TRETINOIN- tretinoin capsule
Glenmark Pharmaceuticals Inc., USA
WARNINGS 1. Experienced Physician and Institution Patients with acute promyelocytic leukemia (APL) are at high risk in general and can have severe adverse reactions to tretinoin. Tretinoin should therefore be administered only to patients with APL under the strict supervision of a physician who is experienced in the management of patients with acute leukemia and in a facility with laboratory and supportive services sufficient to monitor drug tolerance and protect and maintain a patient compromised by drug toxicity, including respiratory compromise. Use of tretinoin requires that the physician concludes that the possible benefit to the patient outweighs the following known adverse effects of the therapy.2. Retinoic Acid-APL Syndrome About 25% of patients with APL treated with tretinoin have experienced a syndrome called the retinoic acid-APL (RA-APL) syndrome characterized by fever, dyspnea, acute respiratory distress, weight gain, radiographic pulmonary infiltrates, pleural and pericardial effusions, edema, and hepatic, renal, and multi-organ failure. This syndrome has occasionally been accompanied by impaired myocardial contractility and episodic hypotension. It has been observed with or without concomitant leukocytosis. Endotracheal intubation and mechanical ventilation have been required in some cases due to progressive hypoxemia, and several patients have expired with multi-organ failure. The syndrome generally occurs during the first month of treatment, with some cases reported following the first dose of tretinoin.The management of the syndrome has not been defined rigorously, but high-dose steroids given at the first suspicion of the RA-APL syndrome appear to reduce morbidity and mortality. At the first signs suggestive of the syndrome (unexplained fever, dyspnea and/or weight gain, abnormal chest auscultatory findings or radiographic abnormalities), high-dose steroids (dexamethasone 10 mg intravenously administered every 12 hours for 3 days or until the resolution of symptoms) should be immediately initiated, irrespective of the leukocyte count. The majority of patients do not require termination of tretinoin therapy during treatment of the RA-APL syndrome. However, in cases of moderate and severe RA-APL syndrome, temporary interruption of tretinoin therapy should be considered. 3. Leukocytosis at Presentation and Rapidly Evolving Leukocytosis During Tretinoin Treatment During tretinoin treatment about 40% of patients will develop rapidly evolving leukocytosis. Patients who present with high WBC at diagnosis (>5×109 /L) have an increased risk of a further rapid increase in WBC counts. Rapidly evolving leukocytosis is associated with a higher risk of life-threatening complications.If signs and symptoms of the RA-APL syndrome are present together with leukocytosis, treatment with high-dose steroids should be initiated immediately. Some investigators routinely add chemotherapy to tretinoin treatment in the case of patients presenting with a WBC count of >5×109 /L or in the case of a rapid increase in WBC count for patients leukopenic at start of treatment, and have reported a lower incidence of the RA-APL syndrome. Consideration could be given to adding full-dose chemotherapy (including an anthracycline if not contraindicated) to the tretinoin therapy on day 1 or 2 for patients presenting with a WBC count of >5×10 9 /L, or immediately, for patients presenting with a WBC count of <5×109 /L, if the WBC count reaches ≥6×109 /L by day 5, or ≥10×109 /L by day 10, or ≥15×109 /L by day 28.4. Teratogenic Effects. Pregnancy Category D–see WARNINGS There is a high risk that a severely deformed infant will result if tretinoin is administered during pregnancy. If, nonetheless, it is determined that tretinoin represents the best available treatment for a pregnant woman or a woman of childbearing potential, it must be assured that the patient has received full information and warnings of the risk to the fetus if she were to be pregnant and of the risk of possible contraception failure and has been instructed in the need to use two reliable forms of contraception simultaneously during therapy and for 1 month following discontinuation of therapy, and has acknowledged her understanding of the need for using dual contraception, unless abstinence is the chosen method.Within 1 week prior to the institution of tretinoin therapy, the patient should have blood or urine collected for a serum or urine pregnancy test with a sensitivity of at least 50 mIU/mL. When possible, tretinoin therapy should be delayed until a negative result from this test is obtained. When a delay is not possible, the patient should be placed on two reliable forms of contraception. Pregnancy testing and contraception counseling should be repeated monthly throughout the period of tretinoin treatment.
Tretinoin, USP is a retinoid that induces maturation of acute promyelocytic leukemia (APL) cells in culture. It is available in a 10 mg gelatin capsule for oral administration. Each capsule contains the following inactive ingredients: butylated hydroxyanisole, edetate disodium, hydrogenated soybean oil, refined soybean oil and yellow wax (yellow beeswax). The ingredients in the capsule shell include gelatin, glycerin, sorbitol, red iron oxide, titanium dioxide. The ingredients in the edible imprinting ink include ammonium hydroxide, black iron oxide, propylene glycol and shellac. The ingredients in the processing aid Phosal 53 include lecithin, caprylic/capric triglycerides, sunflower mono/diglycerides, oleic acid, ascorbyl palmitate and tocopherol.
Chemically, tretinoin, USP is all-trans retinoic acid and is related to retinol (Vitamin A) and has the following chemical name: Retinoic acid, all trans (all-E)-3,7-Dimethyl-9-(2,6,6-trimethyl-1-cyclohexen-1-yl)-2,4,6,8-nonatetraenoic acid.
It is a yellow to yellow-orange crystalline powder, and has the following structural formula:
C20 H28 O2 Molecular Weight: 300.44
Tretinoin is not a cytolytic agent but instead induces cytodifferentiation and decreased proliferation of APL cells in culture and in vivo. In APL patients, tretinoin treatment produces an initial maturation of the primitive promyelocytes derived from the leukemic clone, followed by a repopulation of the bone marrow and peripheral blood by normal, polyclonal hematopoietic cells in patients achieving complete remission (CR). The exact mechanism of action of tretinoin in APL is unknown.
Tretinoin activity is primarily due to the parent drug. In human pharmacokinetics studies, orally administered drug was well absorbed into the systemic circulation, with approximately two-thirds of the administered radiolabel recovered in the urine. The terminal elimination half-life of tretinoin following initial dosing is 0.5 to 2 hours in patients with APL. There is evidence that tretinoin induces its own metabolism. Plasma tretinoin concentrations decrease on average to one-third of their day 1 values during 1 week of continuous therapy. Mean ± SD peak tretinoin concentrations decreased from 394 ± 89 to 138 ± 139 ng/mL, while area under the curve (AUC) values decreased from 537 ± 191 ng·h/mL to 249 ± 185 ng·h/mL during 45 mg/m2 daily dosing in 7 APL patients. Increasing the dose to “correct” for this change has not increased response.
A single 45 mg/m2 (~80 mg) oral dose to APL patients resulted in a mean ± SD peak tretinoin concentration of 347 ± 266 ng/mL. Time to reach peak concentration was between 1 and 2 hours.
The apparent volume of distribution of tretinoin has not been determined. Tretinoin is greater than 95% bound in plasma, predominately to albumin. Plasma protein binding remains constant over the concentration range of 10 to 500 ng/mL.
Tretinoin metabolites have been identified in plasma and urine. Cytochrome P450 enzymes have been implicated in the oxidative metabolism of tretinoin. Metabolites include 13-cis retinoic acid, 4-oxo trans retinoic acid, 4-oxo cis retinoic acid, and 4-oxo trans retinoic acid glucuronide. In APL patients, daily administration of a 45 mg/m2 dose of tretinoin resulted in an approximately tenfold increase in the urinary excretion of 4-oxo trans retinoic acid glucuronide after 2 to 6 weeks of continuous dosing, when compared to baseline values.
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