munosuppressants, including Envarsus are at increased risk for opportunistic infections (bacterial, fungal, viral, and protozoal). Among these conditions are BK virus associated nephropathy and JC virus associated progressive multifocal leukoencephalopathy (PML). These infections are often related to a high total immunosuppressive burden and may lead to serious or fatal conditions that physicians should consider in the differential diagnosis in immunosuppressed patients with deteriorating renal function or neurological symptoms.
Patients treated with tacrolimus have been reported to develop posterior reversible encephalopathy syndrome (PRES). If patients taking tacrolimus present with symptoms indicating PRES such as headache, altered mental status, seizures, and visual disturbances, a radiological procedure (e.g. MRI) should be performed. If PRES is diagnosed, adequate blood pressure and seizure control, and immediate discontinuation of systemic tacrolimus is advised. Most patients completely recover after appropriate measures are taken.
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 medicinal product associated with PRCA.
Special populations
There is limited experience in non-Caucasian patients and patients at elevated immunological risk (e.g. retransplantation, evidence of panel reactive antibodies, PRA).
Dose reduction may be necessary in patients with severe liver impairment (see section 4.2).
Excipients
Envarsus contains lactose. Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicinal product.
Paediatric population
Envarsus is not recommended for use in children below 18 years of age due to the limited data on safety and/or efficacy
4.5 Interaction with other medicinal products and other forms of interaction
Systemically available tacrolimus is metabolised by hepatic CYP3A4. There is also evidence of gastrointestinal metabolism by CYP3A4 in the intestinal wall. Concomitant use of substances known to inhibit or induce CYP3A4 may affect the metabolism of tacrolimus and thereby increase or decrease tacrolimus blood levels.
It is strongly recommended to closely monitor tacrolimus blood levels, as well as renal function and other side effects, whenever substances which have the potential to alter CYP3A4 metabolism or otherwise influence tacrolimus blood levels are used concomitantly, and to interrupt or adjust the tacrolimus dose as appropriate in order to maintain similar tacrolimus exposure (see sections 4.2 and 4.4).
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; HIV protease inhibitors (e.g. ritonavir, nelfinavir, saquinavir) or Hepatitis C Virus (HCV) protease inhibitors (e.g. telaprevir, boceprevir). Concomitant use of these substances may require decreased tacrolimus doses in nearly all patients.
Pharmacokinetics studies have indicated that the increase in blood levels is mainly a r |
