Soriatane

Soriatane

WARNINGS

(See also BOXED CONTRAINDICATIONS AND WARNINGS.)

Hepatotoxicity

Of the 525 subjects treated in US clinical trials, 2 had clinical jaundice with elevated serum bilirubin and transaminases considered related to treatment with SORIATANE. Liver function test results in these subjects returned to normal after SORIATANE was 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 SORIATANE was discontinued.

The potential of therapy with SORIATANE 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 SORIATANE. Of the 525 subjects treated in clinical trials in the US, treatment was discontinued in 20 (3.8%) due to elevated liver function test results. If hepatotoxicity is suspected during treatment with SORIATANE, the drug should be discontinued and the etiology further investigated.

Ten of 652 subjects treated in US 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.

Hyperostosis

In adults receiving long-term treatment with SORIATANE, 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 SORIATANE. 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 SORIATANE, subjects were prospectively evaluated for evidence of development or change in bony abnormalities of the vertebral column, knees, and ankles.

Vertebral Results

Of 380 subjects treated with SORIATANE, 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.

Skeletal Appendicular Results

Six of 128 subjects treated with SORIATANE 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 SORIATANE is 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 SORIATANE 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 SORIATANE 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 SORIATANE. In addition, elevation of serum triglycerides to greater than 800 mg/dL has been associated with fatal fulminant pancreatitis. Therefore, dietary modifications, reduction in dose of SORIATANE, 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 SORIATANE should be considered.

Ophthalmologic Effects

The eyes and vision of 329 subjects treated with SORIATANE 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 patients: 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 SORIATANE who is experiencing visual difficulties should discontinue the drug and undergo ophthalmologic evaluation.

Pancreatitis

Lipid elevations occur in 25% to 50% of patients treated with SORIATANE. 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 SORIATANE in the absence of hypertriglyceridemia.

Pseudotumor Cerebri

SORIATANE 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 SORIATANE 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 SORIATANE immediately and be referred for neurological evaluation and care. Since both SORIATANE 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 SORIATANE. 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 SORIATANE if capillary leak syndrome develops during therapy.

Exfoliative Dermatitis/Erythroderma

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

PRECAUTIONS

A description of the Do Your P.A.R.T. 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 Do Your P.A.R.T. booklet includes:

  • The Do Your P.A.R.T. Patient Brochure: information on the program requirements, risks of acitretin, and the types of contraceptive methods
  • The Contraceptive Counseling Referral Form for female patients who want to receive free contraception counseling reimbursed by the manufacturer
  • The Patient Agreement/Informed Consent Form for female patients
  • Medication Guide

The Do Your P.A.R.T. program also includes a voluntary patient survey for women of childbearing potential to assess the effectiveness of the SORIATANE Pregnancy Prevention Program Do Your P.A.R.T. Do Your P.A.R.T Program materials are available at www.soriatane.com/doyour-part-Program.html or may be requested by calling 1-888-784-3335 (1-888-STIEFEL).

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 SORIATANE is dispensed.

Females of Reproductive Potential: SORIATANE can cause severe birth defects. Female patients must not be pregnant when therapy with SORIATANE is initiated, they must not become pregnant while taking SORIATANE and for at least 3 years after stopping SORIATANE, 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 SORIATANE and for 2 months after SORIATANE has 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 SORIATANE (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 sign a consent form prior to beginning therapy with SORIATANE (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 SORIATANE 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 SORIATANE. Since other factors may have contributed to these events, it is not known if they are related to SORIATANE. Patients should be counseled to stop taking SORIATANE 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 SORIATANE, 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 SORIATANE. 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 SORIATANE can cause birth defects and women of childbearing potential must not receive blood from patients being treated with SORIATANE.

Because of the relationship of SORIATANE 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 SORIATANE to any other person.

For Prescribers

SORIATANE has not been studied in and is not indicated for treatment of acne.

Phototherapy

Significantly lower doses of phototherapy are required when SORIATANE is used because effects on the stratum corneum induced by SORIATANE can increase the risk of erythema (burning) (see DOSAGE AND ADMINISTRATION).

Carcinogenesis, Mutagenesis, Impairment Of Fertility

Carcinogenesis

A carcinogenesis study of acitretin in Wistar rats, at doses up to 2 mg/kg/day administered 7 days/week for 104 weeks, has been completed. There were no neoplastic lesions observed that were considered to have been related to treatment with acitretin. An 80-week carcinogenesis study in mice has been completed with etretinate, the ethyl ester of acitretin. Blood level data obtained during this study demonstrated that etretinate was metabolized to acitretin and that blood levels of acitretin exceeded those of etretinate at all times studied. In the etretinate study, an increased incidence of blood vessel tumors (hemangiomas and hemangiosarcomas at several different sites) was noted in male, but not female, mice at doses approximately one-half the maximum recommended human therapeutic dose based on a mg/m² comparison.

Mutagenesis

Acitretin was evaluated for mutagenic potential in the Ames test, in the Chinese hamster (V79/HGPRT) assay, in unscheduled DNA synthesis assays using rat hepatocytes and human fibroblasts, and in an in vivo mouse micronucleus assay. No evidence of mutagenicity of acitretin was demonstrated in any of these assays.

Impairment of Fertility

In a fertility study in rats, the fertility of treated animals was not impaired at the highest dosage of acitretin tested, 3 mg/kg/day (approximately one-half the maximum recommended therapeutic dose based on a mg/m² comparison). Chronic toxicity studies in dogs revealed testicular changes (reversible mild to moderate spermatogenic arrest and appearance of multinucleated giant cells) in the highest dosage group (50 then 30 mg/kg/day).

No decreases in sperm count or concentration and no changes in sperm motility or morphology were noted in 31 men (17 psoriatic subjects, 8 subjects with disorders of keratinization, and 6 healthy volunteers) given 30 to 50 mg/day of acitretin for at least 12 weeks. In these trials, no deleterious effects were seen on either testosterone production, LH, or FSH in any of the 31 men.4-6 No deleterious effects were seen on the hypothalamic-pituitary axis in any of the 18 men where it was measured.4,5

Pregnancy

Teratogenic Effects

Pregnancy Category X (see BOXED CONTRAINDICATIONS AND WARNINGS).

In a study in which acitretin was administered to male rats only at a dosage of 5 mg/kg/day for 10 weeks (approximate duration of one spermatogenic cycle) prior to and during mating with untreated female rats, no teratogenic effects were observed in the progeny (see BOXED CONTRAINDICATIONS AND WARNINGSfor information about male use of SORIATANE).

Nonteratogenic Effects

In rats dosed at 3 mg/kg/day (approximately one-half the maximum recommended therapeutic dose based on a mg/m² comparison), slightly decreased pup survival and delayed incisor eruption were noted. At the next lowest dose tested, 1 mg/kg/day, no treatment-related adverse effects were observed.

Pediatric Use

Safety and effectiveness in pediatric patients have not been established. No clinical trials have been conducted in pediatric subjects. Ossification of interosseous ligaments and tendons of the extremities, skeletal hyperostoses, decreases in bone mineral density, and premature epiphyseal closure have been reported in children taking other systemic retinoids, including etretinate, a metabolite of SORIATANE. A causal relationship between these effects and SORIATANE has not been established. While it is not known that these occurrences are more severe or more frequent in children, there is special concern in pediatric patients because of the implications for growth potential (see WARNINGS: Hyperostosis).

Geriatric Use

Clinical trials of SORIATANE did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently than younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger subjects. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy. A 2-fold increase in acitretin plasma concentrations was seen in healthy elderly subjects compared with young subjects, although the elimination half-life did not change (see CLINICAL PHARMACOLOGY: Special Populations).

REFERENCES

2. Maier H, Honigsmann H: Concentration of etretinate in plasma and subcutaneous fat after long-term acitretin. Lancet 348:1107, 1996.

4. Sigg C, et al.: Andrological investigations in patients treated with etretin. Dermatologica 175:48-49, 1987.

5. Parsch EM, et al.: Andrological investigation in men treated with acitretin (Ro 10-1670). Andrologia 22:479-482, 1990.

6. Kadar L, et al.: Spermatological investigations in psoriatic patients treated with acitretin. In: Pharmacology of Retinoids in the Skin; Reichert U. et al., ed, KARGER, Basel, vol. 3, pp 253-254, 1988.

Last reviewed on RxList: 6/3/2014
This monograph has been modified to include the generic and brand name in many instances.

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