Vesanoid (Retinoic Acid Tretinoin)

VESANOID™

Roche

All-trans Retinoic Acid Tretinoin

Differentiation Inducing Agent

Caution: All-trans retinoic acid should be administered to patients with APL only under the strict supervision of a physician who is experienced in the treatment of hematological/oncological diseases.

Action And Clinical Pharmacology: All-trans retinoic acid is a natural metabolite of retinol and belongs to the class of compounds known as retinoids, which are structurally related to vitamin A and comprise natural and synthetic analogs. In vitro studies with all-trans retinoic acid have demonstrated induction of differentiation and inhibition of cell proliferation in transformed hemopoietic cell lines, including human myeloid leukemia cell lines.

Acute promyelocytic leukemia (APL) is associated with a nonrandom chromosomal abnormality characterized by balanced and reciprocal translocations between the long arm of chromosomes 15 and 17 [t(15;17)(q22;q21)]. The gene encoding the retinoic acid receptor-alpha (RAR-a) is located on chromosome 17. A previously unidentified gene, PML, that may act as a transcription factor, is located on chromosome 15. The 15;17 translocation fuses the genes for PML and RAR-a, resulting in the synthesis of 2 reciprocal fusion transcripts, PML/RAR-a (found in all patients) and RAR-a/PML (found in about 2/3 of patients). PML/RAR-a may inhibit the differentiation of myeloid cells, resulting in carcinogenesis, an effect which may be overcome by the use of high doses of all-trans retinoic acid. Orally administered all-trans retinoic acid induces a high rate of complete remissions in patients with APL.

Pharmacokinetics: 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.

Single Dose: 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/m 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 Doses: 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.

Pharmacokinetics in Pediatric Patients: 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/mday, 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 M (180, 190 and 490 ng/mL) were observed following doses of 22.5, 30 and 40 mg/m AUC values for these doses were 1.29, 1.13 and 3.35 M (387, 339 and 1 005 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/m. 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.

Pharmacokinetics in renal and hepatic impairment: The pharmacokinetics of all-trans retinoic acid in patients with compromised kidney or liver function have not been studied.

Indications And Clinical Uses: 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.

Contra-Indications: Pregnancy: All-trans retinoic acid is highly teratogenic; therefore it is contraindicated during pregnancy. All-trans retinoic acid must not be used by women of child-bearing 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.

All-trans retinoic acid is contraindicated in patients with a known hypersensitivity to all-trans retinoic acid or related compounds.

Manufacturers’ Warnings In Clinical States: All-trans retinoic acid should be administered to patients with APL only under the strict supervision of a physician who is experienced in the treatment of hematological/oncological diseases.

Retinoic Acid Syndrome: 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, shortness of breath, acute respiratory distress, pulmonary infiltrates, hyperleukocytosis, hypotension, pleural effusions, and hepatic, renal and multiorgan failure (Retinoic Acid syndrome). Untreated, this syndrome can 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.

The Retinoic Acid syndrome may also be prevented by initiating treatment with concomitant full-dose chemotherapy if a significant increase in the leukocyte count is observed. The following therapeutic regimen is recommended: patients initiating all-trans retinoic acid therapy with a low leukocyte count (
Patients initiating all-trans retinoic acid therapy with an elevated leukocyte count (>10´10L) concomitant chemotherapy should be started immediately.

Mortality and morbidity is reduced by following these treatment recommendations in patients with this syndrome. All-trans retinoic acid therapy can continue.

Pregnancy:

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 in any amount even for short periods or within 1 month of its discontinuation. 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:

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.

She is capable of complying with the mandatory contraception measures.

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.

Therapy should not begin until the second or third day of the next normal menstrual period.

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.

All these measures should be considered in relationship to the severity of the disease and the urgency of the treatment.

Lactation: Nursing should be discontinued if therapy with all-trans retinoic acid is initiated.

Precautions: Drug Interactions : Drugs affecting the hepatic cytochrome P450 enzyme system function may interact with all-trans retinoic acid, leading to a change of blood levels.

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. Cytochrome P450 inhibitors, such as ketoconazole, may potentially enhance the therapeutic efficacy of all-trans retinoic acid.

Renal and Hepatic Impairment: The pharmacokinetics of all-trans acid in patients with compromised kidney or liver function have not been studied. The need for dosage adjustments in patients with renal or hepatic impairment is unknown.

Adverse Reactions: The safety profile of all-trans retinoic acid has been evaluated retrospectively in a small number of patients.

In persons treated with the recommended daily doses of all-trans retinoic acid, the following adverse events were observed frequently (in about 1/4 of the patients or more) signs and symptoms of the hypervitaminosis A syndrome (including xeroderma, lip and mouth dryness, cheilitis, rash, edema, nausea, vomiting and bone pain). Headache, fever, shivering, fatigue, back pain, chest pain, dyspnea, coughing, abdominal pain, dermal bleeding, and elevation in serum triglycerides, cholesterol and transaminases may also be observed.

The following adverse events, considered remotely, possibly or probably related to drug treatment have been reported in less than 1/4 of all APL patients treated with all-trans retinoic acid in the clinical trials:

  • Autonomic Nervous System: tachycardia, hypertension, hypotension, flushing, pallor, red extremities.
  • Body as a Whole: generalized pain, abdominal distention, post traumatic pain, chest discomfort, hypothermia.
  • Cardiovascular System: cardiac failure, cyanosis, heart enlarged.
  • Central and Peripheral Nervous System: dizziness, confusion, intracranial hypertension, light headed feeling, flank pain, numbness of extremities, abnormal gait, leg weakness, neurologic reaction, inguinal pain, visual field defects, hyporeflexia.
  • Dermatological: pruritus, increased sweating, alopecia, dry scalp, nasal dryness, nail disorder, photosensitivity reaction, xerophthalmia.
  • Gastrointestinal: abdominal pain, diarrhea, constipation, blisters in the mouth, stomach upset, dysphagia, buccal mucosa ulceration, stomatitis, flatulence, ulcer.
  • Metabolic and Nutritional Disorders: weight changes, edema of extremities, acidosis, gout, dehydration, fluid overload, moonface.
  • Musculoskeletal: musculoskeletal pain.
  • Platelet, Bleeding and Clotting: disseminated intravascular coagulation (DIC), nosebleed and other bleeding disorders.
  • Psychiatric: generalized weakness, anxiety, lethargy, depression, malaise, insomnia, anorexia, agitation, forgetfulness.
  • Resistance Mechanism Disorders: infection, septicemia, moniliasis.
  • Respiratory: pleural effusion, nasal congestion, pharyngitis, rale, respiratory insufficiency, wheezing expiratory, pneumonia, respiratory distress, tachypnea, pharynx irritation, pulmonary infiltration, hypoxia, sinusitis, bronchial asthma.
  • Special Senses: blurred vision, visual disturbance, photophobia, conjunctivitis, decreased vision, changes in visual acuity, ear fullness, earache, ear buzzing.
  • Urinary: dysuria, kidney failure, urinary tract infection, micturition frequency, renal insufficiency, cystitis.

Based on the information presently available, these adverse events do not represent permanent or irreversible hazards. It may be advisable to interrupt or discontinue the therapy, depending on the alternative options available to the patient.

Symptoms of the Retinoic Acid syndrome in APL have been frequently reported and may be life-threatening unless treated (see Warnings).

Symptoms And Treatment Of Overdose: Symptoms and Treatment: Cases of acute overdosage with all-trans retinoic acid have not been reported. Cases of overdose would be expected to show largely reversible effects characteristic of hypervitaminosis A. The recommended dose is one-third of the maximum tolerated dose in solid tumor patients and below the maximum tolerated dose in children.

Dosage: A total daily dose of 45 mg/mbody surface divided in 2 equal doses is recommended for oral administration to APL patients, including pediatric and geriatric patients. Treatment should be continued for 30 to 90 days until complete remission has been achieved. After complete remission, standard chemotherapy should be initiated immediately.

Availability And Storage: 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.

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