Tacrolimus 0,5 mg/1,0 mg/5,0 mg Capsules

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

General statement: Tacrolimus therapy requires careful monitoring by adequately qualified and equipped personnel. It should only be prescribed, and changes in immunosuppressive therapy should be initiated by medical practitioners experienced in immunosuppressive therapy and the management of transplant patients. The dosage recommendations given below for oral administration are intended to act as a guideline. TACROLIMUS TEVA doses should be adjusted according to individual patient requirements. If the clinical condition of the patient allows oral dosing, administration of oral TACROLIMUS TEVA should start as soon as practicable. In some liver transplantation patients, therapy has commenced orally by administering the capsule contents suspended in water via and intranasal gastric tube. TACROLIMUS TEVA is normally administered together with other immunosuppressive medicines. In isolated cases, successful maintenance therapy with TACROLIMUS TEVA alone has also been described. TACROLIMUS TEVA 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) u2013 general considerations: Continuous immunosuppression with TACROLIMUS TEVA 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 TEVA have all been used to manage rejection episodes. If signs of toxicity are noted, the dose of TACROLIMUS TEVA 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 TEVA may be altered, requiring adjustment of the TACROLIMUS TEVA dose.

Whole blood concentration monitoring: Various assays have been used to measure blood or plasma levels of TACROLIMUS TEVA. 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. Blood concentration monitoring is not a replacement for renal and liver function monitoring and tissue biopsies. Two methods have been used for the assay of tacrolimus, a micro particle enzyme immunoassay (MEIA) and an enzyme linked immunosorbent assay (ELISA). Both methods have been used for the assays must be made with detailed knowledge of the assay methods and biological matrices employed. Whole blood is the matrix of choice and specimens should be collected into tubes containing ethylene diamine tetra acetic acid (EDTA) anticoagulant. Heparin anticoagulant is not recommended because of the tendency to form clots during 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. TACROLIMUS TEVA 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 necessary to measure blood levels on a daily basis. Blood concentration monitoring 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 medicine-medicine interactions. Clinical experience suggests that the majority of patients can be successfully managed if the blood concentrations of TACROLIMUS TEVA 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.

Primary immunosuppression u2013 Adult patients: Liver transplantation Oral administration: Initially, an oral dose of TACROLIMUS TEVA in a range from 0,10 to 0,20 mg/kg/day should be administered is two divided doses. Initial oral doses have been administered in a range from 0,02 to 0,03 mg/kg/day. Kidney transplantation Initial administration: Initially, an oral dose of TACROLIMUS TEVA 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, initial intravenous administration should commence 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, initial intravenous administration should commence as a continuous 24 hour infusion. Maintenance therapy with TACROLIMUS TEVA in liver or kidney transplant recipients: It is necessary to continue immunosuppression with oral TACROLIMUS TEVA to maintain graft survival. Dosage recommendations should be based on individual patient experience (see introductory remark above). There is a trend towards the use of lower doses of TACROLIMUS TEVA during maintenance therapy. Dosing should be primarily based on clinical assessments of rejection and tolerability.

Rescue therapy with TACROLIMUS TEVA: In patients experiencing rejection episodes that are unresponsive to conventional immunosuppressive therapy, TACROLIMUS TEVA treatment should begin with the initial dose recommended for primary immunosuppression in that particular allograft. Conversion from ciclosporin to TACROLIMUS TEVA: The combined administration of ciclosporin and TACROLIMUS TEVA is contraindicated (see section 4.3) as TACROLIMUS TEVA 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 TACROLIMUS TEVA based therapy. It is recommended that ciclosporin blood levels are monitored prior to the administration of TACROLIMUS TEVA. The most appropriate time to initiate TACROLIMUS TEVA 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. 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 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, intravenous administration should commence as a continuous 24 hour infusion.

Special populations: Hepatic impairment: A dose reduction may be necessary in patients with pre- and/or post-operative impairment, e.g. early graft dysfunction. Renal 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 output, is recommended. Race: In comparison to Caucasians, Black patients may require higher doses to achieve similar trough levels. Elderly population: There is no evidence presently available to suggest that doses should be altered in elderly patients. Paediatric population: The safety and efficacy of TACROLIMUS TEVA in children under 18 years of age have not yet been established (see section 4.4). Limited data are available but no recommendation on a dosage can be made.

Mode of administration: Oral 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 sections 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 blister must be used within 12 months. Patients should be cautioned not to swallow the desiccant contained within the aluminium wrapper. Duration and onset of oral administration: To suppress graft rejection, the capsules normally have to be taken continuously. Therefore, no limitation of duration can be given.

Hypersensitivity to tacrolimus or to any of the excipients listed in section 6.1 and other macrolides. Pregnancy and lactation (see section 4.6). As TACROLIMUS TEVA 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.

Prolonged-release formulations of tacrolimus are not inter-changeable with immediate-release formulations of tacrolimus without careful monitoring and supervision by a transplant specialist. TACROLIMUS TEVA is not recommended for use in children below 18 years due to limited data on safety and/or efficacy. Tuberculosis must be excluded prior to TACROLIMUS TEVA treatment. TACROLIMUS TEVA therapy requires careful monitoring in units equipped and staffed with adequate laboratory and supportive medical resources. TACROLIMUS TEVA 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. Patients should be thoroughly controlled. In particular, during the first months post-transplant, close monitoring of the patient is required. 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 TEVA. Patients should be maintained on a single formulation of TACROLIMUS TEVA 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 TEVA 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) with TACROLIMUS TEVA 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 TACROLIMUS TEVA 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 tacrolimus, 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, phenytoin, carbamazepine), with TACROLIMUS TEVA 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 TACROLIMUS TEVA 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 tacrolimus, thereby leading to supratherapeutic 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 TEVA 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 TACROLIMUS TEVA dose may be required (see section 4.5). Herbal preparations: Herbal preparations containing St. John's wort (Hypericum perforatum) or other herbal preparations should be avoided when taking TACROLIMUS TEVA due to the risk of interactions that lead to either a decrease in blood concentrations of tacrolimus and reduced clinical effect of TACROLIMUS TEVA, or an increase in blood concentrations of tacrolimus and risk of TACROLIMUS TEVA toxicity (see section 4.5). Other interactions: The combined administration of ciclosporin and TACROLIMUS TEVA is contra-indicated and care should be taken when administering TACROLIMUS TEVA to patients who have previously received ciclosporin (see sections 4.2 and 4.5).

Metabolic interactions: Systemically available TACROLIMUS TEVA is metabolised by hepatic CYP3A4. There is also evidence of gastrointestinal metabolism by CYP3A4 in the intestinal wall. Concomitant use of medicines 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 TEVA 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 TEVA dose if appropriate in order to maintain similar TACROLIMUS TEVA exposure (see sections 4.2 and 4.4).

Similarly, patients should be closely monitored when using TACROLIMUS TEVA concomitantly with multiple substances that affect CYP3A4 as the effects on tacrolimus exposure may be enhanced or counteracted. Medicines which have effects on tacrolimus, as contained in TACROLIMUS TEVA 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 medicine that is co-administered with TACROLIMUS TEVA 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.

Medicines which have effects on tacrolimus Medicine/Substance Class or Name Drug interaction effect Recommendations concerning co-administration Grapefruit or grapefruit juice May increase tacrolimus whole blood trough concentrations and increase the risk of serious adverse reactions (e.g., neurotoxicity, QT-prolongation) (see section 4.4). Avoid grapefruit or grapefruit juice. Ciclosporin May increase tacrolimus whole blood trough concentrations. In addition, synergistic/additive nephrotoxic effects can occur. The simultaneous use of ciclosporin and tacrolimus should be avoided (see section 4.4). Products known to have nephrotoxic or neurotoxic effects: May enhance nephrotoxic or neurotoxic effects of tacrolimus. Concurrent use of tacrolimus with medicines known to have nephrotoxic effects should be avoided. When co-administration cannot be avoided, aminoglycosides, gyrase inhibitors, vancomycin, sulfamethoxazole + trimethoprim, NSAIDs, ganciclovir, acyclovir, amphotericin B, ibuprofen, cidofovir, foscarnet monitor renal function and other side effects and adjust tacrolimus dose if needed. Strong CYP3A4 inhibitors: antifungal medicines (e.g., ketoconazole, itraconazole, posaconazole, voriconazole), the macrolide antibiotics (e.g., telithromycin, troleandomycin, clarithromycin, josamycin), HIV protease inhibitors (e.g. ritonavir, nelfinavir, saquinavir), HCV protease inhibitors (e.g. telaprevir, boceprevir, and the combination of ombitasvir and paritaprevir with ritonavir, when used with and without dasabuvir), nefazodone, the pharmacokinetic enhancer cobicistat, and may increase tacrolimus whole blood trough concentrations and increase the risk of serious adverse reactions (e.g., nephrotoxicity, neurotoxicity, QT-prolongation) which requires close monitoring (see section 4.4). Rapid and sharp increases in tacrolimus levels may occur, as early as within 1 to 3 days after coadministration, despite immediate reduction of tacrolimus dose. Overall tacrolimus exposure may increase > 5 fold. When ritonavir combinations are co-administered, tacrolimus exposure may increase > 50 fold. Nearly all patients may require a reduction in tacrolimus dose and It is recommended that concomitant use should be avoided. If co-administration of a strong CYP3A4 inhibitor is unavoidable, consider omitting the dose of tacrolimus the day the strong CYP3A4 inhibitor is initiated. Reinitiate tacrolimus the next day at a reduced dose based on tacrolimus blood concentrations. Changes in both tacrolimus dose and/or dosing frequency should be individualized and adjusted as needed based on tacrolimus trough concentrations, which should be assessed at initiation, monitored frequently throughout (starting within the first few days) and re-evaluated on and after completion of the CYP3A4 inhibitor. Upon completion, appropriate dose and dosing frequency of tacrolimus should be guided by tacrolimus blood concentrations. Monitor renal function, the kinase inhibitors idelalisib, ceritinib. Strong interactions have also been observed with the macrolide antibiotic erythromycin. Moderate or weak CYP3A4 inhibitors: antifungal medicines (e.g., fluconazole, isavuconazole, clotrimazole, miconazole), the macrolide antibiotics (e.g., azithromycin), calcium channel blockers (e.g., nifedipine, nicardipine, diltiazem, verapamil), amiodarone, danazol, ethinylestradiol, lansoprazole, omeprazole, the HCV antivirals elbasvir/grazoprevir and glecaprevir/pibrentasvir, the CMV antiviral letermovir, and the tyrosine kinase inhibitors nilotinib, crizotinib and imatinib and (Chinese) may increase tacrolimus whole blood trough concentrations and increase the risk of serious adverse reactions (e.g., neurotoxicity, QT-prolongation) (see section 4.4). A rapid increase in tacrolimus level may occur. Monitor tacrolimus whole blood trough concentrations frequently, starting within the first few days of co-administration. Reduce tacrolimus dose if needed (see section 4.2). Monitor renal function, ECG for QT-prolongation, and other side effects closely.

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

Breast feeding: TACROLIMUS TEVA is excreted into breast milk. As detrimental effects on the new-born cannot be excluded, women should not breast-feed whilst receiving TACROLIMUS TEVA.

Fertility: A negative effect of TACROLIMUS TEVA on male fertility in the form of reduced sperm counts and motility was observed in rats (see section 5.3).

TACROLIMUS TEVA may cause visual and neurological disturbances. Patients treated with TACROLIMUS TEVA who are affected by such disorders should not drive or operate dangerous machines. This effect may be enhanced if TACROLIMUS TEVA is administered in association with alcohol.

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

Infections and infestations: As is well known for other potent immunosuppressive agents, patients receiving TACROLIMUS TEVA are frequently at increased risk for infections (viral, bacterial, fungal, and 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 TACROLIMUS TEVA.

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 and skin malignancies have been reported in association with TACROLIMUS TEVA 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, febrile neutropenia.

Immune system disorders: Allergic and anaphylactoid reactions have been observed in patients receiving tacrolimus (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, appetite decreased, 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, writing impaired, nervous system disorders. Less frequent: Coma, central nervous system haemorrhages and cerebrovascular accidents, paralysis and paresis, encephalopathy, speech and language abnormalities, amnesia, hypertonia, myasthenia. Frequency unknown: Posterior reversible encephalopathy syndrome (PRES).

Eye disorders: Frequent: Vision blurred, photophobia, eye disorders. Less frequent: Cataract, blindness. Frequency unknown: Optic neuropathy.

Ear and labyrinth disorders: Frequent: Tinnitus. Less frequent: Hypoacusis, deafness neurosensory, hearing impaired.

Cardiac disorders: Frequent: Ischaemic coronary artery disorders, tachycardia. Less frequent: Ventricular dysrhythmias and cardiac arrest, heart failures, cardiomyopathies, ventricular hypertrophy, supraventricular dysrhythmias, palpitations, pericardial effusion, Torsades de Pointes.

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

Respiratory, thoracic and mediastinal disorders: Frequent: Dyspnoea, parenchymal lung disorders, pleural effusion, pharyngitis, cough, nasal congestion and inflammations. Less frequent: Respiratory failures, respiratory tract disorders, asthma, and 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: Ileus paralytic, acute and chronic pancreatitis, gastrooesophageal reflux disease, impaired gastric emptying, subileus, pancreatic pseudocyst.

Hepatobiliary disorders: Frequent: Cholestasis and jaundice, hepatocellular damage and hepatitis, cholangitis. Less frequent: Hepatic artery thrombosis, venoocclusive liver disease, hepatic failure, bile duct stenosis.

Skin and subcutaneous tissue disorders: Frequent: Pruritus, rash, alopecias, acne, sweating increased. Less frequent: Dermatitis, photosensitivity, toxic epidermal necrolysis (Lyell's syndrome), and Stevens Johnson syndrome.

Musculoskeletal and connective tissue disorders: Frequent: Arthralgia, muscle spasms, pain in extremity, 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.

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. Medication errors, including inadvertent, unintentional or unsupervised substitution of immediate- or prolonged release TACROLIMUS TEVA formulations, have been observed. A number of associated cases of transplant rejection have been reported (frequency cannot be estimated from available data).

Description of selected adverse reactions: Pain in extremity has been described in a number of published case reports as part of Calcineurin Inhibitor Induced Pain Syndrome (CIPS). This typically presents as a bilateral and symmetrical, severe, ascending pain in the lower extremities and may be associated with supra therapeutic levels of TACROLIMUS TEVA. The syndrome may respond to tacrolimus dose reduction. In some cases, it was necessary to switch to alternative immunosuppression.

Reporting of suspected adverse reactions: Reporting suspected adverse reactions after authorisation of the medicine is important. It allows continued monitoring of the benefit/risk balance of the medicine. Health care providers are asked to report any suspected adverse reactions to SAHPRA via the 6.04 Adverse Reactions Reporting Form, found online under SAHPRAu2019s publications: https://www.sahpra.org.za/Publications/Index/8

Earlier clinical experience (when initial induction doses were 2 or 3 times greater than those currently recommended) suggested that symptoms of overdosage may include renal, neurological, and cardiac disturbances, glucose intolerance, hypertension, and electrolyte disorders (e.g. hyperkalaemia). Over-immunosuppression may increase the risk for severe infections. Liver function clearly influences all pre- and postoperative pharmacokinetic variables. Patients with failing liver grafts or those switched from other immunosuppressive therapy to TACROLIMUS TEVA should be monitored carefully to avoid overdosage. 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 TEVA 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 TEVA 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.