Colistin (Powder) Instructions for Use

Marketing Authorization Holder

Teva Pharmaceutical Industries, Ltd. (Israel)

Manufactured By

Xellia Pharmaceuticals, ApS (Denmark)

Packaging and Quality Control Release

PENN PHARMACEUTICAL SERVICES, Limited (United Kingdom)

ATC Code

J01XB01 (Colistin)

Active Substance

Colistimethate sodium (Rec.INN registered by WHO)

Dosage Form

Colistin

Powder for preparation of solution for inhalation 1000000 IU: vial 28 pcs. with solvent

Dosage Form, Packaging, and Composition

Powder for preparation of solution for inhalation white or almost white, hygroscopic.

80 mg (1000000 IU) – vials of colorless glass with a capacity of 10 ml (28) in a kit with solvent (amp. 28 pcs.) – cardboard packs with dividers^×.

^× protective stickers may be additionally applied.

Clinical-Pharmacological Group

Antibiotic for inhalation use

Pharmacotherapeutic Group

Systemic antibacterial agents; other antibacterial agents; polymyxins

Pharmacological Action

Cyclic polypeptide antibiotic. Colistimethate sodium is produced by Bacillus polymyxa, subspecies colistinus. Colistimethate is the methanesulfonate of colistin. Colistimethate sodium exerts a bactericidal effect on gram-negative microorganisms, both dividing and resting, by altering the structure and function of the outer and cytoplasmic membranes.

The drug is active against Pseudomonas aeruginosa, Haemophilus influenzae, Acinetobacter spp., Citrobacter spp., Enterobacter spp., Klebsiella spp., Salmonella spp., Shigella spp.

It is not active against Burkholderia cepacia and Staphylococcus aureus.

Caution is required when determining the susceptibility or resistance of pathogens when using colistimethate sodium by inhalation.

Pharmacokinetics

Absorption

The absorption of colistimethate sodium after inhalation is characterized by significant individual variations. The C_max of colistimethate sodium in blood serum after inhalation of a dose of 2 million IU ranges from undetectable levels to 280 µg/L. Comparing these values with the drug concentration in serum after parenteral administration leads to the conclusion that absorption is less than 2%.

Distribution

At 1 hour and 4 hours after inhalation of the drug at a dose of 1 million IU, the concentration of colistimethate sodium in sputum is 183.6 mg/L and 22.8 mg/L, respectively. Approximately 15% of the administered dose accumulates in the lungs.

Colistimethate sodium crosses the placental barrier and is excreted in breast milk.

Elimination

Colistimethate sodium is excreted with expectorated sputum. The small portion of the drug that enters the systemic circulation is excreted primarily by glomerular filtration. Within 8 hours, about 60% of the absorbed dose is excreted unchanged by the kidneys.

After inhalation of the drug at a dose of 2 million IU, the mean cumulative renal excretion is approximately 1%.

Pharmacokinetics in special clinical cases

The pharmacokinetics of colistimethate sodium in patients with renal impairment has not been studied. However, due to the low systemic bioavailability of the drug, the risk of adverse reactions is low.

Indications

• Treatment of respiratory tract infections caused by Pseudomonas aeruginosa in cystic fibrosis.

ICD codes

Dosage Regimen

The drug is used by inhalation.

For adults and children over 6 years the daily dose of the drug is from 2 million IU to 6 million IU depending on the severity of the disease. Usually, 1 million IU is prescribed 2 times/day with a 12-hour interval.

The duration of eradication therapy for primary colonization/infection caused by Pseudomonas aeruginosa is from 3 weeks to 3 months. There are no time limits for the duration of therapy for chronic infection caused by Pseudomonas aeruginosa.

In patients with renal impairment dose reduction of the drug is not required.

Adverse Reactions

Allergic reactions angioedema.

From the CNS and peripheral nervous system dizziness, paresthesia.

From the respiratory system bronchospasm (>10%), increased cough, increased sputum production, mucositis (inflammation of the respiratory tract mucosa), pharyngitis, dyspnea.

From the digestive system nausea, heartburn.

From the urinary system acute renal failure.

Contraindications

• Children under 6 years of age;
• Hypersensitivity to the components of the drug.

With caution the drug should be used in bronchial asthma, renal impairment, hemoptysis, during pregnancy.

Use in Pregnancy and Lactation

Due to the risk of nephro- and neurotoxic reactions in the fetus, Colistin should be used during pregnancy under medical supervision with caution and only for vital indications.

If it is necessary to use Colistin during lactation, breastfeeding should be discontinued.

Use in Renal Impairment

In patients with renal impairment dose reduction of the drug is not required.

Special Precautions

Inhalation medications, including Colistin, may cause acute bronchoconstriction in sensitive patients. Therefore, the first dose of Colistin for inhalation should be administered under the supervision of experienced medical personnel, and inhalation should be preceded by the use of a bronchodilator if it is part of the patient’s therapy regimen. FEV1 should be measured before and after inhalation of Colistin. If a patient not receiving bronchodilators shows signs of drug-induced bronchial obstruction, the test should be repeated at the next use of Colistin, adding a bronchodilator.

The first use of Colistin should be carried out under the supervision of medical personnel experienced in working with patients suffering from cystic fibrosis.

In patients with renal impairment, careful monitoring for possible development of nervous system side effects and regular monitoring of renal function is necessary.

A break should be taken between inhalations of dornase alfa and inhalation of Colistin.

During treatment with Colistin, the appearance of resistant strains of Pseudomonas aeruginosa is possible in rare cases. After discontinuation and/or modification of therapy, the effectiveness of the drug may be restored.

During treatment with the drug, the patient should refrain from consuming alcohol.

Effect on ability to drive vehicles and mechanisms

During the treatment period, it is necessary to refrain from driving vehicles and engaging in other potentially hazardous activities that require increased concentration and speed of psychomotor reactions.

Rules for using the drug

1. The vial with powder is opened by removing the aluminum cap with first-opening control and opening the rubber stopper.
2. The ampoule with solvent is opened using a file or an ampoule opener.
3. The entire contents of the ampoule are poured into the vial with powder. The powder dissolves with gentle shaking. Vigorous shaking should be avoided due to excessive foam formation.
4. The solution is poured into a nebulizer and used by inhalation according to the nebulizer manufacturer’s instructions.
5. The patient performs the Colistin inhalation procedure in a sitting or standing position, in a normal calm state, taking as deep breaths as possible through the nebulizer mouthpiece. Using a nose clip can facilitate inhalation through the mouth.
6. After each use, the inhaler should be rinsed and disinfected, following the manufacturer’s instructions.

In patients receiving other types of inhalation therapy, inhalation of Colistin should be performed immediately after using a bronchodilator, and also after chest physiotherapy procedures.

Overdose

Symptoms from the CNS and peripheral nervous system – dizziness, paresthesia, diplopia (due to paresis of the eye muscles), ptosis, general weakness, speech disorders, areflexia, visual disturbances, dysphagia, seizures and coma; neuromuscular blockade can cause death due to respiratory paralysis; from the urinary system – damage to renal tubular epithelial cells and tubular necrosis.

Treatment symptomatic therapy, peritoneal dialysis (or hemodialysis) is advisable; mechanical ventilation. Calcium gluconate and neostigmine do not relieve neuromuscular blockade.

Drug Interactions

With simultaneous use of Colistin with inhalation anesthetics (ether, halothane), muscle relaxants or curare-like drugs (tubocurarine, succinylcholine) or aminoglycosides, careful monitoring for possible development of neurotoxic reactions is necessary.

With simultaneous use of Colistin with potentially nephrotoxic drugs (aminoglycosides, cephalosporins, cyclosporine), increased nephrotoxicity is possible.

Pharmaceutical interaction

The prepared solution of Colistin should not be mixed with other medications.

Storage Conditions

List B. The drug should be stored out of the reach of children at a temperature not exceeding 25°C (77°F). Store in the original packaging to protect the contents from light.

Shelf Life

Shelf life – 4 years.

The prepared solution of Colistin for inhalation remains stable for up to 6 hours at room temperature.

Dispensing Status

The drug is dispensed by prescription.

Important Safety Information

This information is for educational purposes only and does not replace professional medical advice. Always consult your doctor before use. Dosage and side effects may vary. Use only as prescribed.