Acitretin

Retinoids bind cytosolic retinoic acid-binding protein (CRABP) that acts as the intracellular carrier transporting it to the nucleus. In the nucleus, retinoids impact transcription by binding two families of nuclear receptors: retinoic acid receptors (RARs) and retinoid X receptors (RXR). RAR and RXR families contain three receptor subtypes: alpha, beta, and gamma that are encoded by different genes. RAR can bind with RXR forming a heterodimer. RXR can bind with itself, forming a homodimer, or bind with other nuclear receptors such as thyroid hormone receptor, vitamin D3 receptor, and peripheral peroxidase-activated receptor (PPAR). Dimers of RAR/RXR or RXR/RXR bind to DNA regulatory sequences in the promoter region, retinoid acid response elements (RAREs). Once the ligand binds, it undergoes a conformational change to release co-repressors and recruit co-activators. The retinoid-receptor complex may antagonize the action of other transcription factors, thus working indirectly. Acitretin competes with RA for CRABP. Acitretin can activate but does not bind to multiple RARs.[5][6]

Acitretin has anti-inflammatory and anti-proliferative effects. It normalizes keratinocyte differentiation in the epithelium. It also hinders the expression of proinflammatory cytokines like interleukin-6 (IL-6), migration inhibitory factor-related protein-8 (MRP-8), and interferon-gamma. The agent acts by binding and activating all nuclear subtypes of retinoid X-receptors and retinoic acid receptors.

Pharmacokinetics

Absorption: Generally administered with food and reaches peak plasma concentration in 2.7 hours (2-5 hours).

Plasma Protein Binding: 99.9%

Metabolism: The initial metabolism of acitretin involves isomerization; this differs from isotretinoin, where the initial metabolism is oxidation. Acitretin converts to isoacitretin. Acitretin is ultimately eliminated in the bile as beta-glucuronide derivatives or through the kidneys as soluble metabolites. Acitretin can undergo reverse metabolism to etretinate when acitretin is used in combination with alcohol.

Excretion:  Its metabolites, as well as conjugates of acitretin and cis-acitretin, are excreted in the feces (34% to 54%) and urine (16% to 53%).

Terminal Elimination Half-life: Following multiple-dose, acitretin has a half-life of 49 hours, and cis-acitretin has 63 hours.

Initial: Administer 25 to 50 mg orally daily as a single dose with the main meal.

Maintenance: Administer 25 to 50 mg orally daily after initial response to treatment. The maintenance dose should have its basis in clinical efficacy and tolerability.

Acitretin is available in 10 mg and 25 mg in hard gelatin capsules. In psoriasis treatment with acitretin, improvement is seen approximately at weeks 4 to 6. The maximum benefit may take between 3 to 4 months. Treatment dosing is initiated at 25 mg orally once daily. When the disease is stable, dosing is often reduced to 10 mg orally once daily or 25 mg orally every other day as a maintenance protocol. Treatment with acitretin leads to decreased plaque thickness, scaling, and pruritis. However, there is not much reduction in body surface area (BSA).

In combination with phototherapy, dosing is recommended at 25 mg orally once daily for two weeks before phototherapy, with a need to decrease the initial dose of ultraviolet (UV) light. If a patient is already on a stable dose of UV light and is starting acitretin, reduce the dose by 30% to 50% approximately seven days after initiation of acitretin.

Specific Patients Population 

• Patient with Hepatic Impairment: There is no dose adjustment guidance in the manufacturer label for patients with hepatic impairment. However, the use of acitretin is contraindicated in patients with severe hepatic impairment.
• Patient with Renal Impairment: A 53 % reduction of acitretin plasma concentrations was observed in patients with end-stage renal disease. The drug was not able to be removed by hemodialysis in these subjects.
• Pregnant Women: It is considered a pregnancy category X medicine. As per the box warning, acitretin must not be given to pregnant patients, patients who intend to become pregnant during therapy, or at least three years following discontinuation of treatment. Significant human fetal abnormalities have been reported with the administration of acitretin.
• Breastfeeding Women: Due to the potential for serious adverse reactions to infants, the manufacturer recommends avoiding acitretin in nursing mothers as the drug presents in breast milk.[7]
• Pediatric Patients: The safety and efficacy of acitretin are not established for pediatric patients.
• Geriatric Patients: In a multiple-dose trial, a 2-fold increase in acitretin plasma concentrations were observed in geriatric patients.

A high amount of vitamin A produces a wide spectrum of signs and symptoms primarily of the musculoskeletal, mucocutaneous, neuropsychiatric, central nervous systems, and hepatic systems. Many of the adverse reactions reported using acitretin capsules resemble those of the hypervitaminosis A syndrome. Following adverse reactions are reported in clinical trials and post-marketing experience.[8]

Cardiovascular: Flushing, acute myocardial infarction, thromboembolism, stroke

Immune System Disorders: Hypersensitivity, including angioedema and urticaria 

Nervous System: Headache, pain, rigors; myopathy with peripheral neuropathy which improved upon discontinuation of the acitretin.

Psychiatric: Aggressive feelings, depression, insomnia, self-injurious behavior, and/or suicidal thoughts have been reported. Since other factors may have contributed to psychiatric events, it is not known if they are related to acitretin.

Reproductive: Vulvo-vaginitis (due to Candida albicans)

Skin and Appendages: Thinning of the skin, exfoliation of the skin, xeroderma, nail disease, pruritus, erythematous rash, paronychia, particularly on the palms and soles; nail fragility, madarosis, alopecia, paresthesia, hyperesthesia, and exfoliative dermatitis

Vascular Disorders: Capillary leak syndrome

Miscellaneous: xerophthalmia, visual problems, cheilitis, rhinitis, pseudotumor cerebri, tinnitus, and epistaxis, hepatitis

Laboratory Abnormality: Hypercholesterolemia, increased liver enzymes, increased creatinine phosphokinase, hepatotoxicity, hypertriglyceridemia, hyperglycemia, hypoglycemia, reticulocytosis

Absolute Contraindications

• Pregnancy or woman who is likely to become pregnant
• Non-compliance with contraception
• Nursing mothers

Hypersensitivity to drug or components, pregnancy, intent to become pregnant within three years after treatment discontinuation, severe hepatic or renal dysfunction, chronic abnormally elevated blood lipid levels, or concomitant use with methotrexate or tetracyclines.

It is vital that clinicians who prescribe acitretin to women of childbearing age ensure that they do not get pregnant for at least three years after discontinuing the medication. 

United States Boxed Warning

Female patients should abstain from ethanol during therapy and for at least two months after discontinuing treatment.

Caution

• Concomitant administration with methotrexate increases the risk of hepatic adverse effects.
• Concomitant administration with cyclosporine increases the risk of hypertriglyceridemia.
• Acitretin can undergo reverse metabolism to etretinate with acitretin if used in combination with alcohol.[9]
• The use of other vitamin A compounds can lead to hypervitaminosis A-like toxicities.
• The combination of tetracyclines and retinoids can lead to pseudotumor cerebri and should be avoided.

Individuals prescribed acitretin should receive counsel against giving blood donations for at least three years. The drug is known to remain in the blood for a long time, and the risk of genetic defects is high.

• Lipid profile
• Liver function tests[10]
• Complete blood count (CBC)
• Blood glucose in patients with diabetes
• Evaluation of bone abnormalities and visual problems
• Serum pregnancy testing

Toxicity

Acitretin must be withdrawn all at once in case of acute overdosage. Overdose symptoms are similar to acute hypervitaminosis A (headache and vertigo). In both mice and rats, the acute oral toxicity (LD50) of acitretin was only observed at greater than 4,000 mg per kg dose. In one case report of an overdose, a 32-year old adult male patient with Darier’s disease took 525 mg single dose. Later, he has vomited for several hours; however, he did not experience any other ill effects. One case of fulminant hepatic failure following an intentional overdose of 600 mg of acitretin was reported where the patient demonstrated a rapid recovery and did not require liver transplantation.[11] If any female patients of childbearing potential take an overdose of acitretin, a pregnancy test is recommended at the time of overdose and needed to council patient as per box contraindication and warning related to potential birth defects. Also, need to encourage patients to use contraceptives for at least three years’ duration after the overdose.

Enhancing Healthcare Team Outcomes

Acitretin is frequently used to treat several skin disorders, including acne, psoriasis, lichen planus, and discoid lupus. While the drug is effective, it is crucial for interprofessional healthcare team members, including pharmacists, nurse practitioners, PAs, and primary care clinicians, to know its potential adverse effects. Clinicians should never prescribe the drug to a pregnant female because of the risk of teratogenicity. Also, the FDA has issued several boxed warnings about the risk of hepatitis when combining the agent with alcohol or methotrexate. When prescribing acitretin, the patient must understand the potential adverse effects and the importance of avoiding alcohol.[12][13]

Given the warnings, it is apparent that an interprofessional team is the best means to manage acitretin therapy. Once the prescriber has decided to give the patient the drug, nursing can counsel on the patient's dosing, administration, and the potential teratogenicity if the patient is female. The pharmacist will verify dosing and perform medication reconciliation, alerting the prescriber of any issues. Nursing can also chart the therapeutic progress of the condition treated, so the prescriber can adjust therapy as needed. Through this interprofessional team paradigm, acitretin can deliver maximal benefit with minimal downside, resulting in better patient outcomes. [Level 5]