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.
Topical Tretinoin gel and cream FDA approved for:
Oral tretinoin is FDA approved for the following:
Brand names for oral retinoids include the following:
FDA Off-Label Uses
Interesting Topics Requiring Further Studies for Use
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.
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:
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.
For the treatment of APL, the administration is typical with a meal; capsules are not to be opened or crushed.
APL Treatment - Adult:
APL Treatment - Pediatric:
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.
Black Box Warnings:
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:
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:
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.
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.
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. 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.
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.
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.
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.
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