Advagraf · 4.3 Contraindications · 1

HOS-094488 · has-adverse-reaction-information · PDF-Seite 15

The adverse reaction profile associated with immunosuppressive agents is often difficult to establish owing to the underlying disease and the concurrent use of multiple medicinal products. The most commonly reported adverse reactions (occurring in > 10% of patients) are tremor, renal impairment, hyperglycaemic conditions, diabetes mellitus, hyperkalaemia, infections, hypertension and insomnia. The frequency of adverse reactions is defined as follows: very common (≥ 1/10); common (≥ 1/100 to < 1/10); uncommon (≥ 1/1,000 to < 1/100); rare (≥ 1/10,000 to < 1/1,000); very rare (< 1/10,000), not known (cannot be estimated from the available data). Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness. Infections and infestations As is well known for other potent immunosuppressive agents, patients receiving tacrolimus are frequently at increased risk for infections (viral, bacterial, fungal, protozoal). The course of pre- existing infections may be aggravated. Both generalised and localised infections can occur. Cases of CMV infection, BK virus associated nephropathy, as well as cases of JC virus associated progressive multifocal leukoencephalopathy (PML), have been reported in patients treated with immunosuppressants, including Advagraf. Neoplasms benign, malignant and unspecified (incl. cysts and polyps) Patients receiving immunosuppressive therapy are at increased risk of developing malignancies. Benign as well as malignant neoplasms including EBV-associated lymphoproliferative disorders, skin malignancies and Kaposi’s sarcoma have been reported in association with tacrolimus treatment. Blood and lymphatic system disorders common: anaemia, thrombocytopenia, leukopenia, red blood cell analyses abnormal, leukocytosis uncommon: coagulopathies, pancytopenia, neutropenia, coagulation and bleeding analyses, abnormal, thrombotic microangiopathy rare: thrombotic thrombocytopenic purpura, hypoprothrombinaemia not known: pure red cell aplasia, agranulocytosis, haemolytic anaemia, febrile neutropenia Immune system disorders Allergic and anaphylactoid reactions have been observed in patients receiving tacrolimus (see section 4.4). Endocrine disorders rare: hirsutism Metabolism and nutrition disorders very common: diabetes mellitus, hyperglycaemic conditions, hyperkalaemia common: metabolic acidoses, other electrolyte abnormali

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HOS-094484 · has-contraindication-information · PDF-Seite 6

Hypersensitivity to tacrolimus, or to any of the excipients listed in section 6.1. Hypersensitivity to other macrolides.

HOS-094483 · has-indication-information · PDF-Seite 3

Prophylaxis of transplant rejection in adult kidney or liver allograft recipients. Treatment of allograft rejection resistant to treatment with other immunosuppressive medicinal products in adult patients.

HOS-094486 · has-interaction-information · PDF-Seite 10

Metabolic interactions Systemically available tacrolimus is metabolised by hepatic CYP3A4. There is also evidence of gastrointestinal metabolism by CYP3A4 in the intestinal wall. Concomitant use of medicinal products or herbal remedies known to inhibit or induce CYP3A4 may affect the metabolism of tacrolimus and thereby increase or decrease tacrolimus blood levels. Similarly, discontinuation of such products or herbal remedies may affect the rate of metabolism of tacrolimus and thereby the blood levels of tacrolimus. Pharmacokinetics studies have indicated that the increase in tacrolimus blood levels when co- administered with inhibitors of CYP3A4 is mainly a result of increase in oral bioavailability of tacrolimus owing to the inhibition of gastrointestinal metabolism. Effect on hepatic clearance is less pronounced. It is recommended strongly to closely monitor tacrolimus blood levels under supervision of a transplant specialist, as well as, monitor for graft function, QT prolongation (with ECG), renal function and other side effects including neurotoxicity, whenever substances which have the potential to alter CYP3A4 metabolism are used concomitantly, and to adjust or interrupt the tacrolimus dose if appropriate in order to maintain similar tacrolimus exposure (see sections 4.2 and 4.4). Similarly, patients should be closely monitored when using tacrolimus concomitantly with multiple substances that affect CYP3A4 as the effects on tacrolimus exposure may be enhanced or counteracted. Medicinal products which have effects on tacrolimus are listed in the table below. The examples of drug-drug interactions are not intended to be inclusive or comprehensive and therefore the label of each drug that is co-administered with tacrolimus should be consulted for information related to the route of metabolism, interaction pathways, potential risks, and specific actions to be taken with regards to co-administration. Medicinal products which have effects on tacrolimus Drug/Substance Class or Drug interaction effect Recommendations concerning Name co-administration Grapefruit or grapefruit juice May increase tacrolimus whole Avoid grapefruit or grapefruit blood trough concentrations and juice. increase the risk of serious adverse reactions (e.g., neurotoxic

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HOS-094487 · has-pregnancy-information · PDF-Seite 14

Pregnancy Data from women show that tacrolimus crosses the placenta. There is a risk for hyperkalaemia in the newborn (e.g. incidence in neonates of 7.2%, i.e., 8 of 111) which tends to normalise spontaneously. Tacrolimus treatment can be considered in pregnant women, when there is no safer alternative and when the perceived benefit justifies the potential risk to the foetus. In case of in utero exposure, monitoring of the newborn for the potential adverse events of tacrolimus is recommended (in particular effects on the kidneys). Results from a non-interventional post-authorisation safety study [EUPAS37025] A post-authorisation safety study analysed 2,905 pregnancies from the Transplant Pregnancy Registry International (TPRI), assessing outcomes in women treated with tacrolimus (383 reported prospectively, including 247 kidney and 136 liver transplant patients), and those on other immunosuppressants. Based on limited data (289 prospectively-reported pregnancies with 1st trimester tacrolimus exposure), study results did not indicate an increased risk of major malformations. A higher prevalence of spontaneous abortion was observed among women treated with tacrolimus compared with alternative immunosuppressants. Among kidney transplant patients there was also a higher prevalence of pre-eclampsia in women treated with tacrolimus. However, overall, there were insufficient evidence to conclude on the risk of these outcomes. Among kidney and liver transplant patients exposed to tacrolimus, 45% - 55% of their live births were premature, with 75% - 85% having a normal birth weight for gestational age. Similar results were observed for other immunosuppressants, although conclusions were hindered by limited evidence. In rats and rabbits, tacrolimus caused embryofoetal toxicity at doses which demonstrated maternal toxicity (see section 5.3). Breast-feeding Human data demonstrate that tacrolimus is excreted in breast milk. As detrimental effects on the newborn cannot be excluded, women should not breast-feed whilst receiving Advagraf. Fertility A negative effect of tacrolimus on male fertility in the form of reduced sperm counts and motility was observed in rats (see section 5.3). 14

HOS-094485 · has-warning-information · PDF-Seite 6

Medication errors, including inadvertent, unintentional or unsupervised substitution of immediate- or prolonged-release tacrolimus formulations, have been observed. 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. Patients should be maintained on a single formulation of tacrolimus with the corresponding daily dosing regimen; alterations in formulation or regimen should only take place under the close supervision of a transplant specialist (see sections 4.2 and 4.8). Advagraf is not recommended for use in children below 18 years due to limited data on safety and/or efficacy. For treatment of allograft rejection resistant to treatment with other immunosuppressive medicinal products in adult patients clinical data are not yet available for the prolonged-release formulation Advagraf. For prophylaxis of transplant rejection in adult heart allograft recipients clinical data are not yet available for Advagraf. During the initial post-transplant period, monitoring of the following parameters should be undertaken on a routine basis: blood pressure, ECG, neurological and visual status, fasting blood glucose levels, electrolytes (particularly potassium), liver and renal function tests, haematology parameters, coagulation values, and plasma protein determinations. If clinically relevant changes are seen, adjustments of the immunosuppressive regimen should be considered. Substances with potential for interaction Inhibitors or inducers of CYP3A4 should only be co-administered with tacrolimus after consulting a transplant specialist, due to the potential for drug interactions resulting in serious adverse reactions including rejection or toxicity (see section 4.5). CYP3A4 inhibitors Concomitant use with CYP3A4 inhibitors may increase tacrolimus blood levels, which could lead to serious adverse reactions, including nephrotoxicity, neurotoxicity and QT prolongation. It is recommended that concomitant use of strong CYP3A4 inhibitors (such as ritonavir, cobicistat, ketoconazole, itraconazole, posaconazole, voriconazole, telithromycin, clarithromycin or josamycin) 6 with tacrolimus should be avoided. If unavoidable, tacrolimus blood levels should be monitored frequently, starting within the first few days of co-administration, under the supervision of a transplant specialist, to adjust the tac

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