Special Warning : אזהרת שימוש

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.

Neotigason is contra-indicated in women of childbearing potential unless 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.


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• 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 Neotigason.

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 Neotigason, 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.


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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 Neotigason, 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 Neotigason.

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 
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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 Neotigason, 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, Neotigason 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 
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treatment. Neotigason 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 Neotigason, 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 Neotigason should be promptly and fully investigated to exclude possible acitretin-induced bone changes. If clinically significant bone or joint changes are found, Neotigason 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.
Neotigason 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 patients:
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.

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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

Neotigason 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 Neotigason 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.

Excipients
Sodium
This medicine contains less than 1 mmol sodium (23 mg) per capsule, that is to say essentially ‘sodium-free’.
Glucose
This medicine contains glucose. For details please see section 4.3.



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Effects on Driving

4.7    Effects on ability to drive and use machines

Decreased night vision has been reported with Neotigason therapy (see section 4.8 “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).