0.75mg, 1mg, 4mg prolonged-release tablet

Tacrolimus (as monohydrate) Please refer to Summary of Product Characteristics (SmPC) before prescribing Prescribing information Presentation Envarsus prolonged-release tablets containing 0.75mg, 1mg and 4mg of tacrolimus (as monohydrate) Indications Prophylaxis of transplant rejection in adult kidney or liver allograft recipients and treatment of allograft

rejection resistant to treatment with other

immunosuppressive medicinal products in adult patients Dosage and administration Envarsus is a once-a-day oral formulation of tacrolimus. Envarsus therapy requires careful monitoring by adequately qualified and equipped personnel. This medicinal product should only be prescribed, and changes in immunosuppressive therapy be initiated, by physicians experienced in immunosuppressive therapy and the management of transplant patients. 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. The recommended initial doses presented below are intended to act solely as a guideline. Envarsus is routinely administered in conjunction with other immunosuppressive agents in the initial post-operative period. The dose may vary depending upon the immunosuppressive regimen chosen. Envarsus dosing should primarily be based on clinical assessments of rejection and tolerability in each patient individually aided by blood level monitoring. If clinical signs of rejection are apparent, alteration of the immunosuppressive regimen should be considered. As tacrolimus is a substance with low clearance, adjustments to the Envarsus dose regimen may take several days before steady state is achieved. Envarsus doses are usually reduced in the post-transplant period. Post-transplant changes in the condition of the patient may alter the pharmacokinetics of tacrolimus and may necessitate further dose adjustments. Prophylaxis of kidney transplant rejection: Envarsus therapy should commence at a dose of 0.17 mg/ kg/day administered once daily in the morning. Administration should commence within 24 hours after the completion of surgery. Prophylaxis of liver transplant rejection: Envarsus therapy should commence at a dose of 0.11 – 0.13 mg/kg/day administered once daily in the morning. Administration should commence within 24 hours after the completion of surgery. Conversion of Prograf- or Advagraf-treated patients to Envarsus - allograft transplant patients: Allograft transplant patients maintained on twice daily Prograf (immediate-release) or Advagraf (once daily) dosing requiring conversion to once daily Envarsus should be converted on a 1:0.7 (mg:mg) total daily dose basis and the Envarsus maintenance dose should, therefore, be 30% less than the Prograf or Advagraf dose. Envarsus should be administered in the morning. When converting from tacrolimus immediate-release products (e.g. Prograf capsules) or from Advagraf prolonged-release capsules to Envarsus, trough levels should be measured prior to conversion and within two weeks after conversion. Dose adjustments should be made to ensure that similar systemic exposure is maintained after the switch. In comparison to Caucasians, black patients may require higher tacrolimus doses to achieve similar trough levels. In clinical studies patients converted from twice daily Prograf were converted to Envarsus using a 1:0.85 (mg:mg) conversion. Conversion from ciclosporin to tacrolimus: Care should be taken when converting patients from ciclosporin-based to tacrolimus-based therapy. The combined administration of ciclosporin and tacrolimus is not recommended. Envarsus 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-based 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. Treatment of allograft rejection: Increased doses of tacrolimus, supplemental corticosteroid therapy, and introduction of short courses of mono-/ polyclonal antibodies have all been used to manage rejection episodes. If signs of toxicity such as severe adverse reactions are noted, the dose of Envarsus may need to be reduced. Treatment of allograft rejection after kidney or liver transplantation: For conversion from other immunosuppressants to once daily Envarsus, treatment should begin with the initial oral dose recommended in kidney and liver transplantation respectively for prophylaxis of transplant rejection. Therapeutic drug monitoring: Dosing should primarily be based on clinical assessments of rejection and tolerability in each individual patient aided by whole blood tacrolimus trough level monitoring. As an aid to optimise dosing, several immunoassays are available for determining tacrolimus concentrations in whole blood. Comparisons of concentrations from the published literature to individual values in clinical practice should be assessed with care and knowledge of the assay methods employed. In current clinical practice, whole blood levels are monitored using immunoassay methods. The relationship between tacrolimus trough levels and systemic exposure (AUC0-24

) is well correlated and is similar between the immediate-release

formulation and Envarsus. Blood trough levels of tacrolimus should be monitored during the post-transplantation period. Tacrolimus blood trough levels should be determined approximately 24 hours post-dosing of Envarsus, just prior to the next dose. Blood trough levels of tacrolimus should also be closely monitored following conversion from tacrolimus products, dose adjustments, changes in the immunosuppressive

regimen, or co-administration of substances which may alter tacrolimus whole blood concentrations. The frequency of blood level monitoring should be based on clinical needs. As tacrolimus is a substance with low clearance, following adjustments to the Envarsus dose regimen it may take several days before the targeted steady state is achieved. Data from clinical studies suggest that the majority of patients can be successfully managed if tacrolimus blood trough levels are maintained below 20ng/ml. It is necessary to consider the clinical condition of the patient when interpreting whole blood levels. In clinical practice, whole blood trough levels have generally been in the range of 5-20 ng/ml in kidney transplant patients in the early post-transplant period, and 5-15 ng/ml during subsequent maintenance therapy. See SmPC for dosage adjustments in special populations. Method of administration: Envarsus should be taken once daily in the morning, swallowed whole with fluid (preferably water) immediately following removal from the blister. Envarsus should generally be taken on an empty stomach to achieve maximal absorption. Contraindications Hypersensitivity to active substance or excipients. Hypersensitivity to macrolides. Warnings and precautions Medication errors, including inadvertent, unintentional or unsupervised substitution of immediate- or prolonged-release tacrolimus formulations, have been observed with tacrolimus. 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. Envarsus is not recommended for use in children below 18 years of age due to the limited data on safety and/or efficacy. 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. Gastrointestinal perforation has been reported in patients treated with tacrolimus, adequate treatments should be considered immediately after suspected symptoms or signs occur. Extra monitoring of tacrolimus concentrations is recommended during episodes of diarrhoea. Cardiomyopathies have been observed in tacrolimus treated patients on rare occasions. Most cases have been reversible, occurring 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 receiving substantial immunosuppression should be monitored, using such procedures as echocardiography or ECG pre- and post-transplant (e.g. initially at 3 months and then at 9-12 months). If abnormalities develop, dose reduction of Envarsus or change of treatment to another immunosuppressive agent should be considered. Tacrolimus may prolong the QT interval, caution should be exercised in patients with diagnosed or suspected Congenital Long QT Syndrome. Patients treated with tacrolimus have been reported to develop EBV- associated lymphoproliferative disorders. Risk factors include using a combination of immunosuppressives, such as antilymphocytic antibodies (e.g. basiliximab, daclizumab) concomitantly, or EBV-Viral Capsid Antigen (VCA)-negative patients. Therefore, in this patient group, EBV-VCA serology should be ascertained before starting treatment with Envarsus. 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 potent

compounds, the risk of secondary cancer is unknown. Exposure to sunlight and UV light should be limited. Patients

immunosuppressive treated with

immunosuppressants, 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 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. 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. Dose reduction may be necessary in patients with severe liver impairment. 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. (Refer to SmPC for full list of interactions). Side effects Very common: tremor, renal impairment, hyperglycaemic

References: 1. Bunnapradist S, Ciechanowski K, West-Thielke P, et al. Conversion From Twice-Daily Tacrolimus to Once-Daily Extended Release Tacrolimus (LCPT): The Phase III Randomized MELT Trial. Am J Transplant 2013;13:760-9. 2. Budde K, Bunnapradist S, Grinyo JM, et al. Novel Once-Daily Extended-Release Tacrolimus (LCPT) Versus Twice-Daily Tacrolimus in De Novo Kidney Transplants: One-Year Results of Phase III, Double-Blind, Randomized Trial. American Journal of Transplantation 2014;14:2796-2806. 3. Bunnapradist S et al. LCPT once-daily extended-release tacrolimus tablets versus twice-daily capsules: a pooled analysis of two phase 3 trials in important de novo and stable kidney transplant recipient subgroups. Transplant International. 2016;29:603-11.

Envarsus® is a registered trademark of Veloxis Pharmaceuticals A/S Ltd. Prograf® Date of preparation: July 2016. CHENV20160649

is a registered trademark of Astellas Pharma Europe Ltd.

conditions, diabetes mellitus, hyperkalaemia, infections, hypertension, insomnia, headache, diarrhoea, nausea, abnormal liver function tests Common: anaemia, thrombocytopenia, leukopenia, abnormal red blood cell analyses,

leukocytosis, anorexia, metabolic acidoses, other

electrolyte abnormalities, hyponatraemia, fluid overload, hyperuricaemia, hypomagnesaemia, hypokalaemia, hypocalcaemia, decreased appetite, hypercholesterolaemia,

hyperlipidaemia, hypertriglyceridaemia,

hypophosphataemia, confusion and disorientation, depression, anxiety symptoms, hallucination, mental disorders, depressed mood, mood disorders and disturbances, nightmare, nervous system disorders, seizures, disturbances in consciousness, peripheral neuropathies, dizziness, paraesthesias and dyaesthesias, writing impaired, eye disorders, blurred vision, photophobia, tinnitus, ischaemic coronary artery disorders, tachycardia, thromboembolic and ischaemic events, vascular hypotensive disorders, haemorrhage, peripheral vascular disorders, parenchymal lung disorders, dyspnoea, pleural effusion, cough, pharyngitis, nasal congestion and inflammations, gastro-intestinal (GI) signs and symptoms, vomiting, GI and abdominal pains, GI inflammatory conditions, GI haemorrhages, GI ulceration and perforation, ascites, stomatitis and ulceration, constipation, dyspeptic signs and symptoms, flatulence, bloating and distension, loose stools, bile duct disorders, hepatocellular damage and hepatitis, cholestasis and jaundice, rash, pruritus, alopecias, acne, increased sweating, arthralgia, back pain, muscle cramps, pain in limb, renal failure, acute renal failure, toxic nephropathy, renal tubular necrosis, urinary abnormalities, oliguria, bladder and urethral symptoms, febrile disorders, pain and discomfort, asthenic conditions, oedema, disturbed body temperature perception, increased blood alkaline phosphatase, increased weight, primary graft dysfunction. In clinical studies in kidney transplant patients receiving Envarsus, the most frequent adverse reactions (at least in 2% of patients) were tremor, diabetes mellitus, blood creatinine increased, urinary tract infection, hypertension, BK virus infection, renal impairment, diarrhoea, toxicity to various agents, and toxic nephropathy. Among the most frequent adverse reactions (at least in 2% of patients) in clinical studies in liver transplant patients receiving Envarsus were tremor, headache, fatigue, hyperkalaemia, hypertension, renal failure, blood creatinine increased, dizziness, hepatitis C, muscle spasms, tinea infection, leukopenia,

sinusitis, disorder, and URTI. Uncommon: coagulopathies,

pancytopenia, neutropenia, abnormal coagulation and bleeding analyses, dehydration, hypoglycaemia, hypoproteinaemia, hyperphosphataemia, psychotic

encephalopathy, arrhythmias, central nervous cardiomyopathies, system

haemorrhages and cerebrovascular accidents, coma, speech and language abnormalities, paralysis and paresis, amnesia, cataract, hypoacusis, heart failures, ventricular arrhythmias and cardiac arrest, supraventricular

abnormal ECG

investigations, ventricular hypertrophy, palpitations, abnormal heart rate and pulse investigations, deep limb venous thrombosis, shock, infarction, respiratory failures, respiratory tract disorders, asthma, acute and chronic pancreatitis, peritonitis, increased blood amylase, paralytic ileus, gastrooesophageal reflux disease, impaired gastric emptying, dermatitis, photosensitivity, joint disorders, haemolytic uraemic syndrome, anuria, dysmenorrhoea and uterine bleeding, decreased weight, influenza like illness, increased blood lactate dehydrogenase, feeling jittery, feeling abnormal, multi-organ failure, chest pressure sensation, temperature intolerance. Rare: thrombotic

thrombocytopenic purpura,

hypoprothrombinaemia, hirsutism, hypertonia, blindness, neurosensory deafness, pericardial effusion, acute respiratory distress syndrome, pancreatic pseudocyst, subileus, veno-occlusive liver disease, hepatic artery thrombosis, toxic epidermal necrolysis (Lyell’s syndrome), fall, ulcer, chest tightness, decreased mobility, thirst. Very rare: myasthenia, impaired hearing, abnormal echocardiogram, hepatic failure, Stevens Johnson Syndrome, nephropathy, haemorrhagic cystitis, increased fat tissue. Not Known: pure red cell aplasia, agranulocytosis, haemolytic anaemia, allergic and anaphylactoid reactions (Refer to SmPC for full list of adverse reactions) Legal category POM Packs and prices 0.75mg £44.33 1x30 tablets, 1mg £59.10 1x30 tablets, 4mg £236.40 1x30 tablets Marketing authorisation numbers EU/1/14/935/001, EU/1/14/935/004, EU/1/14/935/007. Full prescribing information is available on request from the UK Distributor Chiesi Limited, 333 Styal Road, Manchester, M22 5LG Date of preparation July 2015

For the UK: Adverse events should be reported. Reporting forms and information can be found at

Adverse events should also be reported to Chiesi Limited, (address as above) Tel: +44(0)161 488 5555.

For Ireland: Adverse events should be reported to

HPRA Pharmacovigilance, Earlsfort Terrace, IRL, Dublin 2, Tel: +353 1 6764971, Fax: +353 1 6762517,

Website:, e-mail: Adverse events should also be reported to Chiesi Limited, (address as above) Tel: +44(0)161 488 5555.

Prolonged-release tacrolimus tablets

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