Colistimethate Sodium  (colistin)

Colistimethate sodium  (Colistin) - Coly-Mycin®

Usual Diluents

Standard Dilution [Amount of drug] [Infusion volume] [Infusion rate]

2. Continuous Infusion - Slowly inject one-half of the total daily dose over 3 to 5 minutes. Add the remaining half of the total daily dose of colistimethate for injection to one of the following:

0.9% NaCl
5% dextrose in 0.9% NaCl
5% dextrose in water
5% dextrose in 0.45% NaCl
5% dextrose in 0.225% NaCl
Lactated Ringer's solution

There are not sufficient data to recommend usage of colistimethate for injection with other drugs or other than the above listed infusion solutions.

Administer the second half of the total daily dose by slow intravenous infusion, starting 1 to 2 hours after the initial dose, over the next 22 to 23 hours. In the presence of impaired renal function, reduce the infusion rate depending on the degree of renal impairment.

The choice of intravenous solution and the volume to be employed are dictated by the requirements of fluid and electrolyte management.

Any infusion solution containing colistimethate sodium should be freshly prepared and used for no longer than 24 hours.

3. Alternative method - not listed in package insert but available in specialized references: Intermittent infusion: [Prescribed dose] [50 - 100 ml] [30 minutes]

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Colistin dosing calculator (beta) - output based on the latest guidelines located (July 2014). Package insert guidelines in many cases may lead to sub-therapeutic steady state concentrations (Css) based on the MIC for the target organism(s), and the site and severity of the infection.
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Stability / Miscellaneous

Stability:
Solution (IVPB): 24 hours RT or REF.

Vial: Store reconstituted solution in refrigerator 2° to 8°C (36° to 46°F) or between 20° to 25°C (68° to 77°F), and use within 7 days.

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FOR INTRAMUSCULAR AND INTRAVENOUS USE
To reduce the development of drug-resistant bacteria and maintain the effectiveness of colistimethate for injection and other antibacterial drugs, colistimethate for injection should be used only to treat or prevent infections that are proven or strongly suspected to be caused by bacteria.

DESCRIPTION
Colistimethate for injection (colistimethate sodium) is a sterile parenteral antibiotic product which, when reconstituted (see Reconstitution), is suitable for intramuscular or intravenous administration.

Each vial contains colistimethate sodium or pentasodium colistinmethanesulfonate (equivalent to 150 mg colistin base). Colistimethate sodium appears as a white to slightly yellow lyophilized cake. The sodium content is approximately 0.099 mg (0.0043 mEq) of sodium per milligram of Colistin. Colistimethate sodium is a polypeptide antibiotic with an approximate molecular weight of 1750.

CLINICAL PHARMACOLOGY
Microbiology:
Colistimethate sodium is a surface active agent which penetrates into and disrupts the bacterial cell membrane. It has been shown to have bactericidal activity against most strains of the following microorganisms, both in vitro and in clinical infections as described in the INDICATIONS AND USAGE section:

Aerobic gram-negative microorganisms: Enterobacter aerogenes, Escherichia coli, Klebsiella pneumoniae, and Pseudomonas aeruginosa.

Susceptibility Tests: Colistimethate sodium is no longer listed as an antimicrobial for routine testing and reporting by clinical microbiology laboratories.

INDICATIONS AND USAGE
Colistimethate for injection 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 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 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 and other antibacterial drugs, colistimethate for injection 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.

CONTRAINDICATIONS
The use of colistimethate for injection is contraindicated for patients with a history of sensitivity to the drug or any of its components.

WARNINGS
Maximum daily dose should not exceed 5 mg/kg/day (2.3 mg/lb) 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.

Overdosage can result in renal insufficiency, muscle weakness, and apnea (see OVERDOSAGE section). See package insert for 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.

Pseudomembranous colitis has been reported with nearly all antimicrobial agents, and may range in severity from mild to life-threatening. Therefore, it is important to consider this diagnosis in patients who present with diarrhea subsequent to the administration of antibacterial agents.

Treatment with antibacterial agents alters the normal flora of the colon and may permit overgrowth of clostridia. Studies indicate that a toxin produced by Clostridium difficile is a primary cause of "antibiotic-associated colitis."

After the diagnosis of pseudomembranous colitis has been established, appropriate therapeutic measures should be initiated. Mild cases of pseudomembranous colitis usually respond to drug discontinuation alone. In moderate-to-severe cases, consideration should be given to management with fluids and electrolytes, protein supplementation, and treatment with an antibacterial drug clinically effective against Clostridium difficile colitis.

PRECAUTIONS
General
Since colistimethate for injection is eliminated mainly by renal excretion, it should be used with caution when the possibility of impaired renal function exists. The decline in renal function with advanced age should be considered.

When actual renal impairment is present, colistimethate for injection may be used, but the greatest caution should be exercised and the dosage should be reduced in proportion to the extent of the impairment. Administration of amounts of colistimethate for injection in excess of renal excretory capacity will lead to high serum levels and can result in further impairment of renal function, initiating a cycle which, if not recognized, can lead to acute renal insufficiency, renal shutdown, and further concentration of the antibiotic to toxic levels in the body. At this point, interference of nerve transmission at neuromuscular junctions may occur and result in muscle weakness and apnea (see OVERDOSAGE section).

Signs indicating the development of impaired renal function include: diminishing urine output, rising BUN and serum creatinine and decreased creatinine clearance. Therapy with colistimethate for injection should be discontinued immediately if signs of impaired renal function occur. However, if it is necessary to reinstate the drug, dosing should be adjusted accordingly after drug plasma levels have fallen (see DOSAGE AND ADMINISTRATION section).

Prescribing colistimethate for injection in the absence of a proven or strongly suspected bacterial infection or a prophylactic indication is unlikely to provide benefit to the patient and increases the risk of the development of drug-resistant bacteria.

see package insert for additional information....

OVERDOSAGE
Overdosage with colistimethate sodium can cause neuromuscular blockade characterized by paresthesia, lethargy, confusion, dizziness, ataxia, nystagmus, disorders of speech and apnea. Respiratory muscle paralysis may lead to apnea, respiratory arrest and death. Overdosage with the drug can also cause acute renal failure, manifested as decreased urine output and increases in serum concentrations of BUN and creatinine.

As in any case of overdose, colistimethate sodium therapy should be discontinued and general supportive measures should be utilized.

It is unknown whether colistimethate sodium can be removed by hemodialysis or peritoneal dialysis in overdose cases.

DOSAGE AND ADMINISTRATION
Important:
Colistimethate for injection is supplied in vials containing colistimethate sodium equivalent to 150 mg colistin base activity per vial.

Reconstitution:
The 150 mg vial should be reconstituted with 2.0 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:
Colistimethate for injection should be given in 2 to 4 divided doses at dose levels of 2.5 to 5 mg/kg per day 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 should be reduced in the presence of renal impairment. Modifications of dosage in the presence of renal impairment are presented in Table 1:

INTRAVENOUS ADMINISTRATION
1. Direct Intermittent Administration - Slowly inject one-half of the total daily dose over a period of 3 to 5 minutes every 12 hours.

2. Continuous Infusion - Slowly inject one-half of the total daily dose over 3 to 5 minutes. Add the remaining half of the total daily dose of colistimethate for injection to one of the following:

0.9% NaCl
5% dextrose in 0.9% NaCl
5% dextrose in water
5% dextrose in 0.45% NaCl
5% dextrose in 0.225% NaCl
Lactated Ringer's solution
10% invert sugar solution

There are not sufficient data to recommend usage of colistimethate for injection with other drugs or other than the above listed infusion solutions.

Administer the second half of the total daily dose by slow intravenous infusion, starting 1 to 2 hours after the initial dose, over the next 22 to 23 hours. In the presence of impaired renal function, reduce the infusion rate depending on the degree of renal impairment.

The choice of intravenous solution and the volume to be employed are dictated by the requirements of fluid and electrolyte management.

Any infusion solution containing colistimethate sodium should be freshly prepared and used for no longer than 24 hours.

HOW SUPPLIED
Colistimethate for injection is supplied in vials containing colistimethate sodium (equivalent to 150 mg colistin base per vial). Colistimethate sodium appears as a white to slightly yellow lyophilized cake and is available as one vial per carton.

NDC 0574-0858-01

Store between 20° - 25°C (68° - 77°F)[See USP Controlled Room Temperature].

Store reconstituted solution in refrigerator 2° to 8°C (36° to 46°F) or between 20° to 25°C (68° to 77°F), and use within 7 days.

Reference(s)