Soriatane (Acitretin) - Drug Interactions, Contraindications, Overdosage, etc

DRUG INTERACTIONS

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.

Ethanol

Clinical 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 two-way crossover study, 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/kg body weight). A mean peak etretinate concentration of 59 ng/mL (range 22 to 105 ng/mL) was observed, and extrapolation of AUC values indicated that the formation of etretinate in this study 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 patients on acitretin therapy in several foreign studies (10 to 80 mg/day), 16% had measurable etretinate levels (>5 ng/mL).

Etretinate has a much longer elimination half-life compared to that of acitretin. In one study the apparent mean terminal half-life after 6 months of therapy was approximately 120 days (range 84 to 168 days). In another study of 47 patients treated chronically with etretinate, 5 had detectable serum drug levels (in the range of 0.5 to 12 ng/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.

OVERDOSAGE

In the event of acute overdosage, SORIATANE Capsules must be withdrawn at once. Symptoms of overdose are identical to acute hypervitaminosis A, ie, headache and vertigo. The acute oral toxicity (LD₅₀) of acitretin in both mice and rats was greater than 4000 mg/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 SORIATANE Capsules 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.

CONTRAINDICATIONS

Pregnancy Category X

(see boxed CONTRAINDICATIONS AND WARNINGS).

SORIATANE Capsules are 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 SORIATANE Capsules is also contraindicated (see PRECAUTIONS: Drug Interactions ).

Since both SORIATANE Capsules and tetracyclines can cause increased intracranial pressure, their combined use is contraindicated (see WARNINGS: Pseudotumor Cerebri ).

SORIATANE Capsules are contraindicated in cases of hypersensitivity to the preparation (acitretin or excipients) or to other retinoids.

REFERENCES

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). Andrologia 22:479-482, 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.

PATIENT AGREEMENT/INFORMED CONSENT FOR FEMALE PATIENTS

To be completed by the patient* and signed by her prescriber

CAUSES BIRTH DEFECTS/DO NOT GET PREGNANT<logo>

*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 SORIATANE^® (acitretin) Capsules 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 SORIATANE Capsules in any amount even for short periods of time. Birth defects have also happened in babies of women who became pregnant after stopping SORIATANE Capsules treatment.

INITIAL: ___________

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

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 SORIATANE Capsules therapy, and for 2 months after I stop taking SORIATANE Capsules.

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 SORIATANE Capsules, for the entire time of SORIATANE Capsules therapy, and for at least 3 years after SORIATANE Capsules treatment has stopped.

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, injectable/implantable/insertable/topical (patch) hormonal birth control products, and IUDs (intrauterine devices). Secondary: Latex 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). 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 during my SORIATANE Capsules treatment because certain birth control methods may not work if I am taking certain medicines or herbal products (for example, Saint 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 SORIATANE Capsules. I will then have pregnancy tests on a monthly basis during my SORIATANE Capsules therapy as instructed by my prescriber. In addition, for at least 3 years after the end of my treatment with SORIATANE Capsules, I will have a pregnancy test every 3 months.

INITIAL: ___________

10. I understand that I should not start taking SORIATANE Capsules 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 contraceptive (birth control) counseling session and pregnancy testing.

INITIAL: ___________

13. I understand that on a monthly basis during SORIATANE Capsules therapy and every 3 months for at least 3 years after stopping SORIATANE Capsules treatment 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 SORIATANE 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 SORIATANE Capsules treatment.

INITIAL: ___________

15. If I do become pregnant while on SORIATANE Capsules or at any time within 3 years of stopping SORIATANE Capsules, I understand that I should report my pregnancy to Stiefel at 1-888-500-DERM (3376) or to the Food and Drug Administration (FDA) MedWatch program at 1-800-FDA-1088. The information I share will be kept confidential (private) and will help the company and the FDA evaluate the pregnancy prevention program to prevent birth defects.

INITIAL: ___________

I have received a copy of the Do Your P.A.R.T™ brochure. My prescriber has answered all my questions about SORIATANE Capsules. I understand that it is my responsibility to follow my doctor’s instructions, and not to get pregnant during SORIATANE Capsules treatment or for at least 3 years after I stop taking SORIATANE Capsules.

I now authorize my prescriber, ______________________________________________________, to begin my treatment with SORIATANE 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 SORIATANE Capsules and have answered those questions to the best of my ability.

Prescriber signature: _______________________________________

Date: __________________