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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 VESANOID (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%).
APL patients treated with VESANOID (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 VESANOID (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 VESANOID (tretinoin) may require high-dose steroids because of these symptoms. The majority of patients do not require termination of VESANOID (tretinoin) therapy during treatment of the syndrome.
Body as a Whole
General disorders related to VESANOID (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 VESANOID (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 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.
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
Miscellaneous Adverse Events
Additional Adverse Reactions Reported With VESANOID (tretinoin)
Rare cases of thrombocytosis have been reported.
Miscellaneous Adverse Events
Rare cases of vasculitis, predominantly involving the skin, have been reported.
Read the Vesanoid (tretinoin) Side Effects Center for a complete guide to possible side effects
Limited clinical data on potential drug interactions are available.
Drugs Metabolized By the Hepatic P450 System
As VESANOID (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 VESANOID (tretinoin) .
Agents Known to Cause Pseudotumor Cerebri/Intracranial Hypertension (Such as Tetracyclines)
VESANOID (tretinoin) may cause pseudotumor cerebri/intracranial hypertension. Concomitant administration of VESANOID (tretinoin) and agents known to cause pseudotumor cerebri/intracranial hypertension as well might increase the risk of this condition (see WARNINGS).
As with other retinoids, VESANOID (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 VESANOID (tretinoin) and anti-fibrinolytic agents. Therefore, caution should be exercised when administering VESANOID (tretinoin) concomitantly with these agents (see PRECAUTIONS: General).
Effect of Food
No data on the effect of food on the absorption of VESANOID (tretinoin) are available. The absorption of retinoids as a class has been shown to be enhanced when taken together with food.This monograph has been modified to include the generic and brand name in many instances.
Last reviewed on RxList: 9/24/2008
Additional Vesanoid Information
Report Problems to the Food and Drug Administration
You are encouraged to report negative side effects of prescription drugs to the FDA. Visit the FDA MedWatch website or call 1-800-FDA-1088.
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