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Drug Monographs
Treatment Regimens
Scientific Name:
AMSACRINE
Brand Name(s):
AMSA P-D®

Drug Monograph

Pharmacology

Mechanism of Action

Amsacrine has been shown to inhibit DNA synthesis by binding to, and intercalating with, DNA and inhibition of topoisomerase 2 activity.

Pharmacokinetics

Oral Absorption
yes (poorly absorbed)
Distribution
brain, gall bladder, kidney
Cross blood brain barrier?  minimal CNS penetration
Vd: 1.67 L/kg; 87.1 L/m2
PPB: 98%
Metabolism:
extensively in liver to amsacrine-glutathione conjugate
Metabolite(s): active- none known
inactive- in bile- major metabolite: 5'-gluthatione conjugate
Excretion:
primarily excreted in bile; >50% in feces within 2 hours; also by kidney
urine: 35% within 72 hours; 20% as intact drug
t½ a: 4.2 minutes     t½ b: 1.4 hours
Cl: 150 mL/min/m2
(17.2 hours with severe liver dysfunction, bilirubin >34 mmol/L)

Side Effects

IMMEDIATE ONSET  (hours to days)

• anaphylaxis
vein irritation or pain (phlebitis)
nausea and vomiting (30%), diarrhea (30%)
urine discolouration (orange)
increased uric acid levels (hyperuricemia)
• heart problems (cardiac arrhythmias)

EARLY ONSET  (days to weeks)

• low WBC, RBC, platelets (myelosuppression, nadir 11-13 days, recovery 17-25
   days)
mouth sores (stomatitis)
• heart problems (cardiac arrhythmias, hypotension, tachycardia)
• liver problems (hyperbilirubinemia, jaundice)
• skin problems (rash, alopecia)
• abdominal pain
• central nervous system problems (headache, confusion; seizures - rare)

DELAYED/LATE ONSET

• infertility

Therapeutics

Approved Indications

Acute leukemia

Routes

Intermittent IV
(adults: in 250-500 mL over 60-90 minutes)
(children: in 150-250 mL over 1-2 hours)

Administration

• Mix in 250-500mL bag (5% Dextrose - NOT Normal Saline); Infuse over 60 to 90 minutes.

IV Compatibility

Dextrose 5% only

Dosing

Induction:
• q3-4w: 75-125 mg/m²/day IV x 5 days

Maintenance:
• q4-8w: 50% dose depending on peripheral blood counts

Dosage escalation:
• increase by 20% in the second and each subsequent course if no significant toxicity in the preceding course, and if marrow hypoplasia has not been achieved

Pediatric: q2-3w: 75-150 mg/m²/day IV x 5 days

Dose Adjustment Criteria

Hepatic dysfunction:
Reduce dose if bilirubin elevated (40% if Bili = 26-51µmol/L or AST = 60-180IU/L; Omit if Bili > 51 or AST >180IU/L)  (Suggested action)

Renal Failure:
Decrease by 25% for BUN >7.5µmol/L or creatinine >140µmol/L or >ULN (upper limit of normal)

Antiemetic Risk

HIGH RISK (30-90% of patients)
• Use a serotonin receptor antagonist PLUS dexamethasone pre-chemotherapy and post-chemotherapy

Contraindications

• Known hypersensitivity to amsacrine • Pregnancy and breast feeding

Monitoring

Clinical Monitoring

RECOMMENDED CRITERIA
• Complete blood count including differential, platelets and hemoglobin (CBC) before each cycle of treatment
• Baseline liver function tests [serum alkaline phosphatase, GGT, ALT, AST & Bilirubin levels (serum proteins may be added if indicated)]

SUGGESTED CRITERIA
• Cardiac function & serum potassium (especially if pretreated with anthracyclines)
CARDIAC  (See Doxorubicin for rating scale)
Rated If Prior Anthracyclines Given At Doses Approaching Cardiotoxicity Threshold

Extravasation Hazard

VESICANT (tissue damage on extravasation). Management- stop IV, aspirate, elevate limb, cold intermittent compresses. Follow Extravasation Guidelines.

Significant Interactions

Doxorubicin, methotrexate, phenobarbital, warfarin.

Product Information

Commercial Product Description

Glass ampuls with 75mg/1.5mL Amsacrine (red-orange solution).

Pharmaceutical Considerations

Injection:
Package of one ampul containing amsacrine 50 mg/mL (75 mg/1.5 mL) N,N-dimethylacetamide and one vial containing 13.5 mL of 0.035 M L-lactic acid diluent; ampul and vial preservative-free; store at room temperature.

Preparation:
Transfer 1.5 mL from the ampul to the vial which contains the diluent to give a stock solution of amsacrine 5 mg/mL. Use only the diluent provided. A glass syringe is preferred for this transfer step but a plastic syringe may be used, provided that the solution remains in the syringe no longer than 15 minutes.

Reconstituted solution for injection:
Clear, orange-red solution. The manufacturer states that the stock solution is chemically stable for 24 hours at room temperature, protected from direct sunlight. Trissel states that it is physically and chemically stable for at least 48 hours at room temperature under ambient light.

Diluted solution for infusion:
Compatible only with D5W; incompatible with chloride-containing solutions. The manufacturer recommends that the dose be diluted in 500 mL D5W and states that, because it is preservative-free, the diluted solution be used within 24 hours if stored at room temperature or 72 hours if refrigerated. However, they state that the diluted solution has been shown to be chemically stable for up to 7 days in an Abbott plastic container or glass bottle. Trissel states that 75 mg amsacrine in 500 mL D5W is physically and chemically stable for at least 48 hours at room temperature in ambient light. Some manufacturers’ evacuated glass bottles may contain residual amounts of sodium chloride solution from the manufacturing process. Such bottles must not be used for amsacrine since incompatibility with the chloride ion may result in precipitation of the amsacrine. Amsacrine reacts with plastic; however, amsacrine diluted in D5W for infusion does not react with plastic infusion tubing.

Compatible with ondansetron. It is recommended that amsacrine not be mixed with other drugs.

Handling Risk Level

Carcinogen 2BKNOWN HAZARDOUS DRUG
IARC Carcinogen Risk Group 2B (Possible Carcinogen)

  • This drug must be handled using precuations outlined in CCNS Policies for Occupational Safety, Preparing Cancer Chemotherapy and Administering Cancer Chemotherapy

Note

HANDLING RISK LEVEL:

HAZARD RISK LEVEL 1
IARC Carcinogen Risk Group 2B (Possible Carcinogen)
• This drug must be handled using precuations outlined in CCNS Policies for Preparing Cancer Chemotherapy and Administering Cancer Chemotherapy
• Go to "Additional Information" tab (above) for links to CCNS Policies

Availability & Funding

Administrative Information (Nova Scotia)

• CCNS Provincial Formulary Status- Specialized Level • Capital Health Only • CDHA Formulary Status: Non-Formulary • Pharmacare Formulary Status: Non-Formulary NOTE: It is recommended to limit ordering of this medication to standard preprinted order forms, for patient safety.