Acitretin: Package Insert and Label Information (Page 3 of 6)

INDICATIONS AND USAGE

Acitretin capsules are indicated for the treatment of severe psoriasis in adults. Because of significant adverse effects associated with its use, acitretin capsules should be prescribed only by those knowledgeable in the systemic use of retinoids. In females of reproductive potential, acitretin capsules should be reserved for non-pregnant patients who are unresponsive to other therapies or whose clinical condition contraindicates the use of other treatments (see boxed CONTRAINDICATIONS AND WARNINGS — Acitretin capsules can cause severe birth defects).

Most patients experience relapse of psoriasis after discontinuing therapy. Subsequent courses, when clinically indicated, have produced efficacy results similar to the initial course of therapy.

CONTRAINDICATIONS

Pregnancy Category X

(See boxed CONTRAINDICATIONS AND WARNINGS.)

Acitretin capsules are contraindicated in patients with severely impaired liver or kidney function and in patients with chronic abnormally elevated blood lipid values (see boxed WARNINGS: Hepatotoxicity,WARNINGS: Lipids and Possible Cardiovascular Effects, and PRECAUTIONS).

An increased risk of hepatitis has been reported to result from combined use of methotrexate and etretinate. Consequently, the combination of methotrexate with acitretin capsules is also contraindicated (see PRECAUTIONS: Drug Interactions).

Since both acitretin capsules and tetracyclines can cause increased intracranial pressure, their combined use is contraindicated (see WARNINGS: Pseudotumor Cerebri).

Acitretin capsules are contraindicated in cases of hypersensitivity (e.g., angioedema, urticaria) to the preparation (acitretin or excipients) or to other retinoids.

WARNINGS

(See also boxed CONTRAINDICATIONS AND WARNINGS.)

Hepatotoxicity: Of the 525 subjects treated in U.S. clinical trials, 2 had clinical jaundice with elevated serum bilirubin and transaminases considered related to treatment with acitretin capsules. Liver function test results in these subjects returned to normal after acitretin capsules were discontinued. Two of the 1,289 subjects treated in European clinical trials developed biopsy-confirmed toxic hepatitis. A second biopsy in one of these subjects revealed nodule formation suggestive of cirrhosis. One subject in a Canadian clinical trial of 63 subjects developed a 3-fold increase of transaminases. A liver biopsy of this subject showed mild lobular disarray, multifocal hepatocyte loss, and mild triaditis of the portal tracts compatible with acute reversible hepatic injury. The subject’s transaminase levels returned to normal 2 months after acitretin capsules were discontinued.

The potential of therapy with acitretin capsules to induce hepatotoxicity was prospectively evaluated using liver biopsies in an open-label trial of 128 subjects. Pretreatment and posttreatment biopsies were available for 87 subjects. A comparison of liver biopsy findings before and after therapy revealed 49 (58%) subjects showed no change, 21 (25%) improved, and 14 (17%) subjects had a worsening of their liver biopsy status. For 6 subjects, the classification changed from class 0 (no pathology) to class I (normal fatty infiltration; nuclear variability and portal inflammation; both mild); for 7 subjects, the change was from class I to class II (fatty infiltration, nuclear variability, portal inflammation, and focal necrosis; all moderate to severe); and for 1 subject, the change was from class II to class IIIb (fibrosis, moderate to severe). No correlation could be found between liver function test result abnormalities and the change in liver biopsy status, and no cumulative dose relationship was found.

Elevations of AST (SGOT), ALT (SGPT), GGT (GGTP), or LDH have occurred in approximately 1 in 3 subjects treated with acitretin capsules. Of the 525 subjects treated in clinical trials in the U.S., treatment was discontinued in 20 (3.8%) due to elevated liver function test results. If hepatotoxicity is suspected during treatment with acitretin capsules, the drug should be discontinued and the etiology further investigated.

Ten of 652 subjects treated in U.S. clinical trials of etretinate, of which acitretin is the active metabolite, had clinical or histologic hepatitis considered to be possibly or probably related to etretinate treatment.

There have been reports of hepatitis-related deaths worldwide; a few of these subjects had received etretinate for a month or less before presenting with hepatic symptoms or signs.

Skeletal Abnormalities

In adults receiving long-term treatment with acitretin capsules, appropriate examinations should be periodically performed in view of possible ossification abnormalities (see ADVERSE REACTIONS). Because the frequency and severity of iatrogenic bony abnormality in adults is low, periodic radiography is only warranted in the presence of symptoms or long-term use of acitretin capsules. If such disorders arise, the continuation of therapy should be discussed with the patient on the basis of a careful risk/benefit analysis. In clinical trials with acitretin capsules, subjects were prospectively evaluated for evidence of development or change in bony abnormalities of the vertebral column, knees, and ankles.

Of 380 subjects treated with acitretin capsules, 15% had preexisting abnormalities of the spine which showed new changes or progression of preexisting findings. Changes included degenerative spurs, anterior bridging of spinal vertebrae, diffuse idiopathic skeletal hyperostosis, ligament calcification, and narrowing and destruction of a cervical disc space. De novo changes (formation of small spurs) were seen in 3 subjects after 1½ to 2½ years.

Six of 128 subjects treated with acitretin capsules showed abnormalities in the knees and ankles before treatment that progressed during treatment. In 5, these changes involved the formation of additional spurs or enlargement of existing spurs. The sixth subject had degenerative joint disease which worsened. No subjects developed spurs de novo. Clinical complaints did not predict radiographic changes.

Lipids and Possible Cardiovascular Effects

Blood lipid determinations should be performed before acitretin capsules are administered and again at intervals of 1 to 2 weeks until the lipid response to the drug is established, usually within 4 to 8 weeks. In subjects receiving acitretin capsules during clinical trials, 66% and 33% experienced elevation in triglycerides and cholesterol, respectively. Decreased high density lipoproteins (HDL) occurred in 40% of subjects. These effects of acitretin capsules were generally reversible upon cessation of therapy.

Subjects with an increased tendency to develop hypertriglyceridemia included those with disturbances of lipid metabolism, diabetes mellitus, obesity, increased alcohol intake, or a familial history of these conditions. Because of the risk of hypertriglyceridemia, serum lipids must be more closely monitored in high-risk patients and during long-term treatment.

Hypertriglyceridemia and lowered HDL may increase a patient’s cardiovascular risk status. Although no causal relationship has been established, there have been postmarketing reports of acute myocardial infarction or thromboembolic events in patients on therapy with acitretin capsules. In addition, elevation of serum triglycerides to greater than 800 mg per dL has been associated with fatal fulminant pancreatitis. Therefore, dietary modifications, reduction in dose of acitretin capsules, or drug therapy should be employed to control significant elevations of triglycerides. If, despite these measures, hypertriglyceridemia and low HDL levels persist, the discontinuation of acitretin capsules should be considered.

Ophthalmologic Effects

The eyes and vision of 329 subjects treated with acitretin capsules were examined by ophthalmologists. The findings included dry eyes (23%), irritation of eyes (9%), and brow and lash loss (5%). The following were reported in less than 5% of subjects: Bell’s Palsy, blepharitis and/or crusting of lids, blurred vision, conjunctivitis, corneal epithelial abnormality, cortical cataract, decreased night vision, diplopia, itchy eyes or eyelids, nuclear cataract, pannus, papilledema, photophobia, posterior subcapsular cataract, recurrent sties, and subepithelial corneal lesions.

Any patient treated with acitretin capsules who is experiencing visual difficulties should discontinue the drug and undergo ophthalmologic evaluation.

Pancreatitis

Lipid elevations occur in 25% to 50% of subjects treated with acitretin capsules. Triglyceride increases sufficient to be associated with pancreatitis are much less common, although fatal fulminant pancreatitis has been reported. There have been rare reports of pancreatitis during therapy with acitretin capsules in the absence of hypertriglyceridemia.

Pseudotumor Cerebri

Acitretin capsules and other retinoids administered orally have been associated with cases of pseudotumor cerebri (benign intracranial hypertension). Some of these events involved concomitant use of isotretinoin and tetracyclines. However, the event seen in a single patient receiving acitretin capsules was not associated with tetracycline use. Early signs and symptoms include papilledema, headache, nausea and vomiting, and visual disturbances. Patients with these signs and symptoms should be examined for papilledema and, if present, should discontinue acitretin capsules immediately and be referred for neurological evaluation and care. Since both acitretin capsules and tetracyclines can cause increased intracranial pressure, their combined use is contraindicated (see CONTRAINDICATIONS).

Capillary Leak Syndrome

Capillary leak syndrome, a potential manifestation of retinoic acid syndrome, has been reported in patients receiving acitretin capsules. Features of this syndrome may include localized or generalized edema with secondary weight gain, fever, and hypotension. Rhabdomyolysis and myalgias have been reported in association with capillary leak syndrome, and laboratory tests may reveal neutrophilia, hypoalbuminemia, and an elevated hematocrit. Discontinue acitretin capsules if capillary leak syndrome develops during therapy.

Exfoliative Dermatitis/Erythroderma

Exfoliative dermatitis/erythroderma has been reported in patients receiving acitretin capsules. Discontinue acitretin capsules if exfoliative dermatitis/erythroderma occurs during therapy.

PRECAUTIONS

A description of the MyMAC materials is provided below. The main goals of the materials are to explain the program requirements, to reinforce the educational messages, and to assess program effectiveness.

The MyMAC booklet includes:

The MyMAC Patient Brochure: information on the program requirements, risks of acitretin, and the types of contraceptive methods
The Contraception Counseling Referral Form for female patients who want to receive free contraception counseling reimbursed by the manufacturer
The Patient Agreement/Informed Consent for Female Patients form
Medication Guide

The MyMAC program also includes a voluntary patient survey for women of childbearing potential to assess the effectiveness of the acitretin capsules Pregnancy Prevention Program, MyMAC. MyMAC program materials are available at www.acitretincommitment.com or may be requested by calling 1-877-446-3679 (1-877-4-INFO-RX).

Information for Patients

(See Medication Guide for all patients and Patient Agreement/Informed Consent for Female Patients at end of professional labeling).

Patients should be instructed to read the Medication Guide supplied as required by law when acitretin capsules are dispensed.

Females of Reproductive Potential

Acitretin capsules can cause severe birth defects. Female patients must not be pregnant when therapy with acitretin capsules is initiated, they must not become pregnant while taking acitretin capsules and for at least 3 years after stopping acitretin capsules, so that the drug can be eliminated to below a blood concentration that would be associated with an increased incidence of birth defects. Because this threshold has not been established for acitretin in humans and because elimination rates vary among patients, the duration of posttherapy contraception to achieve adequate elimination cannot be calculated precisely (see boxed CONTRAINDICATIONS AND WARNINGS).

Females of reproductive potential should also be advised that they must not ingest beverages or products containing ethanol while taking acitretin capsules and for 2 months after acitretin capsules have been discontinued. This allows for elimination of the acitretin which can be converted to etretinate in the presence of alcohol.

Female patients should be advised that any method of birth control can fail, including tubal ligation, and that microdosed progestin “minipill” preparations are not recommended for use with acitretin capsules (see CLINICAL PHARMACOLOGY: Pharmacokinetic Drug Interactions). Data from one patient who received a very low-dosed progestin contraceptive (levonorgestrel 0.03 mg) had a significant increase of the progesterone level after 3 menstrual cycles during acitretin treatment.2

Female patients should be advised to contact their physician, women’s health centers, pharmacies, or hospital emergency rooms for information about how to obtain Emergency Contraception if sexual intercourse occurs without using 2 effective forms of contraception simultaneously. A 24-hour, toll-free number (1-888-858-5236) is also available for patients to receive automated birth control and emergency contraception information.

Female patients should sign a consent form prior to beginning therapy with acitretin capsules (see boxed CONTRAINDICATIONS AND WARNINGS).

Nursing Mothers

Studies on lactating rats have shown that etretinate is excreted in the milk. There is one prospective case report where acitretin is reported to be excreted in human milk. Therefore, nursing mothers should not receive acitretin capsules prior to or during nursing because of the potential for serious adverse reactions in nursing infants.

All Patients

Depression and/or other psychiatric symptoms such as aggressive feelings or thoughts of self-harm have been reported. These events, including self-injurious behavior, have been reported in patients taking other systemically administered retinoids, as well as in patients taking acitretin capsules. Since other factors may have contributed to these events, it is not known if they are related to acitretin capsules. Patients should be counseled to stop taking acitretin capsules and notify their prescriber immediately if they experience psychiatric symptoms.

Patients should be advised that a transient worsening of psoriasis is sometimes seen during the initial treatment period. Patients should be advised that they may have to wait 2 to 3 months before they get the full benefit of acitretin capsules, although some patients may achieve significant improvements within the first 8 weeks of treatment as demonstrated in clinical trials.

Decreased night vision has been reported during therapy with acitretin capsules. Patients should be advised of this potential problem and warned to be cautious when driving or operating any vehicle at night. Visual problems should be carefully monitored (see WARNINGS and ADVERSE REACTIONS). Patients should be advised that they may experience decreased tolerance to contact lenses during the treatment period and sometimes after treatment has stopped.

Patients should not donate blood during and for at least 3 years following therapy because acitretin capsules can cause birth defects and women of childbearing potential must not receive blood from patients being treated with acitretin capsules.

Because of the relationship of acitretin to vitamin A, patients should be advised against taking vitamin A supplements in excess of minimum recommended daily allowances to avoid possible additive toxic effects.

Patients should avoid the use of sun lamps and excessive exposure to sunlight (non-medical UV exposure) because the effects of UV light are enhanced by retinoids.

Patients should be advised that they must not give their acitretin capsules to any other person.

For Prescribers

Acitretin capsules have not been studied in and is not indicated for treatment of acne.

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