Colomycin injection

INSTRUCTIONS for medical use of the medicinal product Colomycin Injection (Colomycin Injection)

Composition:

Active substance: colistimethate sodium;

1 vial contains 1,000,000 IU or 2,000,000 IU, equivalent to 33.3 mg or 66.6 mg of colistimethate sodium.

Pharmaceutical form. Powder for solution for injection, infusion, or inhalation.

Main physicochemical properties: white or almost white, hygroscopic powder.

Pharmacotherapeutic group. Antibacterial agents for systemic use.

ATC code J01X B01.

Pharmacological properties.

Pharmacodynamics.

Mechanism of action

Colistin is a cyclic polypeptide antibacterial agent belonging to the polymyxin group. Polymyxins damage cell membranes, resulting in physiological effects that are lethal to bacteria. Polymyxins act selectively against aerobic Gram-negative bacteria, which have a hydrophobic outer membrane.

Resistance

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

Cross-resistance between colistin (polymyxin E) and polymyxin B is possible. Since the mechanism of action of polymyxins differs from that of other antibiotics, resistance to colistin and polymyxin via the aforementioned mechanism does not imply resistance to other classes of drugs.

Pharmacokinetic/pharmacodynamic relationship

Polymyxins have been reported to exhibit concentration-dependent bactericidal activity against susceptible bacteria. The fAUC (free drug area under the curve)/MIC (minimum inhibitory concentration) ratio is considered to correlate with clinical efficacy.

Table 1

EUCAST* breakpoints

	Susceptible (S)	Resistant (R)**
Acinetobacter	S ≤ 2	R > 2 mg/l
Enterobacteriaceae	S ≤ 2	R > 2 mg/l
Pseudomonas spp	S ≤ 4	R > 4 mg/l

* EUCAST (European Committee on Antimicrobial Susceptibility Testing).

** Breakpoint concentrations refer to a dose of 2–3 million IU × 3. A loading dose (9 million IU) may be required.

Susceptibility

The prevalence of acquired resistance may vary according to geographical location and time for selected bacterial species; therefore, local information on resistance should be sought, especially when treating severe infections. When prescribing this medicinal product, local resistance rates of microorganisms to sodium colistimethate should be taken into account. If local resistance prevalence renders the usefulness of the drug questionable for certain types of infections, this should be considered and expert advice sought.

Generally susceptible species

Acinetobacter baumannii

Haemophilus influenzae

Klebsiella spp.

Pseudomonas aeruginosa

Species for which acquired resistance may be problematic

Stenotrophomonas maltophilia

Achromobacter xylosoxidans (previously known as Alcaligenes xylosoxidans)

Naturally resistant organisms

Burkholderia cepacia and related species

Proteus species

Providencia species

Serratia species

Pharmacokinetics

Absorption

Data on the pharmacokinetics of sodium colistimethate and colistin are limited. Evidence suggests that pharmacokinetics in critically ill patients differ from those in patients with less severe physiological disturbances and in healthy volunteers.

Following infusion of sodium colistimethate, the inactive prodrug is converted into active colistin. Peak plasma concentrations of colistin are delayed, reaching up to 7 hours after administration of sodium colistimethate in critically ill patients.

Gastrointestinal absorption in healthy volunteers is minimal.

When administered by nebulization, variable absorption has been reported, depending on aerosol particle size, nebulizer system, and lung condition. In studies involving healthy volunteers and patients with various infections, plasma concentrations of the drug have ranged from zero to potentially therapeutic levels of 4 mg/L or higher. Therefore, the possibility of systemic absorption should always be considered when administering the drug by inhalation.

Distribution

The volume of distribution of colistin in healthy volunteers is low and approximately corresponds to extracellular fluid. The volume of distribution is relatively increased in critically ill patients. Plasma protein binding is moderate and decreases at higher concentrations. Penetration into cerebrospinal fluid is minimal in the absence of meningeal inflammation, but increases when meningeal inflammation is present.

Both sodium colistimethate and colistin exhibit linear pharmacokinetics within the clinically relevant dosage range.

Elimination

Approximately 30% of sodium colistimethate is converted to colistin in healthy volunteers. Its clearance depends on creatinine clearance, and with decreasing renal function, a greater proportion of sodium colistimethate is converted to colistin. In patients with significantly impaired renal function (creatinine clearance < 30 mL/min), the conversion rate may reach 60–70%. Sodium colistimethate is eliminated by the kidneys via glomerular filtration. In healthy volunteers, 60 to 70% of sodium colistimethate is excreted unchanged in urine within 24 hours.

Elimination of active colistin is poorly characterized. Colistin undergoes substantial renal tubular reabsorption and may be eliminated via non-renal pathways or undergo renal metabolism, with potential for renal accumulation. Colistin clearance decreases with impaired renal function, likely due to increased conversion of sodium colistimethate.

The elimination half-life of colistin in healthy volunteers and patients with cystic fibrosis is approximately 3 and 4 hours, respectively, with a total clearance of about 3 L/h. In critically ill patients, the elimination half-life is prolonged to approximately 9–18 hours.

Clinical characteristics.

Indications.

Intravenous administration of the medicinal product is indicated in adults and children, including newborns, for the treatment of severe infections caused by specific aerobic Gram-negative pathogens in patients with limited treatment options.

The medicinal product as inhalation is also indicated in adults and children with cystic fibrosis for the treatment of chronic pulmonary infections caused by Pseudomonas aeruginosa.

Official recommendations on the appropriate use of antibacterial agents should be followed.

Contraindications.

Hypersensitivity to sodium colistimethate (colistin) or polymyxin B.

Special precautions.

Inhalation of antibiotics as a procedure may provoke bronchospasm. Bronchospasm can be prevented or terminated with appropriate β2-agonists; if this fails, treatment should be discontinued.

Interaction with other medicinal products and other forms of interaction.

Concomitant administration of sodium colistimethate with other medicinal products having neurotoxic and/or nephrotoxic effects requires great caution.

Concomitant administration of different dosage forms of sodium colistimethate should be done with caution due to lack of experience and the potential for cumulative toxicity.

In vivo interaction studies have not been conducted. The mechanism of conversion of sodium colistimethate into the active substance, colistin, has not been studied. The clearance mechanism of colistin, particularly renal elimination, has also not been described. Sodium colistimethate or colistin did not induce the activity of any of the tested P450 (CYP) enzymes (CYP1A2, 2B6, 2C8, 2C9, 2C19, and 3A4/5) in in vitro studies with human hepatocytes.

The potential for drug interactions should be considered when prescribing Colomycin Injection together with medicinal products that inhibit or induce drug-metabolizing enzymes, or with medicinal products that are substrates for renal transport mechanisms.

Due to the effect of colistin on acetylcholine release, non-depolarizing muscle relaxants should be administered with caution to patients receiving sodium colistimethate, as their effects may be prolonged.

Concomitant use of sodium colistimethate with macrolide antibiotics such as azithromycin and clarithromycin, or fluoroquinolones such as norfloxacin and ciprofloxacin, should be done with caution in patients with myasthenia gravis.

Concomitant administration of sodium colistimethate with other medicinal products having neurotoxic and/or nephrotoxic potential should be avoided. These include aminoglycoside antibiotics such as gentamicin, amikacin, netilmicin, and tobramycin. Concomitant use with cephalosporin antibiotics may increase the risk of nephrotoxicity.

Special precautions for use.

Concomitant use of intravenous sodium colistimethate with another antibacterial agent should be considered whenever possible, taking into account the susceptibility of the causative pathogen(s) to treatment. Since development of resistance to intravenous colistin has been reported, particularly when used as monotherapy, concomitant administration with another antibacterial agent should be considered to prevent emergence of resistance.

Clinical data on the efficacy and safety of intravenous sodium colistimethate are limited. Recommended doses in all subpopulations are based on limited data (clinical and pharmacokinetic/pharmacodynamic data). In particular, there are limited data on the safety of high doses (> 6,000,000 IU/day), use of loading doses, and use in special patient groups (patients with renal impairment and children). Sodium colistimethate should be used only when other, more commonly used antibiotics are ineffective or unsuitable.

In all patients, renal function should be assessed at the start of treatment and monitored during therapy. The dose of sodium colistimethate should be adjusted according to creatinine clearance. Sodium colistimethate is excreted by the kidneys and is nephrotoxic if high serum concentrations are achieved. Patients with hypovolemia or those receiving other potentially nephrotoxic drugs have an increased risk of nephrotoxic effects of colistin. Renal function impairment has generally been reported after administration of doses higher than recommended via intravenous or intramuscular routes in patients with normal renal function, or in the absence of dose reduction in patients with impaired renal function, or with concomitant use of other nephrotoxic antibiotics. In some studies, nephrotoxicity has been associated with cumulative dose and duration of treatment. The benefit of prolonged treatment should be weighed against the potential increased risk of nephrotoxicity.

Several cases of pseudo-Bartter syndrome have been reported in children and adults following intravenous administration of sodium colistimethate. If such cases are suspected, monitoring of serum electrolyte levels should be initiated and appropriate treatment implemented; however, without discontinuation of sodium colistimethate, normalization of electrolyte imbalance may not be achieved.

High serum concentrations of sodium colistimethate, which may be associated with overdose or lack of dose reduction in patients with impaired renal function, have been reported to cause neurotoxic effects such as facial paraesthesia, muscle weakness, vertigo, slurred speech, vasomotor instability, visual disturbances, confusion, psychosis, and apnea. Dose reduction of colistimethate may alleviate symptoms. Monitoring for perioral and extremity paraesthesia, which are signs of overdose, is required. Neurotoxic reactions are unlikely during inhalation therapy; however, patients (especially those with renal impairment) should be observed for such reactions, and renal function should also be monitored.

Caution is required when administering sodium colistimethate to infants (under 1 year of age), as renal function in this age group is not fully mature. Furthermore, the impact of immature renal and metabolic function on the conversion of sodium colistimethate to colistin is unknown.

If an allergic reaction occurs, treatment with colistimethate sodium must be discontinued and appropriate measures taken.

Sodium colistimethate is known to reduce presynaptic release of acetylcholine at the neuromuscular junction; therefore, it should be used with extreme caution in patients with myasthenia gravis (due to the risk of neuromuscular blockade) and only if clearly necessary.

Respiratory arrest has been reported after intramuscular administration of sodium colistimethate. Renal impairment increases the likelihood of apnea and neuromuscular blockade following administration of sodium colistimethate.

Special caution is required when administering the drug to patients with porphyria.

Antibiotic-associated colitis and pseudomembranous colitis have been reported with the use of nearly all antibacterial agents, including sodium colistimethate. The severity may range from mild to life-threatening. This diagnosis should be considered in patients who develop diarrhea during or after treatment with sodium colistimethate. Discontinuation of therapy and initiation of specific treatment for Clostridium difficile may be required. Medicinal products that inhibit peristalsis should not be used.

Intravenous sodium colistimethate does not cross the blood-brain barrier in clinically significant amounts. Intrathecal or intraventricular administration of sodium colistimethate for the treatment of meningitis has not been systematically studied in clinical trials; only case reports support its use. Data on dosing are very limited. The most frequently observed adverse effect with use of colistimethate has been aseptic meningitis.

Inhalation of sodium colistimethate may cause cough or bronchospasm. The first dose should be administered under medical supervision. Use of the recommended dose of a bronchodilator (e.g., a β2-agonist) is recommended, especially if this is part of the patient's current therapeutic regimen. Bronchial hyperreactivity in the presence of a bronchodilator may indicate an allergic reaction, and administration of colistimethate should be discontinued. Bronchospasm that occurs requires treatment.

The instructions for use of the medicinal product must not be disregarded, as this may harm health.

Use during pregnancy or breastfeeding.

There are insufficient data on the use of sodium colistimethate in pregnant women. Single-dose studies in pregnant women have shown that sodium colistimethate crosses the placental barrier; therefore, there may be a risk of fetotoxicity if administered during pregnancy.

Data on the potential genotoxicity of the drug are limited, and data on carcinogenicity of sodium colistimethate are lacking. In vitro studies have demonstrated that sodium colistimethate causes chromosomal aberrations in human lymphocytes. This effect may be related to a reduction in the mitotic index, which was also observed.

Sodium colistimethate may be used during pregnancy only if the benefit outweighs the potential risk.

Sodium colistimethate passes into breast milk. Sodium colistimethate may be used during breastfeeding only if clearly necessary.

Ability to affect reaction speed when driving or operating machinery.

Neurotoxicity, including dizziness, confusion, and visual disturbances, may develop during parenteral treatment with sodium colistimethate. Patients should be advised to avoid driving or operating machinery if such effects occur.

Method of Administration and Dosage.

SYSTEMIC USE

The dose of the medicinal product and duration of treatment depend on the severity of the infection and the patient's clinical response. Therapeutic recommendations should be followed.

The dose of the medicinal product is expressed in international units (IU) of sodium colistimethate. The table below provides conversion of IU of sodium colistimethate into milligrams (mg) of sodium colistimethate, as well as into mg of colistin base activity (CBA).

Dosage conversion. In the European Union, the dose of sodium colistimethate is prescribed and administered exclusively in IU. The product labeling indicates the number of IU per vial. Confusion and medication errors have occurred due to different expressions of the dose related to the content of the active substance. In the United States and other regions of the world, the dose is expressed in milligrams of colistin base activity (mg CBA). The conversion table below is provided for informational purposes only, and the values should be considered nominal and approximate.

Table 2

Conversion of dosage units for sodium colistimethate

Active substance content		≈ mass of sodium colistimethate (mg)*
MO	≈ mg BAU
12 500	0.4	1
150 000	5	12
1 000 000	34	80
4 500 000	150	360
9 000 000	300	720

* Nominal content of the active substance in the medicinal product – 12,500 IU/mg.

Dosage

The dosage recommendations below are based on limited population pharmacokinetic data obtained in critically ill patients.

Adults and adolescents

Maintenance dose – 9 million IU per day, divided into 2–3 doses.

Critically ill patients should receive a loading dose of 9 million IU. The optimal time interval to the first maintenance dose has not been established.

Modeling suggests that patients with normal renal function may require loading and maintenance doses of up to 12 million IU in some cases. However, clinical experience with such doses is extremely limited, and their safety has not been established.

The loading dose should be administered to patients with normal and impaired renal function, including those undergoing hemodialysis.

Renal impairment

Dosage adjustment is required in patients with renal impairment; however, pharmacokinetic data available for patients with reduced renal function are very limited.

For patients with creatinine clearance < 50 mL/min, the following dosage adjustment is recommended.

Table 3

Dosage adjustment according to creatinine clearance

Creatinine clearance	Daily dose
< 50–30	5.5–7.5 million IU
< 30–10	4.5–5.5 million IU
< 10	3.5 million IU

For patients with creatinine clearance < 50 mL/min, the recommended dosing regimen is twice daily.

Hemodialysis and continuous hemodiafiltration

Colistin is likely eliminated by dialysis via conventional hemodialysis and continuous venovenous hemodiafiltration. There are very limited data from population pharmacokinetic studies involving a small number of hemodialysis patients. It is not possible to provide definitive dosing recommendations. The following regimens may be used.

Hemodialysis. On non-dialysis days: 2.25 million IU daily (2.2–2.3 million IU daily). On hemodialysis days: 3 million IU daily, administered after the hemodialysis session. The recommended frequency is twice daily.

Continuous venovenous hemodiafiltration. As in patients with normal renal function. The recommended frequency is three times daily.

Hepatic impairment

There are no data regarding patients with hepatic impairment. Colistimethate sodium should be used with caution in these patients.

Elderly patients

Dose adjustment is not required in elderly patients with normal renal function.

Children

Data on pediatric dosing are very limited. Renal maturity should be taken into account when determining dosage. The dose should be based on lean body weight.

Children ≤ 40 kg: 75,000–150,000 IU/kg/day, divided into three doses.

For children with body weight above 40 kg, adult dosing recommendations should be followed.

Doses > 150,000 IU/kg/day have been reported in children with cystic fibrosis.

There are no data on the use or size of loading dose in critically ill children.

There are no dosing recommendations for children with impaired renal function.

Method of administration

Colomycin Injection is administered intravenously as a slow infusion over 30–60 minutes. Patients with a totally implanted venous access device (TIVAD) may tolerate a bolus injection of up to 2 million IU in 10 mL, administered over at least 5 minutes.

Colistimethate sodium undergoes hydrolysis to the active substance colistin in aqueous solution. When preparing the dose, especially if combining several vials, reconstitution must be performed under strict aseptic technique.

AEROSOL INHALATION

Inhaled colistimethate sodium is recommended to be used under the supervision of a physician experienced in its use.

Dose

The dose may be adjusted according to the severity of illness and clinical response.

The following doses are recommended.

Inhalation administration

Adults, adolescents, and children aged ≥ 2 years

1–2 million IU 2–3 times daily (maximum dose – 6 million IU/day).

Children under 2 years of age

0.5–1 million IU twice daily (maximum dose – 2 million IU/day).

Appropriate clinical guidelines regarding treatment regimen, including duration of therapy, frequency, and concomitant use of other antibacterial agents, should be followed.

Elderly patients

Dose adjustment is not required.

Renal impairment

Dose adjustment is not required; however, caution is necessary when administering to patients with renal impairment.

Hepatic impairment

Dose adjustment is not required.

Method of administration

Administered by inhalation.

Colistimethate sodium undergoes hydrolysis to the active substance colistin in aqueous solution. If other treatments are used, they should be administered according to the physician's recommendations. See the dose conversion table above.

Preparation of solution

For bolus injection

Reconstitute the vial contents with no more than 10 mL of water for injections or 0.9% sodium chloride solution.

For infusion

The reconstituted contents of the vial may be further diluted, usually with 50 mL of 0.9% sodium chloride solution.

For nebulizer inhalation

Reconstitute the vial contents with water for injections to obtain a hypotonic solution, or with a 50:50 mixture of water for injections and 0.9% sodium chloride solution to obtain an isotonic solution, or with 0.9% sodium chloride solution to obtain a hypertonic solution.

The reconstitution volume should comply with the nebulizer device instructions, usually not exceeding 4 mL.

The nebulized solution may be aerosolized into open air or through a filter. The nebulizer should be used in a well-ventilated room.

During reconstitution, gentle shaking is recommended to avoid foam formation.

The solution is intended for single use only, and any unused portion must be discarded.

Reconstituted solutions

Hydrolysis of colistimethate is significantly increased upon reconstitution and dilution below the critical micelle concentration of approximately 80,000 IU/mL. Solutions with lower concentrations must be used immediately.

For solutions intended for bolus injection or inhalation, chemical and physical stability of the reconstituted solution in the original vial at concentrations ≥ 80,000 IU/mL has been demonstrated for 24 hours at 2–8 °C.

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

If the solution is not used immediately, responsibility for the storage duration and conditions of the ready-to-use solution lies with the user.

Infusion solutions that have been diluted beyond the original vial volume and/or at concentrations < 80,000 IU/mL must be used immediately.

Children. May be used from birth.

Overdose.

Overdose of the drug may cause neuromuscular blockade, which in turn may lead to muscle weakness, apnea, and respiratory arrest. Overdose may cause acute renal failure, characterized by decreased urine output and increased plasma concentrations of BUN (blood urea nitrogen) and creatinine.

There is no specific antidote. Supportive therapy is recommended. Measures to enhance colistin elimination, such as forced diuresis using mannitol, prolonged hemodialysis, or peritoneal dialysis, may be considered, although their efficacy is unknown.

Adverse Reactions

The likelihood of developing adverse reactions may be related to age, renal function, and the patient's condition.

Neurological reactions have been reported in 27% of patients with cystic fibrosis. These reactions were usually mild and resolved spontaneously during or after discontinuation of treatment.

Neurotoxicity may be associated with overdosage, insufficient dose reduction in patients with renal impairment, or concomitant use of neuromuscular blockers or other drugs with similar neurological effects. Dose reduction may alleviate these symptoms. Adverse effects may include apnea, transient sensory disturbances (such as facial paresthesia and dizziness), pruritus, urticaria, ataxia, hypotension, and rarely vasomotor instability, slurred speech, visual disturbances, confusion, or psychosis.

Renal adverse effects (including renal dysfunction) usually occurred after administration of doses exceeding the recommended ones in patients with normal renal function, due to insufficient dose adjustment in patients with renal impairment, or as a result of concomitant use of other nephrotoxic drugs. These reactions are usually reversible upon discontinuation of treatment.

Cases of pseudo-Bartter syndrome have been reported with unknown frequency following intravenous administration of sodium colistimethate (see section "Special Warnings and Precautions for Use").

In patients with cystic fibrosis treated with recommended doses of the drug, nephrotoxic reactions occurred rarely (less than 1% of patients). Signs of nephrotoxicity were reported in approximately 20% of severely ill hospitalized patients without cystic fibrosis.

Hypersensitivity reactions, including skin rash and drug fever, have been reported. If such symptoms occur, treatment with the drug should be discontinued.

Irritation may occur at the injection site.

Inhalation Use

Inhalation may cause cough or bronchospasm.

Reports include sore throat and oral cavity pain, which may be due to Candida albicans infection or hypersensitivity. Skin rash may also indicate hypersensitivity. If such symptoms occur, treatment should be discontinued.

Reporting suspected adverse reactions. All suspected adverse reactions and cases of lack of drug efficacy should be reported via the following link: https://aisf.dec.gov.ua

**Shelf life. **3 years.

Storage conditions. Store in the original packaging at a temperature not exceeding 25 °C, out of reach of children.

Incompatibilities.

Mixed infusions, injections, or inhalations containing sodium colistimethate should be avoided.

Packaging.

10 vials per cardboard box.

Vials are stoppered with chlorobutyl rubber closures and sealed with an aluminum crimp cap with a red flip-off plastic cap for the 1,000,000 IU dose and a lilac flip-off plastic cap for the 2,000,000 IU dose.

Prescription category. Prescription only.

Manufacturers.

Milmount Healthcare Limited.

Merckle GmbH.

Manufacturers' addresses and locations of operations.

Block 7, City North Business Campus, Stamullen, K32 YD60, Ireland.

Ludwig-Merckle-Strasse 3, 89143 Blaubeuren, Germany.