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tretinoin 10 mg capsule

Out of Stock Manufacturer GLENMARK PHARMA 68462079201
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Uses

Acute Promyelocytic Leukemia

Tretinoin is used for remission induction in acute promyelocytic leukemia (APL), French-American-British classification M3 including the M3 variant, characterized by the presence of certain genetic markers (i.e., 15;17 chromosomal translocation and/or PML/RAR-α gene) in patients with relapsed or refractory disease following anthracycline-based chemotherapy or in patients for whom anthracycline therapy is contraindicated. Tretinoin also is added to induction with chemotherapy as initial treatment for APL in patients with previously untreated disease.

Tretinoin is indicated for induction of remission, and patients with disease in remission following completion of induction therapy should receive consolidation and/or maintenance therapy for APL. For patients with APL that fails to respond or relapses following induction therapy with anthracycline-based therapy and tretinoin, induction therapy with arsenic trioxide is recommended.

APL is associated with a translocation between the long arms of chromosomes 15 and 17 [t(15;17)]. The 15;17 translocation results in fusion of the genes for promyelocytic leukemia (PML) and retinoic acid receptor-alpha (RAR-α), leading to 2 reciprocal fusion transcripts, PML/RAR-α and RAR-α/PML; the PML/RAR-α fusion protein is thought to play a role in leukemogenesis. Although therapy with tretinoin may be initiated based on the morphologic diagnosis of APL, cytogenetic evaluation to confirm presence of the 15;17 translocation should be performed. If this genetic marker is absent, molecular diagnostic testing for the PML/RAR-α fusion protein should be performed. The response rate to tretinoin has been determined only in patients with the 15;17 translocation and/or the PML/RAR-α gene, and alternative therapy should be considered in patients with APL lacking these genetic markers. Limited evidence indicates that response to tretinoin is poor in patients with a variant t(11;17) chromosomal abnormality.

Induction regimens are used to rapidly reduce the tumor burden to achieve complete remission, which generally is defined as less than 5% leukemic blast cells in the bone marrow and normalization of peripheral blood cell counts. Conventional induction therapy for APL consists of a combination of cytotoxic agents (i.e., an anthracycline and cytarabine), and results in a complete remission in about 60-80% of patients. The rate of early mortality is relatively high in patients with APL undergoing induction therapy, mainly secondary to intracranial or pulmonary hemorrhage in association with disseminated intravascular coagulation, fibrinolysis, and thrombocytopenia. Induction therapy with cytotoxic agents often initially worsens coagulopathy associated with APL, and aggressive replacement of platelets and clotting factors is necessary; although low-dose heparin therapy is used by some clinicians for anticoagulation, other clinicians do not recommend this approach. In contrast, induction therapy with tretinoin typically results in improvement of the coagulopathy associated with APL, and prophylactic heparin therapy generally is not required. However, tretinoin therapy is associated with complications including leukocytosis and a syndrome of respiratory distress described as the retinoic acid-APL syndrome.

The optimal postremission management of patients with APL receiving remission induction therapy with tretinoin has not been established. Patients with disease in complete remission should receive consolidation and/or maintenance therapy for APL following completion of induction therapy. Because of hypercatabolism of tretinoin with prolonged administration (see Pharmacokinetics), clinical resistance appears to result from continued therapy with the drug (see Pharmacology); however, the use of tretinoin in an intermittent maintenance regimen has been investigated.

Treatment for Relapsed or Refractory Disease

The current indication for tretinoin is based principally on the results from an open-label, single-arm trial and on data from 2 cohorts of compassionate cases treated in multiple centers under the direction of the National Cancer Institute. All patients received tretinoin 45 mg/m daily as a divided oral dose for up to 90 days or 30 days beyond attainment of a complete remission. In the clinical trial, tretinoin therapy was associated with a complete remission rate of 80% in the 20 patients with relapsed APL and 73% in the 15 patients with previously untreated APL; median survival was 10.8 months in the patients with relapsed disease. In the 2 cohorts of compassionate cases of APL, complete remission rates of 50-52% in patients with relapsed disease and 36-68% in patients with previously untreated disease were reported. The median time to achieve a complete remission was between 40-50 days (range: 2-120 days) in all patients studied. Most of the patients in these studies also received cytotoxic chemotherapy during the remission phase. The treatment outcomes observed with tretinoin in these patients compare favorably to the 30-50% complete remission rate and median survival of 6 months or less associated with cytotoxic chemotherapy alone in the treatment of relapsed APL.

Among 4 patients in whom cytogenetic analysis failed to detect the t(15;17) translocation, treatment with tretinoin resulted in a response in 3 patients. Although molecular genetic studies were not performed, these cases probably involved a masked translocation resulting in PML/RAR-α fusion. Responses to tretinoin have not been reported in cases of APL in which PML/RAR-α fusion has been shown to be absent. Although tretinoin has been used to induce second remissions in patients with APL that has relapsed following prior treatment with tretinoin, results have been inconsistent; continuous treatment with tretinoin results in resistance to the drug secondary to increased catabolism and decrease in plasma concentrations (see Pharmacokinetics), and response may be more likely for late relapse occurring after discontinuation of tretinoin therapy.

Limited data on the clinical use of tretinoin in children are available. (See Precautions and Contraindications: Pediatric Precautions.). A complete remission rate of 67% (8 of 10 males and 2 of 5 females) was reported in 15 pediatric patients (age range: 1-16 years) receiving tretinoin induction therapy for APL.

Initial Treatment for Newly Diagosed Disease

Tretinoin is added to induction with chemotherapy as initial treatment for acute promyelocytic leukemia in patients with previously untreated disease. Although tretinoin has not been shown to increase the complete remission rate or lower morbidity and mortality during induction therapy for APL compared with cytotoxic chemotherapy, the results of 2 large randomized trials have demonstrated that relapse-free (and, in one of the studies, overall) survival is prolonged in patients with previously untreated APL who receive tretinoin as a part of their treatment. In a randomized, multicenter trial in 346 patients with newly diagnosed APL, induction therapy with tretinoin was shown to be superior to induction therapy with standard chemotherapy (daunorubicin and cytarabine) with similar rates of complete remission and early mortality but prolonged disease-free and overall survival resulting from a reduced rate of relapse. Another randomized trial was terminated early when the addition of tretinoin to induction therapy with daunorubicin and cytarabine was shown to result in an increased rate of event-free survival. Long-term follow-up shows that the results of these randomized trials have been maintained.

Based on these findings, most clinicians recommend the addition of tretinoin to induction with chemotherapy as initial treatment for acute promyelocytic leukemia. Although the optimal regimen for induction therapy has not been established, data from initial randomized trials suggests that tretinoin should be administered concurrently with anthracycline-based chemotherapy for newly diagnosed APL. In one of these randomized trials, the use of maintenance therapy (continuous low-dose chemotherapy with mercaptopurine and methotrexate) following induction and consolidation therapy for APL was shown to reduce the rate of relapse and increase the 2-year survival rate. Maintenance regimens including tretinoin have been shown to increase the rate of disease-free or event-free survival.

Acne, Photoaging, and Other Dermatologic Conditions

For topical uses, see Tretinoin 84:16.

Dosage and Administration

Administration

Tretinoin is administered orally. The effect of food on the absorption of tretinoin is not known; however, the absorption of other retinoids has been shown to be enhanced when administered with food.

Dosage

Acute Promyelocytic Leukemia

For the induction of remission in patients with APL, the recommended dosage of tretinoin is 45 mg/m daily administered in 2 evenly divided doses. The manufacturer states that tretinoin therapy should be continued until 30 days after complete remission is achieved, or for a total of 90 days, whichever occurs first. Some clinicians report that tretinoin therapy should be continued until complete remission is achieved, or for a total of 90 days, whichever occurs first. Unless contraindicated, consolidation and/or maintenance chemotherapy for APL should be administered to all patients following induction therapy.

If tretinoin therapy has been initiated according to morphologic diagnosis of APL, but the presence of certain genetic markers (i.e., 15;17 chromosomal translocation and/or PML/RAR-α gene) is not confirmed in subsequent diagnostic studies and the disease is not responding, the drug should be discontinued and alternative treatment for acute myeloid leukemia should be considered.

Dosage Modification for Toxicity

Retinoic Acid-APL Syndrome

Temporary discontinuance of tretinoin therapy should be considered in patients experiencing moderate or severe retinoic acid-APL syndrome. (See Retinoic Acid-APL Syndrome under Cautions: Adverse Effects.)

Hepatic Toxicity

Temporary discontinuance of tretinoin therapy should be considered in patients with serum transaminase concentrations exceeding 5 times the upper limit of normal.

Toxicity in Children

The manufacturer recommends increased caution in the use of tretinoin in pediatric patients. Dosage reduction may be considered for pediatric patients who experience serious or intolerable drug toxicity; however, the safety and efficacy of tretinoin dosages less than 45 mg/m daily in pediatric patients have not been established.

Cautions

Adverse Effects

Virtually all patients receiving tretinoin experience adverse effects, including headache, fever, weakness, and fatigue. The most common adverse effects of tretinoin therapy are similar to those reported in patients receiving high dosages of vitamin A. These adverse effects of tretinoin usually are reversible and do not require discontinuance of the drug. Severe adverse effects associated with tretinoin therapy include potentially fatal retinoic acid-APL syndrome (also known as APL differentiation syndrome) and rapidly evolving leukocytosis. Some adverse events, such as GI hemorrhage, cerebral hemorrhage, infections, disseminated intravascular coagulation, pneumonia, and septicemia, are common in patients with APL regardless of treatment.

The incidence of adverse effects associated with tretinoin is derived principally from data from 181 patients receiving the drug for up to 90 days (or 30 days beyond attainment of a complete response) in an uncontrolled clinical study or under a compassionate-use protocol.

Retinoic Acid-APL Syndrome

Retinoic acid-APL (RA-APL) syndrome (also known as APL differentiation syndrome), characterized by fever, dyspnea, acute respiratory distress, weight gain, pulmonary infiltrates, pleural and pericardial effusions, edema, hepatic failure, renal failure, and multiorgan failure, occurs in approximately 25% of patients receiving tretinoin for the treatment of APL. RA-APL syndrome occasionally has been accompanied by impaired myocardial contractility and episodic hypotension and can occur with or without concomitant leukocytosis. In severe cases, progressive hypoxemia requiring endotracheal intubation and mechanical ventilation may occur, and deaths secondary to progressive hypoxemia and multiorgan failure have been reported. Onset of the syndrome generally is within the first month of treatment and can occur after the first dose of tretinoin. Manifestations suggestive of the RA-APL syndrome may occur in 60% or more of patients receiving tretinoin therapy for APL.

The cause of RA-APL syndrome is not known. Potential mechanisms of the syndrome include release of vasoactive cytokines, increased expression of adhesion molecules on myeloid cell surfaces (leading to enhanced cellular adherence to capillary endothelium and focal endothelial leakage), and development of migratory properties during leukemic cell differentiation.

Optimal treatment for RA-APL syndrome has not been established. However, high-dose corticosteroid treatment (e.g., dexamethasone 10 mg IV every 12 hours for at least 3 days or until resolution of symptoms) appears to reduce morbidity and mortality associated with the syndrome. High-dose corticosteroid treatment should be instituted immediately in patients with signs or symptoms suggestive of the syndrome (e.g., fever, dyspnea, weight gain, abnormal chest auscultatory findings, radiographic abnormalities) regardless of the leukocyte count. High-dose corticosteroid treatment of manifestations associated with RA-APL syndrome may be required in 60% or more of patients receiving tretinoin as induction therapy for APL. Patients successfully treated for RA-APL syndrome may experience a recurrence of the syndrome; if the syndrome recurs, another course of corticosteroid treatment should be initiated. Discontinuance of tretinoin therapy is not required in most patients during treatment for RA-APL syndrome; however, this condition may be fatal, so discontinuance of tretinoin therapy should be considered in patients experiencing moderate or severe RA-APL syndrome.

Hematologic Effects

Leukocytosis

Rapidly evolving leukocytosis occurs in approximately 40% of patients receiving tretinoin. Rapidly evolving leukocytosis is associated with an increased risk of life-threatening complications in patients receiving tretinoin. Rarely, leukocytosis may exacerbate coagulopathy in patients with APL. Possible mechanisms leading to leukocytosis associated with tretinoin include a transient increase in survival of leukemic cells, ''release'' from the bone marrow, or mitosis in a cell population still capable of self-renewal (i.e., prior to its maturation to a stage at which it is no longer capable of further replication). Isolated cases of basophilia have been reported in patients receiving tretinoin.

The optimal management of leukocytosis associated with tretinoin has not been established. Treatment with high-dose steroids should be initiated immediately in patients with leukocytosis who develop signs or symptoms of RA-APL syndrome (see Cautions: Retinoic Acid-APL Syndrome). In patients with a baseline leukocyte count exceeding 5000/mm, or in patients who initially are leukopenic and subsequently develop a rapid increase in leukocyte count, some investigators routinely add chemotherapy agents to tretinoin treatment; the addition of such chemotherapy reportedly has been associated with a lower incidence of the RA-APL syndrome. According to the manufacturer, it may be appropriate to add full-dose chemotherapy (including an anthracycline unless contraindicated) to tretinoin therapy on day 1 or 2 in patients with a baseline leukocyte count exceeding 5000/mm; such chemotherapy may be initiated immediately in patients with a baseline leukocyte count less than 5000/mm who subsequently develop a leukocyte count exceeding 6000/mm by day 5, 10,000/mm by day 10, or 15,000/mm by day 28.

Hemorrhage

Hemorrhage has been reported in 60% of patients receiving tretinoin. In a randomized, multicenter trial comparing tretinoin with combination chemotherapy (daunorubicin and cytarabine) for remission induction in patients with APL, there was no significant difference in the incidence of severe hemorrhage associated with the 2 treatments.

Disseminated Intravascular Coagulation

Disseminated intravascular coagulation occurs in 26% of patients receiving tretinoin as induction therapy for APL. According to most clinicians, patients who develop disseminated intravascular coagulation should receive transfusions of platelets and fresh frozen plasma sufficient to maintain a platelet count of at least 50,000/mm and a fibrinogen level of at least 100 mg/dL. Recommendations for additional treatment in this situation vary; some clinicians suggest use of heparin in patients with marked or persistent elevation of fibrin degradation products or thrombosis, and use of fibrinolytic inhibitors (e.g., aminocaproic acid) in patients with imminent or life-threatening retinal or intracranial hemorrhage.

Other Hematologic Effects

Bone marrow necrosis, sometimes fatal, has been reported in several patients receiving hydroxyurea during tretinoin therapy.(See: Drug Interactions: Hydroxyurea.) Thrombocytosis has been reported rarely in patients receiving tretinoin.

Infectious Complications

Infection has been reported in 58% of patients receiving tretinoin for induction therapy of APL. Specific infections reported in patients receiving the drug include pneumonia in 14% of patients and cellulitis in 8% of patients. In a randomized, multicenter trial comparing tretinoin with combination chemotherapy (daunorubicin and cytarabine) for remission induction in patients with APL, the incidence of serious infections was greater in patients receiving chemotherapy (52%) than in those receiving tretinoin (25%).

Respiratory Effects

Adverse respiratory effects have been observed frequently in patients receiving tretinoin and often occur as a manifestation of retinoic acid-APL syndrome. (See Cautions: Retinoic Acid-APL Syndrome.) In a randomized, multicenter trial comparing tretinoin with combination chemotherapy (daunorubicin and cytarabine) for remission induction in patients with APL, the incidence of severe pulmonary toxicity was greater in patients receiving tretinoin than in those receiving chemotherapy (21 versus 6%, respectively). According to the database for 181 patients receiving tretinoin, upper respiratory tract disorders, dyspnea, and respiratory insufficiency occurred in 63, 60, and 26%, respectively. Pleural effusion, rales, expiratory wheezing, lower respiratory tract disorders, and pulmonary infiltration have been reported in 20, 14, 14, 9, and 6% of patients, respectively. Other adverse respiratory effects, each reported in 3% of patients receiving tretinoin, include bronchial asthma, pulmonary edema, laryngeal edema, and unspecified pulmonary disease.

Metabolic Effects

Reversible hypercholesterolemia and/or hypertriglyceridemia occur in up to 60% of patients receiving tretinoin. The clinical importance of transient elevations in cholesterol and triglycerides is not known; however, venous thrombosis and myocardial infarction have been reported in patients who otherwise are at low risk for these conditions. Weight gain has been reported in 23% of patients receiving tretinoin. Other adverse metabolic effects associated with tretinoin include acidosis and hypothermia, each occurring in 3% of patients. Hypercalcemia has been reported rarely in patients receiving the drug.

Hepatic Effects

Adverse hepatic effects may occur as a manifestation of retinoic acid-APL syndrome in patients receiving tretinoin. (See Retinoic Acid-APL Syndrome under Cautions: Adverse Effects.) Elevations in liver function test results occur in 50-60% of patients receiving tretinoin. In most cases, discontinuance of tretinoin is not required, and liver function test abnormalities usually resolve during or after treatment. Temporary discontinuance of tretinoin should be considered in patients with serum transaminase concentrations exceeding 5 times the upper limit of normal. Other adverse hepatic effects reported in patients receiving tretinoin include hepatosplenomegaly in 9%, and hepatitis, ascites, and unspecified liver disorder, each in 3% of patients.

Nervous System Effects

Pseudotumor cerebri

Pseudotumor cerebri (intracranial hypertension) has been reported in approximately 9% of patients receiving tretinoin. The risk of pseudotumor cerebri associated with the drug appears to be higher in pediatric patients. Patients receiving tretinoin who develop signs and symptoms of pseudotumor cerebri, such as papilledema, headache, nausea, vomiting, and visual disturbances, should be evaluated and treated appropriately; in some cases, narcotic analgesics, corticosteroids, and lumbar puncture may be required.

Headache

Headache occurs in 86% of patients receiving tretinoin. Headache associated with tretinoin typically occurs several hours after drug administration and usually responds to mild analgesics; tolerance to this adverse effect usually occurs with continued therapy.

Other Nervous System Effects

Cerebrovascular accident has been reported rarely in patients receiving tretinoin. Dizziness has been reported in 20%, and paresthesias in 17%, of patients receiving tretinoin. Anxiety, insomnia, depression, and confusion occurred in 17, 14, 14, and 11% of patients receiving the drug. Cerebral hemorrhage was reported in 9% of patients receiving tretinoin. Agitation and hallucinations have been reported in 9 and 6% of patients, respectively. Other adverse neurologic effects, each reported in 3% of patients receiving tretinoin, include abnormal gait, agnosia, aphasia, asterixis, cerebellar edema, cerebellar disorders, convulsions, coma, CNS depression, dysarthria, encephalopathy, facial paralysis, hemiplegia, hyporeflexia, hypotaxia, absent light reflex, neurologic reaction, spinal cord disorder, tremor, leg weakness, unconsciousness, dementia, forgetfulness, somnolence, and slow speech.

Dermatologic Effects

Dryness

As with other retinoids, dryness of the skin and/or mucous membranes is common, occurring in 77% of patients receiving tretinoin. Dryness of the skin and mucous membranes can be treated with topical lubricants if necessary and usually does not require discontinuance or attenuation of tretinoin therapy.

Other Dermatologic Effects

Rash has been reported in 54% of patients receiving tretinoin. Pruritus and increased sweating each were observed in 20% of patients. Alopecia and skin changes each occurred in 14% of patients receiving the drug.

Sweet's syndrome (acute febrile neutrophilic dermatosis) and necrotizing vasculitis are uncommon adverse effects associated with tretinoin. Leukemia cutis (leukemic infiltration of the skin) has been reported in patients receiving tretinoin. Isolated cases of erythema nodosum also have been reported in patients receiving tretinoin. Genital ulceration and rare cases of vasculitis, mainly involving the skin, have been reported in patients receiving tretinoin.

GI Effects

Nausea and vomiting occur in 57% of patients receiving tretinoin. GI hemorrhage and mucositis have been reported in 34 and 26%, respectively, of patients receiving the drug. Abdominal pain, diarrhea, and constipation have occurred in 31, 23, and 17% of patients, respectively. Anorexia and weight loss each have been reported in 17% of patients receiving tretinoin. Other adverse GI effects associated with tretinoin include unspecified GI disorder, dyspepsia, abdominal distension, and ulcer in 26, 14, 11, and 3% of patients, respectively.

Pancreatic Effects

Pancreatitis has been reported rarely in patients receiving tretinoin.

Musculoskeletal Effects

Bone pain was reported in 77% of patients with APL receiving tretinoin. Myalgia, flank pain, and bone inflammation have been observed in 14, 9, and 3%, respectively, of patients receiving the drug. Bone pain and arthralgia associated with tretinoin usually occur early in treatment and diminish with continued therapy. In some cases, treatment with parenteral opiate analgesics may be required for pain relief. Myositis associated with tretinoin has been reported rarely.

Cardiovascular Effects

Cardiac failure occurred in 6% of patients receiving tretinoin, and cardiac arrest, myocardial infarction, stroke, and pulmonary hypertension each occurred in 3% of patients. There is a risk of arterial or venous thrombosis, involving any organ system, during the first month of tretinoin therapy. Cerebrovascular accident, myocardial infarction, and renal infarct have occurred in patients receiving tretinoin. Thromboembolic events, including fatal pulmonary embolism, have been reported in patients receiving tretinoin. In one patient receiving tretinoin, fatal thromboembolism occurred during concomitant therapy with an antifibrinolytic agent for the prophylaxis of hemorrhage associated with APL.

Peripheral edema occurs in 52% of patients receiving tretinoin. Chest discomfort, edema, arrhythmias, and flushing have been reported in 32, 29, 23, and 23% of patients, respectively. Hypotension and hypertension occurred in 14 and 11% of patients receiving tretinoin. Phlebitis has been reported in 11% of patients; other types of vasculitis have been reported rarely. Other adverse cardiovascular effects, each reported in 3% of patients receiving tretinoin, include cardiomegaly, heart murmur, ischemia, myocarditis, pericarditis, and secondary cardiomyopathy.

Renal Effects

Adverse renal effects may occur as a manifestation of retinoic acid-APL syndrome in patients receiving tretinoin. (See Retinoic Acid-APL Syndrome under Cautions: Adverse Effects.) Renal insufficiency has been reported in 11% of patients receiving tretinoin, and acute renal failure and renal tubular necrosis each occurred in 3% of patients. Granulomatous tubulointerstitial nephritis has been reported in a patient receiving tretinoin as induction therapy for APL.

Genitourinary Effects

Dysuria, urinary frequency, and enlarged prostate have been reported in 9, 3, and 3%, respectively, of patients receiving tretinoin. Scrotal and penile ulcerations also have been reported in patients receiving tretinoin.

Otic Effects

Earache or a feeling of fullness in the ears occurred in 23% of patients receiving tretinoin. Hearing loss and other unspecified otic disorders have been reported in 6% of patients; irreversible hearing loss has occurred in less than 1% of patients.

Ocular Effects

Visual disturbances and ocular disorders each have been reported in 17% of patients receiving tretinoin. Altered visual acuity and visual field defects were reported in 6 and 3% of patients, respectively.

Local Effects

Injection site reactions have been observed in 17% of patients receiving tretinoin.

Other Adverse Effects

Fever occurred in 83% of patients with APL receiving tretinoin. Malaise, shivering, and pain have been reported in 66, 63, and 37% of patients, respectively. Pallor was reported in 6% of patients receiving the drug. Lymphatic disorders (including cervical and tonsillar lymphadenopathy), facial edema, and fluid imbalance each have been reported in 6% of patients receiving tretinoin. Hyperhistaminemia and organomegaly rarely have been reported in patients receiving the drug.

Precautions and Contraindications

The manufacturer states that tretinoin should be administered only to patients with acute promyelocytic leukemia (APL). Because patients with APL are at high risk for medical complications in general and tretinoin can cause severe adverse reactions, this drug should be administered under the strict supervision of a qualified clinician experienced in the management of patients with acute leukemia and only when the potential benefits of tretinoin therapy are thought to outweigh the known adverse effects as well as other possible risks. In addition, appropriate diagnostic and treatment facilities must be readily available in case the patient develops severe toxicity, such as respiratory compromise. Patients receiving tretinoin should be observed closely for leukocytosis or respiratory compromise. Laboratory tests, including hematologic profile, coagulation parameters, liver function tests, and serum triglyceride and cholesterol concentrations should be monitored frequently in patients receiving tretinoin. Supportive care appropriate for patients with APL, such as prophylaxis for bleeding and prompt therapy for infection, should be maintained during tretinoin therapy.

Clinical manifestations associated with RA-APL syndrome (also known as APL differentiation syndrome), with or without leukocytosis, may occur in 60% or more of patients receiving tretinoin and require high-dose corticosteroid therapy. This syndrome, which can be fatal, occurs in about 25% of patients receiving tretinoin. Patients presenting with a high leukocyte count at diagnosis (i.e., exceeding 5000/mm) have an increased risk of a rapid further increase in leukocyte count.(See Retinoic Acid-APL Syndrome and Hematologic Effects, in Cautions.)

Tretinoin and other retinoids have been associated with pseudotumor cerebri, a form of intracranial hypertension, particularly in pediatric patients.(See: Cautions: Nervous System Effects.)

Liver function tests should be monitored carefully during tretinoin therapy.(See: Cautions: Hepatic Effects and Dosage: Dosage Modification for Toxicity: Hepatic Toxicity.) Frequent monitoring of serum cholesterol and triglyceride concentrations and clinical assessment of cardiac status is advised in patients receiving tretinoin regardless of history of cardiac conditions.(See Cardiovascular Effects and Metabolic Effects, in Cautions.)

Patients should be informed that their ability to drive or operate machinery may be impaired during tretinoin therapy, particularly if they are experiencing dizziness or severe headache.

Tretinoin is a known teratogen and special precautions and instruction are necessary in women of childbearing potential or pregnant women receiving the drug. Patients should be fully informed of the risks of fetal harm and contraceptive failure.(See: Cautions: Pregnancy, Fertility, and Lactation.)

Tretinoin is contraindicated in patients with known hypersensitivity to tretinoin, any of its components, or other retinoids or in patients who are sensitive to parabens, which are used as preservatives in commercially available tretinoin capsules.

Tretinoin therapy is not indicated in patients with subtypes of AML other than APL, and cytogenetic and molecular diagnostic studies should be performed to identify appropriate candidates.

Pediatric Precautions

The manufacturer states that safety and efficacy of tretinoin in infants younger than 1 year of age have not been established. Clinical data on the use of tretinoin in children are limited (see Uses: Acute Promyelocytic Leukemia). Tretinoin therapy is associated with severe headache and pseudotumor cerebri, requiring treatment with analgesics and lumbar puncture, in some pediatric patients. The manufacturer recommends increased caution in the use of tretinoin in pediatric patients. Dosage reduction may be appropriate for pediatric patients who experience severe adverse effects; however, the safety and efficacy of tretinoin dosages below 45 mg/m daily have not been established in pediatric patients.

Geriatric Precautions

Approximately 20% of the patients enrolled in clinical studies of tretinoin were 60 years of age or older. Although no overall differences in efficacy or safety have been observed between geriatric and younger patients to date, the possibility that some older patients may exhibit increased sensitivity to the drug cannot be ruled out.

Mutagenicity and Carcinogenicity

Tretinoin was not mutagenic in the Ames test or the CHO/HGRPT gene mutation assay. In human diploid fibroblasts, a twofold increase in the sister chromatid exchange has been demonstrated. Clastogenic or aneuploidogenic effects were not demonstrated when tretinoin was tested in other chromosome aberration assays, including an in vitro assay in human peripheral lymphocytes and an in vivo mouse micronucleus assay.

Long-term studies to evaluate the carcinogenicity of tretinoin have not been performed to date. Therapy-related myelodysplasia, acute myeloid leukemia, or a combination of both has been reported in patients receiving tretinoin during induction and consolidation therapy for APL. When administered in mice at a dose of 30 mg/kg daily (about 2 times the recommended human dose on a mg/m basis), tretinoin was associated with an increased rate of diethylnitrosamine-induced liver adenomas and carcinomas.

Pregnancy, Fertility, and Lactation

Pregnancy

Tretinoin may cause fetal harm and the risk of birth of a severely deformed infant is high in pregnant women receiving the drug, but potential benefits may be acceptable in certain conditions despite possible risks to the fetus.

Experience with tretinoin administered to pregnant women is limited; however, increased spontaneous abortions and major fetal abnormalities have been documented in humans with the use of other retinoids. Reported defects, sometimes fatal, include abnormalities of the CNS, musculoskeletal system, external ear, eye, thymus, and great vessels, as well as facial dysmorphia, cleft palate, and parathyroid hormone deficiency. Low IQ scores (i.e., below 85), with or without obvious CNS abnormalities, also have been reported. According to the manufacturer, all fetuses exposed during pregnancy can be affected, and currently there is no antepartum method for determining whether a fetus is affected. In 2 women, tretinoin 45 mg/m daily was administered during the second trimester of pregnancy, and both patients received consolidation chemotherapy after delivery. One woman delivered an infant at 30 weeks' gestation by cesarean section who required resuscitation for a cardiac arrhythmia followed by cardiac arrest. In the other case, no abnormalities were observed during pregnancy or at birth in twins born at 32 weeks' gestation; however, extensive vaginal and perineal ruptures led to severe perinatal and postnatal bleeding in the mother, and whether tretinoin therapy may have contributed to the fragility of the perineum and vagina and the severe bleeding during delivery is not known.

Tretinoin is teratogenic and embryotoxic in mice, rats, hamsters, rabbits, and pigtail monkeys. In all animals studied, the drug caused fetal resorptions and a decrease in live fetuses. Gross external, soft tissue, and skeletal deformities occurred at dosages exceeding 0.7 mg/kg daily, 2 mg/kg daily, or 7 mg/kg daily (approximately one-twentieth, one-fourth, and one-half the recommended human dosage on a mg/m basis) in mice, rats, and hamsters, respectively, and at a dosage of 10 mg/kg daily (approximately 4 times the recommended human dosage on a mg/m basis) in pigtail monkeys.

There are no adequate and well-controlled studies to date using tretinoin in pregnant women. There is a high risk of a severely deformed infant if tretinoin is administered to a pregnant woman. Tretinoin should be used during pregnancy only in life-threatening situations or severe disease for which safer drugs cannot be used or are ineffective. When the drug is administered during pregnancy or if the patient becomes pregnant while receiving the drug, the patient should be informed of the high risk of a severely deformed fetus, and the desirability of continuing or terminating the pregnancy should be discussed. Effective contraception must be used by all women during tretinoin therapy and for 1 month following discontinuance of the drug. Contraception must be used by all women receiving tretinoin (including those with a history of infertility or menopause) unless a hysterectomy has been performed. Unless abstinence is the chosen method, it is recommended that 2 reliable forms of contraception be used simultaneously. Progestin-only preparations (i.e., minipill) may be an inadequate method of contraception during tretinoin therapy. A reliable blood or urine pregnancy test with a sensitivity of at least 50 mIU/mL should be performed within 1 week prior to the initiation of tretinoin therapy. Whenever possible, initiation of therapy should be delayed until a negative pregnancy test result is obtained. When a delay is not possible, the patient should be placed on 2 reliable forms of contraception. Pregnancy testing and contraception counseling should be repeated monthly during tretinoin therapy.

Fertility

When administered at dosages of up to 5 mg/kg daily (about two-thirds the recommended human dosage on a mg/m basis), no adverse effects of tretinoin on fertility or reproductive performance were observed in rats. Minimal to marked testicular degeneration and increased numbers of immature spermatozoa were observed in dogs receiving tretinoin 10 mg/kg daily (about 4 times the equivalent human dosage in mg/m) during a 6-week toxicology study.

Lactation

It is not known whether tretinoin is distributed into milk. Because of the potential for serious adverse reactions to tretinoin in nursing infants, women should be advised to discontinue nursing during tretinoin therapy.

Drug Interactions

Drugs Affecting Hepatic Microsomal Enzymes

Although specific studies have not been performed and the clinical importance has not been determined, concomitant use of drugs that affect cytochrome P-450 (CYP) hepatic microsomal enzymes, such as the CYP3A4, CYP2C8, and CYP2E isoenzymes, could alter the metabolism of tretinoin. Metabolism of tretinoin is mediated by CYP microsomal enzymes, and the possibility exists that drugs that induce these enzymes (e.g., rifampin, corticosteroids, phenobarbital, pentobarbital) may reduce plasma tretinoin concentrations. Conversely, concomitant use of tretinoin with drugs that inhibit the CYP enzymes (e.g., ketoconazole, cimetidine, erythromycin, verapamil, diltiazem, cyclosporine) may increase plasma tretinoin concentrations. Currently, it is not known whether concomitant use of drugs affecting the CYP enzyme system alters the efficacy or toxicity of tretinoin.

In a small number of patients receiving daily dosages of tretinoin for 4 consecutive weeks, oral administration of ketoconazole 400-1200 mg 1 hour prior to the tretinoin dose on day 29 was associated with a 72% increase in the mean area under the plasma concentration-time curve (AUC) for tretinoin.

Hydroxyurea

Concurrent use of hydroxyurea, which is cytotoxic to cells in S phase, and tretinoin, which induces cells to enter the S phase, may cause a synergistic effect leading to massive cell lysis. Bone marrow necrosis, sometimes fatal, has been reported in patients receiving hydroxyurea during tretinoin therapy. Although some clinicians have administered hydroxyurea in conjunction with tretinoin therapy to reduce leukocytosis, the safety and efficacy of this practice have not been established, and caution is recommended in the use of hydroxyurea in patients receiving tretinoin.

Agents Known to Cause Pseudotumor Cerebri/Intracranial Hypertension

Risk of pseudotumor cerebri (intracranial hypertension) is increased in patients receiving tretinoin. Concomitant use of other agents known to cause pseudotumor cerebri or intracranial hypertension, such as tetracyclines, may increase the risk of this condition in patients receiving tretinoin.

Fibrinolytic Inhibitors

Fatal thrombotic complications have been reported rarely in patients receiving tretinoin and fibrinolytic inhibitors, such as tranexamic acid, aminocaproic acid, or aprotinin. Caution is advised when tretinoin is used concomitantly with antifibrinolytic agents.

Vitamin A

The same as for other retinoids, tretinoin must not be used concomitantly with vitamin A because concomitant use could exacerbate symptoms of hypervitaminosis A.

Pharmacokinetics

The pharmacokinetics of tretinoin have not been evaluated separately by gender or ethnic group.

Absorption

Because an IV dosage form of tretinoin is not available, the pharmacokinetics of the drug (e.g., bioavailability, volume of distribution) have not been fully characterized. However, the results of some studies indicate that there is extensive intrapatient and interpatient variability.

Tretinoin is readily absorbed from the GI tract, and peak plasma concentrations are achieved in about 1-2 hours. The bioavailability of tretinoin has been estimated to be about 50%, and marked interpatient variation has been observed. In patients with APL who received a single oral dose of tretinoin 45 mg/m, peak plasma concentrations of tretinoin ranged from 95 to about 948 ng/mL. In a pharmacokinetic study involving children receiving single doses of tretinoin, peak plasma concentration and area under the plasma concentration-time curve (AUC) increased in a nonlinear manner relative to increases in dose.

Evidence suggests that tretinoin induces its own metabolism. (See Pharmacokinetics: Elimination.) During 1 week of continuous therapy, plasma concentrations of tretinoin decrease to an average of one-third of the plasma concentrations observed on the first day. In a small number of pediatric patients who received tretinoin daily for 28 days, the mean area under the plasma concentration-time curve on day 28 was approximately one-fifth that determined on day one.

The absorption of retinoids generally has been shown to be enhanced by coadministration with food; however, the effect of food on the absorption of tretinoin has not been evaluated. Because tretinoin is fat-soluble, some clinicians have suggested that a fat-restricted diet may cause reduced bioavailability of the drug.

Distribution

Distribution of tretinoin into body tissues and fluids has not been fully characterized. The apparent volume of distribution of tretinoin has not been determined. Tretinoin does not appear to be distributed into the CSF and probably is not effective for treating leukemia in the CNS.

Plasma protein binding (principally to albumin) of tretinoin exceeds 95% and remains constant at plasma concentrations ranging from 10-500 ng/mL.

Oral tretinoin has been shown to cross the placenta in animal studies, and the drug is recognized as a potent teratogen. It is not known whether tretinoin distributes into milk.

Elimination

In patients with APL receiving tretinoin orally, a terminal elimination half-life of 0.5-2 hours has been reported following initial dosing.

The precise metabolic pathway of tretinoin has not been fully elucidated. Although various metabolites have been identified, the activity of tretinoin results mainly from the parent drug. Stereoisomerization of tretinoin occurs in the liver, followed by oxidation. Cytochrome P-450 (CYP) isoenzymes (e.g., CYP3A4, CYP2C8, CYP2E) have been implicated in the oxidative metabolism of the drug. Metabolites are excreted as glucuronide conjugates in urine and bile. Metabolites of tretinoin that have been identified include 13-cis retinoic acid, 4-oxo trans retinoic acid, 4-oxo cis retinoic acid, and 4-oxo trans retinoic acid glucuronide.

Evidence suggests that tretinoin induces its own metabolism. In patients with APL receiving 45 mg/m tretinoin daily, urinary excretion of 4-oxo trans retinoic acid glucuronide increased approximately tenfold over the course of 2-6 weeks of continuous therapy, suggesting that increased metabolism of tretinoin may be the primary mechanism leading to the decreased plasma drug concentrations observed during continued administration. Possible mechanisms for the increased clearance of tretinoin with continuous daily dosing of the drug include induction of CYP enzymes or oxidative cofactors and increased expression of cellular retinoic acid binding proteins. Increasing the dosage of tretinoin to compensate for the apparent autoinduction has not been shown to increase therapeutic response. Reduced plasma retinoid concentrations have been associated with relapse and clinical resistance, and some investigators suggest that the clinical failure of tretinoin may be related to a lack of sustained effective concentrations of the drug during prolonged treatment.

Following oral administration of radiolabeled tretinoin at doses of 2.75 and 50 mg, greater than 90% of the radioactivity was recovered in urine and feces. Based on pharmacokinetic data from 3 individuals, approximately 63% of radioactivity was excreted in urine within 72 hours, and 31% was recovered in feces within 6 days.

The effect of renal or hepatic impairment on the elimination of tretinoin has not been established.

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