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| DESCRIPCION La tretinoína, conocida como ácido retinoico todo-trans, es un derivado natural de la vitamina A. Al igual que esta vitamina, los retinoides son factores importantes de la regulación celular, tanto en lo que se refiere a la reproducción como a su proliferación y diferenciación. Sin embargo, a diferencia de la vitamina A, retinoides no se convierten en rodopsina , que es necesaria para la visión nocturna . La tretinoin tópica está indicado en el tratamiento del acné moderado (por ejemplo, gradosIi-III) y de la piel fotodañada . Tretinoin tópico también se ha utilizado en el tratamiento sintomático de los trastornos de la queratinización como follicularis de la ictiosis y queratosis. La tretinoína representa una nueva clase de medicamentos contra el cáncer al actuar sobre los factores de diferenciación. La tretinoina oral se utiliza en el tratamiento de la leucemia promielocítica aguda (APL) y en el tratamiento del sarcoma de Kaposi. En el tratamiento de la APL , tretinoína ofrece que un tratamiento menos tóxico que la quimioterapia convencional. Mecanismo de acción : los retinoides son mediadores intracrinos y paracrinos de la diferenciación y la proliferación celular, la apoptosis (muerte celular programada) y la reproducción. Las células regulan la formación de isómeros retinoides específicos dependiendo de la acción celular necesaria. Los numerosos efectos de retinoides reflejan la compleja biología de los receptores nucleares que median la actividad retinoide. Los receptores de los retinoides se dividen en los receptores X retinoides (RXRs) y los receptores del ácido retinoico (RARs); ambos tipos pueden ser divididos en 3 subtipos : alfa , beta y gamma. Estos subtipos de receptores se dividen en muchas isoformas. Los receptores de retinoides son estructuralmente similares pero tienen diferentes afinidades para los diferentes tipos de retinoides y su distribución varía en todo el cuerpo dando por resultado una amplia gama de acciones. La tretinoína se une a los tres RARs, pero no al RXRs excepto en concentraciones muy altas. Los receptores RAR-alfa y beta RAR se han asociado con el desarrollo de la leucemia promielocítica aguda y al cáncer de células escamosas respectivamente. El RAR-gamma se asocia a los efectos de los retinoides en rel hueso y tejidos mucocutáneos. Spanish English Trastornos de la piel : Atando a RARs , tretinoína modifica la expresión génica , síntesis de proteínas posteriores y crecimiento de la célula epitelial y la diferenciación . No se ha establecido si los efectos clínicos de la tretinoína son mediados a través de la activación de RARs , otros mecanismos como la irritación o ambos . Tretinoína parece prevenir cohesión celular caliente y aumentar el recambio celular epidérmico y actividad mitótica . Posteriormente , en pacientes con acné , se produce la expulsión de los comedones existentes , y se evita la formación de nuevos comedones por desprendimiento y expulsión de células córneas del folículo . Tretinoína reduce las capas celulares del estrato córneo . La bacteria implicada en el acné , la Propionibacterium acnes y la producción de sebo se ven afectados . Una acción adicional de tretinoína puede implicar la inhibición de la queratinización , que explicaría su eficacia en el tratamiento de trastornos de la queratinización . Indications...Dosage ara el tratamiento de vulgaris de acné : dosificación tópica (Retin-A® crema , gel o gel de microesferas ; Crema de Altinac™ ; Avita™ gel o crema aprobado por la FDA): adultos , adolescentes y niños > 12 años : aplicar una fina capa a las áreas afectadas una vez al día al acostarse . Hasta seis semanas de la terapia puede ser necesaria antes de que la mejora es evidente . Esto puede estar seguido de una pauta de dosificación reducida . ímites de dosis máxima : CONTRAINDICACIONES
Tretinoin should be used cautiously in patients who experience retinoid hypersensitivity reactions to vitamin A or other retinoids because cross-sensitivity between agents is possible. True contact allergy to tretinoin is rare. Topical tretinoin is classified as FDA pregnancy risk category C and oral tretinoin as FDA pregnancy risk category D. Teratogenic and embryotoxic effects have been demonstrated in animals receiving oral tretinoin or large doses (i.e., many times greater than the normal human dose) of topical tretinoin. Adequate and well-controlled trials have not been performed in humans, but increased spontaneous abortions and major human fetal abnormalities have occurred when pregnant women received other retinoids. There have been 30 case reports of temporally-associated, congenital malformations during 25 years of clinical use of Retin-A®. The significance of these spontaneous reports in terms of risk to the fetus is not known. Avoid use of topical tretinoin over large areas of skin or for prolonged periods. The benefit-risk profile should be considered before prescribing. There is a high risk of birth defects if oral tretinoin is administered during pregnancy. Females of childbearing potential must use two reliable forms of contraception simultaneously during oral tretinoin therapy and for one month following discontinuation of therapy, unless abstinence is the chosen method. Contraception must be used even when there is a history of infertility or menopause, unless a hysterectomy has been performed.
Within one week of beginning tretinoin oral therapy, the patient should have a negative pregnancy test; if possible, treatment with tretinoin should be delayed until the results of the pregnancy test are known. Pregnancy testing and counseling should occur monthly during oral tretinoin therapy. It is unknown whether tretinoin is distributed into breast milk. Breast-feeding should be discontinued in women receiving oral tretinoin. Topical use of tretinoin for photoaging should be discontinued in nursing mothers until after completion of the nursing period. Topical tretinoin is flammable; do not use near heat, open flame, or while smoking. Topical tretinoin should be avoided, if possible, in patients with eczema because severe irritation of eczematous skin is likely. Treatment with topical tretinoin should be postponed until sunburn has resolved to avoid exacerbation of the irritation, inflammation, and dryness associated with sunburned skin. Patients with a skin photosensitivity disorder should be closely evaluated prior to receiving topical tretinoin therapy. If sun exposure cannot be avoided during topical tretinoin therapy, sunscreen products and physical sun blocks (protective clothing, hats) are recommended for protection of treated areas. Sunlight (UV) exposure potentiates the inflammatory effects of tretinoin. Patients who may have considerable sun exposure due to their occupation and those patients with inherent sensitivity to sunlight should exercise particular caution when using topical tretinoin. Tretinoin cream, gel, and liquid are for external use only. Avoid ocular exposure, including eyelids, and contact with the mouth. If eye contact occurs, rinse thoroughly with large amounts of water. Apply only to affected areas; accidental exposure to unaffected skin may cause irritation. Oral tretinoin should not be administered to patients who have paraben hypersensitivity. Paraben is used as a preservative in the gelatin capsule. In the treatment of acute promyelocytic leukemia, high initial leukocyte counts or rapidly increasing leukocyte counts (i.e., leukocytosis) during treatment may be predictive of retinoic acid-acute promyelocytic leukemia (RA-APL) syndrome (see Adverse Reactions). Some clinicians routinely add chemotherapy to oral tretinoin therapy when patients present with a WBC count > 5000/mm3 or in the case of a rapid increase in WBC count in leukopenic patients at the start of treatment. Consideration could be given to adding chemotherapy (usually cytarabine and an anthracycline, if not contraindicated) to tretinoin therapy on day 1 or 2 for patients presenting with a WBC count > 5000/mm3 or immediately, for patients presenting with a WBC count of < 5000/mm3, if the WBC count reaches >= 6000/mm3 by day 5, >= 10,000/mm3 by day 10, or >= 15,000/mm3 by day 28. The majority of patients do not require discontinuation of tretinoin therapy during RA-APL syndrome. Close monitoring of WBC and clinical signs during oral tretinoin therapy will aid in the proper management of this syndrome. Elevated hepatic enzymes has been reported in patients receiving oral tretinoin. Patients with hepatic disease could be more prone to developing this condition. It is recommended that if the serum hepatic enzyme levels are greater than 5 times the upper limit of normal, consideration should be given to temporarily discontinuing oral tretinoin therapy. Children are prone to developing severe headache and pseudotumor cerebri while receiving oral tretinoin. For relief, some patients may require treatment with analgesics or lumbar puncture. The safety and efficacy of oral tretinoin in infants have not been established. Oral tretinoin should be used cautiously in patients with hyperlipidemia. Hypercholesterolemia and/or hypertriglyceridemia occurs in as many as 60% of patients receiving oral tretinoin. Monitor the lipid profile while patients are receiving oral tretinoin. INTERACCIONES s Keratolytic agents or products that contain keratolytic agents, such as benzoyl peroxide, resorcinol, sulfur, salicylic acid, lactic acid, and medicated or abrasive soaps or cleansers, can potentiate the skin irritation caused by tretinoin. Concurrent application of these agents on areas treated with tretinoin should be avoided. Similarly, products that contain alcohol, lime, menthol, spices, or perfumes can further dry and irritate the skin and should not be used with tretinoin. Concurrent oral tretinoin therapy with drugs that affect the hepatic cytochrome (CYP) P450 enzyme system can result in significant increases or decreases in serum tretinoin levels. In patients who had received oral tretinoin daily for 4 consecutive weeks, a 72% increase in tretinoin plasma concentrations was observed when ketoconazole was given 1 hour before the tretinoin dose. No specific studies have been done with oral tretinoin and other inducers or inhibitors of CYP450 isoenzymes, however, patients should be closely monitored for decreased clinical effects or tretinoin toxicity while receiving concomitant therapy. Patients should avoid supplementation with vitamin A or treatment with other retinoids during treatment with systemic or topical tretinoin therapy to avoid potential additive toxic effects. Cholestyramine or colestipol can bind with and possibly decrease the oral absorption of oral tretinoin. Retinoids, vitamin A analogs, may increase the effects of photosensitizing agents used during photodynamic therapy. Administer with caution to patients who are also taking drugs known to be photosensitizers such as quinolones (particularly sparfloxacin), phenothiazines, sulfonamides, sulfonylureas, tetracyclines, and thiazide diuretics. Topical tretinoin therapy is not recommended in patients receiving other agents that cause photosensitivity. Due the effect of orlistat on fat absorption and lower levels of fat-soluble vitamins during clinical trials, the bioavailability of orally administered tretinoin may be decreased during concurrent therapy. Close monitoring of patients receiving oral tretinoin therapy with orlistat is recommended. REACCIONES ADVERSAS Skin changes can occur with both topical and oral tretinoin, but more so with topical therapy. Almost all patients report a local inflammatory response, which is reversible following discontinuance of topical treatment. Skin irritation, such as mild stinging or feeling of warmth, can occur on the treated areas when applying the medication. Xerosis (dry skin), scaling, and erythema occur frequently and appear to be part of the therapeutic effect of topical tretinoin. Xerosis, including cheilitis, was reported in the majority of patients receiving oral tretinoin. If severe erythema, edema, vesicle formation, or crusting develops, topical tretinoin should be discontinued until skin integrity is restored. Therapy may be reinitiated with less frequent application or a lower concentration. Skin hyperpigmentation and skin hypopigmentation have been reported in about 2% of patients with topical tretinoin therapy, with resolution following discontinuation of tretinoin. Some patients experience increased photosensitivity during topical or oral tretinoin therapy. During topical therapy patients should use sunscreen (minimum SPF 15) and protective clothing. Patients with a sunburn should not use topical tretinoin until fully recovered. Oral tretinoin therapy and acute promyelocytic leukemia (APL) are associated with a significant number of adverse reactions affecting almost all organ systems. The most frequently reported adverse events associated with oral tretinoin are similar to those experienced by patients receiving high doses of vitamin A (hypervitaminosis A). The most common adverse effects to oral tretinoin therapy include headache (86%), fever (83%), bone pain (77%), nausea/vomiting (57%), rash (unspecified) (54%), stomatitis (26%), pruritus (20%), diaphoresis (20%), visual impairment or ocular disorders (17%), alopecia (14%), skin changes (14%), changes in visual acuity (6%), bone inflammation (3%), visual field defects (3%). Rapidly evolving leukocytosis develops in approximately 20% of acute promyelocytic leukemia patients receiving oral tretinoin and has been associated with other complications. Patients who have a high white blood cell (WBC) count at diagnosis have a greater risk of a further rapid increase in WBC counts. The manufacturer reports that some clinicians routinely add chemotherapy to oral tretinoin on day 1 or 2 in patients who present with a WBC count of > 5000/mm3 or immediately in patients who are leukopenic (< 5000/mm3) at the start of treatment who then have a rapid increase in WBC count to >= 6000/mm3 by day 5, or >= 10,000/mm3 by day 10, or >= 15,000/mm3 by day 28. Approximately 25% of acute promyelocytic leukemia (APL) patients treated with oral tretinoin develop retinoic acid-APL (RA-APL) syndrome. The RA-APL syndrome is characterized by fever, dyspnea, weight gain, peripheral edema, radiographic pulmonary infiltrates, and pleural or pericardial effusions. Impaired myocardial contractility and episodic hypotension have occasionally accompanied this syndrome. It may occur with or without leukocytosis. Respiratory signs/symptoms are most commonly associated with RA-APL syndrome. Respiratory adverse reactions include upper respiratory tract disorders (63%), dyspnea (60%), respiratory insufficiency (26%), pleural effusion (20%), pneumonia (14%), rales (14%), expiratory wheezing (14%), lower respiratory tract disorders (9%), pulmonary infiltrates (6%), bronchial asthma (3%), pulmonary edema (3%), and laryngeal edema (3%). Endotracheal intubation and mechanical ventilation have been required in some cases due to progressive hypoxemia, and several patients have died with multisystem organ failure. RA-APL syndrome usually occurs within the first month of treatment, with some cases following the first dose of oral tretinoin. The management of RA-APL syndrome has not been defined, but high-dose corticosteroids (dexamethasone 10 mg IV every 12 hours for 3 days or until symptoms resolve) started at the first suspicion of the syndrome appear to reduce morbidity and mortality. Sixty percent or more of patients treated with oral tretinoin may require high-dose steroids because of these symptoms. The majority of patients do not require discontinuation of tretinoin therapy during the treatment of RA-APL syndrome. Gastrointestinal adverse reactions frequently occur with oral tretinoin therapy for acute promyelocytic leukemia. Adverse reactions reported at an incidence of >= 3% include GI bleeding (34%), abdominal pain (31%), diarrhea (23%), constipation (17%), dyspepsia (14%), abdominal distention (11%), hepatomegaly (9%), splenomegaly (9%), hepatitis (3%), and ulcer (3%). Elevated hepatic enzymes may be reported in 50—60% of patients receiving oral tretinoin. Cardiovascular adverse reactions occurring in >= 3% of patients receiving oral tretinoin for acute promyelocytic leukemia include arrhythmias (23%), flushing (23%), hypotension (14%), hypertension (11%), phlebitis (11%), heart failure (6%), and for 3% of patients: cardiac arrest, myocardial infarction, cardiomegaly, heart murmur, ischemia, stroke, myocarditis, pericarditis, pulmonary hypertension, and secondary cardiomyopathy. Central nervous system adverse reactions associated with oral tretinoin therapy for acute promyelocytic leukemia include dizziness (20%), paresthesias (17%), anxiety (17%), insomnia (14%), depression (14%), confusion (11%), intracranial bleeding (9%), increased intracranial pressure (9%), agitation (9%), hallucinations (6%), and for 3% of patients: abnormal gait (ataxia), agnosia, aphasia, asterixis, cerebellar edema, cerebellar disorders, seizures, coma, CNS depression, dysarthria (slurred speech), encephalopathy, facial paralysis, hemiplegia, hyporeflexia, hypotaxia, tremor, leg weakness, dementia, forgetfulness, drowsiness, and slow speech. Oral tretinoin consistently produces adverse reactions associated with the ear. Otalgia and feeling of fullness in the ears were reported in 23% of patients receiving oral tretinoin. Hearing loss and other unspecified auricular adverse effects occurred in 6% of patients. Irreversible hearing loss was infrequent (< 1%). Oral tretinoin produces hyperlipidemia in as many as 60% of patients. Hypercholesterolemia and/or hypertriglyceridemia develop during treatment with tretinoin and is reversible following discontinuation. Hypercalcemia and hypocalcemia have been seen rarely. Other adverse reactions occurring at an incidence of >= 3% during oral tretinoin therapy for acute promyelocytic leukemia include malaise or fatigue (66%), shivering (63%), bleeding (60%), pain (37%), chest discomfort (32%), disseminated intravascular coagulation (26%), myalgia (14%), renal insufficiency (11%), costovertebral pain (9%), dysuria (9%), cellulitis (8%), facial edema (6%), fluid imbalance (6%), pallor (6%), lymph disorders (6%), and occurring in 3% of patients: acute renal failure (unspecified), ascites, enlarged prostate, hypothermia, metabolic acidosis, renal tubular necrosis, and urinary urgency/frequency. Isolated cases of erythema nodosum, basophilia and hyperhistaminemia, myositis, organomegaly, pancreatitis, pseudotumor cerebri (especially in children), and Sweet's syndrome have been reported. Teratogenesis is a serious concern with tretinoin; vitamin A analogs are well-known teratogens. Teratogenic and embryotoxic effects have been demonstrated in animals receiving oral tretinoin. It is expected that tretinoin will cause fetal harm when administered to a pregnant woman and that there is a high risk of producing a severely deformed infant. Adequate and well-controlled trials have not been performed in humans, but increased spontaneous abortions and major human fetal abnormalities have occurred when pregnant women received other retinoids.
Tretinoin, ATRA Altinac™, Avita™, Renova®, Retin-A®, Vesanoid® | Atragen®, Avita™, Renova®, Retin-A®, Vesanoid® | Altinac™ | Retin-A® Micro® |
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