Tretinoin

( trans-Retinoic Acid , Vitamin A Acid )

Pronunciation: TREH-tih-NO-in
Class: Retinoid

Trade Names

Atralin
- Gel 0.05%

Avita
- Cream 0.025%
- Gel 0.025%

Refissa
- Cream 0.05% (emollient base)

Renova
- Cream 0.02%
- Cream 0.05%

Retin-A
- Cream 0.025%
- Cream 0.05%
- Cream 0.1%
- Gel 0.025%
- Gel 0.01%

Retin-A Micro
- Gel 0.04%
- Gel 0.1%

Tretinoin
- Capsules 10 mg

Rejuva-A (Canada)
Retisol-A (Canada)
Stieva-A (Canada)
Vesanoid (Canada)

Pharmacology

Topical

Decreases cohesiveness and stimulates mitotic activity and turnover of follicular epithelial cells, resulting in decreased formation and increased extrusion of comedones.

PO

Induces maturation of acute promyelocytic leukemia cells followed by a repopulation of the bone marrow and peripheral blood by normal, polyclonal hematopoietic cells in patients achieving complete remission.

Pharmacokinetics

Absorption

C max is approximately 347 ng/mL. T max is 1 or 2 h. Orally, tretinoin is well absorbed into systemic circulation.

Distribution

Vd is not yet determined. Tretinoin is more than 95% protein bound (primarily to albumin). Binding remains constant over the concentration range of 10 to 500 ng/mL.

Metabolism

CYP-450 (CYP3A4, 2C8, and 2E) enzymes have been implicated in the oxidative metabolism of tretinoin. Metabolites are 13-cis retinoic acid, 4-oxo trans retinoic acid, 4-oxo cis retinoic acid, 4-oxo trans retinoic acid glucuronide. Metabolites have been identified in plasma and urine. Tretinoin's activity is primarily caused by the parent drug. There is evidence that tretinoin induces its own metabolism.

Elimination

Tretinoin's t ½ is 0.5 to 2 h. 63% is excreted in urine and 31% in feces.

Peak

1 to 2 h.

Indications and Usage

Topical treatment of acne vulgaris; as an adjunctive agent for use in the mitigation of fine wrinkles, mottled hyperpigmentation, and tactile roughness of facial skin; PO treatment for acute promyelocytic leukemia (APL).

Contraindications

Do not use if sunburned, have eczema, highly sensitive to the sun, or with skin irritation ( Renova only); hypersensitivity to tretinoin or any of its components.

Dosage and Administration

Treatment of Acne
Adults and children

Topical Apply lightly to affected area once daily before bedtime.

Treatment of Fine Wrinkles, Hyperpigmentation, and Tactile Roughness of Facial Skin
Adults

Topical Apply lightly to affected area. Use smallest amount possible.

Acute Myelocytic Leukemia
Adults and children (older than 1 yr of age)

PO 45 mg/m 2 /day in 2 divided doses. Continue therapy for a max duration of 90 days or for 30 days after achieving complete remission, whichever is shorter.

Storage/Stability

Store creams and gels below 86°F. Store microsphere gel at controlled room temperature (59° to 77°F). Store capsules at controlled room temperature (59° to 86°F). Protect from light.

Drug Interactions

Agents known to cause pseudotumor cerebri (eg, tetracycline)

The risk of this condition occurring may be increased.

Antifibrinolytic agents (eg, aminocaproic acid, aprotinin, tranexamic acid)

Fatal thrombotic complications have been reported.

Benzoyl peroxide, cosmetics with drying effects, resorcinol, salicylic acid, soaps, or sulfur

May result in significant skin irritation.

CYP-450

Elimination may be altered by agents that inhibit or induce CYP-450 enzymes.

Photosensitizers (eg, fluoroquinolones, phenothiazines, sulfonamides, tetracyclines, thiazide diuretics)

May augment photosensitivity.

Vitamin A

Because symptoms of hypervitaminosis A may be exacerbated, do not give with vitamin A.

Laboratory Test Interactions

None well documented.

Adverse Reactions

Unless otherwise stated, the rates of occurrence of the following adverse reactions are with oral administration.

Cardiovascular

Arrhythmias (23%); hypotension (14%); hypertension, phlebitis (11%); cardiac failure (6%); cardiac arrest, enlarged heart, heart murmur, ischemia, MI, myocarditis, pericarditis, pulmonary hypertension, secondary cardiomyopathy, stroke (3%).

CNS

Headache (86%); dizziness (20%); anorexia, anxiety, paresthesias (17%); depression, insomnia (14%); confusion (11%); agitation, cerebral hemorrhage, intracranial hypertension, (9%); hallucination (6%); abnormal gait, agnosia, aphasia, asterixis, cerebellar disorders, cerebellar edema, CNS depression, coma, convulsions, dementia, dysarthria, encephalopathy, facial paralysis, forgetfulness, hemiplegia, hyporeflexia, hypotonia, leg weakness, neurologic reaction, no light reflex, slow speech, somnolence, spinal cord disorder, tremor, unconsciousness (3%).

Dermatologic

Skin/mucous membrane dryness (77%); rash (54%); flushing (23%); increased sweating, pruritus (20%); injection-site reaction (17%); alopecia, skin changes (14%); burning/stinging, dryness, erythema, hyper- or hypopigmentation, irritation, itching, peeling, photosensitivity, red, edematous, blistered, or crusted skin (topical).

EENT

Ocular disorders, visual disturbances (17%); changes in visual acuity, hearing loss/unspecified ear disorders (6%); larynx edema, visual field defects (3%).

GI

Nausea/vomiting (57%); GI hemorrhage (34%); abdominal pain (31%); mucositis, other GI disorders (26%); diarrhea (23%); constipation (17%); dyspepsia (14%); abdominal distention (11%); hepatosplenomegaly (9%); ulcer (3%).

Genitourinary

Renal insufficiency (11%); dysuria (9%); acute renal failure, enlarged prostate, micturition, renal tubular necrosis (3%).

Hepatic

Hepatitis, unspecified liver disorders (3%).

Hematologic-Lymphatic

Disseminated intravascular coagulation (26%); lymph disorders (6%).

Lab Tests

Elevated LFTs (50% to 60%).

Metabolic-Nutritional

Weight increase (23%); weight decrease (17%); fluid imbalance (6%); acidosis (3%).

Musculoskeletal

Bone pain (77%); myalgia (14%); flank pain (9%); bone inflammation (3%).

Respiratory

Upper respiratory tract disorders (63%); dyspnea (60%); respiratory insufficiency (26%); pleural effusion (20%); expiratory wheezing, pneumonia, rales (14%); lower respiratory tract disorders (9%); pulmonary infiltration (6%); bronchial asthma, pulmonary edema, unspecified pulmonary disease (3%).

Miscellaneous

Fever (83%); shivering (63%); malaise (66%); hemorrhage (60%); infections (58%); peripheral edema (52%); pain (37%); chest discomfort (32%); edema (29%); cellulitis (8%); face edema, pallor (6%); ascites, hypothermia (3%).

Precautions

Warnings

Experienced physician and institution

Patients with APL are at high risk in general and can have severe adverse reactions to tretinoin. Administer tretinoin only to APL patients under the strict supervision of a physician who is experienced in the management of patients with acute leukemia and in a facility with laboratory and supportive services sufficient to monitor drug tolerance and protect and maintain a patient compromised by drug toxicity, including respiratory compromise. Use of tretinoin requires the physician conclude that the possible benefit to the patient outweighs the following known adverse effects of the therapy.

Retinoic acid-APL syndrome

Occurs in about 25% of APL patients treated with tretinoin, typically occurring within 1 mo of therapy. It is characterized by fever, dyspnea, weight gain, radiographic pulmonary infiltrates, and pleural or pericardial effusions. It is occasionally accompanied by impaired myocardial contractility and episodic hypotension.

Leukocytosis

It has been reported in about 40% of patients during therapy. High WBC (greater than 5 × 10 9 /L) at diagnosis indicates increased risk. If signs and symptoms of the RA-APL syndrome are present together with leukocytosis, initiate treatment with high-dose steroids immediately.

Teratogenicity Pregnancy

Category D . There is a high risk that a severely deformed infant will result if tretinoin is administered during pregnancy. The patient must receive full information and warnings of the risk to the fetus. Instruct in the need to use 2 reliable forms of contraception simultaneously during therapy and for 1 mo following discontinuation of therapy.

Within 1 wk prior to institution of tretinoin therapy, the patient should have blood or urine collected for a serum or urine pregnancy test. Repeat pregnancy testing and contraception counseling monthly throughout the period of treatment.


Pregnancy

Category C (topical); Category D (PO).

Lactation

Undetermined.

Children

Safety and efficacy in patients younger than 18 yr of age not established ( Renova only). Safety and efficacy not established in children younger than 12 yr of age ( Retin-A ).

Photosensitivity

Tumorigenic potential of ultraviolet radiation may be accelerated. Photosensitization may occur.

External use only

Keep away from eyes, mouth, angles of nose, mucous membranes, and open wounds.

Irritation

May cause severe local irritation. May need to use less often or discontinue temporarily or completely (topical).

Lipids

Up to 60% of patients experienced hypercholesterolemia or hypertriglyceridemia, which were reversible upon completion of treatment (PO).

Pseudotumor cerebri

Retinoids, including tretinoin, have been associated with pseudotumor cerebri (benign intracranial hypertension), especially in children.

Overdosage

Symptoms

Blistering, cracking of the skin, pain, redness (topical); abdominal pain, ataxia, cheilosis, dizziness, facial flushing, headache (PO).

Patient Information

  • Topical
  • Advise patient to read patient information leaflet before using the first time and with each refill.
  • Advise patient that this is a serious medicine and to use only as part of a comprehensive program that includes the use of sunscreens, non-oil-based moisturizers, and avoidance of exposure to direct sunlight and the use of sunlamps.
  • Inform patient that topical therapeutic response should be seen after 3 to 6 wk, but may not be optimal for 12 wk.
  • Advise patient that acne symptoms may worsen initially, but not to discontinue therapy at this time.
  • Caution patient with preexisting sunburn not to apply tretinoin until fully recovered from the sunburn because of heightened susceptibility to sunlight as a result of using tretinoin.
  • Advise patient to apply medication once daily, using enough medication to cover the affected area(s) lightly, before bedtime. Caution patient that more frequent or heavier application does not improve acne more rapidly nor provide better results than once daily therapy, but will cause more redness, peeling, and discomfort at application site(s).
  • Instruct patient to thoroughly, but gently, cleanse area with mild, non-medicated soap and allow to dry for 20 to 30 min before applying tretinoin; to avoid application around eyes, mouth, angle of nose, mucus membranes, eczematous skin, and open wounds; and to thoroughly wash hands immediately after application.
  • Caution patient that tretinoin gels (except Retin-A Micro ) are flammable and to avoid smoking, fire, and flame during use.
  • Advise patient to avoid unnecessary exposure to sunlight and tanning lamps, and to use sunscreen and wear protective clothing when outside (even on hazy days) to avoid photosensitivity reactions during therapy. Advise patient that if sunburn occurs, to discontinue therapy with tretinoin until the skin has recovered.
  • Caution patient to avoid excessive exposure to wind and cold while using tretinoin and notify health care provider if any of the following occur after exposure to sunlight or artificial UV light (eg, sunlamp): sensation of skin burning, redness, swelling, blistering, rash, itching.
  • Advise patient that normal use of cosmetics is allowed, but to avoid oil-based cosmetics.
  • Advise patient not to apply other acne products at the same time as tretinoin, and not to apply tretinoin more than once daily.
  • Advise patient that medicated soaps and cosmetics that have a strong drying effect and products with high concentrations of alcohol, astringents, spices, or lime (eg, shaving lotion) may worsen dry skin.
  • Explain that temporary hypopigmentation or hyperpigmentation may occur at application site.
  • Advise patient that if severe redness and peeling occurs at site of application to apply medication less frequently. If severe redness and peeling persists with reduced frequency of application, advise patient to temporarily discontinue therapy until fully recovered. Instruct patient to discontinue use and consult health care provider if sensitivity or increased irritation continues or reoccurs.
  • Oral
  • Explain that medication is used for induction of remission of leukemia and that maintenance therapy will be needed following successful induction.
  • Advise patient to take prescribed dose twice daily with meals.
  • Advise patient that if a dose is missed, to take it as soon as possible, but if close to the next dose, not to double the dose to catch up, and take the next dose as scheduled.
  • Advise patient, family, or caregiver to immediately report any of the following to the health care provider: difficulty breathing; rapid weight gain; visual changes; fever, chills, or other signs of infection; sore throat; unusual bruising or bleeding.
  • Advise patient, family, or caregiver to inform health care provider of any of the following: persistent severe headache; persistent nausea; vomiting; severe skin or mucus membrane dryness.
  • Advise patient that drug may cause dizziness or confusion and to use caution while driving or performing other tasks requiring mental alertness.
  • Instruct sexually active women, unless they have had a hysterectomy, to use 2 reliable forms of contraception during and for 1 mo following completion of therapy.
  • Caution patient not to take any supplemental vitamin A or use products containing vitamin A (eg, multivitamins) during treatment with tretinoin.

Copyright © 2009 Wolters Kluwer Health.

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