ACITRETIN

Reproductive:

Vulvo-vaginitis due to Candida albicans.

Skin and Appendages:

Thinning of the skin, skin fragility, and scaling may occur all over the body, particularly on the palms and soles; nail fragility is frequently observed. Madarosis and exfoliative dermatitis/erythroderma have been reported (see WARNINGS ).

Vascular Disorders:

Capillary leak syndrome (see WARNINGS ).

Clinical Trials:

During clinical trials with acitretin, 513 of 525 (98%) subjects reported a total of 3,545 adverse events. One-hundred sixteen subjects (22%) left trials prematurely, primarily because of adverse experiences involving the mucous membranes and skin.

Three subjects died. Two of the deaths were not drug-related (pancreatic adenocarcinoma and lung cancer); the other subject died of an acute myocardial infarction, considered remotely related to drug therapy. In clinical trials, acitretin was associated with elevations in liver function test results or triglyceride levels and hepatitis.

The tables below list by body system and frequency the adverse events reported during clinical trials of 525 subjects with psoriasis. Table 3. Adverse Events Frequently Reported during Clinical Trials Percent of Subjects Reporting (N=525) Body System >75% 50% to 75% 25% to 50% 10% to 25% CNS Rigors Eye Disorders Xerophthalmia Mucous Membranes Cheilitis Rhinitis Dry mouth Epistaxis Musculoskeletal Arthralgia Spinal hyperostosis (progression of existing lesions) Skin and Appendages Alopecia Skin peeling Dry skin Nail disorder Pruritus Erythematous rash Hyperesthesia Paresthesia Paronychia Skin atrophy Sticky skin Table 4.

Adverse Events Less Frequently Reported during Clinical Trials (Some of Which May Bear No Relationship to Therapy) Percent of Subjects Reporting (N=525) Body Sytem 1% to 10% ≤ 1% Body as a Whole Anorexia Edema Fatigue Hot flashes Increased appetite Alcohol intolerance Dizziness Fever Influenza-like symptoms Malaise Moniliasis Muscle weakness Weight increase Cardiovascular Flushing Chest pain Cyanosis Increased bleeding time Intermittent claudication Peripheral ischemia CNS (also see Psychiatric) Headache Pain Abnormal gait Migraine Neuritis Pseudotumor cerebri (intracranial hypertension) Eye Disorders Abnormal/ blurred vision Blepharitis Conjunctivitis/ irritation Corneal epithelial abnormality Decreased night vision/night blindness Eye abnormality Eye pain Photophobia Abnormal lacrimation Chalazion Conjunctival hemorrhage Corneal ulceration Diplopia Ectropion Itchy eyes and lids Papilledema Recurrent sties Subepithelial corneal lesions Gastrointestinal Abdominal pain Diarrhea Nausea Tongue disorder Constipation Dyspepsia Esophagitis Gastritis Gastroenteritis Glossitis Hemorrhoids Melena Tenesmus Tongue ulceration Liver and Biliary Hepatic function abnormal Hepatitis Jaundice Mucous Membranes Gingival bleeding Gingivitis Increased saliva Stomatitis Thirst Ulcerative stomatitis Altered saliva Anal disorder Gum hyperplasia Hemorrhage Pharyngitis Musculoskeletal Arthritis Arthrosis Back pain Hypertonia Myalgia Osteodynia Peripheral joint hyperostosis (progression of existing lesions) Bone disorder Olecranon bursitis Spinal hyperostosis (new lesions) Tendonitis Psychiatric Depression Insomnia Somnolence Anxiety Dysphonia Libido decreased Nervousness Reproductive Atrophic vaginitis Leukorrhea Respiratory Sinusitis Coughing Increased sputum Laryngitis Skin and Appendages Abnormal skin odor Abnormal hair texture Bullous eruption Cold/clammy skin Dermatitis Increased sweating Infection Psoriasiform rash Purpura Pyogenic granuloma Rash Seborrhea Skin fissures Skin ulceration Sunburn Acne Breast pain Cyst Eczema Fungal infection Furunculosis Hair discoloration Herpes simplex Hyperkeratosis Hypertrichosis Hypoesthesia Impaired healing Otitis media Otitis externa Photosensitivity reaction Psoriasis aggravated Scleroderma Skin nodule Skin hypertrophy Skin disorder Skin irritation Sweat gland disorder Urticaria Verrucae Special Senses/ Other Earache Taste perversion Tinnitus Ceruminosis Deafness Taste loss Urinary Abnormal urine Dysuria Penis disorder Laboratory: Therapy with acitretin 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 subjects treated with acitretin. In most subjects, elevations were slight to moderate and returned to normal either during continuation of therapy or after cessation of treatment.

In subjects receiving acitretin during clinical trials, 66% and 33% experienced elevation in triglycerides and cholesterol, respectively. Decreased high density lipoproteins (HDL) occurred in 40% (see WARNINGS ). Transient, usually reversible elevations of alkaline phosphatase have been observed.

Table 5 lists the laboratory abnormalities reported during clinical trials. Table 5. Abnormal Laboratory Test Results Reported during Clinical Trials Percent of Subjects Reporting Body System 50% to 75% 25% to 50% 10% to 25% 1% to 10% Electrolytes Increased: –Phosphorus –Potassium –Sodium Increased and decreased: -Magnesium Decreased: –Phosphorus –Potassium –Sodium Increased and decreased: -Calcium -Chloride Hematologic Increased: –Reticulocytes Decreased: –Hematocrit –Hemoglobin –WBC Increased: –Haptoglobin –Neutrophils –WBC Increased: –Bands –Basophils –Eosinophils –Hematocrit –Hemoglobin –Lymphocytes –Monocytes Decreased: –Haptoglobin –Lymphocytes –Neutrophils –Reticulocytes Increased or decreased: –Platelets –RBC Hepatic Increased: –Cholesterol –LDH –SGOT –SGPT Decreased: –HDL cholesterol Increased: –Alkaline phosphatase –Direct bilirubin –GGTP Increased: –Globulin –Total bilirubin –Total protein Increased and decreased: –Serum albumin Miscellaneous Increased: –Triglycerides Increased: –CPK –Fasting blood sugar Decreased: –Fasting blood sugar –High occult blood Increased and decreased: –Iron Renal Increased: –Uric acid Increased: –BUN –Creatinine Urinary WBC in urine Acetonuria Hematuria RBC in urine Glycosuria Proteinuria

8%) due to elevated liver function test results. If hepatotoxicity is suspected during treatment with acitretin, 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.

Skeletal Abnormalities:

In adults receiving long-term treatment with acitretin, 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.

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, 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, 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 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 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 acitretin 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 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. 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, 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 should be considered.

Ophthalmologic Effects:

The eyes and vision of 329 subjects treated with acitretin 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 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. 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 in the absence of hypertriglyceridemia.

Pseudotumor Cerebri:

Acitretin 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 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 immediately and be referred for neurological evaluation and care.

Since both acitretin 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. 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 if capillary leak syndrome develops during therapy.

Exfoliative Dermatitis/Erythroderma:

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