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2. QUALITATIVE AND QUANTITATIVE COMPOSITION
Each prolonged-release hard capsule contains 3 mg tacrolimus (as monohydrate).
Excipients with known effect:
Each capsule contains 306.52 mg lactose.
For the full list of excipients, see section 6.1.
4.2 Posology and method of administration
This can lead to graft rejection or increased incidence of adverse reactions, including under- or overimmunosuppression, due to clinically relevant differences in systemic exposure to tacrolimus
In de novo kidney and liver transplant patients AUC0-24 of tacrolimus for Advagraf on Day 1 was 30% and 50% lower respectively, when compared with that for the immediate release capsules (Prograf) at equivalent doses
Special populations
Hepatic impairment
Paediatric patients
The safety and efficacy of Advagraf in children under 18 years of age have not yet been established. Limited data are available but no recommendation on a posology can be made.
4.3 Contraindications
Hypersensitivity to tacrolimus, or to any of the excipients listed in section 6.1
4.4 Special warnings and precautions for use
This has led to serious adverse reactions, including graft rejection, or other adverse reactions which could be a consequence of either under- or over-exposure to tacrolimus.
Lymphoproliferative disorders and malignancies
Patients treated with tacrolimus have been reported to develop Epstein-Barr Virus (EBV)-associated lymphoproliferative disorders (see section 4.8).
Excipients
Advagraf capsules contain lactose.
4.6 Fertility, pregnancy and lactation Pregnancy Limited data from organ transplant recipients show no evidence of an increased risk of adverse reactions on the course and outcome of pregnancy under tacrolimus treatment compared with other immunosuppressive medicinal products. Breast-feeding 4.7 Effects on ability to drive and use machines Tacrolimus may cause visual and neurological disturbances. This effect may be enhanced if tacrolimus is administered in association with alcohol. 5. PHARMACOLOGICAL PROPERTIES 5.1 Pharmacodynamic properties Pharmacotherapeutic group: Immunosuppressants, calcineurin inhibitors, ATC code: L04AD02 6.5 Nature and contents of container Transparent PVC/PVDC aluminium blister or unit-dose perforated blister wrapped in an aluminium wrapper with a desiccant containing 10 capsules per blister. 9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION Date of first authorisation: 23/04/2007 Date of latest renewal: 23/04/2012 10. DATE OF REVISION OF THE TEXT Detailed information on this medicinal product is available on the website of the European Medicines Agency http://www.ema.europa.eu.
Pregnancy
Limited data from organ transplant recipients show no evidence of an increased risk of adverse reactions on the course and outcome of pregnancy under tacrolimus treatment compared with other immunosuppressive medicinal products.
Breast-feeding
4.7 Effects on ability to drive and use machines Tacrolimus may cause visual and neurological disturbances. This effect may be enhanced if tacrolimus is administered in association with alcohol. 5. PHARMACOLOGICAL PROPERTIES 5.1 Pharmacodynamic properties Pharmacotherapeutic group: Immunosuppressants, calcineurin inhibitors, ATC code: L04AD02 6.5 Nature and contents of container Transparent PVC/PVDC aluminium blister or unit-dose perforated blister wrapped in an aluminium wrapper with a desiccant containing 10 capsules per blister. 9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION Date of first authorisation: 23/04/2007 Date of latest renewal: 23/04/2012 10. DATE OF REVISION OF THE TEXT Detailed information on this medicinal product is available on the website of the European Medicines Agency http://www.ema.europa.eu.
4.7 Effects on ability to drive and use machines
Tacrolimus may cause visual and neurological disturbances. This effect may be enhanced if tacrolimus is administered in association with alcohol.
5. PHARMACOLOGICAL PROPERTIES
5.1 Pharmacodynamic properties
Pharmacotherapeutic group: Immunosuppressants, calcineurin inhibitors, ATC code: L04AD02
6.5 Nature and contents of container
Transparent PVC/PVDC aluminium blister or unit-dose perforated blister wrapped in an aluminium wrapper with a desiccant containing 10 capsules per blister.
9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION
Date of first authorisation: 23/04/2007
Date of latest renewal: 23/04/2012
10. DATE OF REVISION OF THE TEXT
Detailed information on this medicinal product is available on the website of the European Medicines Agency http://www.ema.europa.eu.
Blood and lymphatic system disorders
common:
anaemia, thrombocytopenia, leukopenia, red blood cell analyses abnormal, leukocytosis
uncommon:
coagulopathies, pancytopenia, neutropenia, coagulation and bleeding analyses, abnormal
rare:
thrombotic thrombocytopenic purpura, hypoprothrombinaemia
not known: pure red cell aplasia, agranulocytosis, haemolytic anaemia
Pure Red Cell Aplasia Cases of pure red cell aplasia (PRCA) have been reported in patients treated with tacrolimus. All patients reported risk factors for PRCA such as parvovirus B19 infection, underlying disease or concomitant medications associated with PRCA. 4.5 Interaction with other medicinal products and other forms of interaction CYP3A4 inhibitors potentially leading to increased tacrolimus blood levels Clinically the following substances have been shown to increase tacrolimus blood levels: Strong interactions have been observed with antifungal agents such as ketoconazole, fluconazole, itraconazole and voriconazole, the macrolide antibiotic erythromycin or HIV protease inhibitors (e.g. ritonavir). 4.8 Undesirable effects Blood and lymphatic system disorders common: anaemia, thrombocytopenia, leukopenia, red blood cell analyses abnormal, leukocytosis uncommon: coagulopathies, pancytopenia, neutropenia, coagulation and bleeding analyses, abnormal rare: thrombotic thrombocytopenic purpura, hypoprothrombinaemia not known: pure red cell aplasia 10. DATE OF REVISION OF THE TEXT 09/2011
Pure Red Cell Aplasia
Cases of pure red cell aplasia (PRCA) have been reported in patients treated with tacrolimus. All patients reported risk factors for PRCA such as parvovirus B19 infection, underlying disease or concomitant medications associated with PRCA.
4.5 Interaction with other medicinal products and other forms of interaction CYP3A4 inhibitors potentially leading to increased tacrolimus blood levels Clinically the following substances have been shown to increase tacrolimus blood levels: Strong interactions have been observed with antifungal agents such as ketoconazole, fluconazole, itraconazole and voriconazole, the macrolide antibiotic erythromycin or HIV protease inhibitors (e.g. ritonavir). 4.8 Undesirable effects Blood and lymphatic system disorders common: anaemia, thrombocytopenia, leukopenia, red blood cell analyses abnormal, leukocytosis uncommon: coagulopathies, pancytopenia, neutropenia, coagulation and bleeding analyses, abnormal rare: thrombotic thrombocytopenic purpura, hypoprothrombinaemia not known: pure red cell aplasia 10. DATE OF REVISION OF THE TEXT 09/2011
CYP3A4 inhibitors potentially leading to increased tacrolimus blood levels
Clinically the following substances have been shown to increase tacrolimus blood levels:
Strong interactions have been observed with antifungal agents such as ketoconazole, fluconazole, itraconazole and voriconazole, the macrolide antibiotic erythromycin or HIV protease inhibitors (e.g. ritonavir).
not known: pure red cell aplasia
09/2011
Section 6.5 Nature and contents of container
Unit-dose perforated blister
Packs sizes: 30x1, 50x1 and 100x1 prolonged-release hard capsule in unit-dose perforated blisters.
8. Marketing Authorisation Number
EU/1/07/387/021
EU/1/07/387/022
EU/1/07/387/023
10. Date of Revision of the Text
08/2010