Professional Drug Information > Acitretin

Acitretin (Systemic)

VA CLASSIFICATION
Primary: DE801

Commonly used brand name(s): Soriatane.

Other commonly used names are
13-cis-acitretin , etretin, and isoetretin .
Note: For a listing of dosage forms and brand names by country availability, see Dosage Forms section(s).



Category:


Antipsoriatic (systemic)—

keratinization stabilizer (systemic)—

Indications

Note: Bracketed information in the Indications section refers to uses that are not included in U.S. product labeling.

General considerations

Note: FOR INFORMATION REGARDING PROBLEMS THAT HAVE OCCURRED DURING PREGNANCY SEE THE PREGNANCY/REPRODUCTION SECTION OF PRECAUTIONS TO CONSIDER.

Since acitretin is a teratogen in pregnant females and can cause serious and severe side effects in both males and females, it should be prescribed only by physicians experienced in its use. It is not known if the concentration of acitretin in seminal fluid is sufficient to pose a risk to a fetus. Acitretin should not be used in females of childbearing potential, unless the patient is unresponsive to or intolerant of other treatments, and can accept routine clinical monitoring and the strict criteria for avoiding use of alcohol and preventing pregnancy before and after treatment is discontinued ^{01}.

FOR FEMALES OF CHILDBEARING POTENTIAL:    • The duration of teratogenic risk has not been determined ^{74}. The minimum plasma concentration of acitretin and its active metabolite etretinate that is associated with teratogenicity is not known ^{72}. The sensitivity of tests to detect plasma concentrations of acitretin and its metabolites, 13-cis acitretin and etretinate, is inadequate. Also, testing for acitretin and its metabolites in plasma poorly predicts the presence or absence of these teratogens in subcutaneous tissue after acitretin treatment is stopped. ^{{01} {03} {72}}
   • Use of acitretin is contraindicated in females of childbearing potential, unless all of the following criteria have been met ^{{01} {02}}:    —Patient shows severe, disfiguring, recalcitrant psoriasis or one of the accepted indications ^{{01} {72}}.
   —Patient understands treatment instructions and intends to follow them ^{{01} {72}}.
   —Patient is capable of complying with the mandatory contraceptive measures. Two effective forms of contraception should be used at least 1 month before therapy begins, during therapy, and for an undetermined amount of time following discontinuation of therapy, at least 2 years, according to Canadian labeling, or 3 years, according to U.S. labeling. A planned pregnancy should be discussed with the physician for a recommendation of timing. ^{{01} {72}}
   —Patient receives both verbal and written warnings of the hazards associated with pregnancy during and following acitretin therapy and she acknowledges in writing her responsibility to avoid pregnancy ^{{01} {72}}.
   —Patient is not pregnant, as concluded from a negative pregnancy test. The pregnancy test should be performed after normal menstrual cycles are achieved and within 1 week prior to initiation of acitretin therapy ^{72}. If acitretin therapy is initiated, it should begin within the same week as the pregnancy test, on Day 2 or Day 3 of the menstrual period ^{{01} {72}}.



For males and females:    • During treatment and for 2 months after acitretin treatment discontinuation— Patients should not drink alcohol-containing beverages to avoid the prolonged effects of etretinate, an active metabolite of acitretin, that may accumulate from alcohol-induced transesterification ^{04}. Alcohol is a major factor for inducing the conversion of acitretin to etretinate. ^{01} It is not known what other substances may also induce this conversion. ^{72}
   • During treatment and for several years after acitretin treatment discontinuation— Patients should not donate blood intended for transfusion purposes for 2 years, according to Canadian labeling, or for 3 years, according to U.S. labeling. Although the risk is small, a blood transfusion from such donors to pregnant women during their first trimester may expose the fetus to the medication. ^{{01} {72}}


Accepted

[Keratinization disorders (treatment)]such as: [Erythroderma, ichthyosiform]¹ ; [Ichthyosis, lamellar]¹ ; [Keratosis follicularis]¹—Acitretin is indicated to treat inherited disorders of keratinization ^{{23} {28} {62}}, such as bullous or nonbullous ichthyosiform erythroderma ^{23}, keratosis follicularis ^{{20} {21}}, and lamellar ichthyosis ^{{22} {23}}. Best results are obtained in treatment of keratosis follicularis (also called Darier's disease), severe recessive X-linked ichthyosis, and nonbullous congenital ichthyosis, such as erythrodermic or nonerythrodermic lamellar ichthyosis. Patients with bullous ichthyosiform erythroderma may experience improvement of their condition under less aggressive treatment with a low-dose regimen ^{{23} {71}}.

Psoriasis, severe (treatment)—Acitretin is indicated to treat symptoms of severe erythrodermic and generalized pustular psoriasis that involve more than 10% of the patient's body surface area, especially when psoriasis is physically, occupationally, or psychologically disabling ^{{01} {06} {07} {08} {09} {10} {11} {12} {13} {50}}. Acitretin is indicated for the treatment of localized palmoplantar pustulosis, but the localized condition is more recalcitrant to treatment than is generalized, severe psoriasis ^{{17} {18}}.
—When treating severe plaque psoriasis, other therapies that have been added to a regimen of acitretin monotherapy after 1 or 2 months include ultraviolet B (UVB) light ^{14} or psoralen plus ultraviolet A (UVA) light (PUVA) ^{{15} {16}}, topical corticosteroids, or anthralin ointments ^{64}.

Acceptance not established
There are published case reports of using the retinoids, acitretin or etretinate, in the treatment of other disorders of keratinization, including cutaneous lichen planus, erythrokeratodermia variabilis ^{{23} {71}}, palmoplantar keratoses (including mal de Meleda and Papillon-Lefevre syndrome) ^{23}, pityriasis rubra pilaris ^{{28} {69}}, and Sjogren-Larsson syndrome ^{23}. Other studies are needed to evaluate fully acitretin's efficacy in the treatment of these conditions. Some children with Netherton's syndrome ^{23} and keratosis pilaris experienced a worsening of their condition when treated with acitretin for several weeks; acitretin therapy was withdrawn ^{23}.

Acitretin has been used in conjunction with interferon-alpha 2a to treat cutaneous T-cell lymphoma when there was no known internal organ involvement ^{{25} {71}}.

Small studies have been done using acitretin prophylactically in the treatment of keratotic skin lesions or skin cancer. Acitretin prevented development of new keratotic skin lesions in renal transplant patients who had a history of extensive keratotic skin lesions and/or recurrent squamous cell and basal cell carcinomas ^{49}. Additional studies are needed.

Acitretin has been used as monotherapy in the treatment of psoriasis associated with human immunodeficiency virus (HIV) infection. Although acitretin does not appear to have immunosuppressive properties capable of worsening a compromised immune system, additional studies are needed to assess acitretin's immunosuppressive properties in HIV-positive patients ^{24}.

Unaccepted
An in vitro study reported that acitretin was totally ineffective in the treatment of acute myelocytic leukemia ^{26}.

Mild disorders of keratinization, including autosomal dominant ichthyosis vulgaris and mild recessive X-linked ichthyosis that can be controlled with topical medications generally should not be treated with acitretin because of risk-benefit issues ^{62}. Also, acitretin treatment may cause skin erosions and exacerbate the epidermolytic form of palmoplantar keratoderma ^{{70} {71}}.

Acitretin is not efficacious and is not used to treat severe nodulocystic acne ^{29}.

¹ Not included in Canadian product labeling.

Pharmacology/Pharmacokinetics

Note: The length of time that etretinate (a metabolite of acitretin) remains in the blood has not been determined ^{{27} {63}}.


Physicochemical characteristics:

Chemical group—
    Acitretin is considered a second-generation retinoid and a synthetic aromatic analog of vitamin A ^{28}.
Molecular weight—
    326.44 ^{02}

pKa—
    5 ^{01}

Mechanism of action/Effect:

The exact mechanism of action for acitretin is not known. One possible explanation is altered gene expression through nuclear retinoic acid receptors (RARs) and binding to DNA to cause transcription or transrepression changes in protein synthesis. Although acitretin binds to all three classes of RARs (alpha, beta, and gamma receptors), it binds selectively to beta and gamma receptors to modify gene expression. ^{28}

Antipsoriatic—Studies suggest that acitretin affects immune response, epidermal proliferation, and glycoprotein synthesis in the skin. Specifically, acitretin helps to normalize cell differentiation and thin the cornified layer by directly reducing the keratinocytes' rate of proliferation. Acitretin's anti-inflammatory and antiproliferative actions in the skin decrease epidermal and dermal inflammation and reduce the scaling, erythema, and thickness of psoriatic lesions. ^{01}

Keratolytic (systemic)—Acitretin is thought to interfere with the terminal differentiation of keratinocytes ^{68}.

Absorption:

The mean absolute bioavailability of acitretin is 59% (range, 36 to 95%) ^{01}. The dose absorbed is linear up to 50 mg a day, but may become nonproportional or nonlinear for doses greater than 50 mg a day ^{{31} {63}}. The rate and extent of acitretin absorption are doubled when 50 mg of acitretin is given with food when compared with the absorption of the same dose given under fasting conditions ^{01}.

As judged from the area under the plasma concentration–time curve (AUC), the amount absorbed, corrected for body weight and dose, shows a six-fold systemic interindividual variation for the metabolite etretinate ^{33}.

Distribution:

The mean accumulation ratio is 1.2 for acitretin and 6.6 for the cis-metabolite ^{72}. Acitretin has not been shown to accumulate in any particular organ; however, etretinate (an active metabolite) does accumulate in fat and, to a lesser degree, in the liver; lower tissue concentrations are found in the kidneys, brain, and testes ^{32}. Five hours after acitretin administration, etretinate concentrations in the subcutaneous fat exceed those found in the plasma; however, accumulation does not occur ^{34}. In one patient given acitretin orally, the concentration of etretinate in the adrenal glands exceeded that found in the fat tissue ^{32}.

Patients receiving 30 mg of acitretin once a day for 30 days showed skin concentrations of acitretin that were 10 times higher than those observed in the plasma and 3 to 5 times higher than the skin concentrations of its metabolite, 13-cis acitretin ^{01}. Concentrations of acitretin and 13-cis acitretin are higher in lesional skin than in uninvolved skin. ^{35}

Protein binding:

Acitretin and its metabolite etretinate are highly bound to plasma proteins (> 99%). Acitretin is primarily bound to albumin (91%) ^{{01} {36}} and etretinate is primarily bound to low-density lipoprotein (48%) ^{36}.

Biotransformation:

Acitretin is metabolized to other active metabolites, including 13-cis acitretin and etretinate, following oral administration ^{01}. No detectable etretinate was formed when a single dose of 100 mg of acitretin was administered without ingestion of alcohol, but the potential for its formation cannot be ruled out ^{72}. Other metabolites are likely to occur ^{37}.

The relative formation of the 13-cis acitretin does not change regardless of acitretin dose, dose formulation (capsules versus solution), and ingestion with or without food. Ingestion of alcohol increases the conversion of acitretin to etretinate (an active metabolite), even after discontinuation of treatment. ^{04}

One crossover study of 10 healthy volunteers who took 100 mg of acitretin and 1.4 grams per kg of body weight of ethanol over approximately 3 hours showed a mean peak plasma concentration of 59 nanograms of etretinate per mL (range, 22 to 105 nanograms per mL), a concentration that is comparable to receiving a 5-mg dose of etretinate ^{72}. In another study where protocol did not restrict patients from drinking alcohol, 57.5% of 240 patients taking 5 to 60 mg of acitretin a day for treatment of psoriasis had plasma etretinate concentrations of 5 to 62 nanograms per mL; 27% of patients showed a measurable trace of etretinate in their plasma. ^{04}

Half-life:


Elimination:

Acitretin: 49 hours (range, 33 to 96 hours ^{{01} {72}}; some studies have shown the upper limit of the half-life to be as high as 120 hours) ^{37}.

13-cis acitretin (active metabolite): 63 hours (range, 28 to 157 hours) ^{72}.

Etretinate (active metabolite): 120 days, mean (range, up to 168 days). ^{72}


Peak serum concentration:

Single dose of 50 mg acitretin—196 to 728 nanograms per mL ^{01}.

At multiple doses of 10 to 50 mg acitretin a day—The dose-related trough steady-state plasma concentrations are between 6 and 25 nanograms per mL for acitretin; the serum concentration for the 13-cis metabolite is about five times higher than that of acitretin. ^{01}

Time to peak effect:

Single dose of 50 mg acitretin: 2 to 5 hours ^{01}.

At doses of 10 to 50 mg acitretin a day, steady-state plasma concentrations are reached within 2 weeks ^{01}.

Elimination:
    For acitretin or 13-cis acitretin conjugates, 34 to 54% renal and 16 to 53% fecal. ^{72} No acitretin or 13-cis acitretin (active metabolite) was recovered in the urine. ^{{01} {37}}
    If alcohol is taken during treatment with acitretin, more than 98% of etretinate would be eliminated after 2 years, assuming a mean half-life of 120 days. Using the upper limit of the half-life of 168 days, more than 98% of etretinate would be eliminated after 3 years. ^{72} One woman who ingested alcohol sporadically during acitretin therapy showed detectable plasma and subcutaneous fat concentrations of etretinate 52 months after discontinuing acitretin treatment. ^{72}


In dialysis—
        For patients taking a single 50-mg dose of acitretin, the mean AUC values of acitretin and 13-cis acitretin (active metabolite) were about 50% less in patients undergoing hemodialysis compared to patients without renal failure. No retinoids were detectable in the dialysate. ^{38}



Precautions to Consider

Cross-sensitivity and/or related problems

Patients sensitive to isotretinoin, tretinoin, or vitamin A derivatives may be sensitive to this medication also, since acitretin is related to both retinoic acid and retinol (vitamin A) ^{72}. Also, allergy to parabens should be considered ^{72}.

Carcinogenicity

Male and female Wistar rats given acitretin in doses of 0.5, 1, or 2 mg per kg of body weight (mg/kg) a day for 104 weeks showed a greater incidence of non-neoplastic bone lesions compared to two control groups not given acitretin. Neoplastic lesions that developed in the endocrine and reproductive organs and the skin were consistent with those that developed in the control rats, and were not associated with use of acitretin ^{01}.

Mutagenicity

Acitretin is not mutagenic according to the following in vitro tests: Ames test, hamster HGPRT assay, unscheduled DNA synthesis in rat hepatocytes, induction of chromosomal aberrations in human lymphocytes, and mouse micronucleus assay ^{01}.

Pregnancy/Reproduction

The inability to detect plasma acitretin and its metabolite etretinate is a poor predictor of the absence of these teratogens in tissue after discontinuation of acitretin treatment ^{{03} {39}}.
Fertility—
A small study of acitretin's effect in eight men showed no changes in sperm concentrations ^{65}. However, for male patients taking acitretin, it is not known whether residual acitretin in seminal fluid during treatment or after treatment has been discontinued poses a risk to a fetus. The maximum acitretin concentration observed in human seminal fluid from systemic use of acitretin or etretinate was 12.5 nanograms per mL, which would transfer approximately 125 nanograms of acitretin per 10 mL of ejaculate. Of the four reported cases with known fetal outcomes in pregnant women whose male partner took acitretin, one infant was normal, two spontaneous abortions occurred, and one fetus had bilateral cystic hygromas and multiple cardiopulmonary malformations. ^{72}

One study of dogs given doses of acitretin larger than 30 mg/kg per day for 1 year showed that a few of the dogs experienced spermatogenic arrest at 6 months of treatment, which improved by the end of the study ^{01}.

Pregnancy—
Acitretin is teratogenic in humans and is contraindicated during pregnancy ^{{01} {40} {41} {42}}. Unless abstinence is the chosen method, it is recommended that the patient use two forms of effective contraception to prevent pregnancy ^{01} during treatment and for at least 2 years, according to Canadian labeling, or for at least 3 years, according to U.S. labeling, after acitretin has been discontinued ^{{01} {40}}.

The duration of teratogenic risk is not known ^{74}. Teratogenic risk may continue longer if the mother has ingested alcoholic beverages during acitretin treatment. Whenever an unexpected pregnancy occurs during the time of teratogenic risk, the risk-benefit ratio of continuing the pregnancy must be considered. Major human fetal abnormalities ^{{01} {40}} associated wth the use of acitretin or its metabolite etretinate include ^{40}:    • Anophthalmia;
   • Heart defects;
   • Microcephalus; and
   • Skeletal or connective tissue abnormalities, including absence of terminal phalanges, alterations of the skull and cervical vertebra, and malformations of hip, ankle, and forearm; facial dysmorphia; high palate; low-set ears; meningomyelocele; multiple synostoses; and syndactyly.


In one study of pregnant rats given acitretin in doses of 0 (control group), 0.3, 1, and 3 mg/kg a day, no drug-related parental mortality and no signs of parental toxicity were noted; however, in the 3 mg/kg group, fewer offspring survived (24% mortality compared to 8.8% for the control group). In addition, developmental tests showed hair growth, ear opening, auditory startle, pupillary contraction, and memory retention were affected. According to another study in rats, 7.5 mg/kg of acitretin per day was the highest dose that did not show teratogenic effects. Pregnant rats given 7.5 mg/kg of actitretin or higher produced fewer pups and, at doses greater than 7.5 mg/kg, their fetuses developed skeletal adverse effects, such as a cleft palate and abnormally shaped long bones. ^{01}

In one study of pregnant mice given acitretin in doses of 0 (control group), 1, 3, and 10 mg/kg of acitretin per day, no drug-related maternal mortality and no signs of parental toxicity were noted. No teratogenic effects were seen in fetuses whose mothers received 1 mg/kg of acitretin per day. However, maternal doses of 3 and 10 mg/kg of acitretin per day caused fetal skeletal malformations (cervical, neural arches, and long bones) and soft tissue malformations (exencephaly, cleft palate, unilateral kidney agenesis, and enlarged renal pelvis). ^{01}

In one study of pregnant rabbits given acitretin in doses of 0 (control group), 0.2, 0.6, and 2 mg/kg of acitretin per day, no drug-related parental mortality and no signs of parental toxicity were noted. No teratogenic effects were seen in fetuses whose mothers received 0.2 mg/kg of acitretin per day. However, maternal doses of 0.6 mg/kg of acitretin per day resulted in a low incidence of cleft palate and brain anomalies in fetuses. Maternal doses of 2 mg/kg of acitretin per day caused teratogenic effects in fetuses, including open eyes, ectrodactyly, spina bifida, ectopia of abdominal viscera, and bilateral apical deficiencies of the distal phalanges of forelimbs and hind limbs. ^{01}

Breast-feeding

It is not known if acitretin is distributed into human breast milk ^{67}. Acitretin is not recommended for use in women who are breast-feeding. Breast-feeding is not recommended for an undetermined period, at least 2 or 3 years, after acitretin has been discontinued because of acitretin's potential to cause adverse effects in nursing infants. ^{01}

Pediatrics

Safety and efficacy have not been established ^{01}. Acitretin is not routinely recommended for use in children because of its potential side/adverse effects, including skeletal hyperostosis and skeletal growth retardation resulting from premature epiphyseal closure and ossification of bones and tendons ^{{43} {62}}.

If acitretin is used in children with severe forms of keratinization unresponsive to alternative therapies, bone age should be evaluated before treatment initiation and annually during treatment. In children, radiographic studies to determine bone age, including radiographs (x-rays) of the knees, should be done before acitretin therapy is initiated, followed by annual monitoring of bone by scintigraphy (bone scans) and/or radiography. Special attention should be given to any child experiencing pain or limitation of motion ^{62}.


Geriatrics


Steady-state trough concentrations of acitretin for males 64 to 72 years of age were double compared with those for healthy males 24 to 32 years of age. Although the harmonic mean for the terminal half-life was similar at 53 and 54 hours in these age groups, the range was greater in older patients (37 to 96 hours compared with 39 to 70 hours in the younger adults), potentially making some older patients more sensitive to acitretin's effect. ^{01}


Dental

Acitretin can increase or decrease saliva production ^{01}. Continuing dryness of the mouth may increase the risk of dental disease, including tooth decay, gum disease, and fungal infection. Having regular dental checkups and using artificial saliva or dissolving sugarless candy or ice in the mouth may help to reduce the incidence of dental problems.

Drug interactions and/or related problems
The following drug interactions and/or related problems have been selected on the basis of their potential clinical significance (possible mechanism in parentheses where appropriate)—not necessarily inclusive (» = major clinical significance):


Note: Combinations containing any of the following medications, depending on the amount present, may also interact with this medication.

» Alcoholic beverages    (concurrent use with acitretin causes increased metabolic conversion of acitretin to etretinate, which accumulates in the body. This increase in accumulation of etretinate increases the potential for teratogenicity in females using acitretin and for side/adverse effects in males and females, since etretinate is eliminated from the body much more slowly than acitretin ^{{01} {04} {44} {68}})


» Cyclosporine    (etretinate has been shown to inhibit the metabolism of cyclosporine and its metabolites by 33 to 45% via cytochrome P450 enzymes; acitretin may have a similar effect. Etretinate has been used therapeutically to reduce the needed dose of cyclosporine; however, some studies have failed to show a clear advantage to this use of etretinate ^{{45} {46} {47}})


Glyburide    (concurrent use may enhance glucose clearance as shown in three of seven healthy males; glyburide dose may need adjustment ^{72})


» Hepatotoxic medications, especially methotrexate    (concurrent use with acitretin may increase the risk of hepatoxicity, such as that seen when etretinate and methotrexate have been used together; concurrent use is not recommended ^{01})


» Hydantoin    (although not clinically proven ^{71}, acitretin may potentially increase the free-fraction of hydantoins by causing protein-binding displacement of phenytoin or other hydantoins; changes of dose may be necessary ^{01})


» Oral contraceptives, progestin-only    (contraceptive effect of progestins may be diminished with concurrent use of acitretin; it is not known if acitretin reduces the effect of other progestational contraceptives, such as implants or injections ^{72}. Acitretin has not been shown to reduce the efficacy of estrogen and progestin oral contraceptives ^{48})


Retinoids, other, systemic, such as:
» Etretinate
» Isotretinoin
» Tretinoin, oral
Vitamin A and its derivatives, including vitamin supplements containing vitamin A or
Retinoids, topical, such as adapalene and tretinoin     (concurrent use of retinoids or doses of vitamin A larger than the minimum recommended daily allowance (RDA) increases risk of clinical symptoms resembling those of excessive vitamin A intake or toxicity, also called hypervitaminosis A ^{72})


Sensitivity to retinoids, vitamin A (also called retinol), or their derivatives
» Tetracycline, oral    (can increase intracranial pressure; concomitant use with acitretin is not recommended because of the combination's potential to exacerbate this effect ^{72})



Laboratory value alterations
The following have been selected on the basis of their potential clinical significance (possible effect in parentheses where appropriate)—not necessarily inclusive (» = major clinical significance):

With physiology/laboratory test values
Alanine aminotransferase (ALT [SGPT]) and
Aspartate aminotransferase (AST [SGOT]) and
Lactate dehydrogenase (LDH)    (serum values increase in about 20 to 28% of patients taking acitretin; this effect is considered dose-related and may be transient ^{{01} {06} {11} {18}})


Cholesterol, total, serum and
Triglyceride, serum    (increased serum total cholesterol concentrations occur in 9 to 33% of patients. Although triglyceride levels associated with pancreatitis are rare, hypertriglyceridemia occurs in about 66% of patients. These effects may be reversible upon reduction of dose or upon discontinuation of this medication ^{{06} {08} {15} {18} {49}})


High-density lipoprotein (HDL)    (decreased serum HDL concentrations occur in 30 to 40% of patients and are reversible upon dose reduction for many patients or upon discontinuation of this medication ^{06})


Medical considerations/Contraindications
The medical considerations/contraindications included have been selected on the basis of their potential clinical significance (reasons given in parentheses where appropriate)— not necessarily inclusive (» = major clinical significance).


Except under special circumstances, this medication should not be used when the following medical problems exist:
» Allergy to parabens^{72}
» Hyperlipidemia, intractable, or history of or
» Pancreatitis    (66% of patients receiving acitretin in the clinical trials experienced an elevation in serum triglycerides, 9 to 33% of patients experienced elevated serum cholesterol, and 30 to 40% of patients developed a decrease in high-density lipoproteins; these trends reversed upon treatment discontinuation. If serum lipid levels cannot be controlled, acitretin treatment should be withdrawn to avoid increasing the patient's risk of cardiovascular disease and pancreatitis. Patients likely to develop intractable hyperlipidemia include those with diabetes mellitus, obesity, increased alcohol intake, or familial history of these conditions ^{{49} {50} {52}})


» Hypervitaminosis A, or history of or
» Hypersensitivity to etretinate, isotretinoin, tretinoin, or vitamin A and its derivatives    (these conditions may be exacerbated with use of acitretin ^{72})


Risk-benefit should be considered when the following medical problems exist
Diabetes mellitus, type 1 or 2 or
Pancreatitis, history of    (acitretin may mildly increase or decrease glucose tolerance or increase serum lipid levels in these patients; pancreatitis may be exacerbated in patients with a history of pancreatitis; some patients with diabetes mellitus may require dose adjustment in their diabetes therapy regimens ^{71})


» Hepatic disease, severe or
» Renal disease, severe    (severe renal or hepatic function impairment can delay the elimination of acitretin and its metabolites, and, if a significant amount of drug accumulates, it potentially can make these conditions worse ^{01})

    (a preliminary study of a single dose of 50 mg of acitretin in patients with end-stage renal failure showed that the pharmacokinetics of acitretin remain unaltered; however, there is concern that if acitretin is metabolized to etretinate, it may accumulate in fat tissues and prolong drug elimination ^{{49} {50} {51}})



Patient monitoring
The following may be especially important in patient monitoring (other tests may be warranted in some patients, depending on condition; » = major clinical significance):

Bone-age determinations or
Bone radiography (x-rays), including x-rays of the knees    (recommended in children prior to therapy and yearly during therapy to determine effects on epiphyseal centers and as recommended by physician for older patients to evaluate the possibility of hyperostosis during long-term or recurrent courses of acitretin therapy ^{01}. Some physicians recommend baseline evaluation for older patients if long-term therapy is anticipated and repeat bone tests only if patient becomes symptomatic ^{73})


» Contraceptive counseling and
» Pregnancy testing    (within 1 week before initiating treatment with acitretin, a negative pregnancy test should be obtained after a normal menstrual cycle has been established. Then acitretin treatment should be initiated on Day 2 or 3 of the menstrual cycle. Regularly testing for possible pregnancy is recommended, as well as counseling on importance of beginning contraception 1 month before treatment initiation ^{01} and continuing the contraception counseling for as long as needed or appropriate; these measures should include patients with a history of infertility or tubal ligation ^{72})


» Hepatic function tests    (recommended before initiation, every 1 to 2 weeks during the first 2 months after treatment initiation, and then every 3 months during treatment or as clinically indicated ^{72}. Weekly checking is recommended if liver test results are abnormal and medication should be withdrawn if results worsen. If liver test results do not return to normal after withdrawal of acitretin treatment, continued monitoring for at least 3 months is advised ^{01})


» Lipoprotein profile, serum    (determinations recommended in patients under fasting conditions prior to therapy and at 1- to 2-week intervals during therapy until the lipid response is established, usually within 4 to 8 weeks. Following consumption of alcohol, 36 hours should elapse before blood lipid determination ^{01})

    (restricting dietary fat and alcohol intake and, when appropriate, lowering body weight are ways that patients can control significant serum concentration increases in triglycerides and decreases in high-density lipoproteins; discontinuation of retinoid should be considered if abnormal lipid or lipoprotein serum concentrations persist ^{{01} {49}})


Monitoring etretinate concentrations, plasma    (some clinicians monitor plasma concentrations of etretinate, an active metabolite, to help assess patients taking acitretin and advise them in planning a future pregnancy; however, most studies have found that the absence of etretinate in plasma does not predict its absence in tissues and most clinicians do not monitor etretinate concentrations, even in cases of pregnancy ^{{04} {53}})


Ophthalmologic examinations    (regular monitoring may be indicated since 29% of patients taking acitretin experience medication-related ophthalmic effects from acitretin; medication should be discontinued and neurological diagnosis and care considered for patients developing early symptoms of pseudotumor cerebri [benign intracranial hypertension], such as severe or continuing headache, nausea and vomiting, or blurred vision or other changes in vision. Also, medication should be discontinued and ophthalmologic examination should be done when any changes in vision occur ^{30})






Side/Adverse Effects
The following side/adverse effects have been selected on the basis of their potential clinical significance (possible signs and symptoms in parentheses where appropriate)—not necessarily inclusive:

Those indicating need for medical attention
Incidence more frequent
    
Arthralgia
hypertonia
myalgia
or spinal hyperostosis ^{{01}{13}{43}{50}{55}{56}{57}}(back pain; bone or joint pain; difficulty in moving or walking; stiff, painful muscles)
    
headache ^{01}
    
nausea ^{01}
    
vomiting ^{01}

Incidence less frequent
    
Ophthalmologic effects, including blepharitis
conjunctivitis
eye irritation
photophobia
or other visual problems (blurred vision; eye pain; loss of eyebrows or lashes; redness or swelling of the eyelid; redness of the eyes; sensitivity of eyes to light; watery eyes)^{01}{58}{64}
    
paronychia ^{01}{18}{64}(loosening of the fingernails; redness or soreness around fingernails)

Incidence rare
    
Dermatologic effects, such as abnormal skin odor
dermatitis
or psoriasiform rash (skin irritation or rash, including rash that looks like psoriasis), fissuring
hypertrophy
infection
or ulceration of skin ^{01}{59}(cracking of skin; redness of skin), otitis externa (itchy or painful ears), paresthesia (abnormal sensation of burning or stinging of skin), pyogenic granuloma
or purpura (small spots in skin where bleeding occurred)
    
hepatitis
jaundice
or pancreatitis (abdominal pain; darkened urine; yellowing of the skin or eyes)^{13}{51}{60}
    
influenza-like symptoms
laryngitis
or pharyngitis (coughing; hoarseness; trouble in speaking)
    
ophthalmologic effects, such as cortical, nuclear, and posterior subcapsular cataracts, pannus, or subepithelial corneal lesions (eye pain; trouble in seeing), decreased night vision (decreased vision after sunset and before sunrise), pseudotumor cerebri (blurred or double vision; continuing severe headache, nausea, and vomiting), or recurring stye (sore on the edge of the eyelid)
    
vulvovaginitis (thick, white, curd-like vaginal discharge; vaginal itching or irritation)—due to Candida albicans^{61}



Those indicating need for medical attention only if they continue or are bothersome
Incidence more frequent
    
Alopecia (loss of hair)—may be reversible after treatment discontinuation^{18}{64}
    
dermatologic effects, such as ceruminosis (increased amount of ear wax), chapped lips or cheilitis (chapped, red, or swollen lips), dry, irritated mucous membranes of nose or rhinitis (dry or runny nose; nosebleeds), pruritus (itching skin), scaling and peeling of eyelids, fingertips, palms, or soles of feet
and sticky skin^{11}{15}{64}
    
difficulty in wearing contact lenses
    
gingivitis or stomatitis (irritation in mouth or swollen gums; mouth ulcers)^{64}
    
photosensitivity (increased ability to sunburn)
    
xerophthalmia (dryness of eyes)^{58}—23%
    
unusual thirst ^{64}

Incidence less frequent
    
Constipation^{64}
diarrhea ^{64}
    
fatigue^{64}
    
increased sweating ^{64}





Overdose
For more information on the management of overdose or unintentional ingestion, contact a Poison Control Center (see Poison Control Center Listing ).

Clinical effects of overdose
The following effects have been selected on the basis of their potential clinical significance (possible signs and symptoms in parentheses where appropriate)—not necessarily inclusive:
Acute and/or chronic
    
Drowsiness ^{01}
    
intracranial pressure, elevated ^{01}(continuing severe headache, nausea, and vomiting)
    
irritability ^{01}
    
itchy skin ^{01}


Treatment of overdose
Acute overdose with acitretin has not been reported, but symptoms are probably similar to those of vitamin A toxicity ^{01}.

To decrease absorption—Evacuation of stomach should be considered within 2 hours of ingestion of acute overdose. Medication should be discontinued in patients with symptoms of overdose who were given therapeutic doses. ^{01}

Monitoring—Monitor for increased intracranial pressure ^{01}. Female patients of childbearing potential should have a pregnancy test at time of overdose ^{01} and, if positive, teratogenic risk and continuance of pregnancy should be discussed ^{01}.

Supportive care—Female patients of childbearing potential need to use an effective contraceptive method for 2 or 3 years after overdose ^{01}. Patients in whom intentional overdose is confirmed or suspected should be referred for psychiatric consultation.


Patient Consultation
As an aid to patient consultation, refer to Advice for the Patient, Acitretin (Systemic) .
In providing consultation, consider emphasizing the following selected information (» = major clinical significance):

Before using this medication
»   Conditions affecting use, especially:
Sensitivity to acitretin, etretinate, isotretinoin, tretinoin, or vitamin A or its derivatives, or allergy to parabens

Pregnancy—Contraindicated for use during pregnancy; can cause birth defects of skeletal, heart, and connective tissue. Pregnancy is not recommended for at least 2 or 3 years after discontinuation of acitretin. Use of alcohol and alcohol products is prohibited; recommended waiting period may be longer if alcohol is consumed during treatment. Also, for women of childbearing potential, two effective forms of birth control should be used at least 1 month prior to initiating acitretin therapy, and continued for at least 2 to 3 years after acitretin therapy is stopped





Breast-feeding—Not recommended for use during breast-feeding; breast-feeding is not recommended for at least 2 or 3 years after discontinuing use of acitretin because of its potential adverse effects in nursing babies





Use in children—Use is not recommended, unless other medications fail and treatable condition is severe enough to be disabling; children may be more sensitive to medication; use warrants special monitoring for skeletal side effects, such as ossification of tendons and bones, to avoid premature long bone closure, short adult stature, hyperostosis, and limitation of motion






Use in the elderly—Geriatric patients may be more sensitive to medication since some patients, when compared to younger adults, may have higher acitretin serum concentrations resulting from slower elimination
Other medications, especially alcoholic beverages; cyclosporine; hepatotoxic medications, including methotrexate; hydantoin; progestin-only oral contraceptives; retinoids, other (systemic and topical); or tetracyclines
Other medical problems, especially hepatic disease, severe; hyperlipidemia (intractable); hypersensitivity to vitamin A or its derivatives; hypervitaminosis A; pancreatitis; or renal disease, severe

Proper use of this medication
» Reading accompanying patient information before using this medication

» Taking acitretin dose with a main meal or with a glass of milk

» For women—Special precautions are needed before beginning treatment to ensure that the patient is not pregnant, such as using an effective form of birth control for 30 days before initiating treatment, obtaining a negative pregnancy test after a normal menstrual period pattern has been established and within 1 week before initiating treatment, then starting medication on Day 2 or 3 of menstrual period. Women of reproductive age or potential are required to use two forms of contraception during treatment, beginning at least 1 month before initiation of treatment with acitretin. These women are required to continue contraception for an indeterminate time after medication is discontinued, for at least 2 years per Canadian labeling or for at least 3 years per U.S. labeling

» Proper dosing
Missed dose: Taking as soon as possible; not taking if almost time for next dose; not doubling doses.

» Proper storage

Precautions while using this medication
» Regular visits to physician to check progress during therapy and for up to 2 years after treatment is discontinued, especially in women wanting to become pregnant, children, and the elderly

» Checking with physician if skin condition does not improve within 8 to 12 weeks; expecting that skin irritation may occur or skin condition may worsen within the first several weeks of treatment but will lessen in severity with continued use

» Importance of not drinking alcoholic beverages or products containing alcohol during treatment and for 2 months after treatment discontinuation. Teratogenic risk may continue for longer periods of time if alcohol was consumed during acitretin treatment

» Importance of not donating blood for transfusion purposes during treatment and for at least 2 or 3 years after discontinuing treatment with acitretin as specified by physician

» Understanding that vision impairment can occur, including sudden night vision impairment, photophobia, blurred vision, or dryness of eyes. Vision problems can make driving a car or operating machinery dangerous

Checking with physician anytime vision problems occur; wearing contact lenses may be uncomfortable

Understanding that dental problems can occur resulting from dryness of mouth and may increase dental disease, including tooth decay, gum disease, and fungus infections; regular dental appointments are needed and use of sugarless candy or saliva substitute or melting ice in mouth may be necessary to lessen dental problems

Minimizing exposure of skin to wind, cold temperatures, and sunlight, including on cloudy days, to avoid sunburn, dryness, or irritation, especially during the first months of treatment. Also, not using artificial sunlight or sunlamp, unless directed otherwise by physician

Using sunscreen preparations (minimum sun protection factor [SPF] of 15) and wearing protective clothing over exposed areas and UV-blocking sunglasses when sunlight exposure cannot be avoided; avoiding direct sunlight between 10 a.m. and 3 p.m.; checking with physician at any time skin becomes too dry or irritated; choosing proper skin products to reduce skin dryness or irritation

Either checking with health care professional before using or avoiding use of topical acne or skin products containing a peeling agent (benzoyl peroxide, resorcinol, salicylic acid, or sulfur), irritating hair products (permanents or hair removal products), sun-sensitizing skin products (including products containing limes or spices), alcohol-containing skin products, or drying or abrasive skin products (some cosmetics, soaps, or skin cleansers)

Not using vitamin A or vitamin A–containing supplement in doses that exceed the minimum recommended daily allowances (RDA)


Side/adverse effects
Signs of potential side effects, especially arthralgia, hypertonia, myalgia, or spinal hyperostosis; headache; nausea; vomiting; ophthalmologic effects, including blepharitis, conjunctivitis, eye irritation, photophobia, or other visual problems; paronychia; dermatologic effects, such as abnormal skin odor, dermatitis or psoriasiform rash, fissuring, hypertrophy, infection, or ulceration of skin, otitis externa, paresthesia, pyogenic granuloma, or purpura; hepatitis, jaundice, or pancreatitis; influenza-like symptoms, laryngitis, or pharyngitis; ophthalmologic effects such as cortical, nuclear, and posterior subcapsular cataracts, pannus, or subepithelial corneal lesions, decreased night vision, pseudotumor cerebri, or recurring stye; and vulvovaginitis


General Dosing Information
It is recommended that acitretin be prescribed only by physicians knowledgeable in the systemic use of retinoids ^{01}. The product labeling includes a consent form for female patients of reproductive age or potential to read and sign after physician counseling ^{72}.

Patients previously taking etretinate should continue to follow the contraception recommendations for etretinate. ^{72}

There is a significant interpatient variation in absorption and metabolism of acitretin, of treatment efficacy, ability to tolerate treatment, and progress of psoriasis or keratinization condition. The dosage of acitretin should be individualized to achieve the maximal therapeutic response possible with a tolerable level of side effects. ^{01}

Transient worsening of psoriasis commonly occurs on initiation of acitretin treatment ^{{01} {72}}. The full effect of acitretin may take 2 to 3 months, and its action can continue after treatment is discontinued ^{72}. Treatment should be discontinued when psoriatic lesions are sufficiently resolved, and treatment reinstituted at initiation doses for relapses as needed. ^{72}

Patients unresponsive to treatment with acitretin may be responsive to etretinate ^{54}. When switching from etretinate to acitretin, a 20% reduction is recommended if the etretinate dose is greater than 0.75 mg per kg of body weight (mg/kg) a day or if side effects are dose-limiting. Otherwise the same dose can be used. ^{{23} {66}}

Other treatments that have been added to a patient's regimen after 1 or 2 months of acitretin monotherapy include ultraviolet B (UVB) light, PUVA (8-methoxypsoralen plus ultraviolet A [UVA] light), bath PUVA (trimethylpsoralen bath plus UVA), topical corticosteroids, or anthralin ointments ^{64}. Dose reduction of acitretin may be required before beginning these other treatments.

Diet/Nutrition
Take with main meal of the day or with milk. Patient should follow a cholesterol-free diet for best results to lower serum cholesterol ^{63}.


Oral Dosage Forms

Note: Bracketed uses in the Dosage Forms section refer to categories of use and/or indications that are not included in U.S. product labeling.

ACITRETIN TABLETS

Usual adult dose
Antipsoriatic (systemic)
Initial: Oral, 25 or 50 mg a day (or 0.5 mg per kg of body weight a day) as a single dose; dose may be increased up to 75 mg a day after four weeks, if needed and tolerated ^{01}.

Maintenance: Oral, 25 to 50 mg a day, increased if needed to 75 mg a day ^{01}.

Note: Lower doses of acitretin are used when initiating combination therapy in the treatment of severe plaque psoriasis ^{{15} {16} {25}}.


[Keratinization stabilizer (systemic)]
Initial: Oral, 25 mg a day; dose may be increased up to 75 mg a day after four weeks, if needed and tolerated ^{01}.

Maintenance: Oral, 10 to 50 mg a day ^{01}.


Usual pediatric dose
Antipsoriatic
Safety and efficacy have not been established.

[Keratinization stabilizer (systemic)]
Initial: Oral, 0.5 mg per kg of body weight once a day. May be increased to 1 mg per kg a day for limited periods of time as needed, not to exceed a total dose of 35 mg a day. ^{71}

Maintenance: Oral, 20 mg or lower once a day for prolonged treatment.


Usual pediatric prescribing limits
Oral, 35 mg a day.

Usual geriatric dose
See Usual adult dose .

Strength(s) usually available
U.S.—


10 mg (Rx) [Soriatane (gelatin)^{72}]


25 mg (Rx) [Soriatane (gelatin)^{72}]

Canada—


10 mg (Rx) [Soriatane (gelatin)^{01}]


25 mg (Rx) [Soriatane (gelatin)^{01}]

Packaging and storage:
Store between 15 and 30 ºC (59 and 86 ºF), unless otherwise specified by manufacturer. Protect from light. ^{01} Keep in a tightly closed container ^{72}.

Auxiliary labeling:
   • Do not take this medication if you become pregnant.
   • Take with food.
   • Do not drink alcoholic beverages when taking this medication.
   • Avoid prolonged or excessive exposure to sunlight.
   • May cause dizziness or blurred vision.
   • This medication may impair your ability to drive or operate machinery. Use care until you become familar with its effects.

Note: Include patient directions when dispensing.
Counsel female patients about using two forms of birth control 1 month before starting treatment, during treatment, and for at least 2 years, according to Canadian labeling, or for at least 3 years, according to U.S. labeling, after discontinuing treatment.
Counsel male and female patients:    • Not to donate blood for transfusion during treatment and for at least 2 years, according to Canadian labeling, or for at least 3 years, according to U.S. labeling, after discontinuing treatment.
   • Not to drink alcoholic beverages during treatment and for at least 2 months after discontinuing treatment.
   • To be aware that sudden night vision inadequacies can occur, which can be hazardous when operating a vehicle.

Developed: 04/24/1998

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57. 
    
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