Special Warning : אזהרת שימוש

4.4   Special warnings and precautions for use

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

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

•     Toctino is indicated for use in adults who have severe chronic hand eczema that is unresponsive to treatment with potent topical corticosteroids (see section 4.1).
•     The potential for pregnancy must be assed 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 1 month 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 amenorrhoea she must follow all of 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 1 month after stopping treatment.
•     She has acknowledged that she has understood the hazards and necessary precautions associated with the use of alitretinoin.

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 1 month after cessation of treatment.
•     Negative pregnancy test results have been obtained before, during and 1 month after the end of treatment. The dates and results of pregnancy tests should be documented.

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.

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 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.

Pregnancy testing
According to local practice, medically supervised pregnancy tests with a minimum sensitivity of 25 mIU/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 alitretinoin.

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 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.

End of treatment
1 month after stopping treatment, women should undergo a final pregnancy test.

Prescribing and dispensing restrictions
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.

Male patients
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.

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 1 month following discontinuation of alitretinoin 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 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.

Psychiatric disorders
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.

UV light
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.

Skin and subcutaneous tissues disorders
Patients who experience dryness of the skin and lips should be advised to use a skin moisturizing ointment or cream and a lip balm.

Musculo-skeletal and connective tissue disorders
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 creatine phosphokinase values have been observed in patients treated with alitretinoin.


Eye disorders
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.

Benign intracranial hypertension
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.

Lipid Metabolism
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.

Pancreatitis
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.

Thyroid function
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].

Hepatobiliary disorders
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.

Gastrointestinal disorders
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.

Allergic reactions
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.

High risk patients
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.

Sorbitol
Toctino capsules contain sorbitol. Patients with rare hereditary problems of fructose intolerance should not take this medicine.

Effects on Driving

4.7   Effects on ability to drive and use machines

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.