The product labeling information includes all published material associated to a drug. Product labeling documents include information like generic names, active ingredients, ingredient strength dosage, routes of administration, appearance, usage, warnings, inactive ingredients, etc.
Acitretin, USP (micronized), a retinoid, is available in 10 mg, 17.5 mg, and 25 mg gelatin capsules for oral administration. Chemically, acitretin is all-trans-9-(4-methoxy-2,3,6-trimethylphenyl)-3,7-dimethyl-2,4,6,8-nonatetraenoic acid. It is a metabolite of etretinate and is related to both retinoic acid and retinol (vitamin A). It is a yellow to greenish-yellow crystalline powder. The structural formula is:C21H26O3 M.W. 326.43Each capsule contains acitretin, USP (micronized) 10 mg, 17.5 mg, and 25 mg. Inactive ingredients are crospovidone, microcrystalline cellulose, poloxamer, povidone, sodium ascorbate and sodium lauryl sulfate.The 10 mg, 17.5, and 25 mg gelatin capsule shells contain gelatin and titanium dioxide. The 10 mg and 25 mg capsule shells also contain D&C yellow no. 10, FD&C blue no. 1, and FD&C red no. 40. The 17.5 mg capsule shells also contain red iron oxide and yellow iron oxide. The 25 mg gelatin capsule shells also contain FD&C yellow no. 6. The edible imprinting ink contains black iron oxide, D&C yellow no. 10 aluminum lake, FD&C blue no. 1 aluminum lake, FD&C blue no. 2 aluminum lake, FD&C red no. 40 aluminum lake, propylene glycol and shellac glaze.Meets USP Dissolution Test 2.
The mechanism of action of acitretin is unknown.
AbsorptionOral absorption of acitretin is optimal when given with food. For this reason, acitretin was given with food in all of the following trials. After administration of a single 50-mg oral dose of acitretin to 18 healthy subjects, maximum plasma concentrations ranged from 196 to 728 ng per mL (mean: 416 ng per mL) and were achieved in 2 to 5 hours (mean: 2.7 hours). The oral absorption of acitretin is linear and proportional with increasing doses from 25 to 100 mg. 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.DistributionAcitretin is more than 99.9% bound to plasma proteins, primarily albumin.Metabolism (See Pharmacokinetic Drug Interactions, Ethanol.)Following oral absorption, 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 of oral administration of acitretin. Both parent compound and isomer are further metabolized into chain-shortened breakdown products and conjugates, which are excreted. Following multiple-dose administration of acitretin, steady-state concentrations of acitretin and cis-acitretin in plasma are achieved within approximately 3 weeks.EliminationThe chain-shortened metabolites and conjugates of acitretin and cis-acitretin are ultimately excreted in the feces (34% to 54%) and urine (16% to 53%). The terminal elimination half-life of acitretin following multiple-dose administration 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). The accumulation ratio of the parent compound is 1.2; that of cis-acitretin is 6.6.
PsoriasisIn an 8-week trial of acitretin pharmacokinetics in subjects with psoriasis, mean steady-state trough concentrations of acitretin increased in a dose-proportional manner with dosages ranging from 10 to 50 mg daily. Acitretin plasma concentrations were nonmeasurable (< 4 ng per mL) in all subjects 3 weeks after cessation of therapy.ElderlyIn a multiple-dose trial in healthy young (n = 6) and elderly (n = 8) subjects, a 2-fold increase in acitretin plasma concentrations were seen in elderly subjects, although the elimination half-life did not change.Renal FailurePlasma concentrations of acitretin were significantly (59.3%) lower in subjects with end-stage renal failure (n = 6) when compared with age-matched controls, following single 50-mg oral doses. Acitretin was not removed by hemodialysis in these subjects.
Pharmacokinetic Drug Interactions
(See also boxed CONTRAINDICATIONS AND WARNINGS and PRECAUTIONS, Drug Interactions)In studies of in vivo pharmacokinetic drug interactions, no interaction was seen between acitretin and cimetidine, digoxin, phenprocoumon, or glyburide.EthanolClinical evidence has shown that etretinate (a retinoid with a much longer half-life, see below) can be formed with concurrent ingestion of acitretin and ethanol. In a 2-way crossover trial, all 10 subjects formed etretinate with concurrent ingestion of a single 100-mg oral dose of acitretin during a 3-hour period of ethanol ingestion (total ethanol, approximately 1.4 g per kg body weight). A mean peak etretinate concentration of 59 ng per mL (range: 22 to 105 ng per mL) was observed, and extrapolation of AUC values indicated that the formation of etretinate in this trial was comparable to a single 5-mg oral dose of etretinate. There was no detectable formation of etretinate when a single 100-mg oral dose of acitretin was administered without concurrent ethanol ingestion, although the formation of etretinate without concurrent ethanol ingestion cannot be excluded (see boxed CONTRAINDICATIONS AND WARNINGS). Of 93 evaluable psoriatic subjects on acitretin therapy in several foreign trials (10 to 80 mg per day), 16% had measurable etretinate levels (>5 ng per mL).Etretinate has a much longer elimination half-life compared with that of acitretin. In one trial the apparent mean terminal half-life after 6 months of therapy was approximately 120 days (range: 84 to 168 days). In another trial of 47 subjects treated chronically with etretinate, 5 had detectable serum drug levels (in the range of 0.5 to 12 ng per mL) 2.1 to 2.9 years after therapy was discontinued. The long half-life appears to be due to storage of etretinate in adipose tissue.Progestin-only ContraceptivesIt has not been established if there is a pharmacokinetic interaction between acitretin and combined oral contraceptives. However, it has been established that acitretin interferes with the contraceptive effect of microdosed progestin preparations.1 Microdosed “minipill” progestin preparations are not recommended for use with acitretin. It is not known whether other progestin-only contraceptives, such as implants and injectables, are adequate methods of contraception during acitretin therapy.
In 2 double-blind, placebo-controlled trials, acitretin was administered once daily to subjects with severe psoriasis (e.g., covering at least 10% to 20% of the body surface area). At 8 weeks (see Table 1) subjects treated in Trial A with 50 mg of acitretin per day showed significant improvements (P ≤ 0.05) relative to baseline and to placebo in the physician’s global evaluation and in the mean ratings of severity of psoriasis (scaling, thickness, and erythema). In Trial B, differences from baseline and from placebo were statistically significant (P ≤ 0.05) for all variables at both the 25-mg and 50-mg doses; it should be noted for Trial B that no statistical adjustment for multiplicity was carried out.Table 1. Summary of the Efficacy Results of the 8-Week Double-Blind Phase of Trials A and B of AcitretinEfficacyVariablesTrial ATrial BTotal Daily DoseTotal Daily DosePlacebo(N = 29)50 mg(N = 29)Placebo(N = 72)25 mg(N = 74)50 mg(N = 71)Physician’s Global EvaluationBaseline 4.624.554.434.374.49Mean Change After 8 Weeks−0.29−2.00a−0.06−1.06a−1.57aScalingBaseline 4.103.763.974.114.10Mean Change After 8 Weeks−0.22−1.62a−0.21−1.50a−1.78aThicknessBaseline 4.104.104.034.114.20Mean Change After 8 Weeks−0.39−2.1a−0.18−1.43a−2.11aErythemaBaseline4.214.594.424.244.45Mean Change After 8 Weeks−0.33−2.10a−0.37−1.12a−1.65a a Values were statistically significantly different from placebo and from baseline (P ≤ 0.05). No adjustment for multiplicity was done for Trial B. The efficacy variables consisted of: the mean severity rating of scale, lesion thickness, erythema, and the physician’s global evaluation of the current status of the disease. Ratings of scaling, erythema, and lesion thickness, and the ratings of the global assessments were made using a 7-point scale (0 = none, 1 = trace, 2 = mild, 3 = mild-moderate, 4 = moderate, 5 = moderate-severe, 6 = severe).A subset of 141 subjects from both pivotal Trials A and B continued to receive acitretin in an open fashion for up to 24 weeks. At the end of the treatment period, all efficacy variables, as indicated in Table 2, were significantly improved (P ≤ 0.01) from baseline, including extent of psoriasis, mean ratings of psoriasis severity, and physician’s global evaluation.Table 2. Summary of the First Course of Therapy with Acitretin (24 Weeks)VariablesTrial ATrial BMean Total Daily Dose of Acitretin (mg) 42.843.1Mean Duration of Therapy (Weeks) 21.122.6Physician’s Global Evaluation N = 39N = 98Baseline 4.514.43Mean Change from Baseline −2.26a−2.60aScaling N = 59N = 132Baseline 3.974.07Mean Change from Baseline −2.15a−2.42aThickness N = 59N = 132Baseline 4.004.12Mean Change from Baseline −2.44a−2.66aErythema N = 59N = 132Baseline 4.354.33Mean Change from Baseline −2.31a−2.29aa Indicates that the difference from baseline was statistically significant (P ≤ 0.01). The efficacy variables consisted of: the mean severity rating of scale, lesion thickness, erythema, and the physician’s global evaluation of the current status of the disease. Ratings of scaling, erythema, and lesion thickness, and the ratings of the global assessments were made using a 7-point scale (0 = none, 1 = trace, 2 = mild, 3 = mild-moderate, 4 = moderate, 5 = moderate-severe, 6 = severe).All efficacy variables improved significantly in a subset of 55 subjects from Trial A treated for a second, 6-month maintenance course of therapy (for a total of 12 months of treatment); a small subset of subjects (n = 4) from Trial A continued to improve after a third 6-month course of therapy (for a total of 18 months of treatment).
Indications And Usage
Acitretin Capsules are indicated for the treatment of severe psoriasis in adults. Because of significant adverse effects associated with its use, Acitretin Capsules should be prescribed only by those knowledgeable in the systemic use of retinoids. In females of reproductive potential, Acitretin Capsules should be reserved for non-pregnant patients who are unresponsive to other therapies or whose clinical condition contraindicates the use of other treatments (see boxed CONTRAINDICATIONS AND WARNINGS — Acitretin Capsules can cause severe birth defects).Most patients experience relapse of psoriasis after discontinuing therapy. Subsequent courses, when clinically indicated, have produced efficacy results similar to the initial course of therapy.
Pregnancy Category X(See boxed CONTRAINDICATIONS AND WARNINGS.)Acitretin is contraindicated in patients with severely impaired liver or kidney function and in patients with chronic abnormally elevated blood lipid values (see boxed WARNINGS, Hepatotoxicity; WARNINGS, Lipids and Possible Cardiovascular Effects; and PRECAUTIONS).An increased risk of hepatitis has been reported to result from combined use of methotrexate and etretinate. Consequently, the combination of methotrexate with acitretin is also contraindicated (see PRECAUTIONS, Drug Interactions).Since both acitretin and tetracyclines can cause increased intracranial pressure, their combined use is contraindicated (see WARNINGS, Pseudotumor Cerebri).Acitretin is contraindicated in cases of hypersensitivity (e.g., angioedema, urticaria) to the preparation (acitretin or excipients) or to other retinoids.
(See also boxed CONTRAINDICATIONS AND WARNINGS.)HepatotoxicityOf the 525 subjects treated in U.S. clinical trials, 2 had clinical jaundice with elevated serum bilirubin and transaminases considered related to treatment with acitretin. Liver function test results in these subjects returned to normal after acitretin was discontinued. Two of the 1,289 subjects treated in European clinical trials developed biopsy-confirmed toxic hepatitis. A second biopsy in one of these subjects revealed nodule formation suggestive of cirrhosis. One subject in a Canadian clinical trial of 63 subjects developed a 3-fold increase of transaminases. A liver biopsy of this subject showed mild lobular disarray, multifocal hepatocyte loss, and mild triaditis of the portal tracts compatible with acute reversible hepatic injury. The subject’s transaminase levels returned to normal 2 months after acitretin was discontinued.The potential of therapy with acitretin to induce hepatotoxicity was prospectively evaluated using liver biopsies in an open-label trial of 128 subjects. Pretreatment and posttreatment biopsies were available for 87 subjects. A comparison of liver biopsy findings before and after therapy revealed 49 (58%) subjects showed no change, 21 (25%) improved, and 14 (17%) subjects had a worsening of their liver biopsy status. For 6 subjects, the classification changed from class 0 (no pathology) to class I (normal fatty infiltration; nuclear variability and portal inflammation; both mild); for 7 subjects, the change was from class I to class II (fatty infiltration, nuclear variability, portal inflammation, and focal necrosis; all moderate to severe); and for 1 subject, the change was from class II to class IIIb (fibrosis, moderate to severe). No correlation could be found between liver function test result abnormalities and the change in liver biopsy status, and no cumulative dose relationship was found.Elevations of AST (SGOT), ALT (SGPT), GGT (GGTP), or LDH have occurred in approximately 1 in 3 subjects treated with acitretin. Of the 525 subjects treated in clinical trials in the U.S., treatment was discontinued in 20 (3.8%) due to elevated liver function test results. If hepatotoxicity is suspected during treatment with acitretin, the drug should be discontinued and the etiology further investigated.Ten of 652 subjects treated in U.S. clinical trials of etretinate, of which acitretin is the active metabolite, had clinical or histologic hepatitis considered to be possibly or probably related to etretinate treatment. There have been reports of hepatitis-related deaths worldwide; a few of these subjects had received etretinate for a month or less before presenting with hepatic symptoms or signs.
In adults receiving long-term treatment with acitretin, appropriate examinations should be periodically performed in view of possible ossification abnormalities (see ADVERSE REACTIONS). Because the frequency and severity of iatrogenic bony abnormality in adults is low, periodic radiography is only warranted in the presence of symptoms or long-term use of acitretin. If such disorders arise, the continuation of therapy should be discussed with the patient on the basis of a careful risk/benefit analysis. In clinical trials with acitretin, subjects were prospectively evaluated for evidence of development or change in bony abnormalities of the vertebral column, knees, and ankles.Of 380 subjects treated with acitretin, 15% had preexisting abnormalities of the spine which showed new changes or progression of preexisting findings. Changes included degenerative spurs, anterior bridging of spinal vertebrae, diffuse idiopathic skeletal hyperostosis, ligament calcification, and narrowing and destruction of a cervical disc space. De novo changes (formation of small spurs) were seen in 3 subjects after 1½ to 2½ years.Six of 128 subjects treated with acitretin showed abnormalities in the knees and ankles before treatment that progressed during treatment. In 5, these changes involved the formation of additional spurs or enlargement of existing spurs. The sixth subject had degenerative joint disease which worsened. No subjects developed spurs de novo. Clinical complaints did not predict radiographic changes.
Lipids And Possible Cardiovascular Effects
Blood lipid determinations should be performed before acitretin is administered and again at intervals of 1 to 2 weeks until the lipid response to the drug is established, usually within 4 to 8 weeks. In subjects receiving acitretin during clinical trials, 66% and 33% experienced elevation in triglycerides and cholesterol, respectively. Decreased high density lipoproteins (HDL) occurred in 40% of subjects. These effects of acitretin were generally reversible upon cessation of therapy.Subjects with an increased tendency to develop hypertriglyceridemia included those with disturbances of lipid metabolism, diabetes mellitus, obesity, increased alcohol intake, or a familial history of these conditions. Because of the risk of hypertriglyceridemia, serum lipids must be more closely monitored in high-risk patients and during long-term treatment.Hypertriglyceridemia and lowered HDL may increase a patient’s cardiovascular risk status. Although no causal relationship has been established, there have been postmarketing reports of acute myocardial infarction or thromboembolic events in patients on therapy with acitretin. In addition, elevation of serum triglycerides to greater than 800 mg per dL has been associated with fatal fulminant pancreatitis. Therefore, dietary modifications, reduction in dose of acitretin, 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.
The eyes and vision of 329 subjects treated with acitretin were examined by ophthalmologists. The findings included dry eyes (23%), irritation of eyes (9%), and brow and lash loss (5%). The following were reported in less than 5% of subjects: Bell’s palsy, blepharitis and/or crusting of lids, blurred vision, conjunctivitis, corneal epithelial abnormality, cortical cataract, decreased night vision, diplopia, itchy eyes or eyelids, nuclear cataract, pannus, papilledema, photophobia, posterior subcapsular cataract, recurrent sties, and subepithelial corneal lesions.Any patient treated with acitretin who is experiencing visual difficulties should discontinue the drug and undergo ophthalmologic evaluation.
Lipid elevations occur in 25% to 50% of subjects treated with acitretin. Triglyceride increases sufficient to be associated with pancreatitis are much less common, although fatal fulminant pancreatitis has been reported. There have been rare reports of pancreatitis during therapy with acitretin in the absence of hypertriglyceridemia.
Acitretin and other retinoids administered orally have been associated with cases of pseudotumor cerebri (benign intracranial hypertension). Some of these events involved concomitant use of isotretinoin and tetracyclines. However, the event seen in a single patient receiving acitretin was not associated with tetracycline use. Early signs and symptoms include papilledema, headache, nausea and vomiting, and visual disturbances. Patients with these signs and symptoms should be examined for papilledema and, if present, should discontinue acitretin immediately and be referred for neurological evaluation and care. Since both acitretin and tetracyclines can cause increased intracranial pressure, their combined use is contraindicated (see CONTRAINDICATIONS).
Capillary Leak Syndrome
Capillary leak syndrome, a potential manifestation of retinoic acid syndrome, has been reported in patients receiving acitretin. Features of this syndrome may include localized or generalized edema with secondary weight gain, fever, and hypotension. Rhabdomyolysis and myalgias have been reported in association with capillary leak syndrome, and laboratory tests may reveal neutrophilia, hypoalbuminemia, and an elevated hematocrit. Discontinue acitretin if capillary leak syndrome develops during therapy.
Exfoliative dermatitis/erythroderma has been reported in patients receiving acitretin. Discontinue acitretin if exfoliative dermatitis/erythroderma occurs during therapy.
- A description of the T.A.P.P. materials is provided below. The main goals of the materials are to explain the program requirements, to reinforce the educational messages, and to assess program effectiveness.The T.A.P.P. booklet includes:The T.A.P.P. Patient Brochure: information on the program requirements, risks of acitretin, and the types of contraceptive methodsThe Contraception Counseling Referral Form for female patients who want to receive free contraception counseling reimbursed by the manufacturerThe Patient Agreement/Informed Consent for Female Patients formMedication GuideThe T.A.P.P. program also includes a voluntary patient survey for women of childbearing potential to assess the effectiveness of the Acitretin Pregnancy Prevention Program T.A.P.P. T.A.P.P. Program materials are available at http://www.tevagenerics.com/acitretin or may be requested by calling 1-855-850-2138.Information for Patients(See Medication Guide for all patients and Patient Agreement/Informed Consent for Female Patients at end of professional labeling.)Patients should be instructed to read the Medication Guide supplied as required by law when acitretin capsules are dispensed.
Females Of Reproductive Potential
Acitretin can cause severe birth defects. Female patients must not be pregnant when therapy with acitretin is initiated, they must not become pregnant while taking acitretin and for at least 3 years after stopping acitretin, so that the drug can be eliminated to below a blood concentration that would be associated with an increased incidence of birth defects. Because this threshold has not been established for acitretin in humans and because elimination rates vary among patients, the duration of posttherapy contraception to achieve adequate elimination cannot be calculated precisely (see boxed CONTRAINDICATIONS AND WARNINGS).Females of reproductive potential should also be advised that they must not ingest beverages or products containing ethanol while taking acitretin and for 2 months after acitretin has been discontinued. This allows for elimination of the acitretin which can be converted to etretinate in the presence of alcohol.Female patients should be advised that any method of birth control can fail, including tubal ligation, and that microdosed progestin “minipill” preparations are not recommended for use with acitretin (see CLINICAL PHARMACOLOGY, Pharmacokinetic Drug Interactions). Data from one patient who received a very low-dosed progestin contraceptive (levonorgestrel 0.03 mg) had a significant increase of the progesterone level after 3 menstrual cycles during acitretin treatment.2Female patients should be advised to contact their physician, women’s health centers, pharmacies, or hospital emergency rooms for information about how to obtain Emergency Contraception if sexual intercourse occurs without using 2 effective forms of contraception simultaneously. A 24-hour, toll-free number (1-855-850-2138) is also available for patients to receive automated birth control and emergency contraception information.Female patients should sign a consent form prior to beginning therapy with acitretin (see boxed CONTRAINDICATIONS AND WARNINGS).
Studies on lactating rats have shown that etretinate is excreted in the milk. There is one prospective case report where acitretin is reported to be excreted in human milk. Therefore, nursing mothers should not receive acitretin prior to or during nursing because of the potential for serious adverse reactions in nursing infants.
Depression and/or other psychiatric symptoms such as aggressive feelings or thoughts of self-harm have been reported. These events, including self-injurious behavior, have been reported in patients taking other systemically administered retinoids, as well as in patients taking acitretin. Since other factors may have contributed to these events, it is not known if they are related to acitretin. Patients should be counseled to stop taking acitretin and notify their prescriber immediately if they experience psychiatric symptoms.Patients should be advised that a transient worsening of psoriasis is sometimes seen during the initial treatment period. Patients should be advised that they may have to wait 2 to 3 months before they get the full benefit of acitretin, although some patients may achieve significant improvements within the first 8 weeks of treatment as demonstrated in clinical trials.Decreased night vision has been reported during therapy with acitretin. Patients should be advised of this potential problem and warned to be cautious when driving or operating any vehicle at night. Visual problems should be carefully monitored (see WARNINGS and ADVERSE REACTIONS). Patients should be advised that they may experience decreased tolerance to contact lenses during the treatment period and sometimes after treatment has stopped.Patients should not donate blood during and for at least 3 years following therapy because acitretin can cause birth defects and women of childbearing potential must not receive blood from patients being treated with acitretin.Because of the relationship of acitretin to vitamin A, patients should be advised against taking vitamin A supplements in excess of minimum recommended daily allowances to avoid possible additive toxic effects.Patients should avoid the use of sun lamps and excessive exposure to sunlight (non-medical UV exposure) because the effects of UV light are enhanced by retinoids.Patients should be advised that they must not give their acitretin capsules to any other person.
Acitretin has not been studied in and is not indicated for treatment of acne.
Significantly lower doses of phototherapy are required when acitretin is used because effects on the stratum corneum induced by acitretin can increase the risk of erythema (burning) (see DOSAGE AND ADMINISTRATION).
EthanolClinical evidence has shown that etretinate can be formed with concurrent ingestion of acitretin and ethanol (see boxed CONTRAINDICATIONS AND WARNINGS and CLINICAL PHARMACOLOGY, Pharmacokinetics).GlyburideIn a trial of 7 healthy male volunteers, acitretin treatment potentiated the blood glucose-lowering effect of glyburide (a sulfonylurea similar to chlorpropamide) in 3 of the 7 subjects. Repeating the trial with 6 healthy male volunteers in the absence of glyburide did not detect an effect of acitretin on glucose tolerance. Careful supervision of diabetic patients under treatment with acitretin is recommended (see CLINICAL PHARMACOLOGY, Pharmacokinetics and DOSAGE AND ADMINISTRATION).Hormonal ContraceptivesIt has not been established if there is a pharmacokinetic interaction between acitretin and combined oral contraceptives. However, it has been established that acitretin interferes with the contraceptive effect of microdosed progestin “minipill” preparations. Microdosed “minipill” progestin preparations are not recommended for use with acitretin (see CLINICAL PHARMACOLOGY, Pharmacokinetic Drug Interactions). It is not known whether other progestin-only contraceptives, such as implants and injectables, are adequate methods of contraception during acitretin therapy.MethotrexateAn increased risk of hepatitis has been reported to result from combined use of methotrexate and etretinate. Consequently, the combination of methotrexate with acitretin is also contraindicated (see CONTRAINDICATIONS).PhenytoinIf acitretin is given concurrently with phenytoin, the protein binding of phenytoin may be reduced.TetracyclinesSince both acitretin and tetracyclines can cause increased intracranial pressure, their combined use is contraindicated (see CONTRAINDICATIONS and WARNINGS, Pseudotumor Cerebri).Vitamin A and Oral RetinoidsConcomitant administration of vitamin A and/or other oral retinoids with acitretin must be avoided because of the risk of hypervitaminosis A.OtherThere appears to be no pharmacokinetic interaction between acitretin and cimetidine, digoxin, or glyburide. Investigations into the effect of acitretin on the protein binding of anticoagulants of the coumarin type (warfarin) revealed no interaction.
If significant abnormal laboratory results are obtained, either dosage reduction with careful monitoring or treatment discontinuation is recommended, depending on clinical judgment.Blood SugarSome patients receiving retinoids have experienced problems with blood sugar control. In addition, new cases of diabetes have been diagnosed during retinoid therapy, including diabetic ketoacidosis. In diabetics, blood-sugar levels should be monitored very carefully.LipidsIn clinical trials, the incidence of hypertriglyceridemia was 66%, hypercholesterolemia was 33%, and that of decreased HDL was 40%. Pretreatment and follow-up measurements should be obtained under fasting conditions. It is recommended that these tests be performed weekly or every other week until the lipid response to acitretin has stabilized (see WARNINGS).Liver Function TestsElevations of AST (SGOT), ALT (SGPT), or LDH were experienced by approximately 1 in 3 patients treated with acitretin. It is recommended that these tests be performed prior to initiation of therapy with acitretin, at 1- to 2-week intervals until stable, and thereafter at intervals as clinically indicated (see CONTRAINDICATIONS and boxed WARNINGS).
Carcinogenesis, Mutagenesis, Impairment Of Fertility
CarcinogenesisA carcinogenesis study of acitretin in Wistar rats, at doses up to 2 mg per kg per day administered 7 days per week for 104 weeks, has been completed. There were no neoplastic lesions observed that were considered to have been related to treatment with acitretin. An 80-week carcinogenesis study in mice has been completed with etretinate, the ethyl ester of acitretin. Blood level data obtained during this study demonstrated that etretinate was metabolized to acitretin and that blood levels of acitretin exceeded those of etretinate at all times studied. In the etretinate study, an increased incidence of blood vessel tumors (hemangiomas and hemangiosarcomas at several different sites) was noted in male, but not female, mice at doses approximately one-half the maximum recommended human therapeutic dose based on a mg-per-m2 comparison.MutagenesisAcitretin was evaluated for mutagenic potential in the Ames test, in the Chinese hamster (V79/HGPRT) assay, in unscheduled DNA synthesis assays using rat hepatocytes and human fibroblasts, and in an in vivo mouse micronucleus assay. No evidence of mutagenicity of acitretin was demonstrated in any of these assays.Impairment of FertilityIn a fertility study in rats, the fertility of treated animals was not impaired at the highest dosage of acitretin tested, 3 mg per kg per day (approximately one-half the maximum recommended therapeutic dose based on a mg-per-m2 comparison). Chronic toxicity studies in dogs revealed testicular changes (reversible mild to moderate spermatogenic arrest and appearance of multinucleated giant cells) in the highest dosage group (50 then 30 mg per kg per day).No decreases in sperm count or concentration and no changes in sperm motility or morphology were noted in 31 men (17 psoriatic subjects, 8 subjects with disorders of keratinization, and 6 healthy volunteers) given 30 to 50 mg per day of acitretin for at least 12 weeks. In these trials, no deleterious effects were seen on either testosterone production, LH, or FSH in any of the 31 men.4-6 No deleterious effects were seen on the hypothalamic-pituitary axis in any of the 18 men where it was measured.4,5
Teratogenic EffectsPregnancy Category X(See boxed CONTRAINDICATIONS AND WARNINGS).In a study in which acitretin was administered to male rats only at a dosage of 5 mg per kg per day for 10 weeks (approximate duration of one spermatogenic cycle) prior to and during mating with untreated female rats, no teratogenic effects were observed in the progeny (see boxed CONTRAINDICATIONS AND WARNINGS for information about male use of acitretin).Nonteratogenic EffectsIn rats dosed at 3 mg per kg per day (approximately one-half the maximum recommended therapeutic dose based on a mg-per-m2 comparison), slightly decreased pup survival and delayed incisor eruption were noted. At the next lowest dose tested, 1 mg per kg per day, no treatment-related adverse effects were observed.
Safety and effectiveness in pediatric patients have not been established. No clinical trials have been conducted in pediatric subjects. Ossification of interosseous ligaments and tendons of the extremities, skeletal hyperostoses, decreases in bone mineral density, and premature epiphyseal closure have been reported in children taking other systemic retinoids, including etretinate, a metabolite of acitretin. A causal relationship between these effects and acitretin has not been established. While it is not known that these occurrences are more severe or more frequent in children, there is special concern in pediatric patients because of the implications for growth potential (see WARNINGS, Hyperostosis).
Clinical trials of acitretin did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently than younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger subjects. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy. A 2-fold increase in acitretin plasma concentrations was seen in healthy elderly subjects compared with young subjects, although the elimination half-life did not change (see CLINICAL PHARMACOLOGY, Special Populations).
Hypervitaminosis A produces a wide spectrum of signs and symptoms primarily of the mucocutaneous, musculoskeletal, hepatic, neuropsychiatric, and central nervous systems. Many of the clinical adverse reactions reported to date with administration of acitretin resemble those of the hypervitaminosis A syndrome.
Adverse Events/Postmarketing Reports
In addition to the events listed in the tables for the clinical trials, the following adverse events have been identified during postapproval use of acitretin. Because these events are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.CardiovascularAcute myocardial infarction, thromboembolism (see WARNINGS), stroke.Immune System DisordersHypersensitivity, including angioedema and urticaria (see CONTRAINDICATIONS).Nervous SystemMyopathy with peripheral neuropathy has been reported during therapy with acitretin. Both conditions improved with discontinuation of the drug.PsychiatricAggressive feelings and/or suicidal thoughts have been reported. These events, including self-injurious behavior, have been reported in patients taking other systemically administered retinoids, as well as in patients taking acitretin. Since other factors may have contributed to these events, it is not known if they are related to acitretin (see PRECAUTIONS).ReproductiveVulvo-vaginitis due to Candida albicans.Skin and AppendagesThinning of the skin, skin fragility, and scaling may occur all over the body, particularly on the palms and soles; nail fragility is frequently observed. Madarosis and exfoliative dermatitis/erythroderma have been reported (see WARNINGS).Vascular DisordersCapillary leak syndrome (see WARNINGS).
During clinical trials with acitretin, 513 of 525 (98%) subjects reported a total of 3,545 adverse events. One-hundred sixteen subjects (22%) left trials prematurely, primarily because of adverse experiences involving the mucous membranes and skin. Three subjects died. Two of the deaths were not drug-related (pancreatic adenocarcinoma and lung cancer); the other subject died of an acute myocardial infarction, considered remotely related to drug therapy. In clinical trials, acitretin was associated with elevations in liver function test results or triglyceride levels and hepatitis.The tables below list by body system and frequency the adverse events reported during clinical trials of 525 subjects with psoriasis.Table 3. Adverse Events Frequently Reported during Clinical Trials Percent of Subjects Reporting (N = 525)Body System> 75%50% to 75%25% to 50%10% to 25%CNS Rigors Eye Disorders Xerophthalmia Mucous Membranes Cheilitis Rhinitis Dry mouth Epistaxis Musculoskeletal ArthralgiaSpinal hyperostosis (progression of existing lesions) Skin and Appendages AlopeciaSkin peeling Dry skinNail disorderPruritus Erythematous rashHyperesthesiaParesthesiaParonychiaSkin atrophySticky skin Table 4. Adverse Events Less Frequently Reported during Clinical Trials (Some of Which May Bear No Relationship to Therapy) Percent of Subjects Reporting (N = 525)Body System 1% to 10%< 1%Body as a Whole AnorexiaEdemaFatigueHot flashesIncreased appetite Alcohol intoleranceDizzinessFeverInfluenza-like symptoms MalaiseMoniliasisMuscle weaknessWeight increase Cardiovascular Flushing Chest painCyanosisIncreased bleeding timeIntermittent claudicationPeripheral ischemiaCNS (also see Psychiatric) HeadachePain Abnormal gait MigraineNeuritis Pseudotumor cerebri (intracranial hypertension)Eye Disorders Abnormal/ blurred visionBlepharitisConjunctivitis/ irritationCorneal epithelial abnormalityDecreased night vision/night blindnessEye abnormalityEye painPhotophobia Abnormal lacrimationChalazionConjunctival hemorrhageCorneal ulcerationDiplopiaEctropionItchy eyes and lidsPapilledemaRecurrent stiesSubepithelial corneal lesionsGastrointestinal Abdominal painDiarrheaNauseaTongue disorder ConstipationDyspepsiaEsophagitisGastritisGastroenteritis GlossitisHemorrhoidsMelenaTenesmusTongue ulceration Liver and Biliary Hepatic function abnormalHepatitisJaundiceMucous Membranes Gingival bleedingGingivitisIncreased saliva StomatitisThirstUlcerative stomatitisAltered salivaAnal disorderGum hyperplasia HemorrhagePharyngitis Musculoskeletal ArthritisArthrosisBack painHypertoniaMyalgia OsteodyniaPeripheral joint hyperostosis (progression of existing lesions) Bone disorderOlecranon bursitisSpinal hyperostosis (new lesions)Tendonitis Psychiatric DepressionInsomniaSomnolenceAnxietyDysphoniaLibido decreasedNervousness Reproductive Atrophic vaginitisLeukorrhea Respiratory SinusitisCoughingIncreased sputumLaryngitis Skin and Appendages Abnormal skin odorAbnormal hair textureBullous eruptionCold/clammy skinDermatitisIncreased sweatingInfectionPsoriasiform rashPurpuraPyogenic granulomaRashSeborrheaSkin fissuresSkin ulcerationSunburnAcneBreast painCystEczemaFungal infectionFurunculosisHair discolorationHerpes simplexHyperkeratosisHypertrichosisHypoesthesiaImpaired healingOtitis mediaOtitis externaPhotosensitivity reactionPsoriasis aggravatedSclerodermaSkin noduleSkin hypertrophySkin disorderSkin irritationSweat gland disorderUrticariaVerrucaeSpecial Senses/ Other EaracheTaste perversionTinnitus CeruminosisDeafnessTaste lossUrinary Abnormal urineDysuriaPenis disorder
Therapy with acitretin induces changes in liver function tests in a significant number of patients. Elevations of AST (SGOT), ALT (SGPT) or LDH were experienced by approximately 1 in 3 subjects treated with acitretin. In most subjects, elevations were slight to moderate and returned to normal either during continuation of therapy or after cessation of treatment. In subjects receiving acitretin during clinical trials, 66% and 33% experienced elevation in triglycerides and cholesterol, respectively. Decreased high density lipoproteins (HDL) occurred in 40% (see WARNINGS). Transient, usually reversible elevations of alkaline phosphatase have been observed.Table 5 lists the laboratory abnormalities reported during clinical trials.Table 5. Abnormal Laboratory Test Results Reported during Clinical Trials Percent of Subjects ReportingBody System 50% to 75%25% to 50%10% to 25%1% to 10%Electrolytes Increased:–Phosphorus–Potassium –SodiumIncreased and decreased: –Magnesium Decreased:–Phosphorus–Potassium –SodiumIncreased and decreased: –Calcium –Chloride Hematologic Increased:–Reticulocytes Decreased:–Hematocrit–Hemoglobin–WBCIncreased: –Haptoglobin–Neutrophils–WBC Increased:–Bands–Basophils–Eosinophils–Hematocrit–Hemoglobin–Lymphocytes–MonocytesDecreased:–Haptoglobin –Lymphocytes –Neutrophils –ReticulocytesIncreased or decreased: –Platelets –RBC Hepatic Increased:–Cholesterol –LDH–SGOT–SGPTDecreased: –HDL cholesterol Increased:–Alkaline phosphatase–Direct bilirubin–GGTP Increased:–Globulin –Total bilirubin–Total proteinIncreased and decreased:–Serum albumin Miscellaneous Increased: –Triglycerides Increased: –CPK–Fasting blood sugar Decreased: –Fasting blood sugar–High occult blood Increased and decreased:–Iron Renal Increased: –Uric acid Increased: –BUN –Creatinine Urinary WBC in urine Acetonuria Hematuria RBC in urine Glycosuria Proteinuria
In the event of acute overdosage, acitretin must be withdrawn at once. Symptoms of overdose are identical to acute hypervitaminosis A (e.g., headache and vertigo). The acute oral toxicity (LD50) of acitretin in both mice and rats was greater than 4,000 mg per kg.In one reported case of overdose, a 32-year-old male with Darier’s disease took 21 x 25-mg capsules (525-mg single dose). He vomited several hours later but experienced no other ill effects.All female patients of childbearing potential who have taken an overdose of acitretin must:1) Have a pregnancy test at the time of overdose; 2) Be counseled as per the boxed CONTRAINDICATIONS AND WARNINGS and PRECAUTIONS sections regarding birth defects and contraceptive use for at least 3 years’ duration after the overdose.
Dosage And Administration
There is intersubject variation in the pharmacokinetics, clinical efficacy, and incidence of side effects with acitretin capsules. A number of the more common side effects are dose-related. Individualization of dosage is required to achieve sufficient therapeutic response while minimizing side effects. Therapy with acitretin capsules should be initiated at 25 to 50 mg per day, given as a single dose with the main meal. Maintenance doses of 25 to 50 mg per day may be given dependent upon an individual patient’s response to initial treatment. Relapses may be treated as outlined for initial therapy.When acitretin capsules are used with phototherapy, the prescriber should decrease the phototherapy dose, dependent on the patient’s individual response (see PRECAUTIONS).Females who have taken TEGISON (etretinate) must continue to follow the contraceptive recommendations for TEGISON. TEGISON is no longer marketed in the U.S.; for information, call 1-888-838-2872.Information for PharmacistsAcitretin capsules must only be dispensed in no more than a monthly supply. An acitretin capsules Medication Guide must be given to the patient each time acitretin capsules are dispensed, as required by law.
Acitretin Capsules USP are available as follows:10 mg: Two-piece hard gelatin capsule with light green opaque cap and white opaque body filled with yellow powder, imprinted in black ink with TEVA on the cap and 1135 on the body, available in bottles of 30 capsules (NDC 0093-1135-56).17.5 mg: Two-piece hard gelatin capsule with yellow opaque cap and yellow opaque body filled with yellow powder, imprinted in black ink with TEVA on the cap and 1138 on the body, available in bottles of 30 capsules (NDC 0093-1138-56).25 mg: Two-piece hard gelatin capsule with light green opaque cap and yellow opaque body filled with yellow powder, imprinted in black ink with TEVA on the cap and 1136 on the body, available in bottles of 30 capsules (NDC 0093-1136-56).Store at 20° to 25°C (68° to 77°F) [See USP Controlled Room Temperature].Dispense in a tight, light-resistant container as defined in the USP with a child-resistant closure (as required).PROTECT FROM LIGHT. AVOID EXPOSURE TO HIGH TEMPERATURES AND HUMIDITY AFTER THE BOTTLE IS OPENED.KEEP THIS AND ALL MEDICATIONS OUT OF THE REACH OF CHILDREN.
1. Berbis Ph, et al.: Arch Dermatol Res (1988) 280:388-389. 2. Maier H, Honigsmann H: Concentration of etretinate in plasma and subcutaneous fat after long-term acitretin. Lancet 348:1107, 1996. 3. Geiger JM, Walker M: Is there a reproductive safety risk in male patients treated with acitretin (Neotigason/Soriatane)? Dermatology 205:105-107, 2002. 4. Sigg C, et al.: Andrological investigations in patients treated with etretin. Dermatologica 175:48-49, 1987. 5. Parsch EM, et al.: Andrological investigation in men treated with acitretin (Ro 10-1670). Andrologia22:479-482, 1990. 6. Kadar L, et al.: Spermatological investigations in psoriatic patients treated with acitretin. In: Pharmacology of Retinoids in the Skin; Reichert U. et al., ed, KARGER, Basel, vol. 3, pp 253-254, 1988. All brand names listed are the registered trademarks of their respective owners and are not trademarks of Teva Pharmaceuticals USA.Manufactured In India By:Watson Pharma Private LimitedVerna, Salcette Goa 403 722 IndiaManufactured For:Teva Pharmaceuticals USA, Inc.North Wales, PA 19454Rev. C 10/2017
Patient Agreement/Informed Consent For Female Patients
- To be completed by the patient* and signed by her prescriber*Must also be initialed by the parent or guardian of a minor patient (under age 18)Read each item below and initial in the space provided to show that you understand each item. Do not sign this consent and do not take acitretin capsules if there is anything that you do not understand._____________________________________________________________(Patient’s name)I understand that there is a very high risk that my unborn baby could have severe birth defects if I am pregnant or become pregnant while taking acitretin capsules in any amount even for short periods of time. Birth defects have also happened in babies of women who became pregnant after stopping treatment with acitretin capsules.INITIAL: ___________I understand that I must not become pregnant while taking acitretin capsules and for at least 3 years after the end of my treatment with acitretin capsules.INITIAL: ___________I know that I must avoid all alcohol, including drinks, food, medicines, and over-the-counter products that contain alcohol. I understand that the risk of birth defects may last longer than 3 years if I swallow any form of alcohol during therapy with acitretin capsules, and for 2 months after I stop taking acitretin capsules.INITIAL: ___________I understand that I must not have sexual intercourse, or I must use 2 separate, effective forms of birth control at the same time. The only exceptions are if I have had surgery to remove the womb (a hysterectomy) or my prescriber has told me I have gone completely through menopause.INITIAL: ___________I understand that I have to use 2 effective forms of birth control (contraception) at the same time for at least 1 month before starting acitretin capsules, for the entire time of therapy with acitretin capsules, and for at least 3 years after stopping acitretin capsules.INITIAL: ___________I understand that any form of birth control can fail. Therefore, I must use 2 different methods at the same time, every time I have sexual intercourse.INITIAL: ___________I understand that the following are considered effective forms of birth control: Primary: Tubal ligation (having my tubes tied), partner’s vasectomy, birth control pills, (not progestin-only “minipills”), injectable/implantable/insertable/topical (patch) hormonal birth control products, and IUDs (intrauterine devices). Secondary: Condoms (with or without spermicide, which is a special cream or jelly that kills sperm), diaphragms and cervical caps (which must be used with a spermicide), and vaginal sponges (contains spermicide). I understand that at least 1 of my 2 methods of birth control must be a primary method.INITIAL: ___________I will talk with my prescriber about any medicines or dietary supplements I plan to take while taking acitretin capsules because certain birth control methods may not work if I am taking certain medicines or herbal products (for example, St. John’s wort).INITIAL: ___________Unless I have had a hysterectomy or my prescriber says I have gone completely through menopause, I understand that I must have 2 negative pregnancy test results before I can get a prescription to start acitretin capsules. I understand that if the second pregnancy test is negative, I must start taking my acitretin capsules within 7 days of the specimen collection. I will then have pregnancy tests on a monthly basis during therapy with acitretin capsules as instructed by my prescriber. In addition, for at least 3 years after I stop taking acitretin capsules, I will have a pregnancy test every 3 months.INITIAL: ___________I understand that I should not start taking acitretin capsules until I am sure that I am not pregnant and have negative results from 2 pregnancy tests.INITIAL: ___________I have received information on emergency contraception (birth control), including information on its availability over-the-counter.INITIAL: ___________I understand that my prescriber can give me a referral for a free contraception (birth control) counseling session and pregnancy testing.INITIAL: ___________I understand that on a monthly basis during therapy with acitretin capsules and every 3 months for at least 3 years after stopping acitretin capsules that I should receive counseling from my prescriber about contraception (birth control) and behaviors associated with an increased risk of pregnancy.INITIAL: ___________I understand that I must stop taking acitretin capsules right away and call my prescriber if I get pregnant, miss my menstrual period, stop using birth control, or have sexual intercourse without using my 2 birth control methods during and at least 3 years after stopping acitretin capsules.INITIAL: ___________If I do become pregnant while on acitretin capsules or at any time within 3 years of stopping acitretin capsules, I understand that I should report my pregnancy to Teva Pharmaceuticals USA, Inc. at 1-888-838-2872 or to the Food and Drug Administration (FDA) MedWatch program at 1-800-FDA-1088. The information I share will be kept confidential (private) unless disclosure is legally required. This will help the company and the FDA evaluate the pregnancy prevention program to prevent birth defects.INITIAL: ___________I have received a copy of the T.A.P.P. brochure. My prescriber has answered all my questions about acitretin capsules. I understand that it is my responsibility to follow my doctor’s instructions, and not to get pregnant during treatment with acitretin capsules or for at least 3 years after I stop taking acitretin capsules.I now authorize my prescriber, ___________________________________________________, to begin my treatment with acitretin capsules.Patient signature: ________________________________________Date: ___________________Parent/guardian signature (if under age 18): ____________________Date: ___________________Please print: Patient name and address: ______________________________________________________________________________________________________________________________Telephone: ______________________________________________________I have fully explained to the patient, _______________________________________________, the nature and purpose of the treatment described above and the risks to females of childbearing potential. I have asked the patient if she has any questions regarding her treatment with acitretin capsules and have answered those questions to the best of my ability.Prescriber signature: _______________________________________Date: __________________Manufactured In India By:Watson Pharma Private LimitedVerna, Salcette Goa 403 722 IndiaManufactured For:Teva Pharmaceuticals USA, Inc.North Wales, PA 19454Rev. B 10/2017
Package/Label Display Panel
NDC 0093-1135-56Acitretin Capsules USP 10 mgPHARMACIST: Dispense the accompanying Medication Guide to each patient.CAUSES BIRTH DEFECTSDO NOT GET PREGNANTRx only30 CAPSULESTEVA
NDC 0093-1138-56Acitretin Capsules USP 17.5 mgPHARMACIST: Dispense the accompanying Medication Guide to each patient.CAUSES BIRTH DEFECTSDO NOT GET PREGNANTRx only30 CAPSULESTEVA
NDC 0093-1136-56Acitretin Capsules USP 25 mgPHARMACIST: Dispense the accompanying Medication Guide to each patient.CAUSES BIRTH DEFECTSDO NOT GET PREGNANTRx only30 CAPSULESTEVA
* Please review the disclaimer below.