Tretinoin is used for the induction of remission in adults and pediatric patients 1 year of age and older with acute promyelocytic leukemia (APL) characterized by the presence of certain genetic markers (i.e., 15;17 chromosomal translocation and/or PML / RAR- gene); the drug is FDA-labeled for use in such patients with relapsed or refractory disease following anthracycline-based chemotherapy or in patients for whom anthracycline therapy is contraindicated.1, 16 Tretinoin also has been used for consolidation and maintenance therapy†.6, 7, 13, 43
Tretinoin therapy may be initiated based on the morphologic diagnosis of APL; however, the manufacturer states that the diagnosis should be confirmed with cytogenetic studies to detect the presence of the t(15;17) translocation genetic marker or molecular diagnostic testing for the PML/RAR-α fusion protein.1 Tretinoin is not recommended for use in patients without these genetic markers.1
Treatment for Relapsed or Refractory Disease
The current indication for tretinoin is based principally on data from an open-label, single-arm trial and from 2 cohorts of compassionate cases treated in multiple centers under the direction of the National Cancer Institute (NCI).1 All patients received tretinoin 45 mg/m2 daily as a divided oral dose for up to 90 days or 30 days beyond attainment of a complete remission.1 In the clinical trial, tretinoin therapy was associated with a complete remission rate of 80% in the 20 patients with relapsed APL and 73% in the 15 patients with previously untreated APL; median survival was 10.8 months in the patients with relapsed disease.1 In the 2 cohorts of compassionate cases of APL, complete remission rates of 50-52% in patients with relapsed disease and 36-68% in patients with previously untreated disease were reported.1 The median time to achieve a complete remission was between 40-50 days (range: 2-120 days) in all patients studied.1 Most of the patients in these studies also received cytotoxic chemotherapy during the remission phase.1
Although tretinoin has been used to induce second remissions in patients with APL that has relapsed following prior treatment with tretinoin, results have been inconsistent;2, 9 continuous treatment with tretinoin results in resistance to the drug secondary to increased catabolism and decrease in plasma concentrations, and response may be more likely for late relapse occurring after discontinuation of tretinoin therapy.38, 42
Limited data on the clinical use of tretinoin in children are available.1, 6, 13 A complete remission rate of 67% (8 of 10 males and 2 of 5 females) was reported in 15 pediatric patients (age range: 1-16 years) receiving tretinoin induction therapy for APL.1
Initial Treatment for Newly Diagnosed Disease
Tretinoin also has been used as initial treatment in patients with newly diagnosed APL†.6, 7, 8, 13 The NCI includes the combination of tretinoin and arsenic trioxide as an initial treatment option in newly diagnosed patients with low- to intermediate-risk disease.8, 13
In early studies, the combination of tretinoin and cytotoxic chemotherapy was shown to be superior over chemotherapy alone in patients with newly diagnosed APL.6, 7, 8, 15, 37, 38 More recently, the efficacy and toxicity of tretinoin plus arsenic trioxide was compared with tretinoin plus chemotherapy in a phase 3, randomized, open-label study in patients with newly diagnosed low- to intermediate-risk APL.41 The primary endpoint was event-free survival (defined as no achievement of hematologic complete remission [CR] after induction therapy, no achievement of molecular CR after 3 consolidation courses, molecular relapse, hematologic relapse, or death).41 The 2-year event-free survival rate was 97% in the tretinoin plus arsenic trioxide group and 86% in the tretinoin plus chemotherapy group.41
The treatment of APL has evolved rapidly over the past several decades with the introduction of tretinoin and arsenic trioxide.43 While traditional cytotoxic chemotherapy is still used in certain patients (e.g., high-risk), it is possible to treat APL without the use of chemotherapy.13, 43 APL is a distinct subtype of acute myeloid leukemia (AML) that has a specific sensitivity to tretinoin, which acts as a differentiating agent, and to arsenic trioxide, a proapoptotic agent; high complete recovery rates and long-term disease-free survival in APL have been demonstrated with the combination of the 2 drugs.8, 13 With the inclusion of arsenic trioxide in current treatment regimens, the use of traditional chemotherapy is increasingly restricted to the induction phase for high-risk patients.13 Current guidelines for APL include various treatment options; selection of an appropriate regimen is determined by the patient's risk category (low, intermediate, or high based on white blood cell [WBC] counts).8
Experts currently recommend the use of tretinoin in combination with arsenic trioxide for initial treatment† of APL in patients with low- to intermediate-risk disease (WBC count ≤10,000/mm3).8, 13, 43 The combination of tretinoin and chemotherapy, followed by arsenic trioxide-based consolidation therapy is recommended for newly-diagnosed patients with high-risk disease (WBC >10,000/mm3).8, 13, 43
Because of data indicating that children with APL have a similar response to the combination of tretinoin and arsenic trioxide as adults, experts recommend the use of these 2 agents alone in standard-risk patients, and with short-course chemotherapy during induction in high-risk patients, as the optimal therapeutic approach for children with APL.13
Although tretinoin is only FDA-labeled for use in induction therapy, the drug also has been used for consolidation therapy† and is included in current guidelines for this use.13, 43 For patients who are treated with tretinoin and arsenic trioxide, maintenance therapy is not likely to be necessary.43, 47, 48
Tretinoin is administered orally in 2 equally divided doses.1 Take capsules with a meal and swallow the capsules whole with water; do not chew, dissolve, or open.1
Do not take a missed dose of tretinoin unless it is more than 10 hours until the next scheduled dose.1
If vomiting occurs after administration, do not take an additional dose.1 Continue with the next scheduled dose.1
Store at 20-25ºC; protect from light.1
For the induction of remission, the recommended dosage of tretinoin is 45 mg/m2 daily administered in 2 evenly divided doses until complete remission is documented.1 The manufacturer states that tretinoin therapy should be continued until 30 days after complete remission is achieved or 90 days of treatment have elapsed, whichever occurs first.1
Although tretinoin is not FDA-labeled for consolidation therapy† in patients with APL, the drug has been used for postremission consolidation at a dosage of 45 mg/m2 alternating 7 days on and 7 days off for a total of 28 weeks.43 An alternative consolidation regimen that has been used is 45 mg/m2 daily for 2 weeks every 4 weeks for a total of 7 cycles (28 weeks total).43
For the induction of remission in pediatric patients ≥1 year of age with APL, the recommended dosage of tretinoin is 45 mg/m2 daily administered in 2 evenly divided doses until complete remission is documented.1 The manufacturer states that tretinoin therapy should be continued until 30 days after complete remission is achieved, or for a total of 90 days, whichever occurs first.1
The maximum tolerated dose is lower in pediatric patients than adults.1 Dosage reduction may be considered for pediatric patients who experience serious or intolerable drug toxicity.1 A lower daily dose of 25 mg/m2 has been used in the pediatric population, which is thought to decrease the incidence of intracranial hypertension.43
Dosage Modification for Toxicity
Withholding tretinoin therapy until resolution should be considered in patients experiencing moderate or severe differentiation syndrome.1
Withholding tretinoin therapy until resolution should be considered in patients with liver function test results >5 times the upper limit of normal.1
Tretinoin, a retinoid, may cause fetal harm; embryo-fetal loss and malformations occur when administered to pregnant women.1 A boxed warning about the risk of teratogenic effects has been included in the prescribing information for the drug.1
Retinoids are associated with an increased risk of major congenital malformations, spontaneous abortions, and premature births following exposure during human pregnancy.1 In animals, tretinoin has teratogenic and embryotoxic effects at doses less than the human dose on a mg/m2 basis.1
Apprise pregnant women of the potential fetal risk.1 Advise females of reproductive potential to use 2 effective contraceptive methods during treatment and for 1 month following the last tretinoin dose.1 Advise male patients with female partners of reproductive potential to use effective contraception during treatment and for 1 week following the last dose.1
Differentiation syndrome, a condition characterized by fever, dyspnea, acute respiratory distress, weight gain, pulmonary infiltrates, pleural and pericardial effusions, edema, and hepatic, renal, and multiorgan failure, has been reported in about 26% of patients with APL treated with tretinoin.1, 20 A boxed warning about this risk has been included in the prescribing information for tretinoin.1 The syndrome has been accompanied by impaired myocardial contractility and episodic hypotension, and can occur with or without concomitant leukocytosis.1 Onset generally occurs within the first month of treatment and can occur after a single dose.1 Endotracheal intubation and mechanical ventilation were required in some cases due to progressive hypoxemia and several fatalities have occurred due to multi-organ failure.1 At the first signs or symptoms of differentiation syndrome, dexamethasone 10 mg IV every 12 hours should be immediately administered and continued until signs and symptoms have abated for at least 3 days.1 Hemodynamic monitoring should also occur until sign and symptom resolution.1 Consider withholding tretinoin therapy for moderate and severe disease until resolution.1
Other Warnings and Precautions
Rapidly evolving leukocytosis has been reported in approximately 40% of patients receiving tretinoin capsules and is associated with an increased risk of life-threatening complications.1 Patients with a baseline white blood cell (WBC) count >5000 cells/mm3 have an increased leukocytosis risk while those who receive concomitant chemotherapy may be at a reduced risk.1
Consider administration of cytoreductive chemotherapy (e.g., an anthracycline if not contraindicated or hydroxyurea) with tretinoin in patients with leukocytosis, as clinically indicated.1
Patients Without the t(15;17) Translocation or PML/RAR Fusion
Initiation of therapy with tretinoin may be based on the morphological diagnosis of APL, but the diagnosis should be confirmed with detection of the t(15;17) translocation genetic marker by cytogenetic studies or PML/RARα fusion via molecular diagnostic techniques.1 Tretinoin is not recommended for use in patients without these genetic markers.1
Retinoids, including tretinoin, have been associated with intracranial hypertension, especially in pediatric patients.1 Early signs and symptoms of intracranial hypertension include papilledema, headache, nausea, vomiting, and visual disturbances.1 Evaluate patients with these symptoms for intracranial hypertension and, if present, perform a neurological assessment and initiate appropriate therapy.1
Consider dose reduction, interruption of therapy, or discontinuation of tretinoin as necessary.1 The concomitant use of other agents known to cause intracranial hypertension, such as tetracyclines, might increase the risk of this condition.1 Avoid concomitant use of tretinoin with other agents that can cause intracranial hypertension.1
Up to 60% of patients receiving tretinoin have experienced hypercholesterolemia and/or hypertriglyceridemia, which may be reversible upon completion of treatment.1 The clinical consequences of elevations of triglycerides and cholesterol are unknown, but venous thrombosis and myocardial infarction (MI) have been reported in patients who ordinarily are at low risk for such complications.1
Monitor fasting triglycerides and cholesterol at baseline and periodically during treatment.1
Elevated liver function test results have been reported in 50 to 60% of patients receiving tretinoin.1 The majority of these abnormalities resolve without interruption of tretinoin or after completion of treatment.1
Liver function test results should be carefully monitored at baseline and during tretinoin treatment as clinically indicated.1 Consider withholding therapy if liver function test results reach >5 times the upper limit of normal (ULN) until resolution.1
Venous and arterial thromboembolic events (e.g., cerebrovascular accident, MI, renal infarct) have occurred with tretinoin therapy.1 Events may occur during the initial month of treatment and patients administered anti-fibrinolytics may be at an increased risk for their occurrence.1
Avoid concomitant use of tretinoin and anti-fibrinolytics (e.g., tranexamic acid, aminocaproic acid).1
Tretinoin is a retinoid and increased spontaneous abortions and major fetal abnormalities related to the use of retinoids in humans have been documented.1 Reported malformations include abnormalities of the CNS, musculoskeletal system, external ear, eye, thymus, and great vessels as well as facial dysmorphia, cleft palate, and parathyroid hormone deficiency.1 Some of the reported abnomalities resulted in fatalities.1
It is not known whether tretinoin is distributed into human milk.1 The effects of tretinoin on the breastfed child or milk production are also unknown.1 Due to the potential for serious adverse effects in nursing infants, women should not breastfeed during treatment with tretinoin and for 1 week after the last dose.1
Females and Males of Reproductive Potential
Tretinoin can cause embryo-fetal loss and malformations when administered to pregnant women.1
Verify pregnancy status in females of reproductive potential prior to initiating tretinoin therapy.1 These females must have a negative pregnancy test within 1 week prior to therapy initiation with a test sensitivity of at least 50 mIU/mL.1
Females of reproductive potential should either abstain from sexual intercourse or use 2 effective contraceptive methods during therapy and for 1 month after the last dose.1 Two contraceptive methods are indicated even in the setting of a history of infertility, unless due to hysterectomy.1 Male patients with female partners of reproductive potential should use effective contraception during treatment and for 1 week after the last dose.1
Based on testicular toxicities in dogs, tretinoin may impair male fertility.1 The reversibility of this effect is unknown.1
Safety and efficacy of tretinoin have been established in pediatric patients ≥1 year of age.1 The maximum tolerated dose is lower in pediatric patients as compared to adults.1
Some pediatric patients experience severe headache and intracranial hypertension during therapy, requiring treatment with analgesics and lumbar puncture.1, 12
Dosage reduction may be appropriate if serious and/or intolerable adverse effects occur.1
In clinical studies, 21% of patients were 60 years of age or greater.1 No overall differences in safety or effectiveness were seen between older and younger patients.1
The manufacturer states that the pharmacokinetics of tretinoin have not been evaluated in individuals with hepatic impairment.1
The manufacturer states that the pharmacokinetics of tretinoin have not been evaluated in individuals with renal impairment.1
The most common adverse reactions (≥30%) with tretinoin therapy include headache, fever, skin/mucous membrane dryness, bone pain, malaise, shivering, upper respiratory tract disorders, dyspnea, hemorrhage, infections, nausea/vomiting, rash, peripheral edema, leukocytosis, pain, GI hemorrhage, chest discomfort, and abdominal pain.1
Drugs Affecting Hepatic Microsomal Enzymes
The concomitant use of tretinoin with a strong CYP3A4 inhibitor (e.g., ketoconazole) increases tretinoin plasma concentrations, which may lead to increased adverse reactions.1 Avoid concurrent administration of tretinoin with strong CYP3A inhibitors if possible.1 Monitor these patients more frequently for adverse reactions if concurrent administration cannot be avoided.1
The concomitant use of tretinoin with strong CYP3A4 inducers may reduce tretinoin plasma concentrations, which may lead to reduced efficacy.1 Avoid concurrent administration of tretinoin with strong CYP3A inducers if possible.1
Drugs Known to Cause Intracranial Hypertension
Intracranial hypertension has been reported in patients receiving tretinoin.1 Concomitant use of other agents known to cause intracranial hypertension, such as tetracyclines, may increase the risk of this condition in patients receiving tretinoin.1 Avoid coadministration of tretinoin with drugs known to cause intracranial hypertension.1
Fatal thrombotic complications have been reported in patients receiving tretinoin and concurrent use of fibrinolytic inhibitors, such as tranexamic acid or aminocaproic acid, may increase this risk.1 Avoid concomitant use of tretinoin with antifibrinolytic agents.1
Concurrent use of hydroxyurea, which is cytotoxic to cells in S phase, and tretinoin, which induces cells to enter the S phase, may cause a synergistic effect leading to massive cell lysis.29 Bone marrow necrosis, sometimes fatal, has been reported in patients receiving hydroxyurea during tretinoin therapy.29 Although some clinicians have administered hydroxyurea in conjunction with tretinoin therapy to reduce leukocytosis,6, 9 the safety and efficacy of this practice have not been established,9 and caution is recommended in the use of hydroxyurea in patients receiving tretinoin.29
Like other retinoids, concomitant use of tretinoin with vitamin A should be avoided due to a risk of vitamin A related adverse reactions.1
Tretinoin is a retinoid that induces cytodifferentiation and decreased proliferation of acute promyelocytic leukemia (APL) cells in culture and in vivo.1 The precise mechanism(s) of action of tretinoin has not been fully elucidated.1, 10 The PML/RAR-α fusion protein resulting from the 15;17 chromosomal translocation appears to block myeloid differentiation at the promyelocyte stage, possibly by complexing and inactivating wild-type PML or by inhibiting the normal retinoic acid signaling pathway.2 In patients with APL who achieve a complete remission with tretinoin therapy, the drug causes an initial maturation of the primitive promyelocytes derived from the cellular leukemic clone followed by a repopulation of the bone marrow and peripheral blood by normal, polyclonal hematopoietic cells.1 Observations supporting cellular differentiation effects as a mechanism of tretinoin include the absence of bone marrow hypoplasia during induction, the appearance of immunophenotypically unique “intermediate cells” expressing both mature and immature cell surface antigens, and the presence of both Auer rods and the 15;17 translocation in morphologically mature granulocytes until a late stage of induction.9, 10 The mechanism by which the population of malignant cells is eliminated is not fully understood but appears to involve apoptosis (programmed cell death).9 Following induction therapy, the PML/RAR-α fusion protein can be detected in the majority of patients, suggesting that tretinoin alone does not eradicate the leukemic clone.2
Following oral administration of tretinoin, the time to reach peak concentrations was 1 to 2 hours.1 The absolute bioavailability was approximately 50%.1 The effect of food on absorption has not been evaluated; however, retinoid absorption is generally enhanced with food.1 Protein binding is >95%, primarily to albumin.1 The terminal elimination half-life of tretinoin following initial dosing in patients with APL is 0.5 to 2 hours.1 Tretinoin is metabolized in the liver by cytochrome P-450 (CYP) isoenzymes CYP3A4, 2C8, and 2E and undergoes glucuronidation by UGT2B7; evidence exists that tretinoin induces its own metabolism.1 Two of its metabolites, 4-oxo retinoic acid and 4-oxo trans retinoic acid glucuronide, have 33% of the pharmacological activity of the parent compound.1 The drug is excreted in the feces (31% within 6 days) and urine (63% within 72 hours).1 The effect of age, sex, race, renal impairment, and hepatic impairment on the pharmacokinetics of tretinoin is unknown.1
Additional Information
The American Society of Health-System Pharmacists, Inc. represents that the information provided in the accompanying monograph was formulated with a reasonable standard of care, and in conformity with professional standards in the field. Readers are advised that decisions regarding use of drugs are complex medical decisions requiring the independent, informed decision of an appropriate health care professional, and that the information contained in the monograph is provided for informational purposes only. The manufacturer's labeling should be consulted for more detailed information. The American Society of Health-System Pharmacists, Inc. does not endorse or recommend the use of any drug. The information contained in the monograph is not a substitute for medical care.
Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.
Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.
Routes | Dosage Forms | Strengths | Brand Names | Manufacturer |
|---|---|---|---|---|
Oral | Capsules | 10 mg* | Tretinoin Capsules |
* available from one or more manufacturer, distributor, and/or repackager by generic (nonproprietary) name
1. Par Pharmaceuticals. Tretinoin capsules prescribing information. Chestnut Ridge, NY; 2023 Mar.
2. Gillis JC, Goa KL. Tretinoin: a review of its pharmacodynamic and pharmacokinetic properties and use in the management of acute promyelocytic leukemia. Drugs . 1995; 50:897-923. [PubMed 8586032]
6. Tallman MS, Andersen JW, Schiffer CA et al. All-trans-retinoic acid in acute promyelocytic leukemia. N Engl J Med . 1997; 337:1021-8. [PubMed 9321529]
7. Fenaux P, Degos L. Differentiation therapy for acute promyelocytic leukemia. N Engl J Med . 1997; 337:1076-7. [PubMed 9321537]
8. Adult acute myeloid leukemia. From: PDQ. Physician data query (database). Bethesda, MD: National Cancer Institute; 2023 Jan 18.
9. Warrell RP Jr, De The H, Wang ZY et al. Acute promyelocytic leukemia. N Engl J Med . 1993; 329:177-89. [PubMed 8515790]
10. Chomienne C, Ballerini P, Balitrand N et al. All-trans retinoic acid in acute promyelocytic leukemias. II. In vitro studies: structure-function relationship. Blood . 1990; 76:1710-7. [PubMed 2224120]
12. Smith MA, Adamson PC, Balis FM et al. Phase I and pharmacokinetic evaluation of all- trans retinoic acid in pediatric patients with cancer. J Clin Oncol . 1992; 10:1666-73. [PubMed 1403049]
13. Childhood acute myeloid leukemia/other myeloid malignancies. From: PDQ. Physician data query (database). Bethesda, MD: National Cancer Institute; 2022 Aug 11.
15. Fenaux P, Le Deley MC, Castaigne S et al. Effect of all transretinoic acid in newly diagnosed acute promyelocytic leukemia: results of a multicenter randomized trial. Blood . 1993; 82:3241-9. [PubMed 8241496]
16. Anon. Drugs of choice for cancer. Treat Guidel Med Lett . 2003; 1:41-52.
20. Frankel SR, Eardley A, Lauwers G et al. The “retinoic acid syndrome” in acute promyelocytic leukemia. Ann Intern Med . 1992; 117:292-6. [PubMed 1637024]
29. Limentani SA, Pretell JO, Potter D et al. Bone marrow necrosis in two patients with acute promyelocytic leukemia during treatment with all-trans retinoic acid. Am J Hematol . 1994; 47:50-5. [PubMed 8042616]
37. Tallman MS, Andersen JW, Schiffer CA et al. All- trans retinoic acid in acute promyelocytic leukemia: long-term outcome and prognostic factor analysis from the North American Intergroup protocol. Blood . 2002; 100:4298-302. [PubMed 12393590]
38. Fenaux P, Chevret S, Guerci A et al. Long-term follow-up confirms the benefit of all-trans retinoic acid in acute promyelocytic leukemia. European APL group. Leukemia . 2000; 14:1371-7. [PubMed 10942231]
41. Lo-Coco F, Avvisati G, Vignetti M et al. Retinoic acid and arsenic trioxide for acute promyelocytic leukemia. N Engl J Med. 2013 Jul 11;369(2):111-21. [PubMed 23841729]
42. Muindi J, Frankel SR, Miller WH Jr et al. Continuous treatment with all-trans retinoic acid causes a progressive reduction in plasma drug concentrations: implications for relapse and retinoid “resistance” in patients with acute promyelocytic leukemia. Blood . 1992; 79:299-303. [PubMed 1309668]
43. Osman AEG, Anderson J, Churpek JE, et al. Treatment of Acute Promyelocytic Leukemia in Adults. ASCO. 2018; 14: 649-58.
47. Kutny MA, Alonzo TA, Abla, O et al. Assessment of Arsenic Trioxide and All-trans Retinoic Acid for the Treatment of Pediatric Acute Promyelocytic Leukemia. JAMA Oncol. 2022 Jan; 8(1): 1-9.
48. Conneely SE and Stevens AM. Advances in Pediatric Acute Promyelocytic Leukemia. Children. 2020 Feb.