Tretinoin (Systemic )
VA CLASSIFICATION
Primary: AN900
Commonly used brand name(s): Vesanoid.
Note: For a listing of dosage forms and brand names by country availability, see Dosage Forms section(s).
Category:
Antineoplastic—
Indications
Accepted
Leukemia, acute promyelocytic (treatment)—Tretinoin is indicated for induction of remission in patients with acute promyelocytic leukemia (APL) (French-American-British [FAB] subtype M3, including the M3 variant, of acute myelocytic leukemia). Responses to tretinoin have not been observed in patients who lack the genetic marker characteristic of APL, i.e., the t(15;17) translocation that produces the PML/RAR alpha gene; other treatment should be considered for patients in whom a diagnosis of APL cannot be confirmed by detection of t(15;17) translocation or PML/RAR alpha fusion. Tretinoin should be used only for patients who are refractory to, or who have relapsed from, anthracycline-based chemotherapy, or for whom anthracycline-based chemotherapy is contraindicated. {01}
Note: After induction therapy with tretinoin has been completed, the patient should receive appropriate remission consolidation and/or maintenance therapy with other agent(s) {01}.
Pharmacology/Pharmacokinetics
Physicochemical characteristics:
Chemical group—
Tretinoin (all- trans retinoic acid) is a retinoid chemically related to retinol (Vitamin A) {01}.
Molecular weight—
300.44 {01}
Mechanism of action/Effect:
The precise mechanism of action has not been established. Tretinoin is not a cytolytic agent. It induces cytodifferentiation and decreases proliferation of acute promyelocytic leukemia cells. In patients who achieve complete remission, tretinoin therapy results in an initial maturation of the primitive promyelocytes derived from the leukemic clone, followed by a repopulation of the bone marrow and peripheral blood with normal, polyclonal hematopoietic cells. {01}
Absorption:
Tretinoin is well absorbed after oral administration. Whether coadministration with food affects tretinoin absorption has not been established. However, administration with food has been shown to enhance absorption of other retinoids. {01}
Protein binding:
Very high (> 95%), primarily to albumin {01}.
Biotransformation:
Hepatic, via oxidative metabolism by cytochrome P-450 (CYP) enzymes. Tretinoin probably induces its own metabolism; after 1 week of continuous therapy, the plasma concentration and the area under the tretinoin concentration–time curve (AUC) are substantially lower than on the first day of treatment. {01}
Half-life:
Elimination—0.5 to 2 hours {01}.
Time to peak plasma concentration:
1 to 2 hours after an oral dose {01}.
Peak plasma concentration:
Following a single oral dose of 45 mg per square meter of body surface area (mg/m 2)—347 ± 266 nanograms/mL {01}.
Note: In a study in seven patients, plasma concentrations determined after 1 week of treatment with 45 mg/m 2 per day were approximately one-third of those measured on Day 1 of treatment {01}.
Time to peak effect:
Median time to complete remission in clinical trials was 40 to 50 days (range, 2 to 120 days) {01}.
Elimination:
Renal and fecal; in studies using radiolabeled tretinoin, approximately 63% of the radioactivity was recovered in the urine within 72 hours and 31% in the feces within 6 days {01}.
Precautions to Consider
Cross-sensitivity and/or related problems
Patients sensitive to other retinoids may be sensitive to tretinoin also {01}.
Carcinogenicity/Tumorigenicity
Long-term studies in animals have not been done. In short-term studies in mice receiving 30 mg per kg of body weight (mg/kg) per day (approximately twice the human dose on a mg per square meter of body surface area [mg/m 2] basis), tretinoin increased the rate of diethylnitrosamine-induced hepatic adenomas and carcinomas. {01}
Mutagenicity
No evidence of mutagenicity was found in the Ames and Chinese hamster V79 cell HGPRT tests. Tretinoin produced a twofold increase in sister chromatid exchange in human diploid fibroblasts. However, no clastogenic or aneuploidogenic effect was demonstrated in other chromosome aberration assays, including an in vitro assay in human peripheral lymphocytes and an in vivo mouse micronucleus test. {01}
Pregnancy/Reproduction
Fertility—
Tretinoin caused increased fetal resorptions in all animal species studied (mice, rats, hamsters, rabbits, and pigtail monkeys), but caused no other adverse effects on fertility or on reproductive performance in rats given up to 5 mg/kg per day (approximately two-thirds the human dose on a mg/m 2 basis). Testicular degeneration and increased numbers of immature spermatozoa were observed in a 6-week study in dogs receiving 10 mg/kg per day (approximately 4 times the human dose on a mg/m 2 basis). {01}
Pregnancy—
Adequate and well-controlled studies with tretinoin have not been done in humans, but other retinoids have caused spontaneous abortions and major fetal abnormalities. Reported defects, some of which were fatal, include abnormalities of the central nervous system (CNS), musculoskeletal system, external ear, thymus, eye, and great vessels; facial dysmorphia; cleft palate; parathyroid hormone deficiency; and cases of below-average intelligence (intelligence quotient lower than 85) with or without apparent CNS abnormalities. There is a high risk of a severely deformed infant being born to a woman receiving tretinoin during pregnancy. {01}
Administration of tretinoin to a female patient requires that the following criteria be met:
• Two reliable forms of contraception should be used simultaneously during, and for 1 month after discontinuation of, tretinoin therapy. Contraception should be used even after menopause, unless a hysterectomy has been performed. {01}
• Pregnancy testing using a highly sensitive test should be performed within 1 week before treatment is started. If possible, treatment should be delayed until the test results are available. If treatment cannot be delayed, the patient should be placed on two forms of contraception. {01}
• The patient must receive full information and warnings about the risk to the fetus if she becomes pregnant, the possibility of contraception failure, and the need to use two forms of contraception simultaneously during and following treatment. Proof that the patient understands and acknowledges the need for using two methods of contraception simultaneously should be obtained. {01}
• Pregnancy testing and contraception counseling should be repeated on a monthly basis during treatment {01}.
If a patient becomes pregnant during tretinoin therapy, the physician and patient should discuss the advisability of continuing or terminating the pregnancy {01}.
Tretinoin demonstrated teratogenic and embryotoxic effects and caused a decrease in the number of live fetuses in all animal species studied (mice, rats, hamsters, rabbits, and pigtail monkeys). Gross external, soft tissue, and skeletal abnormalities occurred with doses higher than 0.7 mg/kg per day in mice, 2 mg/kg per day in rats, and 7 mg/kg per day in hamsters, and with a dose of 10 mg/kg per day (the only dose studied) in pigtail monkeys. These doses are approximately equivalent to one-twentieth, one-fourth, one-half, and four times the human dose on a mg/m 2 basis, respectively. {01}
FDA Pregnancy Category D {01}.
Breast-feeding
It is not known whether tretinoin is distributed into breast milk. However, because of the risk of serious adverse effects in nursing infants, it is recommended that breast-feeding be discontinued prior to initiation of tretinoin therapy. {01}
Pediatrics
Patients younger than 1 year of age: Safety and efficacy have not been established {01}.
Patients 1 year of age and older: Clinical data in pediatric patients is limited. Fifteen patients 1 to 16 years of age received tretinoin in clinical trials. Complete remission was achieved in 10 patients (67%). However, particular caution is recommended when tretinoin is administered to children because the risk of retinoid-induced severe headache and pseudotumor cerebri is higher in this age group than in adults. Also, studies have shown that the maximal tolerated dose is lower in children than in adults (60 mg/m 2 per day versus 195 mg/m 2 per day, respectively). A reduction in dose may be considered if serious and/or intolerable toxicity occurs during treatment. However, the efficacy and safety of tretinoin in doses lower than 45 mg/m 2 per day have not been evaluated in pediatric patients. {01}
Drug interactions and/or related problems
The following drug interactions and/or related problems have been selected on the basis of their potential clinical significance (possible mechanism in parentheses where appropriate)—not necessarily inclusive (» = major clinical significance):
Note: Combinations containing any of the following medications, depending on the amount present, may also interact with this medication.
» Enzyme inducers, hepatic{01} (see Appendix II ) (inducers of hepatic cytochrome P-450 [CYP] enzymes, such as glucocorticoids, pentobarbital, phenobarbital, and rifampin, may alter the pharmacokinetics of tretinoin; however, whether concurrent use of a hepatic CYP enzyme inducer alters the safety or efficacy of tretinoin has not been established {01})
» Enzyme inhibitors, hepatic{01} (see Appendix II ), especially
» Ketoconazole{01} (administration of 400 to 1000 mg of ketoconazole 1 hour prior to administration of tretinoin on the 29th day of tretinoin therapy resulted in a 72% increase in the mean area under the tretinoin concentration–time curve [AUC]; other medications that generally inhibit hepatic CYP enzymes, such as cimetidine, cyclosporine, diltiazem, erythromycin, and verapamil, may also alter the pharmacokinetics of tretinoin. However, whether concurrent use of a hepatic CYP enzyme inhibitor alters the safety or efficacy of tretinoin has not been established {01})
Laboratory value alterations
The following have been selected on the basis of their potential clinical significance (possible effect in parentheses where appropriate)—not necessarily inclusive (» = major clinical significance):
With physiology/laboratory test values
» Cholesterol, serum{01} , and
» Triglycerides, serum{01} (concentrations were increased in up to 60% of tretinoin-treated patients in clinical trials, but usually returned to pretreatment values after discontinuation of therapy; although the risks of temporary elevations of cholesterol and triglyceride concentrations have not been established, venous thrombosis and myocardial infarction have been reported in patients considered to be at low risk of developing these conditions {01})
Hepatic function tests{01} (elevated hepatic function test results occurred in 50 to 60% of tretinoin-treated patients in clinical trials, but values generally returned to normal during or following completion of therapy {01})
» Leukocyte count{01} (a rapidly evolving increase in leukocyte count may occur during treatment, especially in patients with pre-existing leukocytosis {01})
Medical considerations/Contraindications
The medical considerations/contraindications included have been selected on the basis of their potential clinical significance (reasons given in parentheses where appropriate)— not necessarily inclusive (» = major clinical significance).
Risk-benefit should be considered when the following medical problems exist
» Leukocytosis, pre-existing (leukocyte count > 5 x 10 9/L){01} (high risk of further rapid increase in leukocyte count during therapy, which increases the risk of life-threatening complications, especially the retinoic acid–acute promyelocytic leukemia [RA-APL] syndrome; institution of concurrent full-dose chemotherapy, including an anthracycline if not contraindicated, on Day 1 or Day 2 of tretinoin treatment may decrease the risk of the RA-APL syndrome and should be considered for patients with pre-existing leukocytosis {01})
» Sensitivity to tretinoin or other retinoids{01}
Sensitivity to parabens{01}
Patient monitoring
The following may be especially important in patient monitoring (other tests may be warranted in some patients, depending on condition; » = major clinical significance):
Cholesterol concentrations{01} and
Triglyceride concentrations{01} (should be monitored frequently during therapy)
Hematopoietic profile{01} , especially
» White blood cell (WBC) count{01} (should be monitored frequently during therapy; rapidly evolving leukocytosis occurs in approximately 40% of patients during tretinoin treatment, which increases the risk of life-threatening complications, especially the RA-APL syndrome. If the WBC count reaches ³ 6 x 10 9/L by Day 5, ³ 10 x 10 9/L by Day 10, or ³ 15 x 10 9/L by Day 28 of tretinoin therapy, immediate institution of full-dose chemotherapy, including an anthracycline if not contraindicated, may decrease the risk of the RA-APL syndrome and should be considered {01})
» Hepatic function{01} (should be monitored frequently during therapy; although abnormalities detected in clinical trials usually resolved during or after treatment, approximately 3% of the patients developed hepatitis. Temporary withdrawal of tretinoin should be considered if hepatic function test values are elevated to more than five times the upper limit of normal {01})
Side/Adverse Effects
Note: Almost all patients will experience tretinoin-related adverse effects during treatment, especially fatigue, fever, headache, and weakness. These effects are seldom permanent and generally do not require interruption of therapy. {01}
In addition to the adverse effects listed below, adverse events that are common in patients with acute promyelocytic leukemia were reported in clinical trials, including hemorrhage (incidence 60%), infections (incidence 58%), gastrointestinal bleeding (incidence 34%), disseminated intravascular coagulation (incidence 26%), pneumonia (incidence 14%), cerebral hemorrhage (incidence 9%), hepatosplenomegaly (incidence 9%), and lymph disorders (incidence 6%). {01}
The following side/adverse effects have been selected on the basis of their potential clinical significance (possible signs and symptoms in parentheses where appropriate)—not necessarily inclusive:
Those indicating need for medical attention
Incidence more frequent (10% or higher)
Abdominal distention{01} (swelling of abdomen)
cardiac arrhythmias{01} (irregular heartbeat)
earache or feeling of fullness in the ear{01}
edema{01} (swelling of face, fingers, hands, feet, or lower legs)
fever{01}
hypertension (increase in blood pressure)
hypotension (decrease in blood pressure)
mental depression{01}
phlebitis (pain and swelling in foot or leg)
renal insufficiency{01} (decreased urination; swelling of face, fingers, hands, feet, or lower legs)
retinoic acid–acute promyelocytic leukemia (RA-APL) syndrome{01} (bone pain; discomfort or pain in chest; fever; shortness of breath, troubled breathing, tightness in chest, or wheezing; weight gain)
retinoid toxicity, including mucositis{01} (crusting, redness, pain, or sores in mouth or nose; cracked lips), ocular disorders and visual disturbances{01} (any change in vision), respiratory tract disorders{01} (coughing, sneezing, sore throat, stuffy or runny nose), and skin rash{01}
Note: The RA-APL syndrome occurs in approximately 25% of tretinoin-treated patients and is characterized, in addition to the symptoms listed above, by radiographic pulmonary infiltrates and pleural and/or pericardial effusions. This syndrome has resulted in impaired myocardial contractility, episodic hypotension, progressive hypoxemia requiring respiratory assistance, and fatalities due to multiorgan failure. This complication usually occurs during the first month of treatment; a few cases have appeared following the first dose of tretinoin. Although the RA-APL syndrome may occur without concomitant leukocytosis, the risk may be increased if rapidly evolving leukocytosis occurs during treatment. {01}
Incidence less frequent (3 to 9%)
Bronchial asthma{01} (shortness of breath, troubled breathing, tightness in chest, or wheezing)
cardiac failure{01} (chest pain; shortness of breath or troubled breathing)
cellulitis{01} (swollen area that feels warm and tender)
coma{01} (loss of consciousness)
convulsions{01}
dementia{01} (mood, mental, or personality changes)
difficult or painful urination{01}
flank pain{01} (pain in lower back or side)
fluid imbalance{01}
gastrointestinal tract ulcer{01} (cramping or pain in stomach, severe; heartburn, indigestion, or nausea, severe and continuing)
hallucinations{01}
hearing loss —may rarely be irreversible
hepatitis or other hepatic disorder{01} (yellow eyes or skin)
laryngeal edema{01} (shortness of breath or troubled breathing)
myocardial infarction{01} (feeling of heaviness in chest; pain in back, chest, or left arm; shortness of breath or troubled breathing)
pseudotumor cerebri{01} (headache, severe; nausea and vomiting; papilledema; vision problems)—especially in children
renal failure, acute{01} (decreased urination; swelling of face, hands, fingers, feet, or lower legs)
renal tubular necrosis{01}
somnolence{01} (drowsiness, very severe and continuing)
stroke{01} (difficulty in speaking, slow speech, or inability to speak; inability to move arms, legs, or facial muscles)
Those indicating need for medical attention only if they continue or are bothersome
Incidence more frequent
Anxiety{01}
confusion{01}
constipation{01}
diarrhea{01}
dizziness{01}
flushing{01}
general feeling of discomfort or illness{01}
indigestion{01}
insomnia{01} (trouble sleeping)
loss of appetite{01}
muscle pain{01}
paresthesia{01} (burning, crawling, or tingling feeling in the skin)
retinoid effects{01} (dryness of skin, mouth, or nose; hair loss; headache; itching of skin; nausea and vomiting)
shivering{01}
weight loss{01}
Incidence less frequent
Agitation{01} (anxiety and restlessness)
agnosia{01}
clumsiness or unsteadiness when walking{01}
forgetfulness{01}
frequent urination{01}
weakness in legs{01}
trembling, sometimes with a flapping movement{01}
Overdose
For information on the management of overdose or unintentional ingestion, contact a Poison Control Center (see Poison Control Center listing).
There is no experience with acute overdose of tretinoin in humans. Overdose of other retinoids has caused symptoms such as abdominal pain, ataxia, cheilosis, dizziness, facial flushing, and transient headache. These symptoms resolved without apparent residual effects. {01}
Patient Consultation
As an aid to patient consultation, refer to Advice for the Patient, Tretinoin (Systemic) .
In providing consultation, consider emphasizing the following selected information (» = major clinical significance):
Before taking this medication
» Conditions affecting use, especially:
Sensitivity to tretinoin or other retinoids
Pregnancy—High risk of fetal abnormalities if taken during pregnancy; need to use two effective methods of birth control simultaneously during and for 1 month following therapy
Breast-feeding—Discontinuing breast-feeding prior to treatment because of the risk of adverse effects in nursing infants
Use in children—Higher risk of severe headache and pseudotumor cerebri during treatment
Other medications, especially hepatic enzyme inducers or inhibitors
Proper use of this medication
» Compliance with therapy; not taking more medication than the amount prescribed
» Proper dosing
Missed dose: Taking as soon as possible; checking with physician if not remembered until almost time for next dose
» Proper storage
Precautions while using this medication
» Importance of regular visits to physician during therapy
» Continuing to take medication despite occurrence of expected side effects, such as fever, headache, tiredness, and weakness
» Notifying physician immediately if symptoms of retinoic acid–acute promyelocytic (RA-APL) syndrome or pseudotumor cerebri occur
Side/adverse effects
Notifying physician immediately if fever or symptoms of RA-APL syndrome, bronchial asthma, cardiac failure, convulsions, laryngeal edema, myocardial infarction, pseudotumor cerebri, or stroke occur
Signs of other potential side effects, especially abdominal distention, cardiac arrhythmias, earache or feeling of fullness in the ear, edema, hypertension, hypotension, mental depression, phlebitis, renal insufficiency, retinoid toxicity, cellulitis, dementia, difficult or painful urination, flank pain, gastrointestinal tract ulcer, hallucinations, hearing loss, hepatitis or other hepatic disorder, and somnolence
General Dosing Information
Tretinoin is to be used only under the supervision of a physician experienced in the management of patients with acute leukemia. Use of this medication also requires the availability of laboratory and supportive services capable of monitoring drug tolerance and treating a patient compromised by drug toxicity, including respiratory impairment. {01}
After remission has been achieved with tretinoin, the patient should receive a standard consolidation and/or maintenance chemotherapy regimen for acute promyelocytic leukemia, unless otherwise contraindicated {01}.
For treatment of adverse effects
For the retinoic acid–acute promyelocytic leukemia syndrome: High-dose corticosteroid treatment may reduce morbidity and mortality. It is recommended that such therapy (e.g., 10 mg of dexamethasone intravenously every 12 hours for 3 days or until symptoms abate) be initiated at the first signs and symptoms suggestive of this complication. Discontinuation of tretinoin therapy is usually not necessary. {01}
Oral Dosage Forms
TRETINOIN CAPSULES
Usual adult and adolescent dose
Leukemia, acute promyelocytic
Oral, 45 mg per square meter of body surface area per day, administered in two evenly divided doses. Treatment should be continued for thirty days after complete remission has been achieved or for a maximum of ninety days, whichever occurs first. {01}
Usual pediatric dose
Leukemia, acute promyelocytic
See Usual adult and adolescent dose . A decrease in the dose may be considered for patients who experience serious or intolerable toxicity. However, the efficacy and safety of lower doses have not been established. {01}
Strength(s) usually available
U.S.—
10 mg (Rx) [Vesanoid (beeswax) (butylated hydroxyanisole) (edetate disodium) (hydrogenated soybean oil flakes) (hydrogenated vegetable oils and soybean oil) (glycerin) (yellow iron oxide) (red iron oxide) (titanium dioxide) (methylparaben) (propylparaben){01}]
Packaging and storage:
Store between 15 and 30 °C (59 and 86 °F).
Revised: 08/14/1998
References
- Vesanoid package insert (Roche—US), New 11/95, Rec 12/7/95.
