Colistimethate sodium 1 MIU Powder for nebuliser solution – Summary of Product Characteristics (SmPC) for healthcare professionals

1 NAME OF THE MEDICINAL PRODUCT

Colistimethate sodium 1 MIU Powder for nebuliser solution

2 QUALITATIVE AND QUANTITATIVE COMPOSITION

Each vial contains 1 million International Units of colistimethate sodium.

For excipients, see 6.1.

3 PHARMACEUTICAL FORM

Powder for nebulizer solution

White to almost white powder.

4 CLINICAL PARTICULARS

4.1 Therapeutic indications

Colistimethate sodium by inhalation is indicated for the management of adult and paediatric chronic pulmonary infections due to Pseudomonas aeruginosa in patients with cystic fibrosis (see section 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 colistimethate sodium (CMS) should be administered under the supervision of physicians with appropriate experience in its use.

Posology

The dosage can be adjusted depending on the severity of the condition and clinical response. Recommended dose range:

Administration via inhalation

Adults, adolescents and children ≥ 2 years

1-2 MIU two to three times per day (max 6 MIU/day)

Children < 2 years

0.5-1 MIU twice daily (max 2 MIU/ day)

Relevant clinical guidance on treatment regimens, including duration of treatment, periodicity and co-administration of other antibacterial agents should be adhered to.

ElderlyDose adjustment is not considered necessary

Renal impairment

Dose adjustment is not considered necessary; however caution is advised in patients with renal impairment (see sections 4.4 and 5.2).

Hepatic impairment

Dose adjustment is not considered necessary

Method of administration

For inhalation use.

Colistimethate sodium undergoes hydrolysis to the active substance Colistimethate sodium in aqueous solution. The content of a vial of Colistimethate sodium 1 million International Units should be dissolved in 3ml of water for injection or saline solution (sodium chloride 0.9%) or 50:50 mixture of water for injection and 0.9% sodium chloride.

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

If other treatments are being taken, they should be taken in the order recommended by the physician.

Predicted drug delivery characteristics as studied in vitro (in vitro) employing specifications of the adult breathing pattern and the following nebulizer device for Colistimethate sodium 1 million International Units dissolved in 3 ml of isotonic sodium chloride 0.9% or 50:50 mixture of water for injection and 0.9% sodium chloride. (min – max).

14.37mg CMS /min (12.84 14.27 mg CMS /min (13.77 –

The patient should sit in an upright position during inhalation. Inhalation should be performed applying a normal breathing pattern without interruption.

The nebulizer must be cleaned and disinfected after use as described in instructions of use of the corresponding nebulizer.Dose conversion table:

In the EU, the dose of colistimethate sodium (CMS) must be prescribed and administered only as International Units (IU). The product label states the number of IU per vial.

Confusion and medication errors have occurred because of the different expressions of dose in terms of potency. The dose is expressed in the US, and other parts of the world, as milligrams of Colistimethate sodium base activity (mg CBA).

The following conversion table is prepared for information and the values must be considered nominal and approximate only.

CMS conversion table

≈

*Nominal potency of the drug substance= 12,500 IU/mg

4.3 Contraindications

Hypersensitivity to colistimethate sodium, Colistimethate sodium or to polymyxin B.

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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/Neurotoxicity

Nephrotoxicity or neurotoxicity may occur if the recommended parenteral dose is exceeded. The risk is reduced due to the low bioavailability during inhalation, but ColiFin should be used with caution in patients with renal impairment. Appearance of neurotoxic reactions as well as the renal function should be monitored.

In premature and newborn infants special care should be employed as renal function is only insufficiently developed in this population.

Colistimethate sodium is known to reduce the presynaptic release of acetyl-choline at the neuro-muscular junction and should be used in patients with myasthenia gravis with the greatest caution and only if clearly needed.

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

Caution should be taken with concomitant use with other formulations of colistimethate sodium as there is little experience and there is a possibility of summative toxicity.

No in vivo interaction studies have been performed. The mechanism of conversion of colistimethate sodium to the active substance, colistin, is not characterised. The mechanism of colistin clearance, including renal handling, is equally unknown. Colistimethate sodium or colistin did not induce the activity of any P 450 (CYP) enzyme tested (CYP1A2, 2B6, 2C8,

2C9, 2C19 and 3A4/5) in in vitro studies in human hepatocytes. The potential for drug-drug interactions should be borne in mind when colistimethate is co- administered with drugs known to inhibit or induce drug metabolising enzymes or drugs known to be substrates for renal carrier mechanisms.

Due to the effects of colistin on the release of acetylcholine, non-depolarising muscle relaxants should be used with caution in patients receiving colistimethate sodium as their effects could be prolonged (see section 4.4).

Co-treatment with colistimethate sodium and macrolides such as azithromycin and clarithromycin, or fluoroquinolones such as norfloxacin and ciprofloxacin should be undertaken with caution in patients with myasthenia gravis (see section 4.4).

Concomitant use of colistimethate sodium with other medicinal products of neurotoxic and/or nephrotoxic potential should be avoided. These include the aminoglycoside antibiotics such as gentamicin, amikacin, netilmicin and tobramycin. There may be an increased risk of nephrotoxicity if given concomitantly with cephalosporin antibiotics.

4.6 Fertility, pregnancy and lactation

Pregnancy

There are no adequate data from the use of colistimethate sodium in pregnant women. 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, Preclinical safety data). 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 breast milk. Colistimethate sodium should be administered to breastfeeding women only when clearly needed.

4.7 Effects on ability to drive and use machines

During 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 common 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 (≥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 (cannot be estimated from the available data).

Sore throat or mouth has been reported and may be due to Candida albicans infection or hypersensitivity. Skin rash may also indicate hypersensitivity, if this occurs treatment should be withdrawn.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorization of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the Yellow Card Scheme, website: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.

4.9 Overdose

Overdose can result in neuromuscular blockade that can lead to muscular weakness, apnoea and possible respiratory arrest. Overdose can also cause acute renal failure characterised by decreased urine output and increased serum concentrations of BUN and creatinine.

There is no specific antidote, manage by supportive treatment. Measures to increase the rate of elimination of colistin e.g. mannitol diuresis, prolonged haemodialysis or peritoneal dialysis may be tried, but effectiveness is unknown.

5 PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties

Pharmacotherapeutic group: Antibacterials for systemic use, other antibacterials, polymyxins. ATC Code: J01 XB01

Mechanism of action

Colistimethate sodium is the prodrug of colistin. Colistin a cyclic polypeptide antibacterial agent belonging to the polymyxin group. Polymyxins work by damaging the cell membrane and the resulting physiological effects are lethal to the bacterium. Polymyxins are active against aerobic Gram-negative bacteria that have a hydrophobic outer membrane.

Resistance

Resistant bacteria are characterised by modification of the phosphate groups of lipopolysaccharides, which become substituted with ethanolamine or aminoarabinose. Naturally resistant Gram-negative bacteria, such as Proteus mirabilis and Burkholderia cepacia, show complete substitution of their lipid phosphate by ethanolamine or aminoarabinose.

Cross resistance between colistin (polymyxin E) and polymyxin B is expected. Since the mechanism of action of the polymyxins is different from that of other antibacterial agents, resistance to colistin and polymyxin by the above mechanism alone would not be expected to result in resistance to other drug classes.

PK/PD relationship

Polymyxins have been reported to have a concentration-dependent bactericidal effect on susceptible bacteria. fAUC/ MIC is considered to be correlated with clinical efficacy.

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.

5.2 Pharmacokinetic properties

Absorption

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

When given by nebulisation, variable absorption has been reported that may depend on the aerosol particle size, nebulizer system and lung status. 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.

Distribution

The volume of distribution of colistin in healthy subjects is low and corresponds approximately to extracellular fluid (ECF). The volume of distribution is relevantly enlarged in critically ill subjects. Protein binding is moderate and decreases at higher concentrations. In the absence of meningeal inflammation, penetration into the cerebrospinal fluid (CSF) is minimal but increases in the presence of meningeal inflammation.

Both CMS and colistin display linear PK in the clinically relevant dose range.

Elimination

There is no information on the elimination of colistimethate sodium following nebulisation.

After intravenous administration, it is estimated that approximately 30% of colistimethate sodium is converted to colistin in healthy subjects, its clearance is dependent on creatinine clearance and as renal function decreases, a greater portion of CMS is converted to colistin. In patients with very poor renal function (creatinine clearance <30 mL/min), the extent of conversion could be as high as 60 to 70%. CMS is eliminated predominantly by the kidneys via glomerular filtration. In healthy subjects, 60% to 70% of CMS is excreted unchanged in the urine within 24 hours. The elimination of the active colistin is incompletely characterised. Colistin undergoes extensive renal tubular reabsorption and may either be cleared non-renally or undergo renal metabolism with the potential for renal accumulation. Colistin clearance is decreased in renal impairment, possibly due to increased conversion of CMS. Half-

life of colistin in healthy subjects and those with cystic fibrosis is reported to be around 3h and 4h, respectively, with a total clearance of around 3L/h. In critically ill patients, half-life has been reported to be prolonged to around 9-18h.

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 fetuses respectively. These doses are 0.5 and 1.2 times the maximum daily human dose. In addition, increased resorption occurred at 9.3 mg/kg. 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 SPC.

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

Before opening:

2 years.

Reconstituted solutions:

For solutions for nebulisation, the chemical and physical in-use stability of reconstituted solution in the original vial, with a concentration ≥ 80,000 IU/mL, has been demonstrated for 6 hours at 2 to 8°C and 2 hours in room temperature.

From a microbiological point of view, unless the method of opening/ reconstitution/ dilution precludes the risk of microbial contamination, the product should be used immediately.

If not used immediately, in-use storage times and conditions are the responsibility of user.

6.4 Special precautions for storage

Do not store above 25°C.

Keep the vials in the outer carton in order to protect from light. For storage of solutions following reconstitution refer to 6.3.

6.5 Nature and contents of container

cartons of one or ten vials.

6.6 Special precautions for disposal

Inhalation:

1 - Remove the plastic cap.

2 - Using a syringe, withdraw the required volume of solvent from the solvent container (sterile water or sterile salt water (saline) or a 50:50 mixture of sterile water and sterile 0,9% saline to dissolve the powder as follows: 1 million unit vial: 3ml sterile water or 3 ml sterile 0.9% saline or 1,5 ml sterile water and 1,5ml sterile 0,9% saline).

3 - Pierce the stopper in the centre with the syringe and inject its content slowly into the vial.

4 - Gently turn the vial upside down twice.

5 - Roll the vial gently between both hands to dissolve all the Colistimethate sodium powder visible on the bottom and side of the vial. Do not shake the vial too hard, as this may make the solution foam.

6 - Turn the vial and withdraw all the final solution with the syringe.

7 - Remove the needle from the syringe and fill the solution into the nebulizer. Then, inhale as usual. Use the nebulizer according to the instructions of the manufacturer.

The solution is for single use only and any remaining solution should be discarded.

Any antibiotic residual solution as well as all materials that have been used for administration should be disposed of in accordance with local requirements.

7 MARKETING AUTHORISATION HOLDER

Hikma Farmacêutica (Portugal), S.A. Estrada do Rio da Mó, nº8, 8A/8B Fervença

2705-906 Terrugem SNT Portugal

8 MARKETING AUTHORISATION NUMBER(S)

PL 15413/0143

9 DATE OF FIRST AUTHORISATION/RENEWAL OF THE

AUTHORISATION

16/05/2023

10 DATE OF REVISION OF THE TEXT

16/05/2023