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  • CLASSES

    Antipsoriatic Retinoids

    BOXED WARNING

    Blood donation

    Blood donation should be avoided during and for 3 years following completion of acitretin therapy because women of childbearing potential must not receive blood products from patients being treated with acitretin.

    Requires an experienced clinician

    Acitretin therapy requires an experienced clinician who has special competence in the diagnosis and treatment of severe psoriasis. Health care professionals should understand the risk of teratogenicity and have experience prescribing systemic retinoids, such as acitretin.

    DEA CLASS

    Rx

    DESCRIPTION

    Oral retinoid
    Used for severe psoriasis in adults
    Teratogenic; women must avoid becoming pregnant for at least 3 years after discontinuation and must avoid alcohol

    COMMON BRAND NAMES

    Soriatane

    HOW SUPPLIED

    Acitretin/Soriatane Oral Cap: 10mg, 17.5mg, 25mg

    DOSAGE & INDICATIONS

    For the treatment of adults with severe, recalcitrant psoriasis, including plaque, guttate, erythrodermic, palmar-plantar and pustular types.
    Oral dosage
    Adults

    Initiate at 25 to 50 mg PO once daily with the main meal. Maintenance doses of 25 to 50 mg/day PO may be given dependent upon an individual's response to initial treatment. A meta-analysis of 2 large placebo-controlled trials found that lower-dose regimens of 25 mg/day for the treatment of psoriasis vulgaris are similar in efficacy to higher-dose regimens of 50 mg/day; additionally, the lower-dose regimen is associated with fewer and less severe adverse clinical and laboratory events. It is unclear if this information is applicable to other subtypes of psoriasis. Worsening of psoriasis is sometimes seen during the initial treatment period. Full clinical effects of acitretin may not be seen for 2 to 3 months, although some patients may achieve significant improvement within the first 8 weeks of therapy. When therapy is discontinued, most patients experience a relapse. Relapses may be treated as outlined for initial therapy, and subsequent courses have produced efficacy similar to that of the initial course of therapy. When acitretin is used with phototherapy, significantly lower doses of phototherapy are required due to acitretin-induced effects on the stratum corneum, which can increase the risk of erythema (burning). As compared to either acitretin or UV light monotherapy [either psoralen-ultraviolet A (PUVA) or ultraviolet B (UVB)], the combination regimen enhances efficacy and limits treatment frequency, duration, and cumulative doses.

    For the treatment of lichen planus†.
    Oral dosage
    Adults

    In a placebo-controlled, double-blind study, 30 mg PO once daily was effective in severe cases of lichen planus. A significant number of placebo-treated patients who received acitretin in the open phase of the study also responded favorably.

    For the treatment of hyperkeratotic dermatitis of the palms (eczema† keratoticum).
    Oral dosage
    Adults

    In a single-blind, placebo-controlled study, 30 mg PO once daily resulted in a 51% reduction in all symptoms in patients as compared to a 9% reduction in the placebo-treated group after 4 weeks of therapy. No further improvement was seen over an additional 4-week period.

    †Indicates off-label use

    MAXIMUM DOSAGE

    Adults

    50 mg/day PO.

    Elderly

    50 mg/day PO.

    Adolescents

    Safety and efficacy have not established.

    Children

    Safety and efficacy have not established.

    DOSING CONSIDERATIONS

    Hepatic Impairment

    Acitretin is contraindicated in patients with severely impaired liver function.

    Renal Impairment

    Dosage should be modified depending on clinical response and degree of renal impairment, but no quantitative recommendations are available. Acitretin is contraindicated in patients with severely impaired renal function.

    ADMINISTRATION

     
    NOTE: Acitretin (Soriatane) should only be prescribed by physicians who have special competence in the diagnosis and treatment of severe psoriasis, are experienced in the use of systemic retinoids, and understand the risk of teratogenicity with this drug.
    Female patients must have had 2 negative urine or serum pregnancy tests with a sensitivity of at least 25 milliunits/mL before receiving the initial acitretin prescription (see Contraindications). Pregnancy testing and contraception counseling should be repeated monthly during treatment, and every 3 months for at least 3 years after discontinuing therapy. To encourage compliance, it is recommended that a limited supply of the drug be prescribed.
    Two effective forms of contraception must be used for at least 1 month before beginning acitretin therapy, during therapy, and for at least 3 years following discontinuation of therapy. At least one of these should be a primary form of contraception (i.e., tubal ligation, partner's vasectomy, IUDs, oral contraceptives, and injectable/ implantable/ insertable/ topical hormonal contraceptive products), unless the chosen method is abstinence or the patient has had a hysterectomy or is postmenopausal.
    Patients must have signed a Patient Agreement/Informed Consent for Female Patients that contains warnings about the risks of acitretin therapy prior to receiving a prescription for acitretin.
    Pharmacists: A Soriatane Medication Guide must be given to the patient each time Soriatane is dispensed.

    Oral Administration

    Administer orally with food.

    STORAGE

    Soriatane:
    - Avoid excessive humidity
    - Protect from extreme heat
    - Protect from light
    - Store at controlled room temperature (between 68 and 77 degrees F)

    CONTRAINDICATIONS / PRECAUTIONS

    Ethanol ingestion, male-mediated teratogenicity, pregnancy, pregnancy testing

    Acitretin is classified as FDA pregnancy risk category X. It is teratogenic and is contraindicated in females who are pregnant or who intend to become pregnant during therapy or within 3 years after therapy. Acitretin must also not be used by females who may not use reliable contraception during and for at least 3 years after treatment. Acitretin is a metabolite of etretinate; major human fetal malformations have been associated with the maternal use of both drugs. Ethanol ingestion has been shown to be associated with the transesterification of acitretin to etretinate. Because the half-life of etretinate is significantly longer than acitretin, the duration of teratogenic potential would be increased; therefore, females should avoid ethanol ingestion during and for 2 months after discontinuing therapy. Before initiating therapy in patients of childbearing potential, patients must be told clearly and in detail about the precautions to be taken, the risks involved, and the possible consequences should pregnancy occur during treatment or within 3 years of discontinuing therapy. Counseling regarding contraception must be repeated by the prescriber monthly during therapy and at every 3 months for 3 years after acitretin discontinuation. A Soriatane Patient Referral Form is available from the manufacturer so that patients can receive an initial free contraceptive counseling session and pregnancy testing. Female patients must have had 2 negative urine or serum pregnancy tests with a sensitivity of at least 25 million international units/ml before receiving the initial acitretin prescription. The first test is obtained by the prescriber when the decision is made to pursue acitretin therapy. The second test should be done during the first 5 days of the menstrual period immediately preceding the beginning of acitretin therapy. For patients with amenorrhea, the second test should be done at least 11 days after the last act of unprotected sexual intercourse (without using 2 effective forms of contraception simultaneously). If the second pregnancy test is negative, initiation of treatment should begin within 7 days of the specimen collection; limit to a monthly supply. Obtain a pregnancy test with a sensitivity of at least 25 milliunits monthly during treatment; after acitretin is discontinued, repeat pregnancy testing every 3 months for at least 3 years. Effective contraception must be used for at least 1 month before beginning acitretin therapy, during therapy, and for at least 3 years after discontinuation even where there has been a history of infertility, unless due to hysterectomy or if the woman is clearly postmenopausal. Two reliable forms of contraception (primary and secondary forms) must be used simultaneously unless abstinence is the chosen method. Primary forms of birth control include tubal ligation, partner's vasectomy, intrauterine devices, birth control pills, and non-oral hormonal birth control products while secondary forms include diaphragms, latex condoms, cervical caps, and vaginal sponges; each secondary form must be used with a spermicide. Acitretin interferes with the contraceptive effect of microdose progestin preparations; therefore, these preparations are not recommended for use with acitretin. In addition, prescribers must be cautious to avoid any potential drug interactions that may reduce the effectiveness of hormonal contraception in females who are using hormonal contraception as a primary form of birth. Counsel patients to avoid self-medicating with St. John's Wort, as it may decrease the effectiveness of hormonal contraceptives. For female patients, prescribers must have a signed Patient Agreement/Informed Consent form that describes the warnings and requirements associated with acitretin therapy and pregnancy prior to beginning treatment. Adverse fetal outcomes associated with acitretin and/or etretinate use have included spontaneous abortion, absent hand/wrist, cardiac malformations, chromosomal disorders, decreased cranial volume, facial dysmorphia, GI malformations, limb malformations, meningomyelocele, placental disorder/death, premature birth, stillbirth, and other abnormalities. Because of acitretin's serious teratogenicity, a program called Do Your P.A.R.T program (Pregnancy prevention Actively Required during and after Treatment) has been developed to educate women and their healthcare providers about the risks associated with acitretin therapy. Further, it is not known whether residual acitretin in seminal fluid poses risk to a fetus while a male patient is taking the drug or after it is discontinued. Minimal concentrations (12.5 ng/mL) have been found in the seminal fluid of men receiving acitretin or etretinate and may cause male-mediated teratogenicity. It appears that residual acitretin in seminal fluid poses little, if any, risk to a fetus while a male patient is taking the drug or after it is discontinued; however, the no-effect limit for teratogenicity is not known, and there is no registry for birth defects associated with acitretin. There have been 25 cases of reported conception when the male partner was taking acitretin. The pregnancy outcome is known in 13 of the cases. When acitretin therapy was ongoing at the time of conception, delivery of a healthy neonate occurred in 5 cases, spontaneous abortion occurred in 5 cases, and there was one case of induced abortion. In one case, a spontaneous abortion occurred when acitretin had been discontinued 6—8 months prior to conception. In another case where acitretin had been discontinued about 4 weeks prior to conception, abortion was induced; however, the fetal malformation pattern was not typical of retinoid embryopathy.

    Blood donation

    Blood donation should be avoided during and for 3 years following completion of acitretin therapy because women of childbearing potential must not receive blood products from patients being treated with acitretin.

    Breast-feeding

    According to the manufacturer, women who are nursing should not receive acitretin prior to or during breast-feeding because of the potential for serious adverse reactions in nursing infants. Studies in animals show that etretinate, a metabolite of acitretin, is excreted in the milk. There is one prospective case report where acitretin is reported to be excreted in human breast milk. Consider the benefits of breast-feeding, the risk of potential infant drug exposure, and the risk of an untreated or inadequately treated condition. If a breast-feeding infant experiences an adverse effect related to a maternally ingested drug, healthcare providers are encouraged to report the adverse effect to the FDA.

    Renal failure, renal impairment

    Acitretin is contraindicated in patients with severe renal impairment or renal failure. Plasma concentrations of acitretin after a 50 mg dose were significantly (59.3%) lower in end-stage renal failure patients (n = 6) when compared to age-matched controls. Acitretin was not removed by dialysis in these patients.

    Hepatic disease

    Acitretin is contraindicated in patients with hepatic disease resulting in severe hepatic dysfunction; use has resulted in hepatotoxicity, which has been fatal in some cases. Use caution in patients with mild-to-moderate hepatic disease. Evaluate hepatic function before acitretin initiation, every one to two weeks until stable, and then at intervals as clinically indicated thereafter. If hepatotoxicity is suspected, discontinue acitretin and investigate the etiology. Additionally, there have been reports of an increased risk of hepatotoxicity in patients treated with etretinate and methotrexate concomitantly; therefore, the concurrent use of acitretin and methotrexate is contraindicated.

    Hyperostosis

    In adults receiving long-term treatment with acitretin, appropriate examinations for possible ossification abnormalities (e.g., hyperostosis) should be performed periodically. Because the frequency and severity of iatrogenic bony abnormalities in adults is low, periodic radiography is only warranted in the presence of symptoms or long-term acitretin use. If such disorders arise, the continuation of therapy should be discussed with the patient based on the risks versus benefits.

    Contact lenses, driving or operating machinery, visual disturbance

    Acitretin should be used cautiously in patients with a preexisting visual disturbance. Visual adverse effects were reported during clinical trials. Any patient treated with acitretin who is experiencing visual difficulties should discontinue the drug and undergo ophthalmologic evaluation. Decreased night vision has been reported with acitretin therapy. Patients should be advised of this potential effect and warned to be cautious when driving or operating machinery at night. Patients may experience decreased tolerance to contact lenses during the treatment period and sometimes after treatment has stopped.

    Retinoid hypersensitivity

    Acitretin should be avoided in patients with retinoid hypersensitivity, including hypersensitivity to vitamin A, tretinoin, and isotretinoin, due to the possibility of cross-sensitivity.

    Alcoholism, cardiac disease, diabetes mellitus, hypercholesterolemia, hyperglycemia, hypertriglyceridemia, obesity, pancreatitis

    Use acitretin cautiously in patients with preexisting hypertriglyceridemia or hypercholesterolemia; acitretin is contraindicated in patients with chronic abnormally elevated blood lipid values. Blood lipid determinations, under fasting conditions, should be performed before acitretin is administered, at intervals of 1 to 2 weeks until the lipid response to the drug is established, usually within 4 to 8 weeks, and thereafter at regular intervals as clinically indicated. Hypertriglyceridemia and lowered HDL may increase a patient's cardiovascular risk status; therefore, use acitretin with caution in patients with cardiac disease. There have been post-marketing reports of acute myocardial infarction or thromboembolic events in patients receiving acitretin (see Adverse Reactions). Further, elevations of serum triglycerides to greater than 800 mg/dl have been associated with fatal fulminant pancreatitis. Dietary modifications, reduction in acitretin dose, or drug therapy should be employed to control significant elevations of triglycerides. If, despite these measures, hypertriglyceridemia and low HDL levels persist, the discontinuation of acitretin should be considered. Patients with an increased tendency to develop hypertriglyceridemia include those with diabetes mellitus, increased alcohol intake or alcoholism, obesity, or a familial history of these conditions. Additionally, patients with diabetes mellitus or hyperglycemia may experience loss of blood glucose control; instruct patients with diabetes to monitor their blood glucose carefully.

    Children, infants, neonates

    The safety and effectiveness of acitretin in neonates, infants, children and adolescents have not been established. Ossification of interosseous ligaments and tendons of the extremities, skeletal hyperostoses, and premature epiphyseal closure have been reported with other systemic retinoids.

    Sunlight (UV) exposure

    Patients should avoid the use of sun lamps and excessive sunlight (UV) exposure (non-medical UV exposure) during acitretin therapy. Patients receiving phototherapy in combination with acitretin will require a significant reduction in the phototherapy dose due to increased sensitivity and potential for serious burns. Appropriate protective clothing (e.g., hat) and sunscreen should be used if patients are in the sunlight for an extended period of time.

    Depression, suicidal ideation

    If patients develop feelings of depression or suicidal ideation, they should be counseled to stop taking acitretin and notify their health care provider immediately. Depression and/or other psychiatric symptoms such as aggressive behavior or thoughts of self-harm have been reported during acitretin therapy. Since other factors may have contributed to these events, it is not known if they are related to acitretin.

    Increased intracranial pressure, papilledema

    Acitretin and other retinoids administered orally have been associated with cases of pseudotumor cerebri (benign increased intracranial pressure). Some of these events involved concomitant use of isotretinoin and tetracyclines. The single case reported with acitretin use, however, was not associated with tetracycline use. Early signs and symptoms include headache, nausea/vomiting, visual disturbances, and papilledema. Patients with these signs and symptoms should be examined for papilledema, and if present, should discontinue acitretin immediately and be referred for neurologic evaluation.

    Requires an experienced clinician

    Acitretin therapy requires an experienced clinician who has special competence in the diagnosis and treatment of severe psoriasis. Health care professionals should understand the risk of teratogenicity and have experience prescribing systemic retinoids, such as acitretin.

    ADVERSE REACTIONS

    Severe

    skin atrophy / Delayed / 10.0-25.0
    night blindness / Delayed / 1.0-10.0
    cranial nerve palsies / Delayed / 0-5.0
    ocular hemorrhage / Delayed / 0-1.0
    ectropion / Early / 0-1.0
    papilledema / Delayed / 0-1.0
    pancreatitis / Delayed / 0-1.0
    hypervitaminosis A / Delayed / Incidence not known
    exfoliative dermatitis / Delayed / Incidence not known
    teratogenesis / Delayed / Incidence not known
    spontaneous fetal abortion / Delayed / Incidence not known
    thromboembolism / Delayed / Incidence not known
    stroke / Early / Incidence not known
    myocardial infarction / Delayed / Incidence not known
    suicidal ideation / Delayed / Incidence not known
    diabetic ketoacidosis / Delayed / Incidence not known
    increased intracranial pressure / Early / Incidence not known
    visual impairment / Early / Incidence not known
    capillary leak syndrome / Early / Incidence not known
    rhabdomyolysis / Delayed / Incidence not known
    angioedema / Rapid / Incidence not known

    Moderate

    hypertriglyceridemia / Delayed / 66.0-66.0
    hyperlipidemia / Delayed / 25.0-50.0
    hyperglycemia / Delayed / 25.0-50.0
    elevated hepatic enzymes / Delayed / 33.0-33.0
    hypercholesterolemia / Delayed / 33.0-33.0
    hyperesthesia / Delayed / 10.0-25.0
    hyperostosis / Delayed / 1.0-25.0
    hypoglycemia / Early / 10.0-25.0
    stomatitis / Delayed / 1.0-10.0
    skin ulcer / Delayed / 1.0-10.0
    bullous rash / Early / 1.0-10.0
    psoriaform rash / Delayed / 1.0-10.0
    blepharitis / Early / 1.0-10.0
    hot flashes / Early / 1.0-10.0
    photophobia / Early / 1.0-10.0
    conjunctivitis / Delayed / 1.0-10.0
    edema / Delayed / 1.0-10.0
    blurred vision / Early / 1.0-10.0
    hypertonia / Delayed / 1.0-10.0
    bone pain / Delayed / 1.0-10.0
    depression / Delayed / 1.0-10.0
    cataracts / Delayed / 0-5.0
    pseudotumor cerebri / Delayed / 0-1.0
    hepatitis / Delayed / Incidence not known
    jaundice / Delayed / Incidence not known
    hyperbilirubinemia / Delayed / Incidence not known
    peripheral neuropathy / Delayed / Incidence not known
    myopathy / Delayed / Incidence not known
    diabetes mellitus / Delayed / Incidence not known
    hypotension / Rapid / Incidence not known
    hypoalbuminemia / Delayed / Incidence not known
    vaginitis / Delayed / Incidence not known

    Mild

    alopecia / Delayed / 50.0-75.0
    pruritus / Rapid / 25.0-50.0
    xerosis / Delayed / 25.0-50.0
    rhinitis / Early / 25.0-50.0
    paresthesias / Delayed / 10.0-25.0
    epistaxis / Delayed / 10.0-25.0
    xerostomia / Early / 10.0-25.0
    arthralgia / Delayed / 10.0-25.0
    xerophthalmia / Early / 23.0-23.0
    rash / Early / 1.0-10.0
    seborrhea / Delayed / 1.0-10.0
    hypersalivation / Early / 1.0-10.0
    diaphoresis / Early / 1.0-10.0
    photosensitivity / Delayed / 1.0-10.0
    gingivitis / Delayed / 1.0-10.0
    purpura / Delayed / 1.0-10.0
    flushing / Rapid / 1.0-10.0
    anorexia / Delayed / 1.0-10.0
    infection / Delayed / 1.0-10.0
    nausea / Early / 1.0-10.0
    ocular pain / Early / 1.0-10.0
    fatigue / Early / 1.0-10.0
    appetite stimulation / Delayed / 1.0-10.0
    diarrhea / Early / 1.0-10.0
    abdominal pain / Early / 1.0-10.0
    dysgeusia / Early / 1.0-10.0
    back pain / Delayed / 1.0-10.0
    myalgia / Early / 1.0-10.0
    arthropathy / Delayed / 1.0-10.0
    headache / Early / 1.0-10.0
    otalgia / Early / 1.0-10.0
    insomnia / Early / 1.0-10.0
    tinnitus / Delayed / 1.0-10.0
    sinusitis / Delayed / 1.0-10.0
    ocular irritation / Rapid / 9.0-9.0
    ocular pruritus / Rapid / 0-1.0
    diplopia / Early / 0-1.0
    lacrimation / Early / 0-1.0
    chalazion (meibomian cyst) / Delayed / 0-1.0
    cheilitis / Delayed / 75.0
    vomiting / Early / Incidence not known
    fever / Early / Incidence not known
    weight gain / Delayed / Incidence not known
    urticaria / Rapid / Incidence not known

    DRUG INTERACTIONS

    Acetohexamide: (Moderate) Retinoids have been reported to cause changes in blood sugar control in diabetics. In a study of 7 healthy male volunteers, acitretin treatment potentiated the blood glucose lowering effect of glibenclamide (a sulfonylurea similar to chlorpropamide) in 3 of the 7 subjects. Repeating the study with 6 healthy male volunteers in the absence of glibenclamide did not detect an effect of acitretin on glucose tolerance. Careful supervision of diabetic patients under treatment with acitretin is recommended, especially those taking concomitant sulfonylureas. There appears to be no pharmacokinetic interaction between acitretin and glyburide.
    Aminolevulinic Acid: (Moderate) Acitretin may increase the effects of photosensitizing agents used during photodynamic therapy; significantly lower doses of phototherapy are required when acitretin is used because acitretin-induced effects on the stratum corneum can increase the risk of erythema (burning).
    Chlorpropamide: (Moderate) Retinoids have been reported to cause changes in blood sugar control in diabetics. In a study of 7 healthy male volunteers, acitretin treatment potentiated the blood glucose lowering effect of glibenclamide (a sulfonylurea similar to chlorpropamide) in 3 of the 7 subjects. Repeating the study with 6 healthy male volunteers in the absence of glibenclamide did not detect an effect of acitretin on glucose tolerance. Careful supervision of diabetic patients under treatment with acitretin is recommended, especially those taking concomitant sulfonylureas. There appears to be no pharmacokinetic interaction between acitretin and glyburide.
    Conjugated Estrogens; Medroxyprogesterone: (Major) Acitretin interferes with the contraceptive effect of microdose progestins ('minipill' contraceptive preparations). It is not known if acitretin also interacts with other progestational contraceptives, such as medroxyprogesterone injectables, or if this method is an adequate method of contraception during acitretin therapy. However, female patients should be advised of the possibility that any contraceptive method can fail. Since Acitretin may cause serious birth defects, the patient should use 2 forms of reliable contraception at the same time for at least 1 month before beginning acitretin therapy, during acitretin therapy, and must continue to use them for at least 3 years after acitretin treatment has stopped. It is recommended that the patient either abstain from sexual intercourse or use 2 reliable kinds of birth control at the same time to prevent unwanted pregnancy.
    Elagolix; Estradiol; Norethindrone acetate: (Major) Acitretin reduces the efficacy of oral progestin only contraceptives. Since Acitretin may cause serious birth defects, the patient should use 2 forms of reliable contraception at the same time for at least 1 month before beginning acitretin therapy, during acitretin therapy, and must continue to use them for at least 3 years after acitretin treatment has stopped. It is recommended that the patient either abstain from sexual intercourse or use 2 reliable kinds of birth control at the same time to prevent unwanted pregnancy.
    Eravacycline: (Severe) The concomitant use of acitretin and eravacycline is contraindicated, due to the potential for increased cranial pressure and an increased risk of pseudotumor cerebri (benign intracranial hypertension). Pseudotumor cerebri has been reported with systemic retinoid use alone and early signs and symptoms include papilledema, headache, nausea, vomiting and visual disturbances.
    Estradiol Cypionate; Medroxyprogesterone: (Major) Acitretin interferes with the contraceptive effect of microdose progestins ('minipill' contraceptive preparations). It is not known if acitretin also interacts with other progestational contraceptives, such as medroxyprogesterone injectables, or if this method is an adequate method of contraception during acitretin therapy. However, female patients should be advised of the possibility that any contraceptive method can fail. Since Acitretin may cause serious birth defects, the patient should use 2 forms of reliable contraception at the same time for at least 1 month before beginning acitretin therapy, during acitretin therapy, and must continue to use them for at least 3 years after acitretin treatment has stopped. It is recommended that the patient either abstain from sexual intercourse or use 2 reliable kinds of birth control at the same time to prevent unwanted pregnancy.
    Estradiol; Levonorgestrel: (Major) Acitretin interferes with the contraceptive effect of microdose progestins ('minipill' contraceptive preparations), and may possibly interfere with the effecitivenss of emergency contraceptives like levonorgestrel (e.g., Plan B, Plan B OneStep). It is not known if acitretin also interacts with other progestational contraceptives, such as levonorgestrel implants or IUDs or if these methods are adequate methods of contraception during acitretin therapy. However, female patients should be advised of the possibility that any contraceptive method can fail. Since Acitretin may cause serious birth defects, the patient should use 2 forms of reliable contraception at the same time for at least 1 month before beginning acitretin therapy, during acitretin therapy, and must continue to use them for at least 3 years after acitretin treatment has stopped. It is recommended that the patient either abstain from sexual intercourse or use 2 reliable kinds of birth control at the same time to prevent unwanted pregnancy.
    Estradiol; Norethindrone: (Major) Acitretin reduces the efficacy of oral progestin only contraceptives. Since Acitretin may cause serious birth defects, the patient should use 2 forms of reliable contraception at the same time for at least 1 month before beginning acitretin therapy, during acitretin therapy, and must continue to use them for at least 3 years after acitretin treatment has stopped. It is recommended that the patient either abstain from sexual intercourse or use 2 reliable kinds of birth control at the same time to prevent unwanted pregnancy.
    Ethanol: (Severe) Patients must avoid all ethanol-containing beverages and medicines, including over-the-counter products, during and for 2 months after stopping therapy with acitretin. Concurrent ingestion of ethanol and acitretin results in the conversion of acitretin to etretinate. Because etretinate has a significantly longer elimination half-life than acitretin, coadministration of ethanol and acitretin would increase the duration of teratogenic potential for female patients. It is not known whether substances other than ethanol are associated with transesterification.
    Ethinyl Estradiol; Etonogestrel: (Major) Acitretin interferes with the contraceptive effect of microdose progestins ('minipill' contraceptive preparations). It is not known if acitretin also interacts with other progestational contraceptives, such as etonogestrel implants, or if this method is an adequate method of contraception during acitretin therapy. However, female patients should be advised of the possibility that any contraceptive method can fail. Since Acitretin may cause serious birth defects, the patient should use 2 forms of reliable contraception at the same time for at least 1 month before beginning acitretin therapy, during acitretin therapy, and must continue to use them for at least 3 years after acitretin treatment has stopped. It is recommended that the patient either abstain from sexual intercourse or use 2 reliable kinds of birth control at the same time to prevent unwanted pregnancy.
    Ethinyl Estradiol; Levonorgestrel: (Major) Acitretin interferes with the contraceptive effect of microdose progestins ('minipill' contraceptive preparations), and may possibly interfere with the effecitivenss of emergency contraceptives like levonorgestrel (e.g., Plan B, Plan B OneStep). It is not known if acitretin also interacts with other progestational contraceptives, such as levonorgestrel implants or IUDs or if these methods are adequate methods of contraception during acitretin therapy. However, female patients should be advised of the possibility that any contraceptive method can fail. Since Acitretin may cause serious birth defects, the patient should use 2 forms of reliable contraception at the same time for at least 1 month before beginning acitretin therapy, during acitretin therapy, and must continue to use them for at least 3 years after acitretin treatment has stopped. It is recommended that the patient either abstain from sexual intercourse or use 2 reliable kinds of birth control at the same time to prevent unwanted pregnancy.
    Ethinyl Estradiol; Levonorgestrel; Ferrous bisglycinate: (Major) Acitretin interferes with the contraceptive effect of microdose progestins ('minipill' contraceptive preparations), and may possibly interfere with the effecitivenss of emergency contraceptives like levonorgestrel (e.g., Plan B, Plan B OneStep). It is not known if acitretin also interacts with other progestational contraceptives, such as levonorgestrel implants or IUDs or if these methods are adequate methods of contraception during acitretin therapy. However, female patients should be advised of the possibility that any contraceptive method can fail. Since Acitretin may cause serious birth defects, the patient should use 2 forms of reliable contraception at the same time for at least 1 month before beginning acitretin therapy, during acitretin therapy, and must continue to use them for at least 3 years after acitretin treatment has stopped. It is recommended that the patient either abstain from sexual intercourse or use 2 reliable kinds of birth control at the same time to prevent unwanted pregnancy.
    Ethinyl Estradiol; Levonorgestrel; Folic Acid; Levomefolate: (Major) Acitretin interferes with the contraceptive effect of microdose progestins ('minipill' contraceptive preparations), and may possibly interfere with the effecitivenss of emergency contraceptives like levonorgestrel (e.g., Plan B, Plan B OneStep). It is not known if acitretin also interacts with other progestational contraceptives, such as levonorgestrel implants or IUDs or if these methods are adequate methods of contraception during acitretin therapy. However, female patients should be advised of the possibility that any contraceptive method can fail. Since Acitretin may cause serious birth defects, the patient should use 2 forms of reliable contraception at the same time for at least 1 month before beginning acitretin therapy, during acitretin therapy, and must continue to use them for at least 3 years after acitretin treatment has stopped. It is recommended that the patient either abstain from sexual intercourse or use 2 reliable kinds of birth control at the same time to prevent unwanted pregnancy.
    Ethinyl Estradiol; Norethindrone Acetate: (Major) Acitretin reduces the efficacy of oral progestin only contraceptives. Since Acitretin may cause serious birth defects, the patient should use 2 forms of reliable contraception at the same time for at least 1 month before beginning acitretin therapy, during acitretin therapy, and must continue to use them for at least 3 years after acitretin treatment has stopped. It is recommended that the patient either abstain from sexual intercourse or use 2 reliable kinds of birth control at the same time to prevent unwanted pregnancy.
    Ethinyl Estradiol; Norethindrone Acetate; Ferrous fumarate: (Major) Acitretin reduces the efficacy of oral progestin only contraceptives. Since Acitretin may cause serious birth defects, the patient should use 2 forms of reliable contraception at the same time for at least 1 month before beginning acitretin therapy, during acitretin therapy, and must continue to use them for at least 3 years after acitretin treatment has stopped. It is recommended that the patient either abstain from sexual intercourse or use 2 reliable kinds of birth control at the same time to prevent unwanted pregnancy.
    Ethinyl Estradiol; Norethindrone: (Major) Acitretin reduces the efficacy of oral progestin only contraceptives. Since Acitretin may cause serious birth defects, the patient should use 2 forms of reliable contraception at the same time for at least 1 month before beginning acitretin therapy, during acitretin therapy, and must continue to use them for at least 3 years after acitretin treatment has stopped. It is recommended that the patient either abstain from sexual intercourse or use 2 reliable kinds of birth control at the same time to prevent unwanted pregnancy.
    Ethinyl Estradiol; Norethindrone; Ferrous fumarate: (Major) Acitretin reduces the efficacy of oral progestin only contraceptives. Since Acitretin may cause serious birth defects, the patient should use 2 forms of reliable contraception at the same time for at least 1 month before beginning acitretin therapy, during acitretin therapy, and must continue to use them for at least 3 years after acitretin treatment has stopped. It is recommended that the patient either abstain from sexual intercourse or use 2 reliable kinds of birth control at the same time to prevent unwanted pregnancy.
    Ethinyl Estradiol; Norgestrel: (Major) Acitretin reduces the efficacy of oral progestin only contraceptives. Since Acitretin may cause serious birth defects, the patient should use 2 forms of reliable contraception at the same time for at least 1 month before beginning acitretin therapy, during acitretin therapy, and must continue to use them for at least 3 years after acitretin treatment has stopped. It is recommended that the patient either abstain from sexual intercourse or use 2 reliable kinds of birth control at the same time to prevent unwanted pregnancy.
    Etonogestrel: (Major) Acitretin interferes with the contraceptive effect of microdose progestins ('minipill' contraceptive preparations). It is not known if acitretin also interacts with other progestational contraceptives, such as etonogestrel implants, or if this method is an adequate method of contraception during acitretin therapy. However, female patients should be advised of the possibility that any contraceptive method can fail. Since Acitretin may cause serious birth defects, the patient should use 2 forms of reliable contraception at the same time for at least 1 month before beginning acitretin therapy, during acitretin therapy, and must continue to use them for at least 3 years after acitretin treatment has stopped. It is recommended that the patient either abstain from sexual intercourse or use 2 reliable kinds of birth control at the same time to prevent unwanted pregnancy.
    Fosphenytoin: (Moderate) Acitretin may reduce the protein binding of phenytoin. Free fosphenytoin concentrations may be useful for therapeutic monitoring if both acitretin and fosphenytoin are administered concurrently.
    Glimepiride: (Moderate) Retinoids have been reported to cause changes in blood sugar control in diabetics. In a study of 7 healthy male volunteers, acitretin treatment potentiated the blood glucose lowering effect of glibenclamide (a sulfonylurea similar to chlorpropamide) in 3 of the 7 subjects. Repeating the study with 6 healthy male volunteers in the absence of glibenclamide did not detect an effect of acitretin on glucose tolerance. Careful supervision of diabetic patients under treatment with acitretin is recommended, especially those taking concomitant sulfonylureas. There appears to be no pharmacokinetic interaction between acitretin and glyburide.
    Glimepiride; Pioglitazone: (Moderate) Retinoids have been reported to cause changes in blood sugar control in diabetics. In a study of 7 healthy male volunteers, acitretin treatment potentiated the blood glucose lowering effect of glibenclamide (a sulfonylurea similar to chlorpropamide) in 3 of the 7 subjects. Repeating the study with 6 healthy male volunteers in the absence of glibenclamide did not detect an effect of acitretin on glucose tolerance. Careful supervision of diabetic patients under treatment with acitretin is recommended, especially those taking concomitant sulfonylureas. There appears to be no pharmacokinetic interaction between acitretin and glyburide.
    Glimepiride; Rosiglitazone: (Moderate) Retinoids have been reported to cause changes in blood sugar control in diabetics. In a study of 7 healthy male volunteers, acitretin treatment potentiated the blood glucose lowering effect of glibenclamide (a sulfonylurea similar to chlorpropamide) in 3 of the 7 subjects. Repeating the study with 6 healthy male volunteers in the absence of glibenclamide did not detect an effect of acitretin on glucose tolerance. Careful supervision of diabetic patients under treatment with acitretin is recommended, especially those taking concomitant sulfonylureas. There appears to be no pharmacokinetic interaction between acitretin and glyburide.
    Glipizide: (Moderate) Retinoids have been reported to cause changes in blood sugar control in diabetics. In a study of 7 healthy male volunteers, acitretin treatment potentiated the blood glucose lowering effect of glibenclamide (a sulfonylurea similar to chlorpropamide) in 3 of the 7 subjects. Repeating the study with 6 healthy male volunteers in the absence of glibenclamide did not detect an effect of acitretin on glucose tolerance. Careful supervision of diabetic patients under treatment with acitretin is recommended, especially those taking concomitant sulfonylureas. There appears to be no pharmacokinetic interaction between acitretin and glyburide.
    Glipizide; Metformin: (Moderate) Retinoids have been reported to cause changes in blood sugar control in diabetics. In a study of 7 healthy male volunteers, acitretin treatment potentiated the blood glucose lowering effect of glibenclamide (a sulfonylurea similar to chlorpropamide) in 3 of the 7 subjects. Repeating the study with 6 healthy male volunteers in the absence of glibenclamide did not detect an effect of acitretin on glucose tolerance. Careful supervision of diabetic patients under treatment with acitretin is recommended, especially those taking concomitant sulfonylureas. There appears to be no pharmacokinetic interaction between acitretin and glyburide.
    Glyburide: (Moderate) Retinoids have been reported to cause changes in blood sugar control in diabetics. In a study of 7 healthy male volunteers, acitretin treatment potentiated the blood glucose lowering effect of glibenclamide (a sulfonylurea similar to chlorpropamide) in 3 of the 7 subjects. Repeating the study with 6 healthy male volunteers in the absence of glibenclamide did not detect an effect of acitretin on glucose tolerance. Careful supervision of diabetic patients under treatment with acitretin is recommended, especially those taking concomitant sulfonylureas. There appears to be no pharmacokinetic interaction between acitretin and glyburide.
    Glyburide; Metformin: (Moderate) Retinoids have been reported to cause changes in blood sugar control in diabetics. In a study of 7 healthy male volunteers, acitretin treatment potentiated the blood glucose lowering effect of glibenclamide (a sulfonylurea similar to chlorpropamide) in 3 of the 7 subjects. Repeating the study with 6 healthy male volunteers in the absence of glibenclamide did not detect an effect of acitretin on glucose tolerance. Careful supervision of diabetic patients under treatment with acitretin is recommended, especially those taking concomitant sulfonylureas. There appears to be no pharmacokinetic interaction between acitretin and glyburide.
    Leuprolide; Norethindrone: (Major) Acitretin reduces the efficacy of oral progestin only contraceptives. Since Acitretin may cause serious birth defects, the patient should use 2 forms of reliable contraception at the same time for at least 1 month before beginning acitretin therapy, during acitretin therapy, and must continue to use them for at least 3 years after acitretin treatment has stopped. It is recommended that the patient either abstain from sexual intercourse or use 2 reliable kinds of birth control at the same time to prevent unwanted pregnancy.
    Levonorgestrel: (Major) Acitretin interferes with the contraceptive effect of microdose progestins ('minipill' contraceptive preparations), and may possibly interfere with the effecitivenss of emergency contraceptives like levonorgestrel (e.g., Plan B, Plan B OneStep). It is not known if acitretin also interacts with other progestational contraceptives, such as levonorgestrel implants or IUDs or if these methods are adequate methods of contraception during acitretin therapy. However, female patients should be advised of the possibility that any contraceptive method can fail. Since Acitretin may cause serious birth defects, the patient should use 2 forms of reliable contraception at the same time for at least 1 month before beginning acitretin therapy, during acitretin therapy, and must continue to use them for at least 3 years after acitretin treatment has stopped. It is recommended that the patient either abstain from sexual intercourse or use 2 reliable kinds of birth control at the same time to prevent unwanted pregnancy.
    Medroxyprogesterone: (Major) Acitretin interferes with the contraceptive effect of microdose progestins ('minipill' contraceptive preparations). It is not known if acitretin also interacts with other progestational contraceptives, such as medroxyprogesterone injectables, or if this method is an adequate method of contraception during acitretin therapy. However, female patients should be advised of the possibility that any contraceptive method can fail. Since Acitretin may cause serious birth defects, the patient should use 2 forms of reliable contraception at the same time for at least 1 month before beginning acitretin therapy, during acitretin therapy, and must continue to use them for at least 3 years after acitretin treatment has stopped. It is recommended that the patient either abstain from sexual intercourse or use 2 reliable kinds of birth control at the same time to prevent unwanted pregnancy.
    Mestranol; Norethindrone: (Major) Acitretin reduces the efficacy of oral progestin only contraceptives. Since Acitretin may cause serious birth defects, the patient should use 2 forms of reliable contraception at the same time for at least 1 month before beginning acitretin therapy, during acitretin therapy, and must continue to use them for at least 3 years after acitretin treatment has stopped. It is recommended that the patient either abstain from sexual intercourse or use 2 reliable kinds of birth control at the same time to prevent unwanted pregnancy.
    Methotrexate: (Severe) The combination of methotrexate and acitretin is contraindicated. An increased risk of hepatitis has been reported from the combined use of methotrexate and the retinoid etretinate. Acitretin is the principal active component of etretinate. Although no longer available commercially in the United States, etretinate has been shown to increase methotrexate serum concentrations and cases of hepatotoxicity (e.g., hepatitis) have also been reported in patients receiving etretinate and methotrexate concomitantly.
    Methoxsalen: (Moderate) Use methoxsalen and retinoids together with caution; the risk of severe burns/phototoxicity may be additive. If concurrent use is necessary, closely monitor patients for signs or symptoms of skin toxicity.
    Norethindrone: (Major) Acitretin reduces the efficacy of oral progestin only contraceptives. Since Acitretin may cause serious birth defects, the patient should use 2 forms of reliable contraception at the same time for at least 1 month before beginning acitretin therapy, during acitretin therapy, and must continue to use them for at least 3 years after acitretin treatment has stopped. It is recommended that the patient either abstain from sexual intercourse or use 2 reliable kinds of birth control at the same time to prevent unwanted pregnancy.
    Norgestrel: (Major) Acitretin reduces the efficacy of oral progestin only contraceptives. Since Acitretin may cause serious birth defects, the patient should use 2 forms of reliable contraception at the same time for at least 1 month before beginning acitretin therapy, during acitretin therapy, and must continue to use them for at least 3 years after acitretin treatment has stopped. It is recommended that the patient either abstain from sexual intercourse or use 2 reliable kinds of birth control at the same time to prevent unwanted pregnancy.
    Orlistat: (Moderate) Due the effect of orlistat on fat absorption and the lower serum levels of fat-soluble vitamins noted during clinical trials, the bioavailability of acitretin may be decreased. Close monitoring of patients receiving acitretin with orlistat is recommended.
    Phenytoin: (Moderate) Acitretin reduces the protein binding of phenytoin. Free phenytoin concentrations may be useful for therapeutic monitoring if both acitretin and phenytoin are administered concurrently.
    Photosensitizing agents (topical): (Moderate) Acitretin may increase the effects of photosensitizing agents used during photodynamic therapy; significantly lower doses of phototherapy are required when acitretin is used because acitretin-induced effects on the stratum corneum can increase the risk of erythema (burning).
    Porfimer: (Major) Avoid coadministration of porfimer with retinoids due to the risk of increased photosensitivity. Porfimer is a light-activated drug used in photodynamic therapy; all patients treated with porfimer will be photosensitive. Concomitant use of other photosensitizing agents like retinoids may increase the risk of a photosensitivity reaction.
    Salicylic Acid: (Moderate) Dryness of the skin and mucus membranes are common side effects of retinoid therapy. Simultaneous use of retinoids and topical drying agents, such as salicylic acid, can potentiate the drying effects of retinoids on the skin. Be alert for signs of skin irritation, the offending topical agents may need to be used less often or discontinued during retinoid therapy.
    Segesterone Acetate; Ethinyl Estradiol: (Major) Acitretin interferes with the contraceptive effect of microdose progestins ('minipill' contraceptive preparations). It is not known if acitretin also interacts with other progestational contraceptives, such as segesterone vaginal rings, or if this method is an adequate method of contraception during acitretin therapy. However, female patients should be advised of the possibility that any contraceptive method can fail. Since Acitretin may cause serious birth defects, the patient should use 2 forms of reliable contraception at the same time for at least 1 month before beginning acitretin therapy, during acitretin therapy, and must continue to use them for at least 3 years after acitretin treatment has stopped. It is recommended that the patient either abstain from sexual intercourse or use 2 reliable kinds of birth control at the same time to prevent unwanted pregnancy.
    Sodium Thiosulfate; Salicylic Acid: (Moderate) Dryness of the skin and mucus membranes are common side effects of retinoid therapy. Simultaneous use of retinoids and topical drying agents, such as salicylic acid, can potentiate the drying effects of retinoids on the skin. Be alert for signs of skin irritation, the offending topical agents may need to be used less often or discontinued during retinoid therapy.
    St. John's Wort, Hypericum perforatum: (Major) Because of the teratogenic potential of acitretin, the coadministration of St. John's wort, Hypericum perforatum and acitretin should be avoided in females who are using hormonal contraceptives as their primary form of birth control. St. John's wort, Hypericum perforatum appears to interact with estrogens and oral contraceptives. Breakthrough bleeding and pregnancies have been reported following coadministration of St. John's Wort and hormonal contraception. It is thought that St. John's wort induces hormone metabolism via induction of the hepatic CYP3A4 isoenzyme. It is possible that, as with other CYP3A4 inducers, St. John's wort could also reduce the therapeutic efficacy of non-oral combination contraceptives or progestin-only contraceptives (i.e., norgestrel, levonorgestrel, and medroxyprogesterone).
    Sulfonylureas: (Moderate) Retinoids have been reported to cause changes in blood sugar control in diabetics. In a study of 7 healthy male volunteers, acitretin treatment potentiated the blood glucose lowering effect of glibenclamide (a sulfonylurea similar to chlorpropamide) in 3 of the 7 subjects. Repeating the study with 6 healthy male volunteers in the absence of glibenclamide did not detect an effect of acitretin on glucose tolerance. Careful supervision of diabetic patients under treatment with acitretin is recommended, especially those taking concomitant sulfonylureas. There appears to be no pharmacokinetic interaction between acitretin and glyburide.
    Tetracyclines: (Severe) The concomitant use of acitretin and systemic tetracyclines is contraindicated, due to the potential for increased cranial pressure and an increased risk of pseudotumor cerebri (benign intracranial hypertension). Pseudotumor cerebri has been reported with systemic retinoid use alone and early signs and symptoms include papilledema, headache, nausea, vomiting and visual disturbances.
    Tolazamide: (Moderate) Retinoids have been reported to cause changes in blood sugar control in diabetics. In a study of 7 healthy male volunteers, acitretin treatment potentiated the blood glucose lowering effect of glibenclamide (a sulfonylurea similar to chlorpropamide) in 3 of the 7 subjects. Repeating the study with 6 healthy male volunteers in the absence of glibenclamide did not detect an effect of acitretin on glucose tolerance. Careful supervision of diabetic patients under treatment with acitretin is recommended, especially those taking concomitant sulfonylureas. There appears to be no pharmacokinetic interaction between acitretin and glyburide.
    Tolbutamide: (Moderate) Retinoids have been reported to cause changes in blood sugar control in diabetics. In a study of 7 healthy male volunteers, acitretin treatment potentiated the blood glucose lowering effect of glibenclamide (a sulfonylurea similar to chlorpropamide) in 3 of the 7 subjects. Repeating the study with 6 healthy male volunteers in the absence of glibenclamide did not detect an effect of acitretin on glucose tolerance. Careful supervision of diabetic patients under treatment with acitretin is recommended, especially those taking concomitant sulfonylureas. There appears to be no pharmacokinetic interaction between acitretin and glyburide.
    Verteporfin: (Moderate) Use caution if coadministration of verteporfin with retinoids is necessary due to the risk of increased photosensitivity. Verteporfin is a light-activated drug used in photodynamic therapy; all patients treated with verteporfin will be photosensitive. Concomitant use of other photosensitizing agents like retinoids may increase the risk of a photosensitivity reaction.

    PREGNANCY AND LACTATION

    Pregnancy

    Acitretin is classified as FDA pregnancy risk category X. It is teratogenic and is contraindicated in females who are pregnant or who intend to become pregnant during therapy or within 3 years after therapy. Acitretin must also not be used by females who may not use reliable contraception during and for at least 3 years after treatment. Acitretin is a metabolite of etretinate; major human fetal malformations have been associated with the maternal use of both drugs. Ethanol ingestion has been shown to be associated with the transesterification of acitretin to etretinate. Because the half-life of etretinate is significantly longer than acitretin, the duration of teratogenic potential would be increased; therefore, females should avoid ethanol ingestion during and for 2 months after discontinuing therapy. Before initiating therapy in patients of childbearing potential, patients must be told clearly and in detail about the precautions to be taken, the risks involved, and the possible consequences should pregnancy occur during treatment or within 3 years of discontinuing therapy. Counseling regarding contraception must be repeated by the prescriber monthly during therapy and at every 3 months for 3 years after acitretin discontinuation. A Soriatane Patient Referral Form is available from the manufacturer so that patients can receive an initial free contraceptive counseling session and pregnancy testing. Female patients must have had 2 negative urine or serum pregnancy tests with a sensitivity of at least 25 million international units/ml before receiving the initial acitretin prescription. The first test is obtained by the prescriber when the decision is made to pursue acitretin therapy. The second test should be done during the first 5 days of the menstrual period immediately preceding the beginning of acitretin therapy. For patients with amenorrhea, the second test should be done at least 11 days after the last act of unprotected sexual intercourse (without using 2 effective forms of contraception simultaneously). If the second pregnancy test is negative, initiation of treatment should begin within 7 days of the specimen collection; limit to a monthly supply. Obtain a pregnancy test with a sensitivity of at least 25 milliunits monthly during treatment; after acitretin is discontinued, repeat pregnancy testing every 3 months for at least 3 years. Effective contraception must be used for at least 1 month before beginning acitretin therapy, during therapy, and for at least 3 years after discontinuation even where there has been a history of infertility, unless due to hysterectomy or if the woman is clearly postmenopausal. Two reliable forms of contraception (primary and secondary forms) must be used simultaneously unless abstinence is the chosen method. Primary forms of birth control include tubal ligation, partner's vasectomy, intrauterine devices, birth control pills, and non-oral hormonal birth control products while secondary forms include diaphragms, latex condoms, cervical caps, and vaginal sponges; each secondary form must be used with a spermicide. Acitretin interferes with the contraceptive effect of microdose progestin preparations; therefore, these preparations are not recommended for use with acitretin. In addition, prescribers must be cautious to avoid any potential drug interactions that may reduce the effectiveness of hormonal contraception in females who are using hormonal contraception as a primary form of birth. Counsel patients to avoid self-medicating with St. John's Wort, as it may decrease the effectiveness of hormonal contraceptives. For female patients, prescribers must have a signed Patient Agreement/Informed Consent form that describes the warnings and requirements associated with acitretin therapy and pregnancy prior to beginning treatment. Adverse fetal outcomes associated with acitretin and/or etretinate use have included spontaneous abortion, absent hand/wrist, cardiac malformations, chromosomal disorders, decreased cranial volume, facial dysmorphia, GI malformations, limb malformations, meningomyelocele, placental disorder/death, premature birth, stillbirth, and other abnormalities. Because of acitretin's serious teratogenicity, a program called Do Your P.A.R.T program (Pregnancy prevention Actively Required during and after Treatment) has been developed to educate women and their healthcare providers about the risks associated with acitretin therapy. Further, it is not known whether residual acitretin in seminal fluid poses risk to a fetus while a male patient is taking the drug or after it is discontinued. Minimal concentrations (12.5 ng/mL) have been found in the seminal fluid of men receiving acitretin or etretinate and may cause male-mediated teratogenicity. It appears that residual acitretin in seminal fluid poses little, if any, risk to a fetus while a male patient is taking the drug or after it is discontinued; however, the no-effect limit for teratogenicity is not known, and there is no registry for birth defects associated with acitretin. There have been 25 cases of reported conception when the male partner was taking acitretin. The pregnancy outcome is known in 13 of the cases. When acitretin therapy was ongoing at the time of conception, delivery of a healthy neonate occurred in 5 cases, spontaneous abortion occurred in 5 cases, and there was one case of induced abortion. In one case, a spontaneous abortion occurred when acitretin had been discontinued 6—8 months prior to conception. In another case where acitretin had been discontinued about 4 weeks prior to conception, abortion was induced; however, the fetal malformation pattern was not typical of retinoid embryopathy.

    MECHANISM OF ACTION

    Retinoids are intracrine and paracrine mediators of cell differentiation and proliferation, apoptosis (programmed cell death), and reproduction. Cells regulate the formation of specific retinoid isomers depending upon the cellular action required. The numerous effects of retinoids reflect the complex biology of the nuclear receptors that mediate retinoid activity. Retinoid receptors are divided into retinoid X receptors (RXRs) and retinoic acid receptors (RARs); both types can be further divided into 3 subtypes: Alpha, beta, and gamma. These receptor subtypes are further divided into many isoforms. Retinoid receptors are structurally similar but have different affinities for different types of retinoids and distribution varies throughout the body resulting in a wide range of actions. Skin mainly expresses RAR-gamma and RXR alpha receptors. Acitretin activates all three RARs without measurable receptor binding. The reason for this has not been explained. RAR-alpha and RAR-beta have been associated with the development of acute promyelocytic leukemia and squamous cell cancers, respectively. RAR-gamma is associated with retinoid effects on mucocutaneous tissues and bone. By binding to RARs, acitretin modifies gene expression, subsequent protein synthesis, and epithelial cell growth and differentiation. It has not been established whether the clinical effects of acitretin are mediated through activation of RARs, other mechanisms such as irritation, or both.

    PHARMACOKINETICS

    Acitretin is administered orally. More than 99.9% of acitretin in the plasma is bound to plasma proteins, primarily to albumin.
     
    Acitretin undergoes extensive metabolism and interconversion by simple isomerization to its 13-cis form (cis-acitretin). The formation of cis-acitretin relative to parent compound is not altered by dose or fed/fast conditions. Both the parent compound and isomer are further metabolized into chain-shortened breakdown products and conjugates. Following multiple-dosing, steady-state concentrations of acitretin and cis-acitretin in plasma are achieved within approximately 3 weeks. The chain-shortened metabolites and conjugates are ultimately excreted in the feces (34% to 54%) and urine (16% to 53%). The terminal elimination half-life of acitretin following multiple-dosing is 49 hours (range 33 to 96 hours), and that of cis-acitretin under the same conditions is 63 hours (range 28 to 157 hours). Concurrent ingestion of ethanol with acitretin results in the conversion of acitretin to etretinate, which has a much longer half-life.

    Oral Route

    Oral absorption of acitretin is optimal when administered with food, therefore, in clinical studies, acitretin was given with food. Following administration of a single 50 mg oral dose to 18 healthy subjects, maximum plasma concentrations ranged from 196 to 728 ng/mL (mean 416 ng/mL) and were achieved in 2 to 5 hours (mean 2.7 hours). Approximately 72% (range 47% to 109%) of the administered dose was absorbed after a single 50 mg dose of acitretin was given to 12 healthy subjects.