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Tacrolimus oral twice daily

Presentation

Twice daily oral formulations of tacrolimus

Drugs List

  • ADOPORT 1mg capsules
  • ADOPORT 2mg capsules
  • ADOPORT 500microgram capsules
  • ADOPORT 5mg capsules
  • ADOPORT 750microgram capsules
  • MODIGRAF 1mg granules for oral suspension
  • MODIGRAF 200microgram granules for oral suspension
  • PROGRAF 1mg capsules
  • PROGRAF 500microgram capsules
  • PROGRAF 5mg capsules
  • tacrolimus 1mg capsules
  • tacrolimus 1mg granules for oral suspension sugar-free
  • tacrolimus 200microgram granules for oral suspension sugar-free
  • tacrolimus 2mg capsules
  • tacrolimus 500microgram capsules
  • tacrolimus 5mg capsules
  • tacrolimus 750microgram capsules
  • Therapeutic Indications

    Uses

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

    Dosage

    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 Doses of tacrolimus may be reduced and withdrawal of concomitant immunosuppressive therapy may also be possible during maintenance 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.

    Adults

    Liver transplantation prophylaxis of transplant rejection
    100 to 200 micrograms/kg/day orally in two divided doses. Commence first dose approximately 12 hours after the completion of liver transplant surgery.

    Kidney transplantation prophylaxis of transplant rejection
    200 to 300 micrograms/kg/day orally in two divided doses. Commence first dose within 24 hours of kidney transplant surgery.

    Heart transplantation prophylaxis of transplant rejection Following antibody induction
    75 micrograms/kg/day orally in two divided doses. Commence first dose within 5 days of completion of surgery as soon as the patient's condition is stabilised.

    Heart transplantation prophylaxis of transplant rejection Without antibody induction
    Alternatively, oral tacrolimus can be administered within 12 hours of completion of surgery (reserved for patients without organ dysfunction). Initial dose of 2mg to 4mg daily used in combination with mycophenolate mofetil and corticosteroids or sirolimus and corticosteroids.

    Rejection therapy
    In heart transplanted patients an initial oral dose of 150 micrograms/kg/day in two divided doses.
    In lung transplanted patients an initial oral dose of 100 to 150 micrograms/kg/day has been used.
    In pancreas transplanted patients an initial oral dose of 200 micrograms/kg/day has been used.
    In intestinal transplanted patients an initial oral dose of 300 micrograms/kg/day has been used.

    Children

    Paediatric patients generally require doses 1.5 to 2 times higher than adult doses to achieve similar blood levels.

    Liver transplantation prophylaxis of transplant rejection
    300 micrograms/kg/day in two divided doses, commencing 12 hours after surgery adjusted according to whole blood concentrations.

    Kidney transplantation prophylaxis of transplant rejection
    300 micrograms/kg/day in two divided doses.
    The following alternative dosing schedule may be suitable:
    Children aged 1 month to 18 years old: 100 micrograms/kg twice daily, commencing within 24 hours of surgery adjusted according to whole blood concentrations. The lower doses have been used in adolescents to prevent very high 'trough' concentrations.

    Heart transplantation prophylaxis of transplant rejection Following antibody induction
    100 to 300 micrograms/kg/day orally in two divided doses, within 5 days of transplant, adjusted according to whole blood concentrations.

    Heart transplantation prophylaxis of transplant rejection Without antibody induction:
    The first oral dose should be 300 micrograms/kg/day in two divided doses, starting 8 to 12 hours after discontinuing intravenous therapy.

    Rejection therapy
    In heart transplanted patients an initial oral dose of 200 to 300 micrograms/kg/day in two divided doses.
    In lung transplanted patients an initial oral dose of 100 to 150 micrograms/kg/day has been used.
    In pancreas transplanted patients an initial oral dose of 200 micrograms/kg/day has been used.
    In intestinal transplanted patients an initial oral dose of 300 micrograms/kg/day has been used.

    Additional Dosage Information

    Conversion from ciclosporin
    Co-administration of ciclosporin and tacrolimus 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.

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

    Conversion information is only available for Prograf & Modigraf and may not be the same for other brands
    Substitution should only be made under the close supervision of a transplant specialist.

    Conversion to once-daily formulations of tacrolimus
    Prograf is an immediate release formulation of tacrolimus intended for twice daily administration. It is not interchangeable with prolonged release once-daily formulations without careful therapeutic monitoring. 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.

    Conversion from granules for oral suspension to twice daily capsules
    Patients who are stable on Modigraf granules may be converted to Prograf capsules on a 1 mg : 1 mg total daily dose basis. If equal doses are not possible the total daily dose of Prograf should be rounded up to the nearest amount possible, with the higher dose given in the morning. Tacrolimus trough levels should be monitored before and within 1 week of conversion and if necessary, dose adjustments made in order to maintain similar systemic exposure.

    Conversion from twice daily capsules to granules for oral suspension
    The total daily dose of Modigraf should be equal to the total daily dose of Prograf. If equal quantities are not possible, the total daily dose of Modigraf should be rounded down to the nearest total daily dose possible using whole sachets, with the higher dose given in the morning. Tacrolimus trough levels should be monitored before and within 1 week of conversion and if necessary, dose adjustments made in order to maintain similar systemic exposure.

    Concomitant use of CYP3A4 inhibitors or inducers
    Closely monitor tacrolimus blood levels, renal function and side effects in patients taking substances known to affect CYP3A4 metabolism concomitantly. Interrupt or adjust tacrolimus dose in order to maintain similar tacrolimus exposure.

    Administration

    The capsules should be swallowed whole with fluid preferably water. If necessary, the capsule contents can be suspended in water and administered through a nasogastric tube.

    The granules should be added to the water and stirred. The suspension can be drawn up via syringe or swallowed directly. The cup should then be rinsed with water and the rinsings consumed by the patient. If necessary, the suspension can be administered through a nasogastric tube.

    Therapeutic Drug Monitoring

    Monitoring of whole blood level concentrations
    The majority of patients can be successfully managed if the blood trough concentrations of tacrolimus are maintained below 20 nanograms/ml.
    The following 12-hour trough whole blood levels have been observed:
    Liver: 5 to 20 nanograms/ml early post transplant.
    Kidney and Heart: 10 to 20 nanograms/ml early post transplant.
    In general levels between 5 and 15 nanograms/ml are seen for liver, kidney and heart transplant patients.

    Drug trough 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.

    Contraindications

    Breastfeeding
    Galactosaemia
    Long QT syndrome
    Torsade de pointes

    Precautions and Warnings

    EBV-sero-negative children under 2 years
    Family history of long QT syndrome
    Infection
    Oedema
    Cardiac disorder
    Electrolyte imbalance
    Glucose-galactose malabsorption syndrome
    History of torsade de pointes
    Hypertension
    Hypervolaemia
    Lactose intolerance
    Pregnancy
    Renal impairment
    Severe hepatic 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
    Determine serum EBV status in children under 2yrs before starting treatment
    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
    Refer immediately visual disturbances to a specialist
    Discontinue if posterior reversible encephalopathy syndrome (PRES) develops
    Bioavailability differs with preparations;caution on changing formulations
    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
    Advise patient to use SPF 15+ sunscreen during treatment

    This monograph refers to immediate release formulations that must be taken twice a day: once in the morning and once in the evening. 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.

    Tacrolimus is normally administered with other immunosuppressive drugs in the initial post-transplant period. The dose may vary depending on the regimen used. Tacrolimus should not be given with ciclosporin.

    Weak interactions between tacrolimus and herbal remedies containing Schisandra sphenanthera have been observed.

    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.
    Cardiomyopathy has been reported in children given tacrolimus after transplantation. Patients using the drug should be monitored carefully by echocardiography for hypertrophic changes; dose reduction or discontinuation should be considered if these occur.

    Posterior Reversible Encephalopathy Syndrome (PRES)
    Posterior Reversible Encephalopathy Syndrome (PRES) has been reported in some patients treated with tacrolimus. 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 tacrolimus 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.

    JC virus associated Progressive Multifocal Leukoencephalopathy syndrome (PML)
    JC virus associated Progressive Multifocal Leukoencephalopathy syndrome (PML) has been reported in some patients treated with immunosuppressives. 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 adjustments in immunosuppressive therapy or discontinuation of treatment should be considered.

    BK virus-associated nephropathy
    The occurrence of BK virus-associated nephropathy is often associated with a high total immunosuppressive burden. 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

    Pregnancy

    Use tacrolimus with caution during pregnancy.

    The manufacturer states tacrolimus can be considered for use in pregnancy if there is no safer alternative and when the perceived benefit outweighs the risk to the foetus.

    The drug has been shown to be able to cross the placenta. Limited data from organ transplant recipients show no evidence of increased risk of adverse effects on the course and outcome of pregnancy compared with other immunosuppressive products. However, cases of spontaneous abortion have been reported.

    Monitoring of the newborn is recommended where there has been in utero exposure to tacrolimus, in particular kidney function. There is a risk of interuterine growth retardation, premature delivery (less than 37 weeks) and hyperkalaemia in the newborn (the latter normally resolves untreated).

    In rats and rabbits tacrolimus has been shown to cause embryofoetal toxicity which demonstrated maternal toxicity.

    Lactation

    Tacrolimus is contraindicated during breastfeeding.

    The manufacturer states that women should not breastfeed whilst receiving tacrolimus.

    Human data demonstrate that tacrolimus is excreted into breast milk. Some sources suggest that due to low oral bioavailability a breastfed infant would ingest too little for a clinical effect.

    Counselling

    Advise patient to take on an empty stomach or at least one hour before or 2 to 3 hours after a meal to achieve maximal absorption.

    Advise patient that the total daily dose should be taken in two divided doses, once in the morning and once in the evening.

    Advise patient to know which preparation they use and question any unfamiliar supply.

    Advise patients not to consume grapefruit products. Advise patients not to take St John's Wort concurrently.

    Advise patients that they should not take products containing echinacea.

    Alcohol may enhance side effects.

    Advise patient to report signs of gastrointestinal perforation immediately.

    Advise patient to report headache, seizures, confusion, visual disturbance

    Advise patients to use a high protection sun cream when exposed to sunlight or UV light.

    Advise patient to use barrier or non-hormonal forms of contraception. Advise patient that their ability to perform skilled tasks such as driving and operating machinery may be influenced by side effects such as visual and neurological disturbances.

    Side Effects

    Abdominal pain
    Abnormal liver function tests
    Acne
    Allergic reaction
    Alopecia
    Amnesia
    Anaemia
    Anaphylactoid reaction
    Anxiety
    Asthenia
    BK virus associated with nephropathy
    Cardiac disorders
    Cerebrovascular accident
    Changes in glucose metabolism
    Changes of blood pressure
    Coagulation disorders
    Coma
    Confusion
    Constipation
    Convulsions
    Dehydration
    Depression
    Diabetes mellitus
    Disturbances of appetite
    Dizziness
    Dysmenorrhoea
    Dyspnoea
    ECG changes
    Electrolyte disturbances
    Emotional lability
    Encephalopathy
    Fever
    Gastro-intestinal perforation
    Gastro-intestinal symptoms
    Gastro-intestinal ulceration
    Haematological disorders
    Haemolytic uraemic syndrome
    Haemorrhage
    Hallucinations
    Headache
    Hearing disturbances
    Hepatic disorders
    Hirsutism
    Hyperkalaemia
    Hyperlipidaemia
    Hypertonia
    Hypervolaemia
    Hypoproteinaemia
    Hypoprothrombinaemia
    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
    Insomnia
    Ischaemia
    Leucocytosis
    Leucopenia
    Lymphoproliferative disorders
    Metabolic acidosis
    Musculoskeletal disturbances
    Myasthenia
    Neuropathy
    Neutropenia
    Nightmares
    Oedema
    Ophthalmic disturbances
    Pain
    Pancreatitis
    Pancytopenia
    Paraesthesia
    Paralysis
    Paralytic ileus
    Peritonitis
    Photosensitivity
    Pleural effusion
    Posterior reversible encephalopathy syndrome (PRES)
    Progressive multifocal leukoencephalopathy (PML)
    Prolongation of QT interval
    Pruritus
    Pseudocysts
    Psychosis
    Red cell aplasia
    Renal impairment
    Respiratory disorders
    Respiratory failure
    Skin reactions
    Speech disturbances
    Stevens-Johnson syndrome
    Temperature disturbances
    Thrombocytopenia
    Thromboembolic complications
    Thrombotic microangiopathy
    Thrombotic thrombocytopenic purpura
    Torsades de pointes
    Toxic epidermal necrolysis
    Tremor
    Vascular disorders
    Weight changes

    Overdosage

    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 ( www.toxbase.org ) or if this is unavailable at the backup site ( www.toxbasebackup.org ).

    Further Information

    Last Full Review Date: October 2019

    Reference Sources

    Drugs During Pregnancy and Lactation: Treatment Options and Risk Assessment, 2nd edition (2007) ed. Schaefer, C., Peters, P. and Miller, R. Elsevier, London.

    Drugs in Pregnancy and Lactation: A Reference Guide to Fetal and Neonatal Risk, 9th edition (2011) ed. Briggs, G., Freeman, R. and Yaffe, S. Lippincott Williams & Wilkins, Philadelphia.

    Medications and Mothers' Milk, Sixteenth Edition (2014) Hale, T and Rowe, H, Hale Publishing, Plano, Texas.

    Summary of Product Characteristics: Adoport 0.5mg Capsules. Sandoz Ltd. May 2013.
    Summary of Product Characteristics: Adoport 0.75mg Capsules. Sandoz Ltd. August 2015.
    Summary of Product Characteristics: Adoport 1mg Capsules. Sandoz Ltd. May 2013.
    Summary of Product Characteristics: Adoport 2mg Capsules. Sandoz Ltd. August 2015.
    Summary of Product Characteristics: Adoport 4mg Capsules. Sandoz Ltd. May 2013.

    Summary of Product Characteristics: Capexion 0.5mg Capsules . Actavis. December 2012.
    Summary of Product Characteristics: Capexion 1mg Capsules . Actavis. December 2012.
    Summary of Product Characteristics: Capexion 5mg Capsules . Actavis. December 2012.

    Summary of Product Characteristics: Modigraf Granules for oral suspension. Astellas Pharma Ltd. September 2019.

    Summary of Product Characteristics: Prograf 0.5mg, 1mg, 5mg Capsules. Astellas Pharma Ltd. June 2015.

    Summary of Product Characteristics: Tacni 0.5mg Capsules. Teva Uk Ltd. June 2015.
    Summary of Product Characteristics: Tacni 1mg Capsules. Teva Uk Ltd. June 2015.
    Summary of Product Characteristics: Tacni 5mg Capsules. Teva Uk Ltd. June 2015.

    Summary of Product Characteristics: Vivadex Capsules. Dexcell Pharma Ltd. February 2011.

    MHRA Drug safety Update: Volume 5, Issue 11, June 2012
    https://www.mhra.gov.uk/Safetyinformation/DrugSafetyUpdate/CON155756
    Last accessed: 12 March 2015
    NICE - Evidence Services Available at: www.nice.org.uk
    Last accessed: 27 July 2017.
    US National Library of Medicine. Toxicology Data Network. Drugs and Lactation Database (LactMed).
    Available at: https://toxnet.nlm.nih.gov/cgi-bin/sis/htmlgen?LACT
    Tacrolimus. Last revised: 3 December 2018
    Last accessed: 30 October 2019

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