SYNONYM(S): ATRA; All-trans Retinoic Acid
COMMON TRADE NAME(S): Vesanoid®
Tretinoin is an endogenous metabolite of retinol (vitamin A). It induces terminal differentiation and inhibits cell proliferation in transformed hemopoietic precursor cell lines, including human myeloid lines. Acute Promyelocytic Leukemia (APL) is associated with a specific translocation between chromosomes 15 and 17 (region of retinoic acid receptor - α). The translocation appears to inhibit differentiation and lead to carcinogenesis; tretinoin may overcome this when used in high doses. Tretinoin induces remissions in 64-100% of APL patients, with time to remission usually between 8 and 119 days of therapy (Gillis 1995). Acquired resistance during therapy is common especially with prolonged dosing (4-6 months) possibly due to induction of metabolism or increased expression of cellular retinoic acid binding proteins.
Oral: well absorbed with 50% bioavailability.
Absorption is affected by biliary pH and fatty composition. Effect of food on tretinoin absorption is unclear but increases bioavailability of retinoids as a class. Hence, tretinoin should be administered with food.
Peak plasma concentrations are reached within 1-2 hours. Pharmacokinetics (AUC, peak plasma concentration) initially increase in a higher than dose proportional manner. Prolonged dosing leads to a significant decrease in AUC and plasma levels.
Rapidly and extensively distributed into tissues
|Cross blood brain barrier?||No|
|PPB||>95% (mainly to albumin)|
Primarily by hepatic cytochrome P450 (e.g. CYP3A4, CYP2C8, CYP2E). Metabolites are glucuronidated and excreted in bile and urine. Tretinoin induces its own metabolism, with lower plasma level and AUC after 2-6 weeks of continuous treatment with an increase in urinary excretion of 4-oxo metabolites.
|Active metabolites||Several, including 13-cis isomer|
|Feces||31% within 6 days|
|Urine||63 % within 72 hours|
|Half-life||0.7 hours (range 0.5 - 2 h)|
- For the induction of remission in acute promyelocytic leukemia (either de novo or after relapse following cytotoxic chemotherapy). Consolidation chemotherapy should be given after complete remission.
Extravasation Potential: Not applicable
|ORGAN SITE||SIDE EFFECT* (%)||ONSET**|
|Auditory||Ear pain (23%)||E|
|Hearing impaired (6%) (irreversible in <1%)||E|
|Arterial thromboembolism (3%)||E|
|Flushing (23%)||I E|
|Pericarditis (3%)||E D|
|Dry skin (77%) (including mucosal dryness)||E|
|Erythema nodosum (rare)|
|Nail disorder||E D|
|Other (Sweet's syndrome- rare)||E|
|Photosensitivity (rare)||I E|
|Gastrointestinal||Abdominal distension (11%)||E|
|Abdominal pain (31%)||E|
|Anorexia, weight loss (17%)||E|
|Nausea, vomiting (57%)||I E|
|Weight gain (23%)||E|
|Hypothermia (3%)||I E|
|Other (25%) (retinoic acid syndrome)||I E|
|Disseminated intravascular coagulation (26%)||E|
|Leukocytosis (75%) (hyperleukocytosis)||I E|
|Hepatobiliary||↑ LFTs (60%)||E|
|Metabolic / Endocrine||Acidosis (3%)||E|
|↑ Ca (rare)||E|
|Hyperlipidemia (60%) (increased cholesterol and triglycerides)||E|
|Musculoskeletal||Musculoskeletal pain (77%)||E|
|Nervous System||Anxiety (17%)||E|
|Depression (14%)||E D|
|Headache (86%)||I E|
|Other (9%) (pseudotumour cerebri)||E|
|Other (17%) (visual disturbance)||E|
|Renal||Nephrotoxicity (11%)||E D|
|Cough, dyspnea (60%)||E|
|Lung infiltrate (6%)||E|
|Pleural effusion (20%)||E|
* "Incidence" may refer to an absolute value or the higher value from a reported range.
"Rare" may refer to events with < 1% incidence, reported in post-marketing, phase 1 studies,
isolated data or anecdotal reports.
** I = immediate (onset in hours to days) E = early (days to weeks)
D = delayed (weeks to months) L = late (months to years)
Hypervitaminosis A syndrome is seen in at least 25% of patients, with rash, dry skin and mucosa, edema, nausea, vomiting, bone pain. Headache occurring several hours after tretinoin ingestion is the most common side effect. It differs from that associated with pseudotumour cerebri in that it is often transient, mild in intensity and well-controlled with mild analgesics. Patients usually develop tolerance with continued tretinoin therapy.
Retinoic acid syndrome (RAS) occurs in 20-25% of patients, and is characterized by some or all of the following symptoms: fever, dyspnea, hypotension, bone pain, weight gain, edema, respiratory distress, pulmonary infiltrates, hyperleukocytosis, pleural or pericardial effusion, congestive heart failure, hepatic / renal failure, multi-organ failure and may be fatal. Due to the severity and poor prognosis of the syndrome once the full-blown signs have been developed, prophylaxis or early treatment with chemotherapy, corticosteroids or temporary interruption is required (section E)
Basophilia/ Hyperhistaminemia: Basophilia-associated hyperhistaminemia has been rarely reported in patients with rare basophilic variants of APL. The severity of symptoms depends on the level of plasma histamine. Severe symptoms include tachycardia, shock due to vasodilatation, gastric and duodenal ulceration. Prophylactic H2 or H1 antagonist has been used to prevent symptoms mediated via H2 and H1 receptors.
Pseudotumour cerebri syndrome: Also known as benign or idiopathic intracranial hypertension, it is characterized by signs and symptoms of intracranial hypertension without evidence of infective or space occupying lesions. Symptoms include severe headache which may be aggravated by analgesic or narcotic overuse, nausea and vomiting, papilledema, retinal hemorrhages, visual changes (e.g., intermittent visual loss), and ophthalmoplegia. Cases reported onset of symptoms from 3-17 days to 6 months of tretinoin therapy. Pseudotumour cerebri is more common in children than in adults and may be due to their increased sensitivity to the CNS effects of tretinoin. The cause and appropriate management of pseudotumour cerebri have not been established, but the risk is increased with other drugs known to cause pseudotumour cerebri such as tetracyclines. Narcotic analgesics, corticosteroids, or temporary discontinuation of tretinoin in non-responding cases may help reduce severe headache, nausea and vomiting. Diuretics (acetazolamide, furosemide) or lumbar puncture may reduce CSF pressure.
Sweet's syndrome is a hyperinflammatory reaction of neutrophil infiltration of the skin and internal organs. Symptoms include fever, painful erythematous cutaneous plaques involving the extremities and the trunk, and prominent musculoskeletal involvement (e.g., myositis, fasciitis). The onset of symptoms is about 7-34 days of tretinoin therapy. The cause of the syndrome is unknown and symptoms generally resolve within 48 hours of corticosteroid therapy.
Oral: 45 mg/m2/day (Round dose to the nearest 10 mg) in 2 divided doses.
Continue for 30 days to a maximum of 90 days until complete remission and then give consolidation chemotherapy (anthracycline + cytarabine).
At any time
Add anthracycline-based chemotherapy.
≥ 6, day 1 - day 6
Add full-dose anthracycline-based chemotherapy
Retinoic Acid Syndrome and Toxicity:
- For patients with early signs of the syndrome any time during tretinoin therapy, start dexamethasone 10 mg IV every 12 hours for at least 3 days until symptom resolution.
- Consider temporary interruption of tretinoin with moderate or severe retinoic acid syndrome
- Reduce dose in the event of intractable headaches
Few studies or data are available. Same dosage as for adults. There appears to be an increased risk of pseudotumour cerebri.
- Oral self-administration; drug available by outpatient prescription.
- Should be administered with food.
- Tretinoin capsules should not be opened.
- Avoid grapefruit, starfruit, Seville oranges, their juices or products during treatment.
- Store at room temperature (15-30°C); protect from heat and direct light.
- patients with a history of hypersensitivity reaction to tretinoin or related compounds (e.g. acitretin, isotretinoin, vitamin A)
- patients taking vitamin A
- Use with caution with antifibrinolytic agents (as fatal thrombosis may occur) and with tetracyclines
- Overdose may result in symptoms of hypervitaminosis A; no specific antidote is available but patients should be closely monitored.
- Patients who are drowsy or who have headaches may have reduced ability to operate heavy machinery or motor vehicles.
Other Drug Properties:
Tretinoin is highly teratogenic with a high risk of severe malformations; therefore, it is contraindicated in pregnancy and in women who might become pregnant during or within one month of treatment cessation. All patients of childbearing potential should use effective contraception at least 4 weeks prior to treatment, during and for at least 1 month after treatment cessation. Therapy should not begin until the second or third day of the next normal menstrual period and a pregnancy test should be negative within 2 weeks before starting treatment (Refer to product monograph for full details). Low dose progesterone contraceptives should not be used.
|Drugs inducing P450 (rifampicin, glucocorticoids, Phenobarbital, etc)||↓ blood levels of tretinoin||Induces tretinoin metabolism||Avoid concurrent therapy or use with caution|
|Ketoconazole and drugs inhibiting p450 (cimetidine, erythromycin, cyclosporine, etc)||↑ tretinoin AUC||Inhibits tretinoin metabolism||Avoid concurrent therapy|
|Progesterone (low dose)||↓ contraceptive efficacy of progestogens||Unknown||Avoid concurrent therapy; use alternative methods for contraception|
|Tetracyclines||May ↑ intracranial blood pressure/ pseudotumour cerebri||Additive||Avoid concurrent therapy|
|Vitamin A||May ↑ Tretinoin toxicity||Additive||CONTRAINDICATED|
|Antifibrinolytic agents (e.g. tranexamic acid, aminocaproic acid, aprotinin)||↑ risk of thrombosis||Additive||Avoid concomitant use or use with caution|
|Hydroxyurea||Massive cell lysis and marrow necrosis||Synergistic (tretinoin induces cells to enter S phase; hydroxyurea cytotoxic to S phase cells)||Avoid concomitant use|
|Monitor Type||Monitor Frequency|
|Pregnancy test in patients of childbearing potential||Baseline (within 2 weeks before treatment starts) and at each month|
|Renal function tests||Baseline and regular|
|Liver function tests||Baseline and regular|
|CBC & coagulation||Baseline and frequent (weekly for the first month)|
|Clinical toxicity assessment (including skin, headache, bleeding, infection, Retinoic Acid Syndrome).|
Grade toxicity using the current NCI-CTCAE (Common Terminology Criteria for Adverse Events) version
|Monitor Type||Monitor Frequency|
|Cholesterol and triglycerides||Baseline and regular|
Exceptional Access Program (EAP Website)
- tretinoin (ATRA)
Gillis JC, Goa KL. Tretinoin. A review of its pharmacodynamic and pharmacokinetic properties and use in the management of acute promyelocytic leukemia. Drugs 1995; 50(5):897-923.
Koike T, Tatewaki W, Aoki A, et al. Brief report: severe symptoms of hyperhistaminemia after the treatment of acute promyelocytic leukemia with tretinoin (all-trans-retinoic acid). N Engl J Med 1992;327(6):385-7.
McEvoy GK, editor. AHFS Drug Information 2013. Bethesda: American Society of Health-System Pharmacists, p. 1226-30.
Shimamoto Y, Suga K, Yamaguchi M, et al. Prophylaxis of symptoms of hyperhistaminemia after the treatment of acute promyelocytic leukemia with all-trans retinoic acid. Acta Haematol 1994;92(2):109-12. Tretinoin drug monograph. BCCA Cancer Drug Manual, February 2014.
Product monograph: Vesanoid (tretinoin). Xediton Pharmaceuticals. October 3, 2013.
Tretinoin drug monograph. BCCA Cancer Drug Manual, February 2014.
Yeh YC, Tang HF, Fang IM. Pseudotumor cerebri caused by all-trans-retinoic acid treatment for acute promyelocytic leukemia. Jpn J Ophthalmol. 2006 May-Jun;50(3):295-6.
June 2019 Updated emetic risk category.
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