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Tacrolimus oral once daily


Prolonged release oral formulations of tacrolimus.

Drugs List

  • ADVAGRAF 1mg modified release capsules
  • ADVAGRAF 3mg modified release capsules
  • ADVAGRAF 500microgram modified release capsules
  • ADVAGRAF 5mg modified release capsules
  • DAILIPORT 1mg modified release capsules
  • DAILIPORT 2mg modified release capsules
  • DAILIPORT 3mg modified release capsules
  • DAILIPORT 500microgram modified release capsules
  • DAILIPORT 5mg modified release capsules
  • ENVARSUS 1mg modified release tablet
  • ENVARSUS 4mg modified release tablet
  • ENVARSUS 750microgram modified release tablet
  • tacrolimus 1mg modified release capsules
  • tacrolimus 1mg modified release tablet
  • tacrolimus 2mg modified release capsules
  • tacrolimus 3mg modified release capsules
  • tacrolimus 4mg modified release tablet
  • tacrolimus 500microgram modified release capsules
  • tacrolimus 5mg modified release capsules
  • tacrolimus 750microgram modified release tablet
  • Therapeutic Indications


    Primary immunosuppression in kidney allograft patients
    Primary immunosuppression in liver allograft patients
    Treatment of allograft rejection resistant to other regimens


    There is no limit to the duration of therapy as immunosuppression must be maintained in order to suppress transplant rejection.

    Bioavailability differs with preparations, caution should be exercised on changing formulation.

    Patients should be converted from intravenous to oral medication as soon as individual circumstances permit.

    All indications - maintenance therapy
    If oral therapy cannot be administered due to the clinical condition of the patient then intravenous therapy should be used.
    Doses of tacrolimus are usually reduced during maintenance therapy. It is sometimes possible to withdraw concomitant immunosuppressive therapy. Post transplant improvement in the condition of the patient may alter the pharmacokinetics of tacrolimus and may require dose adjustment.
    Dosing should be based primarily on the clinical assessments of rejection and tolerability in each patient.
    Dose may vary depending upon the immunosuppressive regime.

    This monograph relates only to the specific indications of the once daily prolonged release capsules. Separate monographs for other preparations should be consulted for further information.


    Liver transplantation - prophylaxis of transplant rejection
    Capsules: Initially 100 to 200micrograms/kg given orally once daily in the morning.
    Tablets: Initially 110 to 130micrograms/kg/day.

    Administration should start approximately 12 to 18 hours after the completion of liver transplant surgery and no longer than 24 hours after.

    Kidney transplantation - prophylaxis of transplant rejection
    Capsules: Initially 200 to 300micrograms/kg given orally once daily in the morning.
    Tablets: Initially 170micrograms/kg/day.

    Administration should start within 24 hours of kidney transplant surgery.

    Rejection Therapy
    Increased tacrolimus doses, supplemental corticosteroid therapy and introduction of short courses of mono/polyclonal antibodies have all been used to manage rejection episodes. If signs of toxicity are noted, the dose of tacrolimus may need to be reduced.

    Liver and kidney transplantation - treatment of transplant rejection
    Treatment should begin with the initial oral dose recommended in liver or kidney prophylaxis of transplant rejection when converting from other immunosuppressants to a once daily prolonged release formulation of tacrolimus.

    Heart transplantation - treatment of transplant rejection
    Capsules: In adult patients converted to a once daily prolonged release formulation of tacrolimus, an initial oral dose of 150micrograms/kg/day should be administered in the morning.

    Other allografts transplantation - treatment of transplant rejection
    There is limited clinical experience with a once daily prolonged release formulation of tacrolimus in lung-transplanted, pancreas-transplanted, and intestine-transplanted patients. However, the twice daily tacrolimus formulation has been used.

    Additional Dosage Information

    Conversion from ciclosporin
    Co-administration of ciclosporin and tacrolimus is not recommended as this may increase the half-life of ciclosporin and exacerbate any toxic effects. 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 has been initiated 12 to 24 hours after discontinuation of ciclosporin. Treatment should begin with the initial oral dose recommended for primary immunosuppression as stated above.

    Monitoring of ciclosporin blood levels should be continued following conversion as the clearance of ciclosporin might be affected.

    Conversion from other oral formulations of tacrolimus
    Substitution should only be made under the close supervision of a transplant specialist.

    Tacrolimus trough levels should be monitored before and within 2 weeks of conversion and if necessary dose adjustments made in order to maintain similar systemic exposure.

    Immediate release tacrolimus to Advagraf
    Advagraf is a prolonged release formulation of tacrolimus intended for once-daily administration. Allograft transplant patients maintained on a twice-daily tacrolimus formulation requiring conversion to Advagraf should be converted on an equivalent milligram daily dose basis.

    Immediate release tacrolimus or Advagraf to Envarsus
    Patients requiring conversion from other oral forms of tacrolimus to Envarsus should be converted on a 1 to 0.7mg basis. Therefore the maintenance dose of Envarsus should be 30% less than other oral formulations of tacrolimus.

    Immediate release tacrolimus to Dailiport
    Patients requiring conversion from twice-daily tacrolimus immediate-release to Dailiport should be converted on a 1 to 1mg daily dose basis.


    The capsules should be swallowed whole with fluid, preferably water.

    Therapeutic Drug Monitoring

    Monitoring of whole blood level concentrations
    The majority of patients can be successfully managed if the blood concentrations of tacrolimus are maintained below 20nanograms/ml.
    12-hour trough whole blood levels are generally 5 to 20nanograms/ml early post transplant. Various assays have been used to measure blood concentrations and comparison of the levels in the published literature with those found in practice should be made with a knowledge of the assay methods used. In current practice, immunoassay methods are used.

    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 patient's clinical condition is satisfactory, then the dose should not be adjusted.

    Drug level monitoring is recommended twice weekly during the early post-transplantation period, and following dose adjustment, after switching from another immunosuppressive regimen or following co-administration of drugs which are likely to lead to a drug to drug interaction. Trough blood levels of tacrolimus should be monitored periodically during maintenance therapy. The frequency of blood level monitoring should be based on clinical need. As tacrolimus has a long half-life, it can take several days for adjustments in dosing to be reflected in changes in blood levels.


    Children under 18 years
    Long QT syndrome
    Torsade de pointes

    Precautions and Warnings

    EBV-VCA-sero negative patients
    Family history of long QT syndrome
    Cardiac disorder
    Electrolyte imbalance
    Glucose-galactose malabsorption syndrome
    Hepatic impairment
    History of torsade de pointes
    Lactose intolerance
    Renal impairment

    Administration of live vaccines is not recommended
    Correct electrolyte disorders before treatment
    Advise ability to drive/operate machinery may be affected by side effects
    Afro-Caribbean or black patients may show reduced response
    Treatment to be initiated and supervised by a specialist
    Contains lactose
    Some products may contain soya or soya derivative
    Advise patient to know the product they use and question unfamiliar supply
    Different brands of this product are not interchangeable
    Advise patient to report signs of gastrointestinal perforation immediately
    Blood level monitoring recommended throughout treatment
    Consider immunosuppressant adjustment in the event of PML
    Diarrhoea may compromise absorption and efficacy - monitor patient
    During treatment, careful EBV viral load monitoring is recommended
    Monitor blood counts regularly
    Monitor blood glucose
    Monitor blood pressure
    Monitor coagulation values
    Monitor ECG
    Monitor for and manage hepatitis reactivation during treatment
    Monitor for hypertrophic changes by echocardiography
    Monitor hepatic function
    Monitor neurological function
    Monitor renal function
    Monitor serum electrolytes
    Monitor serum potassium regularly
    Monitor visual status
    Advise patient to report headaches, seizures, confusion, visual disturbance
    Advise patient to report new visual problems and symptoms
    Consider immunosuppressant adjustment if BK virus nephropathy develops
    May reduce effectiveness of vaccinations during treatment
    Oversuppression of immune system may increase susceptibility to infection
    Discontinue if posterior reversible encephalopathy syndrome (PRES) develops
    Discontinue if Progressive multifocal leukoencephalopathy (PML) develops
    Bioavailability differs with preparations;caution on changing formulations
    Consider dose reduction in severe hepatic impairment
    Not licensed for use in children under 18 years
    Advise patient not to take St John's wort concurrently
    Advise patient to consult doctor before any self medication
    Alcohol may enhance side effects
    Advise patient grapefruit products may increase plasma level
    Advise patient to avoid excessive clementine consumption
    Avoid high dietary potassium intake
    Female: Barrier or non-hormonal contraception advised during treatment
    Advise patient to avoid exposure to sunlight and UV rays during treatment

    Oral formulations of tacrolimus are not interchangeable without careful therapeutic monitoring. Substitution should only be made under the close supervision of a transplant specialist.

    Medication errors, including inadvertent, unintentional or unsupervised substitution of immediate or prolonged release tacrolimus formulations, have been observed. This has led to serious adverse events, including graft rejection, or other side effects which could be a consequence of either under- or over-exposure to tacrolimus. Patients should be maintained on a single formulation of tacrolimus with the corresponding daily dosing regimen; alterations in formulation or regimen should only take place under the close supervision of a transplant specialist.

    Cardiac disorders
    Ventricular hypertrophy or hypertrophy of the septum and (rarely) cardiomyopathy have been reported in patients receiving tacrolimus. In general, these have been reversible on dose reduction or discontinuation of the drug. In high risk patients, monitor cardiovascular function using procedure such as echocardiography with or without ECG pre- and post-transplant (e.g. within the first 3 months and at 9 to 12 months). If abnormalities develop, consider dose reduction or an alternative immunosuppressive regimen.

    Posterior Reversible Encephalopathy Syndrome (PRES) also known as Reversible Posterior Leucoencephalopathy Syndrome (RPLS)
    If patients present with symptoms indicating PRES such as headache, altered mental state, seizures and visual disturbances, an MRI should be performed. If PRES is diagnosed, treatment should be discontinued and adequate blood pressure and seizure control administration is advisable. The safety of reinstating treatment in patients previously experiencing PRES is unknown.

    Progressive Multifocal Leukoencephalopathy Syndrome (PML)
    If patients present with symptoms indicating PML such as worsening neurological, cognitive or behavioural signs or symptoms, an MRI should be performed. If PML is diagnosed, treatment should be permanently discontinued.

    BK virus-associated nephropathy
    The occurrence of BK virus-associated nephropathy is primarily observed in renal transplant patients. BK virus-associated nephropathy can progress to renal allograft loss. Monitoring for this serious risk and early intervention by the health care provider is critical. Adjustments in immunosuppression therapy should be considered for patients who develop BK virus-associated nephropathy.

    Pregnancy and Lactation


    Tacrolimus should be used with caution during pregnancy.

    The manufacturer advises caution if tacrolimus is used during pregnancy. At the time of writing there is limited published information regarding the use of tacrolimus during pregnancy. Tacrolimus is known to cross the placenta, there is a risk for premature delivery as well as hyperkalaemia in the newborn. Monitoring of the newborn for adverse events is recommended.


    Tacrolimus is contraindicated during breastfeeding.

    Use of tacrolimus when breastfeeding is contraindicated by the manufacturer. Tacrolimus is present in human breast milk.

    Side Effects

    Abdominal pain
    Abnormal liver function tests
    Allergic reaction
    Anaphylactoid reaction
    BK virus associated with nephropathy
    Cardiac disorders
    Cerebrovascular accident
    Changes in glucose metabolism
    Changes of blood pressure
    Coagulation disorders
    Diabetes mellitus
    Disturbances of appetite
    ECG changes
    Electrolyte disturbances
    Emotional lability
    Gastro-intestinal perforation
    Gastro-intestinal symptoms
    Gastro-intestinal ulceration
    Haematological disorders
    Haemolytic uraemic syndrome
    Hearing disturbances
    Hepatic disorders
    Impaired consciousness
    Increased risk of skin cancer
    Increased susceptibility to development of lymphoma and other malignancies
    Increased susceptibility to infection
    Increased sweating
    Influenza-like syndrome
    Lymphoproliferative disorders
    Metabolic acidosis
    Musculoskeletal disturbances
    Ophthalmic disturbances
    Paralytic ileus
    Pleural effusion
    Posterior reversible encephalopathy syndrome (PRES)
    Progressive multifocal leukoencephalopathy (PML)
    Prolongation of QT interval
    Red cell aplasia
    Renal impairment
    Respiratory disorders
    Respiratory failure
    Skin reactions
    Speech disturbances
    Stevens-Johnson syndrome
    Temperature disturbances
    Thromboembolic complications
    Thrombotic microangiopathy
    Thrombotic thrombocytopenic purpura
    Torsades de pointes
    Toxic epidermal necrolysis
    Vascular disorders
    Weight changes


    It is strongly recommended that the UK National Poisons Information Service be consulted on cases of suspected or actual overdose where there is doubt over the degree of risk or about appropriate management.

    The following number will direct the caller to the relevant local centre (0844) 892 0111

    Information may be obtained if you have access to ToxBase the primary clinical toxicology database of the National Poisons Information Service. This is available via password on the internet ( ) or if this is unavailable at the backup site ( ).

    Further Information

    Last Full Review Date: November 2019

    Reference Sources

    Summary of Product Characteristics: Advagraf 0.5mg, 1mg, 3mg and 5mg prolonged-release hard capsules. Astellas Pharma Ltd. Revised October 2019.
    Summary of Product Characteristics: Envarsus 0.75mg, 1mg and 4mg prolonged-release tablets. Chiesi Ltd. Revised June 2019.
    Summary of Product Characteristics: Dailiport 0.5mg, 1mg, 2mg, 3mg and 5mg prolonged-release capsules. Sandoz Ltd. Revised October 2019.

    MHRA Drug safety Update: Volume 5, Issue 11, June 2012
    Last accessed: 5 February 2015

    NICE Evidence Services Available at: Last accessed: 18 November 2019

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