Acitretin

Low dose progesterone-only products (minipills) may be an inadequate method of contraception during acitretin therapy. Interactions with combined estrogen/progestogen oral contraceptives have not been observed.

In concurrent treatment with phenytoin, it must be remembered that acitretin partially reduces the protein binding of phenytoin. The clinical significance of this is as yet unknown.

Acitretin is contraindicated in pregnant women.

Acitretin is lipophilic and passes into the breast milk. Patients must not breast-feed during treatment with acitretin.

Women of childbearing potential / Contraception in males and females

Acitretin is highly teratogenic. Its use is contraindicated in women who might become pregnant during or within 2 years of the cessation of treatment. The risk of giving birth to a deformed child is exceptionally high if acitretin is taken before or during pregnancy, no matter for how long or at what dosage.

Acitretin is contraindicated in every woman of childbearing potential unless each of the following conditions is met:

1. The patient is suffering from a severe disorder of keratinisation which is resistant to standard therapies.
2. She can be relied on to understand and follow the physician’s instructions.
3. She is capable of taking the stipulated contraceptive measures reliably and without fail.
4. It is absolutely essential that every woman of childbearing potential who is to undergo treatment with acitretin uses effective contraception (preferably 2 complementary methods) without interruption for four weeks before, during and for 2 years after the discontinuation of treatment with acitretin. The patient should be instructed to immediately contact a doctor in case of suspected pregnancy.
5. Therapy should not begin until the second or third day of the next normal menstrual period.
6. At the start of therapy, a negative pregnancy test result (minimum sensitivity of 25mIU/mL) must be obtained up to three days before the first dose is given. During therapy, pregnancy tests should be arranged at 28-day intervals. A negative pregnancy test not older than 3 days is mandatory before prescription is made at these visits. After stopping therapy, pregnancy tests should be performed at 1-3 monthly intervals for a period of 2 years after the last dose is given.
7. Before therapy with acitretin is instituted, the physician must give patients of childbearing potential detailed information about the precautions to be taken, the risk of very severe foetal malformation, and the possible consequences if pregnancy occurs during the course of treatment with acitretin or within 2 years of discontinuing therapy.
8. The same effective and uninterrupted contraceptive measures must be taken every time therapy is repeated, however long the intervening period may have been, and must be continued for 2 years afterwards.
9. Should pregnancy occur, in spite of these precautions, there is a high risk of severe malformation of the foetus (e.g. craniofacial defects, cardiac and vascular or CNS malformations, skeletal and thymic defects.) and the incidence of spontaneous abortion is increased. This risk applies especially during treatment with acitretin and 2 months after treatment. For up to 2 years after acitretin discontinuation, the risk is lower (particularly in women who have not consumed alcohol) but cannot be entirely excluded due to possible formation of etretinate.
10. She must avoid alcohol consumption during treatment and for 2 months after stopping treatment.

Primary contraceptive method is a combination hormonal contraceptive product or an intrauterine device and it is recommended that a condom or diaphragm (cap) is also used. Low dose progesterone-only products (minipills) are not recommended due to indications of possible interference with their contraceptive effect.

For male patients treated with acitretin, available data, based on the level of maternal exposure from the semen and seminal fluid indicate a minimal, if any, risk of teratogenic effects.

Decreased night vision has been reported with Neotigason therapy. 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.

Possible side effects of acitretin occur in varying degrees from patient to patient. Most of the side effects are doserelated and usually reversible with reduction of dosage or discontinuation of therapy.

At the start of treatment with acitretin there may be a transient worsening of the psoriasis symptoms.

The skin and mucous membranes are most commonly affected, and it is recommended that patients should be so advised before treatment is commenced.

The reported adverse reactions are listed below by system organ class and by frequency.

Frequencies are defined as:

Very common (≥1/10)
Common (≥1/100 to <1/10)
Uncommon (≥1/1,000 to <1/100)
Rare (≥1/10,000 to <1/1,000)
Very rare (<1/10,000)
Not known (frequency cannot be estimated from the available data)

Skin and subcutaneous tissue disorders:

Very common:

over 80% of patients experienced: hypervitaminosis A as e.g. dry lips and possibly inflamed lips (using moisturisers or ‘emollients’ from the start of treatment can help to relieve dry skin problems).

40–80% of patients experienced: dry mucous membranes of mouth and nose, peeling of skin, especially the palms of the hands and soles of the feet, rhinitis.

10–40% of patients experienced: nose bleed, scaling and thinning of healthy skin with increased sensitivity, erythema, pruritus, sensation of “burning skin”, sensation of “sticky skin”, dermatitis, hair loss, inflammation of the nail wall, nail fragility.

Common: up to 10% of patients experienced: development of rhagades, inflammation of oral mucosa and gingiva associated with taste disturbances, blistering of the skin, change in pigmentation of the skin and hair, change in growth rate of hair, change in hair structure.

Marked dose dependence has been observed especially with regard to:

• dry skin and mucous membranes, especially of the lips and nose,
• increased sensitivity of the skin and mucous membranes and
• hair loss.

Side effects of the skin and mucous membranes occur rather soon (a few days) after start of treatment, hair loss cannot be expected until several weeks into the treatment.

These side effects are reversible after altering the dose or discontinuation of treatment. However, new growth of hair will take some months, due to the hair growth cycle.

Rare: Increased sensitivity of the skin to light, as a result of which a sunburn can occur after only brief exposure to the sun. In these cases, care must be taken to wear adequate sun protection.

Not known: Madarosis and exfoliative dermatitis.

Eye disorders

Common: Conjunctivitis (10 to 40%), visual disturbances, e.g. xerophthalmia, blurred vision, impaired night vision. Wearing of contact lenses might become impossible. For this reason, patients should wear glasses during treatment with acitretin.

Rare: Inflammation or ulcers of the cornea.

Respiratory, thoracic and mediastinal disorders

Not known: Dysphonia

Musculoskeletal and connective tissue disorders

Uncommon: Myalgia, arthralgia and bone pain.

After long-term treatment with acitretin, bone changes may occur (hyperostosis, thinning of bone, osteoporosis, premature epiphyseal closure) and soft-tissue calcification (extraosseous calcification).

Gastrointestinal tract disorders

Rare: Gastrointestinal symptoms (e.g. nausea, vomiting, abdominal pain, diarrhoea, dyspepsia).

Hepatobiliary disorders

Rare: Hepatitis and jaundice.

Reproductive system and breast disorders

During treatment with acitretin an increase in vulvovaginitis caused by Candida albicans has been observed.

General disorders

Common: Thirst and feeling of cold (10 to 40%).

Uncommon: Peripheral oedema, sensation of heat, dysgeusia, headache.

Investigations

In addition to a possible increase in liver function values, an elevation of blood lipids has also been observed during treatment with acitretin.

The following changes in laboratory values occurred in patients during clinical trials:

• Elevation of triglycerides, total cholesterol, SGPT, creatine phosphokinase, SGOT, γ-GT, alkaline phosphatase, direct bilirubin, lactate dehydrogenase and uric acid
• Lowering of HDL cholesterol.

Occasionally an increase in creatinine, BUN and total bilirubin was observed.

Nervous system disorders

Rare: An increase of intracranial pressure (pseudotumor cerebri) may occur, which may be accompanied by severe headache, lightheadedness, nausea, vomiting, dizziness or visual disturbances, but subsides after discontinuation of treatment. If these symptoms occur the treating physician should be consulted immediately.

Immune system disorders

Not known: Type 1 hypersensitivity.

Vascular disorders

Not known: Capillary Leak Syndrome/retinoic acid syndrome.

Not all the consequences of long-term therapy with acitretin can be estimated as yet.