Instructions Colomycin injection powder for preparation of solution for injection infusion ing 2000000 IU bottle No. 10
Composition
active ingredient: 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.
Dosage 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.
ATX 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 on aerobic Gram-negative bacteria that have a hydrophobic outer membrane.
Resistance
Resistant bacteria are characterized by modification of the phosphate groups of lipopolysaccharides, which are replaced by ethanolamine or aminoarabinose. Innately resistant Gram-negative bacteria, such as Proteus mirabilis and Burkholderia cepacia, have a complete replacement 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 by the aforementioned mechanism does not imply resistance to other drug groups.
Pharmacokinetics/pharmacodynamics relationship
The bactericidal activity of polymyxins against susceptible bacteria has been reported to be concentration-dependent. The fAUC (area under the curve)/MIC (minimum inhibitory concentration) is believed to correlate with clinical efficacy.
Table 1
EUCAST* breakpoints
| Sensitive (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).
** The breakpoints refer to a dose of 2–3 million IU × 3. A loading dose (9 million IU) may be required.
Sensitivity
The prevalence of acquired resistance may vary geographically and over time for selected bacterial species, and therefore it is desirable to obtain local information on resistance, especially when treating severe infections. Local patterns of resistance to colistimethate sodium should be taken into account when prescribing the medicinal product. If the local prevalence of resistance is such that the utility of the product in certain types of infections is questionable, this should be taken into account and expert advice should be sought.
Typically sensitive species
Acinetobacter baumannii
Haemophilus influenzae
Klebsiella spp.
Pseudomonas aeruginosa
Species for which acquired resistance may be a problem
Stenotrophomonas maltophilia
Achromobacter xylosoxidans (formerly 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 colistimethate sodium and colistin are limited. There is evidence that the pharmacokinetics in critically ill patients differ from those in patients with less severe physiological disorders and in healthy volunteers.
After infusion of colistimethate sodium, the inactive prodrug is converted to active colistin. Peak plasma concentrations of colistin are delayed up to 7 hours after administration of colistimethate sodium in critically ill patients.
Absorption from the gastrointestinal tract in healthy volunteers occurs only to a minor extent.
When the drug was administered by nebulization, uneven absorption was reported, depending on the size of the aerosol particles, the nebulizer system, and the condition of the lungs. In studies involving healthy volunteers and patients with various infections, plasma concentrations of the drug were reported to range from zero to potentially therapeutic concentrations of 4 mg/L and above. Therefore, the possibility of systemic absorption should always be considered when administered by inhalation.
Distribution
The volume of distribution of colistin in healthy volunteers is low and approximately corresponds to the extracellular fluid. The volume of distribution is relatively increased in critically ill patients. Binding to blood proteins is moderate and decreases at higher concentrations. In the absence of meningeal inflammation, penetration into the cerebrospinal fluid is minimal, but increases in the presence of meningeal inflammation.
Both colistimethate sodium and colistin exhibit linear pharmacokinetics in the clinically relevant dosage range.
Approximately 30% of colistimethate sodium is converted to colistin in healthy volunteers. Its clearance is dependent on creatinine clearance, and with decreasing renal function, a greater proportion of colistimethate sodium is converted to colistin. In patients with significantly reduced renal function (creatinine clearance < 30 ml/min), the extent of conversion may reach 60-70%. Colistimethate sodium is excreted by the kidneys by glomerular filtration. In healthy volunteers, 60 to 70% of colistimethate sodium is excreted unchanged in the urine within 24 hours.
The elimination of active colistin is poorly understood. Colistin undergoes significant renal tubular reabsorption and may be excreted extrarenal or undergo renal metabolism with potential for renal accumulation. Colistin clearance is reduced in cases of renal impairment, probably due to increased conversion of colistimethate sodium.
The elimination half-life of colistin in healthy volunteers and patients with cystic fibrosis was approximately 3 and 4 hours, respectively, with a total clearance of approximately 3 L/h. In critically ill patients, the half-life increased to approximately 9–18 hours.
Indication
Intravenous administration of the drug is indicated in adults and children, including neonates, for the treatment of severe infections caused by selected aerobic Gram-negative pathogens in patients with limited treatment options.
The drug in the form of inhalation is also indicated for adults and children with cystic fibrosis for the treatment of chronic pulmonary infections caused by Pseudomonas aeruginosa.
Official recommendations for the appropriate use of antibacterial agents should be followed.
Contraindication
Hypersensitivity to colistimethate sodium (colistin) or to polymyxin B.
Special safety precautions
Inhalation of antibiotics as a procedure may cause bronchospasm. Bronchospasm can be avoided or stopped with appropriate β2-agonists, if this does not help, treatment should be stopped.
Interaction with other medicinal products and other types of interactions
The simultaneous use of colistimethate sodium with other drugs that have neurotoxic and/or nephrotoxic effects requires great caution.
Caution should be exercised when prescribing different formulations of colistimethate sodium simultaneously due to lack of experience and the possibility of cumulative toxicity.
No in vivo interaction studies have been performed. The mechanism of conversion of colistimethate sodium to the active substance, colistin, has not been studied. The mechanism of clearance of colistin, in particular renal metabolism, has also not been described. Colistimethate sodium 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 Colomycin Injection is administered with drugs that inhibit or induce drug-metabolizing enzymes or with drugs that are substrates for renal transport mechanisms.
Given the effect of colistin on acetylcholine release, non-depolarizing muscle relaxants should be administered with caution to patients receiving colistimethate sodium, as their effects may be prolonged.
Caution should be exercised when colistimethate sodium is used concomitantly with macrolide antibiotics such as azithromycin and clarithromycin, or fluoroquinolones such as norfloxacin and ciprofloxacin, in patients with myasthenia gravis.
The concomitant use of colistimethate sodium with other drugs with neurotoxic and/or nephrotoxic potential should be avoided. These include aminoglycoside antibiotics such as gentamicin, amikacin, netilmicin and tobramycin. The risk of nephrotoxicity may be increased when used concomitantly with cephalosporin antibiotics.
Application features
Concomitant use of intravenous colistimethate sodium with another antibacterial agent should be considered, whenever possible, taking into account the susceptibility of the pathogen(s) to the treatment. Since the development of resistance to intravenous colistin has been reported, especially when used as monotherapy, concomitant use with another antibacterial agent should be considered to prevent the development of resistance.
It is recommended that renal function be assessed at the start of treatment and monitored during treatment. The dose of colistimethate sodium should be adjusted according to creatinine clearance. Colistimethate sodium is excreted by the kidneys and is nephrotoxic if high serum concentrations are reached. Patients who are hypovolemic or who are receiving other potentially nephrotoxic drugs are at increased risk of nephrotoxicity from colistin. Renal impairment has been reported, usually after administration of doses higher than those recommended for intravenous or intramuscular administration in patients with normal renal function, or without dose reduction for intravenous or intramuscular administration 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 potentially increased risk of nephrotoxicity.
Several cases of pseudo-Bartter syndrome have been reported in children and adults with intravenous colistimethate sodium. If such cases are suspected, serum electrolyte monitoring should be initiated and appropriate treatment should be instituted, but normalization of the electrolyte imbalance may not be achieved without discontinuation of colistimethate sodium.
High serum concentrations of colistimethate sodium, which may be associated with overdose or lack of dose reduction in patients with renal impairment, have been reported to result in neurotoxic effects such as facial paresthesia, muscle weakness, vertigo, slurred speech, vasomotor instability, visual disturbances, confusion, psychosis and apnea. Reduction of the colistimethate dose may alleviate symptoms. Monitoring for perioral and limb paresthesias, which are signs of overdose, is necessary. Neurotoxic reactions are unlikely to occur with inhalation therapy, but patients (especially those with renal impairment) should be observed for these reactions and renal function should be monitored.
Caution is advised when administering colistimethate sodium to infants (under 1 year of age) as renal function in this age group is not yet mature. Furthermore, the effect of immature renal and metabolic function on the conversion of colistimethate sodium to colistin is unknown.
If an allergic reaction occurs, treatment with colistimethate sodium should be discontinued and appropriate measures taken.
Colistimethate sodium is known to reduce the presynaptic release of acetylcholine at the neuromuscular junction, so it should be used with extreme caution in patients with myasthenia gravis (due to the possibility of neuromuscular blockade) and only in case of urgent need.
Respiratory arrest has been reported following intramuscular administration of colistimethate sodium. Impaired renal function increases the likelihood of apnea and neuromuscular blockade following administration of colistimethate sodium.
Special caution should be exercised when using the drug in patients with porphyria.
Antibiotic-associated colitis and pseudomembranous colitis have been reported with nearly all antibacterial agents and may occur with colistimethate sodium. They may range in severity from mild to life-threatening. This diagnosis should be considered in patients who develop diarrhoea during or after the use of colistimethate sodium. Discontinuation of therapy and specific measures for the treatment of Clostridium difficile may be necessary. Medicinal products that inhibit peristalsis should not be used.
When administered intravenously, colistimethate sodium does not cross the blood-brain barrier in clinically significant amounts. Intrathecal or intraventricular use of colistimethate sodium for the treatment of meningitis has not been systematically studied in clinical trials, and only isolated case reports support its use. Data on dosage are very limited. The most common adverse event observed with colistimethate sodium is aseptic meningitis.
Inhalation of colistimethate sodium may cause coughing or bronchospasm. It is recommended that the first dose be administered under medical supervision. It is recommended that the recommended amount of bronchodilator (e.g., β2-agonist) be used, especially if this is part of the patient's current therapeutic regimen. Bronchial hyperresponsiveness in the presence of a bronchodilator may indicate an allergic reaction and colistimethate should be discontinued. Bronchospasm that occurs should be treated.
You should not violate the rules for using the medicine, this may harm your health.
Use during pregnancy or breastfeeding
Data on the potential genotoxicity of colistimethate sodium are limited and no data on the carcinogenicity of colistimethate sodium are available. Colistimethate sodium has been shown to cause chromosomal aberrations in human lymphocytes in vitro. This effect may be related to the reduction in mitotic index that was also observed.
Colistimethate sodium should be used during pregnancy only if the benefit outweighs the potential risk.
Colistimethate sodium passes into breast milk. Colistimethate sodium should be used during breastfeeding only if clearly needed.
Ability to influence reaction speed when driving vehicles or other mechanisms
Neurotoxicity, including dizziness, confusion and visual disturbances, may occur during parenteral treatment with colistimethate sodium. Patients should be advised to avoid driving or operating machinery if these effects occur.
Method of administration and doses
SYSTEMIC APPLICATION
The dose 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 drug is indicated in international units (IU) of colistimethate sodium. The table for converting IU of colistimethate sodium into milligrams (mg) of colistimethate sodium, as well as into mg of colistin base activity (BAA), is given below.
Dose conversion. In the EU, colistimethate sodium is dosed and administered in IU only. The product label indicates the number of IU per vial. Confusion and medical errors have arisen due to different expressions of dose in relation to the active substance content. In the USA and other regions of the world, the dose is stated in milligrams of colistin base activity (mg BAA). The unit conversion table is provided for information only and should be considered nominal and approximate.
Table 2
Conversion of colistimethate sodium dose units
| Active ingredient content | ≈ mass of colistimethate sodium (mg)* |
| MO | ≈ mg LBC |
| 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 drug substance is 12,500 IU/mg.
Dose
The following dosage recommendations are based on limited population pharmacokinetic data obtained in critically ill patients.
Adults and adolescents
The maintenance dose is 9 million IU per day, divided into 2–3 doses.
A loading dose of 9 million IU should be administered to critically ill patients. The most appropriate time interval to the first maintenance dose has not been established.
Modeling suggests that loading and maintenance doses of up to 12 million IU may be required in some cases in patients with normal renal function. However, clinical experience with such doses is extremely limited and their safety has not been established.
A loading dose is used in patients with normal and reduced renal function, including those on hemodialysis.
Kidney dysfunction
Dosage adjustment is necessary in patients with impaired renal function, however, pharmacokinetic data available in 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 based on 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, twice daily dosing is recommended.
Hemodialysis and continuous hemo(dia)filtration
Colistin is likely to be dialysable by conventional haemodialysis and continuous venovenous haemo(dia)filtration. There are very limited data from population pharmacokinetic studies with a small number of haemodialysis patients. No clear dose recommendations can be given. The following regimens may be used.
Hemodialysis. Non-hemodialysis days: 2.25 million IU/day (2.2–2.3 million IU/day). Hemodialysis days: 3 million IU/day on hemodialysis days, administered after hemodialysis session. Twice daily administration is recommended.
Continuous venovenous hemo(dia)filtration. As in patients with normal renal function. Recommended to be used three times daily.
Liver failure
There are no data in patients with hepatic impairment. Colistimethate sodium should be used with caution in these patients.
Elderly patients
No dose adjustment is necessary for elderly patients with normal renal function.
Children
Dosage data for children are very limited. When selecting a dose, renal maturity should be taken into account. The dose should be based on lean body mass.
Children ≤ 40 kg: 75,000–150,000 IU/kg/day, divided into 3 doses.
For children weighing more than 40 kg, the adult dosage recommendations should be followed.
There are no data on the use or size of the loading dose for critically ill children.
There are no dosage recommendations for children with reduced kidney function.
Method of application
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. For the preparation of a dose, especially if a combination of several vials is required, the reconstitution of the required dose should be carried out with strict adherence to aseptic technique.
AEROSOL INHALATION
Colistimethate sodium inhalation is recommended to be used under the supervision of a physician with appropriate experience in its use.
Dose
The dose may be adjusted depending on the severity of the condition and clinical response.
The following doses are recommended.
Inhalation
Adults, adolescents and children aged ≥ 2 years
1–2 million IU 2–3 times a day (maximum dose – 6 million IU/day).
Children < 2 years old
0.5–1 million IU 2 times a day (maximum dose – 2 million IU/day).
Appropriate clinical guidelines regarding treatment regimens, including duration of treatment, frequency, and concomitant use of other antibacterial agents, should be followed.
Elderly patients
No dose adjustment is necessary.
Kidney failure
No dose adjustment is required, however, caution is required when used in patients with renal insufficiency.
Liver failure
No dose adjustment is necessary.
Method of application
It is used in the form of inhalations.
Colistimethate sodium is hydrolyzed to the active ingredient colistin in aqueous solution. If other treatment is used, it should be used as recommended by a physician. See dose conversion table above.
Solution preparation
For bolus injection
Reconstitute the contents of the vial with no more than 10 ml of water for injections or 0.9% sodium chloride solution.
For infusion
The contents of the vial after reconstitution can be diluted, usually with 50 ml of 0.9% sodium chloride solution.
For inhalation using a nebulizer
Reconstitute the contents of the vial 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 be in accordance with the instructions for use of the nebulizer device, usually no more than 4 ml.
You can spray the solution from the nebulizer into the open air or through a filter. The nebulizer should be used in a well-ventilated room.
During reconstitution, shake gently to avoid foaming.
The solution is for single use only and any remaining solution should be discarded.
Reconstituted solutions
Hydrolysis of colistimethate is significantly increased by reconstitution and dilution below the critical micelle concentration of approximately 80,000 IU per ml. Solutions with lower concentrations should be used immediately.
For solutions for bolus injection or inhalation, chemical and physical in-use stability of the reconstituted solution in the original vial, at a concentration ≥ 80,000 IU/mL, has been demonstrated for 24 hours at 2–8°C.
From a microbiological point of view, the solution should be used immediately unless the method of opening/reconstitution/dilution precludes the risk of microbial contamination.
If not used immediately, in-use storage times and conditions prior to use are the responsibility of the user.
Infusion solutions that have been diluted beyond the original vial volume and/or with a concentration < 80,000 IU/mL should be used immediately.
Children. Apply to children 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 ASA (blood urea nitrogen) and creatinine.
There is no specific antidote. Supportive care is recommended. Measures to increase the rate of colistin excretion, such as forced diuresis with mannitol, prolonged hemodialysis, or peritoneal hemodialysis, may be used, but their effectiveness is unknown.
Side effects
The likelihood of developing adverse events may be related to age, renal function, and the patient's condition.
Neurotoxicity may be associated with overdose, insufficient dose reduction in patients with renal insufficiency, and concomitant use of neuromuscular blocking agents 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 reactions (including renal dysfunction) have generally occurred after doses exceeding the recommended dose in patients with normal renal function, or due to insufficient dose reduction in patients with renal insufficiency, or as a result of concomitant use of other nephrotoxic drugs. These reactions are usually reversible upon discontinuation of treatment.
Pseudo-Bartter syndrome has been reported with an unknown frequency following intravenous administration of colistimethate sodium (see section 4.4).
In patients with cystic fibrosis treated with recommended doses of the drug, nephrotoxicity reactions occurred rarely (less than 1% of patients). In critically ill hospitalized patients without cystic fibrosis, signs of nephrotoxicity were reported in approximately 20% of cases.
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 coughing or bronchospasm.
Sore throat and mouth have been reported, which may be due to Candida albicans infection or hypersensitivity. Skin rashes may also indicate hypersensitivity. If such symptoms occur, treatment should be discontinued.
Reporting of suspected adverse reactions. All cases of suspected adverse reactions and lack of efficacy of the drug should be reported via the link: https://aisf.dec.gov.ua
Expiration date
3 years.
Storage conditions
Store in the original packaging at a temperature not exceeding 25 °C, out of the reach of children.
Incompatibility
Mixed infusions, injections and inhalations containing colistimethate sodium should be avoided.
Packaging
10 bottles in a cardboard box.
The vials are closed with chlorobutyl rubber stoppers and sealed with an aluminum crimp cap with a red plastic flip-off cap for the 1,000,000 IU dosage and with a purple plastic flip-off cap for the 2,000,000 IU dosage.
Vacation category
According to the recipe.
Producer
Millmount Healthcare Limited.
Merkle GmbH.
Location of manufacturers and addresses of their place of business.
Unit 7, City North Business Campus, Stamullen, K32 YD60, Ireland.
Ludwig-Merkle-Strasse 3, 89143 Blaubeuren, Germany.
