Tacrolimus parenteral
- Drugs List
- Therapeutic Indications
- Dosage
- Administration
- Contraindications
- Precautions and Warnings
- Pregnancy and Lactation
- Side Effects
- Monograph
Presentation
Concentrate for solution for infusion containing tacrolimus
Drugs List
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
Intravenous therapy should not continue for more than 7 days. Patients should be converted from intravenous to oral medication as soon as individual circumstances permit. In general Tacrolimus oral formulations should be used for maintenance therapy.
Adults
Liver transplantation - prophylaxis of transplant rejection
10 to 50 microgram/kg per day as a continuous 24-hour infusion.
Commence first dose approximately 12 hours after completion of surgery.
Kidney transplantation - prophylaxis of transplant rejection
50 to 100 microgram/kg per day as a continuous 24-hour infusion.
Commence first dose approximately 24 hours after completion of surgery.
Heart transplantation - prophylaxis of transplant rejection
Following antibody induction 10 to 20 microgram/kg per day as a continuous 24-hour infusion.
Commence within 5 day of completion of surgery.
Children
Liver transplantation - prophylaxis of transplant rejection
50microgram/kg per day as a continuous 24-hour infusion.
The following alternative dosing schedule may be suitable:
Children 1 month to 18 years
Treatment starting 12 hours after transplant by continuous intravenous infusion (only if oral route inappropriate) may continue for up to 7 days with dose adjusted according to whole blood concentration.
Kidney transplantation - prophylaxis of transplant rejection
75microgram/kg to 100microgram/kg per day as a continuous 24-hour infusion
The following alternative dosing schedule may be suitable:
Children 1 month to 18 years
Treatment starting 24 hours after transplant by continuous intravenous infusion (only if oral route inappropriate) may continue for up to 7 days with dose adjusted according to whole blood concentration.
Heart transplantation - prophylaxis of transplant rejection
Without antibody induction intravenous therapy should be started at 30microgram/kg to 50microgram/kg per day as a continuous 24-hour infusion, to achieve tacrolimus whole blood concentrations of 15nanograms/ml to 25nanograms/ml.
The following alternative dosing schedule may be suitable:
Without antibody induction (starting 12 hours after transplant)
Children 1 month to 18 years
Treatment by continuous intravenous infusion may continue for up to 7 days with dose adjusted according to whole blood concentration.
Following antibody induction information for oral preparations should be consulted.
Neonates
Liver transplantation - prophylaxis of transplant rejection (unlicensed)
50micrograms/kg over 24 hours for up to 7 days (then transfer to oral therapy), adjusted according to whole-blood concentration.
Kidney transplantation - prophylaxis of transplant rejection (unlicensed)
75microgram/kg to 100microgram/kg over 24 hours for up to 7 days (then transfer to oral therapy), adjusted according to whole-blood concentration.
Heart transplantation - prophylaxis of transplant rejection (unlicensed)
Without antibody induction 30microgram/kg to 50microgram/kg over 24hours for up to 7 days (then transfer to oral therapy), adjusted according to whole-blood concentration.
Following antibody induction information for oral preparations should be consulted.
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.
Administration
For intravenous infusion after dilution.
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 20 nanograms/ml.
12-hour trough whole blood levels are generally 5 to 20 nanograms/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
Breastfeeding
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
Hepatic impairment
History of torsade de pointes
Hypertension
Hypervolaemia
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
Consider prophylactic antihistamines for high risk patients
Treatment to be initiated and supervised by a specialist
Contains alcohol
Infusion concentrate contains polyoxyethylene hydrogenated castor oil
Dilute and use as an infusion
Patient should be converted to oral therapy as soon as possible
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 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
Consider immunosuppressant adjustment if BK virus nephropathy develops
May reduce effectiveness of vaccinations during treatment
Discontinue if posterior reversible encephalopathy syndrome (PRES) develops
Consider dose reduction in severe hepatic impairment
Advise patient not to take St John's wort concurrently
Advise patient to consult doctor before any self medication
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
Apply sunscreen (SPF15+) to areas at risk of sunlight exposure post therapy
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)
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 immunosuppressant 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.
Weak interactions between tacrolimus and herbal remedies containing Schisandra sphenanthera have been observed.
Pregnancy and Lactation
Pregnancy
Tacrolimus should be used with caution in pregnancy.
Human data show that the drug is 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.
Due to the need for treatment, 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. 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.
The use of all medication in pregnancy should be avoided whenever possible; particularly in the first trimester. Non-drug treatments should also be considered. When essential, a medication with the best safety record over time should be chosen, employing the lowest effective dose for the shortest possible time. Polypharmacy should be avoided. Teratogens taken in the pre-embryonic period, often quoted as lasting until 14-17 days post-conception, are believed to have an all-or-nothing effect. Where drugs have a short half-life, and when the date of conception is certain, this may allow women to be reassured where drug exposure has occurred within this time frame. Further advice may be available from the UK National Teratology Information Service (NTIS) and through ToxBase, available via password on the internet ( www.toxbase.org ) or if this is unavailable at the backup site ( www.toxbasebackup.org ).
Animal data - Teratogenic at doses which also demonstrated maternal toxicity
Crosses placenta? - Yes
Lactation
Contraindicated in breastfeeding.
Human data demonstrate that tacrolimus is excreted into breast milk. As detrimental effects on the newborn cannot be excluded, the manufacturer states that women should not breastfeed whilst receiving tacrolimus. However some sources suggest that due to low oral bioavailability a breastfed infant would ingest too little for a clinical effect.
Neonates, infants born prematurely, those with low birth weight, those with an unstable gastrointestinal function or who have serious illnesses may require special consideration. For any infant, if a drug is prescribed to the nursing mother, it should be at the lowest practical dose and for the shortest time. When drug administration is unavoidable and breastfeeding is to continue, minimisation of exposure of the infant to the drug may sometimes be achieved by timing the maternal doses to just after a feeding episode. Infants exposed to drugs via breast milk should be monitored for unusual signs or symptoms. Interactions between the drug received by the infant from the mother's milk and medication prescribed for the infant should also be considered, for example, when the drug given to the infant may prevent metabolism of the drug received via breast milk.
Specialist advice is available from the UK Drugs in Lactation Advisory Service at https://www.midlandsmedicines.nhs.uk/content.asp?section=6&subsection=17&pageIdx=1
Considered suitable or recommended by manufacturer? - No
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
Local pain
Lymphoproliferative disorders
Metabolic acidosis
Musculoskeletal disturbances
Myasthenia
Neuropathy
Neutropenia
Nightmares
Oedema
Ophthalmic disturbances
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 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: February 2013
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, 14th Edition (2010) Hale, T. Hale Publishing, Amarillo, Texas.
Summary of Product Characteristics: Prograf Concentrate for solution for infusion. Astellas Pharma Ltd. Revised June 2015.
The Renal Drug Handbook. 3rd edition. (2009) ed. Ashley, C and Currie, Radcliffe Publishing Ltd, Abingdon.
MHRA Drug safety Update: Volume 5, Issue 11, June 2012
https://www.mhra.gov.uk/Safetyinformation/DrugSafetyUpdate/CON155756
Last accessed: January 29, 2013
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: 15 January, 2013
Last accessed: January 29, 2013
NICE Evidence Services Available at: www.nice.org.uk Last accessed: 18 August 2017
Medscape UK | Univadis prescription drug monographs & interactions are based on FDB Multilex Content
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