Soriatane

Concomitant administration of vitamin A and other systemic retinoids must be avoided due to the risk of possible additive toxic effects.

The concomitant administration of methotrexate and etretinate has been associated with hepatitis, a similar increased hepatitis risk may be expected with the combined use of SORIATANE and methotrexate.

Concomitant use of SORIATANE and tetracyclines should be avoided due to the risk of possible additive effects (see Precautions, Benign Intracranial Hypertension (Pseudotumor Cerebri)).

If SORIATANE is given concurrently with phenytoin, it must be remembered that SORIATANE partially reduces phenytoin's protein binding.

Preliminary studies indicated that SORIATANE does not influence the endogenous progesterone plasma concentrations induced by oral contraceptives. Microdosed progesterone preparations (minipills) may be an inadequate method of contraception during SORIATANE therapy.

Concomitant administration of phenprocoumon and SORIATANE does not alter the hypothrombinemic effect of phenprocoumon or the plasma disposition of SORIATANE.

The pharmacokinetics of SORIATANE and digoxin are not altered by concomitant multiple dose regimens of these two drugs.

Concomitant administration of cimetidine did not alter the oral bioavailability of SORIATANE or the isomerization to its 13-cis form. Single oral doses of SORIATANE did not affect the steady state plasma concentration or renal clearance of cimetidine.

Limited data which could not be duplicated, indicated that SORIATANE treatment either increased insulin sensitivity directly or interacted with glyburide to do so. Careful supervision of diabetic patients under treatment with SORIATANE is recommended.

SORIATANE is a derivative of vitamin A. To avoid the risk of additive toxic effects, patients should be advised against taking other systemic retinoids or vitamin supplements containing vitamin A.

Drug related ophthalmic effects (dry eyes, irritation of eyes, brow and lash loss, blepharitis and/or crusting of lids, photophobia, redness, recurrent styes, pannus and subepithelial corneal lesions) were noted during treatment with SORIATANE in 29% of 252 patients who were followed with ophthalmic examinations. Patients should be advised that they may experience decreased tolerance to contact lenses during the initial treatment period.

Occupational Hazards: Overall in clinical studies, decreased night vision was reported by two patients and blurring of vision by three patients. Patients should be advised of these potential problems and warned to be cautious when driving or operating any vehicle at night.

The following additional ophthalmic effects have occurred in patients taking etretinate, of which SORIATANE is the active metabolite: decreased visual acuity, minimal posterior subcapsular cataract, iritis, blot retinal hemorrhage and scotoma.

Any patient receiving SORIATANE therapy, experiencing visual difficulties should discontinue this drug and undergo ophthalmic evaluation.

Safety and efficacy of SORIATANE in children have not been established. Ossification of interosseous ligaments and tendons of the extremities, skeletal hyperostosis and premature epiphyseal closure have been reported with other systemic retinoids, including TEGISON (etretinate) of which SORIATANE is the active metabolite. Due to the uncertain effect of long term SORIATANE therapy on growth and skeletal development, SORIATANE should only be used in pediatric patients with the most severe forms of keratinization disorders for which there are no effective alternative therapies. Pretreatment X-rays for bone age including X-rays of the knees are advised. Bone scans (scintigraphs) and/or X-rays should be considered at yearly intervals when monitoring children on long-term therapy. In addition pain or limitation of movement should be evaluated by appropriate radiological examination.

Patients should be advised that a transient worsening of their psoriasis may occur during the initial SORIATANE (acitretin) treatment period.

It is recommended that blood donation for transfusion purposes be deferred during therapy with SORIATANE and for an undetermined period of time of at least two years duration after discontinuation of treatment. Theoretically, blood from such donors could present a small risk to the fetus if transfused to a pregnant mother during the first trimester of pregnancy (see Contraindications).

In diabetics, retinoids can either improve or worsen glucose tolerance. Blood-sugar levels must therefore be checked more frequently than usual in the early stages of treatment (see Drug Interactions).

SORIATANE and other retinoids have been associated with cases of pseudotumour cerebri (benign intracranial hypertension). Early symptoms and signs of benign intracranial hypertension include headache, nausea and vomiting and, visual disturbances. Patients with these symptoms should be examined for papilledema and if present, they should discontinue SORIATANE immediately and be referred for neurological diagnosis and care.

As tetracyclines can also cause an increase in intracranial pressure, their combination with SORIATANE should be avoided.

Blood lipid determinations should be performed before SORIATANE is administered and again at intervals of one or two weeks until the lipid response to the drug is established, which is usually within four to eight weeks. Approximately 65% of patients receiving SORIATANE during clinical trials experienced an elevation in serum triglycerides. Approximately 30% developed a decrease in high density lipoproteins (HDL). Approximately 9% experienced elevated serum cholesterol levels. These effects of SORIATANE were reversible upon cessation of therapy.

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

Hypertriglyceridemia and lowered HDL may increase a patient’s cardiovascular risk status. In addition, elevation of serum triglycerides to greater than 800 mg/dL has been associated with acute pancreatitis. Therefore, every attempt should be made to control significant elevations of triglycerides or HDL decreases by reduction of weight or restriction of dietary fat and alcohol intake while continuing SORIATANE therapy.

If, despite these measures, hypertriglyceridemia and low HDL levels persist, the discontinuation of SORIATANE should be considered. An associated risk of atherogenesis cannot be ruled out if these conditions persist.

Due to an increased hepatitis risk, the combined use of SORIATANE and methotrexate should be avoided.

Each brown and yellow, hard gelatin capsule (No. 1) with “ACTAVIS” in black lettering contains: acitretin 25 mg. Nonmedicinal ingredients: gelatin, glucose, liquid, spray-dried, microcrystalline cellulose and sodium ascorbate; gelatin capsule shell: iron oxide (yellow, black and red) and titanium dioxide. Push-through blister packages of 30. Store at 15-25°C. Protect from heat and light. The product is sensitive to moisture. Therefore store in original package. Keep out of reach of children. The medicine should not be used after the expiry date (EXP) shown on the package.

Each brown and white, hard gelatin capsule (No. 4) with “ACTAVIS” in black lettering contains: acitretin 10 mg. Nonmedicinal ingredients: gelatin, glucose, liquid, spray-dried, microcrystalline cellulose and sodium ascorbate; gelatin capsule shell: iron oxide (yellow, black and red) and titanium dioxide. Push-through blister packages of 30. Store at 15-25°C. Protect from heat and light. The product is sensitive to moisture. Therefore store in original package. Keep out of reach of children. The medicine should not be used after the expiry date (EXP) shown on the package.

SORIATANE (acitretin) is contraindicated in pregnancy. Retinoids are known to cause severe birth defects in a very high percentage of infants exposed to them in utero (see Warnings, Pregnancy).

Females must not become pregnant while taking SORIATANE and effective contraception must be practised for an undetermined period of time of at least two years following discontinuation of SORIATANE. Thereafter, the patient and physician should assess the risks and desirability of discontinuing effective contraception, based on the most current information available. Measurable levels of etretinate (TEGISON), the prodrug of acitretin, have been detected in plasma samples of patients administered SORIATANE. The use of alcohol appears to be a factor contributing to the interconversion of acitretin back to etretinate. Ethanol must not be ingested during treatment with SORIATANE as clinical evidence has shown that etretinate can be formed with concurrent ingestion of acitretin and alcohol. Ethanol should be avoided for two months after cessation of therapy. The length of time necessary to wait after termination of SORIATANE treatment to ensure that no etretinate will be detectable in the blood has not been determined. Etretinate has a long elimination phase. When etretinate has been used as primary therapy, etretinate has been found in the blood of some patients up to 2.9 years after discontinuation of treatment.

SORIATANE is contraindicated in females of childbearing potential unless all of the following conditions apply:

1. The patient has severe psoriasis or other severe disorders of keratinization which are resistant to standard therapies.

   
   

2. The patient is reliable in understanding and carrying out instructions.

   
   

3. The patient is able to comply with mandatory contraceptive measures.

   
   

4. The patient has received, and acknowledged understanding of, a careful oral and printed explanation of the hazards of fetal exposure to SORIATANE and the risk of possible contraception failure. This explanation may include showing a line drawing to the patient of an infant with the characteristic external deformities resulting from retinoid exposure during pregnancy.

   
   

5. The patient has had a serum or urine pregnancy test with a sensitivity of at least 50 mIU/mL with a negative result, performed in a licensed laboratory, within two weeks prior to initiating therapy. The patient has had two or three days of the next normal menstrual period before SORIATANE therapy is initiated.

   
   

6. The same effective and uninterrupted contraceptive measures must be taken every time therapy is repeated, however long the intervening period may have been and must be continued for 2 years afterwards.

   
   

(Regarding items 2 to 5, see Warnings, Pregnancy.)

SORIATANE is also contraindicated in patients with severely impaired hepatic or renal function, intractable hyperlipidemia, hypervitaminosis A or hypersensitivity to vitamin A or its metabolites.

SORIATANE should not be administered in cases of hypersensitivity to any excipients of the drug product (see Supplied).

Clinical data indicate that acitretin is excreted in human milk. Therefore, nursing mothers should not receive SORIATANE because of the potential for serious adverse reactions in nursing infants. Women should not breast-feed for an undetermined period of time of at least two years following discontinuation of SORIATANE.

In clinical trials with SORIATANE, patients were prospectively evaluated for evidence of development or change in bony abnormalities of the vertebral column following six months of treatment. Of 262 patients treated with SORIATANE, 7% had pre-existing abnormalities of the spine which showed new changes or progression of pre-existing findings. Changes included degenerative spurs, anterior bridging of spinal vertebrae, diffuse idiopathic skeletal hyperostosis, and narrowing and destruction of cervical disc space. These existing abnormalities may be in some part attributable to the underlying psoriasis and/or the patient’s age. During the six-month period of observation, no bone changes were seen in patients who had normal pretreatment X-rays. Other retinoids including TEGISON (etretinate), of which SORIATANE is the active metabolite, have been associated with the development of extraosseous calcification and/or hyperostosis. Calcification of the ligaments of the spine, tendon insertions of the arms and legs, and intraosseous membranes of the arms and legs, have been reported. Hyperostotic changes of the vertebrae, forearms, hips, acetabula, legs and calcanei have also been reported. It is not clear whether the extraosseous calcification and/or hyperostosis are progressive. Pre-treatment radiographs of the cervical, thoracic and lumbar spine may be useful when monitoring patients on long-term SORIATANE therapy. Early recognition of musculoskeletal symptoms associated with SORIATANE therapy may be important. There is some evidence that scintigraphic changes appear before radiographic findings. Scintigraphic changes may disappear after discontinuation of SORIATANE treatment, however, radiographic changes may persist. Bone scintigraphy may be important in monitoring patients on SORIATANE therapy since scintigraphic changes seem to precede radiographic changes.

In adults receiving long-term treatment with SORIATANE, appropriate examinations should be periodically performed in view of possible ossification abnormalities. If such disorders arise, the continuation of therapy should be discussed with the patient on the basis of a careful risk/benefit analysis. In one patient, spinal hyperostosis and calcification of spinal ligaments, resulting in compression of the spinal chord, appeared after several years’ therapy with TEGISON.

Pregnancy, Pregnancy Testing and Contraception: The use of systemic retinoids in humans has been associated with congenital abnormalities. There is an extremely high risk that major human fetal abnormalities will occur if pregnancy occurs during treatment with SORIATANE (acetretin). Potentially any exposed fetus can be affected. Major fetal abnormalities associated with retinoid administration during pregnancy have been reported; including meningomyelocoele, meningoencephalocoele, multiple synostosis, facial dysmorphia, anophthalmia, syndactyly, absences of terminal phalanges, malformations of hip, ankle and forearm, low set ears, high palate, decreased cranial volume and alterations of the skull and cervical vertebrae on X-ray.

Female patients of childbearing potential must not be given SORIATANE until pregnancy is excluded. A serum or urine pregnancy test with a sensitivity of at least 50 mIU/mL must be performed within two weeks prior to starting SORIATANE treatment. SORIATANE treatment should start on the second or third day of the next normal menstrual period following this negative pregnancy test.

Effective contraception must be used for at least one month before starting SORIATANE treatment, during treatment and for an undetermined period of time of at least two years duration after discontinuation of treatment (see Contraindications). Thereafter, the patient and physician should assess the risks and desirability of discontinuing effective contraception, based on the most current information available. It is recommended that two reliable forms of contraception be used simultaneously unless abstinence is the chosen method.

Pregnancy occurring during treatment with SORIATANE and for an undetermined period of time of at least two years duration after its discontinuation carries the risk of fetal malformation (see Warnings above). Females must be fully counselled on the serious risks to the fetus should they become pregnant whilst undergoing SORIATANE treatment or after discontinuation of SORIATANE treatment. If pregnancy does occur during this time the physician and patient should discuss the desirability of continuing the pregnancy.

It is strongly recommended that all female patients of childbearing potential treated with SORIATANE have monthly pregnancy tests during treatment and at regular intervals for an undetermined period of time of at least 2 years duration after the discontinuation of treatment. These pregnancy tests will: a) Serve primarily to reinforce to the patient the necessity of avoiding pregnancy. b) In the event of accidental pregnancy, provide the physician and patient an immediate opportunity to discuss the serious risk to the fetus from this exposure to SORIATANE and the desirability of continuing the pregnancy in view of the potential teratogenic effect of SORIATANE (see Warnings above).

Women of childbearing potential who have switched from TEGISON (etretinate) therapy to SORIATANE must continue to follow the contraceptive recommendations for TEGISON when on SORIATANE therapy.

Hepatic function should be checked before starting treatment with SORIATANE every 1-2 weeks for the first 2 months after commencement and then every 3 months during treatment. If abnormal results are obtained, weekly checks should be instituted. If hepatic function fails to return to normal or deteriorates further, SORIATANE must be withdrawn. In such cases it is advisable to continue monitoring hepatic function for at least 3 months. Elevations of AST, ALT or LDH have occurred in 20-28% of patients treated with SORIATANE. One of the 329 patients treated in clinical trials had clinical jaundice with elevated serum bilirubin and transaminases considered possibly related to SORIATANE treatment. Liver function test results in this patient returned to normal after SORIATANE was discontinued.

If hepatotoxicity is suspected during treatment with SORIATANE, the drug should be discontinued and the etiology further investigated.

Ten of 652 patients treated in 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 four reports of hepatitis-related deaths worldwide; two of these patients had received etretinate for a month or less before presenting with hepatic symptoms.

To date, there has been no experience with acute overdose of SORIATANE (acitretin). In the event of acute overdosage, evacuation of the stomach should be considered during the first few hours after this overdose. Signs and symptoms of overdosage with SORIATANE would probably be similar to acute vitamin A toxicity, i.e., severe headache, nausea or vomiting, drowsiness, irritability, and pruritus. Elevated intracranial pressure has been reported with both acute and chronic vitamin A overdoses as well as in patients treated with therapeutic doses of SORIATANE. Patients with a SORIATANE overdose should be monitored closely for signs of increased intracranial pressure. If overdosage occurs in patients already receiving therapeutic doses of SORIATANE, the drug must be discontinued immediately.

All female patients of childbearing potential who have taken an overdose of SORIATANE must:

1. Have a pregnancy test at the time of the overdose.

   
   

2. Use an effective form of contraception for an undetermined period of time of at least two years duration after the overdose.

   
   

If the pregnancy test is positive, the patient should be fully counselled on the serious risk to the fetus from this exposure to SORIATANE and the physician and patient should discuss the desirability of continuing the pregnancy (see Contraindications and Warnings).

See Symptoms.

Maintenance doses of 10 mg to a maximum of 50 mg per day may be given for disorders of keratinization.

Maintenance doses of 25 to 50 mg per day may be given after initial response to treatment. The maintenance dose should be based on clinical efficacy and tolerability. It may be necessary in some cases to increase the dose to a maximum of 75 mg per day.

In general, therapy should be terminated when lesions have resolved sufficiently. Relapses may be treated as outlined for initial therapy.

SORIATANE therapy should be initiated at 25 mg per day, given as a single dose with the main meal. If by four weeks the response is unsatisfactory, and in the absence of toxicity, the daily dose may be gradually increased to a maximum of 75 mg per day. The dose may be reduced if necessary to minimize side effects.