Instructions Colistin Zentiva powder for solution for injection or infusion 2000000 IU vial No. 10
Composition
active ingredient: colistimethate;
1 vial contains sterile colistimethate sodium 1,000,000 IU or 2,000,000 IU;
1 vial of the drug contains not less than 1 mmol (23 mg) of sodium.
Dosage form
Powder for solution for injection or infusion.
Main physicochemical properties: white or almost white powder.
Pharmacotherapeutic group
Antibacterials for systemic use. ATX code J01X B01.
Pharmacological properties
Pharmacodynamics.
Mechanism of action
Colistimethate sodium is a cyclic polypeptide antibiotic derived from Bacillus polymyxa var. colistinus and belongs to the polymyxin group. Polymyxin antibiotics are cationic agents that act by damaging cell membranes. As a result, their physiological effect is lethal to bacteria. Polymyxins act selectively on 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 is different 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 shown to be concentration-dependent. The AUC (area under the pharmacokinetic concentration-time 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.
Checkpoints
The proposed general MIC for the identification of bacteria susceptible to colistimethate sodium is ≤ 4 mg/L.
Bacteria for which the colistimethate sodium MIC is ≥ 8 mg/L are considered resistant.
Sensitivity
The prevalence of acquired resistance may vary geographically and over time for the selected bacterial species, and therefore it is advisable to obtain local information on resistance, particularly when treating severe infections. If necessary, if the local prevalence of resistance is such that the benefit of the drug in some types of infections is questionable, professional advice should be sought.
The most sensitive species:
Acinetobacter*spp., Citrobacter spp., Escherichia coli, Haemophilus influenzae, Pseudomonas aeruginosa.
Typically susceptible species: Acinetobacter baumannii, Haemophilus influenza, Klebsiella spp., Pseudomonas aeruginosa.
Species for which acquired resistance may be problematic:
Stenotrophomonas maltophilia, Achromobacter xylosoxidans (formerly known as Alcaligenes xylosoxidans).
Naturally resistant organisms:
Burkholderia cepacia and related species, Proteus species, Providencia species, Serratia species.
Anaerobes: all gram-positive microorganisms.
*In vitro results may not correlate with clinical efficacy in the case of Acinetobacter spp.
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 complex physiological disorders and in healthy volunteers. The following data are based on studies using high-performance liquid chromatography (HPLC) to determine the plasma concentrations of colistimethate sodium/colistin.
After infusion of colistimethate sodium, the inactive prodrug is converted to the active colistin. The maximum plasma concentration (Cmax) of colistin is reached with a delay of up to 7 hours after administration of colistimethate sodium in critically ill patients.
Absorption from the digestive tract in healthy volunteers occurs only to a minor extent.
Distribution
In patients with cystic fibrosis, after administration of 7.5 mg/kg/day in divided doses administered as a 30-minute intravenous infusion until stable, Cmax was 23±6 mg/L and Cmin was 4.5±4 mg/L after 8 hours. In another study in which 2 million units were administered every 8 hours for 12 days, Cmax was 12.9 mg/L (range 5.7-29.6 mg/L) and Cmin was 2.76 mg/L (range 1-6.2 mg/L). In healthy volunteers given a bolus injection of 150 mg (approximately 2 million units), Cmax of 18 mg/L was observed 10 minutes after injection.
Both colistimethate sodium and colistin exhibit linear pharmacokinetics in the clinically relevant dosage range.
Breeding
Approximately 30% of colistimethate sodium is converted to colistin in healthy volunteers. Its clearance depends on creatinine clearance, with a decrease in renal function, a greater part of colistimethate sodium is converted to colistin. In patients with significantly reduced renal function (creatinine clearance < 30 ml/min), the 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/hour. In critically ill patients, the half-life increased to approximately 9–18 hours.
Binding to blood proteins is insignificant. Polymyxins accumulate in the liver, kidneys, brain, heart and muscles.
In studies in patients with cystic fibrosis, the steady-state volume of distribution was 0.09 l/kg.
In vivo, colistimethate sodium is converted to the base. Since 80% of the dose can be found in the urine as unchanged drug and the drug is not excreted in the bile, it can be assumed that the remaining drug is inactivated in the tissues. The mechanism of inactivation is unknown.
The main route of elimination after parenteral administration is renal excretion. 40% of a parenteral dose is recovered in the urine within 8 hours and approximately 80% after 24 hours. Since colistimethate sodium is largely excreted in the urine, patients with renal insufficiency require a dose reduction to prevent accumulation of the drug.
After intravenous administration to healthy adult volunteers, the elimination half-life is approximately 1.5 hours. In a study in which patients with cystic fibrosis were administered a single 30-minute intravenous infusion, the half-life was 3.4 ± 1.4 hours.
The kinetics of colistimethate sodium are similar in children and adults, including the elderly, provided that renal function is normal. Although data on the use of the drug in infants are limited, it is assumed that the kinetics of the drug in infants are similar to those in children and adults, but it should be borne in mind that there may be a higher maximum serum concentration and a longer half-life in such patients, and therefore it is necessary to monitor the level of the drug in the blood serum.
Indication
Treatment of certain severe infections caused by Gram-negative bacteria, including lower respiratory tract and urinary tract infections, when more widely used systemic antibacterial agents are contraindicated or ineffective due to the development of bacterial resistance.
Contraindication
Hypersensitivity to colistimethate sodium (colistin) or to polymyxin B.
The patient has myasthenia gravis.
Interaction with other medicinal products and other types of interactions
The simultaneous use of colistimethate sodium with other drugs that exhibit 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 Colistin Zentiva is administered with drugs that inhibit or induce drug-metabolizing enzymes or with drugs 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 colistimethate sodium, as their effects may be prolonged (see section 4.4).
Caution should be exercised when colistimethate sodium is administered 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.
Neuromuscular blocking agents and diethyl ether should be used with extreme caution in patients receiving colistimethate sodium.
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.
Clinical data on the efficacy and safety of intravenous colistimethate sodium are limited. The 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) and loading doses, and in special patient groups (patients with renal impairment and children). Colistimethate sodium should only be used when other, more commonly used antibiotics are ineffective or unacceptable.
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 (see section 4.2). Colistimethate sodium is excreted by the kidneys and is nephrotoxic if high serum concentrations are reached. Patients with hypovolemia or those receiving other potentially nephrotoxic drugs are at increased risk of nephrotoxicity from colistin (see sections 4.5 and 4.8). Renal impairment has been reported, usually after higher than recommended doses given intravenously or intramuscularly in patients with normal renal function, or in the absence of dose reduction given intravenously or intramuscularly 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 benefits of prolonged treatment should be weighed against the potentially increased risk of nephrotoxicity.
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. Reducing the colistimethate dose may alleviate symptoms. Monitoring for perioral and limb paresthesias, which are signs of overdose, is necessary.
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 great caution in patients with myasthenia gravis (due to the possibility of neuromuscular blockade) and only when absolutely necessary.
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 (see section 4.8). 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 administration 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 reaction observed with colistimethate sodium is aseptic meningitis (see section 4.8).
If Clostridium difficile-associated diarrhea is suspected or confirmed, antibiotic therapy that is not effective against Clostridium difficile should be discontinued. Appropriate fluid and electrolyte replacement, protein supplementation, antibiotic therapy to which Clostridium difficile is sensitive, and surgical evaluation should be considered as clinically indicated. Antiperistaltic drugs are contraindicated in such cases.
This medicine contains less than 1 mmol sodium (23 mg) per vial, i.e. essentially 'sodium-free'.
Use during pregnancy or breastfeeding
There are no adequate data from the use of colistimethate sodium in pregnant women. A single-dose study in pregnant women has shown that colistimethate sodium crosses the placental barrier, and therefore there may be a risk of fetotoxicity when repeated doses are administered to pregnant women.
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 to the woman outweighs the potential risk to the fetus.
Colistimethate sodium passes into breast milk in small concentrations, so breastfeeding should be discontinued during treatment with the drug.
Ability to influence reaction speed when driving vehicles or other mechanisms
Dizziness, confusion and visual disturbances may occur during treatment with colistimethate sodium. Patients should be advised to avoid driving or operating machinery.
You should not violate the rules for using the medicine, as this may harm your health.
Method of administration and doses
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 milligrams of colistin base activity (BAA), is given below.
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, it is recommended to use the drug twice daily.
For patients with creatinine clearance < 50 mL/min, the following dosage adjustment is recommended (see Table 3).
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
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 dosage 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. It is recommended to administer twice daily.
Continuous venovenous hemo(dia)filtration. As in patients with normal renal function. Recommended to be used 3 times daily.
Liver failure
There are no data in patients with hepatic impairment. Colistimethate sodium should be used with caution in these 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.
Doses >150,000 IU/kg/day have been reported in children with cystic fibrosis.
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.
Intrathecal and intragastric administration
Based on limited data, a dose of 125,000 IU/day is recommended for adults.
Doses for intrathecal administration should not exceed the recommended doses for intragastric administration.
There are no specific dosage recommendations in children for intrathecal and intragastric administration.
Method of application
The drug is administered intravenously as a slow infusion over 30–60 minutes.
Patients with a totally implanted venous access device (TIVAD) can 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.
The dose of colistimethate sodium is prescribed and used only in MO.
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 diluted with 50 ml of 0.9% sodium chloride solution.
Reconstituted solutions
Hydrolysis of colistimethate is significantly increased by reconstitution and dilution below the critical micelle concentration of approximately 80,000 IU per milliliter. 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 of ≥ 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.
Used for 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 blood urea nitrogen (BUN) and creatinine concentrations in the blood plasma.
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 reactions 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 reactions 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 a frequency of "not known" 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.
Neurological reactions were reported in 27% of patients with cystic fibrosis. These reactions were usually mild and resolved spontaneously during or after treatment discontinuation.
Hypersensitivity reactions have been reported, including skin rash, drug fever, or angioedema. If adverse reactions occur, treatment with the drug should be discontinued.
Irritation may occur at the injection site.
Immune system disorders: hypersensitivity reactions such as skin rashes and angioedema.
Nervous system: neurotoxicity (facial and oral paresthesias), headache, muscle weakness, dizziness, ataxia.
Skin: itching.
From the urinary system: renal dysfunction caused by an increase in blood creatinine and/or urea and/or a decrease in creatinine clearance; renal failure.
General disorders and administration site conditions: injection site reactions.
Reporting of suspected adverse reactions
Reporting of suspected adverse reactions after the registration of a medicinal product is important. It allows monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals should report any suspected adverse reactions.
Incompatibility.
Mixed infusions and injections containing colistimethate sodium should be avoided.
Expiration date
3 years.
Storage conditions
Store at a temperature not exceeding 25 °C.
Keep out of reach of children.
The solution remains physically and chemically stable for 24 hours at 4 °C.
From a microbiological point of view, the solution should be used immediately. If not used immediately, in-use storage times and conditions prior to use are the responsibility of the user. The solution would normally not be stored longer than 24 hours at 2-8°C, unless reconstituted or diluted in controlled and validated sterile conditions.
Packaging
10 ml in a colorless borosilicate glass type I bottle with a red flip-off cap. 1 or 10 bottles in a cardboard box.
Vacation category
According to the recipe.
Producer
Xellia Pharmaceuticals ApS.
Location of the manufacturer and address of its place of business.
Dalslandsgade 11, 2300 Copenhagen S, Denmark.
