Colistin zentiva

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT COLISTIN ZENTIVA

Composition:

Active substance: colistimethate;

1 vial contains 1,000,000 IU or 2,000,000 IU of sterile sodium colistimethate;

1 vial of the medicinal product contains sodium of not less than 1 mmol (23 mg).

Pharmaceutical form. Powder for solution for injection or infusion.

Main physicochemical characteristics: white or almost white powder.

Pharmacotherapeutic group.

Antibacterial agents for systemic use. ATC 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 bacterial cell membranes. As a result, their physiological effect is lethal to bacteria. Polymyxins selectively act against Gram-negative bacteria, which have a hydrophobic outer membrane.

Resistance

Resistant bacteria are characterized by modification of the phosphate groups of lipopolysaccharides, which are substituted with 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 antimicrobial agents.

Pharmacokinetic/pharmacodynamic relationship

The bactericidal activity of polymyxins against susceptible bacteria has been shown to be concentration-dependent. The AUC (area under the concentration-time curve)/MIC (minimum inhibitory concentration) ratio is considered to correlate with clinical efficacy.

Table 1

EUCAST* susceptibility 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 patterns should be obtained, especially when treating severe infections. If necessary, when local resistance prevalence renders the usefulness of the drug questionable for certain types of infections, professional consultation should be sought.

Usually 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 and may be reached up to 7 hours after administration of sodium colistimethate in critically ill patients.

Gastrointestinal absorption in healthy volunteers is minimal.

When administered via 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 ranged from zero to potentially therapeutic levels of 4 mg/L or higher. Therefore, systemic absorption should always be considered possible when administered 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; with declining 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, 60–70% of sodium colistimethate is excreted unchanged in urine within 24 hours.

Elimination of the active colistin is not well characterized. Colistin undergoes substantial renal tubular reabsorption and may be eliminated via extrarenal pathways or undergo renal metabolism, potentially leading to 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 approximately 3 L/hour. In critically ill patients, the elimination half-life is prolonged to approximately 9–18 hours.

Clinical characteristics.

Indications.

Intravenous administration of the drug 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.

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

Contraindications.

Hypersensitivity to sodium colistimethate (colistin) or polymyxin B.

Interaction with other medicinal products and other forms of interaction.

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

Concomitant use of different dosage forms of sodium colistimethate should be administered cautiously 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. In in vitro studies with human hepatocytes, 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).

The potential for drug interactions should be considered when Zentiva Colistin is administered 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 used with caution in patients receiving sodium colistimethate, as their effects may be prolonged (see section "Special warnings and precautions for use").

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

Concomitant use 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 administration 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 use 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-dose regimens (> 6,000,000 IU/day), on the use of loading doses, and in special patient populations (patients with renal impairment and children). Sodium colistimethate should be used only when other, more commonly used antibiotics are ineffective or unsuitable.

Renal function should be assessed in all patients at the beginning of treatment and monitored throughout therapy. The dose of sodium colistimethate should be adjusted according to creatinine clearance (see section "Dosage and administration"). 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 (see sections "Interaction with other medicinal products and other forms of interaction", "Undesirable effects"). Cases of renal function impairment have been reported, usually after administration of doses higher than recommended via intravenous or intramuscular routes in patients with normal renal function, or without dose reduction in patients with renal impairment, 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.

Cases of pseudo-Bartter syndrome have been reported in both children and adults following intravenous administration of sodium colistimethate. In suspected cases, monitoring of serum electrolyte levels should be initiated and appropriate treatment administered; 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 renal impairment, have been reported to cause neurotoxic effects such as facial paraesthesia, muscle weakness, vertigo, slurred speech, vasomotor instability, visual disturbances, confusion, psychosis, and apnoea. Dose reduction of colistimethate may alleviate symptoms. Monitoring for perioral paraesthesia and paraesthesia of extremities, which are signs of overdose, is required.

Caution is required when administering sodium colistimethate to infants (under 1 year of age), as renal function in this age group is not yet 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 sodium colistimethate should 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 needed.

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

Particular caution should be exercised when administering the drug to patients with porphyria.

Antibiotic-associated colitis and pseudomembranous colitis have been reported with 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 diarrhoea during or after treatment with sodium colistimethate (see section "Undesirable effects"). Discontinuation of therapy and specific treatment for Clostridium difficile may be required. Antiperistaltic agents should not be used.

Sodium colistimethate does not cross the blood-brain barrier in clinically significant amounts after intravenous administration. 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 administration of sodium colistimethate has been aseptic meningitis (see section "Undesirable effects").

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

Use during pregnancy or breast-feeding.

There are insufficient data on the use of sodium colistimethate in pregnant women. Studies with single doses in pregnant women have shown that sodium colistimethate crosses the placental barrier; therefore, repeated doses administered during pregnancy may pose a risk of fetotoxicity.

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 should be used during pregnancy only if the benefit to the woman outweighs the potential risk to the fetus.

Sodium colistimethate passes into breast milk in low concentrations; therefore, breastfeeding should preferably be discontinued during treatment with this medicinal product.

Ability to affect reaction speed when driving or operating machinery.

Dizziness, confusion, and visual disturbances may occur during treatment with sodium colistimethate. Patients should be advised to avoid driving or operating machinery.

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

Method of administration and dosage.

The dose of the drug 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 expressed in international units (IU) of sodium colistimethate. The conversion table of international units (IU) of sodium colistimethate to milligrams (mg) of sodium colistimethate, as well as to milligrams of colistin base activity (CBA), is provided below.

Table 2

Conversion of dosage units of sodium colistimethate

Active substance content		≈ colistimethate sodium mass (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 – 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 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 both normal and impaired renal function, including those on 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 adjustments are recommended (see Table 3).

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, it is recommended to administer the drug twice daily.

Hemodialysis and continuous hem(o)diafiltration

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

Hemodialysis. Non-hemodialysis days: 2.25 million IU daily (2.2–2.3 million IU daily). Hemodialysis days: 3 million IU daily on hemodialysis days, administered after the hemodialysis session. It is recommended to administer the drug twice daily.

Continuous venovenous hem(o)diafiltration. As in patients with normal renal function. It is recommended to administer the drug three times daily.

Hepatic impairment

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

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

Children

Data on pediatric dosing are very limited. Dose selection should take into account renal maturity. The dose should be based on body muscle mass.

Children ≤ 40 kg. 75,000–150,000 IU/kg/day, divided into 3 doses.

For children with body weight greater than 40 kg, follow the dosing recommendations for adults.

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

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

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

Route of administration

The drug 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 a combination of several vials is required, reconstitution must be performed with strict adherence to aseptic technique.

The dose of colistimethate sodium is prescribed and administered only in IU.

Preparation of solution

For bolus injection

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

For infusion

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

Reconstituted solutions

Hydrolysis of colistimethate significantly increases upon reconstitution and dilution below the critical micelle concentration of approximately 80,000 IU per milliliter. 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, except in cases where the method of opening/reconstitution/dilution excludes the risk of microbial contamination.

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

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

Children.

Can be administered 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 blood urea nitrogen (BUN) and plasma creatinine concentrations.

There is no specific antidote. Supportive therapy is recommended. Measures to enhance the elimination rate of colistin such as forced diuresis using mannitol, prolonged hemodialysis, or peritoneal dialysis may be considered, 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 impairment, and concomitant use of neuromuscular blockers 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 impaired kidney function) usually occurred after 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 administration of other nephrotoxic drugs. These reactions are usually reversible upon discontinuation of treatment.

After intravenous administration of sodium colistimethate, cases of pseudo-Bartter syndrome have been reported with unknown frequency (see section "Special precautions for use").

After intravenous administration of sodium colistimethate, cases of pseudo-Bartter syndrome have been reported with frequency "unknown" (see section "Special precautions for use").

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

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

Hypersensitivity reactions have been reported, including skin rash, drug fever, or angioneurotic edema. If adverse reactions occur, treatment with the drug should be discontinued.

Irritation at the injection site may occur.

Reporting of suspected adverse reactions

Reporting of suspected adverse reactions after marketing authorization is important. It allows continuous monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals should report any suspected adverse reactions.

Incompatibilities

Mixed infusions and injections containing colistimethate sodium should be avoided.

Shelf life 3 years.

Storage conditions

Store at a temperature not exceeding 25 °C.

Keep out of reach and sight of children.

The solution remains physically and chemically stable for 24 hours at 4 °C.

From a microbiological standpoint, the solution should be used immediately. If not used immediately, the user is responsible for the storage duration and conditions. Generally, the solution should be stored for no longer than 24 hours at 2–8 °C, except for reconstituted and diluted solutions prepared under controlled and validated sterile conditions.

Packaging

Powder 1,000,000 IU in a 10 ml vial made of colorless borosilicate glass type I with a red "flip-off" cap.

Powder 2,000,000 IU in a 10 ml vial made of colorless borosilicate glass type I with a pale lilac "flip-off" cap.

1 or 10 vials per cardboard pack.

Prescription status Prescription only.

Manufacturer

Xellia Pharmaceuticals ApS.

Manufacturer's address and place of business

Dalslandsgade 11, 2300 Copenhagen C, Denmark.