COLISTIMETHATE SODIUM

Colistimethate is an antibiotic that has been shown to have bactericidal activity against aerobic gram-negative microorganisms.

Colistimethate is particularly indicated when the infection is caused by sensitive strains of Pseudomonas aeruginosa.

For the treatment of acute or chronic infections due to sensitive strains of certain gram-negative bacilli, particularly Pseudomonas aeruginosa.

Colistimethate is a polymyxin antibiotic agent.

Originally, colistimethate sodium was thought to be less toxic than polymyxin B; however, if the drugs are administered at comparable doses, their toxicities may be similar.

Polymyxins are cationic polypeptides that disrupt the bacterial cell membrane through a detergentlike mechanism.

With the development of less toxic agents, such as extended-spectrum penicillins and cephalosporins, parenteral polymyxin use was largely abandoned, except for the treatment of multidrug-resistant pulmonary infections in patients with cystic fibrosis.

More recently, however, the emergence of multidrug-resistant gram-negative bacteria, such as Pseudomonas aeruginosa and Acinetobacter baumannii, and the lack of new antimicrobial agents have led to the revived use of the polymyxins.

Very poor absorption from gastrointestinal tract.

As 80% of the dose can be recovered unchanged in the urine, and there is no biliary excretion, it can be assumed that the remaining drug is inactivated in the tissues, however the mechanism is unknown.

2-3 hours following either intravenous or intramuscular administration in adults and in the pediatric population, including premature infants.

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LD in rats is 5450 mg/kg.

Respiratory muscle paralysis may lead to apnea, respiratory arrest and death.

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 dosedependent 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.

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.

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.

The use of Colistimethate for

Injection, USP is contraindicated for patients with a history of sensitivity to the drug or any of its components.

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.

• 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 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 Note: The suggested total daily dose is calculated from colistin base activity.

Clearance (mL/min) ≥80 50-79 30-49 10-29 Dosage Schedule 2.5 to 5 mg/kg, divided into 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 INTRAVENOUS ADMINISTRATION Direct Intermittent Administration.

• Slowly inject one-half of the total daily dose over a period of to 5 minutes every 12 hours.

• Slowly inject one-half of the total daily dose over to 5 minutes.

Add the remaining half of the total daily dose of Colistimethate for Injection, USP to one of the following: 0.9% NaCI 5% dextrose in 0.9% NaCI 5% dextrose in water 5% dextrose in 0.45% NaCI 5% dextrose in 0.225% NaCI 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 to 2 hours after the initial dose, over the next 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 final intravenous infusion solution containing colistimethate sodium should be freshly prepared and used for no longer than 24 hours.

ADMINISTRATION 1.

Injection, administer by deep intramuscular injection into a large muscle mass (such as the gluteal muscles or lateral part of the thigh).

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

Colistimethate for

Injection, USP is supplied in vials containing colistimethate sodium (equivalent to 150 mg colistin base activity per vial) as a white to slightly yellow Iyophilized cake.

NDC-70594-023-09: one individual vial.

Store between 20° to 25°C (68° to 77°F). .

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.

Store between 20° to 25°C (68° to 77°F). .

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.

Colistimethate sodium given intramuscularly during organogenesis to rabbits at 4.15 and 9.3 mg/kg resulted in talipes varus in 2.6% and 2.9% of fetuses, respectively.

These doses are 0.25 and 0.55 times the maximum daily human dose based on mg/m 2.

In addition, increased resorption occurred at 9.3 mg/kg. Colistimethate sodium was not teratogenic in rats at 4.15 or 9.3 mg/kg. These doses are 0.13 and 0.30 times the maximum daily human dose based on mg/m 2.

There are no adequate and well-controlled studies in pregnant women.

Since colistimethate sodium is transferred across the placental barrier in humans, it should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

It is not known whether colistimethate sodium is excreted in human breast milk.

However, colistin sulphate is excreted in human breast milk.

Therefore, caution should be exercised when colistimethate sodium is administered to nursing women.

In clinical studies, colistimethate 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.

Clinical studies of colistimethate sodium did not include sufficient numbers of subjects aged and over to determine whether they respond differently from younger subjects.

Other reported clinical experience has not identified differences in responses between the elderly and younger patients.

In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.

This drug is known to be substantially excreted by the kidney, and the risk of toxic reactions to this drug may be greater in patients with impaired renal function.

Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function.