Acitretin

Acitretin: Drug information
Copyright 1978-2011 Lexicomp, Inc. All rights reserved.
(For additional information see “Acitretin: Patient drug information”)

ALERT: U.S. Boxed Warning The FDA-approved labeling includes a boxed warning. See Warnings/Precautions section for a concise summary of this information. For verbatim wording of the boxed warning, consult the product labeling or www.fda.gov.
Brand Names: U.S. Soriatane®
Brand Names: Canada Soriatane®
Medication Guide An FDA-approved patient medication guide, which is available with the product information and at file://www.fda.gov/downloads/Drugs/DrugSafety/ucm089133.pdf, must be dispensed with this medication.
Pharmacologic Category Retinoid-Like Compound
Dosing: Adult
Psoriasis: Oral: Individualization of dosage is required to achieve maximum therapeutic response while minimizing side effects

Initial therapy: Therapy should be initiated at 25-50 mg/day, given as a single dose with the main meal

Maintenance: Doses of 25-50 mg/day may be given after initial response to treatment; the maintenance dose should be based on clinical efficacy and tolerability

American Academy of Dermatology recommends: 10-50 mg/day as a single dose; doses ≤25 mg/day are used to decrease side effects (Menter, 2009)

Dosing: Geriatric Refer to adult dosing.
Dosing: Renal Impairment There are no dosage adjustments provided in manufacturer’s labeling.
Hemodialysis: Not removed by hemodialysis

Dosing: Hepatic Impairment There are no dosage adjustments provided in manufacturer’s labeling.
Dosage Forms: U.S. Excipient information presented when available (limited, particularly for generics); consult specific product labeling.
Capsule, oral:

Soriatane®: 10 mg, 17.5 mg, 25 mg

Generic Equivalent Available: U.S. No
Administration Administer with food, preferably with the main meal of the day.
Use Treatment of severe psoriasis
Medication Safety Issues
Sound-alike/look-alike issues:
Soriatane® may be confused with Loxitane®, sertraline, Sonata®

Adverse Reactions Significant
>10%:

Central nervous system: Hyperesthesia (10% to 25%)

Dermatologic: Cheilitis (>75%), alopecia (50% to 75%), skin peeling (50% to 75%), dry skin (25% to 50%), nail disorder (25% to 50%), pruritus (25% to 50%), erythematous rash (10% to 25%), paronychia (10% to 25%), skin atrophy (10% to 25%), sticky skin (10% to 25%)

Endocrine & metabolic: Hypertriglyceridemia (50% to 75%), fasting blood sugar increased (25% to 50%), HDL decreased (25% to 50%), hypercholesterolemia (25% to 50%), fasting blood sugar decreased (10% to 25%), magnesium increased/decreased (10% to 25%), phosphorus increased (10% to 25%), potassium increased (10% to 25%), sodium increased (10% to 25%)

Gastrointestinal: Xerostomia (10% to 25%)

Hematologic: Reticulocytes increased (25% to 50%), haptoglobin increased (10% to 25%), hematocrit decreased (10% to 25%), hemoglobin decreased (10% to 25%), neutrophils increased (10% to 25%), WBC increased/decreased (10% to 25%)

Hepatic: Liver function tests increased (25% to 50%), alkaline phosphatase increased (10% to 25%), direct bilirubin increased (10% to 25%), GGTP increased (10% to 25%)

Neuromuscular & skeletal: CPK increased (25% to 50%), arthralgia (10% to 25%), paresthesia (10% to 25%), rigors (10% to 25%), spinal hyperostosis progression (10% to 25%)

Ocular: Xerophthalmia (10% to 25%)

Renal: WBC in urine (25% to 50%), acetonuria (10% to 25%), hematuria (10% to 25%), RBC in urine (10% to 25%), uric acid increased (10% to 25%)

Respiratory: Rhinitis (25% to 50%), epistaxis (10% to 25%)

1% to 10%:

Cardiovascular: Edema, flushing

Central nervous system: Depression, fatigue, headache, insomnia, pain, somnolence

Dermatologic: Bullous eruption, cold/clammy skin, dermatitis, fissures, hair texture change, psoriasiform rash, purpura, pyogenic granuloma, rash, seborrhea, skin odor, sunburn, ulcers

Endocrine & metabolic: Calcium increased or decreased, chloride increased or decreased, hot flashes, iron increased/decreased, phosphorus decreased, potassium decreased, sodium decreased

Gastrointestinal: Abdominal pain, anorexia, appetite increased, diarrhea, gingival bleeding, gingivitis, nausea, saliva increased, stomatitis, taste disturbance, thirst, tongue disorder, ulcerative stomatitis

Hematologic: Haptoglobin decreased, hematocrit increased, hemoglobin increased, neutrophils decreased, RBC increased/decreased, reticulocytes decreased

Hepatic: Total bilirubin increased

Neuromuscular & skeletal: Arthritis, arthrosis, back pain, Bell’s palsy, hypertonia, myalgia, osteodynia, peripheral joint hyperostosis

Ocular: Blepharitis, blurred vision, cataract, conjunctivitis, corneal epithelial abnormality, diplopia, eye pain, eyebrow or eyelash loss, night blindness, photophobia

Otic: Earache, tinnitus

Renal: Albumin decreased/increased, BUN increased, creatinine increased, glycosuria, proteinuria

Respiratory: Sinusitis

Miscellaneous: Diaphoresis increased

<1% (Limited to important or life-threatening): Abnormal gait, acne, aggression, anal disorder, anxiety, bleeding time increased, bone disorder, breast pain, chalazion, chest pain, ceruminosis, cirrhosis, conjunctival hemorrhage, constipation, corneal lesions, corneal ulceration, cough, cyanosis, cyst, deafness, diplopia, dizziness, dyspepsia, dysphonia, dysuria, ectropion, eczema, esophagitis, ethanol intolerance, fever, flu-like syndrome, fungal infection, furunculosis, gastritis, gastroenteritis, glossitis, gum hyperplasia, hair discoloration, healing impaired, hemorrhage, hemorrhoids, hepatic dysfunction, hepatitis, herpes simplex, hyperkeratosis, hypertrichosis, hypoesthesia, intermittent claudication, itchy eyes, jaundice, lacrimation abnormal, laryngitis, leukorrhea, libido decreased, malaise, melena, MI, migraine, moniliasis, muscle weakness, myopathy with peripheral neuropathy, nail fragility, nervousness, neuritis, olecranon bursitis, otitis media, pancreatitis, papilledema, peripheral ischemia, pharyngitis, photosensitivity, pseudotumor cerebri, recurrent sties, scaling of skin, scleroderma, skin fragility or thinning, skin hypertrophy, skin nodule, spinal hyperostosis (new lesion), sputum increased, suicidal thoughts, taste loss, tendonitis, tenesmus, thromboembolism, tongue ulceration, urticaria, vaginitis, vulvovaginitis, wart, weight gain

Contraindications Hypersensitivity to acitretin, other retinoids, or any component of the formulation; patients who are pregnant or intend on becoming pregnant; severe hepatic or renal dysfunction; chronically-elevated blood lipid levels; concomitant use with methotrexate or tetracyclines
Acitretin is contraindicated in females of childbearing potential unless all of the following conditions apply.

1) Patient has severe psoriasis unresponsive to other therapy or if clinical condition contraindicates other treatments.

2) Patient must have two negative urine or serum pregnancy tests prior to therapy.

3) Patient must have pregnancy test repeated monthly during therapy. After discontinuation of therapy, a pregnancy test must be repeated every 3 months for at least 3 years.

4) Patient must commit to using two effective forms of birth control starting 1 month prior to acitretin treatment and for 3 years after discontinuation. Prescriber must counsel patient about contraception every month during therapy and every 3 months following discontinuation for at least 3 years.

5) Patient is reliable in understanding and carrying out instructions.

6) Patient has received, and acknowledged, understanding of a careful oral and printed explanation of the hazards of fetal exposure to acitretin and the risk of possible contraception failure. Patient must sign an agreement/informed consent document stating that she understands these risks and that she should not consume ethanol during therapy or for 2 months after discontinuation.

Warnings/Precautions
Boxed warnings:

• Blood donation: See “Other warnings/precautions” below.

• Ethanol use: See “Concurrent drug therapy issues” below.

• Hepatotoxicity: See “Concerns related to adverse effects” below.

• Medication guide: See “Other warnings/precautions” below.

• Pregnancy: See “Special populations” below.

Concerns related to adverse effects:

• Depression: Depression, including thoughts of self-harm have been reported; use with caution in patients with a history of mental illness.

• Hepatotoxicity: [U.S. Boxed Warning]: Changes in transaminases occur in up to 1/3 of patients. Monitor for hepatotoxicity; discontinue if significant elevations of liver enzymes occur.

• Hyperostosis: Patients receiving long-term treatment should be periodically examined for bony abnormalities; risk vs benefit of therapy should be considered if abnormalities occur.

• Lipid effects: Lipid changes including, increased triglycerides, increased cholesterol, and decreased HDL are common (up to 66%); increased triglycerides may lead to pancreatitis. Use with caution in patients at risk of hypertriglyceridemia.

• Photosensitivity: May be photosensitizing; minimize sun or other UV exposure to treated areas. The risk of burning is increased with phototherapy; decreased doses are required.

• Pseudotumor cerebri: Rarely associated with pseudotumor cerebri.

• Visual disturbances: May cause adverse effects to the eyes and vision, including a decrease in night vision or decreased tolerance to contact lenses. Use caution when operating vehicles at night; discontinue if visual changes occur.

Concurrent drug therapy issues:

• Ethanol use: [U.S. Boxed Warning]: Female patients should abstain from ethanol or ethanol-containing products during therapy and for 2 months after discontinuation.

• Tetracyclines: Pseudotumor cerebri (benign intracranial hypertension) has been reported with use of tetracyclines and acitretin independently; concomitant use is contraindicated.

Special populations:

• Pediatrics: Growth potential may be affected. Long-term use of high-dose oral retinoids within this population has been associated with decreased bone mineral density, skeletal hyperostosis, and ossification of interosseous tendons and ligaments of the extremities (Menter, 2009).

• Pregnancy: [U.S. Boxed Warning]: Not for use by women who are pregnant or want to become pregnant; patient should not get pregnant for at least 3 years after discontinuation. The Do Your P.A.R.T. (Pregnancy Prevention Actively Required During and After Treatment) program explains teratogenic risks and requirements expected of females of childbearing potential to prevent pregnancies from occurring during use and 3 years following discontinuation; this should be used to educate patients and healthcare providers.

Other warnings/precautions:

• Appropriate use: Not for the treatment of acne

• Blood donation: [U.S. Boxed Warning]: All patients should be advised not to donate blood during therapy or for 3 years following completion of therapy.

• Medication guide: [U.S. Boxed Warning]: All patients must be provided with a medication guide each time acitretin is dispensed. Female patients must also sign an informed consent prior to therapy.

• Worsening of disease: Transient worsening of psoriasis may initially occur; patients should be advised that it may take 2-3 months to achieve the full benefits of treatment.

Drug Interactions
(For additional information: Launch Lexi-Interact™ Drug Interactions Program )
Alcohol (Ethyl): May enhance the teratogenic effect of Acitretin. Risk X: Avoid combination

Contraceptives (Estrogens): Retinoic Acid Derivatives may diminish the therapeutic effect of Contraceptives (Estrogens). Two forms of contraception are recommended in females of child-bearing potential during retinoic acid derivative therapy. Risk C: Monitor therapy

Contraceptives (Progestins): Acitretin may diminish the therapeutic effect of Contraceptives (Progestins). Contraceptive failure is possible. Management: Given the potential for progestin-only preparations to fail to prevent pregnancy during acitretin therapy, such products should not be relied upon. Alternative, nonhormonal forms of contraception must be employed during acitretin therapy. Risk D: Consider therapy modification

Contraceptives (Progestins): Retinoic Acid Derivatives may diminish the therapeutic effect of Contraceptives (Progestins). Retinoic Acid Derivatives may decrease the serum concentration of Contraceptives (Progestins). Management: Two forms of effective contraception should be used in patients receiving retinoic acid derivatives. Particularly, microdosed progesterone-only preparations may be inadequately effective. Risk D: Consider therapy modification

Methotrexate: Acitretin may enhance the hepatotoxic effect of Methotrexate. Risk X: Avoid combination

Porfimer: Photosensitizing Agents may enhance the photosensitizing effect of Porfimer. Risk C: Monitor therapy

Tetracycline Derivatives: May enhance the adverse/toxic effect of Retinoic Acid Derivatives. The development of pseudotumor cerebri is of particular concern. Risk X: Avoid combination

Vitamin A: Retinoic Acid Derivatives may enhance the adverse/toxic effect of Vitamin A. Risk X: Avoid combination

Vitamin A: May enhance the adverse/toxic effect of Retinoid-like Compounds. Risk D: Consider therapy modification

Ethanol/Nutrition/Herb Interactions Ethanol: Use leads to formation of etretinate, a teratogenic metabolite with a prolonged half-life; concomitant use of ethanol or ethanol-containing products is contraindicated.
Pregnancy Risk Factor X (show table)
Pregnancy Implications [U.S. Boxed Warning]: Not for use by women who are pregnant or intend to become pregnant. Acitretin is teratogenic in humans. Severe birth defects have been reported when conception occurred during treatment or after therapy was complete. Patients should not get pregnant for at least 3 years after discontinuation. In addition, because ethanol forms a teratogenic metabolite and would increase the duration of teratogenic potential, ethanol should not be consumed during treatment or for 2 months after discontinuation. The Do Your P.A.R.T. (Pregnancy Prevention Actively Required During and After Treatment) program explains teratogenic risks and requirements expected of females of childbearing potential. Limited amounts of acitretin are found in seminal fluid; although it appears this poses little risk to a fetus, the actual risk of teratogenicity is not known. Any pregnancy which occurs during treatment, or within 3 years after treatment is discontinued, should be reported to the manufacturer at 1-888-784-3335 or to the FDA at 1-800-FDA-1088.
Lactation Enters breast milk/not recommended
Breast-Feeding Considerations Acitretin should not be given prior to or during nursing due to the potential for adverse effects in the nursing infant.
Dietary Considerations Take with food. Avoid ingestion of additional sources of exogenous vitamin A (in excess of RDA); use of ethanol and ethanol-containing products is contraindicated.
Monitoring Parameters Lipid profile (baseline and at 1- to 2-week intervals for 4-8 weeks); liver function tests (baseline, and at 1- to 2-week intervals until stable, then as clinically indicated); blood glucose in patients with diabetes; bone abnormalities (with long-term use); pregnancy tests (2 negative tests prior to therapy initiation, monthly during treatment, and every 3 months for ≥3 years after discontinuation of therapy)
The American Academy of Dermatology recommends: CBC and renal function tests (baseline and then every 12 weeks); liver function tests (every 2 weeks for the first 8 weeks, then every 6-12 weeks thereafter) (Menter, 2009)

International Brand Names Acetec (IN); Neotigason (AR, AT, AU, BB, BE, BF, BG, BJ, BM, BR, BS, BZ, CH, CI, CL, CN, CO, CZ, DE, DK, EC, EE, EG, ET, FI, GB, GH, GM, GN, GR, GY, HK, HN, IE, IL, IT, JM, KE, KP, LR, MA, ML, MR, MU, MW, MX, MY, NE, NG, NL, NO, PE, PH, PL, PT, PY, SC, SD, SE, SG, SL, SN, SR, TH, TN, TR, TT, TW, TZ, UG, UY, VE, ZA, ZM, ZW); Soriatane (FR)
Pharmacodynamics/Kinetics Etretinate has been detected in serum for up to 3 years following therapy, possibly due to storage in adipose tissue.
Onset of action: May take 2-3 months for full effect; improvement may be seen within 8 weeks.

Absorption: Oral: ~72% absorbed when given with food

Protein binding: >99% bound, primarily to albumin

Metabolism: Metabolized to cis-acitretin; both compounds are further metabolized. Concomitant ethanol use leads to the formation of etretinate (active).

Half-life elimination: Acitretin: 49 hours (range: 33-96); cis-acitretin: 63 hours (range: 28-157); etretinate: 120 days (range: up to 168 days)

Time to peak: 2-5 hours

Excretion: Feces (34% to 54%); urine (16% to 53%)

REFERENCES
Menter A, Gottlieb A, Feldman SR,, et al, “Guidelines of Care for the Management of Psoriasis and Psoriatic Arthritis: Section 1. Overview of Psoriasis and Guidelines of Care for the Treatment of Psoriasis With Biologics,” J Am Acad Dermatol, 2008, 58(5):826-50. [PubMed 18423260]
Menter A, Korman NJ, Elmets CA, et al, “Guidelines of Care for the Management of Psoriasis and Psoriatic Arthritis: Section 4. Guidelines of Care for the Management and Treatment of Psoriasis With Traditional Systemic Agents,” J Am Acad Dermatol, 2009, 61(3):451-85. [PubMed 19493586]