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  • Toctino
    / Neopharm Scientific


    Active Ingredient
    Alitretinoin 10 mg, 30 mg

    Status in Israel
    RX

    Presentation and Status in Health Basket

    Presentation Basket Yarpa Pharmasoft

    Soft Capsules

    30 X 10 mg

    partial basket chart 26067 20719

    Soft Capsules

    30 X 30 mg

    partial basket chart 26066 20718

    Related information


    Dosage

    Toctino should only be prescribed by dermatologists, or physicians with experience in the use of systemic retinoids who have full understanding of the risks of systemic retinoid therapy and monitoring requirements. Prescriptions of Toctino for women of childbearing potential should be limited to 30 days of treatment and continuation of treatment requires a new prescription. Ideally, pregnancy testing, issuing a prescription and dispensing of Toctino should occur on the same day.
    The recommended dose for Toctino is 10 mg or 30 mg once daily.
    The recommended starting dose for Toctino is 30 mg once daily. A dose reduction to 10 mg once daily may be considered in patients with unacceptable adverse reactions to the 30 mg dose. In studies investigating 10 mg and 30 mg daily doses, both doses resulted in clearing of the disease. The 30 mg dose provided a more rapid response and a higher response rate. The 10 mg daily dose was associated with fewer adverse events.
    Duration of treatment: A treatment course of Toctino may be given for 12 to 24 weeks depending on response. Discontinuation of therapy is recommended in patients who have achieved clear or almost clear hands earlier than 24 weeks. Discontinuation of therapy should also be considered for patients who still have
    severe disease after the initial 12 weeks of continuous treatment.
    Retreatment: In the event of relapse, patients may benefit from further treatment courses of Toctino.
    Method of administration: The capsules should be taken with a main meal once daily, preferably at the same time each day.
    Toctino should not be prescribed if the patient’s eczema can be adequately controlled by standard measures, including skin protection, avoidance of allergens and irritants, and treatment with potent topical corticosteroids.
    Paediatric population: Toctino is not recommended for use in patients under 18 years of age.
    Renal impairment: Toctino is contraindicated in patients with severe or end stage renal impairment.
    Toctino is not recommended for use in patients with moderate renal impairment as there is insufficient data.
    No alteration of dosage or dosing frequency is required in patients with mild renal impairment.
    Hepatic impairment: Toctino is contraindicated in patients with hepatic impairment.
    Elderly: No alteration of dosage and dosing frequency is required in patients over 65 years.


    Indications

    Toctino is indicated for use in adults who have severe chronic hand eczema that is unresponsive to treatment with potent topical corticosteroids.
    Patients in whom the eczema has predominantly hyperkeratotic features are more likely to respond to treatment than in those in whom the eczema predominantly presents as pompholyx.


    Contra-Indications

    Pregnancy is an absolute contraindication to treatment with Toctino.
    Toctino is contraindicated in woman of childbearing potential unless all of the conditions of the Pregnancy Prevention Programme are met.
    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
    • With hepatic insufficiency
    • With severe renal insufficiency
    • With uncontrolled hypercholesterolemia
    • With uncontrolled hypertriglyceridemia
    • With uncontrolled hypothyroidism
    • With hypervitaminosis A
    • With hypersensitivity either to alitretinoin, to other retinoids or to any of the excipients, in particular in case of allergies to peanut or soya.
    • Receiving concomitant treatment with tetracyclines.


    Special Precautions

    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.
    • 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.
    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.
    Patientsshould 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. 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 creatinine 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. 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.
    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.


    Side Effects

    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.
    See prescribing information for full details.


    Drug interactions

    Pharmacokinetic interaction: Alitretinoin is metabolized by cytochrome P450 (CYP) 2C9, CYP2C8, CYP3A4 and undergoes isomerisation.
    Concomitant medications that may affect the pharmacokinetics of alitretinoin: 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.
    Effect of alitretinoin on the pharmacokinetics of concomitant medications: 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 coadministered with alitretinoin. The effects on other similar medicinal products have not been studied.
    Alitretinoin did not affect the pharmacokinetics of ketoconazole or ciclosporin.
    Pharmacodynamic interactions: 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.


    Pregnancy and Lactation

    Pregnancy: Pregnancy is an absolute contraindication to treatment with Toctino. 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.
    Lactation: 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.
    See prescribing information for full details.


    Overdose

    Alitretinoin is a derivative of vitamin A. Alitretinoin has been administered in oncological clinical studies at dosages of more than 10-times of the therapeutic dosage given for chronic hand eczema. The adverse effects observed were consistent with retinoid toxicity, and included severe headache, diarrhoea, facial flushing, hypertriglyceridemia. These effects were reversible.


    Important notes

    Storage: Toctino 10 mg – Do not store above 30°C. Store in the original package. Keep the blister in the outer carton in order to protect from light.
    Toctino 30 mg – Do not store above 25°C. Store in the original package. Keep the blister in the outer carton in order to protect from light.


    Manufacturer
    Swiss Caps Inc.
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