- 1. Name of the medicinal product
- 2. Qualitative and quantitative composition
- 3. Pharmaceutical form
- 4. Clinical particulars
- 4.1 Therapeutic indications
- 4.2 Posology and method of administration
- 4.3 Contraindications
- 4.4 Special warnings and precautions for use
- 4.5 Interaction with other medicinal products and other forms of interaction
- 4.6 Fertility, pregnancy and lactation
- 4.7 Effects on ability to drive and use machines
- 4.8 Undesirable effects
- 4.9 Overdose
- 5. Pharmacological properties
- 5.1 Pharmacodynamic properties
- 5.2 Pharmacokinetic properties
- 5.3 Preclinical safety data
- 6. Pharmaceutical particulars
- 6.1 List of excipients
- 6.2 Incompatibilities
- 6.3 Shelf life
- 6.4 Special precautions for storage
- 6.5 Nature and contents of container
- 6.6 Special precautions for disposal and other handling
- 7. Marketing authorisation holder
- 8. Marketing authorisation number(s)
- 9. Date of first authorisation/renewal of the authorisation
- 10. Date of revision of the text
PosologyAcitretin 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.AdultsInitial 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.ElderlyDosage recommendations are the same as for other adults.Paediatric populationIn 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 long-term side-effects.
Combination therapyOther 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 administrationAcitretin capsules are for oral administration.
|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).|
Paediatric populationSince 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.
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.
Women of childbearing potential / Contraception in males and females
|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).|
PregnancyAcitretin is contraindicated in pregnant women (see section 4.3).
BreastfeedingAcitretin must not be given to nursing mothers (see section 4.3).
|Infections and infestations|
|Frequency not known||Vulvo-vaginitis due to Candida albicans|
|Immune system disorders|
|Frequency not known||Type 1 hypersensitivity|
|Nervous system disorders|
|Very rare||Benign intracranial hypertension (see section 4.4)|
|Very common||Drying of and inflammation of mucous membranes (e.g. conjunctivitis, xerophthalmia)*|
|Very rare||Night blindness (see section 4.4), ulcerative keratitis|
|Ear and labyrinth disorders|
|Frequency not known||Hearing impaired, tinnitus|
|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)|
|Very common||Dry mouth, thirst|
|Common||Stomatitis, gastro-intestinal disorders (e.g. abdominal pain, diarrhoea, nausea, vomiting)|
|Frequency not known||Dysgeusia, rectal haemorrhage|
|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|
|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|
|Frequency not known||malaise, drowsiness|
|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)|
DiabeticsRetinoids can either improve or worsen glucose tolerance (see section 4.4).
Reporting of suspected adverse reactionsReporting 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
Mechanism of actionRetinol (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.
AbsorptionAcitretin 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%).
DistributionAcitretin 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.BiotransformationAcitretin 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).
EliminationMultiple-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.
Capsule content:Glucose, liquid, spray-driedSodium ascorbateGelatinPurified waterMicrocrystalline cellulose
Capsule shell:GelatinIron oxide black (E172)Iron oxide yellow (E172)Iron oxide red (E172)Titanium dioxide (E171)
Printing ink:ShellacN-Butyl alcoholIsopropyl alcoholPropylene glycolAmmonium hydroxideIron oxide black (E172)
Actavis UK Ltd
Whiddon Valley, Barnstaple, Devon, EX32 8NS, UK
+44 (0)1271 346 106
+44 (0)1271 311 200
+44 (0)1271 385 257