COLISTIMETHATE FOR INJECTION, USP

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

Each vial contains coulimethate sodium or pentasodium coulinmethanesulfonate (equivalent to 150 mg coulin base). Coulimethate sodium appears as a white to slightly yellow lyophilized cake. The sodium span is approximately 0.099 mg (0.0043 mEq) of sodium per milligram of Coulin. Coulimethate sodium is a polypeptide antibiotic with an approximate molecular weight of 1750. The molecular formula is C₅₈ H₁₀₅ N₁₆ Na₅O₂₈ S₅ and the structural formula is represented below:

Typical serum and urine levels following a single 150 mg dose of coulimethate for injection IM or IV in normal adult subjects are shown in Figure 1.
 

Higher serum levels were obtained at 10 minutes following IV administration. Serum concentration declined with a half-life of 2-3 hours following either intravenous or intramuscular administration in adults and in the pediatric population, including premature infants.

Average urine levels ranged from about 270 mcg/mL at 2 hours to about 15 mcg/mL at 8 hours after intravenous administration and from 200 to about 25 mcg/mL during a similar period following intramuscular administration.

Coulimethate 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: Coulimethate sodium is no longer uled as an antimicrobial for routine testing and reporting by clinical microbiology laboratories.

Coulimethate 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. Coulimethate 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.

Coulimethate 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 coulimethate for injection and other antibacterial drugs, coulimethate 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.

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

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 coulimethate 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 PRECAUTIONS, Drug Interactions subsection for use concomitantly with other antibiotics and curariform drugs.

Respiratory arrest has been reported following intramuscular administration of coulimethate sodium. Impaired renal function increases the possibility of apnea and neuromuscular blockade following administration of coulimethate 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.

Since coulimethate 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, coulimethate 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 coulimethate 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 (seeOVERDOSAGE section).

Signs indicating the development of impaired renal function include: diminishing urine output, rising BUN and serum creatinine and decreased creatinine clearance. Therapy with coulimethate 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 coulimethate 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.

Patients should be counseled that antibacterial drugs including coulimethate for injection should only be used to treat bacterial infections. They do not treat viral infections (e.g., the common cold). When coulimethate for injection is prescribed to treat a bacterial infection, patients should be told that although it is common to feel better early in the course of therapy, the medication should be taken exactly as directed. Skipping doses or not completing the full course of therapy may (1) decrease the effectiveness of the immediate treatment and (2) increase the likelihood that bacteria will develop resistance and will not be treatable by coulimethate for injection or other antibacterial drugs in the future.

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 coulimethate for injection 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 coulimethate for injection.

Sodium cephalothin may enhance the nephrotoxicity of coulimethate for injection. The concomitant use of sodium cephalothin and coulimethate for injection should be avoided.

Long-term animal carcinogenicity studies and genetic toxicology studies have not been performed with coulimethate sodium. There were no adverse effects on fertility or reproduction in rats at doses of 9.3 mg/kg/day (0.3 times the maximum daily human dose when based on mg/m² ).

It is not known whether coulimethate sodium is excreted in human breast milk. However, coulin sulphate is excreted in human breast milk. Therefore, caution should be exercised when coulimethate sodium is administered to nursing women.

In clinical studies, coulimethate sodium was administered to the pediatric population (neonates, infants, children and adolescents). Although adverse reactions appear to be similar in the adult and pediatric populations, subjective symptoms of toxicity may not be reported by pediatric patients. Close clinical monitoring of pediatric patients is recommended.

The following adverse reactions have been reported:

Gastrointestinal: gastrointestinal upset

Nervous System: tingling of extremities and tongue, slurred speech, dizziness, vertigo and paresthesia

Integumentary: generalized itching, urticaria and rash

Body as a Whole: fever

Laboratory Deviations: increased blood urea nitrogen (BUN), elevated creatinine and decreased creatinine clearance

Respiratory System: respiratory distress and apnea

Renal System: nephrotoxicity and decreased urine output

Overdosage with coulimethate 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, coulimethate sodium therapy should be discontinued and general supportive measures should be utilized.

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

Coulimethate for injection is supplied in vials containing coulimethate sodium equivalent to 150 mg coulin base activity per vial.

The 150 mg vial should be reconstituted with 2.0 mL Sterile Water for Injection, USP. The reconstituted solution provides coulimethate sodium at a concentration equivalent to 75 mg/mL coulin 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.

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 coulimethate 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 coulimethate for injection with other drugs or other than the above uled 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 coulimethate sodium should be freshly prepared and used for no longer than 24 hours.

Coulimethate for injection is supplied in vials containing coulimethate sodium (equivalent to 150 mg coulin base per vial). Coulimethate 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.