POLYMYXIN B: 644 Adverse Event Reports & Safety Profile

DESCRIPTION Polymyxin B for Injection, USP is one of a group of basic polypeptide antibiotics derived from B polymyxa (B aerosporous) . Polymyxin B sulfate is the sulfate salt of Polymyxins B 1 and B 2 , which are produced by the growth of Bacillus polymyxa (Prazmowski) Migula (Fam. Bacillacea). Polymyxin B sulfate, USP is a white or off-white powder. It has a potency of not less than 6,000 polymyxin B units per mg, calculated on the anhydrous basis. The structural formulae are: Each vial contains 500,000 polymyxin B units for parenteral or ophthalmic administration. Polymyxin B for Injection, USP is a sterile, white lyophilized cake or powder, suitable for preparation of sterile solutions for intramuscular, intravenous drip, intrathecal, or ophthalmic use. In the medical literature, dosages have frequently been given in terms of equivalent weights of pure polymyxin B base. Each milligram of pure polymyxin B base is equivalent to 10,000 units of polymyxin B and each microgram of pure polymyxin B base is equivalent to 10 units of polymyxin B. Aqueous solutions of polymyxin B sulfate may be stored up to 12 months without significant loss of potency if kept under refrigeration. In the interest of safety, solutions for parenteral use should be stored under refrigeration and any unused portion should be discarded after 72 hours. Polymyxin B sulfate should not be stored in alkaline solutions since they are less stable. Polymyxin B Sulfate Chemical Structure

INDICATIONS AND USAGE Acute Infections Caused by Susceptible Strains of Pseudomonas aeruginosa . Polymyxin B sulfate is a drug of choice in the treatment of infections of the urinary tract, meninges, and bloodstream caused by susceptible strains of Ps. aeruginosa. It may also be used topically and subconjunctivally in the treatment of infections of the eye caused by susceptible strains of Ps. aeruginosa . It may be indicated in serious infections caused by susceptible strains of the following organisms, when less potentially toxic drugs are ineffective or contraindicated: H. influenzae , specifically meningeal infections. Escherichia coli , specifically urinary tract infections. Aerobacter aerogenes , specifically bacteremia. Klebsiella pneumoniae , specifically bacteremia. NOTE: IN MENINGEAL INFECTIONS, POLYMYXIN B SULFATE SHOULD BE ADMINISTERED ONLY BY THE INTRATHECAL ROUTE. To reduce the development of drug-resistant bacteria and maintain the effectiveness of polymyxin B and other antibacterial drugs, polymyxin B should be used only to treat or prevent infections that are proven or strongly suspected to be caused by susceptible bacteria. When culture and susceptibility information are available, they should be considered in selecting or modifying antibacterial therapy. In the absence of such data, local epidemiology and susceptibility patterns may contribute to the empiric selection of therapy.

DOSAGE AND ADMINISTRATION PARENTERAL: Intravenous.

Dissolve

500,000 polymyxin B units in 300 to 500 mL solutions for parenteral 5% Dextrose Injection for continuous drip. Adults and children. 15,000 to 25,000 units/kg body weight/day in individuals with normal kidney function. This amount should be reduced from 15,000 units/kg downward for individuals with kidney impairment. Infusions may be given every 12 hours; however, the total daily dose must not exceed 25,000 units/kg/day. Infants. Infants with normal kidney function may receive up to 40,000 units/kg/day without adverse effects. Intramuscular. Not recommended routinely because of severe pain at injection sites, particularly in infants and children.

Dissolve

500,000 Polymyxin B units in 2 mL Sterile Water for Injection or 0.9 % Sodium Chloride Injection or Procaine Hydrochloride Injection 1%. Adults and children. 25,000 to 30,000 units/kg/day. This should be reduced in the presence of renal impairment. The dosage may be divided and given at either 4 or 6 hour intervals. Infants. Infants with normal kidney function may receive up to 40,000 units/kg/day without adverse effects. Note: Doses as high as 45,000 units/kg/day have been used in limited clinical studies in treating prematures and newborn infants for sepsis caused by Ps aeruginosa. Intrathecal . A treatment of choice for Ps aeruginosa meningitis.

Dissolve

500,000 polymyxin B units in 10 mL 0.9 % Sodium Chloride Injection USP for 50,000 units per mL dosage unit. Adults and children over 2 years of age. Dosage is 50,000 units once daily intrathecally for 3 to 4 days, then 50,000 units once every other day for at least 2 weeks after cultures of the cerebrospinal fluid are negative and sugar content has returned to normal. Children under 2 years of age. 20,000 units once daily, intrathecally for 3 to 4 days or 25,000 units once every other day. Continue with a dose of 25,000 units once every other day for at least 2 weeks after cultures of the cerebrospinal fluid are negative and sugar content has returned to normal. IN THE INTEREST OF SAFETY, SOLUTIONS OF PARENTERAL USE SHOULD BE STORED UNDER REFRIGERATION, AND ANY UNUSED PORTIONS SHOULD BE DISCARDED AFTER 72 HOURS. TOPICAL: Ophthalmic .

Dissolve

500,000 polymyxin B units in 20 to 50 mL sterile water for injection or 0.9% sodium chloride injection, USP for a 10,000 to 25,000 units per mL concentration. For the treatment of Ps aeruginosa infections of the eye, a concentration of 0.1 percent to 0.25 percent (10,000 units to 25,000 units per mL) is administered 1 to 3 drops every hour, increasing the intervals as response indicates. Subconjunctival injection of up to 100,000 units/day may be used for the treatment of Ps aeruginosa infections of the cornea and conjunctiva. Note: Avoid total systemic and ophthalmic instillation over 25,000 units/kg/day.

CONTRAINDICATIONS Trimethoprim Sulfate and Polymyxin B Sulfate Ophthalmic Solution is contraindicated in patients with known hypersensitivity to any of its components.

ADVERSE REACTIONS See WARNING box. Nephrotoxic reactions Albuminuria, cylinduria, azotemia, and rising blood levels without any increase in dosage. Renal system reactions electrolyte and acid/base abnormalities (i.e.,Pseudo-Bartter syndrome) Neurotoxic reactions Facial flushing, dizziness progressing to ataxia, drowsiness, peripheral paresthesias (circumoral and stocking glove), apnea due to concurrent use of curariform muscle relaxants, other neurotoxic drugs or inadvertent overdosage, and signs of meningeal irritation with intrathecal administration, e.g., fever, headache, stiff neck and increased cell count and protein cerebrospinal fluid. Other reactions occasionally reported Drug fever, urticarial rash, pain (severe) at intramuscular injection sites, and thrombophlebitis at intravenous injection sites. To report SUSPECTED ADVERSE REACTIONS, contact Xellia Pharmaceuticals Inc at [email protected] or 1-833-295-6953, or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

WARNINGS Clostridium difficile associated diarrhea (CDAD) has been reported with use of nearly all antibacterial agents, including Polymyxin B for Injection, and may range in severity from mild diarrhea to fatal colitis. Treatment with antibacterial agents alters the normal flora of the colon leading to overgrowth of C. difficile . C. difficile produces toxins A and B which contribute to the development of CDAD. Hypertoxin producing strains of C. difficile cause increased morbidity and mortality, as these infections can be refractory to antimicrobial therapy and may require colectomy. CDAD must be considered in all patients who present with diarrhea following antibiotic use. Careful medical history is necessary since CDAD has been reported to occur over two months after the administration of antibacterial agents. If CDAD is suspected or confirmed, ongoing antibiotic use not directed against C. difficile may need to be discontinued. Appropriate fluid and electrolyte management, protein supplementation, antibiotic treatment of C. difficile , and surgical evaluation should be instituted as clinically indicated. Electrolyte and Acid/Base Abnormalities Postmarketing cases of renal tubulopathy (i.e., Pseudo-Bartter syndrome) have been identified with the use of intravenous polymyxins, including polymyxin B (see ADVERSE REACTIONS ). All cases reported hypokalemia and metabolic alkalosis. Other common findings included hypocalcemia, hypomagnesemia, increased potassium in the urine, normal serum creatinine, and normal blood pressure. Consider electrolyte monitoring during treatment. Normalization of electrolyte abnormalities may require drug discontinuation.

PRECAUTIONS General As with other antimicrobial preparations, prolonged use may result in overgrowth of nonsusceptible organisms, including fungi. If superinfection occurs, appropriate therapy should be initiated. Information for Patients Avoid contaminating the applicator tip with material from the eye, fingers, or other source. This precaution is necessary if the sterility of the drops is to be maintained. If hypersensitivity reactions such as redness, irritation, swelling, or pain persist or increase, discontinue use immediately and contact your physician. Patients should be advised not to wear contact lenses if they have signs and symptoms of ocular bacterial infections. Repackaged By / Distributed By: RemedyRepack Inc. 625 Kolter Drive, Indiana, PA 15701 (724) 465-8762 Carcinogenesis, Mutagenesis, Impairment of Fertility Carcinogenesis: Long-term studies in animals to evaluate carcinogenic potential have not been conducted with polymyxin B sulfate or trimethoprim. Mutagenesis: Trimethoprim was demonstrated to be non-mutagenic in the Ames assay. In studies at two laboratories no chromosomal damage was detected in cultured Chinese hamster ovary cells at concentrations approximately 500 times human plasma levels after oral administration; at concentrations approximately 1,000 times human plasma levels after oral administration in these same cells, a low level of chromosomal damage was induced at one of the laboratories. Studies to evaluate mutagenic potential have not been conducted with polymyxin B sulfate. Impairment of Fertility: Polymyxin B sulfate has been reported to impair the motility of equine sperm, but its effects on male or female fertility are unknown. No adverse effects on fertility or general reproductive performance were observed in rats given trimethoprim in oral dosages as high as 70 mg/kg/day for males and 14 mg/kg/day for females.

Pregnancy Teratogenic Effects

Animal reproduction studies have not been conducted with polymyxin B sulfate. It is not known whether polymyxin B sulfate can cause fetal harm when administered to a pregnant woman or can affect reproduction capacity. Trimethoprim has been shown to be teratogenic in the rat when given in oral doses 40 times the human dose. In some rabbit studies, the overall increase in fetal loss (dead and resorbed and malformed conceptuses) was associated with oral doses 6 times the human therapeutic dose. While there are no large well-controlled studies on the use of trimethoprim in pregnant women, Brumfitt and Pursell, in a retrospective study, reported the outcome of 186 pregnancies during which the mother received either placebo or oral trimethoprim in combination with sulfamethoxazole. The incidence of congenital abnormalities was 4.5% (3 of 66) in those who received placebo and 3.3% (4 of 120) in those receiving trimethoprim and sulfamethoxazole. There were no abnormalities in the 10 children whose mothers received the drug during the first trimester. In a separate survey, Brumfitt and Pursell also found no congenital abnormalities in 35 children whose mothers had received oral trimethoprim and sulfamethoxazole at the time of conception or shortly thereafter. Because trimethoprim may interfere with folic acid metabolism, trimethoprim should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

Nonteratogenic Effects

The oral administration of trimethoprim to rats at a dose of 70 mg/kg/day commencing with the last third of gestation and continuing through parturition and lactation caused no deleterious effects on gestation or pup growth and survival.

Nursing

Mothers It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when Polymyxin B Sulfate and Trimethoprim Ophthalmic Solution is administered to a nursing woman.

Pediatric Use

Safety and effectiveness in children below the age of 2 months have not been established [see Warnings ] .

Geriatric

Use No overall differences in safety or effectiveness have been observed between elderly and other adult patients.