Coly-Mycin® M Parenteral (Colistimethate for Injection, USP) 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 (150 mg colistin base activity).

Colistimethate sodium is a polypeptide antibiotic with an approximate molecular weight of 1750. The empirical formula is C₅₈H₁₀₅N₁₆Na₅O₂₈S₅ and the structural formula is represented below:

Last updated on RxList: 7/27/2009

Coly-Mycin M Parenteral 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. Coly-Mycin M Parenteral has proven clinically effective in treatment of infections due to the following gram-negative organisms: Enterobacter aerogenes, Escherichia coli, Klebsiella pneumoniae and Pseudomonas aeruginosa.

Coly-Mycin M Parenteral 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 Coly-Mycin M and other antibacterial drugs, Coly-Mycin M 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.

Important: Coly-Mycin M Parenteral 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: Coly-Mycin M Parenteral 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.

TABLE 1. Suggested Modification of Dosage Schedules of Coly-Mycin M Parenteral for Adults with Impaired Renal Function

Renal Function	Degree of Impairment
	Normal	Mild	Moderate	Considerable
Plasma creatinine, mg/100 mL	0.7–1.2	1.3–1.5	1.6–2.5	2.6–4.0
Urea clearance,% of normal	80–100	40–70	25–40	10–25
Dosage
Unit dose of Coly-Mycin M, mg	100–150	75–115	66–150	100–150
Frequency, times/day	4 to 2	2	2 or 1	every 36 hr
Total daily dose, mg	300	150–230	133–150	100
Approximate daily dose, mg/kg/day	5.0	2.5–3.8	2.5	1.5
Note: The suggested unit dose is 2.5–5 mg/kg; however, the time INTERVAL between injections should be increased in the presence of impaired renal function.

Coly-Mycin M Parenteral is supplied in vials containing colistimethate sodium (equivalent to 150 mg colistin base activity per vial) as a white to slightly yellow Iyophilized cake and is available as one vial per carton (NDC 61570-414-51).

Store between 20°-25°C (68°-77°F). (See USP controlled room temperature.)

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

Prescribing Information as of October 2006. Distributed by: Monarch Pharmaceuticals, Inc., Bristol, TN 37620 (A wholly owned subsidiary of King Pharmaceuticals, Inc.). Manufactured by: Parkedale Pharmaceuticals, Inc., Rochester, MI 48307.

Last updated on RxList: 7/27/2009

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

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 Coly-Mycin M Parenteral 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 Coly-Mycin M Parenteral.

Sodium cephalothin may enhance the nephrotoxicity of Coly-Mycin M Parenteral. The concomitant use of sodium cephalothin and Coly-Mycin M Parenteral should be avoided.

Last updated on RxList: 7/27/2009

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 OVERDOSE 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 Coly-Mycin M Parenteral, 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.

General

Since Coly-Mycin M Parenteral 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, Coly-Mycin M Parenteral 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 Coly-Mycin M Parenteral 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 Coly-Mycin M Parenteral 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 Coly-Mycin M 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.

Carcinogenesis, Mutagenesis, Impairment of Fertility

Long-term animal carcinogenicity studies and genetic toxicology studies have not been performed with colistimethate sodium. There were no adverse effects on fertility or reproduction in rats at doses of 9.3 mg/kg/day (0.30 times the maximum daily human dose when based on mg/m²).

Pregnancy - Teratogenic Effects

Pregnancy Category C: 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/m². 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/m². 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.

Nursing Mothers

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.

Geriatric Use

Clinical studies of colistemethate sodium did not include sufficient numbers of subjects aged 65 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.

Pediatric Use

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.

Last updated on RxList: 7/27/2009

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.

The use of Coly-Mycin M Parenteral is contraindicated for patients with a history of sensitivity to the drug or any of its components.

Last updated on RxList: 7/27/2009

Typical serum and urine levels following a single 150 mg dose of Coly-Mycin M Parenteral IM or IV in normal adult subjects are shown in Figure 1.

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.

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 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.

Last updated on RxList: 7/27/2009

Patients should be counseled that antibacterial drugs including Coly-Mycin M should only be used to treat bacterial infections. They do not treat viral infections (e.g., the common cold). When Coly-Mycin M 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 effectivenss of the immediate treatment and (2) increase the likelihood that bacteria will develop resistance and will not be treatable by Coly-Mycin M or other antibacterial drugs in the future.

Diarrhea is a common problem caused by antibiotics which usually ends when the antibiotic is discontinued. Sometimes after starting treatment with antibiotics, patients can develop watery and bloody stools (with or without stomach cramps and fever) even as late as two or more months after having taken the last dose of the antibiotic. If this occurs, patients should contact their physician as soon as possible.

Last updated on RxList: 7/27/2009

IMPORTANT NOTE: This is a summary and does not contain all possible information about this product. For complete information about this product or your specific health needs, ask your health care professional. Always seek the advice of your health care professional if you have any questions about this product or your medical condition. This information is not intended as individual medical advice and does not substitute for the knowledge and judgment of your health care professional. This information does not contain any assurances that this product is safe, effective, or appropriate for you.

COLISTIMETHATE - INJECTION

(koe-lis-ti-METH-ate)

COMMON BRAND NAME(S): Coly-Mycin M

USES: Colistimethate is an antibiotic used to treat certain bacterial infections (gram-negative). It works by killing the bacteria that cause the infection.

This antibiotic treats only bacterial infections. It will not work for viral infections (e.g., common cold, flu). Unnecessary use or misuse of any antibiotic can lead to its decreased effectiveness.

OTHER USES: This section contains uses of this drug that are not listed in the approved professional labeling for the drug but that may be prescribed by your health care professional. Use this drug for a condition that is listed in this section only if it has been so prescribed by your health care professional.

In patients with cystic fibrosis, this antibiotic may also be inhaled to treat serious bacterial lung infections (Pseudomonas aeruginosa). See also Storage section for information about important safety concerns when this medication is inhaled instead of injected.

HOW TO USE: This medication is given by a health care professional. It may be injected into a vein over 3 to 5 minutes or mixed in a solution and given slowly into a vein over 22 to 23 hours. Colistimethate may also be injected into a muscle. Health care professionals must follow all the manufacturer's instructions for properly mixing and giving this drug. Before using, check this product visually for particles or discoloration. If either is present, do not use the liquid. If you have any questions about using this medication properly, consult your doctor or pharmacist.

The dosage, how often the drug is given, and length of treatment depends on your medical condition and response to treatment.

Continue to use this medication until you have received the full amount prescribed, even if symptoms disappear after a few days. Stopping the medication too early may allow bacteria to continue to grow, which may result in a return of the infection.

Tell your doctor if your condition persists or worsens.

SIDE EFFECTS: Nausea, vomiting, and pain/redness/swelling at the injection site may occur. If any of these effects persist or worsen, tell your doctor or pharmacist promptly.

Remember that your doctor has prescribed this medication because he or she has judged that the benefit to you is greater than the risk of side effects. Many people using this medication do not have serious side effects.

Tell your doctor immediately if any of these rare but very serious side effects occur: mental/mood changes (such as confusion, drowsiness, or irritability), numbness/tingling (especially around the lips), strange feeling on the skin of legs/arms, difficulty walking, unsteadiness, slow/shallow breathing, dizziness/feeling of spinning, unexplained fever, slurred speech, muscle weakness, change in the amount of urine, red/pink urine.

This medication may rarely cause a severe intestinal condition (pseudomembranous colitis) due to a type of resistant bacteria. This condition may occur during treatment or weeks to months after treatment has stopped. Do not use anti-diarrhea products or narcotic pain medications if you have any of the following symptoms because these products may make them worse. Tell your doctor immediately if you develop: persistent diarrhea, abdominal or stomach pain/cramping, blood/mucus in your stool.

Use of this medication for prolonged or repeated periods may result in a new infection. Tell your doctor if you notice any symptoms of a new infection (e.g., white patches in your mouth, a change in vaginal discharge).

A very serious allergic reaction to this drug is rare. However, seek immediate medical attention if you notice any symptoms of a serious allergic reaction, including: rash, itching, swelling, severe dizziness, trouble breathing.

This is not a complete list of possible side effects. If you notice other effects not listed above, contact your doctor or pharmacist.

Contact your doctor for medical advice about side effects. The following numbers do not provide medical advice, but in the US you may report side effects to the Food and Drug Administration (FDA) at 1-800-FDA-1088. In Canada, you may call Health Canada at 1-866-234-2345.

PRECAUTIONS: Before using colistimethate, tell your doctor or pharmacist if you are allergic to it; or to polymyxin B or colistin; or if you have any other allergies.

Before using this medication, tell your doctor or pharmacist your medical history, especially of: disease of the nerves/muscles (e.g., myasthenia gravis), kidney disease.

This drug may make you dizzy. Use caution while driving, using machinery, or doing any activity that requires alertness. Avoid alcoholic beverages.

Before having surgery, tell your doctor or dentist that you are using this medication.

Kidney function declines as you grow older. This medication is removed by the kidneys. Therefore, elderly people may be at greater risk for side effects (e.g., kidney problems) while using this drug.

During pregnancy, this medication should be used only when clearly needed. Discuss the risks and benefits with your doctor.

It is not known if this drug passes into breast milk. Consult your doctor before breast-feeding.

DRUG INTERACTIONS: Your doctor or pharmacist may already be aware of any possible drug interactions and may be monitoring you for them. Do not start, stop, or change the dosage of any medicine before checking with your doctor or pharmacist first.

Before using this medication, tell your doctor or pharmacist of all prescription and nonprescription/herbal products you may use, especially of: drugs that can harm the kidneys/nerves (e.g., amphotericin B, sodium citrate, cephalothin, polymyxin B, vancomycin, aminoglycoside antibiotics such as gentamicin, tobramycin, paromomycin), anesthesia drugs or muscle relaxants (e.g., tubocurarine, succinylcholine, gallamine, decamethonium), live vaccines (e.g., flu vaccine inhaled through the nose, polio vaccine taken by mouth).

This document does not contain all possible interactions. Therefore, before using this product, tell your doctor or pharmacist of all the products you use. Keep a list of all your medications with you, and share the list with your doctor and pharmacist.

OVERDOSE: If overdose is suspected, contact your local poison control center or emergency room immediately. US residents can call the US National Poison Hotline at 1-800-222-1222. Canada residents can call a provincial poison control center. Symptoms of overdose may include: extreme drowsiness, slow/shallow breathing, inability to move, seizures.

NOTES: Laboratory and/or medical tests (e.g., kidney function tests) should be performed periodically to monitor your progress or check for side effects. Consult your doctor for more details.

MISSED DOSE: If you miss a dose or your dose is interrupted, contact your doctor or pharmacist promptly to establish a new dosing schedule.

STORAGE: Store unmixed vials in original packaging at room temperature between 68-77 degrees F (20-25 degrees C) away from light and moisture. Do not store in the bathroom. Keep all medicines away from children and pets.

After mixing, store the medication at room temperature or in the refrigerator between 36-46 degrees F (2-8 degrees C). Discard any unused liquid after 7 days.

After further mixing in IV solution, discard mixed solution after 24 hours.

If this medication is to be inhaled with a special device called a nebulizer, use the solution immediately after mixing. Do not mix the solution in advance because doing so increases the risk of serious side effects such as chest pain or trouble breathing. Contact your doctor immediately if either of these side effects occur or if you have any of the side effects listed in the Side Effects section.

Do not flush medications down the toilet or pour them into a drain unless instructed to do so. Properly discard this product when it is expired or no longer needed. Consult your pharmacist or local waste disposal company for more details about how to safely discard this product.

Information last revised July 2008 Copyright(c) 2008 First DataBank, Inc.