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Drug Reference

tacrolimus

calcineurin inhibitor· Brands: Prograf, Advagraf, Envarsus, Adoport, Modigraf, ProtopicIVPOTOP

Mechanism of action
Tacrolimus binds the immunophilin FKBP-12, and the resulting complex inhibits calcineurin, the calcium-calmodulin dependent serine/threonine phosphatase. Calcineurin normally dephosphorylates nuclear factor of activated T cells (NFAT), allowing it to enter the nucleus and drive transcription of interleukin-2 and other cytokines. Blocking this step suppresses T lymphocyte activation, proliferation and effector cytokine release. The action is selective for T cells, reversible, and does not kill lymphocytes: it renders them unresponsive to antigen presentation. Tacrolimus also reduces mast cell and basophil mediator release, which contributes to its benefit in topical use for atopic dermatitis.
Pharmacokinetics
Oral absorption is incomplete and highly variable. Immediate-release bioavailability is roughly 20 to 25%, and is reduced by food, especially fatty meals, and by grapefruit juice. Peak concentrations occur within about 1 to 3 hours for immediate-release and later for prolonged-release preparations. Tacrolimus is highly bound to albumin and alpha-1 acid glycoprotein and distributes extensively into erythrocytes, which is why whole blood is measured for monitoring. It is metabolised by CYP3A4 and CYP3A5 in the liver and gut wall and is a substrate and inhibitor of P-glycoprotein. Elimination is mainly biliary, with less than 1% excreted unchanged in urine, so renal impairment has little effect on clearance. Half-life is around 12 hours for immediate-release and considerably longer for prolonged-release formulations. Topical application to intact skin produces negligible systemic exposure. Doses are individualised by whole blood trough concentration because exposure varies widely between patients.
Indications & dosing

Prophylaxis of renal allograft rejection

Immediate-release capsules or tablets in two divided doses, started within 24 hours of transplant. Dose is titrated to whole-blood trough concentrations, so target ranges and starting doses vary by centre, assay and formulation.

  • adult · PO: 0.1–0.2 mg/kg/day twice daily · Immediate-release capsules or tablets in two divided doses, started within 24 hours of transplant. Dose is titrated to whole-blood trough concentrations, so target ranges and starting doses vary by centre, assay and formulation.

Prophylaxis of hepatic allograft rejection

Given with a corticosteroid and often an antimetabolite. Oral dose is roughly four times the intravenous dose; monitoring of trough levels and renal function is required.

  • adult · PO: 0.1–0.15 mg/kg/day twice daily · Given with a corticosteroid and often an antimetabolite. Oral dose is roughly four times the intravenous dose; monitoring of trough levels and renal function is required.

Prophylaxis of cardiac allograft rejection

Often used with mycophenolate and corticosteroids. Starting dose and target trough range differ from kidney and liver protocols; follow local transplant unit guidance.

  • adult · PO: 0.075 mg/kg/day twice daily · Often used with mycophenolate and corticosteroids. Starting dose and target trough range differ from kidney and liver protocols; follow local transplant unit guidance.

Prophylaxis of transplant rejection when the oral route is not available

Intravenous dose is about one third to one fifth of the oral dose. Give as a continuous infusion and change to oral therapy as soon as it is tolerated.

  • adult · IV: 0.03–0.05 mg/kg/day continuous infusion · Intravenous dose is about one third to one fifth of the oral dose. Give as a continuous infusion and change to oral therapy as soon as it is tolerated.

Prophylaxis of hepatic allograft rejection in children

Children often need higher weight-based doses than adults to reach the same trough concentration. Dose by weight and titrate to levels.

  • pediatric · PO: 0.15–0.2 mg/kg/day twice daily · Children often need higher weight-based doses than adults to reach the same trough concentration. Dose by weight and titrate to levels.

Moderate to severe atopic dermatitis (topical tacrolimus ointment)

Apply a thin layer to affected skin. The 0.1% strength is used in adults and the 0.03% strength in children aged 2 to 15 years. Do not apply to infected or broken skin.

  • adult · TOP: 0.03–0.1 % twice daily · Apply a thin layer to affected skin. The 0.1% strength is used in adults and the 0.03% strength in children aged 2 to 15 years. Do not apply to infected or broken skin.

Prophylaxis of graft-versus-host disease after allogeneic haematopoietic stem cell transplantoff-label

Used with other immunosuppressants, aiming at a higher trough range than in solid organ transplant. Regimens and target levels vary widely between transplant programmes.

  • adult · PO: 0.03–0.06 mg/kg/dose twice daily · Used with other immunosuppressants, aiming at a higher trough range than in solid organ transplant. Regimens and target levels vary widely between transplant programmes.
Contraindications & precautions
  • Known hypersensitivity to tacrolimus or to any excipient of the formulation, including the castor oil derivative used in the intravenous product · Intravenous tacrolimus contains polyoxyl 60 hydrogenated castor oil, which can cause anaphylaxis. Any previous reaction to this vehicle also precludes the intravenous route.
  • Concurrent ciclosporin therapy · Adding or overlapping the two calcineurin inhibitors increases nephrotoxicity and can cause prolonged, unpredictable levels. Stop ciclosporin before starting tacrolimus and allow levels to fall.
  • Administration of live attenuated vaccines while immunosuppressed · Live vaccines can cause disseminated infection in immunocompromised patients. Wait until immunosuppression is reduced, guided by the transplant team and local immunisation policy.
  • Active, uncontrolled systemic infection · Immunosuppression may worsen the infection. Treatment is usually deferred or withheld until the infection is controlled, but this is a specialist decision, especially in graft-threatening rejection.
  • Severe hepatic impairment · Hepatic clearance is markedly reduced, so half-life is prolonged. Doses are reduced and levels checked frequently; some products are contraindicated in severe impairment in certain labels, so follow the local SPC.
  • Co-administration of strong CYP3A4 inhibitors, for example ketoconazole, itraconazole or clarithromycin, without dose adjustment · Levels can rise several-fold and cause nephrotoxicity, neurotoxicity and QT prolongation. Where the combination is unavoidable, reduce the tacrolimus dose and monitor levels closely.
  • Prescribe by brand and formulation: immediate-release and prolonged-release tacrolimus are not interchangeable milligram for milligram. Specify the brand on every prescription and switch products only under specialist supervision with level monitoring.
  • Monitor whole blood trough levels alongside renal function, potassium, magnesium, glucose, blood pressure, full blood count and liver function. Target ranges differ by transplant type, time since transplant and formulation.
  • Check every new medicine for CYP3A4 and P-glycoprotein interactions. Azoles, macrolides and protease inhibitors raise levels and toxicity; rifampicin, carbamazepine, phenytoin and St John's wort lower them and risk rejection. Avoid grapefruit juice.
  • Counsel patients on infection precautions and vaccine timing. Live vaccines are contraindicated during immunosuppression, and inactivated vaccines may produce a weaker response.
  • In pregnancy and breastfeeding, manage only with transplant specialist input. Check local labelling, as several products require effective contraception in women of childbearing potential and in men.
  • Topical tacrolimus is a separate product for atopic eczema and is not interchangeable with oral or intravenous tacrolimus. Do not apply to infected skin, and advise photoprotection because of the long-term skin cancer risk.
Adverse effects
  • Nephrotoxicity: rising creatinine, reduced urine output, acute kidney injury and chronic interstitial fibrosisserious
  • Tremor, often fine and affecting the hands
  • Diarrhoea
  • Hypertension
  • Hyperkalaemiaserious
  • Hyperglycaemia and new-onset diabetes after transplantationserious
  • Hypomagnesaemia
  • Serious opportunistic infection, including cytomegalovirus, Epstein-Barr virus and post-transplant lymphoproliferative disorderserious
  • Posterior reversible encephalopathy syndrome: headache, confusion, seizures, visual disturbanceserious
  • Anaphylaxis with the intravenous formulationserious
Interactions
  • diltiazemmajorAvoid co-prescription if possible. If necessary, reduce tacrolimus dose and monitor blood levels frequently, adjusting dose based on concentrations.
  • ibuprofenmajorAvoid co-prescription where possible. Consider alternative analgesia such as paracetamol. If the combination is necessary, ensure adequate patient hydration and closely monitor renal function (serum creatinine, BUN, urine output) at baseline, then at least weekly for the first month or more frequently if renal dysfunction is evident. Also monitor tacrolimus trough levels as renal function changes can affect its clearance; adjust tacrolimus dose as needed. Advise patients to seek medical attention if they note decreased urine output, swelling, or nausea.
  • fluconazolemajorAvoid co-prescription if possible. If unavoidable, reduce the tacrolimus dose, typically by 50-70%, and monitor tacrolimus trough concentrations frequently (e.g., every 2-3 days) until stable, then adjust accordingly. Monitor renal function, electrolytes, and signs of toxicity. Fluconazole should be stopped or changed to an alternative if possible.
  • rifampicinmajorAvoid concomitant use where possible. If co-administration is unavoidable, increase the tacrolimus dose, guided by frequent trough level monitoring, and adjust therapy when rifampicin is stopped. Consider alternative antitubercular drugs such as rifabutin, which is a weaker inducer, if appropriate.
  • verapamilmajorAvoid co-prescription if possible. If combination is considered necessary, measure tacrolimus trough levels before and after starting verapamil, and at intervals thereafter. Reduce the tacrolimus dose as needed to maintain therapeutic trough concentrations. Monitor renal function and watch for signs of tacrolimus toxicity.
  • clarithromycinmajorAvoid co-prescription where possible. If unavoidable, consider a non-interacting macrolide (e.g., azithromycin) or another antibiotic. If the combination is necessary, reduce the tacrolimus dose (often by 50% or more), monitor trough levels frequently (e.g., every 2-3 days) and adjust based on levels. Monitor renal function, blood glucose, and signs of neurotoxicity.
Renal & hepatic adjustment
  • eGFR 30+: No routine dose change is required for stable chronic kidney disease. Tacrolimus is eliminated mainly by biliary excretion, with less than 1% of a dose excreted unchanged in urine, so renal impairment does not usually alter clearance; continue the existing regimen and monitor trough levels, serum creatinine and potassium closely.
  • eGFR 0–29: No fixed dose reduction is defined, but this group is at high risk of accumulated toxicity. Use the lowest effective dose, check trough levels frequently, and distinguish true drug nephrotoxicity from other causes of acute kidney injury before adjusting the dose.
  • Hepatic impairment (mild): Usually no change in starting dose. Monitor trough levels and liver enzymes more frequently, because hepatic metabolism by CYP3A4 is the main elimination route and exposure may drift upward.
  • Hepatic impairment (moderate): Reduce the starting dose and titrate according to measured trough levels rather than a fixed regimen. Oral bioavailability rises as first-pass metabolism falls, so levels should be checked soon after any change.
  • Hepatic impairment (severe): Substantial dose reduction is needed, with the dose guided entirely by trough concentrations and clinical response. Consider a lower starting dose with prolonged intervals between level checks, and review all interacting drugs before prescribing.
Monitoring, pregnancy & toxicity
  • Whole blood trough concentration (assay method specified by the local laboratory) · Two to three times weekly after starting or changing dose, then at intervals set by the transplant protocol; sample just before the next dose.
  • Serum creatinine and eGFR, urine output · At least twice weekly during initiation and after any dose change, then per protocol; more often if renal function is unstable.
  • Potassium and magnesium · Baseline and regularly thereafter. Hyperkalaemia and hypomagnesaemia are common and can precipitate arrhythmia.
  • Blood glucose and HbA1c · Baseline, then regularly. Tacrolimus causes dose-related new-onset diabetes after transplantation.
  • Blood pressure and lipid profile · At each clinic review; hypertension and dyslipidaemia are common and add to cardiovascular risk.
  • Full blood count, liver enzymes, and neurological and visual symptoms · At each review, with urgent assessment if tremor, headache, confusion, seizures or visual disturbance appear.
  • Pregnancy: Tacrolimus is widely used in pregnancy in transplant recipients and women with autoimmune disease, and is usually continued rather than stopped, since rejection or disease flare poses a greater risk than the drug. It is not considered a major human teratogen, though data are limited and registries report more prematurity and low birth weight, confounded by the underlying condition. Monitor trough levels closely: clearance often rises in later pregnancy and falls after delivery, so doses may need increasing, then reducing. Decide jointly with the transplant or obstetric team.
  • Toxicity: Nephrotoxicity: rising creatinine, reduced urine output and tubular injury, which may be acute or chronic. It is dose-related and can occur even at therapeutic trough levels. · Check the trough level, review all interacting drugs, reduce the dose if the level is high, and exclude dehydration, sepsis, calcineurin inhibitor excess and other nephrotoxins. Management is dose reduction and supportive care; dialysis is not useful for removing the drug because of high protein binding and wide tissue distribution.
  • Toxicity: Neurotoxicity: tremor, paraesthesia, headache, insomnia, confusion, seizures and posterior reversible encephalopathy syndrome with visual disturbance. · Check the level and reduce or hold the dose; obtain urgent neuroimaging if encephalopathy or seizures occur. Most episodes resolve on dose reduction, but symptoms can persist. Reintroduction, if needed, should use a lower dose or an alternative agent.
  • Toxicity: Metabolic and cardiac effects: hyperkalaemia, hypomagnesaemia, hypertension, new-onset diabetes, hyperlipidaemia and QT prolongation, with rare cardiomyopathy at high exposure. · Correct electrolytes, review the ECG if QT prolongation is suspected, treat hypertension and hyperglycaemia, and reduce the dose if levels are high. Avoid other QT-prolonging drugs where possible.
  • Toxicity: Acute overdose: nausea, vomiting, tremor, headache, hyperkalaemia, renal impairment and, at high exposure, arrhythmia. Anaphylaxis and hypersensitivity reactions have been reported with intravenous formulations that contain a polyoxyl castor oil vehicle. · There is no specific antidote. Stop the drug, check the level, give activated charcoal if a substantial oral dose was taken recently and the airway is protected, correct electrolytes and manage seizures or arrhythmia supportively. Haemodialysis and haemofiltration do not remove the drug effectively, so treatment is supportive until levels fall.
Clinical notes
Tacrolimus has a narrow therapeutic index and is monitored by whole blood trough concentrations, with target ranges set by transplant type, time since transplant and local protocol. Principal toxicities are nephrotoxicity, tremor and other neurotoxicity, hypertension, hyperkalaemia, hypomagnesaemia, hyperglycaemia and new-onset diabetes, gastrointestinal upset, and increased infection risk including cytomegalovirus and BK virus. It can prolong the QT interval. CYP3A4 and P-glycoprotein inhibitors such as azoles, macrolides, diltiazem, verapamil and grapefruit raise concentrations, while inducers such as rifampicin, carbamazepine, phenytoin and St John's wort lower them and risk rejection. Live vaccines are contraindicated during immunosuppression. Do not switch between immediate-release and prolonged-release products without supervision and repeat monitoring. Topical tacrolimus for atopic dermatitis is used in short courses on affected areas; occlusive dressings and unsupervised ultraviolet therapy should be avoided.

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BNF; local transplant formulary; product SmPC or prescribing information; local therapeutic drug monitoring protocol