Tretinoin (oral)
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1];
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Overview
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Adult Indications and Dosage
FDA-Labeled Indications and Dosage (Adult)
Indications
Tretinoin Capsules are indicated for the induction of remission in patients with acute promyelocytic leukemia (APL), French-American-British (FAB) classification M3 (including the M3 variant), characterized by the presence of the t(15;17) translocation and/or the presence of the PML/RARα gene who are refractory to, or who have relapsed from, anthracycline chemotherapy, or for whom anthracycline based chemotherapy is contraindicated. Tretinoin is for the induction of remission only. The optimal consolidation or maintenance regimens have not been defined, but all patients should receive an accepted form of remission consolidation and/or maintenance therapy for APL after completion of induction therapy with tretinoin.
Dosage
The recommended dose is 45 mg/m2/day administered as two evenly divided doses until complete remission is documented. Therapy should be discontinued 30 days after achievement of complete remission or after 90 days of treatment, whichever occurs first.
If after initiation of treatment of tretinoin the presence of the t(15;17) translocation is not confirmed by cytogenetics and/or by polymerase chain reaction studies and the patient has not responded to tretinoin, alternative therapy appropriate for acute myelogenous leukemia should be considered.
Tretinoin is for the induction of remission only. Optimal consolidation or maintenance regimens have not been determined. All patients should, therefore, receive a standard consolidation and/or maintenance chemotherapy regimen for APL after induction therapy with tretinoin, unless otherwise contraindicated.
Off-Label Use and Dosage (Adult)
Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Tretinoin (oral) in adult patients.
Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Tretinoin (oral) in adult patients.
Pediatric Indications and Dosage
FDA-Labeled Indications and Dosage (Pediatric)
There is limited information regarding Tretinoin (oral) FDA-Labeled Indications and Dosage (Pediatric) in the drug label.
Off-Label Use and Dosage (Pediatric)
Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Tretinoin (oral) in pediatric patients.
Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Tretinoin (oral) in pediatric patients.
Contraindications
Tretinoin is contraindicated in patients with a known hypersensitivity to tretinoin, any of its components, or other retinoids.
Warnings
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.
Drugs Metabolized By the Hepatic P450 System
As tretinoin is metabolized by the hepatic P450 system, there is a 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 rifampicin, glucocorticoids, phenobarbital and pentobarbital. Medications that generally inhibit hepatic P450 enzymes include ketoconazole, cimetidine, erythromycin, verapamil, diltiazem and cyclosporine. To date there are no data to suggest that co-use with these medications increases or decreases either efficacy or toxicity of tretinoin.
Agents Known to Cause Pseudotumor Cerebri/Intracranial Hypertension (Such as Tetracyclines)
Tretinoin may cause pseudotumor cerebri/intracranial hypertension. Concomitant administration of tretinoin and agents known to cause pseudotumor cerebri/intracranial hypertension as well might increase the risk of this condition (see WARNINGS).
Vitamin A
As with other retinoids, tretinoin must not be administered in combination with vitamin A because symptoms of hypervitaminosis A could be aggravated.
Anti-fibrinolytic Agents (Such as Tranexamic Acid, Aminocaproic Acid, or Aprotinin)
Cases of fatal thrombotic complications have been reported rarely in patients concomitantly treated with tretinoin and anti-fibrinolytic agents. Therefore, caution should be exercised when administering tretinoin concomitantly with these agents (see PRECAUTIONS, GENERAL).
Effect of Food
No data on the effect of food on the absorption of tretinoin are available. The absorption of retinoids as a class has been shown to be enhanced when taken together with food.
Adverse Reactions
Clinical Trials Experience
Virtually all patients experience some drug related toxicity, especially headache, fever, weakness, and fatigue. These adverse effects are seldom permanent or irreversible nor do they usually require interruption of therapy. Some of the adverse events are common in patients with APL, including hemorrhage, infections, gastrointestinal hemorrhage, disseminated intravascular coagulation, pneumonia, septicemia, and cerebral hemorrhage. The following describes the adverse events, regardless of drug relationship, that were observed in patients treated with tretinoin.
Typical Retinoid Toxicity 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
Cases of thrombosis (both venous and arterial) involving various sites (e.g., cerebrovascular accident, myocardial infarction, renal infarct) have been reported rarely (see PRECAUTIONS, GENERAL).
Hematologic
Rare cases of thrombocytosis have been reported.6
Skin
Genital ulceration.7
Miscellaneous Adverse Events
Rare cases of vasculitis, predominantly involving the skin, have been reported.8
Postmarketing Experience
There is limited information regarding Tretinoin (oral) Postmarketing Experience in the drug label.
Drug Interactions
Limited clinical data on potential drug interactions are available.
Use in Specific Populations
Pregnancy
Pregnancy Category (FDA): D 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.
Pregnancy Category (AUS):
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Tretinoin (oral) in women who are pregnant.
Labor and Delivery
There is no FDA guidance on use of Tretinoin (oral) during labor and delivery.
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.
Geriatic 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.
Gender
There is no FDA guidance on the use of Tretinoin (oral) with respect to specific gender populations.
Race
There is no FDA guidance on the use of Tretinoin (oral) with respect to specific racial populations.
Renal Impairment
There is no FDA guidance on the use of Tretinoin (oral) in patients with renal impairment.
Hepatic Impairment
There is no FDA guidance on the use of Tretinoin (oral) in patients with hepatic impairment.
Females of Reproductive Potential and Males
There is no FDA guidance on the use of Tretinoin (oral) in women of reproductive potentials and males.
Immunocompromised Patients
There is no FDA guidance one the use of Tretinoin (oral) in patients who are immunocompromised.
Administration and Monitoring
Administration
There is limited information regarding Tretinoin (oral) Administration in the drug label.
Monitoring
There is limited information regarding Tretinoin (oral) Monitoring in the drug label.
IV Compatibility
There is limited information regarding the compatibility of Tretinoin (oral) and IV administrations.
Overdosage
In case of overdose with tretinoin, reversible signs of hypervitaminosis A (headache, nausea, vomiting, mucocutaneous symptoms) can appear. The maximal tolerated dose in patients with myelodysplastic syndrome or solid tumors was 195 mg/m2/day. The maximal tolerated dose in pediatric patients was lower at 60 mg/m2/day. Overdosage with other retinoids has been associated with transient headache, facial flushing, cheilosis, abdominal pain, dizziness and ataxia. These symptoms have quickly resolved without apparent residual effects.
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.
Pharmacology
There is limited information regarding Tretinoin (oral) Pharmacology in the drug label.
Mechanism of Action
There is limited information regarding Tretinoin (oral) Mechanism of Action in the drug label.
Structure
There is limited information regarding Tretinoin (oral) Structure in the drug label.
Pharmacodynamics
There is limited information regarding Tretinoin (oral) Pharmacodynamics in the drug label.
Pharmacokinetics
There is limited information regarding Tretinoin (oral) Pharmacokinetics in the drug label.
Nonclinical Toxicology
Carcinogenesis, Mutagenesis and Impairment of Fertility 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).
Clinical Studies
There is limited information regarding Tretinoin (oral) Clinical Studies in the drug label.
How Supplied
There is limited information regarding Tretinoin (oral) How Supplied in the drug label.
Storage
There is limited information regarding Tretinoin (oral) Storage in the drug label.
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Patient Counseling Information
WARNING TO FEMALE PATIENTS
YOU MUST NOT BECOME PREGNANT DURING TRETINOIN TREATMENT. There is an extremely high risk that a deformed baby will result if you become pregnant while taking tretinoin, in any amount, for even short periods of time. Potentially any exposed fetuses can be affected. There is also an increased risk of miscarriage. Premature births may also occur.
Effective contraception (birth control) should be discussed with your doctor. Two forms of reliable contraception must be used during therapy, and must be continued for one month after tretinoin treatment has stopped. If directed by your doctor, two forms of reliable contraception must also be used simultaneously for at least one month before beginning therapy. It is recommended that you either abstain from sexual intercourse or use two reliable kinds of birth control at the same time. Birth control must be used even if you think you cannot become pregnant, unless you have had a hysterectomy.
If you are pregnant or become pregnant while on tretinoin therapy or during the month after treatment has stopped, immediately contact your doctor to discuss the desirability of continuing the pregnancy.
YOU MUST NOT TAKE TRETINOIN IF YOU ARE A NURSING MOTHER.
Tretinoin should not be taken by nursing mothers since it is not known whether it is excreted in human milk. Since many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from tretinoin, mothers should discontinue nursing prior to taking this drug.
General guidelines for taking your medication...
Call your doctor if you have any questions or experience any severe or troubling symptoms. Tretinoin does not need to be refrigerated. However, do not expose the capsules to sunlight or excessive heat. Be sure to take your medication as prescribed by your doctor. Read the prescription label on the package carefully. If there is anything you don’t understand, ask your doctor or pharmacist to explain it to you. Keep tretinoin and all medications out of the reach of children. Store at 20° to 25°C (68° to 77°F).
PROTECT FROM LIGHT
Precautions with Alcohol
Alcohol-Tretinoin (oral) interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
Brand Names
There is limited information regarding Tretinoin (oral) Brand Names in the drug label.
Look-Alike Drug Names
There is limited information regarding Tretinoin (oral) Look-Alike Drug Names in the drug label.
Drug Shortage Status
Price
References
The contents of this FDA label are provided by the National Library of Medicine.