Source: Medicines & Healthcare Products Regulatory Agency (GB) Revision Year: 2020 Publisher: GlaxoSmithKline UK Limited, 980 Great West Road, Brentford, Middlesex, TW8 9GS Trading as Stiefel
Pregnancy is an absolute contraindication to treatment with Toctino (see section 4.6).
Toctino is contraindicated in woman of childbearing potential unless all of the conditions of the Pregnancy Prevention Programme are met (see section 4.4).
Toctino contains soya oil and sorbitol. Patients who are allergic to peanut, soya or with rare hereditary fructose intolerance should not take this medicine.
Toctino is contraindicated in nursing mothers.
Toctino is also contraindicated in patients:
Toctino is a powerful human teratogen inducing a high frequency of severe and life threatening birth defects.
Toctino is strictly contraindicated in:
This medicinal product is TERATOGENIC.
Alitretinoin is contraindicated in women of childbearing potential unless all of the following conditions of the Pregnancy Prevention Programme are met:
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:
If pregnancy occurs in a woman treated with Toctino, 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. The risk persists until the product has been completely eliminated, which is within one month following the end of treatment.
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 1 month after stopping treatment with Toctino, even in patients with amenorrhoea.
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.
According to local practice, medically supervised pregnancy tests with a minimum sensitivity of 25 mIU/mL are recommended to be performed, as follows:
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 alitretinoin.
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 amenorrhoea) 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.
1 month after stopping treatment, women should undergo a final pregnancy test.
For women of childbearing potential, the prescription duration of alitretinoin 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 alitretinoin 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.
The available data suggests that the level of maternal exposure from the semen of patients receiving Toctino, is not of a sufficient magnitude to be associated with teratogenic effects of Toctino. Based on non-clinical findings, the male fertility may be compromised by treatment with Toctino (see section 5.3).
Male patients should be reminded that they must not share their medication with anyone, particularly not females.
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 1 month following discontinuation of alitretinoin because of the potential risk to the foetus of a pregnant transfusion recipient.
In order to assist prescribers, pharmacists and patients in avoiding foetal exposure to alitretinoin the Marketing Authorisation Holder will provide educational material to reinforce the warnings about the teratogenicity of alitretinoin, 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.
Depression, depression aggravated, anxiety, aggressive tendencies, mood alterations, psychotic symptoms, and very rarely, suicidal ideation, suicide attempts and suicide have been reported in patients treated with systemic retinoids, including alitretinoin (see section 4.8). Particular care needs to be taken in patients with a history of depression and all patients should be monitored for signs of depression and referred for appropriate treatment if necessary. Prior to initiation of Toctino and at each visit during therapy, patients should be asked about any psychiatric disorder, depression, or mood disturbance. Patients should stop Toctino if they develop depression, mood disturbance, psychosis, or aggression. However, discontinuation of Toctino may be insufficient to alleviate symptoms and therefore further psychiatric or psychological evaluation may be necessary. Awareness by family or friends may be useful to detect mental health deterioration.
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.
Patients who experience dryness of the skin and lips should be advised to use a skin moisturizing ointment or cream and a lip balm.
Treatment with other systemic retinoids has been associated with bone changes including premature epiphyseal closure, hyperostosis, and calcification of tendons and ligaments.
Myalgia, arthralgia and increased serum creatinine phosphokinase values have been observed in patients treated with alitretinoin.
Treatment with alitretinoin has been associated with dry eyes. The symptoms usually resolve after discontinuation of therapy. Dry eyes can be helped by the application of a lubricating eye ointment or by the application of tear replacement therapy. Intolerance to contact lenses may occur which may necessitate the patient to wear glasses during treatment.
Treatment with systemic retinoids has been associated with corneal opacities and keratitis. Decreased night vision has been observed in patients treated with alitretinoin. These effects usually resolve after discontinuation of therapy.
Patients experiencing visual difficulties should be referred to an ophthalmologist. Withdrawal of alitretinoin may be necessary.
Treatment with systemic retinoids, including alitretinoin, has been associated with the occurrence of benign intracranial hypertension, some of which involved concomitant use of tetracyclines (see section 4.3 and section 4.5). Signs and symptoms of benign intracranial hypertension include headache, nausea and vomiting, visual disturbances and papilloedema. Patients who develop signs of benign intracranial hypertension should discontinue alitretinoin immediately.
Alitretinoin has been associated with an increase in plasma cholesterol and triglyceride levels. Serum cholesterol and triglycerides (fasting values) should be monitored. Alitretinoin should be discontinued if hypertriglyceridaemia cannot be controlled at an acceptable level.
Toctino should be discontinued if symptoms of pancreatitis occur (see section 4.8).
Triglyceride levels in excess of 800 mg/dL (9 mmol/L) are sometimes associated with acute pancreatitis, which may be fatal.
Changes in thyroid function tests have been observed in patients receiving alitretinoin, most often noted as a reversible reduction in thyroid stimulating hormone (TSH) levels and T4 [free thyroxine].
Treatment with other systemic retinoids has been associated with transient and reversible increases in liver transaminases. In the event of persistent clinically relevant elevation of transaminase levels, reduction of the dose or discontinuation of treatment should be considered.
Systemic retinoids, including alitretinoin, have been associated with inflammatory bowel disease (including regional ileitis) in patients without a history of intestinal disorders. If severe diarrhoea is observed diagnosis of IBD should be considered and alitretinoin should be discontinued immediately.
Anaphylactic reactions have been rarely reported in systemic retinoids, in some cases after previous topical exposure to retinoids. Allergic cutaneous reactions are reported infrequently. Serious cases of allergic vasculitis, often with purpura (bruises and red patches) of the extremities and extracutaneous involvement have been reported. Severe allergic reactions necessitate interruption of therapy and careful monitoring.
In patients with diabetes, obesity, cardiovascular risk factors or a lipid metabolism disorder undergoing treatment with alitretinoin, more frequent checks of serum values for lipids and/or blood glucose may be necessary.
Toctino capsules contain sorbitol. Patients with rare hereditary problems of fructose intolerance should not take this medicine.
Alitretinoin is metabolized by cytochrome P450 (CYP) 2C9, CYP2C8, CYP3A4 and undergoes isomerisation.
Co-administration with CYP3A4 inhibitors such as ketoconazole increases the plasma level of alitretinoin and therefore dose reduction to 10 mg should be considered. The effects of other inhibitors of CYP3A4 have not been studied.
A reduction in dose to 10 mg should be considered when alitretinoin is co-administered with potent CYP2C9 inhibitors (e.g. fluconazole, miconazole, oxandrolone) or potent CYP2C8 inhibitors (e.g. gemfibrozil).
Simvastatin did not affect the pharmacokinetics of alitretinoin.
No pharmacokinetic interactions were observed when alitretinoin was co-administered with ciclosporin.
Alitretinoin may increase the exposure of CYP2C8 substrates; therefore co-administration with amiodarone (a CYP2C8 substrate with a long half-life and narrow therapeutic index) is not recommended. Caution should be used if alitretinoin is co-administered with other medications that are substrates for CYP2C8 (e.g. paclitaxel, rosiglitazone, repaglinide).
Decreases of <25% in simvastatin and simvastatin acid plasma levels was observed when co-administered with alitretinoin. The effects on other similar medicinal products have not been studied.
Alitretinoin did not affect the pharmacokinetics of ketoconazole or ciclosporin.
Patients should not take vitamin A or other retinoids as concurrent medication due to the risk of hypervitaminosis A.
Cases of benign intracranial hypertension (pseudotumor cerebri) have been reported with concomitant use of retinoids and tetracyclines. Therefore, concomitant treatment with tetracyclines must be avoided (see sections 4.3 and section 4.4).
Pregnancy is an absolute contraindication to treatment with Toctino (see section 4.3). If pregnancy does occur in spite of the pregnancy prevention precautions during treatment with Toctino or in the month following discontinuation of therapy, there is a great risk of very severe and serious malformation of the foetus.
Alitretinoin is a retinoid and therefore is a potent teratogen. The foetal malformations associated with exposure to retinoids include central nervous system abnormalities (hydrocephalus, cerebellar malformation/abnormalities, microcephaly), facial dysmorphia, cleft palate, external ear abnormalities (absence of external ear, small or absent external auditory canals), eye abnormalities (microphthalmia), cardiovascular abnormalities (conotruncal malformations such as tetralogy of Fallot, transposition of great vessels, septal defects), thymus gland abnormality and parathyroid gland abnormalities. There is also an increased incidence of spontaneous abortion (see sections 4.3, 4.4).
Alitretinoin is highly lipophilic, therefore the passage of alitretinoin into human milk is very likely. Due to the potential risk for the exposed child, the use of alitretinoin is contraindicated in nursing mothers.
Small amounts of alitretinoin (above endogenous levels) have been detected in the semen of some healthy volunteers receiving 40 mg of alitretinoin and drug accumulation in semen is not expected. Assuming complete vaginal absorption, these amounts, would have a negligible effect on the endogenous plasma levels of the female partner or a foetus and therefore do not appear to pose a risk to the foetus if the partner is pregnant. Based on non-clinical findings, male fertility may be compromised by treatment with Toctino (see section 5.3).
Decreased night vision has been reported in patients treated with alitretinoin and other retinoids. Patients should be advised of this potential problem and warned to be cautious when driving or operating machines.
The safety and efficacy of Toctino in patients with severe chronic hand eczema (CHE) unresponsive to treatment with potent topical corticosteroids has been evaluated in two randomised, double blind, placebo-controlled clinical studies (see section 5.1).
The most frequent adverse drug reactions (ADRs) observed under alitretinoin therapy are headache (30 mg: 23.9%; 10 mg: 10.8%), erythema (30 mg: 5.5%; 10 mg: 1.7%), nausea (30 mg: 5.1%; 10 mg: 2.4%), flushing (30 mg: 5.9%, 10 mg: 1.6%), and laboratory changes consisting of increased levels of triglycerides (30 mg: 35.4%; 10 mg: 17.0%), increased cholesterol (30 mg: 27.8%; 10 mg: 16.7%), decreased levels of thyroid stimulating hormone (TSH, 30 mg: 8.4%, 10 mg: 6.0%) and decreased levels of free T4 (30 mg: 10.5%; 10 mg: 2.9%). These reversible ADRs are dose dependent and may therefore be alleviated by dose reduction.
Very common (≥1/10)
Common (≥1/100 <1/10)
Uncommon (≥1/1000, <1/100)
Rare (≥1/10,000 <1/1000)
Very Rare (<1/10000)
Unknown
Common: Anaemia, increased iron binding capacity, monocytes decreased; thrombocytes increased
Unknown: Anaphylactic reactions, hypersensitivity
Common: TSH decreased, free T4 decreased
Rare: Depression, depression aggravated, aggressive tendencies, anxiety, mood alterations
Very Rare: Suicide, suicide attempt, suicidal ideation, psychotic disorder, abnormal behaviour
Very common: Headache
Common: Dizziness
Rare: Benign intracranial hypertension
Common: Conjunctivitis, dry eye, eye irritation
Uncommon: Blurred vision, cataract
Unknown: Decreased night vision
Common: Tinnitus
Common: Flushing, hypertension
Rare: Vasculitis
Uncommon: Epistaxis
Common: Nausea, dry mouth, vomiting
Uncommon: Dyspepsia
Unknown: Inflammatory bowel disease
Common: Transaminase increased1
Common: Dry skin, dry lips, cheileitis, eczema1, dermatitis1, erythema, alopecia
Uncommon: Pruritus, rash, skin exfoliation, asteatotic eczema
Rare: Nail disorders, photosensitivity reaction, hair texture changes
Common: Arthralgia1, myalgia1
Uncommon: Exostosis, (hyperostosis), ankylosing spondylitis
Common: Fatigue
Peripheral oedema
Very common: Hypertriglyceridemia, high density lipoprotein decreased, hypercholesterolemia
Common: Blood creatinine phosphokinase increased
1 The overall incidence of adverse events was not higher than those observed in the corresponding placebo group.
The following adverse events have not been observed in clinical trials with alitretinoin, but have been observed with other retinoids: diabetes mellitus, colour blindness (colour vision deficiencies), and contact lens intolerance (see section 4.4).
Changes in bone mineralization and extra-osseous calcifications have been associated with systemic retinoid treatment. In clinical studies with alitretinoin, degenerative changes of the spine and ligamentous calcifications were frequent findings in patients with chronic hand eczema before treatment (baseline), with minor progression in a small number of patients during treatment. These observations were consistent with age dependent degenerative changes. Assessments of bone density (DXA) did not indicate a dose dependent effect on bone mineralization.
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 at: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.
Not applicable.
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