XYLISTIN 0.5 MIU Injection (Colistimethate Sodium for Injection IP (Lyophilized))

Table of Content

For the use of a Registered Medical Practitioner or a Hospital or a Laboratory only

Qualitative and Quantitative Composition

Each vial contains:

Colistimethate Sodium IP ……………………….5,00,000 IU

(IU: International Units)

Dosage Form(S) and Strength(S)

Powder for solution for injection, infusion and inhalation

5,00,000 IU

Clinical Particulars

Therapeutic Indications

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

i) 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.

ii) Treatment by inhalation of Pseudomonas aeruginosa lung infection in patients with cystic fibrosis.

Posology and Method of Administration

Systemic Treatment

XYLISTIN can be given as a 50 mL intravenous infusion over a period of 30 minutes. Patients with a totally implantable venous access device (TIVAD) in place may tolerate a bolus injection of up to 2 million units in 10 mL given over a minimum of 5 minutes (see Reconstitution for Parenteral Administration).

The dose is determined by the severity and type of infection and the age, weight and renal function of the patient. Should clinical or bacteriological response be slow, the dose may be increased as indicated by the patient's condition.

Serum level estimations are recommended, especially in renal impairment, neonates and cystic fibrosis patients. Levels of 10–15 mg/L (approximately 125–200 units/mL) colistimethate sodium should be adequate for most infections.

A minimum of 5 days of treatment is generally recommended. For the treatment of respiratory exacerbations in cystic fibrosis patients, treatment should be continued for up to 12 days.

Children and Adults (Including the Elderly)

Upto 60 kg of Body Weight

50,000 units/kg/day to a maximum of 75,000 units/kg/day. The total daily dose should be divided into three doses given at approximately 8-hour intervals.

Over 60 kg of Body Weight

1–2 million units three times a day. The maximum dose is 6-9 million units in 24 hours.

Anomalous distribution in patients with cystic fibrosis may require higher doses in order to maintain therapeutic serum levels.

Dosage in Patients with Impaired Renal Function

In moderate-to-severe renal impairment, excretion of colistimethate sodium is delayed. Therefore, the dose and dose interval should be adjusted in order to prevent accumulation. The table below is a guide to dose regimen modifications in patients of 60 kg body weight or greater. It is emphasized that further adjustments may have to be made based on blood levels and evidence of toxicity.

Suggested Dosage Adjustment in Renal Impairment

Grade

 Creatinine Clearance (mL/min)

 Over 60 kg Body Weight

Mild

20–50

1–2 million IU every 8 hours

Moderate

10–20

1-2 million IU every 12–18 hours

Severe

<10

1-2 million IU every 18–24 hours

Renal Replacement Therapy

2 million IU after each hemodialysis

2 million IU daily during peritoneal dialysis

Reconstitution for Parenteral Administration

The normal dose should be dissolved in 10–50 mL of 0.9% Sodium Chloride intravenous infusion or Water for Injection to form a clear solution. The solution is for single use only and any remaining solution should be discarded. To avoid frothing reconstitute the vial slowly without vigorous shaking and once reconstituted should be used immediately.

Inhalation Treatment

For local treatment of lower respiratory tract infections, XYLISTIN powder is dissolved in 2–4 mL of Water for Injections or 0.9% Sodium Chloride intravenous infusion for use in a nebulizer attached to an air/oxygen supply (see Reconstitution for Inhalation).

In small, uncontrolled clinical trials, doses of from 500,000 units twice daily up to 2 million units three times daily have been found to be safe and effective in patients with cystic fibrosis.

The following recommended doses are for guidance only and should be adjusted according to clinical response:

Children (<2 Years of Age)

500,000 to 1 million units twice daily

Children (>2 Years of Age) and Adults

1–2 million units twice daily

Reconstitution for Inhalation

The required amount of powder is dissolved, preferably, in 2–4 mL of 0.9% Sodium Chloride solution and poured into the nebulizer. Alternatively, Water for Injections may be used. The solution will be slightly hazy and may froth if shaken. Usually jet or ultrasonic nebulizers are preferred for antibiotic delivery. These should produce the majority of their output in the respirable particle diameter range of 0.5–5.0 microns when used with a suitable compressor. The instructions of the manufacturers should be followed for the operation and care of the nebulizer and compressor.

The output from the nebulizer may be vented to the open air or a filter may be fitted. Nebulization should take place in a well-ventilated room.

The solution is for single use only and any remaining solution should be discarded.

Contraindications

XYLISTIN is contraindicated in patients with known hypersensitivity to colistimethate sodium (colistin) or to polymyxin B and in patients with myasthenia gravis.

Special Warnings and Precautions for Use

General

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

Use with extreme caution in patients with porphyria.

Nephrotoxicity or neurotoxicity may occur if the recommended parenteral dose is exceeded.

Bronchospasm may occur on inhalation of antibiotics. This may be prevented or treated with appropriate use of β2-agonists. If troublesome, treatment should be withdrawn.

Drug Interactions

Concomitant use of colistimethate sodium 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.

Neuromuscular-blocking drugs and ether should be used with extreme caution in patients receiving colistimethate sodium.

Use in Special Populations

Patients with Renal Impairment

Use with caution in renal impairment (see Posology and Method of Administration) as colistimethate sodium is renally excreted. It is advisable to assess baseline renal function and to monitor during treatment. Serum colistimethate sodium concentrations should be monitored.

Patients with Hepatic Impairment

No data available.

Pregnant Women

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

Lactating Women

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

Pediatric Patients

Colistimethate sodium kinetics appears to be similar in children and adults, including the elderly, provided renal function is normal. Limited data are available in use in neonate which suggest kinetics are similar to children and adults but the possibility of higher peak serum levels and prolonged half-life in these patients should be considered and serum levels monitored (see Pharmacokinetic Properties and 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 colistimethate sodium, 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.

Inhalation Treatment

Inhalation may induce coughing or bronchospasm.

Sore throat or mouth has been reported and may be due to Candida albicans infection or hypersensitivity. Skin rash may also indicate hypersensitivity; if this occurs, treatment should be withdrawn.

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

Colistimethate sodium 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.

MIC Breakpoints

The suggested general MIC breakpoint to identify bacteria susceptible to colistimethate sodium is < 4 mg/L Bacteria for which the MIC of colistimethate sodium is 8 mg/L should be considered resistant.

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 colistimethate sodium (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 colistimethate sodium, 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 colistimethate sodium in critically ill patients.

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

When given by nebulization, variable absorption has been reported that may depend on the aerosol particle size, nebulizer system and lung status. Studies in healthy volunteers and patients with various infections have reported serum levels from nil to potentially therapeutic concentrations of 4 mg/L or more. Therefore, the possibility of systemic absorption should always be borne in mind when treating patients by inhalation.

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.

Metabolism

Colistimethate sodium is converted to the base in vivo. As 80% of the dose can be recovered unchanged in the urine and there is no biliary excretion, it can be assumed that the remaining drug is inactivated in the tissues. The mechanism is unknown.

Elimination

It is estimated that approximately 30% of colistimethate sodium 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 colistimethate sodium are lacking. Colistimethate sodium 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, colistimethate sodium 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

Mixing drugs in infusions, injections and nebulizer solutions involving colistimethate sodium should be avoided.

The addition of other antibiotics such as erythromycin, tetracycline, and cephalothin to solutions of XYLISTIN may lead to precipitation.

Shelf-Life

As on the pack.

Packaging Information

XYLISTIN 0.5 MIU…………………..is available in vial of 10 mL

Storage and Handling Instructions

Before Opening

Do not store above 25°C. Protect from light and moisture. 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.

Solutions for Nebulization

Solutions for nebulization have similar in-use stability and should be treated as above. Patients self-treating with nebulized antibiotic should be advised to use solutions immediately after preparation. If this is not possible, solutions should not be stored for longer than 24 hours in a refrigerator.

Patient Counseling Information

● What is XYLISTIN and what is it used for?

XYLISTIN contains the active substance, colistimethate sodium. Colistimethate sodium is an antibiotic. It belongs to a group of antibiotics that are called polymyxins.

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

XYLISTIN is given as an inhalation to treat chronic chest infections in patients with cystic fibrosis. XYLISTIN is used when these infections are caused by specific bacteria called Pseudomonas aeruginosa.

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

Do not use XYLISTIN:

  • If you are allergic (hypersensitive) to colistimethate sodium, colistin or to other polymyxins.

Warnings and Precautions

Talk to your doctor, pharmacist or nurse before using XYLISTIN

  • If you have or have had kidney problems.
  • If you suffer from myasthenia gravis (a rare disease where your muscles are extremely weak and get tired very quickly).
  • If you suffer from porphyria (a rare metabolic disease that some people are born with).
  • If you suffer from asthma

Some people may experience a feeling of tightness in the chest due to narrowing of the airways when inhaling XYLISTIN. Your doctor may prescribe other medicines for inhalation directly before or after using XYLISTIN in order to prevent or treat this.

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

Other medicines and XYLISTIN

Tell your doctor if you are taking, have recently taken or might take any other medicines, including non-prescription medicines. These medicines may interfere with the effects of XYLISTIN.

If you are taking any of the following medicines, you may or may not be able to take XYLISTIN. Sometimes the other medicines must be stopped (if only for a while) or you may need a lower dose of XYLISTIN or you may need to be monitored while you are taking XYLISTIN. In some cases, the level of XYLISTIN 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 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 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 can increase the effects of these medicines. If you have a general anesthetic, let your anesthetist know that you are having XYLISTIN.

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 further increases the risk of muscle weakness and breathing difficulties.

Having XYLISTIN as an infusion at the same time as receiving XYLISTIN as an inhalation can increase your risk of side effects.

Pregnancy and breastfeeding

XYLISTIN 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 enter the milk. If you cannot stop breastfeeding while you take XYLISTIN, 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 is given there may be side effects such as dizziness, confusion or problems with sight such as blurred vision. If these occur, you should not drive or use any tools or operate machinery.

● How to use XYLISTIN?

Depending on the reason, XYLISTIN 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 minutes) into a vein.

XYLISTIN can also be breathed into the lungs as a fine spray, which is made using a machine called a nebulizer. The droplets of the spray produced by the nebulizer are small enough to enter the lungs so that XYLISTIN can reach the site of the bacterial infection.

The dose and the route of giving the medicine is determined by the severity and type of infection and the age, weight and renal function of the patient.

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

Whether XYLISTIN is given into a vein or by inhalation, an allergic reaction is possible.

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 into a vein

Side effects that affect the nervous system are more likely to occur when the dose of XYLISTIN 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 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 is reduced.

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

Side effects associated with inhaling XYLISTIN (nebulization)

The risk of side effects is usually much less when it is given by inhalation because very little XYLISTIN usually reaches the bloodstream when it is given this way.

Possible side effects include coughing, a feeling of tightness in the chest due to narrowing of the airways, sore mouth or throat and thrush (Candida) infections of the mouth or throat.

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?

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.

Do not store above 25°C. Protect from light and moisture.

XYLISTIN solutions for injection and for inhalation should be used immediately after preparation.

● What are the contents of the pack?

Each vial contains the active substance, colistimethate sodium (also called colistin), as an amount of powder equivalent to 5,00,000 international units (0.5 million units).

Details of the Manufacturers

Gufic Biosciences Limited,

N. H. No. 8, Near Grid,

Kabilpore 396424,

Navsari, Gujarat (India)

Marketed by:

Cipla Ltd.

Registered Office:

Cipla House, Peninsula Business Park, Ganpatrao Kadam Marg, Lower Parel,

Mumbai – 400 013, India

Details of Permission or Licence Number with Date

G/28A/5621-A           24/11/2016

Date of Revision

04/02/2020