Acitretin Capsules

Rx only

Acitretin must not be used by females who are pregnant, or who intend to become pregnant during therapy or at any time for at least 3 years following discontinuation of therapy. Acitretin also must not be used by females who may not use reliable contraception while undergoing treatment and for at least 3 years following discontinuation of treatment. Acitretin is a metabolite of etretinate (TEGISON®), and major human fetal abnormalities have been reported with the administration of acitretin and etretinate. Potentially, any fetus exposed can be affected.

Clinical evidence has shown that concurrent ingestion of acitretin and ethanol has been associated with the formation of etretinate, which has a significantly longer elimination half-life than acitretin. Because the longer elimination half-life of etretinate would increase the duration of teratogenic potential for female patients, ethanol must not be ingested by female patients of childbearing potential either during treatment with acitretin or for 2 months after cessation of therapy. This allows for elimination of acitretin, thus removing the substrate for transesterification to etretinate. The mechanism of the metabolic process for conversion of acitretin to etretinate has not been fully defined. It is not known whether substances other than ethanol are associated with transesterification.

Acitretin has been shown to be embryotoxic and/or teratogenic in rabbits, mice, and rats at oral doses of 0.6, 3, and 15 mg per kg, respectively. These doses are approximately 0.2, 0.3, and  3 times the maximum recommended therapeutic dose, respectively, based on a mg-per-m2 comparison.

Major human fetal abnormalities associated with acitretin and/or etretinate administration have been reported including meningomyelocele; meningoencephalocele; multiple synostoses; facial dysmorphia; syndactyly; absence of terminal phalanges; malformations of hip, ankle, and forearm; low-set ears; high palate; decreased cranial volume; cardiovascular malformation; and alterations of the skull and cervical vertebrae. Acitretin should be prescribed only by those 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.

Because of the teratogenicity of acitretin, a program called the Education and Pregnancy Prevention for Acitretin (EPPATM) Program, has been developed to educate women of childbearing potential and their healthcare providers about the serious risks associated with acitretin and to help prevent pregnancies from occurring with the use of this drug and for 3 years after its discontinuation. The EPPATM program requirements are described below and program materials are available at www.acitretinEPPA.com or may be requested by calling 1-877-994-6729 (see also PRECAUTIONS section).

Important Information for Women of Childbearing Potential:

Acitretin should be considered only for women with severe psoriasis unresponsive to other therapies or whose clinical condition contraindicates the use of other treatments.

Females of reproductive potential must not be given a prescription for acitretin until pregnancy is excluded. Acitretin is contraindicated in females of reproductive potential unless the patient meets ALL of the following conditions:

• Must have had 2 negative urine or serum pregnancy tests with a sensitivity of at least 25 mIU per mL before receiving the initial prescription for acitretin. The first test (a screening test) is obtained by the prescriber when the decision is made to pursue therapy with acitretin. The second pregnancy test (a confirmation test) should be done during the first 5 days of the menstrual period immediately preceding the beginning of therapy with acitretin. 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 [birth control] simultaneously).  If the second pregnancy test is negative, initiation of treatment with acitretin should begin within 7 days of the specimen collection.  Acitretin should be limited to a monthly supply.

• Must have a pregnancy test with a sensitivity of at least 25 mIU per mL   repeated every month during treatment with acitretin. The patient must have a negative result from a urine or serum pregnancy test before receiving a prescription for acitretin. To encourage compliance with this recommendation, a monthly supply of the drug should be prescribed. For at least 3 years after discontinuing therapy with acitretin, a pregnancy test must be repeated every 3 months.

• Must have selected and have committed to use 2 effective forms of contraception (birth control) simultaneously, at least 1 of which must be a primary form, unless absolute abstinence is the chosen method, or the patient has undergone a hysterectomy or is clearly postmenopausal.

• Patients must use 2 effective forms of contraception (birth control) simultaneously for at least 1 month prior to initiation of therapy with acitretin, during therapy with acitretin, and for at least 3 years after discontinuing therapy with acitretin. A Contraception Counseling Referral Form is available so that patients can receive an initial free contraception counseling session and pregnancy testing. Counseling about contraception and behaviors associated with an increased risk of pregnancy must be repeated on a monthly basis by the prescriber during therapy with acitretin and every 3 months for at least 3 years following discontinuation of acitretin.

Effective forms of contraception include both primary and secondary forms of contraception. Primary forms of contraception include: tubal ligation, partner’s vasectomy, intrauterine devices, birth control pills, and injectable/implantable/insertable/topical hormonal birth control products. Secondary forms of contraception include condoms (with or without spermicide), diaphragms and cervical caps (which must be used with a spermicide), and vaginal sponges (contains spermicide).

Any birth control method can fail. Therefore, it is critically important that women of childbearing potential use 2 effective forms of contraception (birth control) simultaneously. It 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.

Prescribers are advised to consult the package insert of any medication administered concomitantly with hormonal contraceptives, since some medications may decrease the effectiveness of these birth control products. Patients should be prospectively cautioned not to self-medicate with the herbal supplement St. John’s wort because a possible interaction has been suggested with hormonal contraceptives based on reports of breakthrough bleeding on oral contraceptives shortly after starting St. John’s wort. Pregnancies have been reported by users of combined hormonal contraceptives who also used some form of St. John’s wort (see PRECAUTIONS).

• Must have signed a Patient Agreement/Informed Consent for Female Patients that contains warnings about the risk of potential birth defects if the fetus is exposed to acitretin, about contraceptive failure, about the fact that they must not ingest beverages or products containing ethanol while taking acitretin and for 2 months after treatment with acitretin has been discontinued, and about preventing pregnancy while taking acitretin and for at least 3 years after discontinuing acitretin.

If pregnancy does occur during therapy with acitretin or at any time for at least 3 years following discontinuation of acitretin, the prescriber and patient should discuss the possible effects on the pregnancy. The available information is as follows:

Acitretin, the active metabolite of etretinate, is teratogenic and is contraindicated during pregnancy. The risk of severe fetal malformations is well established when systemic retinoids are taken during pregnancy. Pregnancy must also be prevented after stopping acitretin therapy, while the drug is being eliminated to below a threshold 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 post therapy contraception to achieve adequate elimination cannot be calculated precisely. It is strongly recommended that contraception be continued for at least 3 years after stopping treatment with acitretin, based on the following considerations:

• In the absence of transesterification to form etretinate, greater than 98% of the acitretin would be eliminated within 2 months, assuming a mean elimination half-life of 49 hours.

• In cases where etretinate is formed, as has been demonstrated with concomitant administration of acitretin and ethanol,

     ๐ greater than 98% of the etretinate formed would be eliminated in 2 years, assuming a  

        mean elimination half-life of 120 days.

     ๐ greater than 98% of the etretinate formed would be eliminated in 3 years, based on

          the longest demonstrated elimination half-life of 168 days.

However, etretinate was found in plasma and subcutaneous fat in one patient reported to have had sporadic alcohol intake, 52 months after she stopped acitretin therapy.2

•  Severe birth defects have been reported where conception occurred during the time interval when the patient was being treated with acitretin and/or etretinate. In addition, severe birth defects have also been reported when conception occurred after the mother completed therapy. These cases have been reported both prospectively (before the outcome was known) and retrospectively (after the outcome was known). The events below are listed without distinction as to whether the reported birth defects are consistent with retinoid-induced embryopathy or not.

• There have been 318 prospectively reported cases involving pregnancies and the use of etretinate, acitretin, or both. In 238 of these cases, the conception occurred after the last dose of etretinate (103 cases), acitretin (126), or both (9). Fetal outcome remained unknown in approximately one-half of these cases, of which 62 were terminated and 14 were spontaneous abortions. Fetal outcome is known for the other 118 cases and 15 of the outcomes were abnormal (including cases of absent hand/wrist, clubfoot, GI malformation, hypocalcemia, hypotonia, limb malformation, neonatal apnea/anemia, neonatal ichthyosis, placental disorder/death, undescended testicle, and 5 cases of premature birth). In the 126 prospectively reported cases where conception occurred after the last dose of acitretin only, 43 cases involved conception at least 1 year but less than 2 years after the last dose. There were 3 reports of abnormal outcomes out of these 43 cases (involving limb malformation, GI tract malformations, and premature birth). There were only 4 cases where conception occurred at least 2 years after the last dose but there were no reports of birth defects in these cases.

• There is also a total of 35 retrospectively reported cases where conception occurred at least 1 year after the last dose of etretinate, acitretin, or both. From these cases there are 3 reports of birth defects when the conception occurred at least 1 year but less than 2 years after the last dose of acitretin (including heart malformations, Turner’s Syndrome, and unspecified congenital malformations) and 4 reports of birth defects when conception occurred 2 or more years after the last dose of acitretin (including foot malformation, cardiac malformations [2 cases], and unspecified neonatal and infancy disorder). There were 3 additional abnormal outcomes in cases where conception occurred 2 or more years after the last dose of etretinate (including chromosome disorder, forearm aplasia, and stillbirth).

• Females who have taken TEGISON (etretinate) must continue to follow the contraceptive recommendations for TEGISON. TEGISON is no longer marketed in the US; for information, call Impax Laboratories, Inc. at 1-877-994-6279.

• Patients should not donate blood during and for at least 3 years following the completion of therapy with acitretin because women of childbearing potential must not receive blood from patients being treated with acitretin.

Important Information for Males Taking Acitretin:

Patients should not donate blood during and for at least 3 years following therapy with acitretin because women of childbearing potential must not receive blood from patients being treated with acitretin.

•   Samples of seminal fluid from 3 male patients treated with acitretin and 6 male patients treated with etretinate have been assayed for the presence  of acitretin. The maximum concentration of acitretin observed in the seminal fluid of these men was 12.5 ng per mL. Assuming an ejaculate volume of 10 mL, the amount of drug transferred in semen would be 125 ng, which is 1/200,000 of a single 25 mg capsule. Thus, although 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, the no-effect limit for teratogenicity is unknown and there is no registry for birth defects associated with acitretin. The available data are as follows:

There have been 25 cases of reported conception when the male partner was taking acitretin. The pregnancy outcome is known in 13 of these 25 cases. Of these, 9 reports were retrospective and 4 were prospective (meaning the pregnancy was reported prior to knowledge of the outcome)3.

aFour of 5 cases were prospective.

  bWith malformation pattern not typical of retinoid embryopathy (bilateral cystic hygromas of neck, hypoplasia of lungs bilateral, pulmonary atresia, VSD with overriding truncus arteriosus).

For All Patients: AN ACITRETIN MEDICATION GUIDE MUST BE GIVEN TO THE PATIENT EACH TIME ACITRETIN IS DISPENSED, AS REQUIRED BY LAW.

(See also boxed CONTRAINDICATIONS AND WARNINGS.)

Skeletal Abnormalities:

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.

Ophthalmologic Effects:

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.

Pancreatitis:

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.

Pseudotumor Cerebri:

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:  

Exfoliative dermatitis/erythroderma has been reported in patients receiving acitretin .Discontinue acitretin if exfoliative dermatitis/erythroderma occurs during therapy.

There is intersubject variation in the pharmacokinetics, clinical efficacy, and incidence of side effects with acitretin. 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 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 is used with phototherapy, the prescriber should decrease the phototherapy dose, dependent on the patient’s individual response (see PRECAUTIONS: General).

Females who have taken TEGISON (etretinate) must continue to follow the contraceptive recommendations for TEGISON. TEGISON is no longer marketed in the US; for information, call Impax Laboratories, Inc. at 1-877-994-6729.

Information for Pharmacists:

Acitretin must only be dispensed in no more than a monthly supply.  An Acitretin Medication Guide must be given to the patient each time acitretin is dispensed, as required by law.

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 if there is anything that you do not understand.

 ___________________________________________________________________________________________
 (Patient's name)

1. 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 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.

INITIAL: ___________

2. I understand that I must not become pregnant while taking acitretin and for at least 3 years after the end of my treatment with acitretin.

INITIAL: ___________

3. 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, and for 2 months after I stop taking acitretin.

INITIAL: ___________

4. 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: ___________

5. 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, for the entire time of therapy with acitretin, and for at least 3 years after stopping acitretin.

INITIAL: ___________

6. 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: ___________

7. 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: ___________  

8. I will talk with my prescriber about any medicines or dietary supplements I plan to take while taking acitretin because certain birth control methods may not work if I am taking certain medicines or herbal products (for example, St. John’s wort).

INITIAL: ___________

9. 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.  I understand that if the second pregnancy test is negative, I must start taking my acitretin within 7 days of the specimen collection.  I will then have pregnancy tests on a monthly basis during therapy with acitretin as instructed by my prescriber. In addition, for at least 3 years after I stop taking acitretin, I will have a pregnancy test every 3 months.

INITIAL: ___________

10. I understand that I should not start taking acitretin until I am sure that I am not pregnant and have negative results from 2 pregnancy tests.

INITIAL: ___________

11. I have received information on emergency contraception (birth control).

INITIAL: ___________

12. I understand that my prescriber can give me a referral for a free contraception (birth control) counseling session and pregnancy testing.

INITIAL: ___________

13. I understand that on a monthly basis during therapy with acitretin and every 3 months for at least 3 years after stopping acitretin that I should receive counseling from my prescriber about contraception (birth control) and behaviors associated with an increased risk of pregnancy.

INITIAL: ___________

14. I understand that I must stop taking acitretin 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.

INITIAL: ___________

15. If I do become pregnant while on acitretin or at any time within 3 years of stopping acitretin, I understand that I should report my pregnancy to Impax Generics Medical Information Call Center and its affiliates at 1-877-994-6729 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 Education and Pregnancy Prevention for Acitretin (EPPATM) Program Booklet. My prescriber has answered all my questions about acitretin. I understand that it is my responsibility to follow my doctor’s instructions, and not to get pregnant during treatment with acitretin or for at least 3 years after I stop taking acitretin.

I now authorize my prescriber, ______________________________________________, to begin my treatment with acitretin.

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 and have answered those questions to the best of my ability.

Prescriber signature: _______________________________________

Date: __________________

Revised: November 2016

NDC 0115-1667-08

 NDC 0115-1668-08