Systemic Therapy Program
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Cancer Type

Document Type

Drug Monographs
Treatment Regimens
Scientific Name:
TRETINOIN
Brand Name(s):
ATRA, Vesanoid®

Drug Monograph

Pharmacology

Mechanism of Action

Tretinoin (or, all-Trans Retinoic Acid = ATRA) appears to bind one or more nuclear receptors and inhibits clonal proliferation and/or granylocyte differentiation.

Pharmacokinetics

Oral Absorption:
well absorbed, should be taken during or after meals
Distribution:
enters breast-milk
cross blood brain barrier? No information
Vd: no information 
PPB: very high (>95%), primarily to albumin
Metabolism:
hepatic, via oxidative metabolism by CYT P450, probably auto-induces metabolism, to a glucuronide conjugate, 4-oxo-all-trans-retinoic acid
Excretion:
renal and fecal; 31% in feces within 6 days
Urine: 63% after 72 hours
t½  0.5-2 hours (parent) terminal t½ 10-77 hours
Cl: no information

Side Effects

IMMEDIATE ONSET (hours to days)
* APL Retinoic Acid Syndrome (25%)- fever, dyspnea, short of breath, respiratory distress, hyperleukocytosis, hypotension, pleural effusions, multi-organ failure (occurs with Acute Promyelocytic Leukemia patients within first few days of treatment)
EARLY ONSET (days to weeks)
* thrombosis (risk during first month of treatment)- cerebrovascular accident, myocardial infarctions, renal infarct
   disseminated intravascular coagulation (DIC), nosebleed
* intracranial hypertension/pseudotumor cerebri
* enlarged heart, arrhythmias, cardiac failure
   headache, fever, fatigue
   back pain, chest pain
   dyspnea, coughing- pleural effusion, pulmonary infiltration
   blurred vision, visual disturbance, photophobia, conjunctivitis, changes in visual acuity
   ear fullness, earache, ear buzzing
   dysuria, kidney failure, micturition frequency, renal insufficiency, cystitis
   dermal bleeding, pruritus, increased sweating, alopecia, dry scalp, nasal dryness, photosensitivity reaction.
   elevation in serum triglycerides, cholesterol and transaminases
DELAYED/LATE ONSET (weeks to years)
* teratogenicity in pregnant patients

Therapeutics

Approved Indications

• Leukemia, acute promyelocytic

OTHER ONCOLOGY USES (Not Approved)
• Kaposi’s sarcoma, AIDS-related
• Myelodysplastic syndrome

Routes

Oral

Dosing

Oral:
• 45 mg/m2/day PO in 2 divided doses
• Round dose to the nearest 10 mg.
• Administer with food.

Duration of therapy:
• Treatment should be continued for 30 days after complete remission or for a maximum of 90 days, which ever occurs first.

Pediatric- Oral:
• 45 mg/m2/day PO in 2 divided doses
• Round dose to the nearest 10 mg.
• Administer with food.

Dose Adjustment Criteria

Hepatic or Renal Dysfunction:
Give 25mg/m2 if any organ dysfunction
 (Suggested Action)

Contraindications

• PREGNANCY • Hypersensitivity to retinoic acid, Vitamin.A, other retinoids or parabens • Extreme caution in patients with eczema, patients with sunburn

Monitoring

Clinical Monitoring

RECOMMENDED CRITERIA
• Monitor coagulation profile, triglyceride and cholesterol levels, and liver function tests regularly
• Rating for symptoms of hypervitaminosis A syndrome at each visit (all patients)
• APL Retinoic Acid Syndrome (APL patients only)
• Complete blood count including differential, platelets and hemoglobin (CBC) before and after each treatment-hyperleukocytosis may be first sign
• Regular assessment of pulmonary function & all organ functions
 
HYPERVITAMINOSIS A SYMPTOMS
0. No symptoms
1. Dry mouth, dry lips, dry skin, asymptomatic erythema; mild macular or papular rash
2. Dry eyes, need artificial tears; painful or pruritic dry skin or skin rash area(s); mild edema; mild bone pain
3. Severe dry eyes; generalized painful, pruritic or symptomatic skin rash; dry mouth and lips which interfere with eating; moderate edema or bone pain 
4. Exfoliative dermatitis or ulcerative dermatitis; dry eyes requiring enucleation
RATED AT EACH CLINIC VISIT

SUGGESTED CRITERIA
• APL patients (in first few days of treatment)
• Ratings for shortness of breath and fever, if any evidence of Retinoic Acid Syndrome- fever, dyspnea, short of breath, respiratory distress, hyperleukocytosis, hypotension, pleural effusions, multi-organ failure
 
SHORT OF BREATH
0. No change
1. Abnormal Pulmonary Function Tests
2. Dyspnea on exertion
3. Dyspnea at normal level of activity
4. Dyspnea at rest
 
FEVER
0. None
1. 37.1-38.0oC (98.7-100.4oF)
2. 38.1-40.0oC (100.5-104.0oF)
3. >40oC for <24hrs (>104oF)
4. >40oC for >24hrs, or fever accompanied by hypotension
 RATED IF EVIDENCE OF RETINOIC ACID SYNDROME

Significant Interactions

High exposure to sunlight, UV rays or sun lamps Cytochrome P450 Substrate • Antifibrinolytic agents: may increase thrombogenic effect • Contraceptives (Estrogens, Progestins): may decrease therapeutic effect/serum concentration of these contraceptives. Two forms of effective contraception are recommended in females of child-bearing potential during Tretinoin therapy. Particularly, microdosed progesterone-only preparations may be inadequately effective. • CYP2C8 inducers: may decrease metabolism of Tretinoin • CYP2C8 inhibitors: may decrease metabolism of Tretinoin • Echinacea: may decrease the therapeutic effect of Tretinoin • Leflunomide: may increase toxicity of Leflunomide (specifically, the risk of hematologic toxicity). Consider not using a leflunomide loading dose in patients receiving Tretinoin. Monitor patient for bone marrow suppression at least monthly if using these drugs concurrently. • Multivitamins/Fluoride/Minerals (with ADEK, Folate, Iron): may increase toxicity of Tretinoin (avoid combination) • Tacrolimus (topical): may increase the toxicity of Tretinoin (avoid combination) • Tetracycline derivatives: may increase toxicity of Tretinoin. The development of pseudotumor cerebri is especially concerning. (Avoid combination) Vaccines (inactivated, live): may increase toxicity and decrease therapeutic effect of vaccines (avoid combination)

Product Information

Commercial Product Description

Reddish-brown capsules with 10mg Tretinoin.

Pharmaceutical Considerations

Capsules: 10 mg. Store at room temperature. Protect from light. Keep bottle tightly closed.

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- Inpatient use for induction- Specialized Level Capital Health & IWK Only • Ambulatory use for maintenance- Community Level: Prescription ordered on preprinted Physician Standing Order; Indication restriction- Provincial Cancer Drug Formulary • Go to "Additional Information" tab (above) for links to Provincial Formulary of Cancer Drugs • Acute Promyelocytic Leukemia guidelines • Pharmacare Formulary Status- Non-Formulary (oral) • NOTE: It is recommended to limit ordering of this medication to standard preprinted order forms, for patient safety.