Polymyxin B

S01C - Antiinflammatories/antiinfectives in combination ATC S01CA02 Protein approved 1957 Parenteral Topical Black-box warning

JFDA label: Neopred-P eye ear drops

⚠ Black-Box Warning

Appropriate use:
Nephrotoxicity:
Neurotoxicity:
Concurrent therapy:
Neuromuscular blockade:
Use in pregnancy:
Nephrotoxicity
Neuromuscular blockade

Mechanism of Action

Binds to phospholipids, alters permeability, and damages the bacterial cytoplasmic membrane permitting leakage of intracellular constituents

Indications

Approved

Infections, acute
Pseudomonal infections
Serious infections

Off-label

Selective gastrointestinal tract decontamination

Contraindications

Source: Lexicomp

Hypersensitivity to polymyxin B or any component of the formulation Absolute

Adverse Reactions

Very Common >10%Common 1–10%Uncommon 0.1–1% Rare 0.01–0.1%Very Rare <0.01%Not Known

Cardiac disorders (1)

Not Known Facial flushing

Nervous system disorders (4)

Not Known dizziness · drug fever · meningitis (intrathecal administration) · Neurotoxicity (includes ataxia, blurred vision, drowsiness, irritability, numbness of extremities oral paresthesia)

Immune system disorders (1)

Not Known Anaphylactoid reaction

Metabolism and nutrition disorders (4)

Not Known Hypocalcemia · hypochloremia · hypokalemia · hyponatremia

Skin and subcutaneous tissue disorders (1)

Not Known Urticaria

Musculoskeletal and connective tissue disorders (1)

Not Known weakness

General disorders and administration site conditions (1)

Not Known Pain at injection site

Dosing

Source: Lexicomp

Note: Dosing presented as units; 10,000 units = 1 mg CNS infections: Intrathecal: Manufacturer’s labeling: 50,000 units once daily for 3 to 4 days, then every other day for at least 2 weeks after cultures of the CSF are negative Alternate dosing (off-label regimen): Intrathecal, Intraventricular: 50,000 units once daily for 7 days; used in combination with other IV antibiotics (eg, meropenem) (IDSA [Tunkel 2004]; Segal-Maurer 1999) Ocular infections: Ophthalmic: A concentration of 0.1% to 0.25% (10,000 to 25,000 units/mL) is administered as 1 to 3 drops every hour, then increasing the interval as response indicates. A subconjunctival injection of up to 100,000 units/day may be used for P. aeruginosa corneal and conjunctival infections. Note: Avoid total systemic and ophthalmic doses of >25,000 units/kg/day. Systemic infections: Note: Most of the available limited data evaluating polymyxin B for multidrug resistant pathogens cite manufacturer’s labeling dosing of 15,000 to 25,000 units/kg/day IV divided every 12 hours (Furtado 2007; Ouderkirk 2003). More recent publications have cited alternate dosing regimens based on pharmacokinetics/pharmacodynamics data (eg, Monte Carlo simulations) (Sandri 2013a), which support using a loading dose to rapidly achieve target serum concentrations and higher dosing regimens particularly for severe infections (pathogens with an MIC ≤2 mcg/mL); however, actual clinical data employing these higher dosing regimens remain extremely limited. Monitor closely for nephrotoxicity. Dosing based on actual body weight has been suggested for patients within a normal weight range for their height (Kassamali 2015; Pai 2013; Sandri 2013a). Manufacturer’s labeling: IM: 25,000 to 30,000 units/kg/day in divided doses every 4 to 6 hours. Note: Routine IM administration not recommended due to severe pain at injection site. IV: 15,000 to 25,000 units/kg/day in divided doses every 12 hours (maximum: 25,000 units/kg/day) Alternate dosing: Infections (eg, intraabdominal infections, pneumonia [hospital-acquired or ventilator-associated], sepsis), due to susceptible multidrug-resistant gram-negative bacilli (eg, Pseudomonas aeruginosa, Acinetobacter spp) (off-label dose): IV: Severe infections (MIC ≤2 mcg/mL): 25,000 units/kg/dose infused over 2 hours as a one-time loading dose, followed by a maintenance dose of 30,000 units/kg/day divided every 12 hours (Kassamali 2015; Sandri 2013a) or 25,000 to 30,000 units/kg/day in 2 divided doses without a loading dose (IDSA [Kalil 2016]) Moderate infections: (MIC ≤1 mcg/mL): 25,000 units/kg/day divided every 12 hours (Sandri 2013a) Note: Safety data for single doses >30,000 units/kg/dose or for daily doses >2,000,000 units/day are extremely limited. To minimize bacterial regrowth and heteroresistance, consider use in combination with other antibiotics depending on infection site and susceptibilities (Bergen 2015, Kassamali 2015, Rigatto 2015). Monotherapy should only be considered for infections due

(For additional information see "Polymyxin B: Pediatric drug information") Note: Dosing presented as units; 10,000 units = 1 mg. Use extra caution with prescribing and/or dispensing. Multiple routes of administration available for use (eg, IV, IM, intrathecal, ophthalmic) and dosing is different based upon route; use extra precaution to verify dose and route of administration. Severe, life-threatening, multidrug resistant infection (excluding meningitis): Note: From experience in adult patients, safety data for single doses >30,000 units/kg/dose or total daily doses >2,000,000 units/day are extremely limited (Kassamali 2015). Infants: IM: 25,000 to 40,000 units/kg/day divided every 4 to 6 hours; Note: Routine IM administration not recommended due to severe pain at injection site. IV: 15,000 to 40,000 units/kg/day divided every 12 hours Children and Adolescents: IM: 25,000 to 30,000 units/kg/day divided every 4 to 6 hours; Note: Routine IM administration not recommended due to severe pain at injection site. IV: Manufacturer's labeling: 15,000 to 25,000 units/kg/day divided every 12 hours Alternate dosing: Children ≥2 years and Adolescents: Very limited data available: Dosing based on previous recommendations (Hoeprich 1970) and extrapolations from adult pharmacokinetic modeling (Sandri 2013a) which assumes that dosing for pediatric patients ≥2 years and adults is the same (per current manufacturer's labeling); some centers have used the following: Loading dose: 25,000 units/kg Maintenance dose: 25,000 to 30,000 units/kg/day divided every 12 hours; consider higher doses for organisms with higher MIC Meningitis, Pseudomonas aeruginosa or Haemophilus influenzae: Infants and Children or 25,000 units once every other day; continue 25,000 units once every other day for at least 2 weeks after cultures of the CSF are negative Children ≥2 years and Adolescents: Intrathecal: 50,000 units daily as a single dose for 3 to 4 days, then every other day for at least 2 weeks after cultures of CSF are negative CNS infection (VP-shunt infection, ventriculitis): Limited data available: Children and Adolescents: Intraventricular/intrathecal: 20,000 to 50,000 units/day; lower doses should be used in smaller patients (Hoeprich, 1970; IDSA [Tunkel 2004]) Ocular infection, Pseudomonas aeruginosa: Infants, Children, and Adolescents: Ophthalmic: Refer to adult dosing.

Refer to adult dosing.

Note: Manufacturer labeling recommends a dosage reduction in renal impairment however some clinical data suggest that total body clearance of polymyxin B is not altered in renal impairment and that dose adjustment is not necessary (Sandri 2013a; Thamlikitkul 2016). Decreasing daily doses in renal impairment may lead to suboptimal plasma exposure, adverse clinical outcomes and resistance development (Nelson 2015; Sandri 2013a; Zavascki 2008). Some data suggest that non-renal pathways are primarily responsible for elimination. These authors suggest that renal dosage adjustment recommendations should await further data from larger clinical trials (Zavascki 2008). However, use is associated with nephrotoxicity. Recent data suggests polymyxin B undergoes a selective uptake process into renal cells, which plays a primary role in nephrotoxicity potential (Abdelraouf 2014). One small study in patients receiving polymyxin B with a normal baseline renal function observed an overall prevalence rate of nephrotoxicity of 46% with a median onset of 9 days (Dubrovskaya 2015). Manufacturer’s labeling: IV: For individuals with renal impairment, reduce to dose to Alternate recommendations: Adults: CrCl ≥80 mL/minute: IV: 15,000 to 25,000 units/kg/day in divided doses every 12 hours (Evans 1999) CrCl 30 to 80 mL/minute: IV: Loading dose: 25,000 units/kg on day 1, followed by 10,000 to 15,000 units/kg/day thereafter (Evans 1999) CrCl Anuric patients: IV: Loading dose: 25,000 units/kg on day 1, followed by 10,000 units/kg every 5 to 7 days thereafter (Evans 1999) Hemodialysis, peritoneal dialysis: IM: 250,000 units every 24 hours; no supplemental dose necessary (Cunha 1988) CVVHD: No dosage adjustment necessary (Sandri 2013b).

There are no dosage adjustments provided in the manufacturer’s labeling.

Warnings & Precautions

Source: Lexicomp

Local reactions

May cause severe pain at IM injection site or thrombophlebitis at IV infusion site.

Nephrotoxicity

May cause nephrotoxicity; avoid concurrent or sequential use of other nephrotoxic drugs. Usual risk factors include preexisting renal impairment, advanced age and dehydration. Polymyxin B-induced nephrotoxicity may be manifested by albuminuria, cellular casts, and azotemia; monitor BUN, serum creatinine, and urinary analysis at baseline and as clinically indicated. Discontinue therapy with decreasing urinary output and increasing BUN. Data suggest polymyxin B undergoes a selective uptake process into renal cells, which plays a primary role in nephrotoxicity potential (Abdelraouf 2014). One small study in patients receiving polymyxin B with a normal baseline renal function observed an overall prevalence rate of nephrotoxicity of 46% with a median onset of 9 days (Dubrovaskaya 2015).

Neurotoxicity

May cause neurotoxicity, which can also result in respiratory paralysis from neuromuscular blockade especially when the drug is given soon after anesthesia or muscle relaxants. Avoid concurrent or sequential use of other neurotoxic drugs. Avoid concurrent use of curariform muscle relaxants and other neurotoxic drugs (eg, ether, tubocurarine, succinylcholine, gallamine, decamethonium, sodium citrate), which may cause respiratory depression.

Superinfection

Prolonged use may result in fungal or bacterial superinfection, including C. difficile-associated diarrhea (CDAD) and pseudomembranous colitis; CDAD has been observed >2 months postantibiotic treatment. Disease-related concerns:

Renal impairment

Use with caution in patients with impaired renal function; manufacturer’s prescribing information states dosage reduction required, however, recent pharmacokinetic/pharmacodynamic and clinical studies suggest daily dose requirement is not affected by renal function (Sandri 2013a; Nelson 2015; Thamlikitkul 2016). Concurrent drug therapy issues:

Drug-drug interactions

Potentially significant interactions may exist, requiring dose or frequency adjustment, additional monitoring, and/or selection of alternative therapy. Consult drug interactions database for more detailed information Special populations:

Pregnancy

Safety in pregnant women not established. Other warnings/precautions:

IM/Intrathecal/IV administration

Intramuscular/intrathecal/intravenous administration only to hospitalized patients.

Parenteral administration

Polymyxin B sulfate is most toxic when given parenterally; avoid parenteral use whenever possible.

Pregnancy & Lactation

Pregnancy

Teratogenic

[US Boxed Warning]: Safety in pregnant women has not been established. Animal reproduction studies are lacking. A teratogenic potential has not been identified for polymyxin b, but very limited data is available (Heinonen 1977; Kazy 2005). Based on the relative toxicity compared to other antibiotics, systemic use in pregnancy is not recommended (Knothe 1985). Due to poor tissue diffusion, topical use would be expected to have only minimal risk to the mother or fetus (Leachman 2006).

Lactation

It is not known if polymyxin b is excreted in human milk. If present in breast milk, polymyxin b is not absorbed well from a normal gastrointestinal tract. Nondose-related effects could include modification of the bowel flora.

Monitoring

Clinical pearl	Neurologic symptoms and signs of superinfection; renal function (decreasing urine output and increasing BUN may require discontinuance of therapy)

Chemistry & Properties

Formula	C56H98N16O13
Molecular weight	1203.5 g/mol
IUPAC name	N-[(2S)-4-amino-1-[[(2S,3R)-1-[[(2S)-4-amino-1-oxo-1-[[(3S,6S,9S,12S,15R,18R,21S)-6,9,18-tris(2-aminoethyl)-15-benzyl-3-[(1R)-1-hydroxyethyl]-12-(2-methylpropyl)-2,5,8,11,14,17,20-heptaoxo-1,4,7,10,13,16,19-heptazacyclotricos-21-yl]amino]butan-2-yl]amino]-3-hydroxy-1-oxobutan-2-yl]amino]-1-oxobutan-2-yl]-6-methyloctanamide
CAS	1404-26-8
PubChem CID	49800004
InChIKey	`WQVJHHACXVLGBL-BPJDFBQWSA-N`
logP	-2.5 (XLogP -2.5)
Polar surface area	491.0 Å²
H-bond acceptors / donors	18 / 18

SMILES

CCC(C)CCCCC(=O)NC(CCN)C(=O)NC(C(C)O)C(=O)NC(CCN)C(=O)NC1CCNC(=O)C(NC(=O)C(NC(=O)C(NC(=O)C(NC(=O)C(NC(=O)C(NC1=O)CCN)CC2=CC=CC=C2)CC(C)C)CCN)CCN)C(C)O

Biology & Pharmacokinetics

Pharmacokinetics predicted

Bioavailability	70.0%
Half-life	1.844 h
Volume of distribution	0.293 L/kg
Protein binding	8.0%
BBB penetrant	No

Transporters

BCRP (Inhibitor)BSEP (Inhibitor)MRP1 (Inhibitor)OATP1B1 (Inhibitor)OATP1B1 (Inhibitor)OATP1B3 (Inhibitor)P-gp (Inhibitor)P-gp (Substrate)

Drug–drug interactions (72, DDInter)

Interacting drug	Severity	Management
Amikacin	major
Amikacin (liposome)	major
Atracurium	major
Botulinum Toxin Type B	major
Botulinum toxin type A	major
Cidofovir	major
Cisatracurium	major
Deferasirox	major
Diatrizoate	major
Doxacurium	major
Everolimus	major
Gentamicin	major
Human Rho(D) immune globulin	major
Human botulinum neurotoxin A/B immune globulin	major
Human cytomegalovirus immune globulin	major
Human immunoglobulin G (intravenous and subcutaneous)	major
Human immunoglobulin G (intravenous)	major
Inotersen	major
Iodipamide	major
Iodixanol	major
Iohexol	major
Iopamidol	major
Iopromide	major
Iothalamic acid	major
Ioversol	major
Ioxilan	major
Kanamycin	major
Metocurine	major
Mivacurium	major
Neomycin	major
Netilmicin	major
Pancuronium	major
Pipecuronium	major
Plazomicin	major
Rapacuronium	major
Rocuronium	major
Sirolimus	major
Streptomycin	major
Succinylcholine	major
Tacrolimus	major

Showing 40 of 72.

Registered Products (12)

Brand	Form / strength	Pack	Agent	Citizen (JOD)
Otosporin Ear / Drops	Eye/Ear Drops 10 mg/ml, 3400 IU, 10000 IU	5 ml	Suleiman Tannous & Sons Co. Ltd	0.940
multicin Z center oint.	Ointment 3.5 mg, 5000 IU, 400 IU	15 g tube pack varies	MIDDLE EAST PHARMA&CHEMICAL IND/JORDAN	0.970
Detroz-P	Injection 1 mg/ml, 3500 IU/ml, 6000 IU/ml	5 ml	Dar Al Dawa Development and Investment Co Ltd/Jordan	1.140
Cebemyxine e/o	Ophthalmic Ointment 1000000 IU, 430000 IU	5 g tube	Petra Drug Store	1.320
TERRACORTRIL E/E OINTMENT	Ointment 10 mg, 5 mg, 10000 IU	3.5 g tube	Sabbagh Drug Store	1.320
TERRACORTRIL E/E SUSP	Suspension 5.7 mg, 11.400 IU, 17 mg	5 ml	Sabbagh Drug Store	1.350
multicin z center powder	Powder (as Sulphate)3.5 mg/g, (as Sulphate)5000 IU/g, (as zinc)400 IU/g	15 g	MIDDLE EAST PHARMA&CHEMICAL IND/JORDAN	1.560
Neopred-P eye ear drops	Ophthalmic Solution 10000 IU, 5 mg, 5 mg	10 ml	Amman Pharmaceutical Industries Co	1.800
multicin Z center oint.	Ointment 3.5 mg, 5000 IU, 400 IU	30 g tube pack varies	MIDDLE EAST PHARMA&CHEMICAL IND/JORDAN	1.840
Maxitrol Eye Drops	Ophthalmic Solution 1 mg/ml, 6.000 IU/ml, 3.500 IU/ml	5 ml	The Jordan Drugstore Co	2.460
Polygynax 12 Ovules	Ovule 100000 IU, 35000 IU, 35000 IU	12	Quality Drug Store	4.710
Multisol Aerosol 150 gm	Cream 500.000 IU, 150.000 IU, 40.000 IU	150 gm	MIDDLE EAST PHARMA&CHEMICAL IND/JORDAN	7.320