Acitretin - Warnings and Precautions

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.