Information for the Patient
Vesanoid
Pharmacology
All-trans retinoic acid is an endogenous metabolite of vitamin A and is normally present in plasma at concentrations of 2 to 4 ng/mL. All-trans retinoic acid is transported directly via the portal system rather than through the lymphatics and thus absorption does not require specific transport mechanisms. All-trans retinoic acid is highly lipophilic with more than 95% of total drug concentration bound to plasma protein. All-trans retinoic acid is primarily metabolized by liver enzymes and is converted to the 13-cis isomer. Oxidation by P450 isoenzymes leads to the corresponding 4-hydroxy and 4-oxo-compounds. After glucuronidation, these metabolites are excreted in the urine and bile.
Following a single dose of radiolabelled all-trans retinoic acid, about 30% of the total radioactivity was recovered in the feces and about 60% in the urine. Nearly the entire dose was excreted within 3 to 6 days.
A phase I trial of all-trans retinoic acid administered orally twice-daily for treatment courses of 28 days was performed in pediatrics. Cohorts of at least 3 patients were entered at successive all-trans retinoic acid dose levels (from 45 to 80 mg/m2/day, with a twice a day dosing regimen) until dose-limiting toxicity was consistently observed. Twenty-one patients with a median age of 14 years and various types of tumors including 2 patients with APL were entered into the trial.
Pharmacokinetics were determined in 18 patients on day 1 and in 7 patients on day 1 and day 28. Time to peak plasma concentrations was between 1 and 4 hours after dosing. Peak plasma concentrations of all-trans retinoic acid of 0.59, 0.62 and 1.64 µM (180, 190 and 490 ng/mL) were observed following doses of 22.5, 30 and 40 mg/m2. AUC values for these doses were 1.29, 1.13 and 3.35 µM (387, 339 and 1005 ng·h/mL), respectively. Peak plasma concentrations and AUC values did not appear to increase in proportion to dose. A greater than 3-fold increase in AUC was observed following a 30% increase in dose (30 to 40 mg/m2). The average terminal half-life was 0.7 hours. The AUC on day 1 was significantly greater than the AUC on day 28 (mean decrease 78%±30 SD). Quantifiable concentrations of 4-oxo metabolites of all-trans retinoic acid were not observed.
The pharmacokinetics of all-trans retinoic acid in patients with compromised kidney or liver function have not been studied.
The pharmacokinetics of all-trans retinoic acid were investigated in healthy volunteers following a single oral dose of 40 mg of all-trans retinoic acid and in patients with acute promyelocytic leukemia (APL) treated with 45 mg/m2. Maximum plasma concentrations of all-trans retinoic acid were reached within 1 to 2 hours in the APL patients and within 3 to 4 hours in the healthy volunteers. Large intersubject variability was observed. Plasma concentrations declined mono-exponentially with a mean elimination half-life of 0.71 hours. Endogenous levels (2 to 4 ng/mL) were reached 7 to 12 hours after dosing.
Multiple oral doses of all-trans retinoic acid were associated with a significant (about 2-fold) decrease in both the peak plasma levels and the AUC levels, after 2 to 6 weeks of treatment. These changes were associated with a 10-fold increase in urinary excretion of 4-oxo all-trans retinoic acid glucuronide.
The administration of ketoconazole, an inhibitor of the P450 enzyme system, after multiple doses of all-trans retinoic acid, resulted in a greater mean plasma all-trans retinoic acid AUC than after the administration of all-trans retinoic acid alone.
Indications
For the induction of remission in acute promyelocytic leukemia (APL; FAB classification AML-M3). Previously untreated patients, as well as patients who relapsed after, or were refractory to, standard chemotherapy (daunomycin and cytosine arabinoside or equivalent therapies) may be treated with all-trans retinoic acid. Upon achievement of complete remission, full-dose consolidation chemotherapy should be employed. Among patients maintained on all-trans retinoic acid, a loss of responsiveness to all-trans retinoic acid has been reported, with a median time to relapse of 4 to 6 months.
Precautions
As all-trans retinoic acid is metabolized by the hepatic P450 system, there is potential for alteration of pharmacokinetics parameters in patients administered concomitant medications that are also inducers or inhibitors of this system. Medications that generally induce hepatic P450 enzymes include rifampin, glucocorticoids, phenobarbital and pentobarbital. Medications that generally inhibit hepatic P450 enzymes include ketoconazole, cimetidine, erythromycin, verapamil, diltiazem and cyclosporine. There are no data to suggest that co-use with these medications increases or decreases either efficacy or toxicity of all-trans retinoic acid. There are no data on a possible pharmacokinetic interaction between all-trans retinoic acid and daunorubicin and cytosine arabinoside.
Antifibrinolytic agents such as tranexamic acid, aminocaproic acid, and aprotinin: Cases of fatal thrombotic complications have been reported rarely in patients concomitantly treated with all-trans retinoic acid and antifibrinolytic agents. Therefore, caution should be exercised when administering all-trans retinoic acid concomitantly with these agents (see Warnings).
Agents known to cause intracranial hypertension/pseudotumor cerebri such as tetracyclines: All-trans retinoic acid may cause intracranial hypertension/pseudotumor cerebri. Concomitant administration of all-trans retinoic acid and agents known to cause intracranial hypertension/pseudotumor cerebri as well might increase the risk of this condition (see Warnings).
Contraindicated Drug Associations (see Contraindications): Vitamin A: As with other retinoids, all-trans retinoic acid must not be administered in combination with vitamin A because symptoms of hypervitaminosis A could be aggravated.
The pharmacokinetics of all-trans retinoic acid in patients with compromised kidney or liver function have not been studied. As with other retinoids, the need for dosage adjustments in patients with renal or hepatic impairment is unknown, however, a reduction of dose to 25 mg/m2 is recommended as a precautionary measure.
Supplied
Each oval-shaped, soft gelatin capsule, one half reddish-brown opaque and the other half brownish-yellow opaque, contains: tretinoin 10 mg. Nonmedicinal ingredients: gelatin, glycerol, hydrogenated hydrolyzed starch, hydrogenated soybean oil, iron oxide, mannitol, partially hydrogenated soybean oil, sorbitol, soybean oil, titanium dioxide and yellow beeswax. Bottles of 100. Keep the bottle tightly closed. Store at 15 to 30°C. Protect from light.
Contraindications
See Contraindications, Pregnancy.
All-trans retinoic acid is contraindicated in patients with a known hypersensitivity to all-trans retinoic acid or related compounds.
The use of all-trans retinoic acid in combination with vitamin A is contraindicated (see Precautions, Drug Interactions).
All-trans retinoic acid is highly teratogenic; therefore it is contraindicated during pregnancy and in nursing mothers. All-trans retinoic acid must not be used by women of childbearing potential unless effective contraception is practiced for at least 1 month before beginning therapy, during therapy and at least 1 month following discontinuation of therapy.
Warnings
In many patients (20 to 25%) with acute promyelocytic leukemia (APL) treated with all-trans retinoic acid, a syndrome may occur characterized by some or all of the following symptoms: fever, dyspnea, acute respiratory distress, pulmonary infiltrates, hypotension, pleural and pericardial effusions, edema, weight gain, hepatic, renal and multiorgan failure (Retinoic Acid syndrome). RAS is frequently associated with hyperleukocytosis and may be fatal. If symptoms of the Retinoic Acid syndrome become apparent, treatment with a short course of high doses of corticosteroids (i.e., dexamethasone) should be initiated immediately particularly in patients where the syndrome is suspected but hyperleukocytosis is not observed.
During clinical trials hyperleukocytosis has been frequently observed (75%), sometimes associated with the RAS.
For those patients experiencing hyperleukocytosis when they receive all-trans retinoic acid (ATRA) alone, the RAS can be prevented by addition of full-dose anthracycline-based chemotherapy to the all-trans retinoic acid regimen based on the white blood cell (WBC) count. The current therapeutic treatment recommendations are the following:
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Immediate treatment of patients presenting with a WBC count of >5×109/L at diagnosis or at any time with a combination of all-trans retinoic acid and chemotherapy.
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Addition of full-dose chemotherapy to ATRA therapy in patients with a WBC of <5×109/L at day 0 of the treatment with ATRA and if WBC counts become: ≥6×109/L at any time from day 1 to day 6 of treatment and/or ≥10×109/L at any time from day 7 to day 10 of treatment and/or ≥15×109/L at any time from day 11 to day 28 of treatment.
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Treatment with dexamethasone (10 mg every 12 hours for up to maximum 3 days or until resolution of the symptoms), if the patient presents early clinical signs of the syndrome.
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In cases of moderate and severe RAS, temporary interruption of all-trans retinoic acid therapy should be considered.
Mortality and morbidity is reduced by following these treatment recommendations in patients with this syndrome.
There is a risk of thrombosis (both venous and arterial) which may involve any organ system during the first month of treatment (see Adverse Effects). Therefore, caution should be exercised when treating patients with the combination of all-trans retinoic acid and antifibrinolytic agents such as tranexamic acid, aminocaproic acid or aprotinin (see Precautions, Drug Interactions).
Supportive care appropriate for patients with acute promyelocytic leukemia, for example, prophylaxis for bleeding and prompt therapy for infection, should be maintained during therapy with tretinoin. The patient's hematologic profile, coagulation profile, liver function test results, and triglyceride and cholesterol levels should be monitored frequently.
All-trans retinoic acid may cause intracranial hypertension/pseudotumor cerebri. The concomitant use of other agents known to cause intracranial hypertension/pseudotumor cerebri such as tetracyclines might increase the risk of this condition (see Precautions, Drug Interactions).
The ability to drive or operate machinery might be impaired in patients treated with all-trans retinoic acid, particularly if they are experiencing dizziness or severe headache.
Micro-dosed progesterone preparations (“minipill”) may be an inadequate method of contraception during treatment with all-trans retinoic acid.
Nursing should be discontinued if therapy with all-trans retinoic acid is initiated.
Pregnancy: All-trans retinoic acid is highly teratogenic. Its use is contraindicated in pregnant women and women who might become pregnant during or within 1 month of the cessation of treatment. There is an extremely high risk that a deformed infant will result if pregnancy occurs while taking all-trans retinoic acid irrespective of the dose or duration of the treatment. Potentially all exposed fetuses can be affected. Therapy with all-trans retinoic acid should only be started in female patients if each of the following conditions is met:
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The patient is suffering from life-threatening malignancies. She is informed by her physicians of the hazards of becoming pregnant during and within 1 month after treatment with all-trans retinoic acid.
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She is willing to comply with the mandatory contraception measures.
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Every woman of childbearing potential who is to undergo treatment with all-trans retinoic acid uses effective contraception for 4 weeks before, during and for 1 month after discontinuation of treatment with all-trans retinoic acid.
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Therapy should not begin until the second or third day of the next normal menstrual period.
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A negative pregnancy test result must be obtained within the 2 weeks before commencement of treatment. It is advisable to perform additional pregnancy tests at monthly intervals during therapy.
Should pregnancy occur in spite of these precautions during treatment with all-trans retinoic acid or within 1 month after its discontinuation, there is a high risk of severe malformation of the fetus particularly when all-trans retinoic acid was given during the first trimester of pregnancy.
All these measures should be considered in relationship to the severity of the disease and the urgency of the treatment.
Adverse Effects
abdominal pain, diarrhea, constipation, blisters in the mouth, stomach upset, dysphagia, buccal mucosa ulceration, stomatitis, flatulence, ulcer, pancreatitis, diminished appetite.
There is limited safety information on the use of all-trans retinoic acid in children. There have been some reports of increased toxicity in children treated with tretinoin, particularly increased pseudotumor cerebri.
dysuria, kidney failure, urinary tract infection, micturition frequency, renal insufficiency, cystitis.
The decision to interrupt or continue therapy should be based on an evaluation of the benefit of the treatment versus the severity of the side effects.
Postmarketing Experience:
blurred vision, visual disturbance, photophobia, conjunctivitis, decreased vision, changes in visual acuity, ear fullness, earache, ear buzzing.
Occasional cases of hypercalcemia have been reported.
infection, septicemia, moniliasis.
generalized pain, abdominal distention, post-traumatic pain, chest discomfort, hypothermia.
Vasculitis, predominantly involving the skin has been reported rarely.
pleural effusion, nasal congestion, pharyngitis, rale, respiratory insufficiency, asthma-like syndrome, pneumonia, respiratory distress, tachypnea, pharynx irritation, pulmonary infiltration, hypoxia, sinusitis, bronchial asthma.
Sweet's syndrome has been reported uncommonly. Erythema nodosum has been reported rarely.
generalized weakness, anxiety, lethargy, depression, malaise, insomnia, anorexia, agitation, forgetfulness.
cardiac failure, cyanosis, heart enlarged, arrhythmias. Cases of thrombosis (both venous and arterial) involving various sites (e.g. cerebrovascular accident, myocardial infarctions, renal infarct) have been reported uncommonly.
dizziness, confusion, intracranial hypertension, light-headed feeling, flank pain, numbness of extremities, abnormal gait, leg weakness, neurologic reaction, inguinal pain, visual field defects, hyporeflexia, paresthesia.
Thrombocytosis has been reported rarely. Marked basophilia with or without symptomatic hyperhistaminemia has been reported rarely, mainly in patients with the rare APL variant associated with basophilic differentiation.
Myositis has been reported rarely.
disseminated intravascular coagulation (DIC), nosebleed and other bleeding disorders, thrombosis.
tachycardia, hypertension, hypotension, flushing, pallor, red extremities.
Overdose
In cases of overdose with all-trans retinoic acid reversible signs of hypervitaminosis A (headache, nausea, vomiting, mucocutaneous symptoms) can appear. The recommended dose in acute promyelocytic leukemia is one quarter of the maximum tolerated dose in solid tumor patients and below the maximum tolerated dose in children.
There is no specific treatment in the case of an overdose, however, it is important that the patient be treated in a special hematological unit.
Dosage
A total daily dose of 45 mg/m2 body surface divided in 2 equal doses is recommended for oral administration to APL patients, including pediatric and geriatric patients.
This is approximately 8 capsules per adult dose. It is recommended that pediatric patients be treated with 45 mg/m2 unless severe toxicity becomes apparent. Dose reduction should be particularly considered for children with intractable headache.
Treatment should be continued for 30 to 90 days until complete remission has been achieved.
After completion of remission, a course of consolidation chemotherapy including anthracycline and cytosine arabinoside should be initiated immediately; for example, 3 courses in 5- to 6-week intervals.
If there has been a remission with ATRA alone, it is not necessary to modify doses of ATRA if ATRA is used with chemotherapy.
The effect of food on the bioavailability of all-trans retinoic acid has not been characterized. Since the bioavailability of retinoids, as a class, is known to increase in the presence of food, it is recommended that all-trans retinoic acid be administered with a meal or shortly thereafter.
