Graftac 0,5 mg/1 mg/5 mg Capsules

Primary immunosuppression in liver and kidney allograft recipients and liver, kidney or heart allograft rejection resistant to conventional immunosuppressive regimens.

Inadvertent, unintentional or unsupervised switching between immediate- and prolonged release formulations of tacrolimus such as [PRODUCT NAME] is unsafe. This can lead to graft rejection or increased incidence of side effects, including under- or overimmunosuppression, 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 formulation 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 postoperative period in heart transplant patients is problematic and creates difficulties in designing a suitable dosing regimen. Therefore initiation of [PRODUCT NAME] therapy via the intravenous route and conversion to oral dosing, when possible, or initiating [PRODUCT NAME] orally following antibody induction therapy are the two preferable options for use of [PRODUCT NAME] in heart transplant patients.

The dosage recommendations given below are intended to act as a guideline. [PRODUCT NAME] doses should be adjusted according to individual patient requirements. If the clinical condition of the patient allows oral dosing, administration of oral [PRODUCT NAME] 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. [PRODUCT NAME] is normally administered together with other immunosuppressive agents. In isolated cases, successful maintenance therapy with [PRODUCT NAME] alone has also been described. [PRODUCT NAME] 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.

Maintenance therapy in liver and kidney transplant recipients (adults and children) u2013 general considerations: Continuous immunosuppression with [PRODUCT NAME] 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 number of corticosteroids, introduction of short courses of monoclonal antibodies and increase in the dose of [PRODUCT NAME] have all been used to manage rejection episodes. If signs of toxicity are noted, the dose of [PRODUCT NAME] should be reduced. Patients should be instructed not to decrease the dose without the consent of the treating physician.

During the course of the post-transplant improvement of the patient, it is likely that the pharmacokinetics of [PRODUCT NAME] may be altered, requiring adjustment of the [PRODUCT NAME] 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: Initial administration: Initially, an oral dose in a range from 0,15 u2013 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 u2013 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: (see section 4.4) 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 [PRODUCT NAME] in liver or kidney transplant recipients: It is necessary to continue immunosuppression with oral [PRODUCT NAME] to maintain graft survival. Dosage recommendations should be based on individual patient experience (see introductory remarks above). There is a trend towards the use of lower doses of [PRODUCT NAME] during maintenance therapy. Dosing should be primarily based on clinical assessments of rejection and tolerability.

Rescue therapy with [PRODUCT NAME]: In patients experiencing rejection episodes that are unresponsive to conventional immunosuppressive therapy, [PRODUCT NAME] treatment should begin with the initial dose recommended for primary immunosuppression in that particular allograft. The combined administration of ciclosporin and [PRODUCT NAME] is not recommended as [PRODUCT NAME] may increase the half-life of ciclosporin and exacerbate any toxic effects (see section 4.5).

Therefore, care should be taken when converting patients from ciclosporin- to [PRODUCT NAME]-based therapy. It is recommended that ciclosporin blood levels are monitored prior to the administration of [PRODUCT NAME]. The most appropriate time to initiate [PRODUCT NAME] 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.

Dose adjustments in specific patient populations: Patients with liver impairment: A dose reduction may be necessary in patients with pre- and/or postoperative 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 [PRODUCT NAME] doses to achieve similar trough levels. Elderly patient: There is no evidence presently available to suggest that doses should be altered in elderly patients. Paediatric patients: The safety and efficacy of [PRODUCT NAME] 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 (see section 4.4).

Conversion from ciclosporin to [PRODUCT NAME]: Care should be taken when converting patients from ciclosporin-based to tacrolimus-based therapy. [PRODUCT NAME] 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, [PRODUCT NAME] 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.

Various assays have been used to measure blood or plasma levels of [PRODUCT NAME]. Monitoring of tacrolimus blood concentrations in conjunction with other laboratory and clinical parameters is considered an essential aid to patient management for the evaluation of rejection, toxicity, dose adjustments and compliance. Factors influencing frequency of monitoring include but are not limited to hepatic or renal dysfunction, the addition or discontinuation of potentially interacting medicines and the post transplant time interval. Blood concentration monitoring is not a replacement for renal and liver function monitoring and tissue biopsies. Whole blood specimens should be collected into tubes containing ethylene diamine tetra acetic acid (EDTA) anticoagulant. Heparin anticoagulation is not recommended because of the tendency to form clots on storage. Samples that are not analysed immediately should be stored at room temperature or in a refrigerator and assayed within 7 days; if samples are to be kept longer, they should be deep frozen at -20 u00baC for up to 12 months. [PRODUCT NAME] whole blood trough levels should be monitored periodically during maintenance therapy. The frequency of blood level monitoring should be based on clinical needs, but in general, because of its long half-life, it is unnecessary to measure blood levels on a daily basis. Medicine level monitoring (TDM) is recommended during the early post-transplantation period, following dose adjustment, after switching from another immunosuppressive regimen, and following co-administration of medicines which are likely to lead to interactions.

Clinical experience suggests that the majority of patients can be successfully managed if the blood concentrations of [PRODUCT NAME] are maintained below 25 ng/ml. It is necessary to consider the clinical condition of the patient when interpreting whole blood level concentrations. If the blood levels are below the limit of quantification of the assay and the patientu2019s clinical condition is satisfactory, then the dose should not be adjusted.

Method of administration: 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 and 5.2). 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 of dosing: To suppress graft rejection, the capsules normally have to be taken continuously. Therefore, no limitation of duration can be given.

• Hypersensitivity to tacrolimus, or other macrolides.
• Hypersensitivity to any of the excipients listed in section 6.1.
• Pregnancy and lactation (see section 4.6).
• As [PRODUCT NAME] 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.

[PRODUCT NAME] therapy requires careful monitoring in units equipped and staffed with adequate laboratory and supportive medical resources. [PRODUCT NAME] should only be prescribed and changes in immunosuppressive therapy should only be initiated by medical practitioners experienced in immunosuppressive therapy and the management of transplant patients. The medical practitioner responsible for maintenance therapy should have complete information requisite for the follow-up of the patient. Dose and/or blood level adjustment should only be undertaken by the transplant centre responsible for the transplant patient. Prolonged-release formulations of tacrolimus are not interchangeable with immediate-release formulations of tacrolimus, without careful monitoring and supervision by a transplant specialist.

Patients should be thoroughly controlled. In particular, during the first months post-transplant, close monitoring of the patient is required. [PRODUCT NAME] is not recommended for use in children below 18 years due to limited data on safety and/or efficacy. 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 overexposure 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. 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 may increase tacrolimus blood levels, which could lead to serious adverse reactions, including nephrotoxicity and QT prolongation. It is recommended that concomitant use of strong CYP3A4 inhibitors (such as ritonavir, telaprevir, boceprevir, cobicistat, ketoconazole, itraconazole, posaconazole, voriconazole, telithromycin, clarithromycin or josamycin) with [PRODUCT NAME] should be avoided. If unavoidable, tacrolimus blood levels should be monitored frequently, starting within the first few days of coadministration, under the supervision of a transplant specialist, to adjust the [PRODUCT NAME] dose if appropriate in order to maintain similar tacrolimus exposure. Renal function, ECG including the QT interval, and the clinical condition of the patient should also be closely monitored. Dose adjustment needs to be based upon the individual situation of each patient. An immediate dose reduction at the time of treatment initiation may be required (see section 4.5).

Similarly, discontinuation of CYP3A4 inhibitors may affect the rate of metabolism of [PRODUCT NAME], thereby leading to subtherapeutic blood levels of tacrolimus, and therefore requires close monitoring and supervision of a transplant specialist.

CYP3A4 inducers: Concomitant use with CYP3A4 inducers may decrease tacrolimus blood levels, potentially increasing the risk of transplant rejection. It is recommended that concomitant use of strong CYP3A4 inducers (such as rifampicin, rifabutin and anti-epileptic medicine such as phenytoin, carbamazepine), with [PRODUCT NAME] should be avoided. If unavoidable, tacrolimus blood levels should be monitored frequently, starting within the first few days of coadministration, under the supervision of a transplant specialist, to adjust the [PRODUCT NAME] dose if appropriate, in order to maintain similar tacrolimus exposure. Graft function should also be closely monitored (see section 4.5).

Similarly, discontinuation of CYP3A4 inducers may affect the rate of metabolism of [PRODUCT NAME], thereby leading to subtherapeutic blood levels of tacrolimus, and therefore requires close monitoring and supervision of a transplant specialist.

P-glycoprotein: Caution should be observed when co-administering tacrolimus with medicines that inhibit P-glycoprotein, as an increase in tacrolimus levels may occur. Tacrolimus whole blood levels and the clinical condition of the patient should be monitored closely. An adjustment of the [PRODUCT NAME] dose may be required (see section 4.5).

Herbal preparations: Herbal preparations containing St. Johnu2019s Wort (Hypericum perforatum) or other herbal preparations should be avoided when taking tacrolimus [PRODUCT NAME] due to the risk of interactions that lead to 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).

Other interactions: The combined administration of ciclosporin and tacrolimus should be avoided and care should be taken when administering tacrolimus to patients who have previously received ciclosporin (see section 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).

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

Breastfeeding: Human data on effects of [PRODUCT NAME] during the lactation period are limited. It has been demonstrated that tacrolimus is excreted into breast milk in animals. As detrimental effects on the newborn cannot be excluded, women should not breast-feed whilst receiving tacrolimus.

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).

[PRODUCT NAME] is associated with visual and neurological disturbances. Patients treated with [PRODUCT NAME] who are affected by such disorders should not drive a car or operate dangerous machines. This effect may be enhanced if tacrolimus is given together with alcohol.

Infections and infestations: Patients receiving [PRODUCT NAME] are frequently at increased risk for infections (viral, bacterial, mycobacterial, fungal, protozoal). The course of pre-existing infections may be aggravated. Both generalised and localised infections can occur. Cases of BK virus (a member of the Polyomavirus family) associated nephropathy, as well as cases of John Cunningham (JC) virus associated progressive multifocal leukoencephalopathy (PML), have been reported in patients treated with immunosuppressants, including [PRODUCT NAME].

Neoplasms benign, malignant and unspecified (including 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 and skin malignancies have been reported in association with [PRODUCT NAME] treatment.

Blood and lymphatic system disorders: Frequent: anaemia, leukopenia, thrombocytopenia, leukocytosis, red blood cell analyses abnormal. Less frequent: coagulopathies, coagulation and bleeding analyses abnormal, pancytopenia, neutropenia, thrombotic thrombocytopenic purpura, hypoprothrombinaemia, thrombotic microangiopathy. Frequency unknown: pure red cell aplasia, agranulocytosis, haemolytic anaemia.

Immune system disorders: Allergic and anaphylactoid reactions have been observed in patients receiving [PRODUCT NAME] (see section 4.4).

Endocrine disorders: Less frequent: hirsutism.

Metabolism and nutrition disorders: Frequent: hyperglycaemic conditions, diabetes mellitus, hyperkalaemia, hypomagnesaemia, hypophosphataemia, hypokalaemia, hypocalcaemia, hyponatraemia, fluid overload, hyperuricaemia, decreased appetite, anorexia, metabolic acidoses, hyperlipidaemia, hypercholesterolaemia, hypertriglyceridaemia, other electrolyte abnormalities. Less frequent: dehydration, hypoproteinaemia, hyperphosphataemia, hypoglycaemia.

Psychiatric disorders: Frequent: insomnia, anxiety symptoms, confusion and disorientation, depression, depressed mood, mood disorders and disturbances, nightmare, hallucination, mental disorders. Less frequent: psychotic disorder.

Nervous system disorders: Frequent: tremor, headache, seizures, disturbances in consciousness, paraesthesias and dysaesthesias, peripheral neuropathies, dizziness, impaired writing, nervous system disorders. Less frequent: coma, central nervous system haemorrhages and cerebrovascular accidents, paralysis and paresis, encephalopathy, speech and language abnormalities, amnesia, hypertonia, myasthenia.

Eye disorders: Frequent: blurred vision, photophobia, eye disorders. Less frequent: cataract, blindness. Frequency unknown: optic neuropathy.

Ear and labyrinth disorders: Frequent: tinnitus. Less frequent: hypoacusis, neurosensory deafness, impaired hearing.

Cardiac disorders: Frequent: ischaemic coronary artery disorders, tachycardia. Less frequent: ventricular arrhythmias and cardiac arrest, heart failures, cardiomyopathies, ventricular hypertrophy, supraventricular dysrhythmias, palpitations, abnormal ECG investigations, abnormal heart rate and pulse investigations, pericardial effusion, abnormal echocardiogram, QT prolonged Torsades de Pointes.

Vascular disorders: Frequent: hypertension, haemorrhage, thromboembolic and ischaemic events, peripheral vascular disorders, vascular hypotensive disorders. Less frequent: infarction, deep limb venous thrombosis, shock.

Respiratory, thoracic and mediastinal disorders: Frequent: dyspnoea, parenchymal lung disorders, pleural effusion, pharyngitis, cough, nasal congestion and inflammations, respiratory failures, respiratory tract disorders, asthma. Less frequent: acute respiratory distress syndrome.

Gastrointestinal disorders: Frequent: diarrhoea, nausea, gastrointestinal inflammatory conditions, gastrointestinal ulceration and perforation, gastrointestinal haemorrhages, stomatitis and ulceration, ascites, vomiting, gastrointestinal and abdominal pains, dyspeptic signs and symptoms, constipation, flatulence, bloating and distension, loose stools, gastrointestinal signs and symptoms. Less frequent: paralytic ileus, peritonitis, acute and chronic pancreatitis, increased blood amylase, gastroesophageal reflux disease, impaired gastric emptying, subileus, pancreatic pseudocyst.

Hepato-biliary disorders: Frequent: abnormal liver function tests, bile duct disorders, cholestasis and jaundice, hepatocellular damage and hepatitis, cholangitis. Less frequent: hepatic artery thrombosis, veno-occlusive liver disease, hepatic failure, bile duct stenosis.

Skin and subcutaneous tissue disorders: Frequent: pruritus, rash, alopecias, acne, increased sweating. Less frequent: dermatitis, photosensitivity, toxic epidermal necrolysis (Lyellu2019s syndrome), Stevens Johnson syndrome.

Musculoskeletal and connective tissue disorders: Frequent: arthralgia, muscle spasms, pain in limb, back pain. Less frequent: joint disorders, mobility decreased.

Renal and urinary disorders: Frequent: renal impairment, renal failure, renal failure acute, oliguria, renal tubular necrosis, nephropathy toxic, urinary abnormalities, bladder and urethral symptoms. Less frequent: anuria, haemolytic uraemic syndrome, nephropathy, cystitis haemorrhagic.

Reproductive system and breast disorders: Less frequent: dysmenorrhoea and uterine bleeding.

General disorders and administration site conditions: Frequent: asthenic conditions, febrile disorders, oedema, pain and discomfort, body temperature perception disturbed. Less frequent: multi-organ failure, influenza like illness, temperature intolerance, chest pressure sensation, feeling jittery, feeling abnormal, thirst, fall, chest tightness, ulcer, fat tissue increased. Frequency unknown: febrile neutropenia.

Investigations: Frequent: hepatic enzymes and function abnormalities, blood alkaline phosphatase increased, weight increased. Less frequent: amylase increased, ECG investigations abnormal, heart rate and pulse investigations abnormal, weight decreased, blood lactate dehydrogenase increased, echocardiogram abnormal, electrocardiogram QT prolonged.

Injury, poisoning and procedural complications: Frequent: primary graft dysfunction.

Experience with overdose is limited. Several cases of accidental overdose have been reported; symptoms have included tremor, headache, nausea and vomiting, infections, urticaria, lethargy, renal, neurological and cardiac disturbances, glucose intolerance, hypertension, electrolyte disorders (e.g., hyperkalaemia), increases blood urea nitrogen, and elevated serum creatinine concentrations, and increase in alanine aminotransferase levels. Liver function clearly influences all pre- and post-operative pharmacokinetic variables. Patients with failing liver grafts or those switched from other immunosuppressive therapy to [PRODUCT NAME] should be monitored carefully to avoid overdosage. No specific antidote to [PRODUCT NAME] therapy is available. If overdose 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 [PRODUCT NAME] will not be dialysable. In isolated patients with very high plasma levels, hemofiltration or diafiltration have been effective in reducing toxic concentrations. In cases of oral intoxication, gastric lavage and/or the use of adsorbents (such as activated charcoal) may be helpful, if used shortly after intake.