Acitretin

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# Black Box Warning

# Overview
Acitretin is an antipsoriatic that is FDA approved for the treatment of severe psoriasis in adults. There is a Black Box Warning for this drug as shown here.  Common adverse reactions include pruritus, arthralgia and paresthesia..

# Adult Indications and Dosage

## FDA-Labeled Indications and Dosage (Adult)
Acitretin is indicated for the treatment of severe psoriasis in adults.
- Initial dosage: 25 to 50 mg per day, given as a single dose with the main meal.
- Maintenance dosage: 25 to 50 mg per day.

## Off-Label Use and Dosage (Adult)

### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Acitretin in adult patients.

### NonGuideline-Supported Use
- Nonpsoriatic disorder of skin
- Lichen planus
- Prophylaxis of skin cancers in high-risk renal transplant recipients
- Acitretin 30 mg orally daily for 6 months 

# Pediatric Indications and Dosage

## FDA-Labeled Indications and Dosage (Pediatric)
Safety and effectiveness have not been established in pediatric patients

## Off-Label Use and Dosage (Pediatric)

### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Acitretin in pediatric patients.

### NonGuideline-Supported Use
- Lichen planus

# Contraindications
- Pregnancy Category X
- Patients with severely impaired liver or kidney function and in patients with chronic abnormally elevated blood lipid values,
- 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.
- Since both acitretin and tetracyclines can cause increased intracranial pressure, their combined use is contraindicated.
- In cases of hypersensitivity (e.g., angioedema, urticaria) to the preparation (acitretin or excipients) or to other retinoids.

# Warnings
- Of the 525 subjects treated in U.S. clinical trials, 2 had clinical jaundice with elevated serum bilirubin and transaminases considered related to treatment with acitretin. Liver function test results in these subjects returned to normal after acitretin 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 subjects transaminase levels returned to normal 2 months after acitretin was discontinued.
- The potential of therapy with acitretin 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 acitretin. Of the 525 subjects treated in clinical trials in the U.S., treatment was discontinued in 20 (3.8%) 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 U.S. 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.

# Adverse Reactions

## Clinical Trials Experience
During clinical trials with acitretin, 513/525 (98%) of 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.
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%. Transient, usually reversible elevations of alkaline phosphatase have been observed.
TABLE 5 lists the laboratory abnormalities reported during clinical trials.

## Postmarketing Experience
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. 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.
- Acute myocardial infarction
- Thromboembolism, stroke
Hypersensitivity, including angioedema and urticaria.
- Myopathy
- Peripheral neuropathy
Both conditions improved with discontinuation of the drug.
- 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.
- Since other factors may have contributed to these events, it is not known if they are related to acitretin.
- Vulvo-vaginitis due to Candida albicans.
- 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.
- Capillary leak syndrome

# Drug Interactions
Clinical evidence has shown that etretinate can be formed with concurrent ingestion of acitretin and ethanol.
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 is recommended.
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. It is not known whether other progestational contraceptives, such as implants and injectables, are adequate methods of contraception during acitretin therapy.
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.
If acitretin is given concurrently with phenytoin, the protein binding of phenytoin may be reduced.
Since both acitretin and tetracyclines can cause increased intracranial pressure, their combined use is contraindicated.
Concomitant administration of vitamin A and/or other oral retinoids with acitretin must be avoided because of the risk of hypervitaminosis A.
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.

# Use in Specific Populations

### Pregnancy
Pregnancy Category (FDA): X
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.
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.
Pregnancy Category (AUS): X
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Acitretin in women who are pregnant.

### Labor and Delivery
There is no FDA guidance on use of Acitretin during labor and delivery.

### 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 acitretin prior to or during nursing because of the potential for serious adverse reactions in nursing infants.

### 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 acitretin. A causal relationship between these effects and acitretin 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.

### Geriatic Use
Clinical trials of acitretin 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.

### Gender
There is no FDA guidance on the use of Acitretin with respect to specific gender populations.

### Race
There is no FDA guidance on the use of Acitretin with respect to specific racial populations.

### Renal Impairment
Acitretin is contraindicated in patients with severely impaired kidney function

### Hepatic Impairment
Acitretin is contraindicated in patients with severely impaired liver function

### Females of Reproductive Potential and Males
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. No deleterious effects were seen on the hypothalamic-pituitary axis in any of the 18 men where it was measured.

### Immunocompromised Patients
There is no FDA guidance one the use of Acitretin in patients who are immunocompromised.

# Administration and Monitoring

### Administration
Oral

### Monitoring
If significant abnormal laboratory results are obtained, either dosage reduction with careful monitoring or treatment discontinuation is recommended, depending on clinical judgment.

# IV Compatibility
There is limited information regarding the compatibility of Acitretin and IV administrations.

# Overdosage
In the event of acute overdosage, acitretin must be withdrawn at once. Symptoms of overdose are identical to acute hypervitaminosis A (e.g., headache and vertigo). The acute oral toxicity (LD50) of acitretin in both mice and rats was greater than 4,000 mg/kg.
In one reported case of overdose, a 32-year-old male with Dariers disease took 21 x 25 mg capsules (525 mg single dose). He vomited several hours later but experienced no other ill effects.
All female patients of childbearing potential who have taken an overdose of acitretin must:
- Have a pregnancy test at the time of overdose;
- Be counseled as per the boxed CONTRAINDICATIONS AND WARNINGS and PRECAUTIONS sections regarding birth defects and contraceptive use for at least 3 years duration after the overdose.

# Pharmacology

## Mechanism of Action
The mechanism of action of acitretin is unknown.

## Structure
The structural formula is:

## Pharmacodynamics
There is limited information regarding Acitretin Pharmacodynamics in the drug label.

## Pharmacokinetics
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/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.
Acitretin is more than 99.9% bound to plasma proteins, primarily albumin.
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.
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.

## Nonclinical Toxicology
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.
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.

# Clinical Studies
In 2 double-blind, placebo-controlled trials, acitretin was 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 per day showed significant improvements (P  0.05) relative to baseline and to placebo in the physicians 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.
The efficacy variables consisted of: the mean severity rating of scale, lesion thickness, erythema, and the physicians 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 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 physicians global evaluation.
The efficacy variables consisted of: the mean severity rating of scale, lesion thickness, erythema, and the physicians 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).
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 10 mg
- Bottles of 30 capsules
- Acitretin Capsules 17.5 mg
- Bottles of 30 capsules
- Acitretin Capsules 25 mg
- Bottles of 30 capsules

## Storage
Store at 20 to 25C (68 to 77F)

# Images

## Drug Images

## Package and Label Display Panel

# Patient Counseling Information
- 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 acitretin, 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 acitretin. 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. 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 acitretin can cause birth defects and women of childbearing potential must not receive blood from patients being treated with acitretin.
- Because of the relationship of acitretin 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.

# Precautions with Alcohol
Alcohol-Acitretin interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.

# Brand Names
- Soriatane  

# Look-Alike Drug Names
There is limited information regarding Acitretin Look-Alike Drug Names in the drug label.

# Drug Shortage Status

# Price