Colistimethate Sodium

These indications are based on manufacturer information for both originator and generic products. For product specific registered indications, please refer to product specific manufacturer information

South African indications:

• Serious infections resistant to other antibiotics
• Chronic Pseudomonas aeruginosa infections in cystic fibrosis

Contraindications

• Hypersensitivity to the active ingredient or any of its excipients
• Hypersensitivity to polymyxin B

Cautions

• Pregnancy
• Breastfeeding
• Renal impairment (CrCl <50ml/min)
• Hepatic impairment
• Porphyria
• Intravenous colistimethate sodium therapy
• Intravenous colistimethate sodium monotherapy
• High doses (>6M IU (six million IU)/day)
• Patients requiring a loading dose
• Children
• Infants <1 year
• Myasthenia gravis
• Hypovolaemia
• Intrathecal or intraventricular administration in the treatment of meningitis
• May impair ability to drive and operate machinery

Forms avail. in SA and covered in this monograph: inj

Serious infections
- Due to selected aerobic Gram-negative pathogens in patients with limited treatment options

• IV: Loading dose: 9-12M IU (nine to twelve million IU); Maintenance: 9M IU (nine million IU), in 2-3 divided doses as a slow infusion for 30-60mins

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Dosage and treatment duration should take into account the severity of the infection as well as the clinical response. Therapeutic guidelines should be adhered to

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In critically ill patients, a loading dose of 9M IU (nine million IU) should be administered. The most appropriate time interval to the first maintenance dose has not been established. The loading dose applies to patients with normal and impaired renal functions including those on renal replacement therapy

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Loading and maintenance doses of up to 12M IU (twelve million IU) may be required in patients with good renal function in some cases; clinical experience with such doses is extremely limited and safety has not been established

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Patients with a totally implantable venous access device in place may tolerate a bolus injection of up to 2M IU (two million IU) in 10ml given over a minimum of 5mins

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Strict aseptic technique must be adhered to during dose preparation, particularly when combination of multiple vials is needed

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• Intraventricular (inj): 125,000 IU (one hundred and twenty five thousand IU), dly as a slow infusion for 30-60mins
• Intrathecal (inj): 125,000 IU (one hundred and twenty five thousand IU), dly as a slow infusion for 30-60mins

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Intrathecally administered doses should not exceed those recommended for intraventricular use

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When the intrathecal and intraventricular routes of administration are used, the volume administered should not exceed 1ml (reconstituted concentration 125,000 IU(one hundred and twenty five thousand IU)/ml)

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Patients with a totally implantable venous access device (TIVAD) in place may tolerate a bolus injection of up to 2M IU (two million IU) in 10ml given over a minimum of 5 minutes

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Cystic fibrosis
- Chronic pulmonary infections due to Pseudomonas aeruginosa

• Inhaled (inj): 1-2M IU (one to two million IU), 12hrly; Max: 6M IU (six million IU)/24hrs

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Dosage can be adjusted depending on the severity of the condition and clinical response

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Suitable nebulisers are the reusable jet nebulisers including the PARI LC PLUS or the PARI LC SPRING, which are used with a suitable compressor, or the membrane nebuliser namely eFlow rapid

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

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See additional prescribing points for guidance on nebulisation. It is recommended that colistimethate sodium only be administered under the supervision of physicians with appropriate experience in its use

Paed. forms avail. in SA and covered in this monograph: inj

Serious infections
- Due to selected aerobic Gram-negative pathogens in patients with limited treatment options

≤40kg

• IV: 75,000-150,000 IU (seventy five thousand to one hundred and fifty thousand IU)/kg/day divided into 3 doses as a slow infusion for 30-60mins

>40kg

• Consider adult dosage

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Dose should be based on lean body weight. Renal maturity should be taken into consideration when selecting the dose

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No data available regarding the use or magnitude of a loading dose in critically ill children

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No dose recommendations established in children with impaired renal function

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No specific dosing recommendation can be made for intrathecal and intraventricular routes of administration

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Strict aseptic technique must be adhered to during dose preparation, particularly when combination of multiple vials is needed

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Cystic fibrosis
- Chronic pulmonary infections due to Pseudomonas aeruginosa

<2 years

• Inhaled (inj): 0.5-1M IU (five hundred thousand to one million IU), 12hrly; Max: 2M IU (two million IU)/24hrs

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Relevant clinical guidance on treatment regimens, including duration of treatment, periodicity and co-administration of other antibacterial agents should be adhered to

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≥2 years

• See adult dosage

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Use of doses >150,000 IU(one hundred and fifty thousand IU)/kg/day has been reported in children with cystic fibrosis

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Dosage can be adjusted depending on the severity of the condition and clinical response

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Suitable nebulisers are the reusable jet nebulisers including the PARI LC PLUS or the PARI LC SPRING, which are used with a suitable compressor, or the membrane nebuliser namely eFlow rapid

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

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See additional prescribing points for guidance on nebulisation. It is recommended that colistimethate sodium only be administered under the supervision of physicians with appropriate experience in its use

Pregnancy

• Caution; not recommended
• There is no adequate data from the use of colistimethate sodium in pregnant women
• Single dose studies in human pregnancy show that colistimethate sodium crosses the placental barrier and there may be a 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 only be used in pregnancy if the benefit to the mother outweighs the potential risk to the foetus

Breastfeeding

• Caution; not recommended
• Colistimethate sodium is secreted in breast milk. Colistimethate sodium should be administered to breastfeeding women only when clearly needed

Fertility

• There are no data on the effects of colistimethate sodium on human fertility. Effects on male and female fertility have not been evaluated in animal studies

Renal Impairment

• CrCl≥50ml/min: No dose adjustment recommended
• CrCl<50ml/min: Caution; dose adjustment recommended

CrCl (ml/min)	Daily dose
≥50	No adjustment necessary
<50-30	5.5-7.5M IU (five million five hundred thousand to seven million five hundred thousand IU)
<30-10	4.5-5.5M IU (four million five hundred thousand to five million five hundred thousand IU)
<10	3.5M IU (three million five hundred thousand)
Haemodialysis: No-haemodialysis days	2.25M IU(two million two hundred fifty thousand IU)/day (2.2-2.3M IU/day), 12hrly
Haemodialysis: Haemodialysis days	3M IU (three million IU)/day, 12hrly to be given after the haemodialysis session
Continuous veno-venous hemofiltration / continuous venovenous hemodiafiltration	As in patients with normal renal function. 8hrly dosing is recommended

Hepatic Impairment

• Caution; no information available

Elderly

• No dose adjustment recommended
  No dose adjustment is necessary in older patients with normal renal function

Porphyria Information

• Probably not porphyrinogenic (PNP)
  Renal cytotoxicity signaled by reduced GFR is a very common side effect. This motivates reduced doses of the agent in patients with pre-existing renal damage, such is the case in some carriers of acute porphyria, to avoid overdosing
  Common adverse reactions of colistin that can be confused with an acute porphyric attack are nausea and vomiting. These side effects may potentially be porphyrinogenic if leading to a decrease in carbohydrate intake

Drugs in Sport

• Prohibited - At all times
  The intravenous (IV) infusion and/or injection of more than 100mL per 12 hour period of any substance is a prohibited method, even if the substance itself is not prohibited, unless it is received while being treated at the hospital, during surgery, or during clinical diagnostic investigations." If administered by IV outside of a hospital setting and depending on the level of the athlete, the athlete needs to apply for a Therapeutic Use Exemption (TUE) in advance

Central Nervous System Disorders

• Neurotoxicity
• Transient sensory disturbances
  - Facial paraesthesia
  - Vertigo
• Vasomotor instability
• Slurred speech
• Visual disturbances
• Confusion
• Psychosis
• Neurological events (cystic fibrosis patients)

Respiratory Disorders

• Apnoea
• Coughing (inhaled)
• Bronchospasm (inhaled)
• Sore throat (inhaled)

Gastrointestinal Disorders

• Sore mouth (inhaled)

Genitourinary Disorders

• Nephrotoxicity
• Decreased urine output
• Increased urea concentrations
• Increased creatinine concentrations
• Proteinuria
• Haematuria
• Urinary detection of cylinders
• Acute tubular necrosis

Skin and Subcutaneous Tissue Disorders

• Injection site reactions

Immune, Blood and Lymphatic System Disorders

• Hypersensitivity reactions
  - Skin rash
  - Drug fever
• Candida albicans infection (inhaled)

Sensory Disorders

• Blurred vision

• Agents that inhibit peristalsis
• Nephrotoxic agents
• Neurotoxic agents
• Aminoglycoside antibiotics
• Gentamycin
• Amikacin
• Netilmicin
• Tobramycin
• Cephalosporin antibiotics
• Other formulations containing colistimethate sodium
• Agents known to inhibit or induce drug metabolising enzymes
• Agents known to be substrates for renal carrier mechanisms
• Non-depolarising muscle relaxants
• Macrolides (patients with myasthenia gravis)
• Azithromycin (patients with myasthenia gravis)
• Clarithromycin (patients with myasthenia gravis)
• Fluoroquinolones (patients with myasthenia gravis)
• Norfloxacin (patients with myasthenia gravis)
• Ciprofloxacin (patients with myasthenia gravis)

• Creatinine levels
• Blood urea nitrogen

Guidance on nebulisation

• When used by inhalation other inhaled drugs should be
  administered before colistimethate sodium
• Colistimethate sodium reconstitution must be performed using strict aseptic technique and is intended for nebulisation using a suitable nebuliser, mentioned above in Adult Dosing and Paediatric Dosing
• The recommended technique for dissolving the medicinal product is the addition of 3ml isotonic sodium chloride solution (0.9% w/w) to the vial containing colistimethate sodium by gentle shaking
• Due to potential foaming, vigorous shaking should be avoided. The resulting nebulisation should be clear and carefully transferred into the medication reservoir of the nebuliser
• The solution is for single use only and any remaining solution should be discarded
• The nebuliser must be kept according to the instructions of the corresponding nebuliser during operation
• The patient should sit in an upright position and breathing normally during inhalation. Inhalation should be performed without any interruption to normal breathing
• The nebuliser must be cleaned and disinfected after use described in the 'instruction of use' of the corresponding nebuliser
• If other treatments are being taken, they should be taken in the order recommended by the physician

Reconstitution instructions

Bolus injection

• Reconstitute the contents of the vial with not more than 10ml water for injection or 0.9% sodium chloride

Infusion

• The contents of the reconstituted vial may be diluted, usually with 50ml 0.9% sodium chloride
• When the intrathecal and intraventricular routes of administration are used, the volume administered should not exceed 1ml (reconstituted concentration 125,000 IU (one hundred and twenty five thousand IU)/ml)

Inhalation

• Reconstitute the contents of the vial with either water for injections or with sodium chloride 9mg/ml (0.9% solution)

Conversion Table

• The dose is expressed in IU of colistimethate sodium (CMS). A conversion table from CMS in IU to mg of CMS as well as to mg of colistimethate sodium base activity (CBA) can be found below:

Potency		≈ mass of CMS (mg) *
IU	≈ mg CBA
12 500	0.4	1
150 000	5	12
1 000 000	34	80
4 5 000 000	150	360
9 000 000	300	720

^* Nominal potency of the drug substance = 12,500 IU/mg

Colistimethate sodium is a cyclic polypeptide antibacterial agent belonging to the polymyxin group. Polymyxins work by damaging the cell membrane and the resulting physiological effects are lethal to the bacterium. Polymyxins are selective for aerobic Gram-negative bacteria that have a hydrophobic outer membrane.

Spectrum of activity: Acinetobater baumanni; Haemophilus influenzae; Klebsiella spp; Pseudomonas aeruginosa 

Injection (per vial) 1 MU

• Colixin (Alfasigma S.p.A)