Colistin for Antibiotic Resistance

INDICATIONS AND USAGE Colistimethate for Injection, USP is indicated for the treatment of acute or chronic infections due to sensitive strains of certain gram-negative bacilli. It is particularly indicated when the infection is caused by sensitive strains of Pseudomonas aeruginosa . This antibiotic is not indicated for infections due to Proteus or Neisseria . Colistimethate for Injection, USP has proven clinically effective in treatment of infections due to the following gram-negative organisms: Enterobacter aerogenes, Escherichia coli, Klebsiella pneumoniae and Pseudomonas aeruginosa . Colistimethate for Injection, USP may be used to initiate therapy in serious infections that are suspected to be due to gram-negative organisms and in the treatment of infections due to susceptible gram-negative pathogenic bacilli. To reduce the development of drug-resistant bacteria and maintain the effectiveness of Colistimethate for Injection, USP and other antibacterial drugs, Colistimethate for Injection, USP 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 Important Colistimethate for Injection, USP is supplied in vials containing colistimethate sodium equivalent to 150 mg colistin base activity per vial. Reconstitution for Intravenous or Intramuscular Administration The 150 mg vial should be reconstituted with 2 mL Sterile Water for Injection, USP. The reconstituted solution provides colistimethate sodium at a concentration equivalent to 75 mg/mL colistin base activity. During reconstitution swirl gently to avoid frothing. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. If these conditions are observed, the product should not be used. Dosage Adults and Pediatric Patients — Intravenous or Intramuscular Administration The dose of Colistimethate for Injection, USP should be 2.5 to 5 mg/kg per day of colistin base in 2 to 4 divided doses for patients with normal renal function, depending on the severity of the infection. In obese individuals, dosage should be based on ideal body weight. The daily dose and frequency should be reduced for the patients with renal impairment. Suggested modifications of dosage schedule for patients with renal impairment are presented in Table 1. TABLE 1. Suggested Modification of Dosage Schedules of Colistimethate for Injection, USP for Adults with Impaired Renal Function Degree of Renal Impairment Normal Mild Moderate Severe Creatinine Clearance (mL/min) ≥ 80 50 to 79 30 to 49 10 to 29 Dosage Schedule 2.5 to 5 mg/kg, divided into 2 to 4 doses per day 2.5 to 3.8 mg/kg, divided into 2 doses per day 2.5 mg/kg, once daily or divided into 2 doses per day 1.5 mg/kg, every 36 hours Note: The suggested total daily dose is calculated from colistin base activity. Important Colistimethate for Injection, USP is supplied in vials containing colistimethate sodium equivalent to 150 mg colistin base activity per vial. Reconstitution for Intravenous or Intramuscular Administration The 150 mg vial should be reconstituted with 2 mL Sterile Water for Injection, USP. The reconstituted solution provides colistimethate sodium at a concentration equivalent to 75 mg/mL colistin base activity. During reconstitution swirl gently to avoid frothing. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. If these conditions are observed, the product should not be used. Dosage Adults and Pediatric Patients — Intravenous or Intramuscular Administration The dose of Colistimethate for Injection, USP should be 2.5 to 5 mg/kg per day of colistin base in 2 to 4 divided doses for patients with normal renal function, depending on the severity of the infection. In obese individuals, dosage should be based on ideal body weight. The daily dose and frequency should be reduced for the patients with renal impairment. Suggested modifications of dosage schedule for patients with renal impairment are presented in Table 1. TABLE 1. Suggested Modification of Dosage Schedules of Colistimethate for Injection, USP for Adults with Impaired Renal Function Degree of Renal Impairment Normal Mild Moderate Severe Creatinine Clearance (mL/min) ≥ 80 50 to 79 30 to 49 10 to 29 Dosage Schedule 2.5 to 5 mg/kg, divided into 2 to 4 doses per day 2.5 to 3.8 mg/kg, divided into 2 doses per day 2.5 mg/kg, once daily or divided into 2 doses per day 1.5 mg/kg, every 36 hours Note: The suggested total daily dose is calculated from colistin base activity.

WARNINGS Maximum daily dose calculated from colistin base activity should not exceed 5 mg/kg/day with normal renal function. Transient neurological disturbances may occur. These include circumoral paresthesia or numbness, tingling or formication of the extremities, generalized pruritus, vertigo, dizziness, and slurring of speech. For these reasons, patients should be warned not to drive vehicles or use hazardous machinery while on therapy. Reduction of dosage may alleviate symptoms. Therapy need not be discontinued, but such patients should be observed with particular care. Nephrotoxicity can occur and is probably a dose-dependent effect of colistimethate sodium. These manifestations of nephrotoxicity are reversible following discontinuation of the antibiotic. Electrolyte and Acid/Base Abnormalities Postmarketing cases of renal tubulopathy (i.e., Pseudo-Bartter syndrome) have been identified with the use of intravenous colistimethate sodium (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. Overdosage can result in renal insufficiency, muscle weakness, and apnea (see OVERDOSAGE section). See PRECAUTIONS, Drug Interactions subsection for use concomitantly with other antibiotics and curariform drugs. Respiratory arrest has been reported following intramuscular administration of colistimethate sodium. Impaired renal function increases the possibility of apnea and neuromuscular blockade following administration of colistimethate sodium. Therefore, it is important to follow recommended dosing guidelines. See DOSAGE AND ADMINISTRATION section for use in renal impairment. Clostridium difficile associated diarrhea (CDAD) has been reported with use of nearly all antibacterial agents, including Colistimethate for Injection, USP, 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.

Drug Interactions Certain other antibiotics (aminoglycosides and polymyxin) have also been reported to interfere with the nerve transmission at the neuromuscular junction. Based on this reported activity, they should not be given concomitantly with Colistimethate for Injection, USP except with the greatest caution. Curariform muscle relaxants (e.g., tubocurarine) and other drugs, including ether, succinylcholine, gallamine, decamethonium and sodium citrate, potentiate the neuromuscular blocking effect and should be used with extreme caution in patients being treated with Colistimethate for Injection, USP. Sodium cephalothin may enhance the nephrotoxicity of Colistimethate for Injection, USP. The concomitant use of sodium cephalothin and Colistimethate for Injection, USP should be avoided.

ADVERSE REACTIONS The following adverse reactions have been reported: Gastrointestinal: gastrointestinal upset Nervous System: tingling of extremities and tongue, slurred speech, dizziness, vertigo, paresthesia and seizures Integumentary: generalized itching, urticaria and rash Body as a Whole: fever and anaphylaxis Laboratory Deviations: increased blood urea nitrogen (BUN), elevated creatinine and decreased creatinine clearance Respiratory System: respiratory distress and apnea Renal System: electrolyte and acid/base abnormalities (i.e., Pseudo-Bartter syndrome), nephrotoxicity and decreased urine output For medical advice about adverse reactions contact your medical professional. To report SUSPECTED ADVERSE REACTIONS, contact Xellia Pharmaceuticals Inc at 1-833-295-6953, or FDA at 1-800-FDA-1088 or http://www.fda.gov/medwatch/.