ACITRETIN (Page 4 of 9)

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.

PRECAUTIONS

A description of the P.P.E.T. Program 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 P.P.E.T. Program booklet includes:

  • The P.P.E.T. Program Patient Brochure: information on the program requirements, risks of acitretin, and the types of contraceptive methods
  • The Contraception Counseling Referral Form for female patients who want to receive free contraception counseling reimbursed by the manufacturer
  • The Patient Agreement/Informed Consent for Female Patients form
  • Medication Guide

The P.P.E.T. Program also includes a voluntary patient survey for women of childbearing potential to assess the effectiveness of the acitretin Pregnancy Prevention Program P.P.E.T. P.P.E.T Program materials are available at www.sigmapharm.com/PPET or may be requested by calling 1-855-273-0150.

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. 2


Female 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 (1-855-273-0150) 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).

Nursing Mothers:

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.

All Patients:

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.

For Prescribers:

Acitretin has not been studied in and is not indicated for treatment of acne.

Phototherapy:

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 ).

Drug Interactions:

Ethanol:

Clinical evidence has shown that etretinate can be formed with concurrent ingestion of acitretin and ethanol (see boxed CONTRAINDICATIONS AND WARNINGS and CLINICAL PHARMACOLOGY: Pharmacokinetics).

Glyburide:

In 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 Contraceptives:

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 “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.

Methotrexate:

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 CONTRAINDICATIONS).

Phenytoin:

If acitretin is given concurrently with phenytoin, the protein binding of phenytoin may be reduced.

Tetracyclines:

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

Vitamin A and Oral Retinoids:

Concomitant administration of vitamin A and/or other oral retinoids with acitretin must be avoided because of the risk of hypervitaminosis A.

Other:

There 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.

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