The following text is complete prescribing information based on official labeling in effect June 2000.

Soriatane (acitretin), a retinoid, is available in 10 mg and 25 mg gelatin capsules for oral administration. Chemically, acitretin is all- trans -9-(4-methoxy-2,3,6-trimethylphenyl)-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.

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

Gelatin capsule shells contain gelatin, parabens (methyl and propyl), iron oxide (yellow, black, and red), and titanium dioxide. They may also contain benzyl alcohol, butyl paraben, carboxymethylcellulose sodium, edetate calcium disodium, potassium sorbate and/or sodium propionate.

The mechanism of action of Soriatane is unknown.

Absorption: Oral absorption of acitretin is optimal when given with food. For this reason, acitretin was given with food in all of the following studies. After administration of a single 50 mg oral dose of acitretin to 18 healthy subjects, maximum plasma concentrations ranged from 196 to 728 ng/mL (mean 416 ng/mL) and were achieved in 2 to 5 hours (mean 2.7 hours). The oral absorption of acitretin is linear and proportional with increasing doses from 25 to 100 mg. Approximately 72% (range 47% to 109%) of the administered dose was absorbed after a single 50 mg dose of acitretin was given to 12 healthy subjects.

Distribution Acitretin is more than 99.9% bound to plasma proteins, primarily albumin.

Metabolism (see Pharmacokinetic Drug Interactions: Ethanol ): Following oral absorption, acitretin undergoes extensive metabolism and interconversion by simple isomerization to its 13- cis form ( cis -acitretin). The formation of cis -acitretin relative to parent compound is not altered by dose or fed/fast conditions of oral administration of acitretin. Both parent compound and isomer are further metabolized into chain-shortened breakdown products and conjugates which are excreted.

Following multiple-dose administration of acitretin, steady-state concentrations of acitretin and cis -acitretin in plasma are achieved within approximately 3 weeks.

Elimination The chain-shortened metabolites and conjugates of acitretin and cis -acitretin are ultimately excreted in the feces (34% to 54%) and urine (16% to 53%). The terminal elimination half-life of acitretin following multiple-dose administration is 49 hours (range 33 to 96 hours), and that of cis -acitretin under the same conditions is 63 hours (range 28 to 157 hours). The accumulation ratio of the parent compound is 1.2; that of cis -acitretin is 6.6.

Special Populations: Psoriasis In an 8-week study of acitretin pharmacokinetics in patients with psoriasis, mean steady-state trough concentrations of acitretin increased in a dose proportional manner with dosages ranging from 10 to 50 mg daily. Acitretin plasma concentrations were nonmeasurable (<4 ng/mL) in all patients 3 weeks after cessation of therapy.

Elderly: In a multiple-dose study in healthy young (n=6) and elderly (n=8) subjects, a two-fold increase in acitretin plasma concentrations were seen in elderly subjects, although the elimination half-life did not change.

Renal Failure: Plasma concentrations of acitretin were significantly (59.3%) lower in end-stage renal failure subjects (n=6) when compared to age-matched controls, following single 50 mg oral doses. Acitretin was not removed by hemodialysis in these subjects.

Pharmacokinetic Drug Interactions (see also boxed CONTRAINDICATIONS AND and PRECAUTIONS : Drug Interactions ): In studies of in vivo pharmacokinetic drug interactions, no interaction was seen between acitretin and cimetidine, digoxin, phenprocoumon or glyburide.

Ethanol: Clinical evidence has shown that etretinate (a retinoid with a much longer half-life, see below) can be formed with concurrent ingestion of acitretin and ethanol. In a two-way crossover study, all 10 subjects formed etretinate with concurrent ingestion of a single 100 mg oral dose of acitretin during a 3-hour period of ethanol ingestion (total ethanol, approximately 1.4 g/kg body weight). A mean peak etretinate concentration of 59 ng/mL (range 22 to 105 ng/mL) was observed, and extrapolation of AUC values indicated that the formation of etretinate in this study was comparable to a single 5 mg oral dose of etretinate. There was no detectable formation of etretinate when a single 100 mg oral dose of acitretin was administered without concurrent ethanol ingestion, although the formation of etretinate without concurrent ethanol ingestion cannot be excluded (see boxed CONTRAINDICATIONS AND ). Of 93 evaluable psoriatic patients on acitretin therapy in several foreign studies (10 to 80 mg/day), 16% had measurable etretinate levels (>5 ng/mL).

Etretinate has a much longer elimination half-life compared to that of acitretin. In one study the apparent mean terminal half-life after 6 months of therapy was approximately 120 days (range 84 to 168 days). In another study of 47 patients treated chronically with etretinate, 5 had detectable serum drug levels (in the range of 0.5 to 12 ng/mL) 2.1 to 2.9 years after therapy was discontinued. The long half-life appears to be due to storage of etretinate in adipose tissue.

Progestin-only Contraceptives: It has not been established if there is a pharmacokinetic interaction between acitretin and combined oral contraceptives. However, it has been established that acitretin interferes with the contraceptive effect of microdosed progestin preparations. ² It is not known whether other progestational contraceptives, such as implants and injectables, are inadequate methods of contraception during acitretin therapy.

Soriatane is indicated for the treatment of severe psoriasis, including the erythrodermic and generalized pustular types, in adults. Because of significant adverse effects associated with its use, Soriatane should be prescribed only by physicians knowledgeable in the systemic use of retinoids. In females of reproductive potential, Soriatane should be reserved for patients who are unresponsive to other therapies or whose clinical condition contraindicates the use of other treatments.

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

CONTRAINDICATIONS

Pregnancy Category X (see boxed CONTRAINDICATIONS AND )

(See also boxed CONTRAINDICATIONS AND )

Ophthalmologic Effects: The eyes and vision of 329 patients 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' 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.

Hyperostosis: In clinical trials with Soriatane, patients were prospectively evaluated for evidence of development or change in bony abnormalities of the vertebral column, knees and ankles.

Vertebral Results: Of 380 patients 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 patients after 1 ¹ / ₂ to 2 ¹ / ₂ years.

Skeletal Appendicular Results: Six of 128 patients 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 patient had degenerative joint disease which worsened. No patients developed spurs de novo. Clinical complaints did not predict radiographic changes.

Lipids: 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 patients receiving Soriatane during clinical trials, 66% and 33% experienced elevation in triglycerides and cholesterol, respectively. Decreased high density lipoproteins (HDL) occurred in 40%. These effects of Soriatane were generally reversible upon cessation of therapy.

Patients with an increased tendency to develop hypertriglyceridemia included those with diabetes mellitus, obesity, increased alcohol intake or a familial history of these conditions.

Hypertriglyceridemia and lowered HDL may increase a patient' cardiovascular risk status. In addition, elevation of serum triglycerides to greater than 800 mg/dL has been associated with fatal fulminant pancreatitis. Therefore, dietary modifications, reduction in Soriatane dose, or drug therapy should be employed to control significant elevations of triglycerides.

Animal Studies: Subchronic and chronic toxicity studies in rats and dogs revealed dose-related, reversible signs of intolerance typical of retinoids. In rats, decreased body weight gain and increases in serum cholesterol, triglycerides, lipoproteins and alkaline phosphatase were observed; fractures and evidence of healed fractures were also noted. In dogs, signs of intolerance included erythema, skin hypertrophy/hyperplasia and testicular changes. In dogs, the dosages studied were as much as ten times the recommended human dosage; in rats, one to two times. Most of the side effects were readily reversible after cessation of treatment, except for epiphyseal ossification.

Acitretin shares with vitamin A and other retinoids the potential to cause malformations in the offspring of various species, including mouse, rat and rabbit, even at dosage levels recommended for humans. Since acitretin is teratogenic in animals at human dosage levels, females of reproductive potential must not be treated if pregnancy cannot be excluded.

PRECAUTIONS

General: Caution is advised in patients with severely impaired liver or kidney function (see ). Soriatane should not be given to patients who are sensitive to parabens, which are used as preservatives in the gelatin capsule.

Information for Patients: Females of reproductive potential should be advised that they must not be pregnant when Soriatane therapy is initiated and that they should use effective contraception for at least 1 month prior to Soriatane therapy, and while taking Soriatane. Acitretin, the active metabolite of etretinate, is teratogenic and is contraindicated during pregnancy. The risk of severe fetal malformation is well established when systemic retinoids are taken during pregnancy. Pregnancy must also be prevented after stopping acitretin therapy, while the drug is being eliminated to below a threshold 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. It is strongly recommended that contraception be continued for at least 3 years after stopping treatment with acitretin, based on the following considerations:

• In the absence of transesterification to form etretinate, greater than 98% of the acitretin would be eliminated within 2 months, assuming a mean elimination half-life of 49 hours.
• In cases where etretinate is formed, as has been demonstrated with concomitant administration of acitretin and ethanol,
  • greater than 98% of the etretinate formed would be eliminated in 2 years, assuming a mean elimination half-life of 120 days.
  • greater than 98% of the etretinate formed would be eliminated in 3 years, based on the longest demonstrated elimination half-life of 168 days. However, etretinate was found in plasma and subcutaneous fat in one patient reported to have had sporadic alcohol intake, 52 months after she stopped acitretin therapy. ¹

• An increased incidence of birth defects was estimated based on a limited number of cases which have been reported to Roche, which were identified before the outcome was known, and where pregnancy occurred during the time interval when the patient was being treated with acitretin or etretinate. For cases identified after the outcome was known, severe birth defects have been reported where pregnancy occurred during the time interval when the patient was being treated with acitretin or etretinate.
• There have been 202 cases reported before the outcome was known where pregnancy occurred after the last dose of etretinate or acitretin. Fetal outcome remained unknown in approximately one-half of these cases, of which 62 were terminated and 11 were spontaneous abortions. Fetal outcome is known for 103 of these prospectively reported cases. Fifteen of the outcomes were abnormal: hernia, hypocalcemia, hypotonia, undescended testicle, laparoschisis, absent hand/wrist, clubfoot, ichthyosis, apnea/anemia, placental disorder/death and premature birth (5). Birth defects have also been reported retrospectively (ie, after the outcome was known). Among the retrospectively reported cases where pregnancy occurred more than 2 years after the last dose of etretinate or acitretin, there are 2 normal outcomes, 3 unknown outcomes and 7 abnormal outcomes. The 7 abnormal outcomes reported are: malformation unspecified, aplasia of the forearm, stillbirth, right ventricular/aortic duct defect, heart malformation unspecified, and chromosomal disorder (2). For these listed reports, the relationship of the birth defects to the drug is unknown.

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 treatment has been discontinued. This allows for elimination of the acitretin which can be converted to etretinate in the presence of alcohol. They should be advised that certain methods of birth control can fail, including tubal ligation and microdosed progestin "minipill" preparations. 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 three menstrual cycles during acitretin treatment. ² Female patients should sign a consent form prior to beginning Soriatane therapy (see boxed CONTRAINDICATIONS AND ).

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 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 or 3 months before they get the full benefit of Soriatane.

Patients should be advised that they may experience decreased tolerance to contact lenses during the treatment period.

It is recommended that patients not donate blood during and for 3 years following therapy.

Patients should avoid the use of sun lamps and excessive exposure to sunlight because the effects of UV light are enhanced by retinoid therapy.

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

Laboratory Tests: In clinical studies, the incidence of hypertriglyceridemia was 66%, hypercholesterolemia was 33% and that of decreased HDL was 40%. Pretreatment and follow-up measurements should be obtained under fasting conditions. It is recommended that these tests be performed weekly or every other week until the lipid response to Soriatane has stabilized (see ).

Elevations of AST (SGOT), ALT (SGPT) or LDH were experienced by approximately 1 in 3 patients treated with Soriatane. It is recommended that these tests be performed prior to initiation of Soriatane therapy, at 1- to 2-week intervals until stable and thereafter at intervals as clinically indicated.

Certain patients receiving retinoids have experienced problems in the control of their blood sugar. In addition, new cases of diabetes have been diagnosed during retinoid therapy, although no causal relationship has been established.

Drug Interactions: Clinical evidence has shown that etretinate can be formed with concurrent ingestion of acitretin and ethanol (see boxed CONTRAINDICATIONS AND and : ).

In a study of 7 healthy male volunteers, acitretin treatment enhanced clearance of blood glucose in the presence of glibenclamide (a sulfonylurea similar to chlorpropamide) in 3 of the 7 subjects. Repeating the study with 6 healthy male volunteers in the absence of glibenclamide did not detect an effect of acitretin on glucose tolerance. Careful supervision of diabetic patients under treatment with Soriatane is recommended (see : and DOSAGE AND ADMINISTRATION ).

There may be the possibility of an increased risk of hepatotoxicity in patients treated with etretinate and methotrexate concomitantly. Consequently, the concomitant use of Soriatane and methotrexate should be avoided.

There appears to be no pharmacokinetic interaction between acitretin and cimetidine, digoxin, phenprocoumon or glyburide.

It has not been established if there is a pharmacokinetic interaction between acitretin and combined oral contraceptives. However, it has been established that acitretin interferes with the contraceptive effect of microdosed progestin "minipill" preparations. It is not known whether other progestational contraceptives, such as implants and injectables, may be inadequate methods of contraception during acitretin therapy.

Carcinogenesis, Mutagenesis and 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. A 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 5.7 to 7.1 times the maximum recommended human therapeutic dose.

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 three times the maximum recommended therapeutic dose). 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 patients, 8 patients with disorders of keratinization and 6 healthy volunteers) given 30 to 50 mg/day of acitretin for at least 12 weeks. In these studies, no deleterious effects were seen on either testosterone production, LH or FSH in any of the 31 men. ^3-5 No deleterious effects were seen on the hypothalamic-pituitary axis in any of the 18 men where it was measured. ^3,4

Pregnancy: Teratogenic Effects: Pregnancy Category X (see boxed CONTRAINDICATIONS AND ).

Effective contraception must be used by female patients of reproductive potential for at least 1 month before beginning Soriatane therapy, during therapy and for at least 3 years following discontinuation of therapy. This warning applies even where there has been a history of infertility, unless due to hysterectomy.

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.

Samples of seminal fluid from 3 male patients treated with acitretin and 6 male patients treated with etretinate have been assayed for the presence of acitretin. The maximum concentration of acitretin observed in the seminal fluid of these men was 12.5 ng/mL. Assuming an ejaculate volume of 10 mL, the amount of drug transferred in semen would be 125 ng, which is 1/200,000 of a single 25 mg capsule.

It is not known whether residual acitretin in seminal fluid poses risk to a fetus while a male patient is taking the drug or after it is discontinued. There have been five pregnancies reported in which the male partner was undergoing Soriatane treatment. One pregnancy resulted in a normal infant. Two pregnancies ended in spontaneous abortions. In one case the fetus had bilateral cystic hygromas and multiple cardiopulmonary malformations: the relationship of these malformations to the drug is unknown. The outcome of the fifth case is unknown.

Nonteratogenic Effects: In rats dosed at 3 mg/kg/day (approximately three times the maximum recommended therapeutic dose), 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.

Nursing Mothers: Studies on lactating rats have shown that etretinate is excreted in the milk. However, it is not known whether either etretinate or acitretin is excreted in human milk. However, nursing mothers should not receive Soriatane because of the potential for excretion in milk and serious adverse reactions in nursing infants.

Pediatric Use: No clinical studies have been conducted in pediatric patients. Therefore, safety and effectiveness in pediatric patients have not been established. Ossification of interosseous ligaments and tendons of the extremities, skeletal hyperostoses and premature epiphyseal closure have been reported with other systemic retinoids. While it is not known that these occurrences are more severe or more frequent in children, there is concern in pediatric patients because of the implications for growth potential.

ADVERSE EVENTS

During clinical trials with acitretin, 513/525 (98%) of patients reported a total of 3545 adverse events. One-hundred sixteen patients left studies prematurely, primarily because of adverse experiences involving the mucous membranes and skin. Three patients died. Two of the deaths were not drug related (pancreatic adenocarcinoma and lung cancer); the other patient died of an acute myocardial infarction, considered remotely related to drug therapy.

In clinical trials, Soriatane has been associated with elevations in liver function test results or triglyceride levels and hepatitis. A case of fatal fulminant pancreatitis has been reported during Soriatane therapy.

Soriatane has also been associated with a case of pseudotumor cerebri (see ). One case of myopathy with peripheral neuropathy has been reported during Soriatane therapy. Both conditions improved with discontinuation of the drug.

Hypervitaminosis A produces a wide spectrum of signs and symptoms primarily of the mucocutaneous, musculoskeletal, hepatic, and central nervous systems. Many of the clinical adverse reactions reported to date with Soriatane administration resemble those of the hypervitaminosis A syndrome. The tables below list by body system and frequency the adverse events reported during clinical trials of 525 patients with psoriasis.

Laboratory Soriatane therapy induces changes in liver function tests in a significant number of patients. Elevations of AST (SGOT), ALT (SGPT) or LDH were experienced by approximately 1 in 3 patients treated with Soriatane. In most patients, elevations were slight to moderate and returned to normal either during continuation of therapy or after cessation of treatment. In patients receiving Soriatane during clinical trials, 66% and 33% experienced elevation in triglycerides and cholesterol, respectively. Decreased high density lipoproteins (HDL) occurred in 40% (see ).

Table 3 lists the laboratory abnormalities reported during clinical trials.

OVERDOSAGE

One overdose case has been reported. A 32-year-old mentally handicapped male with Darier' disease took 21 × 25 mg capsules (525 mg single dose). He vomited several hours later but experienced no other ill effects. His therapeutic treatment was continued. The acute oral toxicity (LD ₅₀ ) of acitretin in both mice and rats was greater than 4000 mg/kg.

DOSAGE AND ADMINISTRATION

There is intersubject variation in the pharmacokinetics, clinical efficacy and incidence of side effects with Soriatane. A number of the more common side effects are dose related. Individualization of dosage is required to achieve maximum therapeutic response while minimizing side effects. Soriatane therapy should be initiated at 25 or 50 mg per day, given as a single dose with the main meal. Maintenance doses of 25 to 50 mg per day may be given after initial response to treatment; although, in general, therapy should be terminated when lesions have resolved sufficiently. Relapses may be treated as outlined for initial therapy.

Females who have taken Tegison (etretinate) must continue to follow the contraceptive recommendations for Tegison.

HOW SUPPLIED

Brown and white capsules, 10 mg, imprinted SORIATANE 10 ROCHE; Prescription Paks of 30 (NDC 0004-0213-57).

Brown and yellow capsules, 25 mg, imprinted SORIATANE 25 ROCHE; Prescription Paks of 30 (NDC 0004-0214-57).

Store between 15° and 25°C (59° and 77°F). Protect from light. Avoid exposure to high temperatures and humidity after the bottle is opened.

PRODUCT PHOTO(S):

REFERENCES:

1. Maier H, Honigsmann H: Concentration of etretinate in plasma and subcutaneous fat after long-term acitretin. Lancet 348:1107, 1996.
2. Berbis Ph, et al.: Arch Dermatol Res (1988) 280:388-389.
3. Sigg C, et al.: Andrological investigations in patients treated with etretin. Dermatologica 175:48-49, 1987.
4. Parsch EM, et al.: Andrological investigation in men treated with acitretin (Ro 10-1670). Andrologia 22:479-482, 1990.
5. 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.

PATIENT INFORMATION/CONSENT:

IMPORTANT INFORMATION AND FOR ALL PATIENTS:

Small amounts of Soriatane have been detected in the ejaculate of males taking Soriatane. The amount of Soriatane detected corresponds to less than 1/200,000 of a 25 mg dose. You should discuss any questions you have about this information with your physician.

Alcohol intake can cause Soriatane to be changed into a related drug, etretinate, which may not leave the body for many years.

In addition, you must not donate blood during your treatment with Soriatane and for 3 years after you stop taking Soriatane.

It is recommended that you and your doctor schedule appointments regularly to check your body' response to Soriatane. For your health and well-being, be sure to keep your appointments as scheduled.

Do not give your Soriatane capsules to any other person.

IMPORTANT INFORMATION AND FOR FEMALE PATIENTS:

Soriatane must not be used by females who are pregnant or who may become pregnant while undergoing treatment or at any time for at least 3 years after treatment is discontinued.

If you do become pregnant during Soriatane therapy, or at any time for at least 3 years after you stop taking Soriatane, you should discuss with your physician the possible effects on the pregnancy.

Soriatane can cause severe birth defects if it is taken when a female is pregnant. In addition, birth defects have occurred in babies of females who became pregnant after stopping Soriatane treatment. Therefore:

• you must not be pregnant when you start taking Soriatane,
• you must not become pregnant while you are taking Soriatane,
• you must wait at least 3 years after you stop taking Soriatane before becoming pregnant.

Alcohol must be avoided during the entire Soriatane treatment course and for 2 months after you stop taking Soriatane. This is because alcohol intake can cause Soriatane to be changed into a related drug, etretinate. Etretinate may not leave the body for many years and, like Soriatane, can cause severe birth defects. It is recommended that you and your doctor schedule appointments regularly to repeat the pregnancy test and check your body' response to Soriatane. For your health and well-being, be sure to keep your appointments as scheduled.

In addition, you must not donate blood during your treatment with Soriatane and for 3 years after you stop taking Soriatane.

Do not give your Soriatane capsules to any other person.

THE CONSENT FOR FEMALE PATIENTS:

My treatment with Soriatane has been personally explained to me by Dr. ________________________.
The following points of information, among others, have been specifically discussed and made clear:

1.I,____________________________________________________________________________,

(Patient's Name)

understand that Soriatane is used to treat severe psoriasis that is unresponsive to other therapies.

INITIALS: _________________

2.I understand that severe birth defects related to treatment with Soriatane have occurred in babies of women who have taken Soriatane during pregnancy. In addition, birth defects have occurred in babies of women who became pregnant after stopping Soriatane treatment.

INITIALS: _________________

3.I understand that I must not be pregnant when I start taking Soriatane.

INITIALS: _________________

4.I understand that I must not become pregnant while I am taking Soriatane.

INITIALS: _________________

5.I understand that I must wait at least 3 years after I stop taking Soriatane before becoming pregnant.

INITIALS: _________________

6.I have been told by my doctor that effective birth control (contraception) must be used for at least 1 month before starting Soriatane, for the entire duration of Soriatane therapy and for at least 3 years after Soriatane treatment has stopped. My doctor has told me that I must either abstain from sexual intercourse or use two reliable kinds of birth control at the same time. I have also been told that any method of birth control can fail, including tubal ligation or microdosed progestin "minipill" preparations. I must use two forms of reliable birth control simultaneously, even if I think I cannot become pregnant, unless I abstain from sexual intercourse or have had a hysterectomy.

INITIALS: _________________

7.I understand that if I have taken Tegison (etretinate), I must continue to follow the birth control (contraception) recommendations for Tegison.

INITIALS: _________________

8.I know that I must have a blood or urine test done by my doctor that shows I am not pregnant within 1 week before starting Soriatane. I understand that I must wait until the second or third day of my next normal menstrual period before starting Soriatane.

INITIALS: _________________

9.My doctor has told me that I can participate in the "Patient Referral" program for an initial free pregnancy test and birth control counseling session by a consulting physician.

INITIALS: _________________

10.I know that I must immediately stop taking Soriatane if I become pregnant and immediately contact my doctor to discuss possible effects on the pregnancy. I also know that I must immediately contact my doctor if I become pregnant at any time for at least 3 years after stopping Soriatane.

INITIALS: _________________

11.I have carefully read the Soriatane patient brochure, "Important information concerning your treatment with Soriatane," given to me by my doctor. I understand all of its contents and have talked over any questions I have with my doctor.

INITIALS: _________________

12.I am not now pregnant, nor do I plan to become pregnant while taking Soriatane and for at least 3 years after I have completely finished taking Soriatane.

INITIALS: _________________

13.I know that I must avoid ingesting any beverage or product that contains alcohol during the entire Soriatane treatment course and for 2 months after I have completely finished taking Soriatane.

INITIALS: _________________

14.I understand that if I consume any beverage or product that contains alcohol during my treatment with Soriatane or during the 2 months after I stop taking Soriatane, the risk of birth defects will persist for a longer period of time.

INITIALS: _________________

15.I have been told not to donate blood during my treatment with Soriatane and for 3 years after I have completely finished taking Soriatane.

INITIALS: _________________

I now authorize Dr. ________________________________________________
to begin my treatment with Soriatane.

_______________________________________________________________
Patient signature, Parent or Guardian signature if patient is a minor                     Date

_______________________________________________________________
Address
_______________________________________________________________

_______________________________________________________________
Telephone Number

I have fully explained to the patient, ____________________________________ ,
the nature and purpose of the treatment described above and the teratogenic risk. I have asked the patient if there are any questions regarding treatment with Soriatane and have answered those questions to the best of my ability.

_______________________________________________________________
Physician signature                                                                                           Date

                                                                                               Issued: August 1997