Acitretin - Acitretin capsule prescribing information
INDICATIONS AND USAGE
Acitretin capsules are indicated for the treatment of severe psoriasis in adults. Because of significant adverse effects associated with its use, acitretin capsules should be prescribed only by those knowledgeable in the systemic use of retinoids. In females of reproductive potential, acitretin capsules should be reserved for non-pregnant patients who are unresponsive to other therapies or whose clinical condition contraindicates the use of other treatments (see boxed CONTRAINDICATIONS AND WARNINGS - Acitretin capsules can cause severe birth defects).
Most patients experience relapse of psoriasis after discontinuing therapy. Subsequent courses, when clinically indicated, have produced efficacy results similar to the initial course of therapy.
DOSAGE AND ADMINISTRATION
There is intersubject variation in the pharmacokinetics, clinical efficacy, and incidence of side effects with acitretin capsules. A number of the more common side effects are dose-related. Individualization of dosage is required to achieve sufficient therapeutic response while minimizing side effects. Therapy with acitretin capsules should be initiated at 25 to 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 dependent upon an individual patient’s response to initial treatment. Relapses may be treated as outlined for initial therapy.
When acitretin capsules are used with phototherapy, the prescriber should decrease the phototherapy dose, dependent on the patient’s individual response (see PRECAUTIONS: General ).
Females who have taken TEGISON (etretinate) must continue to follow the contraceptive recommendations for TEGISON. TEGISON is no longer marketed in the U.S.; for information, call Mylan at 1-877-446-3679 (1-877-4-INFO-RX).
Information for Pharmacists
Acitretin capsules must only be dispensed in no more than a monthly supply. An acitretin capsules Medication Guide must be given to the patient each time acitretin capsules are dispensed, as required by law.
CONTRAINDICATIONS
Pregnancy
See boxed CONTRAINDICATIONS AND WARNINGS .
Acitretin capsules are contraindicated in patients with severely impaired liver or kidney function and in patients with chronic abnormally elevated blood lipid values (see boxed WARNINGS: Hepatotoxicity , WARNINGS: Lipids and Possible Cardiovascular Effects , and PRECAUTIONS ).
An increased risk of hepatitis has been reported to result from combined use of methotrexate and etretinate. Consequently, the combination of methotrexate with acitretin capsules is also contraindicated (see PRECAUTIONS: Drug Interactions ).
Since both acitretin capsules and tetracyclines can cause increased intracranial pressure, their combined use is contraindicated (see WARNINGS: Pseudotumor Cerebri ).
Acitretin capsules are contraindicated in cases of hypersensitivity (e.g., angioedema, urticaria) to the preparation (acitretin or excipients) or to other retinoids .
ADVERSE REACTIONS
Hypervitaminosis A produces a wide spectrum of signs and symptoms primarily of the mucocutaneous, musculoskeletal, hepatic, neuropsychiatric, and central nervous systems. Many of the clinical adverse reactions reported to date with administration of acitretin capsules resemble those of the hypervitaminosis A syndrome.
Adverse Events/Postmarketing Reports
In addition to the events listed in the tables for the clinical trials, the following adverse events have been identified during postapproval use of acitretin capsules. Because these events are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.
Cardiovascular: Acute myocardial infarction, thromboembolism (see WARNINGS ), stroke.
Immune System Disorders: Hypersensitivity, including angioedema and urticaria (see CONTRAINDICATIONS ).
Nervous System: Myopathy with peripheral neuropathy has been reported during therapy with acitretin capsules. Both conditions improved with discontinuation of the drug.
Psychiatric: Aggressive feelings and/or suicidal thoughts 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 acitretin capsules. Since other factors may have contributed to these events, it is not known if they are related to acitretin capsules (see PRECAUTIONS ).
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 capsules, 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 capsules were 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.
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 |
Body System | 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 capsules 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 capsules. 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 capsules 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.
Body System | 50% to 75% | 25% to 50% | 10% to 25% | 1% to 10% |
Electrolytes | Increased: –Phosphorus –Potassium –Sodium | Decreased: –Phosphorus –Potassium –Sodium | ||
Increased and decreased: –Magnesium | 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 |
Drug Interactions
Ethanol
Clinical evidence has shown that etretinate can be formed with concurrent ingestion of acitretin and ethanol (see boxed CONTRAINDICATIONS AND WARNINGS and CLINICAL PHARMACOLOGY: Pharmacokinetics ).
Glyburide
In a trial of 7 healthy male volunteers, acitretin treatment potentiated the blood glucose-lowering effect of glyburide (a sulfonylurea similar to chlorpropamide) in 3 of the 7 subjects. Repeating the trial with 6 healthy male volunteers in the absence of glyburide did not detect an effect of acitretin on glucose tolerance. Careful supervision of diabetic patients under treatment with acitretin capsules is recommended (see CLINICAL PHARMACOLOGY: Pharmacokinetics and DOSAGE AND ADMINISTRATION ).
Hormonal 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 “minipill” preparations. Microdosed “minipill” progestin preparations are not recommended for use with acitretin capsules (see CLINICAL PHARMACOLOGY: Pharmacokinetic Drug Interactions ). It is not known whether other progestin-only contraceptives, such as implants and injectables, are adequate methods of contraception during acitretin therapy.
Methotrexate
An increased risk of hepatitis has been reported to result from combined use of methotrexate and etretinate. Consequently, the combination of methotrexate with acitretin is also contraindicated (see CONTRAINDICATIONS ).
Phenytoin
If acitretin is given concurrently with phenytoin, the protein binding of phenytoin may be reduced.
Tetracyclines
Since both acitretin and tetracyclines can cause increased intracranial pressure, their combined use is contraindicated (see CONTRAINDICATIONS and WARNINGS: Pseudotumor Cerebri ).
Vitamin A and Oral Retinoids
Concomitant administration of vitamin A and/or other oral retinoids with acitretin must be avoided because of the risk of hypervitaminosis A.
Other
There appears to be no pharmacokinetic interaction between acitretin and cimetidine, digoxin, or glyburide. Investigations into the effect of acitretin on the protein binding of anticoagulants of the coumarin type (warfarin) revealed no interaction.
DESCRIPTION
Acitretin capsules, USP (acitretin), a retinoid, are available in 10-mg or 25-mg gelatin capsules for oral administration. Chemically, acitretin, USP is ( all-E )-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 or greenish crystalline powder with a molecular weight of 326.44. The structural formula is:
Each capsule contains acitretin, edetate disodium, gelatin, maltodextrin, microcrystalline cellulose, poloxamer 407, red iron oxide, sodium ascorbate and titanium dioxide. The 25 mg capsules also contain black iron oxide and yellow iron oxide.
The black imprinting ink for the 10 mg capsules contains black iron oxide, potassium hydroxide, propylene glycol, shellac and strong ammonia solution.
The white imprinting ink for the 25 mg capsules contains povidone, propylene glycol, shellac, sodium hydroxide and titanium dioxide.
CLINICAL PHARMACOLOGY
The mechanism of action of acitretin capsules is unknown.
Pharmacokinetics
Absorption
Oral absorption of acitretin is optimal when given with food. For this reason, acitretin was given with food in all of the following trials. After administration of a single 50-mg oral dose of acitretin to 18 healthy subjects, maximum plasma concentrations ranged from 196 to 728 ng per mL (mean: 416 ng per 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 trial of acitretin pharmacokinetics in subjects 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 per mL) in all subjects 3 weeks after cessation of therapy.
Elderly
In a multiple-dose trial in healthy young (n = 6) and elderly (n = 8) subjects, a 2-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 subjects with end-stage renal failure (n = 6) when compared with 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 WARNINGS 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 2-way crossover trial, 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 per kg body weight). A mean peak etretinate concentration of 59 ng per mL (range: 22 to 105 ng per mL) was observed, and extrapolation of AUC values indicated that the formation of etretinate in this trial 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 WARNINGS ). Of 93 evaluable psoriatic subjects on acitretin therapy in several foreign trials (10 to 80 mg per day), 16% had measurable etretinate levels (> 5 ng per mL).
Etretinate has a much longer elimination half-life compared with that of acitretin. In one trial the apparent mean terminal half-life after 6 months of therapy was approximately 120 days (range: 84 to 168 days). In another trial of 47 subjects treated chronically with etretinate, 5 had detectable serum drug levels (in the range of 0.5 to 12 ng per 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. 1 Microdosed “minipill” progestin preparations are not recommended for use with acitretin capsules. It is not known whether other progestin-only contraceptives, such as implants and injectables, are adequate methods of contraception during acitretin therapy.
CLINICAL STUDIES
In 2 double-blind, placebo-controlled trials, acitretin capsules were administered once daily to subjects with severe psoriasis (e.g., covering at least 10% to 20% of the body surface area). At 8 weeks (see Table 1) subjects treated in Trial A with 50 mg of acitretin capsules per day showed significant improvements ( P ≤ 0.05) relative to baseline and to placebo in the physician’s global evaluation and in the mean ratings of severity of psoriasis (scaling, thickness, and erythema). In Trial B, differences from baseline and from placebo were statistically significant ( P ≤ 0.05) for all variables at both the 25-mg and 50-mg doses; it should be noted for Trial B that no statistical adjustment for multiplicity was carried out.
Efficacy Variables | Trial A | Trial B | |||
Total Daily Dose | Total Daily Dose | ||||
Placebo (N = 29) | 50 mg (N = 29) | Placebo (N = 72) | 25 mg (N = 74) | 50 mg (N = 71) | |
Physician’s Global Evaluation | |||||
Baseline | 4.62 | 4.55 | 4.43 | 4.37 | 4.49 |
Mean Change After 8 Weeks | -0.29 | -2.00 Values were statistically significantly different from placebo and from baseline ( P ≤ 0.05). No adjustment for multiplicity was done for Trial B. | -0.06 | -1.06 | -1.57 |
Scaling | |||||
Baseline | 4.10 | 3.76 | 3.97 | 4.11 | 4.10 |
Mean Change After 8 Weeks | -0.22 | -1.62 | -0.21 | -1.50 | -1.78 |
Thickness | |||||
Baseline | 4.10 | 4.10 | 4.03 | 4.11 | 4.20 |
Mean Change After 8 Weeks | -0.39 | -2.10 | -0.18 | -1.43 | -2.11 |
Erythema | |||||
Baseline | 4.21 | 4.59 | 4.42 | 4.24 | 4.45 |
Mean Change After 8 Weeks | -0.33 | -2.10 | -0.37 | -1.12 | -1.65 |
The efficacy variables consisted of: the mean severity rating of scale, lesion thickness, erythema, and the physician's global evaluation of the current status of the disease. Ratings of scaling, erythema, and lesion thickness, and the ratings of the global assessments were made using a 7-point scale (0 = none, 1 = trace, 2 = mild, 3 = mild-moderate, 4 = moderate, 5 = moderate-severe, 6 = severe).
A subset of 141 subjects from both pivotal Trials A and B continued to receive acitretin capsules in an open fashion for up to 24 weeks. At the end of the treatment period, all efficacy variables, as indicated in Table 2, were significantly improved ( P ≤ 0.01) from baseline, including extent of psoriasis, mean ratings of psoriasis severity, and physician’s global evaluation.
Variables | Trial A | Trial B |
Mean Total Daily Dose of Acitretin Capsules (mg) | 42.8 | 43.1 |
Mean Duration of Therapy (Weeks) | 21.1 | 22.6 |
Physician’s Global Evaluation | N = 39 | N = 98 |
Baseline | 4.51 | 4.43 |
Mean Change from Baseline | -2.26 Indicates that the difference from baseline was statistically significant ( P ≤ 0.01). The efficacy variables consisted of: the mean severity rating of scale, lesion thickness, erythema, and the physician’s global evaluation of the current status of the disease. Ratings of scaling, erythema, and lesion thickness, and the ratings of the global assessments were made using a 7-point scale (0 = none, 1 = trace, 2 = mild, 3 = mild-moderate, 4 = moderate, 5 = moderate-severe, 6 = severe). | -2.60 |
Scaling | N = 59 | N = 132 |
Baseline | 3.97 | 4.07 |
Mean Change from Baseline | -2.15 | -2.42 |
Thickness | N = 59 | N = 132 |
Baseline | 4.00 | 4.12 |
Mean Change from Baseline | -2.44 | -2.66 |
Erythema | N = 59 | N = 132 |
Baseline | 4.35 | 4.33 |
Mean Change from Baseline | -2.31 | -2.29 |
All efficacy variables improved significantly in a subset of 55 subjects from Trial A treated for a second, 6-month maintenance course of therapy (for a total of 12 months of treatment); a small subset of subjects (n = 4) from Trial A continued to improve after a third 6-month course of therapy (for a total of 18 months of treatment).
HOW SUPPLIED
Acitretin Capsules, USP are available containing 10 mg or 25 mg of acitretin, USP.
The 10 mg capsules are hard shell gelatin capsules with a swedish orange opaque cap and swedish orange opaque body filled with yellow granular powder. The capsules are axially printed with MYLAN over AC I 02 in black ink on the cap and body. They are available as follows:
NDC 0378-7020-93 bottles of 30 capsules
The 25 mg capsules are hard shell gelatin capsules with a brown opaque cap and yellow opaque body filled with yellow granular powder. The capsules are axially printed with MYLAN over AC I 13 in white ink on the cap and body. They are available as follows:
NDC 0378-7023-93 bottles of 30 capsules
Store at 20° to 25°C (68° to 77°F). [See USP Controlled Room Temperature.] Protect from light. Avoid exposure to high temperatures and humidity after the bottle is opened.
Dispense in a tight, light-resistant container as defined in the USP using a child-resistant closure.
PHARMACIST: Dispense a Medication Guide with each prescription.
