SUMMARY OF PRODUCT CHARACTERISTICS

1    NAME OF THE MEDICINAL PRODUCT

Neotigason 25mg Capsules Acitretin 25mg Capsules

2    QUALITATIVE AND QUANTITATIVE COMPOSITION

Capsules with brown cap and yellow body with ' sctavis printed in black on the cap and “25” printed in black on the body, containing 25mg acitretin.

Excipient with known effect: Glucose (see section 4.3).

For the full list of excipients, see section 6.1.

3    PHARMACEUTICAL FORM

Capsules for oral administration.

4    CLINICAL PARTICULARS

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. 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.

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 longterm 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.

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

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

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. Contraceptive measures and pregnancy tests must also be taken for 3 years after completion of acitretin treatment (see section 4.6 and 5.2).

Women of childbearing potential must not receive blood from patients being treated with acitretin. Therefore donation of blood by a patient being treated with acitretin is prohibited during and for three years after completion of treatment with acitretin.

Due to the risk of foetal malformations, the medicine must not be passed on to other people. Unused or expired products should be returned to a pharmacy for disposal.

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.

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 musculoskeletal 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.

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.

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.

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. 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

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. 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 (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
Nervous system disort	ers
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 ant	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.

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

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.

5.1    Pharmacodynamic properties

Pharmacotherapeutic group: Antipsoriatics, retinoids for treatment of psoriasis ATC code: D05BB02

Mechanism of action

Retinol (Vitamin A) is known to be essential for normal epithelial growth and differentiation, though the mode of this effect is not yet established. Both retinol and retinoic acid are capable of reversing hyperkeratotic and metaplastic skin changes. However, these effects are generally only obtained at dosages associated with considerable local or systemic toxicity. Acitretin, a synthetic aromatic derivative of retinoic acid, has a favourable therapeutic ratio, with a greater and more specific inhibitory effect on psoriasis and disorders of epithelial keratinisation. The usual therapeutic response to acitretin consists of desquamation (with or without erythema) followed by more normal re-epithelialisation.

Acitretin is the main active metabolite of etretinate.

5.2    Pharmacokinetic properties Absorption

Acitretin reaches peak plasma concentration 1 - 4 hours after ingestion of the drug. Bioavailability of orally administered acitretin is enhanced by food. Bioavailability of a single dose is approximately 60%, but inter-patient variability is considerable (36 - 95%).

Distribution

Acitretin is highly lipophilic and penetrates readily into body tissues. Protein binding of acitretin exceeds 99%. In animal studies, acitretin passed the placental barrier in quantities sufficient to produce foetal malformations. Due to its lipophilic nature, it can be assumed that acitretin passes into breast milk in considerable quantities.

Biotransformation

Acitretin is metabolised by isomerisation into its 13-cis isomer (cis acitretin), by glucuronidation and cleavage of the side chain.

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 (see section 4.4, 4.5 and 4.6).

Elimination

Multiple-dose studies in patients aged 21 - 70 years showed an elimination half-life of approximately 50 hours for acitretin and 60 hours for its main metabolite in plasma, cis acitretin, which is also a teratogen. From the longest elimination half-life observed in these patients for acitretin (96 hours) and cis acitretin (123 hours), and assuming linear kinetics, it can be predicted that more than 99% of the drug is eliminated within 36 days after cessation of long-term therapy. Furthermore, plasma concentrations of acitretin and cis acitretin dropped below the sensitivity limit of the assay (< 6ng/ml) within 36 days following cessation of treatment. Acitretin is excreted entirely in the form of its metabolites, in approximately equal parts via the kidneys and the bile.

5.3 Preclinical safety data

None stated.

6    PHARMACEUTICAL PARTICULARS

6.1    List of excipients

Capsule content:

Glucose, liquid, spray-dried Sodium ascorbate Gelatin Purified water Microcrystalline cellulose

Capsule shell:

Gelatin

Iron oxide black (E172)

Iron oxide yellow (E172)

Iron oxide red (E172)

Titanium dioxide (E171)

Printing ink:

Shellac

N-Butyl alcohol Isopropyl alcohol Propylene glycol Ammonium hydroxide Iron oxide black (E172)

6.2 Incompatibilities

None.

6.3    Shelf life

Acitretin capsules have a shelf-life of 3 years.

6.4    Special precautions for storage

Do not store above 25°C. Store in the original package.

6.5 Nature and contents of container

All aluminium blisters containing 56 capsules.

PVC/PVDC (Duplex) or PVC/PE/PVDC (Triplex) blisters with aluminium cover foil containing 56 or 60 capsules.

Amber glass bottles with metal screw caps containing 30 or 100 capsules.

6.6 Special precautions for disposal

None.

7    MARKETING AUTHORISATION HOLDER

ACTAVIS GROUP PTC EHF

REYKJAVIKURVEGI 76-78

HAFNARFIRDI

IS-220

ICELAND

8    MARKETING AUTHORISATION NUMBER(S)

PL 30306/0097

9    DATE OF FIRST AUTHORISATION/RENEWAL OF THE

AUTHORISATION

18/06/1992 / 02/03/2007

10 DATE OF REVISION OF THE TEXT

19/10/2016