tretinoin (systemic)
Vesanoid

Available forms
Available by prescription only
Capsules: 10 mg

Indications and dosages
 Induction of remission in patients with acute promyelocytic leukemia (APL), French-American-British classification M³ (including the M³ variant), characterized by the presence of the t(15,17) translocation or the presence of PML/RAR alpha gene, who are refractory to, or who have relapsed from, anthracycline chemotherapy or for whom anthracycline-based chemotherapy is contraindicated. Adults and children age 1 and older: 45 mg/m² P.O. daily administered as two evenly divided doses until complete remission is documented. Discontinue therapy 30 days after achievement of complete remission or after 90 days of treatment, whichever occurs first.

Pharmacodynamics
Antineoplastic action: Exact mechanism of action of tretinoin is unknown. Tretinoin produces an initial maturation of primitive promyelocytes derived from the leukemic clone, followed by a repopulation of bone marrow and peripheral blood by normal, polyclonal hematopoietic cells.

Pharmacokinetics
Absorption: Well absorbed from the GI tract.
Distribution: About 95% is bound to plasma protein.
Metabolism: May induce its own metabolism.
Excretion: Excreted in urine and feces. Terminal elimination half-life is 1/2 to 2 hours.

Contraindications and precautions
Contraindicated in patients hypersensitive to retinoids or parabens, which are used as preservatives in the gelatin capsule. Also contraindicated in pregnant or breast-feeding women.

Interactions
Drug-drug. Ketoconazole: Increases tretinoin plasma level. Use together cautiously.

Adverse reactions
CNS: fever, pain, malaise, dizziness, paresthesia, headache, anxiety, insomnia, depression, confusion, CVA, cerebral hemorrhage, intracranial hypertension, agitation, hallucination, abnormal gait, agnosia, aphasia, asterixis, cerebellar edema, cerebellar disorders, seizures, 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.
CV: chest discomfort, arrhythmias, heart failure, hypotension, hypertension, peripheral edema, phlebitis, edema, cardiac failure, cardiac arrest, MI, enlarged heart, heart murmur, ischemia, myocarditis, pericarditis, secondary cardiomyopathy, flushing.
EENT: ear fullness, visual disturbances, ocular disorders, hearing loss, mucositis.
GI: GI hemorrhage, nausea, vomiting, anorexia, abdominal pain, GI disorders, diarrhea, constipation, dyspepsia, abdominal distention, ulcer.
GU: renal insufficiency, acute renal failure, urinary frequency, dysuria, renal tubular necrosis, enlarged prostate.
Hematologic: leukocytosis, hemorrhage, disseminated intravascular coagulation.
Hepatic: hepatitis, hepatosplenomegaly, unspecified liver disorder.
Metabolic: acidosis, hypothermia, fluid imbalance, weight changes.
Musculoskeletal: flank pain, myalgia, bone pain, bone inflammation.
Respiratory: pneumonia, upper respiratory tract disorders, dyspnea, respiratory insufficiency, pleural effusion, crackles, expiratory wheezing, lower respiratory tract disorders, pulmonary infiltrate, bronchial asthma, pulmonary or larynx edema, unspecified pulmonary disease, pulmonary hypertension.
Skin: flushing, skin mucous membrane dryness, pruritus, decreased sweating, alopecia, injection site reactions, skin changes.
Other: infections, shivering, retinoic acid-APL syndrome, septicemia, multiorgan failure, cellulitis, facial edema, pallor, lymph disorder, ascites.

Effects on lab test results
• May increase cholesterol and triglyceride levels.
• May increase liver function test values and WBC count.

Overdose and treatment
Not reported. Overdose with other retinoids has been linked to transient headache, facial flushing, cheilosis, abdominal pain, dizziness, and ataxia. These signs and symptoms have quickly resolved without apparent residual effects.

Special considerations
• Drug must be administered in a facility with laboratory and supportive services sufficient to monitor drug tolerance and protect and maintain patients compromised by drug toxicity.
• For women, a pregnancy test is required within 1 week before tretinoin therapy. When possible, therapy is delayed until a negative result is obtained.
• Patients with high WBC count at diagnosis are at greater risk for rapid increases in WBC count. Rapidly evolving leukocytosis is linked to a higher risk of life-threatening complications.
 ALERT About 25% of patients given drug during clinical studies have experienced retinoic acid-APL syndrome, characterized by fever, dyspnea, weight gain, radiographic pulmonary infiltrates, and pleural or pericardial effusions. This syndrome has occasionally been accompanied by impaired myocardial contractility and episodic hypotension with or without leukocytosis. Some patients have died because of progressive hypoxemia and multiorgan failure. The syndrome generally occurs during the first month of therapy. Treatment with high-dose corticosteroids at the first signs of the syndrome may reduce morbidity and mortality risk.
• Monitor CBC and platelet counts regularly.
• Monitor patients, especially children, for symptoms of pseudotumor cerebri, such as papilledema, headache, nausea, vomiting, and visual disturbances.
• Monitor cholesterol and triglyceride levels and liver function test results.
Pregnant patients
• Drug use is contraindicated during pregnancy.
Breast-feeding patients
• It isn’t known whether drug appears in breast milk. Because of the potential for serious adverse reactions in breast-fed infants, drug shouldn’t be given to breast-feeding women.
Pediatric patients
• Safety and efficacy in children younger than age 1 haven’t been established.

Patient education
• Instruct patient to report signs or symptoms of infection (fever, sore throat, fatigue) or bleeding (easy bruising, nosebleeds, bleeding gums, melena).
• Tell patient to record his temperature daily.

Reactions may be common, uncommon, life-threatening, or COMMON AND LIFE THREATENING.
◆ Canada only
◇ Unlabeled clinical use