Tacrolimus 0,5 Mg/1 Mg/5 Mg Capsules

TACROLIMUS AUSTELL is indicated for primary immunosuppression in liver and kidney allograft recipients and liver, kidney or heart allograft rejection resistant to conventional immunosuppressive regimens.

Posology Inadvertent, unintentional or unsupervised switching between Immediate and prolonged release formulations of tacrolimus is unsafe. This can lead to graft rejection or increased incidence of side effects, including under or over - immunosuppression, due to clinically relevant differences in systemic exposure to tacrolimus. Patients should be maintained on a single formulation of tacrolimus with the corresponding daily dosing regimen; alterations in formulations or regimen should only take place under the close supervision of a transplant specialist. Following conversion to any alternative formulation, therapeutic medicine monitoring must be performed and dose adjustments made to ensure that systemic exposure to tacrolimus is maintained. Absorption of orally administered tacrolimus in the immediate post - operative period in heart transplant patients is problematic and creates difficulties in designing a suitable dosing regimen. Therefore initiation of tacrolimus therapy via the intravenous route and conversion to oral dosing, when possible, or initiating TACROLIMUS AUSTELL orally following antibody induction therapy are the two preferable options for use of TACROLIMUS AUSTELL in heart transplant patients. General statement The dosage recommendations given below for oral administration are intended to act as a guideline. TACROLIMUS AUSTELL doses should be adjusted according to individual patient requirements. If the clinical condition of the patient allows oral dosing, administration of oral tacrolimus, as in TACROLIMUS AUSTELL, should start as soon as practicable. In some liver transplantation patients, therapy has commenced orally by administering the capsule contents suspended in water via an intranasal gastric tube. TACROLIMUS AUSTELL is normally administered together with other immunosuppressive medicines. In isolated cases, successful maintenance therapy with TACROLIMUS AUSTELL alone has also been described. TACROLIMUS AUSTELL should not be given together with ciclosporin (see section 4.3). If allograft rejection or adverse events occur, alteration in the immunosuppressive regimen should be considered.

Mode of intake It is recommended that the oral daily dose should be taken in two divided doses. The capsules should be swallowed with fluid, preferably water. Based on pharmacokinetic considerations, the capsules should be taken on an empty stomach or at least 1 hour before or 2 to 3 hours after a meal to achieve maximal absorption (see section 4.5). The capsules should be taken out of the blister only immediately before intake. After opening the aluminium wrapper, the capsules from the blisters must be used within 12 months. Patients should be cautioned not to swallow the desiccant contained within the aluminium wrapper.

Duration and onset of intake To suppress graft rejection, the capsules normally have to be taken continuously. Therefore, no limitation of duration can be given. Maintenance therapy in liver and kidney transplant recipients (adults and children) u2013 General considerations Continuous immunosuppression with TACROLIMUS AUSTELL is recommended to maintain graft survival. If progression of disease occurs (e.g. signs of acute rejection), alteration of the immunosuppressive regimen should be considered. Increase in the amount of corticosteroids, introduction of short courses of monoclonal antibodies and increase in the dose of TACROLIMUS AUSTELL have all been used to manage rejection episodes. If signs of toxicity are noted, the dose of TACROLIMUS AUSTELL should be reduced. Patients should be instructed not to decrease the dose without the consent of the treating medical practitioner. During the course of the post - transplant improvement of the patient, it is likely that the pharmacokinetics of tacrolimus may be altered, requiring adjustment of the dose.

Primary immunosuppression - adult patients Liver transplantation Initially, an oral dose in a range from 0,10 to 0,20 mg/kg/day should be administered in two divided doses. Initial oral doses have been administered in a range from 0,02 to 0,30 mg/kg/day Kidney transplantation Initially, an oral dose in a range from 0,15 to 0,40 mg/kg/day should be administered in two divided doses. If the clinical condition of the patient does not allow for oral dosing, then an initial intravenous dose of 0,05 to 0,10 mg/kg/24 h should be administered as a continuous infusion within the first 24 hours after the completion of surgery. Patients should be converted from intravenous to oral medication as soon as the individual circumstances permit.

Primary immunosuppression dose levels u2013 paediatric patients Paediatric patients generally require doses 1u00bd to 2 times higher than the recommended adult doses to achieve the same blood levels. Experience with initial oral administration in paediatric patients is limited. Liver and kidney transplantation An initial dose of 0,30 mg/kg/day for liver and kidney transplantation should be administered in two divided doses. If the dose cannot be given orally, an initial intravenous dose of 0,05 mg/kg/day for liver transplantation or 0,10 mg/kg/day for kidney transplantation should be administered as a continuous 24 - hour infusion.

Maintenance therapy with TACROLIMUS AUSTELL in liver or kidney transplant recipients It is necessary to continue immunosuppression with oral TACROLIMUS AUSTELL to maintain graft survival. Dosage recommendations should be based on individual patient experience. There is a trend towards the use of lower doses of TACROLIMUS AUSTELL during maintenance therapy. Dosing should be primarily based on clinical assessments of rejection and tolerability.

Rescue therapy with TACROLIMUS AUSTELL In patients experiencing rejection episodes that are unresponsive to conventional immunosuppressive therapy, TACROLIMUS AUSTELL treatment should begin with the initial dose recommended for primary immunosuppression in that particular allograft. The combined administration of ciclosporin and TACROLIMUS AUSTELL is not recommended as TACROLIMUS AUSTELL may increase the half - life of ciclosporin and exacerbate any toxic effects (see Section 4.3). Therefore, care should be taken when converting patients from ciclosporin - to tacrolimus - based therapy. It is recommended that ciclosporin blood levels are monitored prior to the administration of TACROLIMUS AUSTELL. The most appropriate time to initiate tacrolimus therapy should be based upon information on ciclosporin blood levels and the clinical condition of the patient. Dosing may be delayed in the presence of elevated ciclosporin levels e.g. in patients experiencing renal failure. Monitoring of ciclosporin blood levels should be continued following conversion as the clearance of ciclosporin may be affected.

Heart allograft rejection An initial oral dose of 0,30 mg/kg/day should be administered in two divided doses (e.g. morning and evening). If the clinical condition of the patient prevents oral administration, an intravenous dose of 0,05 mg/kg/day should be administered as a continuous 24 - hour infusion.

Special populations Patients with liver impairment A dose reduction may be necessary in patients with pre - and/or post - operative impairment, e.g. early graft dysfunction. Patients with kidney impairment No adjustment in dose is regarded as necessary on pharmacokinetic principles. However, careful monitoring of renal function, including serial creatinine estimations, calculations of creatinine clearance and monitoring of urine output, is recommended. Race In comparison to caucasians, black patients may require higher doses to achieve similar trough levels. Elderly patients There is no evidence presently available to suggest that doses should be altered in elderly patients. Paediatric patients The safety and efficacy of TACROLIMUS AUSTELL in children under 18 years of age have not yet been established. Limited data are available but no recommendation on a dosage can be made. Conversion from ciclosporin to TACROLIMUS AUSTELL Care should be taken when converting patients from ciclosporin - based to tacrolimus - based therapy. TACROLIMUS AUSTELL therapy should be initiated after considering ciclosporin blood concentrations and the clinical condition of the patient. Dosing should be delayed in the presence of elevated ciclosporin blood levels. In practice, TACROLIMUS AUSTELL therapy has been initiated 12 to 24 hours after discontinuation of ciclosporin. Monitoring of ciclosporin blood levels should be continued following conversion as the clearance of ciclosporin might be affected.

• Known hypersensitivity to tacrolimus, the tacrolimus in TACROLIMUS AUSTELL or other macrolides.
• Pregnancy and lactation (see sections 4.6).
• Known hypersensitivity to other ingredients of the capsules.
• Oral contraceptives (as tacrolimus may alter the metabolism of oral contraceptives), other forms of contraception should be used.
• Concomitant administration of live attenuated vaccines.
• Concomitant administration with ciclosporin.
• Concomitant use with grapefruit juice.

Medication errors, including inadvertent, unintentional or unsupervised substitution of immediate - or prolonged - release tacrolimus formulations, have been observed. This has led to serious adverse events, including graft rejection, or other side effects 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).

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. Prolonged - release formulations of tacrolimus are not interchangeable with immediate - release formulations of tacrolimus without careful monitoring and supervision by a transplant specialist. If clinically relevant changes are seen, adjustments of the immunosuppressive regimen should be considered.

Substances with potential for interaction When substances with a potential for interaction (see section 4.5) - particularly strong inhibitors of CYP3A4 (such as telaprevir, boceprevir, ritonavir, ketoconazole, voriconazole, itraconazole, telithromycin or clarithromycin) or inducers of CYP3A4 (such as rifampicin, rifabutin) u2013 are being combined with tacrolimus, tacrolimus blood levels should be monitored to adjust the tacrolimus dose as appropriate in order to maintain similar tacrolimus exposure.

Herbal preparations containing St. John's wort (Hypericum perforatum) or other herbal preparations should be avoided when taking TACROLIMUS AUSTELL due to the risk of interactions that lead to either a decrease in blood concentrations of tacrolimus and reduced clinical effect of tacrolimus, or an increase in blood concentrations of tacrolimus and risk of tacrolimus toxicity (see section 4.5). The combined administration of ciclosporin and tacrolimus is contraindicated (see section 4.3) and care should be taken when administering tacrolimus to patients who have previously received ciclosporin (see sections 4.2 and 4.5). High potassium intake or potassium - sparing diuretics should be avoided (see section 4.5). Certain combinations of tacrolimus with medicines known to have nephrotoxic or neurotoxic effects may increase the risk of these effects (see section 4.5).

Vaccination Immunosuppressants may affect the response to vaccination and vaccination during treatment with tacrolimus may be less effective. The use of live attenuated vaccines is contraindicated (see section 4.3).

Gastrointestinal disorders Gastrointestinal perforation has been reported in patients treated with tacrolimus. As gastrointestinal perforation is a medically important event that may lead to a life - threatening or serious condition, adequate treatments should be considered immediately after suspected symptoms or signs occur. Since levels of tacrolimus in blood may significantly change during diarrhoea episodes, extra monitoring of tacrolimus concentrations is recommended during episodes of diarrhoea.

Cardiac disorders Ventricular hypertrophy or hypertrophy of the septum, reported as cardiomyopathies, have been observed on rare occasions. Most cases have been reversible, occurring primarily in children with tacrolimus blood trough concentrations much higher than the recommended maximum levels. Other factors observed to increase the risk of these clinical conditions included pre - existing heart disease, corticosteroid usage, hypertension, renal or hepatic dysfunction, infections, fluid overload, and oedema. Accordingly, high - risk patients, particularly young children and those receiving substantial immunosuppression should be monitored, using such procedures as echocardiography or ECG pre - and post - transplant (e.g. initially at three months and then at 9 - 12 months). If abnormalities develop, dose reduction of TACROLIMUS AUSTELL therapy, or change of treatment to another immunosuppressive agent should be considered. Tacrolimus may prolong the QT interval and may cause Torsades de Pointes. Caution should be exercised in patients with risk factors for QT prolongation, including patients with a personal or family history of QT prolongation, congestive heart failure, bradydysrhythmias and electrolyte abnormalities. Caution should also be exercised in patients diagnosed or suspected to have Congenital Long QT Syndrome or acquired QT prolongation or patients on concomitant medications known to prolong the QT interval, induce electrolyte abnormalities or known to increase tacrolimus exposure (see section 4.5).

Lymphoproliferative disorders and malignancies Patients treated with tacrolimus, as contained in TACROLIMUS AUSTELL have been reported to develop Epstein - Barr virus (EBV) - associated lymphoproliferative disorders (see section 4.8). Patients switched to TACROLIMUS AUSTELL therapy should not receive anti - lymphocyte treatment concomitantly. Very young (< 2 years), EBV - VCA - negative children have been reported to have an increased risk of developing lymphoproliferative disorders. Therefore, in this patient group, EBV - VCA serology should be ascertained before starting treatment with TACROLIMUS AUSTELL. During treatment, careful monitoring with EBV - PCR is recommended. Positive EBV - PCR may persist for months and is per se not indicative of lymphoproliferative disease or lymphoma. As with other immunosuppressive medicines, owing to the potential risk of malignant skin changes, exposure to sunlight and UV light should be limited by wearing protective clothing and using a sunscreen with a high protection factor. As with other potent immunosuppressive compounds, the risk of secondary cancer is unknown (see section 4.8).

Posterior reversible encephalopathy syndrome (PRES) 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 control and immediate discontinuation of systemic tacrolimus is advised. Most patients completely recover after appropriate measures are taken.

Eye disorders Eye disorders, sometimes progressing to loss of vision, have been reported in patients treated with tacrolimus. Some cases have reported resolution on switching to alternative immunosuppression. Patients should be advised to report changes in visual acuity, changes in colour vision, blurred vision, or visual field defect, and in such cases, prompt evaluation is recommended with referral to an ophthalmologist as appropriate.

Infections including opportunistic infections Patients treated with immunosuppressants, including TACROLIMUS AUSTELL are at increased risk for infections including opportunistic infections (bacterial, fungal, viral and protozoal) such as BK virus associated nephropathy and JC virus associated progressive multifocal leukoencephalopathy (PML). Patients are also at an increased risk of infections with viral hepatitis (for example, hepatitis B and C reactivation and de novo infection, as well as hepatitis E, which may become chronic). 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 hepatic or renal function or neurological symptoms. Prevention and management should be in accordance with appropriate clinical guidance.

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.

Excipients: lactose intolerance This medicine contains lactose: Patients with rare hereditary problems of galactose intolerance, total lactase deficiency or glucose - galactose malabsorption should not take this medicine.

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. It is therefore strongly recommended to closely monitor tacrolimus blood levels, as well as, QT prolongation (with ECG), renal function and other side effects, whenever substances which have the potential to alter CYP3A4 metabolism 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).

Inhibitors of metabolism Clinically the following substances have been shown to increase tacrolimus blood levels: Strong interactions have been observed with antifungal medicines such as ketoconazole, fluconazole, itraconazole, voriconazole, and isavuconazole, the macrolide antibiotic erythromycin, HIV protease inhibitors (e.g. ritonavir, nelfinavir, saquinavir) or HCV protease inhibitors (e.g. telaprevir, boceprevir, and the combination of ombitasvir and paritaprevir with ritonavir, when used with and without dasabuvir), the pharmacokinetic enhancer cobicistat, and the tyrosine kinase inhibitors nilotinib and imatinib. Concomitant use of these substances may require decreased tacrolimus doses in nearly all patients. Weaker interactions have been observed with clotrimazole, clarithromycin, josamycin, nifedipine, nicardipine, diltiazem, verapamil, amiodarone, danazol, ethinylestradiol, omeprazole, nefazodone and (Chinese) herbal remedies containing extracts of Schisandra sphenanthera.

In vitro the following substances have been shown to be potential inhibitors of tacrolimus metabolism: bromocriptine, cortisone, dapsone, ergotamine, gestodene, lidocaine, mephenytoin, miconazole, midazolam, nilvadipine, norethisterone, quinidine, tamoxifen, troleandomycin. Grapefruit juice has been reported to increase the blood level of tacrolimus and concomitant use is therefore contraindicated (see section 4.3).

Lansoprazole and ciclosporin may potentially inhibit CYP3A4 - mediated metabolism of tacrolimus and thereby increase tacrolimus whole blood concentrations. Other interactions potentially leading to increased tacrolimus blood levels Tacrolimus is extensively bound to plasma proteins. Possible interactions with other medicinal products known to have high affinity for plasma proteins should be considered (e.g., NSAIDs, oral anticoagulants, or oral antidiabetics). Other potential interactions that may increase systemic exposure of tacrolimus include the prokinetic agent metoclopramide, cimetidine and magnesium - aluminium - hydroxide.

Inducers of metabolism Clinically the following substances have been shown to decrease tacrolimus blood levels: Strong interactions have been observed with rifampicin, phenytoin or St. John's Wort (Hypericum perforatum) which may require increased tacrolimus doses in almost all patients. Clinically significant interactions have also been observed with phenobarbital. Maintenance doses of corticosteroids have been shown to reduce tacrolimus blood levels. High dose prednisolone or methylprednisolone administered for the treatment of acute rejection have the potential to increase or decrease tacrolimus blood levels. Carbamazepine, metamizole and isoniazid have the potential to decrease tacrolimus concentrations.

Effect of tacrolimus on the metabolism of other medicinal products Tacrolimus is a known CYP3A4 inhibitor; thus concomitant use of tacrolimus with medicinal products known to be metabolised by CYP3A4 may affect the metabolism of such medicinal products. The half - life of ciclosporin is prolonged when tacrolimus is given concomitantly. In addition, synergistic/additive nephrotoxic effects can occur. For these reasons, the combined administration of ciclosporin and tacrolimus is not recommended and care should be taken when administering tacrolimus to patients who have previously received ciclosporin (see sections 4.2 and 4.4). Tacrolimus has been shown to increase the blood level of phenytoin. As tacrolimus may reduce the clearance of steroid - based contraceptives leading to increased hormone exposure, particular care should be exercised when deciding upon contraceptive measures (see also section 4.3). Limited knowledge of interactions between tacrolimus and statins is available. Available data suggests that the pharmacokinetics of statins are largely unaltered by the co - administration of tacrolimus. Animal data have shown that tacrolimus could potentially decrease the clearance and increase the half - life of pentobarbital and phenazone. Mycophenolic acid. Caution should be exercised when switching combination therapy from ciclosporin, which interferes with enterohepatic recirculation of mycophenolic acid, to tacrolimus, which is devoid of this effect, as this might result in changes of mycophenolic acid exposure. Drugs which interfere with mycophenolic acid's enterohepatic cycle have potential to reduce the plasma level and efficacy of mycophenolic acid. Therapeutic drug monitoring of mycophenolic acid may be appropriate when switching from ciclosporin to tacrolimus or vice versa. Other interactions which have led to clinically detrimental effects Concurrent use of tacrolimus with medicine known to have nephrotoxic or neurotoxic effects may increase these effects (e.g., aminoglycosides, gyrase inhibitors, vancomycin, sulfamethoxazole + trimethoprim, NSAIDs, ganciclovir or acyclovir). Enhanced nephrotoxicity has been observed following the administration of amphotericin B and ibuprofen in conjunction with tacrolimus. As tacrolimus treatment may be associated with hyperkalaemia, or may increase pre - existing hyperkalaemia, high potassium intake, or potassium - sparing diuretics (e.g., amiloride, triamterene, or spironolactone) should be avoided (see section 4.4).

Pregnancy TACROLIMUS AUSTELL is contraindicated in pregnancy. In animal studies (rats and rabbits), TACROLIMUS AUSTELL has been shown to be teratogenic at doses that also demonstrated maternal toxicity. Preclinical and human data show that TACROLIMUS AUSTELL is able to cross the placenta. The possibility of pregnancy should therefore be excluded before initiating TACROLIMUS AUSTELL therapy.

Breastfeeding Human data demonstrate that tacrolimus is excreted into breast milk. As detrimental effects on the newborn cannot be excluded, women should not breast - feed whilst receiving TACROLIMUS AUSTELL (see section 4.3).

Fertility A negative effect of tacrolimus on male fertility in the form of reduced sperm counts and motility was observed in rats.

Tacrolimus may cause visual and neurological disturbances. This effect may be enhanced if TACROLIMUS AUSTELL is administered in association with alcohol.

a) Summary of the safety profile The adverse drug reaction profile associated with immunosuppressive medicines is often difficult to establish owing to the underlying disease and the concurrent use of multiple medications. Many of the adverse drug reactions stated below are reversible and/or respond to dose reduction. Oral administration appears to be associated with a lower incidence of adverse drug reactions compared with intravenous use.

b) Tabulated list of adverse reactions The table below shows all adverse drug reactions (ADRs) observed during clinical trials and postmarket spontaneous reports with Tacrolimus. Frequency estimate: Frequent (u2265 1/100) Less frequent (< 1/100) Not known (cannot be estimated from the available data).

Experience with overdosage is limited. Several cases of accidental overdosage have been reported; symptoms have included tremor, headache, nausea and vomiting, infections, urticaria, lethargy, increased blood urea nitrogen and elevated serum creatinine concentrations, and increase in alanine aminotransferase levels. No specific antidote to TACROLIMUS AUSTELL therapy is available. If overdosage occurs, general supportive measures and symptomatic treatment should be conducted. Based on its high molecular weight, poor aqueous solubility, and extensive erythrocyte and plasma protein binding, it is anticipated that tacrolimus will not be dialysable. In isolated patients with very high plasma levels, haemofiltration or diafiltration have been effective in reducing toxic concentrations. In cases of oral intoxication, the use of adsorbents (such as activated charcoal) may be helpful, if used shortly after intake.