XYLISTIN FORTE PLUS Injection (Colistimethate sodium)

Table of Content

The increasing prevalence of MDR Gram Negative Bacteria (GNB) especially Pseudomonas aeruginosa and Acinetobacter baumannii in India and worldwide, has led to re-evaluation of colistin in clinical practice. Colistimethate sodium was introduced in India in 2008 as Xylistin (1 MIU) and in 2011 as XYLISTIN FORTE (2MIU).

However, pharmacokinetic study conducted by Cipla Ltd. suggests the need for higher dosing especially for MDR Pseudomonal infections. Cipla launches XYLISTIN FORTE PLUS (3 MIU) in India.

Qualitative and Quantitative Composition

Each vial contains:

Colistimethate Sodium IP……………………….30,00,000 IU

(IU: International Units)

Dosage Form(S) and Strength(S)

Powder for solution for injection and infusion

30,00,000 IU

Clinical Particulars

Therapeutic Indications

XYLISTIN FORTE PLUS is indicated in the treatment of the following infections, where sensitivity testing suggests that they are caused by bacteria susceptible to colistin:

  • Intravenous administration for the treatment of some serious infections caused by Gram-negative bacteria, including those of the lower respiratory tract and urinary tract, when more commonly used systemic antibacterial agents may be contraindicated or may be ineffective because of bacterial resistance.

Posology and Method of Administration

Posology

The dose to be administered and the treatment duration should take into account the severity of the infection as well as the clinical response. Therapeutic guidelines should be adhered to. The dose is expressed in IU of colistimethate sodium (CMS).  The following dose recommendations are made based on limited population- pharmacokinetic data in critically ill patients.

Adults and Adolescents

Maintenance dose 9 million IU (MIU)/day in two to three divided doses.

In patients who are critically ill, a loading dose of 9 MIU should be administered.

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 MIU may be required in patients with good renal function in some cases. Clinical experience with such doses is, however, extremely limited, and safety has not been established.

The loading dose applies to patients with normal and impaired renal functions, including those on renal replacement therapy.  

Renal Impairment

Dose adjustments in renal impairment are necessary, but pharmacokinetic data available for patients with impaired renal function is very limited.

The following dose adjustments are suggested as guidance.

Dose reductions are recommended for patients with creatinine clearance <50 mL/min: Twice-daily dosing is recommended.

Creatinine Clearance (mL/min)

Daily Dose

<50–30

5.5–7.5 MIU

<30–10

4.5–5.5 MIU

<10

3.5 MIU

HEMODIALYSIS AND CONTINUOUS HEMO(DIA)FILTRATION

Colistin appears to be dialyzable through conventional hemodialysis and continuous venovenous hemo(dia)filtration (CVVHF, CVVHDF). There are extremely limited data from population-pharmacokinetic studies from very small numbers of patients on renal replacement therapy. Firm dose recommendations cannot be made. The following regimes could be considered.

HEMODIALYSIS (HD)

  • No-HD days: 2.25 MIU/day (2.2–2.3 MIU/day).
  • HD days: 3 MIU/day on hemodialysis days, to be given after the HD session.
  • Twice-daily dosing is recommended.

CVVHF/CVVHDF

As in patients with normal renal function. Thrice-daily dosing is recommended.

Hepatic Impairment

There are no data in patients with hepatic impairment. Caution is advised when administering CMS in these patients.

Geriatric Population

No dose adjustments in older patients with normal renal function are considered necessary.

Pediatric Population

The data supporting the dose regimen in pediatric patients are very limited. Renal maturity should be taken into consideration when selecting the dose. The dose should be based on lean body weight.

CHILDREN (≤40 kg)

75,000–150,000 IU/kg/day divided into three doses.

CHILDREN (>40 kg)

Use of the dosing recommendation for adults should be considered.

The use of doses >150,000 IU/kg/day has been reported in children with cystic fibrosis. There are no data regarding the use or magnitude of a loading dose in critically ill children. No dose recommendations have been established in children with impaired renal function.

Method of Preparation and Administration

CMS can be given as a 50 mL injection over a period of 30–60 minutes.

The normal adult dose should be dissolved in 10–50 mL of 0.9% Sodium Chloride intravenous infusion or Water for Injections to form a clear solution. The solution is for single use only and any remaining solution should be discarded.

Patients with a totally implantable venous access device (TIVAD) in place may tolerate a bolus injection of up to 2 MIU in 10 mL given over a minimum of 5 minutes. CMS undergoes hydrolysis to the active substance, colistin, in aqueous solution. For dose preparation, particularly where combination of multiple vials is needed, reconstitution of the required dose must be performed using strict aseptic technique.

Contraindications

Hypersensitivity to CMS (colistin) or to polymyxin B.

Special Warnings and Precautions for Use

General

NOT TO BE USED IN FOOD-PRODUCING ANIMALS, POULTRY, AQUA FARMING AND ANIMAL FEED SUPPLEMENTS.

Consideration should be given to co-administering intravenous CMS with another antibacterial agent whenever this is possible, taking into account the remaining susceptibilities of the pathogen(s) under treatment. As the development of resistance to intravenous colistin has been reported in particular when it is used as a monotherapy, co-administration with other antibacterial should also be considered in order to prevent the emergence of resistance.

There are limited clinical data on the efficacy and safety of intravenous CMS. The recommended doses in all subpopulations are equally based on limited data (clinical and pharmacokinetic/pharmacodynamics data). In particular, there are limited safety data for the use of high doses (>6 MIU/day) and the use of a loading dose, and for special populations (patients with renal impairment and the pediatric population). CMS should only be used when other, more commonly prescribed antibiotics are not effective or not appropriate.

Renal function monitoring should be performed at the start of treatment and regularly during treatment in all patients. The dose of CMS should be adjusted according to creatinine clearance. Patients who are hypovolemic or those receiving other potentially nephrotoxic drugs are at increased risk of nephrotoxicity from colistin. Nephrotoxicity has been reported to be associated with cumulative dose and treatment duration in some studies. The benefit of prolonged treatment duration should be balanced against the potentially increased risk of renal toxicity.

Caution is advised when administering CMS to infants <1 year of age as renal function is not fully mature in this age group. Further, the effect of immature renal and metabolic function on the conversion of CMS to colistin is not known.

In case of an allergic reaction, treatment with CMS must be discontinued and appropriate measures implemented.

High serum concentrations of CMS, which may be associated with overdosage or failure to reduce the dosage in patients with renal impairment, have been reported to lead to neurotoxic effects such as facial paresthesia, muscle weakness, vertigo, slurred speech, vasomotor instability, visual disturbances, confusion, psychosis and apnea. Monitoring should be performed for perioral paresthesia and paresthesia in the extremities, which are signs of overdose.

CMS is known to reduce the presynaptic release of acetyl-choline at the neuro-muscular junction and should be used in patients with myasthenia gravis with the greatest caution and only if clearly needed.

Respiratory arrest has been reported following intramuscular administration of CMS. Impaired renal function increases the possibility of apnea and neuromuscular blockade following administration of CMS.

CMS should be used with extreme caution in patients with porphyria.

Antibiotic-associated colitis and pseudomembranous colitis have been reported with nearly all antibacterial agents and may occur with CMS. They may range from mild to life-threatening in severity. It is important to consider this diagnosis in patients who develop diarrhea during or after the use of CMS. Discontinuation of therapy and the administration of specific treatment for Clostridium difficile should be considered. Medicinal products that inhibit peristalsis should not be given.

Intravenous CMS does not cross the blood-brain barrier to a clinically relevant extent.

Drug Interactions

Concomitant use of intravenous CMS with other medications that are potentially nephrotoxic or neurotoxic should be undertaken with great caution.

Caution should be taken with concomitant use with other formulations of CMS as there is little experience and there is a possibility of summative toxicity.

No in vivo interaction studies have been performed. The mechanism of conversion of CMS to the active substance, colistin, is not characterized. The mechanism of colistin clearance, including renal handling, is equally unknown. CMS or colistin did not induce the activity of any cytochrome P450 (CYP) enzyme tested (CYP1A2, 2B6, 2C8, 2C9, 2C19 and 3A4/5) in in vitro studies in human hepatocytes.

The potential for drug–drug interactions should be borne in mind when CMS is co-administered with drugs known to inhibit or induce drug-metabolizing enzymes or drugs known to be substrates for renal carrier mechanisms.

Due to the effects of colistin on the release of acetylcholine, non-depolarizing muscle relaxants should be used with caution in patients receiving CMS as their effects could be prolonged.

Co-treatment with CMS and macrolides such as azithromycin and clarithromycin, or fluoroquinolones such as norfloxacin and ciprofloxacin should be undertaken with caution in patients with myasthenia gravis.

Concomitant use of CMS with other medicinal products of neurotoxic and/or nephrotoxic potential should be avoided. These include the aminoglycoside antibiotics such as gentamicin, amikacin, netilmicin and tobramycin. There may be an increased risk of nephrotoxicity if given concomitantly with cephalosporin antibiotics.

Use in Special Populations

Patients with Renal Impairment

Dose adjustments in renal impairment are necessary, but pharmacokinetic data available for patients with impaired renal function is very limited. Please refer to Posology and Method of Administration.

Patients with Hepatic Impairment

There are no data in patients with hepatic impairment. Caution is advised when administering CMS in these patients.

Pregnant Women

There are no adequate data from the use of CMS in pregnant women. Single-dose studies in human pregnancy show that CMS crosses the placental barrier and there may be a risk of fetal toxicity if repeated doses are given to pregnant patients. Animal studies are insufficient with respect to the effect of CMS on reproduction and development. CMS should be used in pregnancy only if the benefit to the mother outweighs the potential risk to the fetus.

Lactating Women

CMS is secreted in breast milk. CMS should be administered to breastfeeding women only when clearly needed.

Pediatric Patients

Please refer to Posology and Method of Administration.

Geriatric Patients

Elderly patients are more likely to have decreased renal function; hence, care should be taken in dose selection and it may be useful to monitor renal function.

Effects on the Ability to Drive and Use Machines

During parenteral treatment with CMS, neurotoxicity may occur with the possibility of dizziness, confusion or visual disturbance. Patients should be warned not to drive or operate machinery if these effects occur.

Undesirable Effects

Systemic Treatment

The likelihood of adverse events may be related to the age, renal function and condition of the patient.

In cystic fibrosis patients, neurological events have been reported in up to 27% of patients. These are generally mild and resolve during or shortly after treatment.

Neurotoxicity may be associated with overdose, failure to reduce the dose in patients with renal insufficiency and concomitant use of either neuromuscular-blocking drugs or other drugs with similar neurological effects. Reducing the dose may alleviate symptoms. Effects may include apnea, transient sensory disturbances (such as facial paresthesia and vertigo) and, rarely, vasomotor instability, slurred speech, visual disturbances, confusion, or psychosis.

Adverse effects on renal function have been reported, usually following use of higher than recommended doses in patients with normal renal function, or failure to reduce the dosage in patients with renal impairment, or during concomitant use of other nephrotoxic drugs. The effects are usually reversible on discontinuation of therapy.

In cystic fibrosis patients treated within the recommended dosage limits, nephrotoxicity appears to be rare (less than 1%). In seriously ill, hospitalized, non-cystic fibrosis patients, signs of nephrotoxicity have been reported in approximately 20% of patients.

Hypersensitivity reactions, including skin rash and drug fever, have been reported. If these occur, treatment should be withdrawn.

Local irritation at the site of injection may occur.

If you experience any side effects, talk to your doctor or pharmacist or write to drugsafety@cipla.com. You can also report side effects directly via the National Pharmacovigilance Programme of India by calling on 1800 267 7779 (Cipla number) or you can report to PvPI on 1800 180 3024.

By reporting the side effects, you can help provide more information on the safety of this product.

Overdose

Overdose can result in neuromuscular blockade that can lead to muscular weakness, apnea, and possible respiratory arrest. Overdose can also cause acute renal failure characterized by decreased urine output and increased serum concentrations of blood urea nitrogen (BUN) and creatinine.

There is no specific antidote, so overdose should be managed by supportive treatment. Measures to increase the rate of elimination of colistin, e.g., mannitol diuresis, prolonged hemodialysis or peritoneal dialysis may be tried, but effectiveness is unknown.

Pharmacological Properties

Mechanism of Action

CMS is a cyclic polypeptide antibiotic derived from Bacillus polymyxa var. colistinus and belongs to the polymyxin group. The polymyxin antibiotics are cationic surface-active agents that work by damaging the cell membrane. The resulting physiological effects are lethal to the bacterium. Polymyxins are selective for aerobic Gram-negative bacteria that have a hydrophobic outer membrane.

Pharmacodynamic Properties

Microbiology          

Commonly Susceptible Species

Acinetobacter species

Klebsiella species

Haemophilus influenzae

Pseudomonas aeruginosa

Species for Which Acquired Resistance May Be a Problem

Stenotrophomonas maltophilia

Achromobacter xylosoxidans (formerly Alcaligenes xylosoxidans)

Inherently Resistant Organisms

Burkholderia cepacia and related species

Proteus species

Providencia species

Serratia species

The prevalence of acquired resistance may vary geographically and with time for selected species and local information on resistance is desirable, particularly when treating severe infections. When necessary, expert advice should be sought when the local prevalence of resistance is such that the utility of the agent in at least some types of infections is questionable.

Resistance

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

Cross-resistance between colistimethate sodium and polymyxin B would be expected. Since the mechanism of action of the polymyxins is different from that of other antibiotics, resistance to colistin and polymyxin by the above mechanism alone would not be expected to result in resistance to other drug classes.

Pharmacokinetic Properties

Absorption

The information on the pharmacokinetics of CMS and colistin is limited. There are indications that pharmacokinetics in critically ill patients differ from those in patients with less severe physiological derangement and from those in healthy volunteers. The following data are based on studies using high-performance liquid chromatography (HPLC) to determine CMS/colistin plasma concentrations.

After infusion of CMS, the inactive pro-drug is converted to active colistin. Peak plasma concentrations of colistin have been shown to occur with a delay of up to 7 hours after administration of CMS in critically ill patients.

Absorption from the gastrointestinal tract does not occur to any appreciable extent in the normal individual.

Distribution

The volume of distribution of colistin in healthy subjects is low and corresponds approximately to extracellular fluid (ECF). The volume of distribution is relevantly enlarged in critically ill subjects. Protein-binding is moderate and decreases at higher concentrations. In the absence of meningeal inflammation, penetration into the cerebrospinal fluid (CSF) is minimal, but increases in the presence of meningeal inflammation.

Both CMS and colistin display linear pharmacokinetics in the clinically relevant dose range.

Elimination

It is estimated that approximately 30% of CMS is converted to colistin in healthy subjects, its clearance is dependent on creatinine clearance and as renal function decreases, a greater portion of CMS is converted to colistin.

In patients with very poor renal function (creatinine clearance <30 mL/min), the extent of conversion could be as high as 60–70%. CMS is eliminated predominantly by the kidneys via glomerular filtration. In healthy subjects, 60–70% of CMS is excreted unchanged in the urine within 24 hours.

The elimination of the active colistin is incompletely characterized. Colistin undergoes extensive renal tubular reabsorption and may either be cleared non-renally or undergo renal metabolism with the potential for renal accumulation. Colistin clearance is decreased in renal impairment, possibly due to increased conversion of CMS.

Half-life of colistin in healthy subjects and those with cystic fibrosis is reported to be around 3 hours and 4 hours, respectively, with a total clearance of around 3 L/hour. In critically ill patients, half-life has been reported to be prolonged to around 9–18 hours.

Non-Clinical Properties

Preclinical Safety Data

Data on potential genotoxicity are limited and carcinogenicity data for CMS are lacking. CMS has been shown to induce chromosomal aberrations in human lymphocytes, in vitro. This effect may be related to a reduction in the mitotic index, which was also observed.

Reproductive toxicity studies in rats and mice do not indicate teratogenic properties. However, CMS given intramuscularly during organogenesis to rabbits at 4.15 mg/kg and 9.3 mg/kg resulted in talipes varus in 2.6% and 2.9% of fetuses, respectively. These doses are 0.5 and 1.2 times the maximum daily human dose. In addition, increased resorption occurred at 9.3 mg/kg.

There are no other preclinical safety data of relevance to the prescriber which are additional to safety data derived from patient exposure and already included in other sections of the pack insert.

Pharmaceutical Particulars

Incompatibilities

Mixed infusions and injection solutions involving CMS should be avoided.

Shelf-Life

As on the pack.

Packaging Information

XYLISTIN FORTE PLUS is available in a vial of 10 mL.

Storage and Handling Instructions

Before Opening

Store below 25°C. Keep the vials in the outer carton.

Reconstituted Solutions

Solutions for Infusion or Injection

Chemical and physical in-use stability for 28 days at 4oC has been demonstrated. From a microbiological point of view, solutions should be used immediately. If not used immediately in-use storage times and conditions prior to use are the responsibility of the user. They would normally be no longer than 24 hours at 2°–8°C, unless reconstituted and diluted under controlled and validated aseptic conditions.

Patient Counseling Information

● What is XYLISTIN FORTE PLUS and what is it used for?

XYLISTIN FORTE PLUS contains the active substance, CMS (colistimethate sodium). CMS is an antibiotic. It belongs to a group of antibiotics that are called polymyxins.

XYLISTIN FORTE PLUS is given by injection to treat some types of serious infections caused by certain bacteria. XYLISTIN FORTE PLUS is used when other antibiotics are not suitable.

● What do you need to know before you use XYLISTIN FORTE PLUS?

Do not use XYLISTIN FORTE PLUS

  • if you are allergic (hypersensitive) to CMS, colistin or to other polymyxins.

Warnings and Precautions

Talk to your doctor, pharmacist or nurse before using XYLISTIN FORTE PLUS

  • if you have or have had kidney problems;
  • if you suffer from myasthenia gravis;
  • if you suffer from porphyria; and,
  • if you suffer from asthma.

In premature and newborn babies, special care should be taken when using XYLISTIN FORTE PLUS as the kidneys are not yet fully developed.

Other medicines and XYLISTIN FORTE PLUS

Tell your doctor if you are taking, have recently taken or might take any other medicines.

If you are taking any of the following medicines, you may or may not be able to take XYLISTIN FORTE PLUS. Sometimes, the other medicines must be stopped (if only for a while) or you may need a lower dose of XYLISTIN FORTE PLUS or you may need to be monitored while you are taking XYLISTIN FORTE PLUS. In some cases, the level of XYLISTIN FORTE PLUS in your blood may have to be measured from time to time to make sure that you are having the right dose:

  • Medicines such as antibiotics called aminoglycosides (which include gentamicin, tobramycin, amikacin and netilmicin) and cephalosporins (which can affect how your kidneys function). Taking such medicines at the same time as XYLISTIN FORTE PLUS can increase the risk of damage to the kidneys.
  • Medicines such as antibiotics called aminoglycosides (which include gentamicin, tobramycin, amikacin and netilmicin), which can affect your nervous system. Taking such medicines at the same time as XYLISTIN FORTE PLUS can increase the risk of side effects in the ears and other parts of your nervous system.
  • Medicines called muscle relaxants, often used during general anesthesia. XYLISTIN FORTE PLUS can increase the effects of these medicines. If you have a general anesthetic, let your anesthetist know that you are having XYLISTIN FORTE PLUS.

If you suffer from myasthenia gravis and are also taking other antibiotics called macrolides (such as azithromycin, clarithromycin or erythromycin) or antibiotics called fluoroquinolones (such as ofloxacin, norfloxacin and ciprofloxacin), taking XYLISTIN FORTE PLUS further increases the risk of muscle weakness and breathing difficulties.

Pregnancy and breastfeeding

XYLISTIN FORTE PLUS is not known to harm the unborn child but like all medicines, it will only be given to a pregnant woman if it is really needed. If you are pregnant, think you may be pregnant or are planning to have a baby ask your doctor for advice before taking this medicine.

Are you breastfeeding? Small amounts of XYLISTIN FORTE PLUS enter the milk. If you cannot stop breastfeeding while you take XYLISTIN FORTE PLUS, you should watch your baby carefully for any signs of illness and tell your doctor if you notice anything wrong.

Driving and using machines

When XYLISTIN FORTE PLUS is given into a vein there may be side effects such as dizziness, confusion or problems with vision. If these occur, you should not drive or operate machinery.

● How to use XYLISTIN FORTE PLUS?

Depending on the reason, XYLISTIN FORTE PLUS may be given by fast injection (over 5 minutes into a special kind of tube in a vein) or slow injection (infusion over about 30–60 minutes) into a vein.

Always use XYLISTIN FORTE PLUS exactly as your doctor has told you. Check with your doctor if you are not sure.

Duration of treatment

Your doctor will decide how long your treatment should last, depending on the severity of the infection. When treating bacterial infections, it is important to complete the full course of treatment so as to prevent worsening of the existing infection.

● What are the possible side effects?

Like all medicines, this medicine can cause side effects although not everybody gets them.

Allergic reactions

Serious allergic reactions can happen even with the very first dose and can include rapid development of rashes, swelling of the face, tongue and neck, inability to breathe due to narrowing of the airways, and loss of consciousness.

If you experience signs of an allergic reaction, you should seek urgent medical attention.

Less severe allergic reactions include skin rashes that appear later during treatment.

Side effects associated with injecting XYLISTIN FORTE PLUS into a vein

Side effects that affect the nervous system are more likely to occur when the dose of XYLISTIN FORTE PLUS is too high, in people who have poor kidneys, or in those who are also taking muscle relaxants or other medicines with a similar effect on how the nerves work.

The most serious of these possible side effects in the nervous system is inability to breathe because of paralysis of the chest muscles.

If you experience any difficulty breathing, you should seek urgent medical attention.

Other possible side effects include numbness or tingling (especially around the face), dizziness or loss of balance, rapid changes in blood pressure or blood flow (including faintness and flushing), slurred speech, problems with vision, confusion and mental problems (including loss of sense of reality). There can be reactions at the site of the injection, such as irritation.

Kidney problems may also occur. These are especially likely in people who already have poor kidneys, or who are given XYLISTIN FORTE PLUS at the same time as other medicines that can cause side effects in the kidneys or who are given a dose that is too high. These problems will normally get better if treatment is stopped or the dose of XYLISTIN FORTE PLUS is reduced.

If you get any side effects, talk to your doctor. This includes any possible side effects not listed in this leaflet.

Reporting of side effects

If you experience any side effects, talk to your doctor or pharmacist or write to drugsafety@cipla.com. You can also report side effects directly via the National Pharmacovigilance Programme of India by calling on 1800 267 7779 (Cipla number) or you can report to PvPI on 1800 180 3024.

By reporting the side effects, you can help provide more information on the safety of this product.

● How should you store XYLISTIN FORTE PLUS?

Keep this medicine out of the sight and reach of children.

Do not use this medicine after the expiry date, which is stated on the vial label after EXP. The expiry date refers to the last date of that month.

Store below 25°C. Keep the vials in the outer carton.

XYLISTIN FORTE PLUS solutions for injection and for infusion should be used immediately after preparation.

● What are the contents of the pack?

Each vial contains the active substance, CMS (also called colistin), as an amount of powder equivalent to 3 million units.

Details of The Manufacturer(S)

CIPLA LTD.,

E-65/66 MIDC Solapur,

Maharashtra - 413006

India

Details of Permission or Licence Number with Date

28A-PD/3280-A dated 18/04/2018

Date of Revision

20/08/2019