4.1. Therapeutic indications

Severe extensive psoriasis which is resistant to other forms of therapy.

Palmo-plantar pustular psoriasis.

Severe congenital ichthyosis.

Severe Darier's disease (keratosis follicularis).

4.2. Posology and method of administration

Posology

Acitretin should only be prescribed by physicians who are experienced in the use of systemic retinoids and understand the risk of teratogenicity associated with acitretin therapy (see section 4.6).

The capsules should be taken once daily with meals or with milk.

There is a wide variation in the absorption and rate of metabolism of Acitretin. This necessitates individual adjustment of dosage. For this reason, the following dosage recommendations can serve only as a guide.

Adults

Initial daily dose should be 25mg or 30mg for 2 to 4 weeks. After this initial treatment period the involved areas of the skin should show a marked response and/or side-effects should be apparent. Following assessment of the initial treatment period, titration of the dose upwards or downwards may be necessary to achieve the desired therapeutic response with the minimum of side-effects. The maintenance dose must be based on clinical efficacy and tolerability. In general, a daily dosage of 25 - 50mg taken for a further 6 to 8 weeks achieves optimal therapeutic results. However, it may be necessary in some cases to increase the dose up to a maximum of 75mg/day.

In patients with Darier's disease a starting dose of 10mg may be appropriate. The dose should be increased cautiously as isomorphic reactions may occur.

Therapy can be discontinued in patients with psoriasis whose lesions have improved sufficiently. Relapses should be treated as described above.

Patients with severe congenital ichthyosis and severe Darier's disease may require therapy beyond 3 months. The lowest effective dosage, not exceeding 50mg/day should be given.

Continuous use beyond 6 months is contraindicated as only limited clinical data are available on patients treated beyond this length of time.

Elderly

Dosage recommendations are the same as for other adults.

Paediatric population

In view of possible severe side-effects associated with long-term treatment, Acitretin is contraindicated in children unless, in the opinion of the physician, the benefits significantly outweigh the risks.

Acitretin should be used only when all alternative therapies have proved inadequate. The dosage should be established according to bodyweight. The daily dosage is about 0.5mg/kg. Higher doses (up to 1mg/kg daily) may be necessary in some cases for limited periods, but only up to a maximum of 35mg/day. The maintenance dose should be kept as low as possible in view of possible long-term side-effects.

Combination therapy

Other dermatological therapy, particularly with keratolytics, should normally be stopped before administration of Acitretin. However, the use of topical corticosteroids or bland emollient ointment may be continued if indicated.

When Acitretin is used in combination with other types of therapy, it may be possible, depending on the individual patient's response, to reduce the dosage of Acitretin.

Method of administration

Acitretin capsules are for oral administration.

4.3. Contraindications

Hypersensitivity to the active substance, to other retinoids or to any of the excipients listed in section 6.1.

Acitretin is highly teratogenic and must not be used by women who are pregnant. The same applies to women of childbearing potential unless strict contraception is practiced 4 weeks before, during and for 3 years after treatment (see section 4.6).

The use of Acitretin is contraindicated in women who are breastfeeding.

Acitretin is contraindicated in patients with severe hepatic or renal impairment and in patients with chronic abnormally elevated blood lipid values.

Since both acitretin and tetracyclines can cause increased intracranial pressure, their combined use is contraindicated. Supplementary treatment with antibiotics such as tetracyclines is therefore contraindicated (see section 4.5).

An increased risk of hepatitis has been reported following the concomitant use of methotrexate and etretinate. Consequently, the concomitant use of methotrexate and Acitretin is contraindicated (see section 4.5).

Concomitant administration of Acitretin with other retinoids or Vitamin A is contraindicated due to the risk of hypervitaminosis A.

Owing to the presence of glucose, patients with rare glucose-galactose malabsorption should not take this medicine.

4.4. Special warnings and precautions for use

Teratogenic effects

Neotigason is a powerful human teratogen inducing a high frequency of severe and life threatening birth defects.

Neotigason is strictly contraindicated in:

- Pregnant women

- Women of childbearing potential unless all of the conditions of the Pregnancy Prevention Programme are met

Pregnancy Prevention Programme

This medicinal product is TERATOGENIC.

Acitretin is contraindicated in women of childbearing potential unless all of the following conditions of the Pregnancy Prevention Programme are met:

• She has severe forms of psoriasis (erythrodermic psoriasis, local or generalized pustular psoriasis) or severe keratinization disorders (congenital ichthyosis, pityriasis rubra pilaris, Darier's disease, other disorders of keratinization which may be resistant to other therapies) (see section “Indications”).

• The potential for pregnancy must be assessed for all female patients.

• She understands the teratogenic risk.

• She understands the need for rigorous follow-up on a monthly basis.

• She understands and accepts the need for effective contraception, without interruption, 1 month before starting treatment, throughout the entire duration of treatment and for 3 years after the end of treatment. At least one highly effective method of contraception (i.e. a user-independent form) or two complementary user-dependent forms of contraception should be used.

• Individual circumstances should be evaluated in each case, when choosing the contraception method, involving the patient in the discussion, to guarantee her engagement and compliance with the chosen measures.

• Even if she has amenorrhea she must follow all the advice on effective contraception.

• She is informed and understands the potential consequences of pregnancy and the need to rapidly consult if there is a risk of pregnancy or if she might be pregnant.

• She understands the need and accepts to undergo regular pregnancy testing before, ideally monthly during treatment and periodically with 1-3 monthly intervals for a period of 3 years after stopping treatment (see section “Fertility, pregnancy and lactation” and 5.2 in the SPC).

• She has acknowledged that she has understood the hazards and necessary precautions associated with the use of acitretin.

These conditions also concern women who are not currently sexually active unless the prescriber considers that there are compelling reasons to indicate that there is no risk of pregnancy.

The prescriber must ensure that:

• The patient complies with the conditions for pregnancy prevention as listed above, including confirmation that she has an adequate level of understanding.

• The patient has acknowledged the aforementioned conditions.

• The patient understands that she must consistently and correctly use one highly effective method of contraception (i.e. a user-independent form) or two complementary user-dependent forms of contraception, for at least 1 month prior to starting treatment and is continuing to use effective contraception throughout the treatment period and for at least 3 years after cessation of treatment.

• Negative pregnancy test results have been obtained before, during and periodically with 1-3 monthly intervals for a period of 3 years after stopping treatment. The dates and results of pregnancy tests should be documented.

If pregnancy occurs in a woman treated with acitretin, treatment must be stopped, and the patient should be referred to a physician specialised or experienced in teratology for evaluation and advice.

If pregnancy occurs after stopping treatment there remains a risk of severe and serious malformation of the foetus. This risk persists until the product has been completely eliminated, which is within 3 years following the end of treatment.

Contraception

Female patients must be provided with comprehensive information on pregnancy prevention and should be referred for contraceptive advice if they are not using effective contraception. If the prescribing physician is not in a position to provide such information the patient should be referred to the relevant healthcare professional

As a minimum requirement, female patients of childbearing potential must use at least one highly effective method of contraception (i.e. a user-independent form), or two complementary user-dependent forms of contraception. Contraception should be used for at least 1 month prior to starting treatment, throughout treatment and continue for at least 3 years after stopping treatment with acitretin, even in patients with amenorrhea.

Individual circumstances should be evaluated in each case, when choosing the contraception method involving the patient in the discussion, to guarantee her engagement and compliance with the chosen measures.

Pregnancy testing

According to local practice, medically supervised pregnancy tests with a minimum sensitivity of 25mUI/mL are recommended to be performed, as follows.

Prior to starting therapy

At least one month after the patient has started using contraception, and shortly (preferably a few days) prior to the first prescription, the patient should undergo a medically supervised pregnancy test. This test should ensure the patient is not pregnant when she starts treatment with acitretin.

Follow-up visits

Follow-up visits should be arranged at regular intervals, ideally monthly. The need for repeated medically supervised pregnancy tests every month should be determined according to local practice including consideration of the patient's sexual activity, recent menstrual history (abnormal menses, missed periods or amenorrhea) and method of contraception. Where indicated, follow-up pregnancy tests should be performed on the day of the prescribing visit or in the 3 days prior to the visit to the prescriber.

End of treatment

Women should undergo pregnancy test periodically with 1-3 monthly intervals for a period of 3 years after stopping treatment.

Prescribing and dispensing restrictions

For women of childbearing potential, the prescription duration of Neotigason should ideally be limited to 30 days in order to support regular follow up, including pregnancy testing and monitoring. Ideally, pregnancy testing, issuing a prescription and dispensing of Neotigason should occur on the same day.

This monthly follow-up will allow ensuring that regular pregnancy testing and monitoring is performed and that the patient is not pregnant before receiving the next cycle of medication.

Male patients

The available data suggest that the level of maternal exposure from the semen of the patients receiving Neotigason is not of a sufficient magnitude to be associated with the teratogenic effects of Neotigason. Male patients should be reminded that they must not share their medication with anyone, particularly not females.

Additional precautions

Patients should be instructed never to give this medicinal product to another person and to return any unused capsules to their pharmacist at the end of treatment.

Patients should not donate blood during therapy and for 3 years following discontinuation of acitretin because of the potential risk to the foetus of a pregnant transfusion recipient.

Educational material

In order to assist prescribers, pharmacists and patients in avoiding foetal exposure to acitretin the Marketing Authorisation Holder will provide educational material to reinforce the warnings about the teratogenicity of acitretin, to provide advice on contraception before therapy is started and to provide guidance on the need for pregnancy testing.

Full patient information about the teratogenic risk and the strict pregnancy prevention measures as specified in the Pregnancy Prevention Programme should be given by the physician to all patients, both male and female.

Psychiatric disorders

Depression, depression aggravated, anxiety, mood alterations and psychotic disorder have been reported in patients treated with systemic retinoids, including acitretin. Particular care should be taken in patients with a history of depression. Patients should be monitored for signs of depression and referred for appropriate treatment if necessary. Awareness by family or friends may be useful to detect mental health deterioration.

Clinical evidence has shown that etretinate can be formed with concurrent ingestion of acitretin and alcohol. Etretinate is highly teratogenic and has a longer half-life (approximately 120 days) than acitretin.

Women of childbearing age must not consume alcohol (in drinks, food or medicines) during treatment with acitretin and for 2 months after cessation of acitretin therapy.

Hepatic function should be checked before starting treatment with Acitretin, every 1 - 2 weeks for the first 2 months after commencement and then every 3 months during treatment. If abnormal results are obtained, weekly checks should be instituted. If hepatic function fails to return to normal or deteriorates further, Acitretin must be withdrawn. In such cases it is advisable to continue monitoring hepatic function for at least 3 months (see section 4.8).

Serum cholesterol and serum triglycerides (fasting values) must be monitored before starting treatment, one month after the commencement and then every 3 months during treatment. Acitretin treatment should be discontinued in case of uncontrolled levels of hypertriglyceridemia or if symptoms of pancreatitis occur.

Decreased night vision has been reported with acitretin 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 (see section 4.8).

There have been rare reports of benign intracranial hypertension. Patients with severe headache, nausea, vomiting, and visual disturbances should discontinue acitretin immediately and be referred for neurologic evaluation and care (see section 4.8).

In adults, especially elderly, receiving long-term treatment with Acitretin, appropriate examinations should be periodically performed in view of possible ossification abnormalities (see section 4.8 ). Any patients complaining of atypical musculo-skeletal symptoms on treatment with Acitretin should be promptly and fully investigated to exclude possible acitretin-induced bone changes. If clinically significant bone or joint changes are found, Acitretin therapy should be discontinued.

Paediatric population

Since there have been occasional reports of bone changes in children, including premature epiphyseal closure, skeletal hyperostosis and extraosseous calcification after long-term treatment with etretinate, these effects may be expected with acitretin. Acitretin therapy in children is not, therefore, recommended. If, in exceptional circumstances, such therapy is undertaken the child should be carefully monitored for any abnormalities of musculo-skeletal development and growth parameters and bone development must be closely monitored.

It should be emphasized that, at the present time, not all the consequences of life-long administration of acitretin are known.

The effects of UV light are enhanced by retinoid therapy, therefore patients should avoid excessive exposure to sunlight and the unsupervised use of sun lamps. Where necessary a sun-protection product with a high protection factor of at least SPF 15 should be used.

Treatment with high dose retinoids can cause mood changes including irritability, aggression and depression.

High risk patient:

In patients with diabetes, alcoholism, obesity, cardiovascular risk factors or a lipid metabolism disorder undergoing treatment with acitretin, more frequent checks are necessary of serum values for lipids,and/or glycaemia and other cardiovascular risk indicators, e.g. blood pressure. In diabetics, retinoids can either improve or worsen glucose tolerance. Blood-sugar levels must therefore be checked more frequently than usual in the early stages of treatment.

For all high risk patients where cardiovascular risk indicators fail to return to normal or deteriorate further, dose reduction or withdrawal of acitretin should be considered.

In diabetic patients, retinoids can alter glucose tolerance. Blood sugar levels should therefore be checked more frequently than usual at the beginning of the treatment period.

Very rare cases of Capillary Leak Syndrome/retinoic acid syndrome have been reported from world-wide post marketing experience.

Very rare cases of Exfoliative dermatitis have been reported from world-wide post marketing experience.

Acitretin should only be prescribed by physicians who are experienced in the use of systemic retinoids and understand the risk of teratogenicity associated with acitretin therapy.

Acitretin is highly teratogenic. 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. Foetal exposure to Acitretin always involves a risk of congenital malformation.

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.

Acitretin has been shown to affect diaphyseal and spongy bone adversely in animals at high doses in excess of those recommended for use in man. Since skeletal hyperostosis and extraosseous calcification have been reported following long-term treatment with etretinate in man, this effect should be expected with acitretin therapy.

Patients should be warned of the possibility of alopecia occurring (see section 4.8 Undesirable effects).

Treatment with high dose retinoids can cause mood changes including irritability, aggression and depression.

Excipient(s)

Sodium

This medicine contains less than 1 mmol sodium (23 mg) per tablet, that is to say essentially 'sodium-free'.

4.5. Interaction with other medicinal products and other forms of interaction

Concomitant administration of methotrexate, tetracyclines or vitamin A and other retinoids with acitretin is contraindicated, see section 4.3. An increased risk of hepatitis has been reported following the concomitant use of methotrexate and etretinate.

Low dose progesterone-only products (minipills) may be an inadequate method of contraception during acitretin therapy, see section 4.6. Interactions with combined estrogen/progestogen oral contraceptives have not been observed.

In a study with healthy volunteers, concurrent intake of a single dose of acitretin together with alcohol led to the formation of etretinate which is highly teratogenic. The mechanism of this metabolic process has not been defined, so it is not clear whether other interacting agents are also possible. Women of childbearing age must therefore not consume alcohol (in drinks, food or medicines) during treatment with acitretin and for 2 months after cessation of acitretin therapy. (See section 4.4 and 5.2).

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.

Interactions between Acitretin and other substances (e.g. digoxin, cimetidine) have not been observed to date.

Investigations into the effect of acitretin on the protein binding of anticoagulants of the coumarin type (warfarin) revealed no interaction.

4.6. Fertility, pregnancy and lactation

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 3 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 3 years after the discontinuation of treatment with acitretin. The patient should be instructed to immediately contact a doctor in case of suspected pregnancy.

Even female patients who normally do not practice contraception because of a history of infertility should be advised to do so, while taking Acitretin.

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 3 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 3 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 3 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 3 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. Therefore, before instituting Acitretin the treating physician must explain clearly and in detail what precautions must be taken. This should include the risks involved and the possible consequences of pregnancy occurring during Acitretin treatment or in the 3 years following its cessation.

10) Women of childbearing age must not consume alcohol (in drinks, food or medicines) during treatment with acitretin and for 2 months after cessation of acitretin therapy (see section 4.4, 4.5 and 5.2).

Primary contraceptive method can be 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.

Pregnancy

Acitretin is contraindicated in pregnant women (see section 4.3).

Breastfeeding

Acitretin must not be given to nursing mothers (see section 4.3).

4.7. Effects on ability to drive and use machines

Decreased night vision has been reported with Acitretin therapy (see section “Undesirable effects”). 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 section 4.8).

4.8. Undesirable effects

Summary of the safety profile

Undesirable effects are seen in most patients receiving acitretin. However, the toxic dose of Acitretin is close to the therapeutic dose and most patients experience some side-effects during the initial period whilst dosage is being adjusted. They are usually reversible with reduction of dosage or discontinuation of therapy.

The skin and mucous membranes are most commonly affected, and it is recommended that patients should be so advised before treatment is commenced. An initial worsening of psoriasis symptoms is sometimes seen at the beginning of the treatment period.

The most frequent undesirable effects observed are symptoms of hypervitaminosis A, e.g. dryness of the lips, which can be alleviated by application of a fatty ointment.

Undesirable effects reported for acitretin in clinical trials or as post-marketing events are listed below by System Organ Class and frequency. The frequencies of adverse events are ranked according to the following:

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 (cannot be estimated from the available data)

Infections and infestations

Frequency not known

Vulvo-vaginitis due to Candida albicans

Immune system disorders

Frequency not known

Type 1 hypersensitivity

Psychiatric disorders

Not known

Altered mood, psychotic disorder

Nervous system disorders

Common

Headache

Uncommon

Dizziness

Rare

Neuropathy peripheral

Very rare

Benign intracranial hypertension (see section 4.4)

Eye disorders

Very common

Drying of and inflammation of mucous membranes (e.g. conjunctivitis, xerophthalmia)*

Uncommon

Vision blurred

Very rare

Night blindness (see section 4.4), ulcerative keratitis

Ear and labyrinth disorders

Frequency not known

Hearing impaired, tinnitus

Vascular disorders

Frequency not known

Flushing, Capillary Leak Syndrome/retinoic acid syndrome

Respiratory, thoracic and mediastinal disorders

Very common

Drying of and inflammation of mucous membranes (e.g.epistaxis and rhinitis)

Frequency not known

Dysphonia

Gastrointestinal disorders

Very common

Dry mouth, thirst

Common

Stomatitis, gastro-intestinal disorders (e.g. abdominal pain, diarrhoea, nausea, vomiting)

Uncommon

Gingivitis

Frequency not known

Dysgeusia, rectal haemorrhage

Hepatobiliary disorders

Uncommon

Hepatitis

Very rare

Jaundice

Skin and subcutaneous tissue disorders

Very common

Cheilitis, pruritus, alopecia, skin exfoliation (all over the body, particularly on the palms and soles)

Common

Skin fragility, sticky skin, dermatitis, hair texture abnormal, brittle nails, paronychia, erythema

Uncommon

Rhagades, dermatitis bullous, photosensitivity reaction

Frequency not known

Pyogenic granuloma, madarosis, dryness of the skin may be associated with scaling, thinning, erythema (especially of the face), hair thinning and frank alopecia**, granulomatous lesions, sweating, rhagades of the corner of the mouth, angioedema, urticaria, exfoliative dermatitis

Musculoskeletal and connective tissue disorders

Common

Arthralgia, myalgia

Very rare

Bone pain, exostosis (maintenance treatment may result in progression of existing spinal hyperostosis, in appearance of new hyperostotic lesions and in extraskeletal calcification, as has been observed in longterm systemic treatment with retinoids) (see section 4.4)

General disorders and administration site conditions

Common

Peripheral oedema

Frequency not known

malaise, drowsiness

Investigations

Very common

Liver function test abnormal (transient, usually reversible elevation of transaminases and alkaline phosphatises) (see section 4.4)

Lipids abnormal (during treatment with high doses of acitretin, reversible elevation of serum triglycerides and serum cholesterol has occurred, especially in high-risk patients and during long-term treatment (see section 4.4).

An associated risk of atherogenesis cannot be ruled out if these conditions persist)

* Dryness of the conjunctivae may lead to mild-to-moderate conjunctivitis or xerophthalmia and result in intolerance of contact lenses; it may be alleviated by lubrication with artificial tears or topical antibiotics.

** Usually noted 4 to 8 weeks after starting therapy and are reversible following discontinuation of Acitretin. Full recovery usually occurs within 6 months of stopping treatment in the majority of patients.

Paediatric population

There have been occasional reports of bone changes in children, including premature epiphyseal closure, skeletal hyperostosis and extraosseous calcification after long-term treatment with etretinate, these effects may be expected with acitretin. In children, growth parameters and bone development must be closely monitored.

Other special populations

Diabetics

Retinoids can either improve or worsen glucose tolerance (see section 4.4).

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the Yellow Card Scheme website: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.

4.9. Overdose

Manifestations of acute Vitamin A toxicity include severe headache, vertigo, nausea or vomiting, drowsiness, irritability and pruritus. Signs and symptoms of accidental or deliberate overdosage with Acitretin would probably be similar. Specific treatment is unnecessary because of the low acute toxicity of the preparation.

Because of the variable absorption of the drug, gastric lavage may be worthwhile within the first few hours after ingestion.