Coly-Mycin M Product Monograph

RECENT MAJOR LABEL CHANGES

TABLE OF CONTENTS

Sections or subsections that are not applicable at the time of authorization are not listed.

RECENT MAJOR LABEL CHANGES ...................................................................................................... 2

TABLE OF CONTENTS ........................................................................................................................ 2

PART I: HEALTH PROFESSIONAL INFORMATION ................................................................................ 4

1 INDICATIONS ....................................................................................................................... 4

2 CONTRAINDICATIONS .......................................................................................................... 4

4 DOSAGE AND ADMINISTRATION .......................................................................................... 4

4.1 Dosing Considerations ......................................................................................................... 4

4.2 Recommended Dose and Dosage Adjustment .................................................................... 4

4.3 Reconstitution ...................................................................................................................... 5

4.4 Administration ..................................................................................................................... 5

5 OVERDOSAGE ...................................................................................................................... 5

6 DOSAGE FORMS, STRENGTHS, COMPOSITION AND PACKAGING ............................................ 5

7 WARNINGS AND PRECAUTIONS ............................................................................................ 6

7.1 Special Populations .............................................................................................................. 6

7.1.1 Pregnant Women .......................................................................................................... 6

7.1.2 Breast-feeding ............................................................................................................... 6

7.1.4 Geriatrics ....................................................................................................................... 7

8 ADVERSE REACTIONS ........................................................................................................... 7

8.5 Post-Market Adverse Reactions ........................................................................................... 7

9 DRUG INTERACTIONS ........................................................................................................... 7

9.2 Drug Interactions Overview ................................................................................................. 7

9.4 Drug-Drug Interactions ........................................................................................................ 8

9.5 Drug-Food Interactions ........................................................................................................ 8

9.6 Drug-Herb Interactions ........................................................................................................ 8

9.7 Drug-Laboratory Test Interactions ....................................................................................... 8

10 CLINICAL PHARMACOLOGY .................................................................................................. 8

10.1 Mechanism of Action ..................................................................................................... 8

10.2 Pharmacodynamics ....................................................................................................... 8

10.3 Pharmacokinetics .......................................................................................................... 8

11 STORAGE, STABILITY AND DISPOSAL ..................................................................................... 9

12 SPECIAL HANDLING INSTRUCTIONS ...................................................................................... 9

PART II: SCIENTIFIC INFORMATION ................................................................................................. 10

13 PHARMACEUTICAL INFORMATION ..................................................................................... 10

14 CLINICAL TRIALS ................................................................................................................. 10

15 MICROBIOLOGY ................................................................................................................. 10

16 NON-CLINICAL TOXICOLOGY ............................................................................................... 10

PATIENT MEDICATION INFORMATION ............................................................................................ 11

PART I: HEALTH PROFESSIONAL INFORMATION

1 INDICATIONS

COLY-MYCIN M (colistimethate sodium for injection U.S.P.) is indicated for:

• the treatment of acute or chronic infections due to sensitive strains of certain gram-negative bacilli. Particularly indicated when the infection is caused by sensitive strains of P. aeruginosa.

This antibiotic is not indicated for infections due to proteus or neisseria. Sodium colistimethate has proven clinically effective in treatment of infections due to the following gram-negative organisms: A. aerogenes, E. coli, K. pneumoniae and P. aeruginosa.

Pending results of appropriate bacteriologic cultures and sensitivity tests, sodium colistimethate may be used to initiate therapy in serious infections that are suspected to be due to gram-negative organisms.

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 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.

2 CONTRAINDICATIONS

• COLY-MYCIN M is contraindicated in patients who are hypersensitive to this drug or to any ingredient in the formulation, including any non-medicinal ingredient, or component of the container. For a complete listing, see 6 DOSAGE FORMS, STRENGTHS, COMPOSITION AND PACKAGING.

4 DOSAGE AND ADMINISTRATION

4.1 Dosing Considerations

• Maximum daily dose of COLY-MYCIN M should not exceed 5 mg/kg/day with normal renal function.
• Since sodium colistimethate 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, sodium colistimethate may be used, but the greatest caution should be exercised and the dosage should be reduced in proportion to the extent of the impairment (see 7 WARNINGS AND PRECAUTIONS, Renal).

4.2 Recommended Dose and Dosage Adjustment

• Average dose is 2.5 mg/kg/day given in 2 to 4 divided doses.
• In the presence of bacteremia, septicemia or other serious infections, greater than average doses may be required.
• Maximal dose of 5 mg/kg/day should not be exceeded in patients with normal renal function.
• Overdosage can result in renal insufficiency, muscle weakness and apnea.
• Reduction of dosage may alleviate symptoms. Therapy need not be discontinued, but such patients should be observed with particular care.

4.3 Reconstitution

Table 1 - Reconstitution

After reconstitution, COLY-MYCIN M solution should be stored refrigerated 2 to 8°C and used within 3 days (or within 24 hours, when stored at controlled room temperature 15 to 30°C).

Any infusion solution containing colistimethate sodium should be freshly prepared and used for no longer than 24 hours (see 11 STORAGE, STABILITY AND DISPOSAL).

4.4 Administration

Intravenous or intramuscular administration.

5 OVERDOSAGE

Symptoms: Dizziness, ataxia, speech disturbances, generalized muscular weakness, apnea and elevated BUN.

Treatment: Usual medical regimen for treatment of oliguria or anuria. Consider dialysis, particularly if a massive overdosage is discovered shortly after administration.

6 DOSAGE FORMS, STRENGTHS, COMPOSITION AND PACKAGING

Table 2 - Dosage Forms, Strengths, Composition and Packaging

Description

Each COLY-MYCIN M vial contains: colistin base activity (as sodium colistimethate) 150 mg as a fluffy, spongy, white to slightly yellow lyophilized cake which forms a clear, aqueous solution when reconstituted with 2.0 mL of Sterile Water for Injection USP. Each mL of reconstituted sterile solution contains: sodium colistimethate equivalent to 75 mg colistin base. Energy: nil. Sodium: <1 mmol (16.6 mg)/vial.

7 WARNINGS AND PRECAUTIONS

Driving and Operating Machinery

Transient neurological disturbances may occur. These include circumoral paresthesias 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.

Endocrine and Metabolism

Cases of pseudo-Bartter syndrome have been reported in patients with the use of colistimethate sodium. In all cases hypokalemia, metabolic alkalosis, and kaliuresis were reported; some cases also involved hypomagnesemia and hypocalcemia. In case reports, electrolyte abnormalities did not completely normalize with electrolyte corrective therapy alone. In all case reports, electrolyte abnormalities eventually resolved or significantly improved following the discontinuation of colistimethate. Consider monitoring electrolytes.

Renal

Administration of amounts of sodium colistimethate 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.

Easily recognized signs indicating the development of impaired renal function are diminishing urine output, rising BUN and serum creatinine. If present, therapy with sodium colistimethate should be discontinued immediately.

If a life-threatening situation exists, therapy may be reinstated at a lower dosage after blood levels have fallen.

Respiratory

If apnea occurs it may be treated with assisted respiration, oxygen, and calcium chloride injections.

Sensitivity/Resistance

Prescribing COLY-MYCIN M in the absence of a proven or strongly suspected bacterial infection is unlikely to provide benefit to the patient and risks the development of drug-resistant bacteria.

7.1 Special Populations

7.1.1 Pregnant Women

The safety of sodium colistimethate during human pregnancy has not been established.

7.1.2 Breast-feeding

It is unknown if COLY-MYCIN M is excreted in human milk. Precaution should be exercised because many drugs can be excreted in human milk.

7.1.4 Geriatrics

Since sodium colistimethate 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.

8 ADVERSE REACTIONS

8.5 Post-Market Adverse Reactions

Respiratory, thoracic and mediastinal disorders:

Respiratory arrest has been reported following IM administration of sodium colistimethate. Impaired renal function increases the possibility of apnea and neuromuscular blockade following administration of sodium cholistimethate. This has generally been due to failure to follow recommended guidelines, usually overdosage, failure to reduce dose commensurate with degree of renal impairment, and/or concomitant use of other antibiotics or drugs with neuromuscular blocking potential.

Renal and urinary disorders:

A decrease in urine output or increase in BUN or serum creatinine can be interpreted as signs of nephrotoxicity, which is probably a dose dependent effect of sodium colistimethate. These manifestations of nephrotoxicity are reversible following discontinuation of the antibiotic.

Increases of BUN have been reported for patients receiving sodium colistimethate at dose levels of 1.6 to 5 mg/kg/day. The BUN values returned to normal following cessation of sodium colistimethate administration.

Metabolic and Nutrition Disorders:

Cases of pseudo-Bartter syndrome have been reported (see 7 WARNINGS AND PRECAUTIONS, Endocrine and Metabolism).

Others:

Paresthesia, tingling of the extremities or tingling of the tongue and generalized itching or urticaria have been reported by patients who received sodium colistimethate by IM or IV injection.

In addition, the following adverse reactions have been reported for sodium colistimethate: drug fever and gastrointestinal upset, vertigo, and slurring of speech. The subjective symptoms reported by the adult may not be manifest in infants or young children, thus requiring close attention to renal function.

9 DRUG INTERACTIONS

9.2 Drug Interactions Overview

Certain other antibiotics (kanamycin, streptomycin, dihydrostreptomycin, polymyxin, neomycin) have also been reported to interfere with the nerve transmission at the neuromuscular junction and thus should not be given concomitantly with sodium colistimethate except with the greatest caution. The antibiotics with a gram positive antimicrobial spectrum, e.g. penicillin, tetracycline, sodium cephalothin, have not been reported to interfere with nerve transmission and, accordingly, would not be expected to potentiate this activity of sodium colistimethate.

9.4 Drug-Drug Interactions

Table 3 - Established or Potential Drug-Drug Interactions

Legend: C = Case Study; CT = Clinical Trial; T = Theoretical

9.5 Drug-Food Interactions

Interactions with food have not been established.

9.6 Drug-Herb Interactions

Interactions with herbal products have not been established.

9.7 Drug-Laboratory Test Interactions

Interactions with laboratory tests have not been established.

10 CLINICAL PHARMACOLOGY

10.1 Mechanism of Action

Sodium colistimethate is the pentasodium salt of the penta (methanesulfonic acid) derivative of colistin. Colistin is a basic polypeptide antibiotic substance produced by the growth of Bacillus polymyxa var. colistinus. Colistin derivatives appear to alter the permeability of the bacterial cytoplasmic membrane, causing leakage of intracellular nucleosides. The drugs are bactericidal in action.

10.2 Pharmacodynamics

Hydrolysis of sodium colistimethate is required for antibacterial activity.

10.3 Pharmacokinetics

Absorption

IM administration of sodium colistimethate with activity equivalent to that of 150 mg of colistin produces peak serum levels of approximately 5 to 7.5 µg/mL within 2 hours. Peak serum levels after IV administration occur within 10 minutes and are higher but decline more rapidly than those achieved after IM administration. The serum half-life is approximately 1.5 hours following IV and 2.75 to 3 hours following IM administration. Blood levels appear to decline more rapidly in children than in adults.

Metabolism:

Hydrolysis of sodium colistimethate is required for antibacterial activity.

Elimination

Sodium colistimethate and its metabolites are excreted primarily by the kidneys; urine levels of the active antibiotic are considerably higher than serum levels. In 24 hours, approximately 66% after IM administration and 75% after IV administration is excreted.

Special Populations and Conditions

• Pediatrics: Blood levels appear to decline more rapidly in children than in adults.
• Renal Insufficiency: Administration of amounts of sodium colistimethate in excess of renal excretory capacity will lead to high serum levels and can result in further impairment of renal function (see 7 WARNINGS AND PRECAUTIONS, Renal).

11 STORAGE, STABILITY AND DISPOSAL

Store COLY-MYCIN M at controlled room temperature between 15°C and 30°C.

After reconstitution, COLY-MYCIN M solution should be stored refrigerated 2°C to 8°C and used within 3 days (or within 24 hours, when stored at controlled room temperature 15°C to 30°C).

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

12 SPECIAL HANDLING INSTRUCTIONS

N/A

PART II: SCIENTIFIC INFORMATION

13 PHARMACEUTICAL INFORMATION

Drug Substance

Proper name: Colistimethate Sodium

Chemical name: Colistimethate Sodium

Molecular formula and molecular mass: C₅₈H₁₀₅N₁₆NaO₂₈S₅ (colistin A component) 1749.82 g/mol

C₅₇M₁₀₃N₁₆Na₅O₂₈S₅ (colistin B component) 1735.80 g/mol

Structural formula:

CH₃

Dbu is L- α, (- diaminobutyric acid; R is CH₃CH₂CH(CH₂)₄ in the colistin A component

CH₃

and CH₃CH(CH₂)₄ in the colistin B component. R¹ is CH₂SO₃Na

Physicochemical properties: fluffy, spongy, white to slightly yellow lyophilized cake. Soluble in water.

14 CLINICAL TRIALS

The clinical trial data on which the original indication was authorized is not available.

15 MICROBIOLOGY

No microbiological information is required for this drug product.

16 NON-CLINICAL TOXICOLOGY

The non-clinical data on which the original indication was authorized is not available.