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Drug Monographs
Treatment Regimens

Scientific Name:
ALTRETAMINE
Brand Name(s):
Hexalen®

Drug Monograph

Pharmacology

Mechanism of Action

Selectively inhibits incorporation of thymidine and uridine into DNA and RNA, inhibiting DNA & RNA synthesis; reactive intermediate metabolites covalently bind to DNA and microsomal proteins, then degrade to melamines.

Pharmacokinetics

Oral Absorption:
Rapidly & well-absorbed (75-89%)
Distribution:
highly lipid-soluble; high concentrations in liver and kidneys, but low concentration in other organs;
Excretion in breast-milk: unknown
Cross blood brain barrier?  No information
Vd: No information
PPB: 6%
Metabolism:
rapid hepatic metabolism, rapid and extensive demethylation, catalyzed by Cyt P450
Metabolite(s): metabilized to reactive intermediates, which covalently bind to microsomal proteins and DNA. Spontaneously degrade to demethylated melanimes (4 major metabolites- N2,N4,N6 trimethylmelamine,  N2,N4 dimethylmelamine, monomethylmelamine, melamine ) and Formaldehyd , also cytotoxic; 5 minor metabolites
Excretion:
renal, b-phase
urine: yes, less than 1% unchanged
t½ b: 13 hours

Side Effects

IMMEDIATE ONSET

• nausea, vomiting (50-70%) anorexia (48%), diarrhea (48%)

EARLY ONSET (days to weeks)

• CNS effects- mood disorders, disorders of conciousness, ataxia- 34%, dizziness,
   vertigo)
myelosuppression

Therapeutics

Approved Indications

Ovarian cancer, recurrent

Routes

Oral

Dosing

Oral:
•  260mg/m2/day in 4 divided doses for 14-21 days; repeat every 28 days (recommended dosing)
•  240-320mg/m2/day in 3-4 divided doses for 21 days; repeat every 6 weeks
•  4-12mg/Kg/day in 3-4 divided doses for 21-90 days
•  Round each dose to nearest 50mg tablet size

Retreatment:
•  Stop initial treatment if GI intolerance, neutropenia, thrombocytopenia or neurotoxicity; when toxicity resolved, resume at 200mg/m2/day

Pediatric: Safety & efficacy not established

Antiemetic Risk

HIGH RISK (30-90% of patients)
• Use a serotonin receptor antagonist PLUS dexamethasone before each dose

Contraindications

• Bone marrow depression, tumour cell-infiltration of the bone marrow • Infection • Severe neurologic toxicities

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)]
• Neurologic toxicity ratings (e.g. sensory, motor, cortical, constipation) at each visit, especially after 3 months’ continuous therapy

SENSORY
0. No change
1. Mild paraesthesia; no deep tendon reflex
2. Mild/moderate sensory loss; moderate paraesthesia
3. Sensory loss interferes with function

CONSTIPATION
0. No change
1. Mild
2. Moderate
3. Severe
4. Ileus >96 hours
Rated at Each Clinic Visit

SUGGESTED CRITERIA
• Regular assessment of neurological function

Significant Interactions

Bone marrow depressants, radiation therapy, monoamine oxidase inhibitors (e.g. selegiline, procarbazine, furazolidone), tricyclic antidepressants, cimetidine, ranitidine, phenobarbital.

Product Information

Commercial Product Description

Brand Name: Hexalen® Capsules with 50mg Altretamine Not Available in Canada

Handling Risk Level

Pregnancy DKNOWN HAZARDOUS DRUG
FDA Pregnancy Risk Factor D

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

Note

HANDLING RISK LEVEL:
HAZARD RISK LEVEL 2
FDA Pregnancy Risk Factor D
• This drug must be handled using precautions outlined in CCNS Policies for Preparing Cancer Chemotherapy and Administering Cancer Chemotherapy and the CCNS Standard for Oral Systemic Therapy for Cancer
• Go to "Additional Information" tab (above) for links to CCNS Policies

Availability & Funding

Administrative Information (Nova Scotia)

• CCNS Provincial Formulary Status- Community Level • Take Home Prescription • CDHA Formulary Status: Non-Formulary • Pharmacare Formulary Status: Non-Formulary



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