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Tretinoin


Tretinoin

Article Author:
Athina Yoham
Article Editor:
Damian Casadesus
Updated:
5/30/2020 2:37:10 PM
For CME on this topic:
Tretinoin CME
PubMed Link:
Tretinoin

Indications

Tretinoin is a generic name for a medication derivative of vitamin A (retinol), also commonly known as Retin-A and all-trans retinoic acid (ATRA). Tretinoin can be given systemically or topically for various indications.

FDA Indications

Topical Tretinoin gel and cream FDA approved for:

  • Topical application for treatment of acne vulgaris [1]
  • Adjunctive palliative treatment of photoaging [2]:
    • Fine facial wrinkles
    • Facial skin roughness
    • Facial mottled hyperpigmentation (i.e., 'liver spots')

Oral tretinoin is FDA approved for the following:

  • In acute promyelocytic leukemia (APL) patients with refractory disease for remission induction who have previously relapsed from anthracycline chemotherapy or those who have a contraindication to anthracycline-based therapy [3]
  • Presence of translocations on chromosomes 15 and 17 t(l5;17) demonstrating French-American-British (FAB) classification M3 (including the M3 variant) [4]
  • Patients who are refractory to or have had a relapse from or have contraindications to anthracycline chemotherapy with the presence of the PML/RARa gene [5][6]
  • Moderate to severe and cystic acne [7][8][9]

Brand names for oral retinoids include the following:

  • Vesanoid (FDA discontinued, not for safety or efficacy reasons, in 2016)
  • Isotretinoin (Accutane) 

FDA Off-Label Uses

  • Acute promyelocytic leukemia patients during the consolidation phase of treatment with combination chemotherapy[10][11] 
    • In adults with APL, tretinoin, in combination with arsenic trioxide, supports tretinoin as a part of the consolidation phase of treatment [12]
  • Acute promyelocytic leukemia patients during the maintenance phase of therapy in intermediate- and high-risk patients on combination chemotherapy [13][14]
    • Combination chemotherapy in pediatrics with APL supports tretinoin use as part of the maintenance phase of treatment [15]
  • Treatment of pre-malignant and malignant skin conditions in high-risk patients diagnosed with actinic keratosis, basal, and squamous cell carcinoma [16][17][18][19]
  • actinic lentigines [20]
  • Psoriasis [21]
  • Ichthyosis congenita, ichthyosis vulgaris, lamellar ichthyosis [22]
  • Cutaneous warts - flat subtype
  • Keratosis follicularis (Darier disease)
  • Epidermolytic hyperkeratosis/Keratinopathic ichthyoses
  • Verruca vulgaris [23]
  • Early stretch marks [24]

Interesting Topics Requiring Further Studies for Use

  • Adult T-cell leukemia/lymphoma [25]
  • The combination of minoxidil with topical tretinoin may show increased hair growth due to increased penetrating ability.[26]

Mechanism of Action

The exact mechanism by which topical tretinoin functions is not completely understood, but current evidence suggests mediation through binding of retinoic acid receptors (RARs) alpha, beta, and gamma along with retinoid X receptors (RXRs) by blocking inflammatory mediators. By doing this, the production of procollagen increases to augment collagen type I and III formations.[27]

RAR-gamma effects are associated with mucocutaneous tissues and bone. Tretinoin's effectiveness as acne medication is because of its ability to modify the abnormal follicular formation that comes from excessive keratinization of epithelial cells. Tretinoin promotes cornified cell detachment and enhances shedding. Tretinoin increases mitotic activity, thereby increasing loosely-adherent corneocytes turnover. By doing so, the comedo contents can be expelled, with a reduction of microcomedo precursor lesion of acne vulgaris.

RAR-alpha and -beta has presented in associated with APL and squamous cell malignancies, respectively.

Retinoic acid binds to retinoic acid receptor alpha, a member of the steroid-thyroid hormone receptor superfamily. RARα forms heterodimers with RXR and binds to retinoic acid response elements that are present in genes involved in cell differentiation.

Again, like topical tretinoin, the exact mechanism of systemic tretinoin is unclear, but is hypothesized to include the following:

  1. Apoptosis and degradation of PML-RAR alpha protein occur by both caspase-mediated cleavage and proteasome-dependent degradation; 
  2. PML-RAR alpha conversion from a transcription repressor (CoR) to an activator (CoA) 
  3. Coordinated gene expression induced by ATRA committed to the differentiation of APL cells.[28]

Systemic Tretinoin produces complete remission by inducing an initial primitive promyelocyte maturation followed by bone marrow and peripheral blood repopulation occurring by normal, polyclonal hematopoietic cells.

Administration

Topical Tretinoin:

  • Topical administration of tretinoin includes applying a thin layer once daily, before bedtime, to the skin where lesions are present. Patients need to keep the medication away from eyes, mouth, nasal creases, and mucous membranes.
  • Dosages vary amongst brands. A commonly used topical tretinoin consists of 0.1%, 0.08%, and 0.04% dosages, should be applied once daily, during the evening, to the skin where acne lesions appear to be present, with enough to cover the entire affected surface in a thin layer.

Oral Tretinoin: 

For the treatment of APL, the administration is typical with a meal; capsules are not to be opened or crushed.

  • Tretinoin has also been sublingually administered by squeezing the contents from the capsule beneath the tongue as well as through enteric and nasogastric tubes.[29][30][31]
  • ATRA must be used in combination with other medications (i.e., arsenic compounds) since remissions induced by ATRA monotherapy are short-lived, lasting only about 3.5 months.[32]
  • Nursing mothers should discontinue nursing before starting oral tretinoin, as there are potentially serious adverse effects in nursing infants. 
  • Dose for systemic treatment of acute promyelocytic leukemia (APL) -2 evenly divided doses of 45 mg/m^2/day administered until complete remission.
  • Patients should take a missed dose as soon as possible unless it is time for the next dose, at which point its recommended to skip the missed dose and proceed with the regular schedule of medication; patients should not take a doubled dose.

Acne Treatment:

  • The recommendation is to take isotretinoin with food (especially with high-fat meals), as this will increase absorption. 
  • A lipid encapsulation of isotretinoin exists and demonstrates increased bioavailability even if the patient has fasted. This form of the medication can be dosed twice daily regardless if fasted or not.[33]
  • The treatment goal's cumulative dose is between 120 to 150mg/kg and is achievable within 20 to 24 weeks.[34]
  • The initial dose is 0.5 mg/kg/day during the first month, followed by an increase to 1 mg/kg/day and can be given once or divided into twice daily. 

APL Treatment - Adult:

  • APL, relapsed or refractory
    • 22.5 mg/m^2 PO bid
      • For induction treatment; discontinue 30 days after transmission or give up to 90 days; concomitant differentiation syndrome prophylaxis recommended for patients with WBC >10,000
    • APL, newly diagnosed 
      • Induction treatment
        • 22.5mg/m^2 PO bid up to 60 days
        • For low-risk disease
        • Use with arsenic trioxide
        • Concomitant differentiation syndrome prophylaxis recommended for patients with WBC >10,000
  • Consolidation treatment 
    • 22.5mg/m^2 PO bid on days 1 to 14, and 29 to 42 of a 56-day cycle x 3 cycles, then on days 1 to 14 or 56-day cycle for cycle 4
    • For low-risk disease
    • Use with arsenic trioxide

APL Treatment - Pediatric:

  • APL, relapsed or refractory
    • 1-year-old and older
      • 22.5mg/m^2 PO bid
      • For induction treatment
      • Discontinue 30 days after transmission or give up to 90 days
      • Concomitant differentiation syndrome prophylaxis recommended for patients with WBC >10,000

Adverse Effects

According to the FDA drug labeled guidelines, the most common adverse effects in topically administered tretinoin are the following: pruritus, skin pain, skin/subcutaneous irritation, erythema, and pharyngitis.

According to the FDA drug labeled guidelines of orally administered tretinoin, most patients will experience drug-related toxicity, such as headache, weakness, fever, and fatigue. Interruption of therapy is rarely required as these adverse effects are rarely permanent or irreversible.

Serious Reactions:

  • RA-APL syndrome
  • Cardiovascular disorders
  • Arrhythmias
  • HTN
  • Pseudotumor cerebri
  • Renal tubular necrosis
  • Hypercalcemia
  • GI disorders
  • Pancreatitis
  • Hallucinations
  • Depression
  • Myositis
  • Erythema nodosum
  • Genital ulcer
  • Vision changes
  • Hearing loss
  • Thrombosis
  • Thrombocytosis
  • Vasculitis

Common Reactions:

  • Headache
  • Fever
  • Edema
  • Bone pain
  • Xeroderma
  • Dry mucous membranes
  • Hyperlipidemia
  • LFTs elevated
  • Dyspnea
  • Nausea/vomiting
  • Abdominal distention/pain
  • Neurologic disturbances
  • Weight changes
  • Chest discomfort
  • Cardiovascular disorders
  • Mucositis
  • Vision changes
  • GI disorders
  • Anxiety/agitation
  • RA-APL syndrome
  • Otalgia
  • Diarrhea
  • Arrhythmia
  • Flushing
  • Pruritus
  • Diaphoresis
  • Dizziness
  • Constipation
  • Paresthesia
  • Alopecia
  • Myalgia
  • Hypotension
  • Insomnia
  • Depression
  • HTN
  • Confusion
  • Dysuria
  • Fluid imbalance
  • Hallucinations
  • CNS depression
  • Renal tubular necrosis
  • Prostate hypertrophy
  • Photosensitivity
  • Rash
  • Ocular abnormalities
  • Genital ulceration [35]

Retinoid Toxicity:

  • Frequently reported adverse effects most are similar to vitamin A toxicity and include the following: headache, nausea/vomiting, bone pain mucositis, rash, fever, pruritus, skin/mucous membrane dryness, visual disturbances, increased sweating, ocular disorders, alopecia, skin changes, bone inflammation, changed visual acuity, visual field defects. Do not administer tretinoin with vitamin A due to symptoms of syndrome of hypervitaminosis A.
  • Pseudotumor cerebri/intracranial hypertension may also occur, especially if given in combination with other medications that increase intracranial hypertension. 

Black Box Warnings: 

  • Retinoic Acid (RA-APL) Syndrome:
    • Retinoic Acid (RA-APL) Syndrome: acute respiratory distress, dyspnea, fever, weight gain, pleural and pericardial effusions, edema, pulmonary infiltrates on chest X-ray and multiorgan failure. (especially renal and hepatic)
    • Myocardial contractility impairment, along with episodic hypotension, observed with or without leukocytosis.
    • Death due to progressive hypoxemia and multiorgan failure.
    • Most commonly occurs during the first month of treatment; however, there have been some cases reported after the first dose.
    • Management: patients should receive high-dose steroids if there is any clinical suspicion as a means to reduce morbidity and mortality related to the syndrome.
  • Leukocytosis
    • There is an increased risk of devastating complications in 40% of patients if the baseline white blood cells (WBC) >5000; high dose steroids should start immediately if retinoic acid-APL syndrome is suspected; addition of chemotherapy may decrease the occurrence of retinoic acid-APL syndrome if WBC baseline is >5000 or if there is a baseline leukopenia with a rapid increase in WBC count on tretinoin treatment.
  • Teratogen
    • There is an increased risk of severe fetal deformities with oral tretinoin.
    • Pregnant women or those of child-bearing are at an increased potential of fetal risk and contraception failure risk.
    • Patients must be on two (2) dependable forms of contraception throughout treatment, followed by one (1) month after discontinuation of tretinoin.
    • Patients must have a negative pregnancy test < one (1) week before starting tretinoin, or if unable to delay treatment, may start with two forms of contraception, as previously mentioned.
    • Pregnancy testing and counseling on contraception should continue every month during treatment. There is no black box warning for topical tretinoin. 

Interaction Characteristics:

  • CYP3A4 substrate
  • Ototoxicity
  • Photosensitivity
  • Thrombogenic effects

Contraindications

According to FDA labeled drug guidelines, contraindications include patients with evidence of hypersensitivity to tretinoin or any of its components.

Pregnancy category: C (US FDA), D (AU TGA)

If administered during pregnancy, there is a significantly high risk of fetal loss and malformations, including the musculoskeletal system, thymus, central nervous system, external ear, eye, and great vessel abnormalities, as well as a cleft palate, facial dysmorphia, and parathyroid hormone deficiency.

In all females undergoing tretinoin therapy, effective contraception must be used throughout treatment then continued for one month following discontinuation. Even if the patient has a history of infertility or menopause contraception must be used, the patient has undergone a hysterectomy. Two (2) reliable forms of contraception are the recommendation to be used simultaneously, even in patients who have a history of infertility or menopause. Abstinence may also be a chosen method of contraception. In patients who have undergone hysterectomy do not need a form of contraception. Discussion of continuing or terminating the pregnancy should occur between patient and physician if there is contraception during treatment.

Alternative treatment options should be considered in patients who lack genetic markers t(15;17) translocation.

Oral tretinoin is also contraindicated during breastfeeding, pregnancy during the first trimester (caution if pregnancy in the second or third trimester), caution in females of reproductive potential, caution in pediatric patients. 

 Topical tretinoin contraindications:

  • Hypersensitivity to the drug, drug class or drug components
  • Caution if hypersensitivity to fish products (0.05% gel, 0.05% lotion forms)
  • Caution if sunburn
  • Caution if photosensitivity
  • Caution if eczema
  • Caution if pregnancy 1st trimester

Monitoring

Patients with acute promyelocytic leukemia (APL) should be under strict supervision by an APL experienced physician, facility as well as supportive services to monitor drug tolerance and toxicity properly) as there can be severe adverse reactions to taking oral tretinoin.

Topical Use Monitoring

Monitor for hypersensitivity, photosensitivity, and any other skin irritation or allergies. 

Systemic Use Monitoring

Monitor APL for side effects (including major, life-threatening side effects such as retinoic acid (RA-APL) syndrome and leukocytosis) and response to treatment. 

Monthly follow-ups visits are required. Complete blood cell count (CBC) with differential, lipid panel, liver function tests (LFTs), PT/INR need frequent checking. Fasting lipid checks are recommended weekly or biweekly to monitor lipid response, but this is relative to the health of the individual. Asymptomatic, young patients without a personal or significant family history of dyslipidemia or diabetes require less frequent laboratory draws mentioned above.

Clinical assessment of the following areas is necessary to assess for treatment response and adverse effects:

  • Perceived worsening/improvement of acne
  • Muscle or bone pain
  • Dryness of skin or mucous membranes
  • Headaches
  • Mood changes, depression symptoms, or suicidality
  • Nosebleeds
  • Vision changes
  • Abdominal pain
  • Bowel symptoms

Women of Childbearing Age

Monthly follow-up visits are typical to fulfill the requirements of the iPLEDGE program (a program to eliminate fetal exposure to isotretinoin).

Due to tretinoin teratogenicity, women of childbearing potential are recommended the use two (2) dependable forms of contraception while on oral tretinoin therapy for APL and one (1) month following discontinuation of treatment; monitoring for pregnancy and contraception counseling repeated monthly while on medication.

Within one (1) week before starting this medication, serum or urine pregnancy test should be collected and tested with a sensitivity of at least 50 mIU/mL within one week.

Delay of treatment should occur until obtaining a negative pregnancy result. If treatment cannot be delayed (in the case of APL treatment), the patient should use two (2) forms of contraception.

Toxicity

Symptoms of overdose with topical tretinoin use may include excessive redness, peeling, and discomfort.

Symptoms of overdose with oral tretinoin include the following cracked and sore lips, redness, headache, flushing, stomach pain, dizziness, loss of coordination.

Case Report: 39-year-old overdosed on 1000mg of tretinoin in a suicide attempt and developed nothing besides some non-bloody diarrhea, which received treatment with hydration and activated charcoal.[36]

In regards to isotretinoin use for acne treatment, triglyceride levels that rise to a mild to a moderate level (300 to 500 mg/dL) do not necessitate a change in dose but instead are manageable with lifestyle modification. If the triglyceride levels rise severely (500 and 800 mg/dL), dose reduction of isotretinoin may be warranted with the addition of a lipid-lowering agent. If severe hypertriglyceridemia occurs (>800 mg/dL), cessation may be necessary due to the risk of acute pancreatitis.[37][38] Cessation of isotretinoin usually results in the resolution of abnormal triglyceride levels. 

If liver enzymes increase to more than three times over baseline, the recommendation is to discontinue isotretinoin. 

If necessary, tretinoin can be stopped abruptly without tapering.

Enhancing Healthcare Team Outcomes

ATRA initiation should be immediate once APL is suspected, especially if the diagnosis supports genetic or molecular data. If molecular or genetic data do not support the diagnosis, then ATRA should no longer be given. In patients with low white blood cell (WBC) count (< or = 10x10^9/L), antileukemic agents or chemotherapy may be delayed until a genetic diagnosis is confirmed. In patients with leukocytosis (>10x10^9/L), chemotherapy should start without delay irrespective of pending diagnostic studies.[5]

Before tretinoin prescription and eventual use, pregnancy status should be negative by way of a urine pregnancy test. Due to the routine use of urine pregnancy tests, complications such as fetal malformations, and risk of fetal loss.   

It is still unknown as to whether oral tretinoin appears in breast milk, but because of potentially serious adverse effects that may take place in breastfed infants, breastfeeding should be strongly discouraged. 

Swift identification of RA-APL syndrome, which is an unpredictable but frequent complication, includes symptoms such as dyspnea, fever, weight gain, pleural and pericardial effusions, acute respiratory distress, pulmonary infiltrates on chest x-ray, edema, and multi-organ failure. After resolved, treatment may continue.[39]

Sunscreen is a requirement for all patients on tretinoins, as there is an increased risk of photosensitivity. Encourage avoidance of exposure to sunlight or tanning beds. Patients should be encouraged to wear protective clothing and use sunscreen (recommended SPF 15 or higher according to tretinoin drug label) when you are outdoors, even on a cloudy day.

Advise patients to avoid using skin products that may cause skin irritation and dryness, such as harsh soaps, shampoos, hair coloring chemicals, hair removers, or skin products that contain alcohol, spices, astringents, or lime. 


References

[1] Rathi SK, Acne vulgaris treatment : the current scenario. Indian journal of dermatology. 2011 Jan;     [PubMed PMID: 21572783]
[2] Mukherjee S,Date A,Patravale V,Korting HC,Roeder A,Weindl G, Retinoids in the treatment of skin aging: an overview of clinical efficacy and safety. Clinical interventions in aging. 2006;     [PubMed PMID: 18046911]
[3] Damery E,Solimando DA Jr,Waddell JA, Arsenic Trioxide and Tretinoin (AsO/ATRA) for Acute Promyelocytic Leukemia (APL). Hospital pharmacy. 2016 Sep;     [PubMed PMID: 27698500]
[4] Chen Z,Wang Y,Wang W,Gong J,Xue Y, All-trans retinoic acid as a single agent induces complete remission in a patient with acute leukemia of M2a subtype. Chinese medical journal. 2002 Jan;     [PubMed PMID: 11930660]
[5] Sanz MA,Fenaux P,Tallman MS,Estey EH,Löwenberg B,Naoe T,Lengfelder E,Döhner H,Burnett AK,Chen SJ,Mathews V,Iland H,Rego E,Kantarjian H,Adès L,Avvisati G,Montesinos P,Platzbecker U,Ravandi F,Russell NH,Lo-Coco F, Management of acute promyelocytic leukemia: updated recommendations from an expert panel of the European LeukemiaNet. Blood. 2019 Apr 11;     [PubMed PMID: 30803991]
[6] McCulloch D,Brown C,Iland H, Retinoic acid and arsenic trioxide in the treatment of acute promyelocytic leukemia: current perspectives. OncoTargets and therapy. 2017;     [PubMed PMID: 28352191]
[7] DiGiovanna JJ,Peck GL, Oral synthetic retinoid treatment in children. Pediatric dermatology. 1983 Jul     [PubMed PMID: 6238291]
[8] Layton A, The use of isotretinoin in acne. Dermato-endocrinology. 2009 May     [PubMed PMID: 20436884]
[9] Leyden JJ,Del Rosso JQ,Baum EW, The use of isotretinoin in the treatment of acne vulgaris: clinical considerations and future directions. The Journal of clinical and aesthetic dermatology. 2014 Feb     [PubMed PMID: 24688620]
[10] Lo-Coco F,Avvisati G,Vignetti M,Breccia M,Gallo E,Rambaldi A,Paoloni F,Fioritoni G,Ferrara F,Specchia G,Cimino G,Diverio D,Borlenghi E,Martinelli G,Di Raimondo F,Di Bona E,Fazi P,Peta A,Bosi A,Carella AM,Fabbiano F,Pogliani EM,Petti MC,Amadori S,Mandelli F, Front-line treatment of acute promyelocytic leukemia with AIDA induction followed by risk-adapted consolidation for adults younger than 61 years: results of the AIDA-2000 trial of the GIMEMA Group. Blood. 2010 Oct 28;     [PubMed PMID: 20644121]
[11] Sanz MA,Montesinos P,Rayón C,Holowiecka A,de la Serna J,Milone G,de Lisa E,Brunet S,Rubio V,Ribera JM,Rivas C,Krsnik I,Bergua J,González J,Díaz-Mediavilla J,Rojas R,Manso F,Ossenkoppele G,González JD,Lowenberg B, Risk-adapted treatment of acute promyelocytic leukemia based on all-trans retinoic acid and anthracycline with addition of cytarabine in consolidation therapy for high-risk patients: further improvements in treatment outcome. Blood. 2010 Jun 24;     [PubMed PMID: 20393132]
[12] Ravandi F,Estey E,Jones D,Faderl S,O'Brien S,Fiorentino J,Pierce S,Blamble D,Estrov Z,Wierda W,Ferrajoli A,Verstovsek S,Garcia-Manero G,Cortes J,Kantarjian H, Effective treatment of acute promyelocytic leukemia with all-trans-retinoic acid, arsenic trioxide, and gemtuzumab ozogamicin. Journal of clinical oncology : official journal of the American Society of Clinical Oncology. 2009 Feb 1;     [PubMed PMID: 19075265]
[13] Sanz MA,Martín G,González M,León A,Rayón C,Rivas C,Colomer D,Amutio E,Capote FJ,Milone GA,De La Serna J,Román J,Barragán E,Bergua J,Escoda L,Parody R,Negri S,Calasanz MJ,Bolufer P, Risk-adapted treatment of acute promyelocytic leukemia with all-trans-retinoic acid and anthracycline monochemotherapy: a multicenter study by the PETHEMA group. Blood. 2004 Feb 15;     [PubMed PMID: 14576047]
[14] Powell BL,Moser B,Stock W,Gallagher RE,Willman CL,Stone RM,Rowe JM,Coutre S,Feusner JH,Gregory J,Couban S,Appelbaum FR,Tallman MS,Larson RA, Arsenic trioxide improves event-free and overall survival for adults with acute promyelocytic leukemia: North American Leukemia Intergroup Study C9710. Blood. 2010 Nov 11;     [PubMed PMID: 20705755]
[15] Ortega JJ,Madero L,Martín G,Verdeguer A,García P,Parody R,Fuster J,Molines A,Novo A,Debén G,Rodríguez A,Conde E,de la Serna J,Allegue MJ,Capote FJ,González JD,Bolufer P,González M,Sanz MA, Treatment with all-trans retinoic acid and anthracycline monochemotherapy for children with acute promyelocytic leukemia: a multicenter study by the PETHEMA Group. Journal of clinical oncology : official journal of the American Society of Clinical Oncology. 2005 Oct 20;     [PubMed PMID: 16234524]
[16] Lever L,Marks R, Topical retinoid treatment for skin cancer: a review. Skin pharmacology : the official journal of the Skin Pharmacology Society. 1991;     [PubMed PMID: 1768423]
[17] Ianhez M,Fleury LF Jr,Miot HA,Bagatin E, Retinoids for prevention and treatment of actinic keratosis. Anais brasileiros de dermatologia. 2013 Jul-Aug;     [PubMed PMID: 24068130]
[18] Cohen JL, Actinic keratosis treatment as a key component of preventive strategies for nonmelanoma skin cancer. The Journal of clinical and aesthetic dermatology. 2010 Jun;     [PubMed PMID: 20725550]
[19] Peck GL, Topical tretinoin in actinic keratosis and basal cell carcinoma. Journal of the American Academy of Dermatology. 1986 Oct;     [PubMed PMID: 3534022]
[20] Goldfarb MT,Ellis CN,Voorhees JJ, Topical tretinoin: its use in daily practice to reverse photoageing. The British journal of dermatology. 1990 Apr;     [PubMed PMID: 2186791]
[21] Huang P,Chandra V,Rastinejad F, Retinoic acid actions through mammalian nuclear receptors. Chemical reviews. 2014 Jan 8;     [PubMed PMID: 24308533]
[22] Digiovanna JJ,Mauro T,Milstone LM,Schmuth M,Toro JR, Systemic retinoids in the management of ichthyoses and related skin types. Dermatologic therapy. 2013 Jan-Feb;     [PubMed PMID: 23384018]
[23] Gaston A,Garry RF, Topical vitamin A treatment of recalcitrant common warts. Virology journal. 2012 Jan 17;     [PubMed PMID: 22251397]
[24]     [PubMed PMID: 8624148]
[25] Maeda Y,Yamaguchi T,Hijikata Y,Tanaka M,Hirase C,Takai S,Morita Y,Sano T,Miyatake J,Tatsumi Y,Kanamaru A, Clinical efficacy of all-trans retinoic acid for treating adult T cell leukemia. Journal of cancer research and clinical oncology. 2008 Jun;     [PubMed PMID: 18008086]
[26]     [PubMed PMID: 18793935]
[27] Kang S, The mechanism of action of topical retinoids. Cutis. 2005 Feb;     [PubMed PMID: 15773538]
[28] Wang ZY, Mechanism of action of all-trans retinoic acid and arsenic trioxide in the treatment of acute promyelocytic leukemia. Gan to kagaku ryoho. Cancer     [PubMed PMID: 11890109]
[29] Kueh YK,Liew PP,Ho PC,Wu TS, Sublingual administration of all-trans-retinoic acid to a comatose patient with acute promyelocytic leukemia. The Annals of pharmacotherapy. 1999 Apr;     [PubMed PMID: 10332546]
[30] Okumura LM,Baruel Okumura PC,Veroneze C, Administration of all-trans retinoic acid through enteral tubes in acute promyelocytic leukemia: the handling of cytotoxic agents and clinical benefits. Revista brasileira de hematologia e hemoterapia. 2017 Jan - Mar;     [PubMed PMID: 28270357]
[31] Abla O,Ribeiro RC, How I treat children and adolescents with acute promyelocytic leukaemia. British journal of haematology. 2014 Jan;     [PubMed PMID: 24117210]
[32] Wang ZY,Chen Z, Differentiation and apoptosis induction therapy in acute promyelocytic leukaemia. The Lancet. Oncology. 2000 Oct;     [PubMed PMID: 11905660]
[33]     [PubMed PMID: 23953888]
[34]     [PubMed PMID: 26897386]
[35] Fukuno K,Tsurumi H,Goto H,Oyama M,Tanabashi S,Moriwaki H, Genital ulcers during treatment with ALL-trans retinoic acid for acute promyelocytic leukemia. Leukemia     [PubMed PMID: 14738157]
[36] Su-Yin A,Wong J,Wiegand T,Olson K, Tretinoin overdose: a first case report. Journal of medical toxicology : official journal of the American College of Medical Toxicology. 2009 Jun;     [PubMed PMID: 19415591]
[37]     [PubMed PMID: 27893168]
[38]     [PubMed PMID: 1449157]
[39] Patatanian E,Thompson DF, Retinoic acid syndrome: a review. Journal of clinical pharmacy and therapeutics. 2008 Aug;     [PubMed PMID: 18613850]