Acitretin

Acitretin is the generic form of the brand-name medicine Soriatane, which is used to treat severe forms of psoriasis, a condition characterized by red, thick, or scaly skin lesions.

This prescription medicine is a retinoid, which is a synthetic form of vitamin A.

The exact way acitretin works to help psoriasis is unknown.

The Food and Drug Administration (FDA) approved acitretin in 1996. It's marketed as Soriatane by Stiefel Laboratories, Inc.

Acitretin Warnings

Acitretin contains a black box warning because it may harm an unborn baby if it's taken during pregnancy.

You shouldn't take acitretin if you're pregnant or might become pregnant within the next three years.

Don't begin taking this medicine until you've had two negative pregnancy tests.

Women who are sexually active and may become pregnant will need to use two forms of birth control for one month before starting on acitretin, as well as during treatment, and for three years after treatment ends.

Acitretin may interfere with how some forms of birth control pills work. Be sure to tell your doctor what type of birth control pills you're taking.

Also, certain herbal supplements — like St. John's wort — may interfere with the effectiveness of hormonal contraceptives, such as birth control pills, patches, implants, injections, and intrauterine devices.

It's important to tell your doctor about all vitamins, supplements, and drugs you take.

Foods, drinks, and medicines that contain alcohol can interact with acitretin and form a substance that may remain in the blood for a long time and harm a fetus.

Don't consume any products that contain alcohol while using acitretin, and for two months after your treatment ends.

A small amount of this medicine is found in the semen of men who take it. It's not known whether the acitretin found in semen can harm a fetus. Talk to your doctor about this risk.

Men and women who take acitretin shouldn't donate blood, either while using the medicine or for up to three years after treatment ends.

Acitretin also contains a black box warning because it could cause liver damage.

Tell your doctor immediately if you develop symptoms of liver problems, which may include:

• Nausea
• Vomiting
• Loss of appetite
• Pain in the upper right part of the stomach
• Yellowing of the skin or eyes
• Dark-colored urine

Before taking acitretin, tell your doctor if you have, or have ever had:

• High cholesterol or triglyceride levels
• A family history of high cholesterol
• Kidney disease
• Diabetes or high blood sugar
• Heart disease
• Spinal problems
• Liver disease
• Depression
• A stroke or mini-stroke
• Joint or bone disease
• Allergies to any medication

Acitretin may affect your ability to see at night, and may also make your eyes dry.

Use caution when driving at night.

If you wear contact lenses and they become uncomfortable, take them out, and tell your doctor about this issue.

This medicine may make your skin more sensitive to the sun. Wear sunscreen and protective clothing when outdoors, and avoid any unnecessary sun exposure.

Acitretin may affect your blood sugar levels. If you have diabetes, be sure to monitor your condition carefully.

Tell your healthcare provider that you're taking acitretin before having a phototherapy treatment.

Your doctor will probably order frequent tests to check your body's response to this medicine. Keep all appointments with your doctor and laboratory.

Your condition may worsen during the first few months of treatment. This doesn't mean acitretin won't work for you, but tell your doctor if this happens.

Pregnancy and Acitretin

Acitretin can cause serious harm to an unborn baby if it's taken during pregnancy.

If you become pregnant while using this medicine, stop taking it immediately and call your doctor.

Follow the steps listed in the Acitretin Warnings section above to ensure that you don't become pregnant while using this medicine.

Don't breastfeed a baby while you're taking acitretin, or for at least three years after stopping treatment.

Acitretin is used to treat severe psoriasis (abnormal growth of skin cells that causes red, thickened, or scaly skin). Acitretin is in a class of medications called retinoids. The way acitretin works is not known.

In case of overdose, call your local poison control center at 1-800-222-1222. If the victim has collapsed or is not breathing, call local emergency services at 911.

Symptoms of overdose may include:

• headache
• dizziness
• vomiting
• upset stomach
• dry, itchy skin
• loss of appetite
• bone or joint pain

If a female who could become pregnant takes an overdose of acitretin, she should take a pregnancy test after the overdose and use two forms of birth control for the next 3 years.

Acitretin can harm an unborn baby or cause birth defects. Do not use acitretin if you are pregnant or plan to become pregnant within 3 years after you stop taking acitretin. Before and during treatment, and for 3 years after treatment, you must have negative pregnancy tests at regular intervals to make sure you are not pregnant.

Do not donate blood while taking acitretin and for at least 3 years after you stop taking it. Donated blood may be given to a pregnant woman and could cause birth defects if the blood contains acitretin.

Women taking acitretin must not drink alcohol during treatment and for at least 2 months after treatment ends. Alcohol can cause acitretin to convert to another substance in your body that can take 3 years or longer to clear from your body. Read the labels of all foods and medicines you consume to make sure they do not contain alcohol.

Acitretin is available only under an agreement that you will use birth control and undergo required pregnancy testing, and that you will not consume alcohol while you are taking acitretin and for 2 months after you stop taking it.

Follow all directions on your prescription label. Do not take this medicine in larger or smaller amounts or for longer than recommended.

Take acitretin with food.

Your psoriasis may seem to get worse at the start of therapy. For best results, keep using the medication as directed. Talk with your doctor if your symptoms do not improve after one course of acitretin treatment.

To be sure this medication is not causing harmful effects, your blood may need to be tested often. Your liver function and cholesterol may also need to be tested.

Never share this medicine with another person, even if they have the same symptoms you have.

Store at room temperature away from moisture, heat, and light.

Take the missed dose as soon as you remember. Skip the missed dose if it is almost time for your next scheduled dose. Do not take extra medicine to make up the missed dose.

Get emergency medical help if you have any of these signs of an allergic reaction: hives; difficult breathing; swelling of your face, lips, tongue, or throat.

Stop using acitretin and call your doctor at once if you have:

• blurred vision, headache or pain behind your eyes, sometimes with nausea and vomiting;

• sudden decrease in night vision;

• depressed mood, aggression, unusual thoughts or behavior, thoughts of hurting yourself;

• loss of feeling in your hands or feet, trouble moving, pain in your back, joints, muscles, or bones;

• mouth sores, swollen or bleeding gums;

• high blood sugar--increased thirst, increased urination, hunger, dry mouth, fruity breath odor, drowsiness, dry skin, weight loss;

• heart attack or stroke symptoms--chest pain or pressure, sudden numbness or weakness (especially on one side of the body), sudden severe headache, problems with speech or balance, swelling or warmth in one or both legs;

• liver problems--nausea, upper stomach pain, itching, tired feeling, loss of appetite, dark urine, clay-colored stools, jaundice (yellowing of the skin or eyes);

• severe skin reaction--itching, redness, pain, or swelling of your skin; red skin rash that spreads and causes blistering and peeling; or

• signs of a blood vessel problem--sudden swelling, rapid weight gain, fever, muscle pain, feeling light-headed.

Common side effects may include:

• dry eyes;

• dry or runny nose, nosebleeds;

• chapped lips, dry mouth;

• peeling skin on your hands and feet, hair loss;

• mild itching, scaling or sticky feeling on your skin;

• weak nails, fragile skin; or

• mild joint pain, muscle stiffness.

This is not a complete list of side effects and others may occur. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

Active metabolite of etretinate (no longer commercially available in US); a retinoid.1 4 7 8 10 11 12 17 18 19

General

• Acitretin should only be prescribed by clinicians who have special competence in diagnosis and treatment of severe psoriasis, are experienced in use of systemic retinoids, and understand risk of teratogenicity.1 (See Do Your PART Program under Cautions, and see Boxed Warning.)

• Individualize dosage according to therapeutic response and the appearance of adverse effects.1

• If a patient misses a dose, the next dose should not be doubled.1

• Patients concomitantly receiving phototherapy may require dosage reduction of phototherapy.1 (See Phototherapy under Cautions.)

Administration

Oral Administration

Administer orally once daily with the main meal.1 15 16 (See Food under Pharmacokinetics.)

Dosage

Adults

Initial dosage: 25–50 mg once daily.1 11

Maintenance dosage: 25–50 mg (dependent on patient's response to initial therapy) once daily.1 11

Relapse dosage: 25–50 mg once daily.1 11

In clinical studies, acitretin therapy was continued for up to 18 months in some patients.1 23

Prescribing Limits

Adults

Dosages >50 mg daily not evaluated in controlled studies.23

Special Populations

Hepatic Impairment

No specific dosage recommendations at this time.1 (See Contraindications under Cautions.)

Renal Impairment

No specific dosage recommendations at this time.1 (See Contraindications under Cautions.)

Geriatric Patients

Select dosage with caution (usually starting at the low end of the dosage range) because of possible age-related decrease in hepatic, renal, and/or cardiac function and concomitant disease and drug therapy.1 (See Absorption: Special Populations, under Pharmacokinetics and also see Elimination: Special Populations, under Pharmacokinetics.)

Contraindications

• Females who are or may become pregnant during acitretin therapy or within at least 3 years following drug discontinuance.1 9 13 (See Fetal/Neonatal Morbidity and Mortality under Cautions and also see Teratogenicity in Boxed Warning.)

• Severely impaired renal or hepatic function.1 3 9 (See Hepatic Effects under Cautions and also see Absorption: Special Populations, under Pharmacokinetics.)

• Chronic, abnormally elevated blood lipids.1 (See Effects on Lipoproteins under Cautions.)

• Concomitant use with methotrexate, tetracyclines, or vitamin A and/or other oral retinoids.1 23 (See Specific Drugs under Interactions.)

• Known hypersensitivity to acitretin, any ingredient in the formulation, or other retinoids.1

Warnings/Precautions

Warnings

Very high risk of severe birth defects if pregnancy occurs while receiving acitretin or upon drug discontinuance (birth defects reported ≥2 years after the last dose of acitretin).1 6 8 9 19 Teratogenicity generally is characterized by malformations involving craniofacial, cardiovascular, skeletal, and CNS structures.1 6 8 9 19 (See Do Your PART Program under Cautions, and see Teratogenicity in Boxed Warning.)

Jaundice, acute hepatic injury, toxic hepatitis, and cirrhosis reported in limited number of patients; generally, transaminase levels returned to normal after drug discontinuance.1 11 19

Elevations of AST, ALT, γ-glutamyltransferase (GGT), or LDH reported in approximately one-third of patients receiving acitretin; elevations generally were mild to moderate and resolved with continued therapy, a reduction in acitretin dosage, or upon drug discontinuance.1 3 7 8 11 17 Transient elevations of alkaline phosphatase also reported.1 8 17 19

Monitor hepatic enzyme levels.1 3 (See Hepatotoxicity in Boxed Warning.) More frequent monitoring recommended if alcoholism, diabetes mellitus, concomitant use of other hepatotoxic drugs, and/or obesity present.3

If hepatotoxicity is suspected during therapy, discontinue acitretin and investigate the cause of the abnormality.1 8

Concomitant use of acitretin and methotrexate contraindicated.1 (See Specific Drugs under Interactions.)

Hyperostosis (including diffuse interstitial skeletal hyperostosis syndrome [DISH]) reported.1 3 5 6 7 8 9 11 17 19 Changes may involve worsening of preexisting skeletal overgrowth.1 3 19

Periodically monitor patients receiving long-term acitretin therapy for ossification abnormalities; radiography recommended only in the presence of symptoms or long-term acitretin use.1 3 17 19 If symptoms arise, consider the potential benefits of continued therapy compared with potential for the development of hyperostosis.1 (See Pediatric Use under Cautions.)

In clinical trials, 66, 33, and 40% of patients experienced elevated triglycerides, elevated cholesterol, and decreased HDL-cholesterol, respectively; lipid abnormalities usually were reversible with cessation of therapy.1 3 7 8 9 11 17

Monitor fasting blood lipid concentrations prior to initiating therapy and at weekly or biweekly intervals until lipid response is established (usually within 4–8 weeks).1 3

Increased risk of hypertriglyceridemia in patients with diabetes mellitus, obesity, increased alcohol intake, lipid metabolism disorder, or familial history of these conditions.1 6 7 8 9 19 Close monitoring of serum lipid and/or glucose in these patients and in patients receiving long-term therapy recommended.1

Use contraindicated in patients with chronic, abnormally elevated blood lipid concentrations.1

Dietary modifications, acitretin dosage reductions, or lipid-lowering agents should be used to control clinically important triglyceride elevations;1 3 8 9 19 consider acitretin discontinuance if hypertriglyceridemia and decreased HDL-cholesterol persist.1

Dry eyes, irritation, and brow/lash loss reported in 23, 9, and 5%, respectively, of acitretin recipients evaluated in one study.1 8 9 15 17 19 Other adverse ocular effects, including decreased night vision, reported in <5% of patients.1 6 8 (See Advice to Patients.)

If visual difficulties occur during therapy, discontinue the drug and perform an ophthalmologic examination.1

Lipid elevations reported in 25–50% of acitretin recipients;1 6 8 19 elevations of triglycerides to concentrations associated with fatal fulminant pancreatitis are rare; however, cases have been reported with acitretin.1 3 8 19 Rare cases of pancreatitis without hypertriglyceridemia also reported.1

Pseudotumor cerebri (benign intracranial hypertension) has been reported with acitretin and other oral retinoids (e.g., isotretinoin); some patients with pseudotumor cerebri were receiving concomitant isotretinoin and tetracycline therapy.1 6 8 15 19 However, also has been reported in one patient receiving acitretin without concomitant tetracycline.1 3

Screen patients who develop manifestations of pseudotumor cerebri (e.g., headache, nausea and vomiting, visual disturbances) for the presence of papilledema and, if present, discontinue the drug immediately and refer to a neurologist for further evaluation and care.1 3 8

Concomitant use of acitretin and tetracyclines contraindicated.1 (See Specific Drugs under Interactions.)

Sensitivity Reactions

Avoid exposure to natural or artificial (e.g., sun lamps) sunlight; effects of UV light enhanced by acitretin.1 3 (See Phototherapy under Cautions.)

General Precautions

Do Your PART program developed to reinforce importance of pregnancy prevention by providing information on risks of fetal exposure to acitretin and to help prevent pregnancy.1 (See Teratogenicity in Boxed Warning and also see Fetal/Neonatal Morbidity and Mortality under Cautions.)

Patient must complete and sign a Patient Agreement/Informed Consent form detailing risks of potential birth defects, contraceptive failure, and alcohol ingestion, and importance of pregnancy prevention during and after drug discontinuance.1 23 A Soriatane Patient/Contraceptive Counseling Referral form also is provided, allowing for free initial contraceptive counseling session and pregnancy testing.1 23 A Medication Guide for all patients and a patient survey for women of childbearing potential also are included.1 23

Prior to issuing the initial prescription for acitretin, exclude pregnancy by 2 negative serum or urine tests (perform second test during the first 5 days of the menstrual period immediately prior to initiation of acitretin therapy); exclude pregnancy by monthly testing during therapy and every 3 months after therapy discontinuance.1 23 Initial testing should be performed by a clinician.1

To enhance compliance with pregnancy testing, a limited supply of acitretin should be prescribed.1

Pregnancy must be prevented by simultaneous use of 2 forms of reliable contraception (unless patient is absolutely abstinent, has undergone a hysterectomy, or is postmenopausal) for at least 1 month prior to therapy initiation, during, and for at least 3 years following cessation of therapy.1 2 3 23 (See Advice to Patients.)

For detailed information regarding the program's requirements, consult the manufacturer's prescribing information; prescribers should contact the manufacturer to obtain information on materials available for the program.1 23 To obtain further information regarding contraception options, patients should contact the Birth Control Counseling line at 800-739-6700.23

Depression and other psychiatric symptoms (e.g., aggressive feelings, self-injurious thoughts or behaviors, suicidal thoughts) reported;1 6 not known whether related to acitretin or to other factors.1 Such events also reported with other systemic retinoids.1

Patients who experience symptoms of depression or other psychiatric symptoms during acitretin therapy should discontinue the drug and immediately notify their prescribing clinician.1

Concomitant use of phototherapy and acitretin may result in increased risk of erythema (e.g., burning); if concomitant use cannot be avoided, substantially reduce the phototherapy dose based upon patient response.1

Specific Populations

Category X.1 8 19 Report all pregnancies during therapy or up to 3 years following discontinuance of drug to Stiefel Laboratories at 888-500-3376 or to FDA MedWatch Program at 800-FDA-1088.1 23 (See Fetal/Neonatal Morbidity and Mortality under Cautions and also see Teratogenicity in Boxed Warning.)

Distributed into milk;1 18 women receiving acitretin should not breast-feed.1 15 23

Safety and efficacy not established.1 23

Ossification of interosseous ligaments and tendons of the extremities, skeletal hyperostoses, decreases in bone mineral density, and premature epiphyseal closure reported in children with other systemic retinoids, including etretinate (no longer commercially available in US).1 9 A causal relationship has not been established between the use of acitretin and these effects, and it is unknown whether these occurrences are more severe or appear more frequently in children.1 However, the manufacturer states that there is special concern because of the implications for growth potential in this population.1

Insufficient clinical trial experience in patients ≥65 years of age to determine whether geriatric patients respond differently than younger adults.1 Other reported clinical experience has not identified differences in responses between geriatric and younger patients.1 (See Geriatric Patients under Dosage and Administration.)

Common Adverse Effects

Cheilitis, alopecia, skin peeling, rhinitis, dry skin, nail disorder, pruritus, rigors, xerophthalmia, dry mouth, epistaxis, arthralgia, spinal hyperostosis, rash, hyperesthesia, paresthesia, paronychia, skin atrophy.1 3 5 6 7 8 9 11 15 17 19

Many reported adverse effects resemble those associated with hypervitaminosis A.1

Laboratory abnormalities (e.g., increased or decreased electrolytes, hematocrit, hemoglobin, and glucose; increased liver transaminases, uric acid, BUN, and total and LDL-cholesterol; decreased HDL-cholesterol).1 (See Hepatic Effects under Cautions and also see Effects on Lipoproteins under Cautions.)

Specific Drugs

Acitretin is not metabolized by hepatic microsomal enzymes.23 (See Metabolism under Pharmacokinetics.)

• Exact mechanism of action in the treatment of psoriasis is not fully understood, but may involve inhibiting the conversion of retinol to retinoic acid, stimulating the metabolism and buffering of retinoic acid by increasing levels of cellular retinoic acid binding protein-2 (CRABP 2), and/or altering the metabolism of endogenous retinoids at the level of degradation.1 4

• Modulates epidermal proliferation and cellular differentiation; demonstrates antiproliferative effect on epidermal keratinocytes in a hyperproliferative system, resulting in decreased scaling, erythema, and thickness of plaques and stratum corneum; promotes cellular proliferation in normoproliferative systems.5 6 8 9 13 17 19

• Activates retinoid X receptors (RXR) and the α, β, and γ subtypes of retinoic acid receptors (RAR); potentiates epidermal growth factor-induced cell growth; increases activity of cyclic adenosine monophosphate (cAMP)-dependent protein kinases, RI (involved in cell proliferation), and RII (involved in cell differentiation and growth inhibition) in deficient areas of psoriatic fibroblasts; inhibits chemotactic responses; decreases polymorphonuclear leukocyte migration/accumulation; and increases the number of Langerhans cells in normal and psoriatic skin.4 6 8 9 17 19

• Exhibits antineoplastic activity in vitro.17

• Has teratogenic effects.1 (See Boxed Warning.)

US labeling:

Psoriasis: Oral: Individualization of dosage is required to achieve maximum therapeutic response while minimizing side effects

Initial: 25 to 50 mg daily, given as a single dose with the main meal

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

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

Canadian labeling:

Psoriasis: Oral:

Initial: 25 mg daily, given as a single dose with the main meal. If response is inadequate after 4 weeks of therapy, the dose may be gradually increased (as tolerated) up to a maximum of 75 mg daily. Reduce dose if necessary to minimize side effects.

Maintenance: 25 to 50 mg daily may be given after initial response to treatment; the maintenance dose should be based on clinical efficacy and tolerability. Maximum: 75 mg daily

Other keratinization disorders: Adults: Oral: 10 to 50 mg daily; maximum: 50 mg daily

There are no dosage adjustments provided in manufacturer’s labeling; use is contraindicated in patients with severely impaired liver function.

SORIATANE (acitretin), a retinoid, is available in 10-mg, 17.5-mg, and 25-mg gelatin capsules for oral administration. Chemically, acitretin is all-trans-9-(4-methoxy-2,3,6trimethylphenyl)-3,7-dimethyl-2,4,6,8-nonatetraenoic acid. It is a metabolite of etretinate and is related to both retinoic acid and retinol (vitamin A). It is a yellow to greenish-yellow powder with a molecular weight of 326.44. The structural formula is:

so

Each capsule contains acitretin, black monogramming ink, gelatin, maltodextrin (a mixture of polysaccharides), microcrystalline cellulose, and sodium ascorbate.

Gelatin capsule shells contain gelatin, iron oxide (yellow, black, and red), and titanium dioxide. They may also contain benzyl alcohol, carboxymethylcellulose sodium, edetate calcium disodium.

Acitretin is part of the drug class:

• Retinoids for treatment of psoriasis

Use is contraindicated. Excreted into human milk: Yes Comments: The effects in the nursing infant are unknown.