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]

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.

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

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

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