Acitretin: A Comprehensive Pharmacological and Clinical Review

1. Introduction to Acitretin

1.1. Overview and Classification

Acitretin is an oral, second-generation, synthetic aromatic retinoid, a class of compounds structurally related to vitamin A. Retinoids are integral to various physiological processes, including the regulation of cellular growth, differentiation, proliferation, and immune responses.[1] Acitretin is the principal active metabolite of etretinate, a first-generation retinoid. The development of acitretin was driven by the aim to provide a therapeutic agent with a more favorable pharmacokinetic profile than etretinate, specifically a shorter elimination half-life, which was anticipated to reduce the duration of teratogenic risk.[2] This intended pharmacokinetic advantage, however, is notably complicated by in vivo metabolic interactions, particularly the re-esterification to etretinate in the presence of alcohol, which extends its teratogenic potential.[3]

Acitretin is primarily indicated for the systemic treatment of severe, recalcitrant psoriasis and other severe disorders of keratinization that have proven unresponsive to conventional topical or systemic therapies.[3] Its development as a metabolite of etretinate reflects a common strategy in pharmaceutical development, where active metabolites are investigated for potentially improved pharmacokinetic or pharmacodynamic characteristics. The initial promise of a shorter duration of teratogenic risk due to acitretin's faster elimination compared to etretinate (half-life of approximately 49-63 hours for acitretin and its cis-isomer, versus approximately 120 days for etretinate [2]) was a significant driver for its adoption. However, the metabolic conversion to etretinate with alcohol consumption underscores the complexities that can arise in clinical pharmacology.

1.2. Identification

Standardized identification of acitretin is crucial due to the existence of multiple synonyms and brand names across various global markets. This ensures clarity in scientific communication, regulatory documentation, and clinical practice.

• DrugBank ID: DB00459 [6]
• CAS Number: 55079-83-9 [11]
• Synonyms: Etretin [17], Ro 10-1670 [17], Ro-10-1670 [17], Trimethylmethoxyphenyl-retinoic acid [19], all-trans-acitretin [18], all-trans-Etretin.[18]
• Key Brand Names: Soriatane® (United States, Canada) [6], Neotigason® (Europe).[8] Other regional brand names include JAMP ACITRETIN and MINT-ACITRETIN in Canada.[25]

The use of universal identifiers like the CAS Registry Number and DrugBank ID is paramount for accurate data retrieval and consistent reporting, preventing ambiguity that could arise from regional variations in nomenclature.

1.3. Chemical Properties

• Chemical Name (IUPAC): (2E,4E,6E,8E)-9-(4-methoxy-2,3,6-trimethylphenyl)-3,7-dimethylnona-2,4,6,8-tetraenoic acid.[11] The all-trans configuration of its polyene chain is vital for its biological activity.[7]
• Molecular Formula: C21H26O3 [6]
• Molecular Weight: Approximately 326.43 - 326.44 g/mol [6]
• Physical State: Acitretin is a yellow to greenish-yellow crystalline powder or solid.[11]
• Solubility: While detailed solubility data are not uniformly provided, its oral formulation in gelatin capsules [7] and the recommendation for administration with food to enhance absorption [6] are indicative of its lipophilic nature. Acitretin is noted to be relatively more water-soluble than etretinate and demonstrates less partitioning into adipose tissue itself.[2]
• Structural Features: The chemical structure of acitretin comprises a substituted aromatic ring linked to a polyisoprenoid side chain characterized by conjugated double bonds (a tetraene system) and a terminal carboxylic acid group.[7] This conjugated tetraene structure renders the molecule susceptible to photo-isomerization, particularly when in solution.[7] The planar all-trans configuration of the side chain, in conjunction with the terminal carboxylic acid moiety, is considered optimal for its interaction with nuclear retinoic acid receptors.[7]

Table 1: Acitretin - Key Drug Information

Property	Detail	Reference(s)
DrugBank ID	DB00459	6
CAS Number	55079-83-9	11
Molecular Formula	C21H26O3	6
Molecular Weight	~326.44 g/mol	6
Key Brand Names	Soriatane® (US, Canada), Neotigason® (Europe), JAMP ACITRETIN (Canada), MINT-ACITRETIN (Canada)	6
Chemical Class	Second-generation synthetic aromatic retinoid	1
IUPAC Name	(2E,4E,6E,8E)-9-(4-methoxy-2,3,6-trimethylphenyl)-3,7-dimethylnona-2,4,6,8-tetraenoic acid	11

2. Mechanism of Action

The therapeutic effects of acitretin, particularly in hyperkeratotic and inflammatory skin disorders like psoriasis, are mediated through its interaction with nuclear retinoid receptors, leading to profound changes in gene expression that normalize epidermal cell behavior and modulate immune responses.

2.1. Interaction with Nuclear Retinoid Receptors (RARs and RXRs)

The precise molecular interactions of acitretin are complex, though it is broadly understood to function by modulating gene expression via nuclear retinoid receptors.[2] Like other retinoids, acitretin is transported into the cell and then to the nucleus, facilitated by cytosolic retinoic acid-binding proteins (CRABPs). Acitretin competes with endogenous retinoic acid for binding to CRABP.[2]

Once in the nucleus, retinoids exert their effects by interacting with two distinct families of nuclear receptors: the Retinoic Acid Receptors (RARs) and the Retinoid X Receptors (RXRs). Each of these receptor families comprises three subtypes, designated alpha (α), beta (β), and gamma (γ), which are encoded by different genes.[2] These receptors function as ligand-activated transcription factors. RARs typically form heterodimers with RXRs (RAR/RXR), while RXRs can form homodimers (RXR/RXR) or heterodimerize with other nuclear receptors, such as the thyroid hormone receptor, vitamin D3 receptor, and peroxisome proliferator-activated receptors (PPARs).[2]

The nature of acitretin's direct interaction with these receptors has been described with some nuance. While some sources broadly state that acitretin targets RARs and RXRs with agonist activity [6], more detailed accounts suggest that acitretin itself "can activate but does not bind to multiple RARs".[2] This implies that acitretin may exert its effects indirectly, possibly by modulating the availability of endogenous ligands for these receptors, or that its metabolites, such as cis-acitretin, are more direct ligands for certain receptor subtypes. The planar all-trans configuration and the terminal carboxylic acid group of acitretin are noted as optimal for RAR activity, suggesting these structural features are critical for its engagement with the retinoid signaling pathway.[712] indicates that acitretin binds to and activates RARs and RXRs. The collective evidence points to an overall agonistic effect on retinoid signaling pathways, leading to the observed therapeutic outcomes.

2.2. Modulation of Gene Expression

Upon ligand binding (either directly by acitretin/metabolites or indirectly through modulation of endogenous ligand availability), the retinoid-receptor complexes (RAR/RXR or RXR/RXR) bind to specific DNA sequences known as Retinoic Acid Response Elements (RAREs), located in the promoter regions of target genes.[2] This binding event triggers a conformational change in the receptor complex, leading to the dissociation of co-repressor proteins and the recruitment of co-activator proteins. This intricate process ultimately initiates or represses the transcription of a multitude of genes involved in cellular growth, differentiation, apoptosis, and inflammation.[2] The ability of acitretin to influence a wide array of genes via these nuclear receptors accounts for its pleiotropic effects, contributing to both its therapeutic efficacy in complex dermatological diseases and its diverse side effect profile.

2.3. Effects on Epidermal Cells in Psoriasis

Psoriasis is characterized by epidermal hyperproliferation, abnormal keratinocyte differentiation, and incomplete cornification. Acitretin addresses these pathological hallmarks:

• Normalization of Keratinocyte Proliferation and Differentiation: Acitretin promotes the normalization of epidermal cell proliferation and differentiation.[2] It inhibits the excessive cell growth (hyperplasia) and aberrant keratinization (the process by which skin cells become thickened due to protein deposition) that are central to psoriatic lesion formation.[6]
• Reduction of Psoriatic Lesions: By controlling these cellular processes, acitretin leads to a reduction in epidermal thickness, plaque formation, and the characteristic scaling associated with psoriasis.[4]

2.4. Anti-inflammatory and Immunomodulatory Effects

Beyond its direct effects on keratinocytes, acitretin also exhibits significant anti-inflammatory and immunomodulatory actions relevant to the pathogenesis of psoriasis:

• Cytokine Modulation: Acitretin hinders the expression of several pro-inflammatory cytokines, including Interleukin-6 (IL-6), migration inhibitory factor-related protein-8 (MRP-8), and interferon-γ (IFN-γ).[2] These cytokines are known to drive the inflammatory cascade in psoriatic skin.
• T-Cell Modulation: It modulates the activity of T-lymphocytes, which are key effector cells in the immune-mediated inflammation characteristic of psoriasis.[12]
• Non-Immunosuppressive Profile: A crucial distinction of acitretin compared to other systemic psoriasis therapies like methotrexate and cyclosporine is its lack of direct, broad immunosuppressive effects.[30] This characteristic makes acitretin a potentially safer therapeutic option for certain patient populations, such as individuals who are immunocompromised, have a history of chronic infections (e.g., HIV, hepatitis B or C), or a history of malignancy, where systemic immunosuppression would be contraindicated.[30] Its mechanism, focused on normalizing keratinocyte function and modulating specific inflammatory pathways rather than general immune suppression, provides a unique therapeutic advantage in these contexts.

3. Pharmacokinetics (ADME)

The pharmacokinetic profile of acitretin is characterized by variable absorption influenced by food, high protein binding, extensive metabolism including isomerization and critical interaction with alcohol, and excretion via both renal and fecal routes.

3.1. Absorption

Acitretin is administered orally, and its absorption is significantly enhanced when taken with food, particularly a meal containing fat.[4] This food effect is a critical factor for consistent bioavailability and therapeutic efficacy. The absorption of acitretin is linear and proportional with increasing doses ranging from 25 mg to 100 mg.[6] Following a single 50 mg oral dose in healthy subjects, approximately 72% (range 47% to 109%) of the administered dose was absorbed.[6] Peak plasma concentrations (Tmax​) are typically reached within 1 to 5 hours post-administration, with various sources citing ranges of 2-5 hours [28], 1-4 hours [8], or a mean of 2.7 hours.[2] The bioavailability of acitretin exhibits considerable inter-patient variability, reported to be approximately 60% but ranging from 36% to 95%.[8]

3.2. Distribution

Once absorbed, acitretin is highly bound to plasma proteins, with over 99.9% associated primarily with albumin.[6] Due to its lipophilic nature, acitretin penetrates readily into body tissues.[8] While specific data on the volume of distribution are not consistently provided [6], its lipophilicity suggests widespread distribution. Studies have confirmed that acitretin is distributed into breast milk [28] and, based on animal studies, it crosses the placental barrier, leading to fetal malformations.[8]

Regarding distribution to the skin, the primary target organ for its therapeutic effects in dermatological conditions, evidence indicates that systemic administration of acitretin results in significant drug concentrations within the skin. Research comparing systemic versus topical administration found that skin concentrations after oral dosing at steady state were comparable to those achieved after a single 24-hour topical application of a saturated acitretin formulation.[32] This confirms effective delivery to the site of action and may also imply that the skin could act as a minor reservoir for the drug.

3.3. Metabolism

Acitretin undergoes extensive metabolism in the body.[6]

• Isomerization: A primary metabolic pathway is the simple isomerization of acitretin (all-trans form) to its 13-cis isomer, known as cis-acitretin or isoacitretin.[2] This metabolite is also pharmacologically active and possesses teratogenic potential. The formation of cis-acitretin relative to the parent compound is not significantly altered by dose or by fed/fast conditions of administration.[24]
• Chain-Shortened Products and Conjugates: Both acitretin and cis-acitretin are further metabolized into chain-shortened breakdown products and undergo conjugation, primarily forming glucuronide derivatives, which are then excreted.[2]
• Re-esterification to Etretinate with Alcohol Consumption: A critically important metabolic interaction occurs with concurrent alcohol (ethanol) consumption. In the presence of alcohol, acitretin undergoes reverse metabolism via esterification to form etretinate.[2] Etretinate is the parent drug of acitretin and is characterized by its high lipophilicity, extensive storage in adipose tissue, and an extremely long elimination half-life (approximately 120 days).[2] This metabolic conversion is of profound clinical significance because etretinate is also a potent teratogen. The formation of etretinate from acitretin in individuals consuming alcohol effectively negates the pharmacokinetic advantage of acitretin's shorter intrinsic half-life and significantly prolongs the period of teratogenic risk. This interaction is the primary reason for the stringent advice against alcohol consumption during and for 2 months after acitretin therapy for women of childbearing potential, and contributes to the 3-year post-treatment contraception requirement.[6]

3.4. Excretion

The metabolites of acitretin, including chain-shortened products and conjugates of both acitretin and cis-acitretin, are eliminated from the body through both renal and fecal routes. Approximately 16% to 53% of the administered dose is excreted in the urine, while 34% to 54% is excreted in the feces.[2]

3.5. Half-life

The elimination half-lives of acitretin and its main metabolites are key determinants of its dosing schedule and the duration of post-treatment precautions:

• Acitretin: Following multiple-dose administration, the terminal elimination half-life of acitretin is approximately 49 to 50 hours, with a reported range of 33 to 96 hours.[2]
• Cis-acitretin: The active 13-cis isomer has a slightly longer elimination half-life, approximately 63 hours, with a range of 28 to 157 hours under similar conditions.[2]
• Etretinate: In contrast, etretinate (the parent drug of acitretin, and its metabolite when alcohol is consumed concurrently) has a markedly longer elimination half-life of approximately 120 days.[2] This long half-life is due to its high lipophilicity and storage in adipose tissue, leading to slow release over an extended period. While one source suggests that more than 99% of etretinate is eliminated within 36 days after cessation of long-term therapy [8], other sources and clinical guidelines consistently emphasize its potential detection and teratogenic risk for up to 3 years post-exposure [9], forming the basis for the extended contraception recommendations.

The significant difference in half-lives, particularly the potential for forming long-lasting etretinate, highlights the critical importance of patient counseling regarding alcohol consumption and long-term contraception.

4. Clinical Applications and Efficacy

Acitretin is an established systemic therapy for several severe dermatological conditions, primarily severe psoriasis and other disorders of keratinization. Its efficacy varies depending on the specific condition, disease subtype, and whether it is used as monotherapy or in combination with other treatments.

4.1. Psoriasis

Acitretin is a cornerstone in the management of severe psoriasis, particularly for specific subtypes and in patients where other therapies are contraindicated or have failed.

4.1.1. Approved Indications

• United States (FDA): Approved for the treatment of severe psoriasis in adults.[2] This generally includes severe plaque-type psoriasis, generalized pustular psoriasis, localized pustular psoriasis (palmoplantar pustulosis), and erythrodermic psoriasis.[2]
• Europe (EMA): Approved for severe extensive psoriasis resistant to other therapies, palmoplantar pustular psoriasis, erythrodermic psoriasis, severe congenital ichthyosis, pityriasis rubra pilaris, and Darier's disease.[3]
• Canada (Health Canada): Approved for severe psoriasis and other disorders of keratinization.[22]

4.1.2. Efficacy as Monotherapy

Acitretin monotherapy demonstrates variable efficacy across different forms of psoriasis:

• Plaque Psoriasis: While effective, acitretin as monotherapy is generally considered less potent for chronic plaque psoriasis compared to some other systemic agents like biologics or cyclosporine.[30] Clinical trials indicate that approximately 50% of patients achieve a 75% improvement in the Psoriasis Area and Severity Index (PASI 75) after 12 weeks, with about 75% achieving PASI 50.[29] Some studies report PASI 75 achievement in 47-69% of patients at 12 weeks, depending on the dose (e.g., 25, 35, or 50 mg/day).[3] Complete remission is achieved in roughly one-third of patients with plaque-type psoriasis.[35] The onset of action for plaque psoriasis is typically slow, with improvements often noted after 8 to 16 weeks, and peak effects may take up to six months.[21] An initial, temporary worsening of psoriasis can sometimes occur at the beginning of treatment.[3]
• Pustular Psoriasis: Acitretin is considered a treatment of choice for generalized and palmoplantar pustular psoriasis.[15] It can lead to a rapid reduction in pustules, often within 4 weeks of initiating therapy.[3] A comparative study involving different doses of acitretin versus methotrexate (MTX) for pustular psoriasis found that high-dose acitretin (0.75 mg/kg/day) was particularly effective, leading to faster symptom relief (erythema, fever, pustules), lower recurrence rates, and greater improvement in GPPASI (Generalized Pustular Psoriasis Area and Severity Index) scores compared to MTX or lower doses of acitretin.[36]
• Erythrodermic Psoriasis (EP): Acitretin is recommended as a first-line systemic treatment for stable erythrodermic psoriasis.[37] A retrospective study involving 81 EP patients treated with acitretin monotherapy (20-60 mg/day) demonstrated a progressive increase in response rates: at 1 week, 2.5% showed a partial response; by 12 weeks, 85.2% achieved a good response (>75% clearance) and 13.6% a partial response (50-75% clearance). Patients whose EP evolved from psoriasis vulgaris and those without concurrent infections tended to have better outcomes.[37] However, some reports indicate inconsistent results with acitretin monotherapy for EP.[38]

4.1.3. Efficacy in Combination Therapies

The efficacy of acitretin, particularly for plaque psoriasis, can be significantly enhanced by using it in combination with other therapeutic modalities. This approach may also allow for lower doses of acitretin, potentially reducing side effects.[4]

• Phototherapy (Re-PUVA and Re-UVB): The combination of acitretin with psoralen plus ultraviolet A (PUVA) light therapy (Re-PUVA) or with ultraviolet B (UVB) phototherapy (Re-UVB) is a well-established and highly effective strategy. This combination increases the efficacy of phototherapy, allowing for reduced treatment frequencies, shorter durations of light exposure, and lower cumulative UV doses, thereby minimizing long-term phototherapy-related risks.[2]
• Topical Agents: Acitretin can be effectively combined with topical corticosteroids or vitamin D3 analogues (e.g., calcipotriol). Such combinations can improve treatment outcomes and may permit the use of lower systemic acitretin doses.[35]
• Other Systemic Agents:
• Biologics: Acitretin is sometimes used concomitantly with biologic agents such as etanercept or infliximab, particularly in difficult-to-treat cases.[21]
• Methotrexate (MTX): Combination therapy with MTX has been explored. While historically there have been concerns about additive hepatotoxicity, a retrospective cohort study found no statistically significant increase in the incidence of hepatic fibrosis (assessed by transient elastography) in psoriasis patients receiving MTX-acitretin combination therapy compared to those receiving MTX monotherapy.[31] Nevertheless, careful liver function monitoring remains crucial with such combinations.
• Cyclosporine: Acitretin may be used in rotation with cyclosporine as part of a long-term management strategy for severe psoriasis.[21] Combination therapy with cyclosporine has shown rapid response in some cases of EP, though failures have also been reported.[38]

4.2. Other Keratinization Disorders

Acitretin is also valuable in treating a range of other severe disorders of keratinization, many of which are approved indications in Europe or are treated off-label in other regions.[5]

• Ichthyoses: Acitretin is an approved treatment for severe congenital ichthyosis by the EMA [14] and is used for various forms of ichthyosis where it normalizes skin cell turnover and reduces scaling.[4] Case reports document successful treatment of congenital ichthyosis, including lamellar ichthyosis, in neonates and children with doses around 1 mg/kg/day, leading to significant improvement in skin lesions and overall condition.[39]
• Darier's Disease (Keratosis Follicularis): This is an approved indication for acitretin in Europe.[14] Clinical evidence (Grade B) supports its use, with studies demonstrating improvement in a majority of patients, though side effects are common, and relapse upon discontinuation is a concern.[41] Combination with abrocitinib has been reported as effective in a case study.[42]
• Lichen Planus: The EMA includes lichen ruber planus of the skin and mucous membranes as an indication for acitretin.[14] It is also used off-label for this condition.[4]
• Palmoplantar Keratodermas (PPK): Acitretin is used to manage the thickened skin on the palms and soles characteristic of various PPKs, improving skin texture.[4]
• Pityriasis Rubra Pilaris (PRP): While not a universally approved indication, it falls under "other severe disorders of keratinization" for which acitretin is used.[5]

4.3. Chemoprevention of Skin Cancer in Transplant Recipients

Organ transplant recipients (OTRs) are at a significantly increased risk of developing non-melanoma skin cancers (NMSCs), particularly squamous cell carcinomas (SCCs). Acitretin is used off-label as a chemopreventive agent in this high-risk population.[2]

• Clinical trial evidence supports this use. A randomized, double-blind, placebo-controlled trial in renal transplant recipients with multiple keratotic lesions demonstrated that acitretin (30 mg/day for 6 months) significantly reduced the development of new SCCs (11% in the acitretin group vs. 47% in the placebo group) and decreased the number of keratotic lesions.[44]
• Another randomized trial in renal transplant recipients found that acitretin (25 mg/day) significantly lowered the number of SCCs compared to a drug-free observation period.[43]
• Lower doses (e.g., 0.2 to 0.4 mg/kg/day) have also shown benefits in reducing actinic keratoses and SCCs, although mucocutaneous side effects often necessitate dose reductions.[43]
• A challenge with retinoid chemoprevention is the tendency for rebound flares of keratotic lesions and skin cancers upon discontinuation of therapy, suggesting that long-term, continuous, or intermittent therapy may be necessary for sustained benefit in high-risk OTRs.[43] The optimal dosing and duration for chemoprevention require careful balancing of efficacy against long-term tolerability.

Table 2: Summary of Acitretin Efficacy in Psoriasis

Psoriasis Type	Treatment Modality	Typical Acitretin Dose Range	Duration of Treatment	Key Efficacy Endpoint(s)	Reported Efficacy	Reference(s)
Plaque Psoriasis	Monotherapy	25-75 mg/day	8-16 weeks; up to 6m	PASI 75, PASI 50, Complete Remission	~50% PASI 75 at 12 weeks; ~75% PASI 50 at 12 weeks; ~33% Complete Remission. Initial worsening possible.	3
	Combination (Re-UVB/PUVA)	Lower doses often possible	Variable	Enhanced PASI response, Reduced UV dose	Increased efficacy, faster response, lower cumulative UV dose compared to phototherapy alone.	21
Pustular Psoriasis	Monotherapy	25-75 mg/day (or weight-based, e.g., 0.75 mg/kg/day)	Weeks to Months	Reduction in pustules, GPPASI improvement, Symptom relief	Treatment of choice. Rapid reduction in pustules (e.g., within 4 weeks). High-dose (0.75 mg/kg/day) showed superior GPPASI50/75/90 improvement and shorter symptom relief time vs. MTX or lower acitretin doses.	3
Erythrodermic Psoriasis	Monotherapy	20-60 mg/day	Weeks to Months	Lesion clearance (>75% good, 50-75% partial)	Retrospective study: 85.2% good response, 13.6% partial response at 12 weeks. Better in EP from psoriasis vulgaris, no infection. Results can be inconsistent.	15

Table 3: Acitretin in Other Dermatological Conditions

Condition	Typical Acitretin Dose Range	Study Type/Level of Evidence	Key Efficacy Outcome	Reference(s)
Ichthyosis (Congenital)	1 mg/kg/day (pediatric case reports)	EMA Approved Indication; Case reports/series	Significant improvement/normalization of skin lesions.	14
Darier's Disease (Keratosis Follicularis)	10-50 mg/day	EMA Approved Indication; Clinical trials (Grade B evidence)	Improvement in lesions; significant side effects common; relapse on discontinuation.	14
Lichen Planus (Skin & Mucous Membranes)	Variable	EMA Approved Indication; Off-label use	Reduction in lesions.	4
Chemoprevention of NMSC in OTRs	0.2-0.4 mg/kg/day or 25-30 mg/day	Randomized Controlled Trials (RCTs), Retrospective studies	Significant reduction in new SCCs and keratotic lesions. Rebound on discontinuation.	2

The spectrum of acitretin's efficacy, being particularly notable for pustular and erythrodermic psoriasis and certain severe keratinization disorders, positions it as a crucial therapeutic agent. Its moderate efficacy as monotherapy for plaque psoriasis is often augmented significantly through combination regimens, especially with phototherapy. This differential efficacy profile guides its strategic placement in dermatological treatment algorithms. Furthermore, the observed dose-dependent efficacy, coupled with a characteristic lag time for clinical improvement and the potential for initial disease flare, necessitates careful patient counseling and expectation management. For the chemoprevention of NMSCs in OTRs, acitretin offers a valuable, albeit challenging, option due to common side effects and the risk of rebound upon cessation, highlighting the need for long-term, meticulously managed therapeutic strategies in this vulnerable patient group.

5. Safety Profile, Tolerability, and Risk Management

The clinical use of acitretin is critically governed by its safety profile, which is dominated by its profound teratogenicity. This necessitates comprehensive risk management strategies, including stringent Pregnancy Prevention Programs (PPPs). Other common adverse effects involve mucocutaneous tissues, lipid metabolism, and liver function, many of which are dose-dependent and manageable.

5.1. Teratogenicity and Pregnancy Prevention (CRITICAL FOCUS)

Acitretin is unequivocally classified as a powerful human teratogen, carrying a high risk of inducing severe and life-threatening birth defects if exposure occurs during pregnancy.[8] Reported major human fetal abnormalities associated with acitretin and/or its parent compound etretinate include, but are not limited to, meningomyelocele, meningoencephalocele, multiple synostoses, facial dysmorphia, syndactyly, absence of terminal phalanges, malformations of the hip, ankle, and forearm, low-set ears, high palate, and severe abnormalities of the brain, ear, eye, heart, thymus gland, and parathyroid gland.[47] Any fetus exposed to acitretin during gestation is potentially at risk.[47] Data from post-marketing surveillance and registries indicate that a significant percentage of exposed pregnancies can result in malformations in live-born infants or are electively terminated due to teratogenic risk.[34]

5.1.1. Pregnancy Prevention Programs (PPPs)

Due to this severe risk, regulatory authorities worldwide mandate stringent PPPs for acitretin. Examples include the "Take Action to Prevent Pregnancy" (T.A.P.P.) program in the United States [47] and similar comprehensive PPPs in Europe and Canada.[25] These programs are designed to educate both female patients of childbearing potential and their healthcare providers about the teratogenic risks and the mandatory requirements to prevent pregnancy during and long after acitretin treatment.[47] It is important to note that the iPLEDGE REMS program is specific to isotretinoin and does not apply to acitretin [50]; acitretin has its own distinct risk management programs like T.A.P.P. or the European Pregnancy Prevention Programme (EPPA™).[46]

5.1.2. Contraceptive Requirements

Females of childbearing potential must adhere to exceptionally strict contraceptive measures:

• Simultaneous Use of Two Effective Forms: Two effective forms of contraception must be used simultaneously, with at least one being a primary method (e.g., hormonal contraception, IUD). This dual contraception must begin at least 1 month before initiating acitretin therapy, continue throughout the entire duration of treatment, and persist for a minimum of 3 years after discontinuing acitretin.[21]
• Ineffectiveness of Progestin-Only Pills: Progestin-only contraceptive pills ("minipills") may have reduced efficacy when used concomitantly with acitretin and are therefore not recommended as a reliable method of contraception during acitretin therapy.[15] Patients should be counseled to use alternative or additional contraceptive methods.

5.1.3. Pregnancy Testing

A rigorous pregnancy testing schedule is integral to the PPP:

• Pre-Treatment: Two negative pregnancy tests are mandatory before initiating acitretin. The first is a screening test performed when the decision to treat is made. The second, confirmatory test must be conducted within the first 5 days of the menstrual period immediately preceding the start of therapy, or at least 11 days after the last act of unprotected sexual intercourse for amenorrheic patients. Treatment should commence within 7 days of this negative confirmatory test.[21] Therapy is typically initiated on the second or third day of the next normal menstrual period.[28]
• During Treatment: Pregnancy tests (urine or serum, sensitivity ≥25 mIU/mL) must be repeated monthly throughout the course of acitretin treatment. Prescriptions are often limited to a monthly supply contingent upon a negative test.[25]
• Post-Treatment: Due to the prolonged elimination of potentially teratogenic levels of the drug or its metabolites (especially etretinate if alcohol was consumed), pregnancy testing must continue every 1 to 3 months for at least 3 years after the last dose of acitretin.[25]

5.1.4. Alcohol Interaction and Extended Teratogenic Risk

The interaction between acitretin and alcohol is of paramount importance regarding teratogenicity:

• Concurrent ingestion of any form of alcohol (including in beverages, foods, or medications) leads to the metabolic re-esterification of acitretin to etretinate.[2]
• Etretinate is a highly lipophilic and potent teratogen with an extremely long elimination half-life (approximately 120 days), leading to its accumulation in adipose tissue and slow release over many months or even years.[2]
• This conversion significantly extends the duration of teratogenic risk. Consequently, females of childbearing potential must strictly avoid consuming alcohol during acitretin treatment and for 2 months after discontinuing acitretin.[6] This 2-month alcohol-free window post-treatment aims to prevent further formation of the long-lasting etretinate. The overall 3-year post-treatment contraception period accounts for the slow elimination of any etretinate that may have already formed, as well as the complete clearance of acitretin and cis-acitretin to sub-teratogenic levels.

5.1.5. Blood Donation Restrictions

Due to the risk of teratogenic retinoids being present in donated blood, which could inadvertently be transfused to a pregnant woman, patients (both male and female) treated with acitretin are prohibited from donating blood during therapy and for at least 3 years after the final dose.[21]

5.1.6. Breastfeeding

Acitretin is contraindicated during breastfeeding as it is likely to pass into breast milk and may harm the nursing infant.[8]

The absolute dominance of teratogenicity in acitretin's risk profile dictates nearly all aspects of its clinical use and regulation. The complex interplay between its own teratogenic nature, that of its active metabolite cis-acitretin, and the potential formation of the long-acting teratogen etretinate (especially with alcohol) necessitates these exceptionally stringent and prolonged precautionary measures.

Table 4: Pregnancy Prevention Program Key Requirements for Acitretin

Requirement Category	Specific Requirement Details	Duration	Reference(s)
Eligibility (Females of Childbearing Potential - FOCBP)	Severe psoriasis unresponsive to other therapies or clinical condition contraindicates other treatments. Must understand and commit to all PPP requirements.	Pre-treatment assessment	15
Contraception	Simultaneous use of two effective forms (one primary) of contraception. Progestin-only "minipills" not recommended.	Start ≥1 month before, during, and for ≥3 years after stopping acitretin.	21
Pregnancy Testing	Two negative tests before initiation. Monthly tests during treatment. Tests every 1-3 months post-treatment.	Before, during, and for ≥3 years after stopping acitretin.	25
Alcohol Avoidance (FOCBP)	Strict avoidance of all alcohol (beverages, food, medicines).	During treatment and for 2 months after stopping acitretin.	6
Blood Donation Ban	All patients (male and female) must not donate blood.	During treatment and for ≥3 years after stopping acitretin.	21
Patient Education/Consent	Comprehensive counseling on teratogenic risks and PPP requirements. Signed informed consent/patient agreement often required.	Before initiating treatment and reinforced throughout.	25

5.2. Common and Serious Adverse Effects

Most adverse effects of acitretin are dose-dependent and generally reversible upon dose reduction or discontinuation of therapy.[15] An initial, transient worsening of psoriasis symptoms can sometimes occur at the beginning of treatment.[3] The skin and mucous membranes are the most frequently affected sites.

Table 5: Common and Serious Adverse Effects of Acitretin

System Organ Class	Adverse Effect	Frequency (Typical)	Management Notes (if available)	Reference(s)
Skin and Subcutaneous Tissue Disorders	Dry lips, cheilitis	Very Common (<100%)	Emollients	15
	Dry skin (xerosis), skin peeling (especially palms/soles), pruritus	Very Common/Common	Emollients, avoid irritants	13
	Alopecia (hair loss)	Common (7-75%)	Often reversible	15
	Nail fragility, paronychia	Common	-	15
	Photosensitivity	Common/Rare	Sun protection essential	15
	Sticky skin sensation, dermatitis, erythema	Very Common/Common	-	15
	Exfoliative dermatitis	Very Rare / Not Known	Discontinue if severe	15
Mucous Membranes	Dry mouth, dry nose, rhinitis	Very Common/Common	Humidification, saline sprays	15
	Epistaxis (nosebleeds)	Common	-	21
Metabolism and Nutrition Disorders	Hypertriglyceridemia, Hypercholesterolemia	Very Common/Common	Diet, lipid-lowering agents if severe, monitoring	2
	Decreased HDL	Common	-	28
Hepatobiliary Disorders	Elevated liver enzymes (transaminitis)	Common (11-28%)	Monitor LFTs, dose adjust/discontinue if persistent/severe	2
	Toxic hepatitis, liver damage/failure	Rare/Serious Rare	Discontinue immediately	2
	Jaundice	Rare	-	15
Musculoskeletal and Connective Tissue Disorders	Myalgia, arthralgia, bone pain	Common/Uncommon	Analgesics	15
	Skeletal hyperostosis, ligament/tendon calcification, premature epiphyseal closure (children, long-term)	Serious Rare (long-term)	Radiographic monitoring for long-term use	13
Nervous System Disorders	Headache	Common	Analgesics	15
	Pseudotumor cerebri (benign intracranial hypertension)	Rare/Serious Rare	Discontinue immediately; avoid tetracyclines	15
Psychiatric Disorders	Depression, anxiety, mood alterations, aggressive tendencies, suicidal ideation	Rare/Serious Rare	Monitor; discontinue if severe; psychiatric consult	2
Eye Disorders	Dry eyes (xerophthalmia), conjunctivitis, eye irritation	Common/Very Common	Artificial tears	15
	Decreased night vision	Common/Serious	Caution driving at night; ophthalmologic evaluation if persistent	15
	Corneal inflammation/ulcers	Rare	Ophthalmologic evaluation	15
Gastrointestinal Disorders	Nausea, vomiting, abdominal pain, diarrhea, dyspepsia	Common/Uncommon	Symptomatic treatment	15
	Pancreatitis (related to hypertriglyceridemia)	Serious Rare	Monitor triglycerides; discontinue if pancreatitis occurs	13
Blood and Lymphatic System Disorders	Changes in blood counts (leukopenia, etc.)	Common (variable)	Monitor CBC	28
	Agranulocytosis	Serious Rare	-	55
General Disorders	Thirst, feeling of cold, fatigue	Common/Very Common	-	15
	Peripheral edema	Uncommon	-	15
Vascular Disorders	Capillary Leak Syndrome / Retinoic Acid Syndrome	Very Rare / Not Known	Discontinue immediately	15

The dose-dependent nature of many common acitretin adverse effects, such as mucocutaneous dryness and hyperlipidemia, allows for potential management through careful dose titration and adjustment.[13] This is a characteristic feature of retinoid therapy and underscores the importance of individualized treatment plans to balance efficacy with tolerability.

5.3. Contraindications

Acitretin is strictly contraindicated in several situations due to its risk profile:

• Pregnancy: Absolute contraindication (Pregnancy Category X in the US) due to severe teratogenicity.[2]
• Females of Childbearing Potential: Contraindicated if unable or unwilling to comply with all terms of the Pregnancy Prevention Program, including the use of two effective forms of contraception simultaneously for at least 1 month before, during, and for 3 years after therapy.[15]
• Breastfeeding: Contraindicated as acitretin passes into breast milk and may harm the infant.[8]
• Severe Hepatic Impairment: Contraindicated.[2]
• Severe Renal Impairment: Contraindicated.[2]
• Chronic Hyperlipidemia: Contraindicated in patients with chronic, abnormally elevated blood lipid values.[15]
• Hypersensitivity: Contraindicated in patients with known hypersensitivity to acitretin, other retinoids, or any excipients in the formulation.[15]
• Concomitant Medications:
• Methotrexate: Contraindicated due to increased risk of hepatitis.[15]
• Tetracyclines: Contraindicated due to increased risk of pseudotumor cerebri.[6]
• Vitamin A or other oral retinoids: Contraindicated due to the risk of hypervitaminosis A and additive toxicity.[6]
• Alcohol: Contraindicated in females of childbearing potential due to conversion to etretinate.[6]
• Low-dose progestogen-only contraceptive pills ("minipills"): Contraindicated as their contraceptive efficacy may be reduced.[15]

5.4. Warnings and Precautions

Specific warnings and precautions accompany acitretin use:

• Hepatotoxicity: Liver function must be monitored before treatment, every 1-2 weeks for the first 2 months, and then every 3 months. Discontinue if clinically significant liver function abnormalities occur or worsen.[2]
• Hyperlipidemia: Fasting blood lipids (cholesterol and triglycerides) must be monitored before treatment, every 1-2 weeks for the first 2 months, and then periodically. If hypertriglyceridemia is uncontrolled, there is a risk of pancreatitis. Manage with diet, lipid-lowering drugs if necessary, or acitretin discontinuation.[2]
• Pancreatitis: Monitor for symptoms, especially in patients with high triglycerides.[16]
• Bone Changes: Long-term therapy, especially in children, may cause skeletal abnormalities like hyperostosis, extraspinal tendon and ligament calcification, and premature epiphyseal closure. Periodic radiological monitoring may be appropriate for long-term users.[13]
• Pseudotumor Cerebri: Patients should be monitored for signs and symptoms (severe headache, nausea, vomiting, visual disturbances). If it occurs, acitretin should be discontinued immediately.[16]
• Ophthalmic Effects: Decreased night vision can occur suddenly. Patients should be cautioned, especially regarding driving at night. Dry eyes are common. Any significant visual problems warrant ophthalmological evaluation.[15]
• Psychiatric Effects: Reports of depression, worsening of pre-existing depression, anxiety, aggressive tendencies, and mood alterations. Patients with a history of depression require careful monitoring. Patients and families should be alerted to report any such symptoms.[2]
• Photosensitivity: Acitretin can increase sensitivity to UV light. Patients should be advised to use sunscreen (SPF 15 or higher) and protective clothing, and avoid excessive sun exposure and sunlamps. Phototherapy doses may need adjustment.[16]
• Diabetes Mellitus: Acitretin can affect glucose tolerance (either improve or worsen). Blood glucose levels should be checked more frequently in diabetic patients, particularly during the early stages of treatment.[16]
• Capillary Leak Syndrome/Retinoic Acid Syndrome: Very rare cases have been reported with systemic retinoids. Patients should be monitored for symptoms like rapid weight gain, edema, and dyspnea.[15]

5.5. Monitoring Requirements

Regular monitoring is essential to manage the risks associated with acitretin therapy:

• Pregnancy Tests (FOCBP): Before starting (two negative tests), monthly during therapy, and every 1-3 months for 3 years after discontinuation.[25]
• Liver Function Tests (LFTs): At baseline, then every 1-2 weeks for the first 2 months of therapy, and thereafter every 3 months during therapy.[2]
• Fasting Lipid Profile (Cholesterol and Triglycerides): At baseline, then every 1-2 weeks for the first 2 months, and then periodically as clinically indicated.[2]
• Blood Glucose: More frequent monitoring in patients with diabetes mellitus.[2]
• Skeletal Assessment: In cases of long-term therapy, especially in children, periodic radiological examination for bone changes (e.g., hyperostosis, premature epiphyseal closure) may be considered.[16]
• Complete Blood Count (CBC), Serum Creatinine: Periodically as clinically indicated.[13]

The extensive and prolonged monitoring requirements, particularly the 3-year post-treatment pregnancy prevention and blood donation ban, create a significant long-term responsibility for both the patient and the prescribing physician. This extended vigilance is unique to acitretin (and previously etretinate) due to the potential for prolonged teratogenic risk.

6. Regulatory Status

Acitretin is an approved medication for severe psoriasis and other keratinization disorders in numerous countries, with regulatory agencies like the FDA (USA), EMA (Europe), and Health Canada imposing stringent risk management measures due to its teratogenic profile.

6.1. FDA (United States Food and Drug Administration)

• Acitretin is approved by the FDA for the treatment of severe psoriasis in adults.[2]
• The primary brand name in the US is Soriatane®.[6]
• Due to its high teratogenic potential, acitretin is subject to a specific risk management program called the "Take Action to Prevent Pregnancy" (T.A.P.P.) program. This program includes mandatory patient education, contraception requirements, and pregnancy testing.[47] It is important to distinguish this from the iPLEDGE REMS, which is for isotretinoin.[50]

6.2. EMA (European Medicines Agency)

• Acitretin is authorized for use in the majority of European Union member states.[14]
• Approved indications under the EMA include severe forms of psoriasis (such as erythrodermic psoriasis and local or generalized pustular psoriasis), severe congenital ichthyosis, pityriasis rubra pilaris, and Darier's disease. It is also indicated for other severe disorders of keratinization that may be resistant to other therapies.[8]
• A common brand name in Europe is Neotigason®.[8]
• The EMA mandates a comprehensive Pregnancy Prevention Programme (PPP) for acitretin, with requirements similar to those in the US, emphasizing contraception, pregnancy testing, and alcohol avoidance.[48]

6.3. Health Canada

• Health Canada has approved acitretin for the treatment of severe psoriasis and other disorders of keratinization.[22]
• Available brand names include JAMP ACITRETIN [26] and MINT-ACITRETIN.[25]
• Similar to other regulatory bodies, Health Canada requires strict adherence to a Pregnancy Prevention Program, detailed in product monographs.[25]

6.4. Risk Management Programs

The severe teratogenicity of acitretin has led to a global consensus among regulatory authorities on the necessity of stringent risk management strategies. These programs universally emphasize:

• Comprehensive Patient Education: Ensuring patients, particularly females of childbearing potential, fully understand the teratogenic risks and the requirements of the PPP.
• Mandatory Contraception: Strict adherence to using two effective forms of contraception simultaneously before, during, and for 3 years after treatment.
• Regular Pregnancy Testing: A schedule of testing before, during, and for 3 years after treatment.
• Restrictions on Alcohol Use: Due to the metabolic conversion to etretinate.
• Blood Donation Prohibitions: To prevent accidental exposure of a pregnant woman to retinoid-containing blood. [23]

While the core indication for severe psoriasis is consistent across these major regulatory bodies, slight nuances exist in the specific approved keratinization disorders. For example, the EMA explicitly lists conditions like ichthyosis and Darier's disease [14], whereas Health Canada uses a broader term "other disorders of keratinization".[22] These differences may arise from variations in the clinical data submitted to each agency or differing interpretations of the risk-benefit profile for these rarer conditions.

7. Dosage and Administration

The dosing of acitretin requires careful individualization based on the specific condition being treated, its severity, patient response, and tolerability, particularly given its narrow therapeutic index and dose-dependent side effects.

7.1. Available Formulations and Strengths

Acitretin is available for oral administration exclusively in capsule form.6

The most commonly available capsule strengths are:

• 10 mg [6]
• 25 mg [6] Other strengths, such as 17.5 mg and 22.5 mg, have also been noted [52], though these may be less common or available only in specific regions.

7.2. Recommended Dosing Regimens

• Psoriasis (Adults):
• Initial Dose: Therapy is typically initiated at a daily dose of 25 mg or 30 mg, taken once daily. Some guidelines suggest a range of 25 mg to 50 mg once daily.[13] An initial phase of 2 to 4 weeks at this dose is common.[15]
• Maintenance Dose: The dose is subsequently adjusted based on therapeutic response and patient tolerability. Maintenance doses usually range from 10 mg to 50 mg daily.[4] For psoriasis, a daily dose of 30 mg for an additional 6 to 8 weeks is often aimed for to achieve optimal therapeutic effect.[15]
• Maximum Dose: The maximum recommended daily dose is generally 75 mg (e.g., three 25 mg capsules).[13] This should not be exceeded.
• Other Keratinization Disorders (e.g., Darier's disease, Ichthyosis):
• Initial Dose: For conditions like Darier's disease, a lower starting dose of 10 mg daily may be appropriate, with cautious upward titration due to the potential for isomorphic reactions (Koebner phenomenon).[15]
• Maintenance Dose: The maintenance dose for these disorders should be kept as low as possible to maintain efficacy while minimizing side effects, possibly less than 10 mg acitretin per day. It should generally not exceed 30 mg per day.[15]
• For severe congenital ichthyosis and severe Darier's disease, therapy may be required for longer than 3 months, and the lowest effective dosage, not exceeding 50 mg/day, should be administered.[15]
• In pediatric cases of ichthyosis, doses around 1 mg/kg/day have been reported in case studies, but pediatric use requires specialist supervision.[39]
• Elderly Patients: Dosage recommendations for elderly patients are generally the same as for other adults.[15]
• Pediatric Use: Acitretin should only be used in children when other treatments have proven ineffective, primarily due to concerns about potential long-term effects on bone growth and development (e.g., premature epiphyseal closure). Dosing must be highly individualized and managed by a specialist.[16]
• Combination Therapy: When acitretin is used in combination with other treatments (e.g., phototherapy, topical agents), it may be possible to reduce the daily dose of acitretin depending on the therapeutic outcome.[15]

The principle of individualization is paramount in acitretin dosing. The narrow therapeutic window means that the optimal dose for one patient may be sub-therapeutic or excessively toxic for another. Careful titration, starting with lower doses and gradually increasing as needed while monitoring for efficacy and side effects, is the standard approach.

7.3. Administration Guidelines

• Timing with Food: Acitretin capsules should be taken once daily with the main meal of the day or with milk.[6] This is crucial because food, particularly fat-containing meals, significantly enhances the oral absorption and bioavailability of acitretin.[6] Consistent administration with food helps to standardize absorption and achieve more predictable therapeutic concentrations.
• Capsule Integrity: The capsules should be swallowed whole with water and must not be opened, crushed, or chewed.[23] If the skin accidentally comes into contact with the contents of a capsule, the exposed area should be washed promptly with water.[23]

7.4. Duration of Therapy

The duration of acitretin treatment varies depending on the condition being treated and the patient's response:

• Psoriasis: For psoriasis, treatment is generally continued until lesions have improved sufficiently. Relapses are common after discontinuation, and subsequent courses may be administered in the same manner as the initial course.[15] Long-term continuous therapy for psoriasis is generally not recommended.[15] Treatment duration is often limited to periods such as up to 3 months [16], although some patients may require longer courses under specialist supervision.
• Keratinization Disorders: Patients with severe congenital ichthyosis and severe Darier's disease may require therapy extending beyond 3 months.[15] In these chronic conditions, long-term maintenance therapy at the lowest effective dose is often necessary.

8. Drug Interactions

Acitretin is subject to several clinically significant drug interactions, some of which are contraindications due to the potential for severe adverse outcomes. These interactions primarily involve additive toxicity, altered metabolism, or interference with contraceptive efficacy.

Table 6: Key Drug Interactions with Acitretin

Interacting Drug/Class	Effect of Interaction	Clinical Significance/Recommendation	Reference(s)
Alcohol (Ethanol)	Converts acitretin to etretinate (highly teratogenic, long half-life).	CRITICAL INTERACTION. FOCBP must avoid alcohol during and for 2 months after acitretin. Extends teratogenic risk.	2
Methotrexate	Increased risk of hepatotoxicity.	CONTRAINDICATED.	15
Tetracyclines (e.g., doxycycline, minocycline, omadacycline, sarecycline)	Increased risk of pseudotumor cerebri (benign intracranial hypertension).	CONTRAINDICATED.	6
Vitamin A and other Oral Retinoids (e.g., isotretinoin, etretinate, palovarotene)	Additive toxicity, risk of hypervitaminosis A.	CONTRAINDICATED/AVOID.	6
Phenytoin	Acitretin may reduce protein binding of phenytoin, potentially increasing free phenytoin levels.	Monitor phenytoin levels and for signs of toxicity.	15
Progestin-only Contraceptives ("Minipills")	Contraceptive effect may be reduced by acitretin.	CONTRAINDICATED as sole/primary contraception. Use alternative/additional effective methods.	15
St. John's Wort	May interfere with the efficacy of hormonal contraceptives.	Avoid concomitant use if relying on hormonal contraception.	46
Glyburide (and potentially other sulfonylureas)	Acitretin may potentiate the blood glucose-lowering effect, risking hypoglycemia.	Careful blood glucose monitoring in diabetic patients.	28
Leflunomide, Teriflunomide, Pexidartinib	Potential for increased/additive hepatotoxicity.	Use with caution, monitor LFTs closely.	6
Valproic Acid	May increase pseudotumor cerebri activity of acitretin.	Monitor for symptoms of increased intracranial pressure.	6
Diethylstilbestrol, Ethynodiol diacetate, Gestrinone, Hydroxyprogesterone caproate, Levonorgestrel, Norgestimate, Norgestrel (Hormonal contraceptives other than minipills)	Therapeutic efficacy of these hormonal agents may be decreased.	Ensure robust contraceptive strategy; consider non-hormonal primary method.	6

Many of the contraindications with acitretin stem from the principle of avoiding additive toxicities. For instance, both acitretin and methotrexate can cause hepatotoxicity; their combined use significantly elevates this risk.[15] Similarly, both acitretin and tetracyclines are independently associated with pseudotumor cerebri; co-administration is contraindicated due to the heightened risk of this serious neurological adverse event.[15] The combination with Vitamin A or other systemic retinoids is avoided to prevent hypervitaminosis A, as their toxic effects are additive.[15]

A particularly critical area of drug interaction concerns contraceptive efficacy. The established interaction reducing the effectiveness of progestin-only "minipills" [21], and the potential for St. John's Wort to interfere with hormonal contraceptives generally [46], directly compromises the cornerstone of acitretin's risk management strategy—effective pregnancy prevention. This underscores the necessity for meticulous contraceptive counseling and the recommendation for two reliable forms of contraception, ideally with one being a non-hormonal primary method if interactions are a concern.

9. Synthesis

Acitretin, with the chemical name (2E,4E,6E,8E)-9-(4-methoxy-2,3,6-trimethylphenyl)-3,7-dimethylnona-2,4,6,8-tetraenoic acid, is a synthetic compound and does not occur naturally.[7] Its chemical synthesis can be achieved through several routes, reflecting its structural relationship to other retinoids, particularly its parent compound, etretinate.

One described synthetic pathway, outlined in Scheme 1 by the IARC, commences with an aryl-substituted pentadienal (compound 1). This starting material undergoes a reaction with a diester (compound 2) in the presence of ethanolic sodium hydroxide to yield a dicarboxylic acid (compound 3). Subsequent decarboxylation of this intermediate primarily affords the 13-cis isomer of acitretin (compound 4). The desired all-trans acitretin is then obtained through isomerization of a benzene and ether solution of compound 4, catalyzed by small amounts of iodine, followed by recrystallization.[7]

Alternative synthetic approaches have also been documented. Given that etretinate (the ethyl ester of acitretin) is readily hydrolyzed to acitretin, several synthetic methods originally developed for etretinate can be adapted for acitretin production.[7] Handbook 5, referenced by IARC, details such syntheses (schemes 1, 2, and 3).[7] Furthermore, large-scale synthesis of acitretin and its derivatives, including etretinate, was described by Bollag et al. (1978).[7]

Patents also provide insight into acitretin synthesis. For example, US Patent 4,105,681 is cited as first disclosing the process for preparing acitretin, which involved reacting 5-(4-methoxy-2,3,6-trimethylphenyl)-3-methyl-penta-2,4-diene-l-triphenyl phosphonium bromide with 3-formyl-crotonic acid butyl ester in the presence of sodium hydride and dimethylformamide. The resultant ester derivative was then hydrolyzed to acitretin.[57] Another patent, WO 2016042573, also pertains to the preparation of acitretin or its intermediates.[57]

The close chemical relationship between acitretin (a carboxylic acid) and etretinate (its ethyl ester) is evident from these synthetic considerations. Acitretin is the active free acid metabolite of etretinate. This structural proximity is fundamental to understanding not only their synthetic interconversion (esterification of acitretin or hydrolysis of etretinate) but also the in vivo metabolic re-esterification of acitretin back to etretinate when alcohol is consumed, a key pharmacokinetic interaction with profound clinical implications.

10. Conclusion

Acitretin stands as a significant oral retinoid in the dermatological armamentarium, primarily valued for its efficacy in managing severe, refractory psoriasis and a range of other debilitating disorders of keratinization. Its mechanism of action, centered on the modulation of keratinocyte differentiation and proliferation via nuclear retinoid receptors (RARs and RXRs), along with its anti-inflammatory properties, underpins its therapeutic benefits.[2] The development of acitretin as an active metabolite of etretinate was a strategic effort to achieve a more favorable pharmacokinetic profile, particularly a shorter half-life, with the aim of reducing the duration of post-treatment teratogenic risk.[3]

However, the clinical utility of acitretin is inextricably linked to a careful and continuous assessment of its risk-benefit profile. The drug's most formidable characteristic is its profound teratogenicity, necessitating strict adherence to comprehensive Pregnancy Prevention Programs globally.[21] These programs mandate rigorous contraception for an extended period (3 years post-treatment), regular pregnancy testing, and absolute avoidance of alcohol during and for 2 months after therapy due to the metabolic conversion of acitretin to the long-lasting teratogen etretinate.[2] The prohibition on blood donation for 3 years post-treatment further underscores the systemic persistence of teratogenic risk.[21]

Beyond teratogenicity, acitretin is associated with a spectrum of common, often dose-dependent, adverse effects, including mucocutaneous dryness, hyperlipidemia, and potential hepatotoxicity, as well as rarer but serious concerns like musculoskeletal changes with long-term use and psychiatric effects.[2] These necessitate diligent patient monitoring, including regular laboratory tests for liver function and lipid levels, and careful dose individualization to optimize efficacy while minimizing toxicity.[2]

The decision to prescribe acitretin demands thorough patient selection, comprehensive counseling on its benefits, risks, and the stringent requirements of its use, particularly for females of childbearing potential. The non-immunosuppressive nature of acitretin offers a distinct advantage over other systemic psoriasis treatments for certain patient populations, such as those with contraindications to immunosuppressive therapies.[30]

In conclusion, acitretin remains a valuable, albeit complex, therapeutic agent. When prescribed by experienced clinicians who are fully cognizant of its pharmacological profile and risks, and when patients are able to adhere strictly to the mandated safety precautions, acitretin can provide significant relief and improve the quality of life for individuals suffering from severe and otherwise intractable skin diseases. The long-term commitment required from both patient and physician for safe use, especially concerning pregnancy prevention, highlights the unique position of acitretin in modern pharmacotherapy.

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