationship

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

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. Breakpoints

EUCAST (European Committee on Antimicrobial Susceptibility Testing, 2010) listed following breakpoints for colistin:

Sensible(S) Resistant(R)*

Acinetobacter spp.    < 2 mg/l    > 2 mg/l

Pseudomonas spp.    < 4 mg/l    > 4 mg/l

Enterobacteriacea spp.    < 2 mg/l    > 2 mg/l

* Breakpoints apply to dosage of 2-3 million I.U. x 3. A loading dose (9 million I.U.) may be needed.

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 Klebsiella species

Species for which acquired resistance may be a problem

Achromobacter xylosoxidans

Stenotrophomonas maltophilia_

Inherently resistant organisms_

Burkholderia cepacia and related species.

Proteus species Providencia species Serratia 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 C_max was determined to be 23 (+6) mg/l and C_min 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 C_max was 12.9 mg/l (5.7 - 29.6 mg/l) and the C_min 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 18 mg/l were observed 10 minutes after injection.

Protein binding is low. Polymyxins persist in the liver, kidney, brain, heart and muscle. 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 12.4 L and 20.4 L 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 I. U. has been suggested, especially in critically ill patients.

In critically ill patients given colistimethate sodium 2 million I. U. and 3 million I. U. three times a day intravenously, peak colistin plasma concentrations of 2.21 and 2.93 mg/l, respectively, were observed.

Biotransformation

Colistimethate sodium is partly converted to the base in vivo.

Elimination

The main route of elimination of unchanged colistimethate sodium after parenteral administration is by renal excretion with around 60% of a parenteral dose recovered in the urine within 8 hours. Because colistimethate sodium is

largely excreted in the urine, dose reduction is required in renal impairment to prevent accumulation. Refer to the table in section 4.2. The free base colistin is excreted by the non-renal route.

After intravenous administration to healthy adults the elimination half-life of colistimethate sodium 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.

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.

Colistimethate sodium kinetics 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.

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 9.3 mg/kg.

No effects were seen on mouse or rat fertility at intravenous doses up to 25 mg/kg/day.

There are no other preclinical safety data of relevance to the prescriber which are additional to safety data derived from patient exposure and already included in other sections of the SmPC.

6.1 List of excipients

None.

6.2 Incompatibilities

Mixed infusions involving colistimethate sodium should be avoided.

6.3 Shelf life

3 years

Reconstituted solutions:

Powder for infusion can be stored after reconstitution for 24 hours between 2°C to 8°C. Storage for more than 24 hours is not recommended due to the risk of microbial contamination of the reconstituted solution.

6.4 Special precautions for storage

Do not store above 25°C. Keep the vials in the outer carton.

For storage conditions after reconstitution of the medicinal product, see section 6.3.

6.5 Nature and contents of container

10 ml colourless glass vials with lilac flip-tear-off caps.

•    1 vial

•    10 vials

•    30 vials

•    60 vials

•    100 vials

Not all pack sizes may be marketed.

6.6 Special precautions for disposal

The normal adult dose of 2 million units should be dissolved in 10-50 ml of 0.9% sodium chloride or 5% glucose solution for infusion to form a clear