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Envarsus is a brand name for Tacrolimus. The medicine, its uses, side effects and dosage are the same regardless of brand.
Used for: Prophylaxis of transplant rejection in adult kidney or liver allograft recipients. 3 Treatment of allograft rejection resistant to treatment with other immunosuppressive medicinal products in adult patients.
Verbatim from this product's EMA label. Tap a section to expand.
Envarsus is a once-a-day oral formulation of tacrolimus. Tacrolimus 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.
Inadvertent, unintentional, or unsupervised switching of immediate- or prolonged-release formulations of tacrolimus is unsafe. This can lead to graft rejection or increased incidence of adverse reactions, including under- or over-immunosuppression, due to clinically relevant differences in systemic exposure to tacrolimus.
8). Following conversion to any alternative formulation, therapeutic drug monitoring must be performed and dose adjustments made to ensure that systemic exposure to tacrolimus is maintained. Posology The recommended initial doses presented below are intended to act solely as a guideline.
Tacrolimus 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 (see below under “Therapeutic drug 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 dose regimen may take several days before steady state is achieved.
To suppress graft rejection, immunosuppression must be maintained; consequently, no limit to the duration of oral therapy can be given. 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.
Missed dose A forgotten dose should be taken as soon as possible on the same day. A double dose should not be taken on the next day. 17 mg/kg/day administered once daily in the morning. Administration should commence within 24 hours after the completion of surgery.
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 Envarsus is not interchangeable with other existing tacrolimus containing medicinal products (immediate-release or prolonged-release) on an equal dose by dose basis.
Summary of the safety profile The most commonly reported adverse reactions for tacrolimus (occurring in >10% of patients) are tremor, renal impairment, hyperglycaemic conditions, diabetes mellitus, hyperkalaemia, infections, hypertension and insomnia.
Tabulated list of adverse reactions The frequency of adverse reactions is defined as follows: very common (≥1/10); common (≥1/100 to <1/10); uncommon (≥1/1 000 to <1/100); rare (≥1/10 000 to <1/1 000); very rare (<1/10 000); not known (cannot be estimated from the available data).
Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness. Infections and infestations Patients receiving tacrolimus are frequently at increased risk for infections (viral, bacterial, fungal, 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.
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 and Kaposi’s sarcoma have been reported in association with tacrolimus treatment.
4). System Organ Class Frequency of adverse reactions Very common Common Uncommon Rare Very rare Not known Blood and lymphatic system disorders anaemia, thrombocyto-penia, leukopenia, red blood cell analyses abnormal, leukocytosis coagulo-pathies, pancytopenia, neutropenia, coagulation and bleeding analyses, abnormal, thrombotic microangio- pathy thrombotic thrombo- cytopenic purpura, hypopro- thrombin- aemia pure red cell aplasia, agranulo- cytosis, haemolytic anaemia, febrile neutropenia Endocrine disorders hirsutism 16 System Organ Class Frequency of adverse reactions Very common Common Uncommon Rare Very rare Not known Metabolism and nutrition disorders diabetes mellitus, hyper- glycaemic conditions, hyper- kalaemia anorexia, metabolic acidoses, other electrolyte ab- normalities, hyponatraemia, fluid overload, hyperuricaemia, hypomagnes- aemia, hypo- kalaemia, hypocalcemia, appetite decreased, hypercholest- erolaemia, hyperlipidaemia, hypertriglycerid- aemia, hypophos- phateaemia dehydration, hypo-glycaemia, hypoprotein- aemia, hyperphos- phataemia Psychiatric disorders insomnia confusion and dis- orientation, depression, anxiety symptoms, hallucination, mental disorders, depressed mood, mood disorders and disturbances, nightmare psychotic disorder Nervous system disorders headache, tremor nervous system disorders, seizures, disturbances in consciousness, peripheral neuropathies, dizziness, paraesthesias and dysaesthesias, writing impaired encephalo- pathy, central nervous system haemorrhages and cerebrovas- cular accidents, coma, speech and language ab-normalities, paralysis and paresis, amnesia hypertonia myasthenia Posterior reversible encephalo- pathy syndrome (PRES) Eye disorders eye disorders, vision blurred, photophobia cataract blindness optic neuropathy Ear and labyrinth disorders tinnitus hypoacusis deafness neurosensory hearing impaired Cardiac disorders ischaemic coronary artery disorders, tachycardia heart failures, ventricular arrhythmias and cardiac arrest, supraventricular arrhythmias, cardiomyo- pathies, ventricular hypertrophy, palpitations pericardial effusion Torsades de pointes 17 System Organ Class Frequency of adverse reactions Very common Common Uncommon Rare Very rare Not known Vascular disorders hypertension thromboembolic and ischaemic events, vascular hypotensive disorders, haemorrhage, peripheral vascular disorders venous thrombosis deep limb, shock, infarction Respiratory, thoracic and mediastinal disorders parenchymal lung disorders, dyspnoea, pleural effusion, cough, pharyngitis, nasal congestion and inflammations respiratory failures, respiratory tract disorders, asthma acute respiratory distress syndrome Gastrointestinal disorders diarrhoea, nausea gastrointestinal signs and symptoms, vomiting, gastro- intestinal and abdominal pains, gastrointestinal inflammatory conditions, gastro- intestinal haem- orrhages, gastrointestinal ulceration and perforation, ascites, stomatitis and ulceration, constipation, dyspeptic signs and symptoms, flatulence, bloating and distension, loose stools acute and chronic pancreatitis, peritonitis, ileus paralytic, gastrooeso- phageal reflux disease, impaired gastric emptying pancreatic pseudocyst, subileus Hepatobiliary disorders bile duct disorders, hepatocellular damage and hepatitis, cholestasis and jaundice veno- occlusive liver disease, hepatic artery thrombosis hepatic failure Skin and subcutaneous tissue disorders rash, pruritus, alopecias, acne, sweating increased dermatitis, photo-sensitivity toxic epidermal necrolysis (Lyell’s syndrome) Stevens- Johnson syndrome Musculoskeletal and connective tissue disorders arthralgia, back pain, muscle cramps, pain in limb joint disorders mobility decreased 18 System Organ Class Frequency of adverse reactions Very common Common Uncommon Rare Very rare Not known Renal and urinary disorders renal impairment renal failure, renal failure acute, nephropathy toxic, renal tubular necrosis, urinary abnormalities, oliguria, bladder and urethral symptoms haemolytic uraemic syndrome, anuria nephropathy, cystitis haem- orrhagic Reproductive system and breast disorders dysmenorrhoea and uterine bleeding General disorders and administration site conditions febrile disorders, pain and discomfort, asthenic conditions, oedema, body temperature perception disturbed influenza like illness, feeling jittery, […]
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.
8). For treatment of allograft rejection resistant to treatment with other immunosuppressive medicinal products in adult patients clinical studies are not yet available for the prolonged-release formulation Envarsus. For prophylaxis of transplant rejection in adult heart, lung, pancreas, or intestine allograft recipients clinical data are not yet available for Envarsus.
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. 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 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 tacrolimus dose if appropriate in order to maintain similar tacrolimus exposure.
1. Hypersensitivity to other macrolides.
Not medical advice. Always read the patient information leaflet and follow your prescriber or pharmacist.
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7 (mg:mg) 4 total daily dose basis and the Envarsus maintenance dose should, therefore, be 30% less than the Prograf or Advagraf dose. 7 (mg:mg) total daily dose basis, the mean systemic exposure to tacrolimus (AUC0-24) was similar to that of immediate-release tacrolimus.
The relationship between tacrolimus trough levels (C24) and systemic exposure (AUC0-24) for Envarsus is similar to that of immediate-release tacrolimus. No studies have been conducted with conversion of patients from Advagraf to Envarsus; however, data from healthy volunteers would suggest that the same conversion rate is applicable as with the conversion from Prograf to Envarsus.
, 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.
It should be noted that black patients may require a higher dose to achieve the targeted trough levels. 5). The combined administration of ciclosporin and tacrolimus is not recommended. Tacrolimus 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. 8), 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 tacrolimus, 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 […]
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. 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 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 tacrolimus dose if appropriate, in order to maintain similar tacrolimus exposure.
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 with drugs 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.
5). 7 Herbal preparations Herbal preparations containing St. 5). 5). 5). 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 should be avoided.
Nephrotoxicity Tacrolimus can result in renal function impairment in post-transplant patients. Acute renal impairment without active intervention may progress to chronic renal impairment. Patients with impaired renal function should be monitored closely as the dosage of tacrolimus may need to be reduced.
5). Concurrent use of tacrolimus with drugs known to have nephrotoxic effects should be avoided. When co-administration cannot be avoided, tacrolimus trough blood level and renal function should be monitored closely and dosage reduction should be considered if nephrotoxicity occurs.
Gastrointestinal disorders Gastrointestinal perforation has been reported in patients treated with tacrolimus. […]