POLYMYXIN B Powder for solution for injection Ref.[10829] Active ingredients: Polymyxin B

Serious Warnings and Precautions

• Polymyxin B for Injection USP is nephrotoxic therefore renal function should be assessed prior to and regularly during treatment. Dose adjustment is required in patients with reduced renal function (See WARNINGS AND PRECAUTIONS, Renal, Monitoring and Laboratory Tests, Renal; ADVERSE REACTIONS; DOSAGE AND ADMINISTRATION).
• Polymyxin B for Injection USP at therapeutic doses may cause serious neurotoxic symptoms as manifested by ataxia, seizure and neuromuscular blockade. These are usually associated with high drug serum levels found in patients with impaired renal function and/or nephrotoxicity (See WARNINGS AND PRECAUTIONS, Neurologic, Respiratory; Monitoring and Laboratory Tests, Neurologic; ADVERSE REACTIONS).
• The concurrent/sequential use of other nephrotoxic drugs including antimicrobials should be avoided with Polymyxin B for Injection USP treatment (See WARNINGS AND PRECAUTIONS, Neurologic, Renal; Monitoring and Laboratory Tests, Renal, DRUG INTERACTIONS, Drug-Drug Interactions).
• The concurrent/sequential use of anaesthetic and other neurotoxic drugs should be avoided with Polymyxin B for Injection USP treatment. The neurotoxicity of polymyxin B sulphate can result in respiratory paralysis from neuromuscular blockade, especially when the drug is given soon after anaesthesia and/or muscle relaxants. If signs of respiratory paralysis appear, assist respiration and withdraw the drug (See WARNINGS AND PRECAUTIONS, Immune, Neurologic, Renal, Respiratory; Monitoring and Laboratory Tests, Renal, Neurologic; DRUG INTERACTIONS, Drug-Drug Interactions).

General

The intramuscular, intravenous, and/or intrathecal administration of Polymyxin B for Injection USP should be restricted to hospitalized patents so as to provide constant clinical supervision. Maximum dosage should not exceed 2.5 mg/kg/day or a total of 200 mg/day in patients with normal renal function.

Intramuscular dosage is not recommended routinely because of severe pain at injection sites. When procaine is used with polymyxin B sulphate to lessen the pain of intramuscular injection, care should be taken not to give; intrathecally or intravenously, solutions that have been prepared with procaine for intramuscular use (See DOSAGE AND ADMINISTRATION).

Polymyxin B sulphate should be used with extreme caution in patients with porphyria.

Polymyxin B sulphate is not active and therefore should not be used for the treatment of bacterial infections caused by gram-negative bacteria (Proteus spp., Providencia spp., Morganella spp., Serratia marcescens, Burkholderia spp., Neisseria spp.), all gram-positive bacteria and anaerobes. It is critical that adjunct therapy be initiated immediately if a concomitant bacterial pathogen is documented or suspected (See INDICATIONS AND CLINICAL USE; ACTION AND CLINICAL PHARMACOLOGY, Mechanism of Action, PART II: SCIENTIFIC INFORMATION, MICROBIOLOGY).

Cardiovascular

QT Interval Prolongation

The effect of polymyxin B sulphate on prolonged cardiac repolarization, QT interval, and increased risk of developing cardiac arrhythmia and torsades de pointes is not known.

Gastrointestinal

Clostridium difficile-associated disease

Clostridium difficile-associated disease (CDAD) has been reported with the use of many antibacterial agents, including polymyxin B sulphate. CDAD may range in severity from mild diarrhea to fatal colitis. It is important to consider this diagnosis in patients who present with diarrhea, symptoms of colitis, pseudomembranous colitis, toxic megacolon, or perforation of colon subsequent to the administration of any antibacterial agent. CDAD has been reported to occur over 2 months after the administration of antibacterial agents.

Treatment with antibacterial agents may alter the normal flora of the colon and may permit overgrowth of Clostridium difficile. C. difficile produces toxins A and B, which contribute to the development of CDAD. CDAD may cause significant morbidity and mortality. CDAD can be refractory to antimicrobial therapy.

If the diagnosis of CDAD is suspected or confirmed, appropriate therapeutic measures should be initiated. Mild cases of CDAD usually respond to discontinuation of antibacterial agents not directed against C. difficile. In moderate to severe cases, consideration should be given to management with fluids and electrolytes, protein supplementation, and treatment with an antibacterial agent clinically effective against C. difficile. Surgical evaluation should be instituted as clinically indicated; as surgical intervention may be required in certain severe cases (See ADVERSE REACTIONS).

Immune

Hypersensitivity Reactions

Serious hypersensitivity reactions including apnea and bronchoconstriction have been reported in patients receiving polymyxin B sulphate by inhalation administration. Anaphylactoid reactions have been reported with parenteral administration of polymyxin B sulphate. Patients with a known allergy to bacitracin are at higher risk of developing hypersensitivity reactions with the use of polymyxins as cross-reactivity between bacitracin and polymyxins exists.

Before therapy with Polymyxin B for Injection USP is instituted, careful inquiry should be made to determine whether the patient has had a previous hypersensitivity reaction to polymyxins or bacitracin. Polymyxin B for Injection USP should not be administered by inhalation. If an allergic reaction occurs, discontinue the drug. Serious acute hypersensitivity (anaphylaxis or air way constriction) requires emergency treatment as clinically indicated (See WARNINGS AND PRECAUTIONS, Neurologic, Respiratory, ADVERSE REACTIONS).

Neurologic

Neurological disturbances including neuromuscular blockade (generalized muscle weakness, respiratory depression or arrest), seizure, circumoral paresthesia or numbness, vertigo, blurred vision, facial flushing, and slurring of speech, have been reported with polymyxin B sulphate at therapeutic doses. These usually occur with high serum drug concentrations found in patients with renal impairment, drug nephrotoxicity or with inhalation of polymyxin B sulphate.

Mild neurological manifestations of polymyxins usually subside after prompt cessation of polymyxin B sulphate therapy. If signs of respiratory paralysis appear, discontinue use of polymyxin B sulphate and other neurotoxic agents immediately. Apnea should be treated with assisted respiration. Avoid concurrent use of nephrotoxic and/or neuromuscular blocking curariform muscle relaxants and other potential neurotoxic drugs, which may precipitate respiratory depression (See WARNINGS AND PRECAUTIONS: Renal, Respiratory; ADVERSE REACTIONS, DRUG INTERACTIONS, Drug-drug Interactions; Monitoring and Laboratory Tests, Neurologic).

Ophthalmic

Subconjunctival administration of polymyxin B sulphate may be painful. Deep seated or walled off Pseudomonas aeruginosa infections cannot be expected to respond to ophthalmic treatment and may require systemic therapy. Therefore, Polymyxin B for Injection USP should not be used for treatment of these infections.

Renal

Polymyxins induce nephrotoxicity by increasing membrane permeability. Rising blood concentrations of polymyxin B, albuminuria, cellular casts, diminishing urine output and rising BUN have been reported with the use of polymyxin B sulphate at therapeutic doses. Acute renal failure has been reported in patients on polymyxin B sulphate therapy. Nephrotoxicity is dose dependent.

Baseline renal function should be assessed prior to and regularly during therapy. Since elderly patients may have impaired renal function, special care should be taken with drug dosing. If renal dysfunction develops, therapy with polymyxin B sulphate should be discontinued immediately. The nephrotoxic effect is usually reversible upon discontinuation of therapy.

In patients with pre-existing renal dysfunction, polymyxin B sulphate dosage adjustment and frequent renal function assessment are required because of the potential for increased drug accumulation under these conditions (See ADVERSE REACTIONS: DRUG INTERACTIONS: Drug-drug Interactions; DOSAGE AND ADMINISTRATION, Patients with Renal Impairment).

The concurrent use of other nephrotoxic drugs including antimicrobials (particularly bacitracin, aminoglycosides, cephaloridine, cephalothin, amphotericin B, paromycin, polymyxin E (colistin) and vancomycin) should be avoided (See DRUG INTERACTIONS, Drug-Drug Interactions; Monitoring and Laboratory Tests, Renal).

Respiratory

Significant deterioration of lung function including apnea, bronchospasm, decreases in vital capacity, forced expiratory volume over one second and maximum voluntary ventilation have been reported following aerosol administration of polymyxin B sulphate. Polymyxin B for Injection USP should not be administered by inhalation (See ADVERSE REACTIONS; DOSAGE AND ADMINISTRATION).

Special Populations

Pregnant Women

Clinical data from the use of polymyxin B sulphate in pregnant women is not available. Polymyxin B for Injection USP should not be used during pregnancy unless the expected benefit to the mother outweighs any possible risk to the fetus. Animal studies are also lacking with respect to embryotoxicity and/or teratogenicity of polymyxin B sulphate.

Nursing Women

It is not known whether polymyxin B sulphate is secreted in breast or animal milk. Because of the potential for unknown effects of the drug in infants being nursed by mothers taking polymyxin B sulphate, a decision should be made to either discontinue nursing or discontinue treatment, taking into account the importance of Polymyxin B for Injection USP drug treatment to the mother and the possible risk to the infant.

Pediatrics (<18 years)

Safety and efficacy of polymyxin B sulphate in children greater than 2 years of age is limited. Renal function should be frequently monitored in this population.

Safety and efficacy of parenteral polymyxin B sulphate in infants less than 2 years of age is limited. A possibility of higher serum levels and prolonged half-life has been reported in infants and neonates, therefore dosage recommendations are not available in this population (See DOSAGE AND ADMINISTRATION; PART II: SCIENTIFIC INFORMATION, DETAILED PHARMACOLOGY).

Geriatrics (≥65 years of age)

Limited data is available on the safety and efficacy of polymyxin B sulphate in the elderly. The decline in renal function with advanced age should be considered and renal function should be assessed prior to and regularly during therapy.

Monitoring and Laboratory Tests

Renal

Consideration should be given to monitoring renal function (albuminuria, cellular casts, blood urea nitrogen (BUN), serum creatinine or creatinine clearance) prior to and regularly during Polymyxin B for Injection USP treatment.

Neurologic

Patients should be monitored for neurologic signs and symptoms (e.g., apnea, numbness, vertigo, blurred vision, facial flushing and slurring of speech) during Polymyxin B for Injection USP therapy.

Drug-Lab Interactions

Consideration should be given to monitoring electrolyte abnormalities such as hypokalemia, hyponatremia, hypochloremia.

Adverse Drug Reaction Overview

The most common drug-related adverse reactions are nephrotoxicity and neurotoxicity, pain at the injection site, urticaria, and electrolyte imbalance.

Clinical Trial Adverse Drug Reactions

Prospective clinical trials were not conducted for polymyxin B sulphate. Therefore drug-related adverse reactions that could occur are derived from adverse drug reporting from retrospective clinical studies.

Renal and Urinary Disorders: albuminuria, cylindruria (urinary cast), azotemia (a diminishing urine output and rising BUN).

Nervous System Disorders: facial flushing, dizziness progressing to ataxia, drowsiness, circumoral, lingual and peripheral paresthesia (stocking-glove distribution), apnea due to concurrent use of curariform muscle relaxants or other neurotoxic drugs, or inadvertent overdosage, signs of meningeal irritation presenting as convulsions and signs of meningismus with intrathecal administration (e.g., fever, headache, seizure, stiff neck and increased cell count and protein in cerebrospinal fluid following intrathecal/intraventricular administration of polymyxin B sulphate).

Immune System Disorders: urticarial rash at intramuscular injection sites. Allergic hypersensitivity following topical application of polymyxin B sulphate has been reported.

General Disorders & Administration Site Conditions: pain (severe) at intramuscular injection sites, and thrombophlebitis at intravenous injection sites.

Less Common Clinical Trial Adverse Drug Reactions (<1%)

Information not available.

Abnormal Hematologic and Clinical Chemistry Findings

Electrolyte imbalance (including hyponatremia, hypochloremia and hypocalcemia) has been reported during parenteral therapy in patients with serious underlying malignant disease.

Eosinophilia has been reported, but the significance of this finding is not established.

Post-Market Adverse Drug Reactions

Eye Disorder: ophthalmic application of polymyxin B sulphate has reported low-grade conjunctivitis

Gastrointestinal Disorders: pseudomembraneous colitis

Immune System Disorders: bronchoconstriction following administration of nebulized polymyxins, anaphylactoid reactions, rash/pruritus, dermatitis and drug fever

Nervous System Disorders: facial paralysis, partial deafness, visual disturbance, vertigo, seizure and neuromuscular weakness and neuromuscular blockade

Renal and Urinary Disorders: acute renal failure

Overview

Concomitant administration of diuretics and potential nephrotoxic and/or neurotoxic agents including antimicrobials increases the likelihood of renal toxicity, whereas non-polarizing muscle relaxants and other neurotoxic drugs increase the likelihood of serious neurotoxicity.

Drug-Drug Interactions

The concurrent use of other nephrotoxic and/or neurotoxic drugs particularly bacitracin, kanamycin, streptomycin, tobramycin, amikacin, cephaloridine, cephalothin, paromycin, polymyxin E (colistin), neomycin, gentamicin, and vancomycin should be avoided (See WARNINGS AND PRECAUTIONS – Neurologic).

Due to the effect of polymyxin B sulphate on the release of acetylcholine, non-polarizing muscle relaxants (ether, tubocurarine, gallamine, decamethonium, sodium citrate), depolarizing muscle relaxant succinylcholine, and other neurotoxic drugs should not be used concurrently with polymyxin B sulphate (See WARNINGS AND PRECAUTIONS, Respiratory).

The concurrent use of polymyxin B sulphate with potent diuretics such as ethacrynic acid or furosemide should be avoided, since diuretics may enhance polymyxin B sulphate toxicity by altering the antibiotic concentration in serum and tissues.

Drug-Food Interactions

Information not available.

Drug-Herb Interactions

Information not available.

Drug-Laboratory Interactions

Information not available.

Drug-Lifestyle Interactions

Information not available.