xerosis
Tretinoin, ATRA Adverse Reactions
Skin changes can occur with both topical and oral tretinoin, but are more common with topical therapy. Almost all patients report a local inflammatory response, which is reversible following discontinuance of topical treatment. Xerosis, including cheilitis, was reported in the majority of patients receiving oral tretinoin. Almost all patients using topical tretinoin reported skin irritation such as peeling, xerosis (dry skin), burning, stinging, erythema, and pruritus. In 24% of all study patients, severe skin irritation led to temporary discontinuation of topical tretinoin 0.02% (about 7%), or led to use of a mild topical corticosteroid. About 5% of patients using tretinoin 0.02%, compared to less than 1% of the control patients, had sufficiently severe local irritation to warrant short-term use of mild topical corticosteroids to alleviate local irritation. About 4% of patients had to discontinue use of topical tretinoin because of adverse reactions. If severe erythema, edema, vesicle formation (e.g., vesicular rash), or crusting develops, topical tretinoin should be discontinued until skin integrity is restored. Therapy may be reinitiated with less frequent application or a lower concentration. Skin hyperpigmentation and skin hypopigmentation have been reported in about 2% of patients with topical tretinoin therapy, with resolution following discontinuation of tretinoin. Some patients experience increased photosensitivity during topical or oral tretinoin therapy; patients should use sunscreen (minimum SPF 15) and protective clothing. Patients with a sunburn should not use topical tretinoin until fully recovered.
Oral tretinoin therapy and acute promyelocytic leukemia (APL) are associated with a significant number of adverse reactions affecting almost all organ systems. The most frequently reported adverse events associated with oral tretinoin are similar to those experienced by patients receiving high doses of vitamin A (hypervitaminosis A). The most common adverse effects to oral tretinoin therapy include headache (86%), fever (83%), bone pain (77%), nausea/vomiting (57%), rash (unspecified) (54%), stomatitis (26%), pruritus (20%), diaphoresis (20%), visual impairment or ocular disorders (17%), alopecia (14%), skin changes (14%), changes in visual acuity (6%), bone inflammation (3%), visual field defects (3%).
Rapidly evolving leukocytosis develops in approximately 20% of acute promyelocytic leukemia patients receiving oral tretinoin and has been associated with other complications. Patients who have a high white blood cell (WBC) count at diagnosis have a greater risk of a further rapid increase in WBC counts. The manufacturer reports that some clinicians routinely add chemotherapy to oral tretinoin on day 1 or 2 in patients who present with a WBC count of > 5000/mm3 or immediately in patients who are leukopenic (< 5000/mm3) at the start of treatment who then have a rapid increase in WBC count to >= 6000/mm3 by day 5, or >= 10,000/mm3 by day 10, or >= 15,000/mm3 by day 28.
Approximately 25% of acute promyelocytic leukemia (APL) patients treated with oral tretinoin develop retinoic acid-APL (RA-APL) syndrome. The RA-APL syndrome is characterized by fever, dyspnea, weight gain, peripheral edema, radiographic pulmonary infiltrates, and pleural or pericardial effusion. Impaired myocardial contractility and episodic decreased blood pressure have occasionally accompanied this syndrome. It may occur with or without leukocytosis. Respiratory signs/symptoms are most commonly associated with RA-APL syndrome. Respiratory adverse reactions include 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 infiltrates (6%), bronchial asthma (3%), pulmonary edema (3%), and laryngeal edema (3%). Endotracheal intubation and mechanical ventilation have been required in some cases due to progressive hypoxia and respiratory depression, and several patients have died with multisystem organ failure. RA-APL syndrome usually occurs within the first month of treatment, with some cases following the first dose of oral tretinoin. The management of RA-APL syndrome has not been defined, but high-dose corticosteroids (dexamethasone 10 mg IV every 12 hours for 3 days or until symptoms resolve) started at the first suspicion of the syndrome appear to reduce morbidity and mortality. Sixty percent or more of patients treated with oral tretinoin may require high-dose steroids because of these symptoms. The majority of patients do not require discontinuation of tretinoin therapy during the treatment of RA-APL syndrome.
Gastrointestinal adverse reactions frequently occur with oral tretinoin therapy for acute promyelocytic leukemia. Adverse reactions reported at an incidence of >= 3% include GI bleeding (34%), abdominal pain (31%), diarrhea (23%), constipation (17%), dyspepsia (14%), abdominal distention (11%), hepatomegaly (9%), splenomegaly (9%), hepatitis (3%), and peptic ulcer (3%). Elevated hepatic enzymes may be reported in 50 - 60% of patients receiving oral tretinoin.
Cardiovascular adverse reactions occurring in >= 3% of patients receiving oral tretinoin for acute promyelocytic leukemia include arrhythmias (23%), flushing (23%), hypotension (14%), hypertension (11%), phlebitis (11%), heart failure (6%), and for 3% of patients: cardiac arrest, myocardial infarction, cardiomegaly, heart murmur, ischemia, stroke, myocarditis, pericarditis, pulmonary hypertension, and secondary cardiomyopathy.
Central nervous system adverse reactions associated with oral tretinoin therapy for acute promyelocytic leukemia include dizziness (20%), paresthesias (17%), anxiety (17%), insomnia (14%), depression (14%), confusion (11%), intracranial bleeding (9%), increased intracranial pressure (9%), agitation (9%), hallucinations (6%), and for 3% of patients: abnormal gait (ataxia), agnosia, aphasia, asterixis, cerebellar edema, cerebellar disorders, seizures, coma, CNS depression, dysarthria (slurred speech), encephalopathy, facial paralysis, hemiplegia, hyporeflexia, hypotaxia, tremor, leg weakness, impaired cognition or forgetfulness, drowsiness, and slow speech. Patients should be warned that activity requiring mental alertness can be affected, as CNS depression can occur.
Oral tretinoin consistently produces adverse reactions associated with the ear. Otalgia and feeling of fullness in the ears were reported in 23% of patients receiving oral tretinoin. Hearing loss and other unspecified auricular adverse effects occurred in 6% of patients. Irreversible hearing loss was infrequent (< 1%).
Oral tretinoin produces hyperlipidemia in as many as 60% of patients. Hypercholesterolemia and/or hypertriglyceridemia develop during treatment with tretinoin and is reversible following discontinuation. Hypercalcemia and hypocalcemia have been seen rarely.
Other adverse reactions occurring at an incidence of >= 3% during oral tretinoin therapy for acute promyelocytic leukemia include malaise or fatigue (66%), shivering (63%), bleeding (60%), pain (37%), chest discomfort (32%), disseminated intravascular coagulation (DIC) (26%), myalgia (14%), renal insufficiency (11%), costovertebral pain (9%), dysuria (9%), cellulitis (8%), facial edema (6%), fluid imbalance (6%), pallor (6%), lymph disorders (6%), and occurring in 3% of patients: acute renal failure (unspecified), ascites, enlarged prostate, hypothermia, metabolic acidosis, renal tubular necrosis, and urinary urgency/frequency. Isolated cases of erythema nodosum, basophilia and hyperhistaminemia, myositis, organomegaly, pancreatitis, pseudotumor cerebri (especially in children), and Sweet’s syndrome have been reported.
Teratogenesis is a serious concern with tretinoin; the vitamin A analogs are well-known teratogens. Teratogenic and embryotoxic effects have been demonstrated in animals receiving oral tretinoin. It is expected that tretinoin will cause fetal harm when administered to a pregnant woman and that there is a high risk of producing a severely deformed infant. Adequate and well-controlled trials have not been performed in humans, but increased spontaneous fetal abortion and major human fetal abnormalities have occurred when pregnant women received other retinoids.
[ Last revised: 10/27/2005 1:52:00 PM ]
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