Tretinoin

Oral
Topical
Class
Vitamin A derivatives
Subclass
Retinoids
Substance name
Tretinoin, all-trans retinoic acid, ATRA
Brand names
Retin-A®, Retin – A Micro®
Common formulations
Capsule
Dosage and administration
Adults patients
Acute promyelocytic leukemia in patients with chromosome 15;17 reciprocal translocation, PML-RARα fusion protein • Induction therapy, if anthracyclines are ineffective or contraindicated
•
45 mg/m² PO daily, in 2 divided doses, until 30 days after complete remission or after 90 days of treatment, whichever occurs first
Acute promyelocytic leukemia • Consolidation therapy • Off-label
•
45 mg/m² PO daily, in 2 divided doses, for 15 days each month for 3 months
Administered in combination with idarubicin (courses 1 and 3) and mitoxantrone (course 2).
Alternative
•
45 mg/m² PO daily, in 2 divided doses, for 2 weeks
Administered in combination with daunorubicin every first 3 days of each week.
Alternative
•
45 mg/m² PO daily, in 2 divided doses, 2 weeks on and 2 weeks off, for 7 courses
Administered in combination with 4 courses of arsenic trioxide.
Acute promyelocytic leukemia • Maintenance therapy • Off-label
•
45 mg/m² PO daily, in 2 divided doses, for 1 week every other week for 1 year
Alternative
•
45 mg/m² PO daily, in 2 divided doses, for 15 days every 3 months for 2 years
Administered in combination with mercaptopurine and methotrexate.
Indications for use
Labeled indications
Adults
•
Treatment of acute promyelocytic leukemia in patients with chromosome 15;17 reciprocal translocation, PML-RARα fusion protein (induction therapy), if anthracyclines are ineffective or contraindicated
Off-label indications
Adults
•
Treatment of acute promyelocytic leukemia (consolidation therapy)
•
Treatment of acute promyelocytic leukemia (maintenance therapy)
Safety risks
Boxed warnings
Increased WBC count
•
Maintain a high level of suspicion, as tretinoin has been associated with an increased risk of rapidly evolving lekocytosis, especially in patients presenting with high WBC count at diagnosis. Consider initiating full-dose chemotherapy (including an anthracycline if not contraindicated) on day 1 or 2 in patients presenting with a WBC count of > 5×10⁹/L, or immediately, in patients presenting with a WBC count of < 5×10⁹/L, if the WBC count reaches ≥ 6×10⁹/L by day 5, or ≥ 10×10⁹/L by day 10, or ≥ 15×10⁹/L by day 28.
Retinoic acid syndrome
•
Maintain a high level of suspicion, as tretinoin can cause retinoic acid syndrome, characterized by fever, dyspnea, acute respiratory distress, weight gain, pulmonary infiltrates, pleural and pericardial effusion, edema, and hepatic, renal, and multiorgan failure, occasional impaired myocardial contractility, and episodic hypotension, generally occurring during the first month of treatment. Administer high-dose cortcosteroids immediately after the first signs of the syndrome are observed, regardless of WBC count. Consider temporarily interrupting tretinoin in cases of moderate and severe retinoic acid syndrome.
Severe adverse reactions
•
Maintain a high level of suspicion, as patients with acute promyelocytic leukemia are at high risk in general and can have severe adverse reactions to oral tretinoin. Administer oral tretinoin under the strict supervision of a physician experienced in the management of acute leukemia and in a facility with laboratory and supportive services sufficient to monitor drug tolerance and manage drug toxicity, including respiratory compromise.
Teratogenesis
•
Do not use in pregnant patients. Verify pregnancy status in females of reproductive potential 1 week before initiating treatment. Advise using two reliable forms of contraception during treatment and for 1 month after the last dose.
Contraindications
Hypersensitivity to tretinoin or its components or to other retinoids
Warnings and precautions
Hypercholesterolemia, increased serum cholesterol, increased serum triglycerides
•
Maintain a high level of suspicion, as tretinoin has been associated with an increased risk of tranient hypercholesterolemia and hypertriglyceridemia, as well as venous thrombosis and myocardial infarction.
Increased liver enzymes
•
Maintain a high level of suspicion, as tretinoin has been associated with an increased risk of elevated LFTs. Monitor LFTs during treatment, and consider temporarily interrupting tretinoin if results are > 5 times the ULN.
Intracranial hypertension
•
Maintain a high level of suspicion, as retinoids have been associated with an increased risk of intracranial hypertension, especially in pediatric patients and with concomitant use of other agents known to increase ICP, such as tetracyclines.
Specific populations
Renal impairment
eGFR 0-90 mL/min/1.73 m²
•
No guidance available.
Renal replacement therapy
Any modality
•
No guidance available.
Hepatic impairment
Any severity
•
No guidance available.
Unexplained abnormality in LFTs
•
Monitor liver function tests. Consider temporarily interrupting tretinoin if results are > 5 times the upper limit of normal.
Pregnancy and breastfeeding
Pregnancy
All trimesters • Australia Category: D, X
•
Do not use. Evidence of fetal harm in humans. Verify pregnancy status in females of reproductive potential one week before initiating treatment. Advise using two reliable forms of contraception during treatment and for one month after the last dose.
Breastfeeding
Do not use during breastfeeding.
Unknown amount excreted in breastmilk.
Unknown drug levels in breastfed infants.
Some adverse effects on lactation reported.
Adverse reactions
Very common > 10%
•
Abdominal distension, cardiac arrhythmias, crackles, disseminated intravascular coagulation, dry mucous membranes, skin dryness, edema, gastrointestinal bleeding, hypertension, hypotension, ↑ LFTs, ↑ WBC count, ↑ serum cholesterol, ↑ serum triglycerides, mucositis, peripheral edema, phlebitis, pleural effusion, pneumonia, renal insufficiency, abdominal pain, anxiety, bleeding, bone pain, burning sensation, chest discomfort, confusion, constipation, depression, diarrhea, dizziness, dyspepsia, dyspnea, ear fullness, ear pain, fever, hair loss, headache, insomnia, loss of appetite, malaise, myalgia, nausea, vomiting, paresthesia, pruritus, sweating, skin flushing, skin rash, visual disturbances, weight gain, weight loss, respiratory insufficiency, retinoic acid syndrome, shivering, wheezing
Common 1-10%
•
Acute tubular necrosis, agitation, ascites, asthma, cardiac arrest, cardiovascular events, cardiomyopathy, cellulitis, cerebral edema, cerebral hemorrhage, intracranial hypertension, coma, dysarthria, hemiplegia, hyporeflexia, tremor, limb weakness, somnolence, memory impairment, slurred speech, agnosia, ↓ body temperature, ↓ visual acuity, dementia, encephalopathy, renal tubular necrosis, enlarged prostate, facial edema, pallor, pulmonary infiltrates, heart failure, heart murmur, gait disturbance, aphasia, asterixis, hepatitis, hepatomegaly, splenomegaly, laryngeal edema, metabolic acidosis, myocardial infarction, myocarditis, pericarditis, pulmonary edema, pulmonary hypertension, renal failure, dysuria, flank pain, hallucinations, seizure, syncope, urinary frequency, visual field defect
Uncommon < 1%
•
Hearing loss, thrombosis
Rare < 0.1%
•
↑ platelet count, vasculitis
Unknown frequency
•
Acute pancreatitis, erythema nodosum, ↑ blood basophils, ↑ serum calcium, genital ulcers, myositis, pericardial effusion, sweet syndrome
Interactions
Drug(s)
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