Tacrolimus oral once daily
- Drugs List
- Therapeutic Indications
- Dosage
- Administration
- Contraindications
- Precautions and Warnings
- Pregnancy and Lactation
- Side Effects
- Monograph
Presentation
Prolonged release oral formulations of tacrolimus.
Drugs List
Therapeutic Indications
Uses
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
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.
Adults
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.
Administration
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.
Contraindications
Children under 18 years
Breastfeeding
Galactosaemia
Long QT syndrome
Torsade de pointes
Precautions and Warnings
EBV-VCA-sero negative patients
Family history of long QT syndrome
Infection
Oedema
Cardiac disorder
Electrolyte imbalance
Glucose-galactose malabsorption syndrome
Hepatic impairment
History of torsade de pointes
Hypertension
Hypervolaemia
Lactose intolerance
Pregnancy
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
Pregnancy
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.
Lactation
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
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: 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
https://www.mhra.gov.uk/Safetyinformation/DrugSafetyUpdate/CON155756
Last accessed: 5 February 2015
NICE Evidence Services Available at: www.nice.org.uk Last accessed: 18 November 2019
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