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.

Pharmacokinetics

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.

Absorption

Tretinoin has been investigated in 114 previously treated APL patients and in 67 previously untreated (“de novo”) patients in one open-label, uncontrolled single investigator clinical study (Memorial Sloan-Kettering Cancer Center [MSKCC]) and in two cohorts of compassionate cases treated by multiple investigators under the auspices of the National Cancer Institute (NCI). All patients received 45 mg/m2/day as a divided oral dose for up to 90 days or 30 days beyond the day that CR was reached. Results are shown in the following table:

The median time to CR was between 40 and 50 days (range: 2 to 120 days). Most patients in these studies received cytotoxic chemotherapy during the remission phase. These results compare to the 30% to 50% CR rate and, ≤ 6 month median survival reported for cytotoxic chemotherapy of APL in the treatment of relapse.

Ten of 15 pediatric cases achieved CR (8 of 10 males and 2 of 5 females). There were insufficient patients of black, Hispanic or Asian derivation to estimate relative response rates in these groups, but responses were seen in each category.

Responses were seen in 3 of 4 patients for whom cytogenetic analysis failed to detect the t(15;17) translocation typically seen in APL. The t(15;17) translocation results in the PML/RARα gene, which appears necessary for this disease. Molecular genetic studies were not conducted in these cases, but it is likely they represent cases with a masked translocation giving rise to PML/RARα. Responses to tretinoin have not been observed in cases in which PML/RARα fusion has been shown to be absent.

INDICATIONS AND USAGE

See boxed WARNINGS

Tretinoin has teratogenic and embryotoxic effects in mice, rats, hamsters, rabbits and pigtail monkeys, and may be expected to cause fetal harm when administered to a pregnant woman. Tretinoin causes fetal resorptions and a decrease in live fetuses in all animals studied. Gross external, soft tissue and skeletal alterations occurred at doses higher than 0.7 mg/kg/day in mice, 2 mg/kg/day in rats, 7 mg/kg/day in hamsters, and at a dose of 10 mg/kg/day, the only dose tested, in pigtail monkeys (about 1/20, 1/4, and 1/2 and 4 times the human dose, respectively, on a mg/m2 basis).

There are no adequate and well-controlled studies in pregnant women. Although experience with humans administered tretinoin is extremely limited, increased spontaneous abortions and major human fetal abnormalities related to the use of other retinoids have been documented in humans. Reported defects include abnormalities of the CNS, musculoskeletal system, external ear, eye, thymus and great vessels; and facial dysmorphia, cleft palate, and parathyroid hormone deficiency. Some of these abnormalities were fatal. Cases of IQ scores less than 85, with or without obvious CNS abnormalities, have also been reported. All fetuses exposed during pregnancy can be affected and at the present time there is no antepartum means of determining which fetuses are and are not affected.

Effective contraception must be used by all females during tretinoin therapy and for 1 month following discontinuation of therapy. Contraception must be used even when there is a history of infertility or menopause, unless a hysterectomy has been performed. Whenever contraception is required, it is recommended that two reliable forms of contraception be used simultaneously, unless abstinence is the chosen method. If pregnancy does occur during treatment, the physician and patient should discuss the desirability of continuing or terminating the pregnancy.

Patients Without the t(15;17) Translocation

Initiation of therapy with tretinoin may be based on the morphological diagnosis of acute promyelocytic leukemia. Confirmation of the diagnosis of APL should be sought by detection of the t(15;17) genetic marker by cytogenetic studies. If these are negative, PML/RARα fusion should be sought using molecular diagnostic techniques. The response rate of other AML subtypes to tretinoin has not been demonstrated; therefore, patients who lack the genetic marker should be considered for alternative treatment.

Retinoic Acid-APL (RA-APL) Syndrome

In up to 25% of patients with APL treated with tretinoin, a syndrome occurs which can be fatal (see boxed WARNINGS and ADVERSE REACTIONS).

Leukocytosis at Presentation and Rapidly Evolving Leukocytosis During Tretinoin Treatment

See boxed WARNINGS.

Pseudotumor Cerebri

Retinoids, including tretinoin, have been associated with pseudotumor cerebri (benign intracranial hypertension), especially in pediatric patients. The concomitant use of other agents known to cause pseudotumor cerebri/intracranial hypertension, such as tetracyclines, might increase the risk of this condition (see PRECAUTIONS, Drug Interactions).2 Early signs and symptoms of pseudotumor cerebri include papilledema, headache, nausea and vomiting, and visual disturbances. Patients with these symptoms should be evaluated for pseudotumor cerebri, and, if present, appropriate care should be instituted in concert with neurological assessment.

Lipids

Up to 60% of patients experienced hypercholesterolemia and/or hypertriglyceridemia, which were reversible upon completion of treatment. The clinical consequences of temporary elevation of triglycerides and cholesterol are unknown, but venous thrombosis and myocardial infarction have been reported in patients who ordinarily are at low risk for such complications.

Elevated Liver Function Test Results

Elevated liver function test results occur in 50% to 60% of patients during treatment. Liver function test results should be carefully monitored during treatment and consideration be given to a temporary withdrawal of tretinoin if test results reach > 5 times the upper limit of normal values. However, the majority of these abnormalities resolve without interruption of tretinoin or after completion of treatment.

PRECAUTIONS

General

Tretinoin has potentially significant toxic side effects in APL patients. Patients undergoing therapy should be closely observed for signs of respiratory compromise and/or leukocytosis (see boxed WARNINGS). Supportive care appropriate for APL patients, e.g., prophylaxis for bleeding, prompt therapy for infection, should be maintained during therapy with tretinoin.

There is a risk of thrombosis (both venous and arterial) which may involve any organ system, during the first month of treatment (see ADVERSE REACTIONS). Therefore, caution should be exercised when treating patients with the combination of tretinoin and anti-fibrinolytic agents, such as tranexamic acid, aminocaproic acid or aprotinin (see Drug Interactions).3,4

The ability to drive or operate machinery might be impaired in patients treated with tretinoin, particularly if they are experiencing dizziness or severe headache.

Microdosed progesterone preparations (“minipill”) may be an inadequate method of contraception during treatment with  tretinoin.5

Laboratory Tests

The patient's hematologic profile, coagulation profile, liver function test results, and triglyceride and cholesterol levels should be monitored frequently.

Drug Interactions

Limited clinical data on potential drug interactions are available.

Drugs Metabolized By the Hepatic P450 System

No long term carcinogenicity studies with tretinoin have been conducted. In short term carcinogenicity studies, tretinoin at a dose of 30 mg/kg/day (about 2 times the human dose on a mg/m2 basis) was shown to increase the rate of diethylnitrosamine (DEN)-induced mouse liver adenomas and carcinomas. Tretinoin was negative when tested in the Ames and Chinese hamster V79 cell HGPRT assays for mutagenicity. A twofold increase in the sister chromatid exchange (SCE) has been demonstrated in human diploid fibroblasts, but other chromosome aberration assays, including an in vitro assay in human peripheral lymphocytes and an in vivo mouse micronucleus assay, did not show a clastogenic or aneuploidogenic effect. Adverse effects on fertility and reproductive performance were not observed in studies conducted in rats at doses up to 5 mg/kg/day (about 2/3 the human dose on a mg/m2 basis). In a 6 week toxicology study in dogs, minimal to marked testicular degeneration, with increased numbers of immature spermatozoa, were observed at 10 mg/kg/day (about 4 times the equivalent human dose in mg/m2).

Nursing Mothers

It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk, and because of the potential for serious adverse reactions from tretinoin in nursing infants, mothers should discontinue nursing prior to taking this drug.

Pediatric Use

There are limited clinical data on the pediatric use of tretinoin. Of 15 pediatric patients (age range: 1 to 16 years) treated with tretinoin, the incidence of complete remission was 67%. Safety and effectiveness in pediatric patients below the age of 1 year have not been established. Some pediatric patients experience severe headache and pseudotumor cerebri, requiring analgesic treatment and lumbar puncture for relief. Increased caution is recommended in the treatment of pediatric patients. Dose reduction may be considered for pediatric patients experiencing serious and/or intolerable toxicity; however, the efficacy and safety of tretinoin at doses lower than 45 mg/m2/day have not been evaluated in the pediatric population.

Geriatric Use

Of the total number of subjects in clinical studies of tretinoin, 21.4% were 60 and over. No overall differences in safety or effectiveness were observed between these subjects and younger subjects, and other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out.

ADVERSE REACTIONS

The most frequently reported adverse events were similar to those described in patients taking high doses of vitamin A and included headache (86%), fever (83%), skin/mucous membrane dryness (77%), bone pain (77%), nausea/vomiting (57%), rash (54%), mucositis (26%), pruritus (20%), increased sweating (20%), visual disturbances (17%), ocular disorders (17%), alopecia (14%), skin changes (14%), changed visual acuity (6%), bone inflammation (3%), visual field defects (3%).

RA-APL Syndrome

APL patients treated with tretinoin have experienced a potentially fatal 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 and has been observed with or without concomitant leukocytosis. Some patients have expired due to progressive hypoxemia and 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 signs of the syndrome appear to reduce morbidity and mortality. Treatment with dexamethasone, 10 mg intravenously administered every 12 hours for 3 days or until resolution of symptoms, should be initiated without delay at the first suspicion of symptoms (one or more of the following: fever, dyspnea, weight gain, abnormal chest auscultatory findings or radiographic abnormalities). Sixty percent or more of patients treated with tretinoin may require high dose steroids because of these symptoms. The majority of patients do not require termination of tretinoin therapy during treatment of the syndrome.

Body as a Whole

General disorders related to tretinoin administration and/or associated with APL included malaise (66%), shivering (63%), hemorrhage (60%), infections (58%), peripheral edema (52%), pain (37%), chest discomfort (32%), edema (29%), disseminated intravascular coagulation (26%), weight increase (23%), injection site reactions (17%), anorexia (17%), weight decrease (17%), myalgia (14%), flank pain (9%), cellulitis (8%), face edema (6%), fluid imbalance (6%), pallor (6%), lymph disorders (6%), acidosis (3%), hypothermia (3%), ascites (3%).

Respiratory System Disorders

Respiratory system disorders were commonly reported in APL patients administered tretinoin. The majority of these events are symptoms of the RA-APL syndrome (see boxed WARNINGS). Respiratory system adverse events included upper respiratory tract disorders (63%), dyspnea (60%), respiratory insufficiency (26%), pleural effusion (20%), pneumonia (14%), rales (14%), expiratory wheezing (14%), lower respiratory tract disorders (9%), pulmonary infiltration (6%), bronchial asthma (3%), pulmonary edema (3%), larynx edema (3%), unspecified pulmonary disease (3%).

Ear Disorders

Ear disorders were consistently reported, with earache or feeling of fullness in the ears reported by 23% of the patients. Hearing loss and other unspecified auricular disorders were observed in 6% of patients, with infrequent (< 1%) reports of irreversible hearing loss.

Gastrointestinal Disorders

GI disorders included GI hemorrhage (34%), abdominal pain (31%), other gastrointestinal disorders (26%), diarrhea (23%), constipation (17%), dyspepsia (14%), abdominal distention (11%), hepatosplenomegaly (9%), hepatitis (3%), ulcer (3%), unspecified liver disorder (3%).

Cardiovascular and Heart Rate and Rhythm Disorders

Arrhythmias (23%), flushing (23%), hypotension (14%), hypertension (11%), phlebitis (11%), cardiac failure (6%) and for 3% of patients: cardiac arrest, myocardial infarction, enlarged heart, heart murmur, ischemia, stroke, myocarditis, pericarditis, pulmonary hypertension, secondary cardiomyopathy.

Central and Peripheral Nervous System Disorders and Psychiatric

Dizziness (20%), paresthesias (17%), anxiety (17%), insomnia (14%), depression (14%), confusion (11%), cerebral hemorrhage (9%), intracranial hypertension (9%), agitation (9%), hallucination (6%) and for 3% of patients: abnormal gait, agnosia, aphasia, asterixis, cerebellar edema, cerebellar disorders, convulsions, coma, CNS depression, dysarthria, encephalopathy, facial paralysis, hemiplegia, hyporeflexia, hypotaxia, no light reflex, neurologic reaction, spinal cord disorder, tremor, leg weakness, unconsciousness, dementia, forgetfulness, somnolence, slow speech.

Urinary System Disorders

Renal insufficiency (11%), dysuria (9%), acute renal failure (3%), micturition frequency (3%), renal tubular necrosis (3%),  enlarged prostate (3%).

Miscellaneous Adverse Events

Isolated cases of erythema nodosum, basophilia and hyperhistaminemia, Sweet's syndrome, organomegaly, hypercalcemia, pancreatitis and myositis have been reported.

Additional Adverse Reactions Reported With Tretinoin

Cardiovascular