Special Warning : אזהרת שימוש

4.4 Special warnings and precautions for use

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

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

• She has severe acne (such as nodular or conglobate acne or acne at risk of permanent scarring) resistant to adequate courses of standard therapy with systemic anti bacterial and topical therapy (see section 4.1 "Therapeutic 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 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 isotretinoin.

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 isotretinoin, 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 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 isotretinoin, 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 isotretinoin.

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
One month after stopping treatment, women should undergo a final pregnancy test.

Prescribing and dispensing restrictions
For women of childbearing potential, the prescription duration of Curatane 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 Curatane should occur on the same day. Dispensing of isotretinoin should occur within a maximum of 7 days of the prescription.

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.

For those patients that are considered by the prescriber to have compelling reasons to indicate that there is no risk of pregnancy, once stable on isotretinoin (after the first 1-3 months), the prescription duration may be for longer than 30 days (up to 12 weeks).

Male patients:
The available data suggests that the level of maternal exposure from the semen of the patients receiving Curatane is not of a sufficient magnitude to be associated with the teratogenic effects of Curatane. 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 isotretinoin because of the potential risk to the foetus of a pregnant transfusion recipient.


Psychiatric disorders
Depression, depression aggravated, anxiety, aggressive tendencies, mood alterations, psychotic symptoms, suicidal ideation, suicide attempts and suicide have been reported in patients treated with isotretinoin (see section 4.8).

Patients, and where appropriate, parents or carers, must be counselled about the risk of psychiatric adverse events with isotretinoin prior to prescription of isotretinoin, and preferably prior to any referral that might include consideration of isotretinoin treatment.

AII patients should have an assessment of their mental health before starting treatment with isotretinoin and be assessed regularly during treatment for developing or worsening psychiatric disorders. Particular care needs to be taken in patients with a history of depression. Patients should be referred for appropriate psychiatric treatment if necessary.
Discontinuation of isotretinoin 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.

Sexual disorders lsotretinoin use may be associated with sexual dysfunction (see section 4.8). There have been reports of long-lasting sexual dysfunction where the symptoms have continued despite discontinuation of isotretinoin.
Patients, and where appropriate, parents or carers, must be counselled about the risk of sexual dysfunction with isotretinoin prior to the prescribing decision, and ideally prior to any referral that might include consideration of isotretinoin treatment. The age and maturity of the patient should be taken into account in choosing the most appropriate counselling approach, including giving the option to discuss without parents or carers present where appropriate.
All patients should be asked about the presence of symptoms or signs of sexual dysfunction prior to starting treatment with isotretinoin, and monitored for the development of new sexual disorders during treatment.

Educational material
In order to assist prescribers, pharmacists and patients in avoiding foetal exposure to isotretinoin the Marketing Authorisation Holder will provide educational material to reinforce the warnings about the teratogenicity of isotretinoin, 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, persons of child-bearing potential (anyone who may be able to get pregnant).
Furthermore, the educational material reinforces the warnings about the risks of isotretinoin, including possible risks to mental health and sexual function.

Skin and subcutaneous tissues disorders
Acute exacerbation of acne is occasionally seen during the initial period but this subsides with continued treatment, usually within 7-10 days, and usually does not require dose adjustment.

Exposure to intense sunlight or to UV rays should be avoided. Where necessary a sun- protection product with a high protection factor of at least SPF 15 should be used.

Aggressive chemical dermabrasion and cutaneous laser treatment should be avoided in patients on isotretinoin for a period of 5-6 months after the end of the treatment because of the risk of hypertrophic scarring in atypical areas and more rarely post inflammatory hyper or hypopigmentation in treated areas. Wax depilation should be avoided in patients on isotretinoin for at least a period of 6 months after treatment because of the risk of epidermal stripping.

Concurrent administration of isotretinoin with topical keratolytic or exfoliative anti-acne agents should be avoided as local irritation may increase (see section 4.5).

Patients should be advised to use a skin moisturising ointment or cream and a lip balm from the start of treatment as isotretinoin is likely to cause dryness of the skin and lips.


There have been post-marketing reports of severe skin reactions (e.g. erythema multiforme (EM), Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN)) associated with isotretinoin use. As these events may be difficult to distinguish from other skin reactions that may occur (see section 4.8), patients should be advised of the signs and symptoms and monitored closely for severe skin reactions. If a severe skin reaction is suspected, isotretinoin treatment should be discontinued.

Allergic reactions
Anaphylactic reactions have been rarely reported, 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.

Eye disorders
Dry eyes, corneal opacities, decreased night vision and keratitis usually resolve after discontinuation of therapy. Cases of dry eyes not resolving after discontinuation of therapy have been reported. 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.
Decreased night vision has also been reported and the onset in some patients was sudden (see section 4.7). Patients experiencing visual difficulties should be referred for an expert ophthalmological opinion. Withdrawal of isotretinoin may be necessary.

Musculo-skeletal and connective tissue disorders
Myalgia, arthralgia and increased serum creatine phosphokinase values have been reported in patients receiving isotretinoin, particularly in those undertaking vigorous physical activity (see section 4.8). In some cases, this may progress to potentially life-threatening rhabdomyolysis.

Bone changes including premature epiphyseal closure, hyperostosis, and calcification of tendons and ligaments have occurred after several years of administration at very high doses for treating disorders of keratinisation. The dose levels, duration of treatment and total cumulative dose in these patients generally far exceeded those recommended for the treatment of acne.
Sacroiliitis has been reported in patients exposed to isotretinoin. To differentiate sacroiliitis from other causes of back pain, in patients with clinical signs of sacroiliitis, further evaluation may be needed including imaging modalities such as MRI. In cases reported post-marketing, sacroiliitis improved after discontinuation of Roaccutane and appropriate treatment.

Benign intracranial hypertension
Cases of benign intracranial hypertension have been reported, 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 benign intracranial hypertension should discontinue isotretinoin immediately.

Hepatobiliary disorders
Liver enzymes should be checked before treatment, 1 month after the start of treatment, and subsequently at 3 monthly intervals unless more frequent monitoring is clinically indicated.
Transient and reversible increases in liver transaminases have been reported. In many cases 
these changes have been within the normal range and values have returned to baseline levels during treatment. However, in the event of persistent clinically relevant elevation of transaminase levels, reduction of the dose or discontinuation of treatment should be considered.

Renal insufficiency
Renal insufficiency and renal failure do not affect the pharmacokinetics of isotretinoin.
Therefore, isotretinoin can be given to patients with renal insufficiency. However, it is recommended that patients are started on a low dose and titrated up to the maximum tolerated dose (see section 4.2).

Lipid Metabolism
Serum lipids (fasting values) should be checked before treatment, 1 month after the start of treatment, and subsequently at 3 monthly intervals unless more frequent monitoring is clinically indicated. Elevated serum lipid values usually return to normal on reduction of the dose or discontinuation of treatment and may also respond to dietary measures.

Isotretinoin has been associated with an increase in plasma triglyceride levels. Isotretinoin should be discontinued if hypertriglyceridaemia cannot be controlled at an acceptable level or if symptoms of pancreatitis occur (see section 4.8). Levels in excess of 800 mg/dL or 9 mmol/L are sometimes associated with acute pancreatitis, which may be fatal.

Gastrointestinal disorders
Isotretinoin has been associated with inflammatory bowel disease (including regional ileitis) in patients without a prior history of intestinal disorders. Patients experiencing severe (haemorrhagic) diarrhoea should discontinue isotretinoin immediately.

High Risk Patients
In patients with diabetes, obesity, alcoholism or a lipid metabolism disorder undergoing treatment with isotretinoin, more frequent checks of serum values for lipids and/or blood glucose may be necessary. Elevated fasting blood sugars have been reported, and new cases of diabetes have been diagnosed during isotretinoin therapy.
Excipients
This medicinal product contains 4.99 mg sorbitol in each 5 mg capsule, 5.30 mg sorbitol in each 10 mg capsule, 6.98 mg sorbitol in each 20 mg capsule, 21.50 mg sorbitol in each 30 mg capsule, and 23.75 mg sorbitol in each 40 mg capsule.
The additive effect of concomitantly administered products containing sorbitol (or fructose) and dietary intake of sorbitol (or fructose) should be taken into account.
The content of sorbitol in medicinal products for oral use may affect the bioavailability of other medicinal products for oral use administered concomitantly.

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