Acitretin

Acitretin is an Retinoic Acid Derivative belonging to pharmacology class of Anti-Acne agent.

Acitretin can be used in the treatment of Psoriasis.

Acitretin is absorbed in the GI tract. Increased absorption w/ food. Bioavailability: Approx 60-70% and get distributed into skin w/ highest concentration in stratum corneum; semen (small amounts). Penetrates adipose tissue, crosses the placenta and enters breast milk. Plasma protein binding: >99.9%, mainly to albumin and undergoes extensive hepatic metabolism and interconversion via simple isomerisation to 13-cis-acitretin and excreted via Urine (16-53%) and faeces (34-54%). Elimination half-life: Approx 2 days.

The common side effects associated with Acitretin include Cheilitis, alopecia, skin peeling, rhinitis, dry skin, nail disorder, pruritus, rigors, xerophthalmia, dry mouth, epistaxis, arthralgia, spinal hyperostosis, rash, hyperaesthesia

Acitretin is available in the form of Capsule.

Binds to and activates all nuclear subtypes (alpha, beta, and gamma) of retinoid X receptors (RXR) and retinoic acid receptors (RAR) to inhibit the expression of the proinflammatory cytokines interleukin-6 (IL-6), migration inhibitory factor-related protein-8 (MRP-8), and interferon-gamma (markers of hyperproliferation and abnormal keratinocyte differentiation). Resulting actions are Anti-Acne and antiproliferative, and keratinocyte differentiation is normalized in the epithelium.

The onset of action for Acitretin may take 3 to 6 months for full response, improvement may be seen within 8 weeks.

Acitretin is available in Capsule.

Administer with food, preferably with the main meal of the day.

Acitretin can be used in the treatment of Psoriasis.

Acitretin is a synthetic aromatic analogue of retinoic acid and an active metabolite of etretinate. The exact mechanism of action has not been established but may be mediated by activation of α, β and γ subtypes of retinoic acid and retinoid X receptors to inhibit the expression of the pro-inflammatory cytokines interleukin-6 (IL-6), migration inhibitory factor-related protein-8 (MRP-8), and interferon-γ, resulting to normalization of epidermal cell proliferation, differentiation and keratinization.

Acitretin is approved for use in the following clinical indications:

Psoriasis: Treatment of severe psoriasis in adults.

Although not approved there have been certain off labelled uses documented for Acitretin which includes:

Disorders of keratinization

Psoriasis: Oral: 10 to 50 mg once daily; reserve doses ≤25 mg/day for patients who do not tolerate higher doses. Note: Individualization of dosage is required to achieve maximum therapeutic response while minimizing side effects.

Disorders of keratinization (non-psoriatic) (off-label use): Oral: Initial: 25 to 35 mg once daily for 4 weeks than adjust dose as needed; maintenance: 10 to 50 mg daily; maximum: 50 mg daily.

Capsule

10 mg, 17.5 mg, 25 mg

Capsule

Should be taken with food. Take w/ main meals or w/ a glass of milk.

Acitretin may be contraindicated in the following conditions:-

Hypersensitivity (eg, angioedema, urticaria) to acitretin, other retinoids, or any component of the formulation; patients who are pregnant or intend on becoming pregnant during therapy or within 3 years after treatment discontinuation; severe hepatic or renal dysfunction; chronic abnormally elevated blood lipid levels; concomitant use with methotrexate or tetracyclines

Significant drug interactions exist, requiring dose/frequency adjustment or avoidance. Consult drug interactions database for more information.

Acitretin is contraindicated in females of childbearing potential unless all of the following conditions apply.

1) Patient has severe psoriasis unresponsive to other therapy or if clinical condition contraindicates other treatments.

2) Patient must have two negative urine or serum pregnancy tests prior to therapy.

3) Patient must have pregnancy test repeated monthly during therapy. After discontinuation of therapy, a pregnancy test must be repeated every 3 months for at least 3 years.

4) Patient must commit to using two effective forms of birth control starting 1 month prior to acitretin treatment and for 3 years after discontinuation. Prescriber must counsel patient about contraception every month during therapy and every 3 months following discontinuation for at least 3 years.

5) Patient is reliable in understanding and carrying out instructions.

6) Patient has received, and acknowledged, understanding of a careful oral and printed explanation of the hazards of fetal exposure to acitretin and the risk of possible contraception failure. Patient must sign an agreement/informed consent document stating that she understands these risks and that she should not consume ethanol during therapy or for 2 months after discontinuation.

The treating physician must closely monitor the patient and keep pharmacovigilance as follows

• Concerns related to adverse effects:

Capillary leak syndrome: Capillary leak syndrome, a potential manifestation of retinoic acid syndrome (differentiation syndrome) has been reported with acitretin use. Capillary leak syndrome features may include localized or generalized edema with secondary weight gain, fever, and hypotension; rhabdomyolysis and myalgias have also been reported. Laboratory tests may show neutrophilia, hypoalbuminemia, and an elevated hematocrit. Discontinue use if capillary leak syndrome develops during therapy.

Depression: Depression, including aggressive behavior and thoughts of self-harm have been reported; use with caution in patients with a history of mental illness.

Exfoliative dermatitis: Exfoliative dermatitis has been reported with acitretin use; discontinue use if exfoliative dermatitis occurs during therapy.

Hepatotoxicity: [US Boxed Warnings]: Hepatitis has been reported (including fatalities); some patients received etretinate for ≤1 month before presenting with hepatic signs or symptoms. Changes in transaminases have occurred in up to ¹/₃ of patients, which generally returned to normal after discontinuation of treatment. Monitor for hepatotoxicity; discontinue if hepatotoxicity is suspected.

Lipid effects: Lipid changes, including increased triglycerides, increased cholesterol, and decreased HDL, are common (up to 66%), which were reversible upon discontinuation of treatment; increased triglycerides may lead to pancreatitis. Fatal fulminant pancreatitis has been reported. Use with caution in patients at risk of hypertriglyceridemia (eg, patients with lipid metabolism disturbances, diabetes mellitus, obesity, increased alcohol intake, or a familial history of these conditions). Consider discontinuation if hypertriglyceridemia and decreased HDL persist. Use is contraindicated in patients with chronic abnormally elevated blood lipid values.

Otic effects: Tinnitus and impaired hearing have been reported with use; consider therapy discontinuation and further evaluation if clinically indicated.

Photosensitivity: May be photosensitizing; minimize sun or other UV exposure to treated areas. The risk of burning is increased with phototherapy; decreased doses are required.

Pseudotumor cerebri: Retinoids, including acitretin, have been associated with pseudotumor cerebri (benign intracranial hypertension). Concurrent use of other drugs associated with this effect (eg, tetracyclines) may increase risk. Early signs and symptoms include papilledema, headache, nausea, vomiting, and visual disturbances. Discontinue use in patients experiencing papilledema.

Skeletal abnormalities: Patients receiving long-term treatment should be periodically examined for bony abnormalities; risk vs benefit of therapy should be considered if abnormalities occur.

Visual disturbances: May cause adverse effects to the eyes and vision, including a decrease in night vision or decreased tolerance to contact lenses. Use caution when operating vehicles at night; discontinue if visual changes occur.

• Disease-related concerns:

Diabetes: Impaired glucose control has been reported with retinoid use. Use with caution in patients with diabetes mellitus; new cases of diabetes have been diagnosed.

There is no sufficient scientific evidence traceable regarding use and safety of Acitretin in concurrent use with alcohol.

Acitretin is present in breast milk.

Information is available from a woman who started acitretin 40 mg per day, 8 months postpartum. The woman discontinued breastfeeding prior to the study. Milk samples were collected prior to the first dose and twice daily for 9 days; maternal serum samples were also collected. Acitretin and its metabolite were detected in breast milk. Total concentrations of acitretin + metabolite remained relatively stable over the study period (30 to 40 ng/mL) showing no diurnal variation. Because acitretin is primarily distributed into milk fat, actual concentrations in breast milk may vary depending upon the lipid and fat content of the milk.

Pregnancy Category (FDA): X

Teratogenic Effects

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.

Nonteratogenic Effects

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.

Avoid ingestion of additional sources of exogenous vitamin A (in excess of RDA); females of childbearing potential should not ingest ethanol and ethanol-containing products during therapy and for 2 months after the last dose of acitretin.

The adverse reactions related to Acitretin can be categorized as:

Common Adverse effects: Cheilitis, Alopecia, Skin Peeling, Rhinitis, Dry Skin, Nail Disorder, Pruritus, Rigors, Xerophthalmia, Dry Mouth, Epistaxis, Arthralgia, Spinal Hyperostosis, Rash, Hyperesthesia

Less Common Adverse effects: Paranesthesia, Paronychia, Skin Atrophy, Decreased Night Vision, Abdominal Pain; Abnormal Hair Texture; Dermatitis

Rare Adverse effects: Diarrhea; Epidermal fragility; Erythema; Headache; Myalgia; Nausea, Vomiting; Peripheral oedema; Psudomotor cerebri, Depression and other Psychiatric Symptoms.

The clinically relevant drug interactions of Acitretin is briefly summarized here

May reduce the protein binding of phenytoin.

Potentially Fatal: Increased risk of hepatitis w/ methotrexate. Increased intracranial pressure w/ tetracyclines. Risk of hypervitaminosis A w/ concomitant vit A and/or other oral retinoids. Interferes w/ the contraceptive effect of low dose progesterone-only products (minipills).

The common side of Acitretin include the following:

Cheilitis, Alopecia, Skin peeling, Rhinitis, Dry skin, Nail disorder, Pruritus, Rigors, Xerophthalmia, Dry mouth, Epistaxis, Arthralgia, Spinal hyperostosis, Rash, Hyperesthesia.

Pregnancy Category (FDA): X

Teratogenic Effects

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.

Nonteratogenic Effects

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.

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 Darier’s disease took 21 x 25 mg capsules (525 mg single dose). He vomited several hours later but experienced no other ill effects.

Pharmacodynamics:

Acitretin is a retinoid. Retinoids have a structure similar to vitamin A and are involved in the normal growth of skin cells. Acitretin works by inhibiting the excessive cell growth and keratinization (process by which skin cells become thickened due to the deposition of a protein within them) seen in psoriasis. It therefore reduces the thickening of the skin, plaque formation and scaling.

Pharmacokinetics:

Absorption: Absorbed in the GI tract. Increased absorption w/ food.

Bioavailability: Approx 60-70%. Time to peak plasma concentration: 1-5 hr.

Distribution: Distributed into skin w/ highest concentration in stratum corneum; semen (small amounts). Penetrates adipose tissue, crosses the placenta and enters breast milk. Plasma protein binding: >99.9%, mainly to albumin.

Metabolism: Undergoes extensive hepatic metabolism and interconversion via simple isomerisation to 13-cis-acitretin.

Excretion: Via Urine (16-53%) and faeces (34-54%). Elimination half-life: Approx 2 days.

1. https://www.uptodate.com/contents/Acitretin -drug-information?search=Acitretin &source=panel_search_result&selectedTitle=1~148&usage_type=panel&kp_tab=drug_general&display_rank=1#F154338
2. https://www.accessdata.fda.gov/drugsatfda_docs/label/2014/022352s017lbl.pdf
3. https://www.medicaid.nv.gov/Downloads/provider/Acitretin _2015-1215.pdf
4. https://www.mims.com/india/drug/info/Acitretin ?type=full&mtype=generic#mechanism-of-action