Continuing Education Activity

Tretinoin is a valuable medication in treating mild, moderate, and severe acne that can be used topically or systemically. Tretinoin is also used systemically in the management of acute promyelocytic leukemia (APL). Tretinoin is a vitamin A derivate in the retinoids class of medications. This activity outlines and reviews the indications, actions, and contraindications of tretinoin as a valuable agent in treating acne vulgaris and APL management and therapy. This activity will highlight the mechanism of action, adverse event profile, and other key factors such as off-label uses, including some indications of APL, pre-malignant and malignant skin conditions, and other common skin conditions such as psoriasis, dosing of both oral and topical treatment options, monitoring of both topical and oral tretinoin use (i.e., with emphasis on reliable contraception) pertinent for members of the interprofessional team and healthcare team in the treatment of mild, moderate, severe acne and acute promyelocytic leukemia and related conditions.

Objectives:

• Explain the importance of monitoring for patients on tretinoin therapy, including target triglyceride and liver function concentrations.
• Summarize the risks associated with initiating tretinoin treatment along with key patient counseling points.
• Identify the most common adverse events associated with tretinoin treatment.
• Outline the importance of how collaboration and coordination among the interprofessional team can enhance patient care when dosing and monitoring tretinoin to improve patient outcomes for patients receiving topical (anti-acne and palliative for photoaging) and oral (antineoplastic) tretinoin.

Indications

Tretinoin is a generic name for a medication derivative of vitamin A (retinol), also commonly known as 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:
  • Fine facial wrinkles[2]
  • Facial skin roughness[2]
  • Facial mottled hyperpigmentation (i.e., 'liver spots')[2]

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(15;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]

FDA Off-Label Uses

• Acute promyelocytic leukemia (APL) 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 are 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 an 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 different brands. A commonly used topical tretinoin consisting 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 nursing infants have potentially serious adverse effects. 
• Dose for systemic treatment of acute promyelocytic leukemia (APL) -2 evenly divided doses of 45 mg/m2/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 it's 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 150 mg/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 twice daily. 

APL Treatment - Adult

• APL, relapsed or refractory
  • 22.5 mg/m2 PO bid
    • For induction treatment; discontinue 30 days after transmission or give up to 90 days; concomitant differentiation syndrome prophylaxis is recommended for patients with WBC >10,000
  • APL, newly diagnosed 
    • Induction treatment
      • 22.5 mg/m2 PO bid up to 60 days
      • For low-risk disease
      • Use with arsenic trioxide
      • Concomitant differentiation syndrome prophylaxis is recommended for patients with WBC >10,000
• Consolidation treatment 
  • 22.5 mg/m2 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
    • 22.5 mg/m2 PO bid
    • For induction treatment
    • Discontinue 30 days after transmission or give up to 90 days
    • Concomitant differentiation syndrome prophylaxis is 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 headaches, 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
• Hypertension
• Pseudotumor cerebri
• Renal tubular necrosis
• Hypercalcemia
• Gastrointestinal 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
• Liver function tests 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
• Hypertension
• 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. 

FDA Boxed 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, was observed with or without leukocytosis.
  • Death due to progressive hypoxemia and multiorgan failure.
  • Most commonly occurs during the first month of treatment; however, some cases have been 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.[36]
• 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.[37]
• Teratogen
  • There is an increased risk of severe fetal deformities with oral tretinoin.
  • Pregnant women or those of child-bearing age 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 less than 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 FDA boxed warning for topical tretinoin.[38]

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, great vessel abnormalities, a cleft palate, facial dysmorphia, and parathyroid hormone deficiency.[36]

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. 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.

In patients who lack genetic markers t(15;17) translocation, alternative treatment options should be considered.

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 formulation 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 individual's health. Asymptomatic, young patients without a personal or significant family history of dyslipidemia or diabetes mellitus require less frequent laboratory draws mentioned above.[39]

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 dependable forms of contraception while on oral tretinoin therapy for APL and one month following discontinuation of treatment; monitoring for pregnancy and contraception counseling repeated monthly while on medication.

Within one week before starting this medication, a 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 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 1000 mg of ingested tretinoin in a suicide attempt and developed nothing besides some non-bloody diarrhea, which received treatment with hydration and activated charcoal.[40]

Regarding isotretinoin use for acne treatment, triglyceride concentrations that rise to mild to moderate concentrations (300 to 500 mg/dL) do not necessitate a change in dose but instead are manageable with lifestyle modification. If the triglyceride concentrations 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.[41][42] Cessation of isotretinoin usually results in the resolution of abnormal triglyceride concentrations.

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 through a urine pregnancy test before eventual prescribing and use of tretinoin; this is 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, 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.[43]

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 the tretinoin drug label) when they 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. 

The healthcare team, e.g., physicians, nurses, pharmacists, etc., need to work together to ensure safe and effective pharmacotherapy with tretinoin (ATRA, isotretinoin) in their patients. [Level 5]