Tacrolimus

(BAN, USAN, rINN)
Tacrolimus Chemical formula
Synonyms: FK-506; FR-900506; Tacrolimús; Tacrolimusum; Takrolimus; Takrolimuusi; Tsukubaenolide. (−)-(3S,4R,5S,8R,9E,12S,14S,15R,16S,18R,19R,26aS)-8-Allyl-5,6,8,11,12,13,14,15,16,17,18,19,24,25,26,26a-hexadecahydro-5,19-dihydroxy-3-{(E)-2[(1R,3R,4R)-4-hydroxy-3-methoxycyclohexyl]-1-methylvinyl}14,16,-dimethoxy-4,10,12,18-tetramethyl-15,19-epoxy-3Hpyrido[2,1c][1,4]oxaazacyclotricosine-1,7,20,21(4H,23H)tetrone monohydrate.
Cyrillic synonym: Такролимус.

💊 Chemical information

Chemical formula: C44H69NO12,H2O = 822.0.
CAS — 104987-11-3 (anhydrous tacrolimus); 10958193-3 (tacrolimus monohydrate).
ATC — D11AX14; L04AD02.
ATC Vet — QD11AX14; QL04AD02.

💊 Adverse Effects, Treatment, and Precautions

The most common adverse effects after systemic use
of tacrolimus include tremor, headache, paraesthesias, nausea and diarrhoea, hypertension, insomnia, and impaired renal function. Disturbances of serum electrolytes, notably hyperkalaemia, and hyperglycaemic conditions, including diabetes mellitus, occur frequently. Hyperlipidaemia, hypercholesterolaemia, and hypertriglyceridaemia are common. Anaemia, leucopenia, and thrombocytopenia also occur commonly. Other common adverse effects include mood changes, anxiety, confusion, dizziness, tinnitus, visual disturbances, peripheral neuropathies, and convulsions; constipation, dyspepsia, gastrointestinal perforation and ulceration, and gastrointestinal haemorrhage; dyspnoea, parenchymal lung disorders, pleural effusions, pharyngitis, cough, nasal congestion and inflammation; alopecia, acne, skin rashes, and pruritus; and arthralgia, muscle cramps, asthenia, febrile disorders, oedema, and liver dysfunction. Tachycardia is common; ventricular arrhythmias, cardiac arrest, heart failure, palpitations, and ECG changes are less frequent. Cardiomyopathies, including ventricular hypertrophy have also been reported; most cases have been reversible, and occurring primarily in children with tacrolimus blood concentrations much higher than the recommended maximum levels. Coagulation disorders, neutropenia, and pancytopenia have occurred, as have asthma, acute respiratory distress syndrome, hypoproteinaemia, deep limb venous thrombosis, paralytic ileus, acute and chronic pancreatitis, and haemolytic uraemic syndrome. Coma, CNS haemorrhage, encephalopathy, amnesia, and speech and language abnormalities have also been reported. There are rare reports of thrombotic thrombocytopenic purpura, hypoprothrombinaemia, and hirsutism. Toxic epidermal necrolysis, Stevens Johnson syndrome, hepatic artery thrombosis, and veno-occlusive liver disease have occurred rarely. Tacrolimus injection is formulated with polyoxyl castor oil: anaphylactoid reactions have occurred, and appropriate means for their management should be available in patients given the injection. Use of tacrolimus should be avoided in patients hypersensitive to macrolides. Dosage reduction may be necessary in patients with hepatic impairment. Care is also required in patients with pre-existing renal impairment, and dosage reduction may prove advisable in such patients. Monitoring of blood concentrations of tacrolimus is recommended in all patients, especially during episodes of diarrhoea as concentrations may be significantly affected. Renal and hepatic function, blood pressure, serum glucose electrolytes, haematological and cardiac function, as well as neurological and visual status, coagulation values, and plasma protein should be monitored regularly. As with other immunosuppressants, patients receiving tacrolimus are at increased risk of infection and malignancy. Intra-uterine devices should be used with caution during immunosuppressive therapy as there is an increased risk of infection. Use of live vaccines should be avoided for the same reason. Tacrolimus may affect visual or neurological function, and patients so affected should not drive or operate dangerous machinery. Top ical tacrolimus has been associated with local irritation and skin disorders including an increased incidence of herpes simplex and zoster infections; headache and ‘flu-like’ symptoms have also been reported. Facial flushing and skin irritation has been reported after consumption of alcohol. Exposure of the skin to sunlight should be minimised and the use of artificial sources of ultraviolet light avoided. Carcinogenicity studies in animals have reported an increase in the incidence of lymphoma and skin cancers associated with topical tacrolimus and rare cases of skin malignancy and lymphoma have been reported in patients (see also below). Skin infections should be treated before starting therapy with topical tacrolimus. It should not be used in immunocompromised patients or those with conditions that might increase systemic absorption of tacrolimus. It must also not be applied to pre-malignant or malignant skin conditions; some malignant skin conditions may mimic eczema.

Breast feeding.

Tacrolimus is distributed into breast milk. Tacrolimus concentrations were measured in milk from a liver transplant recipient on a dose of 100 micrograms/kg daily. The authors estimated that the infant would ingest only 0.06% (0.06 micrograms/kg daily) of the mother’s weight-adjusted dose. No adverse effects were noted in the infant at 2.5 months of age.1 Licensed product information recommends that women should avoid breast feeding while taking tacrolimus.
1. French AE, et al. Milk transfer and neonatal safety of tacrolimus. Ann Pharmacother 2003; 37: 815–18.

Carcinogenicity.

The systemic use of tacrolimus increases the risk of malignancy. Carcinogenicity studies in animals have also reported an increase in the incidence of malignancies associated with the topical calcineurin inhibitors, tacrolimus and pimecrolimus. As of December 2004 the FDA had received reports of 19 cases of lymphoma or cutaneous tumours associated with topical tacrolimus, of which 4 cases were a recurrence or aggravation of a pre-existing malignancy, and 3 other cases were confounded by other possible risk factors. At this same date, the FDA had also received reports of 10 cases of malignancy in patients treated with topical pimecrolimus, including 6 cutaneous tumours. Although the potential for systemic immunosuppression from topical use was unknown and the role of the drug in these cases was uncertain, the FDA recommended that topical calcineurin inhibitors should only be used as a second-line drug for short-term and intermittent treatment of eczema, and that they should not be used in immunocompromised patients or in children younger than 2 years of age.1,2 Similar warnings have been issued in the European Union.3 However, there has been some debate about the risk of malignancy associated with the topical use of these drugs, and a number of groups4-6 have examined the evidence used by the FDA. They found that after topical application in humans the serum concentrations of these drugs were usually low or undetectable, that there was no evidence of systemic immunosuppression as measured by response to childhood immunisation and delayed hypersensitivity, no evidence of an increase in malignancy in clinical studies or compared with the general population, and that none of the reported lymphoma cases resembled the usual presentation and histology seen with systemic immunosuppression-associated lymphoma. They concluded that based on available data the risk of cancer from topical calcineurin inhibitors was theoretical and unknown. A review7 of skin cancer risk found that there was no conclusive evidence from rodent studies to suggest that topical calcineurin inhibitors were associated with an increase in skin cancers, or a potentiation of UV-associated immunosuppression and carcinogenicity. There was also no evidence of an increased risk of skin cancer in human studies. In general, there seems to be agreement that longterm data are still needed to determine the carcinogenic risk, if there is any, from topical tacrolimus and pimecrolimus. Until long-term safety data are available some8 consider that it would be prudent if topical calcineurin inhibitors were:
not used in children under 2 years of age
not used continuously for more than 6 weeks, with an application-free period of up to 2 weeks
avoided in immunocompromised patients
avoided in patients with neoplasia
avoided in those with skin disorders liable to lead to increased systemic absorption Patients should also be encouraged to use a broad-spectrum sunscreen daily on all sunlight-exposed skin.
1. FDA. Alert for healthcare professionals: tacrolimus (marketed as Protopic) 03/05. Available at: http://www.fda.gov/cder/ drug/InfoSheets/HCP/ProtopicHCP.pdf (accessed 18/03/08
2. FDA. Alert for healthcare professionals: pimecrolimus (marketed as Elidel) 03/05. Available at: http://www.fda.gov/cder/ drug/InfoSheets/HCP/ElidelHCP.pdf (accessed 18/03/08
3. Committee on Safety of Medicines/Medicines and Healthcare products Regulatory Agency. Topical tacrolimus (Protopic) and pimecrolimus (Elidel): reports of malignancies. Current Problems 2006; 31: 1–2. Also available at: http://www.mhra.gov.uk/ home/idcplg?IdcService=GET_FILE&dDocName= CON2023860&RevisionSelectionMethod=LatestReleased (accessed 18/03/08
4. Fonacier L, et al. Report of the Topical Calcineurin Inhibitor Task Force of the American College of Allergy, Asthma and Immunology and the American Academy of Allergy, Asthma and Immunology. J Allergy Clin Immunol 2005; 115: 1249–53
5. Bieber T, et al. Consensus statement on the safety profile of topical calcineurin inhibitors. Dermatology 2005; 211: 77–8
6. Berger TG, et al. The use of topical calcineurin inhibitors in dermatology: safety concerns. Report of the American Academy of Dermatology Association Task Force. J Am Acad Dermatol 2006; 54: 818–23
7. Ring J, et al. Review of the potential photo-cocarcinogenicity of topical calcineurin inhibitors: position statement of the European Dermatology Forum. J Eur Acad Dermatol Venereol 2005; 19: 663–71
8. Ring J, et al. The US FDA ’black box’ warning for topical calcineurin inhibitors: an ongoing controversy. Drug Safety 2008; 31: 185–98.

Effects on the blood.

Severe anaemia due to selective depression of erythropoiesis in a patient given tacrolimus resolved when tacrolimus was replaced with ciclosporin.1 More generalised bone marrow suppression,2 post-transplant thrombotic microangiopathy,3 and red cell aplasia4 have also been reported. Hypoplasia occurring in a liver transplant recipient,5 was characterised by a slow but complete recovery after substituting tacrolimus with ciclosporin.
1. Winkler M, et al. Anaemia associated with FK 506 immunosuppression. Lancet 1993; 341: 1035–6
2. de-la-Serna-Higuera C, et al. Tacrolimus-induced bone marrow suppression. Lancet 1997; 350: 714–15
3. Trimarchi HM, et al. FK506-associated thrombotic microangiopathy: report of two cases and review of the literature. Transplantation 1999; 67: 539–44
4. Misra S, et al. Red cell aplasia in children on tacrolimus after liver transplantation. Transplantation 1998; 65: 575–7
5. Nosari A, et al. Bone marrow hypoplasia complicating tacrolimus (FK506) therapy. Int J Hematol 2004; 79: 130–2.

Effects on carbohydrate metabolism.

The development of diabetes mellitus after solid organ transplantation is common,1,2which may be attributed to the diabetogenic effects of immunosuppressive drugs. Incidence has appeared to be increased in both adult3 and paediatric4 renal transplant recipients given tacrolimus. However, a retrospective review2 found no significant difference in incidence between patients receiving tacrolimus or ciclosporin but found instead a correlation between the absence of an antiproliferative agent and the development of diabetes. A retrospective study of liver transplant recipients found that, although those given tacrolimus had a greater incidence of diabetes mellitus, hepatitis C infection was the only factor predictive of its development.1 In contrast, a meta-analysis5 found the incidence of new-onset diabetes mellitus (NODM) to be significantly higher among patients receiving tacrolimus compared with those receiving ciclosporin after solid organ transplantation. An observational study6 confirmed this finding, and found it to be unrelated to corticosteroid dosage, although relatively high doses of corticosteroids were used across the study. A retrospective study7found tacrolimus to be significantly more diabetogenic than ciclosporin, even when corticosteroid dosing was lower with tacrolimus. An analysis of data for 8839 patients8 found the risk of NODM to be greatest with high tacrolimus doses, but the increased risk versus ciclosporin was sustained even with lower tacrolimus doses. Higher corticosteroid doses potentiated the diabetogenic effect of tacrolimus, but even the lowest dosage group for tacrolimus and corticosteroids had higher rates of NODM than all ciclosporin groups; there was no association between corticosteroid dose and NODM for any dosage of ciclosporin. In a small, retrospective study,9 conversion from tacrolimus to ciclosporin resulted in marked improvement of glucose metabolism, and even reversal of diabetes mellitus in a significant proportion of patients.
1. AlDosary AA, et al. Post-liver transplantation diabetes mellitus: an association with hepatitis C. Liver Transpl 2002; 8: 356–61
2. First MR, et al. Posttransplant diabetes mellitus in kidney allograft recipients: incidence, risk factors, and management. Transplantation 2002; 73: 379–86
3. Pirsch JD, et al. A comparison of tacrolimus (FK506) and cyclosporine for immunosuppression after cadaveric renal transplantation. Transplantation 1997; 63: 977–83
4. Al-Uzri A, et al. Posttransplant diabetes mellitus in pediatric renal transplant recipients: a report of the North American Pediatric Renal Transplant Cooperative Study (NAPRTCS). Transplantation 2001; 72: 1020–4
5. Heisel O, et al. New onset diabetes mellitus in patients receiving calcineurin inhibitors: a systematic review and meta-analysis. Am J Transplant 2004; 4: 583–95
6. Kamar N, et al. Diapason Study Group. Diabetes mellitus after kidney transplantation: a French multicentre observational study. Nephrol Dial Transplant 2007; 22: 1986–93
7. Hoitsma AJ, Hilbrands LB. Relative risk of new-onset diabetes during the first year after renal transplantation in patients receiving tacrolimus or cyclosporine immunosuppression. Clin Transplant 2006; 20: 659–64
8. Burroughs TE, et al. Influence of early posttransplantation prednisone and calcineurin inhibitor dosages on the incidence of new-onset diabetes. Clin J Am Soc Nephrol 2007; 2: 517–23
9. Bouchta NB, et al. Conversion from tacrolimus to cyclosporin is associated with a significant improvement of glucose metabolism in patients with new-onset diabetes mellitus after renal transplantation. Transplant Proc 2005; 37: 1857–60.

Effects on the cardiovascular system.

Hypertrophic cardiomyopathy, and in some cases heart failure, has been described in paediatric patients receiving tacrolimus after organ grafting (small bowel or liver).1 Symptoms largely resolved on stopping or reducing dosage. A similar case had been found post mortem in an adult,2 and the UK CSM3 was aware of 29 reported cases worldwide as of July 1995. Echocardiographic monitoring of patients receiving tacrolimus has been recommended, with dose reduction or withdrawal in those who developed hypertrophic changes.3 However, echocardiographic abnormalities may be quite common after orthotopic liver transplantation in adults, with no obvious relationship to the use of tacrolimus,4 and a retrospective analysis concluded that tacrolimus is not a risk factor for hypertrophic cardiomyopathy in adult transplant recipients.5 Severe hypertension was documented in 5 out of 10 paediatric patients who received intravenous tacrolimus after renal transplant surgery. All patients responded to intravenous labetalol. By contrast none of 11 children who received ciclosporin at the same institution developed hypertension.6 However, a review7 concluded that tacrolimus causes less hypertension than ciclosporin, resulting in a better cardiovascular risk profile in renal transplant recipients, and possibly ultimately prolonging graft survival.
1. Atkison P, et al. Hypertrophic cardiomyopathy associated with tacrolimus in paediatric transplant patients. Lancet 1995; 345: 894–6
2. Natazuka T, et al. Immunosuppressive drugs and hypertrophic cardiomyopathy. Lancet 1995; 345: 1644
3. Committee on Safety of Medicines/Medicines Control Agency. Tacrolimus (Prograf) and hypertrophic cardiomyopathy in transplant patients. Current Problems 1995; 21: 6. Also available at: http://www.mhra.gov.uk/home/idcplg?IdcService=GET_FILE& dDocName=CON2015619&RevisionSelectionMethod= LatestReleased (accessed 18/03/08
4. Dollinger MM, et al. Tacrolimus and cardiotoxicity in adult liver transplant recipients. Lancet 1995; 346: 507
5. Coley KC, et al. Lack of tacrolimus-induced cardiomyopathy. Ann Pharmacother 2001; 35: 985–9
6. Booth CJ, et al. Intravenous tacrolimus may induce severe hypertension in renal transplant recipients. Arch Dis Child 1999; 80 (suppl 1): A27
7. Koomans HA, Ligtenberg G. Mechanisms and consequences of arterial hypertension after renal transplantation. Transplantation 2001; 72 (suppl): S9–12.

Effects on the kidneys.

A comparison in patients who had undergone liver transplantation suggested that nephrotoxicity was more of a problem in those receiving tacrolimus than in those given a ciclosporin-based regimen.1 In particular intravenous tacrolimus during the first week after transplantation was associated with acute renal failure in 4 of 20 patients. Furthermore, on follow-up for 1 year, GFR was somewhat lower in the tacrolimus-treated group. A small study compared GFR and effective renal plasma flow (ERPF), at various stages after transplantation, in renal and liver transplant recipients given tacrolimus.2In renal transplant patients, the GFR, although lower than normal, was increased after transplant, and remained stable over 3 months. ERPF, however, was significantly lower at 3 months. In liver transplant recipients, despite being lower than normal, GFR and ERPF were unchanged at 1 year post-transplant.
1. Porayko MK, et al. Nephrotoxic effects of primary immunosuppression with FK-506 and cyclosporine regimens after liver transplantation. Mayo Clin Proc 1994; 69: 105–11
2. Agarwala S, et al. Evaluation of renal function in transplant patients on tacrolimus therapy. J Clin Pharmacol 2002; 42: 798–805.

Effects on the nervous system.

Although many of the symptoms of neurotoxicity induced by tacrolimus are similar to those of ciclosporin, some symptoms such as headaches, tremor, and sleep disturbances, appear to be more prevalent with tacrolimus, and the incidence of tacrolimus-induced neurotoxicity appears to be higher in liver transplant recipients.1 Severe peripheral neuropathy together with signs of cerebral dysfunction has been reported in 2 patients receiving tacrolimus.2 Among other central effects, tacrolimus has also been associated with speech disorders, including severe dysarthria and mutism in 1 patient;3 some degree of speech dysfunction, in the form of an apparent Norwegian accent, appeared to be permanent in this case. Encephalopathy, sometimes occurring within the reversible posterior leukoencephalopathy syndrome (RPLS), has been reported with use of tacrolimus.4-8 Presenting symptoms included acute severe headache, seizures, cortical blindness, disorientation, and hypertension. Miller Fisher syndrome, a variant of Guillain-Barré syndrome, has been attributed to tacrolimus use in a liver transplant recipient.9 Clinical manifestations included ataxia, ophthalmoplegia, and areflexia.
1. Bechstein WO. Neurotoxicity of calcineurin inhibitors: impact and clinical management. Transpl Int 2000; 13: 313–26
2. Ayres RCS, et al. Peripheral neurotoxicity with tacrolimus. Lancet 1994; 343: 862–3
3. Boeve BF, et al. Dysarthria and apraxia of speech associated with FK-506 (tacrolimus). Mayo Clin Proc 1996; 71: 969–72
4. Kiemeneij IM, et al. Acute headache as a presenting symptom of tacrolimus encephalopathy. J Neurol Neurosurg Psychiatry 2003; 74: 1126–7
5. Nakazato T, et al. Reversible posterior leukoencephalopathy syndrome associated with tacrolimus therapy. Intern Med 2003; 42: 624–5
6. Frühauf NR, et al. Late onset of tacrolimus-related posterior leukoencephalopathy after living donor liver transplantation. Liver Transpl 2003; 9: 983–5
7. Schuuring J, et al. Severe tacrolimus leukoencephalopathy after liver transplantation. Am J Neuroradiol 2003; 24: 2085–8
8. Lavigne CM, et al. Tacrolimus leukoencephalopathy: a neuropathologic confirmation. Neurology 2004; 63: 1132–3
9. Kaushik P, et al. Miller Fisher variant of Guillain-Barré syndrome requiring a cardiac pacemaker in a patient on tacrolimus after liver transplantation. Ann Pharmacother 2005; 39: 1124–7.

Effects on skeletal muscle.

Severe acute rhabdomyolysis, leading to fatal acute renal failure, developed in an 18-month-old child given tacrolimus after bone marrow transplantation.1 Seizures, severe rhabdomyolysis, and acute renal failure were reported in a renal transplant patient taking tacrolimus and a monoclonal antibody.2
1. Hibi S, et al. Severe rhabdomyolysis associated with tacrolimus. Lancet 1995; 346: 702
2. Fontana I, et al. Severe rhabdomyolysis and acute renal failure in a kidney transplant patient treated with tacrolimus and chimaeric CD25 monoclonal antibody. Transplant Proc 2004; 36: 711–2.

Effects on the skin.

Three children developed lentigines (small pigmented macules) while receiving long-term (9 months to 4 years) treatment with topical tacrolimus 0.1% for eczema. The lesions developed primarily in the areas where tacrolimus had been applied. Despite withdrawal of tacrolimus, the lentigines still persisted at review 6 to 18 months later. The authors noted that use of tacrolimus was outside the product’s licensed indications, and that the clinical implications of their findings remained uncertain.1
1. Hickey JR, et al. Does topical tacrolimus induce lentigines in children with atopic dermatitis? A report of three cases. Br J Dermatol 2005; 152: 152–4.

Hepatitis.

For the suggestion that dosage requirements of tacrolimus may be reduced in children with hepatitis C see Administration, below.

Infection.

For a report of an increased incidence of CMV disease in renal transplant recipients given a regimen combining tacrolimus and mycophenolate mofetil see under Interactions.

Overdosage.

A report1 of 12 cases of acute overdose with tacrolimus described overdoses of up to 30 times the prescribed dose. Three patients were asymptomatic, while 7 showed mild transient renal and hepatic impairment, nausea, and mild hand tremors. One patient suffered renal failure, histoplasmosis, and sepsis 48 hours after admission for the overdose. The outcome was unknown in one patient. All 8 symptomatic patients recovered when tacrolimus concentrations returned to normal. No specific treatment regimen has been recommended, but patients have been treated with gastric lavage, oral activated charcoal, and phenytoin. The latter is used both to prevent seizures and to enhance tacrolimus metabolism by stimulation of cytochrome P450. Patients should be closely monitored for known signs and symptoms of tacrolimus toxicity. In a further series of 5 cases,2acute ingestion of tacrolimus was reported to be well tolerated, and adequately managed with conservative treatment.
1. Curran CF, et al. Acute overdoses of tacrolimus. Transplantation 1996; 62: 1376
2. Mrvos R, et al. Tacrolimus (FK 506) overdose: a report of five cases. J Toxicol Clin Toxicol 1997; 35: 395–9.

Porphyria.

Data are limited on the use of tacrolimus in patients with porphyria. There has been a report of a patient with acute intermittent porphyria given tacrolimus for 5 days before renal transplantation, and maintenance tacrolimus post-transplantation, without exacerbation of symptoms.1
1. Barone GW, et al. The tolerability of newer immunosuppressive medications in a patient with acute intermittent porphyria. J Clin Pharmacol 2001; 41: 113–5.

Pregnancy.

Tacrolimus crosses the placenta. Licensed product information states that, although systemic tacrolimus has shown abortifacient and teratogenic properties in animal studies, limited data in humans show no evidence of an increased risk of adverse effects on the course and outcome of pregnancy compared with other immunosuppressants. However, use of tacrolimus has been associated with neonatal hyperkalaemia, which appears to normalise spontaneously, and neonatal renal dysfunction; the neonate should be monitored for potential adverse effects. There are no adequate data from the use of topical tacrolimus in pregnancy. Further references.
1. Kainz A, et al. Review of the course and outcome of 100 pregnancies in 84 women treated with tacrolimus. Transplantation 2000; 70: 1718–21
2. Jain AB, et al. Pregnancy after liver transplantation with tacrolimus immunosuppression: a single center’s experience update at 13 years. Transplantation 2003; 76: 827–32
3. Baumgart DC, et al. Uneventful pregnancy and neonatal outcome with tacrolimus in refractory ulcerative colitis. Gut 2005; 54: 1822–3.

💊 Interactions

Increased nephrotoxicity may result if tacrolimus is given with other potentially nephrotoxic drugs: use with ciclosporin should be avoided for this reason. Similarly, concurrent use with neurotoxic drugs should be avoided. High potassium intake or potassium-sparing diuretics should also be avoided in patients receiving tacrolimus. Tacrolimus is metabolised by the cytochrome P450 isoenzyme CYP3A4, and drugs that inhibit this enzyme system, such as azole antifungals, bromocriptine, calcium-channel blockers, cimetidine, some corticosteroids, ciclosporin, danazol, HIV-protease inhibitors, the NNRTI delavirdine, macrolide antibacterials, and metoclopramide, may produce increased blood concentrations of tacrolimus. The metabolism of tacrolimus may also be inhibited by grapefruit juice and they should not be taken together. Equally, inducers of this enzyme system (such as carbamazepine, nevirapine, phenobarbital, phenytoin, rifampicin, and St John’s wort) may reduce blood concentrations of tacrolimus. Sirolimus can also decrease blood concentrations of tacrolimus. For a warning concerning the use of live vaccines in patients receiving immunosuppressants see Adverse Effects and Precautions, above. Facial flushing or skin irritation may occur if alcohol is consumed by patients using topical tacrolimus.
Drugs known to interact with these systems will probably affect tacrolimus concentrations, primarily by influencing oral bioavailability rather than clearance.2 A study3 in vitro found that metabolism of tacrolimus by CYP3A in human liver microsomes was inhibited by bromocriptine, corticosterone, dexamethasone, ergotamine, erythromycin, ethinylestradiol, josamycin, ketoconazole, miconazole, midazolam, nifedipine, omeprazole, tamoxifen, troleandomycin, and verapamil. No effect on tacrolimus metabolism was seen with aspirin, amphotericin B, captopril, cefotaxime, ciprofloxacin, diclofenac, diltiazem, doxycycline, furosemide, glibenclamide, imipramine, lidocaine, paracetamol, prednisolone, progesterone, ranitidine, sulfamethoxazole, trimethoprim, or vancomycin.
1. van Gelder T. Drug interactions with tacrolimus. Drug Safety 2002; 25: 707–12
2. Christians U, et al. Mechanisms of clinically relevant drug interactions associated with tacrolimus. Clin Pharmacokinet 2002; 41: 813–51
3. Christians U, et al. Identification of drugs inhibiting the in vitro metabolism of tacrolimus by human liver microsomes. Br J Clin Pharmacol 1996; 41: 187–90.

Antibacterials.

Increased concentrations of tacrolimus in plasma have been reported with erythromycin;1 the interaction was accompanied by some evidence of nephrotoxicity. A similar interaction has been reported between tacrolimus and clarithromycin.2,3 For reference to the effects of macrolides on tacrolimus metabolism in vitro see above. Treatment with rifampicin has been found to substantially decrease tacrolimus concentrations.4,5 A pharmacokinetic study found that rifampicin induces metabolism of tacrolimus in both the liver and intestine, probably by induction of the cytochrome P450 isoenzyme subfamily CYP3A and P-glycoprotein.6 Both metronidazole7,8 and chloramphenicol9,10 increased the blood concentrations of tacrolimus. This is probably due to inhibition of metabolism, and dosage reduction of the immunosuppressant may be necessary when either drug is given with tacrolimus. A pharmacokinetic study11 found that levofloxacin partially inhibited the metabolism of tacrolimus, and recommended that drug concentrations be monitored when these 2 drugs are used together. Plasma concentrations of tacrolimus are also increased by quinupristin/dalfopristin.
1. Jensen C, et al. Interaction between tacrolimus and erythromycin. Lancet 1994; 344: 825
2. Wolter K, et al. Interaction between FK 506 and clarithromycin in a renal transplant patient. Eur J Clin Pharmacol 1994; 47: 207–8
3. Ibrahim RB, et al. Tacrolimus-clarithromycin interaction in a patient receiving bone marrow transplantation. Ann Pharmacother 2002; 36: 1971–2
4. Furlan V, et al. Interactions between FK506 and rifampicin or erythromycin in pediatric liver recipients. Transplantation 1995; 59: 1217–18
5. Chenhsu R-Y, et al. Renal allograft dysfunction associated with rifampin-tacrolimus interaction. Ann Pharmacother 2000; 34: 27–31
6. Hebert MF, et al. Effects of rifampin on tacrolimus pharmacokinetics in healthy volunteers. J Clin Pharmacol 1999; 39: 91–6
7. Herzig K, Johnson DW. Marked elevation of blood cyclosporin and tacrolimus levels due to concurrent metronidazole therapy. Nephrol Dial Transplant 1999; 14: 521–3
8. Page RL, et al. Potential elevation of tacrolimus trough concentrations with concomitant metronidazole therapy. Ann Pharmacother 2005; 39: 1109–13
9. Schulman SL, et al. Interaction between tacrolimus and chloramphenicol in a renal transplant recipient. Transplantation 1998; 65: 1397–8
10. Mathis AS, et al. Interaction of chloramphenicol and the calcineurin inhibitors in renal transplant recipients. Transpl Infect Dis 2002; 4: 169–74
11. Federico S, et al. Pharmacokinetic interaction between levofloxacin and ciclosporin or tacrolimus in kidney transplant recipients: ciclosporin, tacrolimus and levofloxacin in renal transplantation. Clin Pharmacokinet 2006; 45: 169–75.

Antidepressants.

Tacrolimus trough concentrations reduced sharply in a patient who took St John’s wort, and returned to previous levels on stopping the St John’s wort.1 St John’s wort induces cytochrome P450 isoenzyme CYP3A4, enhancing the metabolism of tacrolimus. A pharmacokinetic study2 confirmed this, finding an increase in tacrolimus clearance; the authors concluded that potential consequences of this interaction in transplant recipients are rejection and graft loss.
1. Bolley R, et al. Tacrolimus-induced nephrotoxicity unmasked by induction of the CYP3A4 system with St John’s wort. Transplantation 2002; 73: 1009
2. Hebert MF, et al. Effects of St. John’s wort (Hypericum perforatum) on tacrolimus pharmacokinetics in healthy volunteers. J Clin Pharmacol 2004; 44: 89–94.

Antiepileptics.

For the effect of tacrolimus on phenytoin, see Immunosuppressants in Phenytoin.

Antifungals.

Elevated plasma-tacrolimus concentrations have been reported in patients given clotrimazole,1 fluconazole,2 or voriconazole3; a reduction in the dose of tacrolimus was likely to be necessary if it were given with an azole antifungal. A study involving tacrolimus and ketoconazole suggested that an increase in the oral bioavailability of tacrolimus from a mean of 14 to 30% when given with the azole was probably due to decreased cytochrome P450 isoenzyme CYP3A4 metabolism in the gut wall, or improved absorption due to inhibition of P-glycoprotein mediated efflux, rather than an effect on hepatic metabolism.4Similarly, a 50% reduction in tacrolimus dosage was found to be necessary when the drug was given with itraconazole.5 It has been suggested that the interaction could be exploited to reduce the cost of immunosuppressant regimens.6 In another study of itraconazole with tacrolimus,7 1 patient required a 20% increase in the dose of tacrolimus, 3 patients required no dose adjustment, and 5 patients required tacrolimus dose reductions, ranging from 20 to 76.5%. The authors concluded that the magnitude of the dose reduction is dependent on the initial tacrolimus serum concentration and the final target concentration.
1. Mieles L, et al. Interaction between FK506 and clotrimazole in a liver transplant recipient. Transplantation 1991; 52: 1086–7
2. Mañez R, et al. Fluconazole therapy in transplant recipients receiving FK506. Transplantation 1994; 57: 1521–3
3. Venkataramanan R, et al. Voriconazole inhibition of the metabolism of tacrolimus in a liver transplant recipient and in human liver microsomes. Antimicrob Agents Chemother 2002; 46: 3091–3
4. Floren LC, et al. Tacrolimus oral bioavailability doubles with coadministration of ketoconazole. Clin Pharmacol Ther 1997; 62: 41–9
5. Capone D, et al. Effects of itraconazole on tacrolimus blood concentrations in a renal transplant recipient. Ann Pharmacother 1999; 33: 1124–5
6. Kramer MR, et al. Dose adjustment and cost of itraconazole prophylaxis in lung transplant recipients receiving cyclosporine and tacrolimus (FK506). Transplant Proc 1997; 29: 2657–9
7. Leather H, et al. Pharmacokinetic evaluation of the drug interaction between intravenous itraconazole and intravenous tacrolimus or intravenous cyclosporin A in allogeneic hematopoietic stem cell transplant recipients. Biol Blood Marrow Transplant 2006; 12: 325–34.

Antivirals.

Ten- to fiftyfold reductions in tacrolimus dosage were necessary to maintain therapeutic tacrolimus trough concentrations, in 6 HIV-positive liver transplant recipients receiving tacrolimus-based immunosuppressive therapy, when antiretroviral therapy including an HIV-protease inhibitor was started postoperatively.1 This effect was more pronounced with nelfinavir than indinavir. In contrast, 4 HIV-positive kidney transplant recipients received antiretroviral therapy without protease inhibitors, and required only conventional doses of tacrolimus. The authors caution that some protease inhibitors can act as both inducers and inhibitors of the cytochrome P450 isoenzyme CYP3A4. While the inhibitory effect appears to predominate when given with tacrolimus, if the protease inhibitor is withdrawn suddenly the CYP3A4 system may remain induced, and a sudden decrease in tacrolimus concentration may occur; this had occurred in one case. For this reason, they concluded that great caution and frequent tacrolimus monitoring are necessary when protease inhibitors are introduced or withdrawn in transplant recipients receiving tacrolimus. Dramatic increases in tacrolimus blood concentrations have been reported after addition of lopinavir/ritonavir in HIV-positive liver transplant recipients.2-4 Some patients did not need further tacrolimus for up to 3 weeks, even with normal hepatic function; with hepatic dysfunction, 1 mg of tacrolimus provided a therapeutic concentration for up to 5 weeks, and in one patient the tacrolimus concentration increased for the next few days with the introduction of lopinavir/ritonavir without any additional dose of tacrolimus. The authors recommended a pre-emptive decrease in tacrolimus dose by at least 50% one day before starting therapy with lopinavir/ritonavir, and withholding tacrolimus for the next few days; therapy should then be guided by therapeutic drug monitoring of tacrolimus blood concentrations.3 The usual dose of tacrolimus while a patient is on lopinavir/ritonavir is expected to be about 0.5 to 1 mg weekly.2,3 In contrast, efavirenz did not appreciably affect tacrolimus pharmacokinetics.4
1. Jain AKB, et al. The interaction between antiretroviral agents and tacrolimus in liver and kidney transplant patients. Liver Transpl 2002; 8: 841–5
2. Schonder KS, et al. Tacrolimus and lopinavir/ritonavir interaction in liver transplantation. Ann Pharmacother 2003; 37: 1793–6
3. Jain AB, et al. Effect of coadministered lopinavir and ritonavir (Kaletra) on tacrolimus blood concentration in liver transplantation patients. Liver Transpl 2003; 9: 954–60
4. Teicher E, et al. Effect of highly active antiretroviral therapy on tacrolimus pharmacokinetics in hepatitis C virus and HIV coinfected liver transplant recipients in the ANRS HC-08 study. Clin Pharmacokinet 2007; 46: 941–52.

Calcium-channel blockers.

Dosage requirements for tacrolimus were substantially reduced in 22 liver graft recipients who also received nifedipine, compared with 28 patients given tacrolimus alone, in a 1-year retrospective study.1 Tacrolimus toxicity has been reported in a liver transplant patient shortly after starting diltiazem.2
1. Seifeldin RA, et al. Nifedipine interaction with tacrolimus in liver transplant recipients. Ann Pharmacother 1997; 31: 571–5
2. Hebert MF, Lam AY. Diltiazem increases tacrolimus concentrations. Ann Pharmacother 1999; 33: 680–2.

Danazol.

Nephrotoxicity and tremors associated with elevated concentrations of tacrolimus developed in a patient given danazol with the immunosuppressant.1 The effect might have been due to inhibition of the metabolism of tacrolimus.
1. Shapiro R, et al. FK 506 interaction with danazol. Lancet 1993; 341: 1344–5.

Deoxyschizandrin.

Mean blood concentrations of tacrolimus in 12 healthy subjects rose from 22.2 to 66.4 nanograms/mL after they had received 13 days of treatment with SchE (Hezheng Pharmaceutical Company, China), an extract of Schisandra sphenanthera containing amongst other ingredients deoxyschizandrin.1 During the study the area under the concentrationtime curve (AUC) of tacrolimus also rose by 164.2% while oral clearance fell by 49%. It was suggested that constituents of Schisandra sphenanthera may act as inhibitors of the cytochrome P450 isoenzyme CYP3A4 and/or P-glycoprotein.
1. Xin H-W, et al. Effects of Schisandra sphenanthera extract on the pharmacokinetics of tacrolimus in healthy volunteers. Br J Clin Pharmacol 2007; 64: 469–75.

Gastrointestinal drugs.

In 2 renal transplant recipients, tacrolimus trough concentrations increased markedly after introduction of lansoprazole and returned to normal after it was stopped.1,2 One of the patients was later given rabeprazole with no effect on tacrolimus concentration.2 The same effects were apparent in a study of healthy subjects,3 with lansoprazole increasing the concentration and decreasing the clearance of tacrolimus, but the degree of interaction was found to depend, at least partly, upon the genetic status of the patients. The authors supposed that certain ethnic groups might be at higher risk for this interaction. In contrast, rabeprazole appears less affected by genotypic status, and had minimal effect on tacrolimus pharmacokinetics; the authors considered it a safer proton pump inhibitor than lansoprazole for those with cytochrome P450 isoenzyme CYP2C19 gene mutation who were receiving tacrolimus. An invitro study suggested that omeprazole inhibited the metabolism of tacrolimus.4 Despite a study reporting no clinically relevant interaction between omeprazole and tacrolimus in renal transplant recipients,5 increased tacrolimus concentrations were reported when a paediatric liver transplant patient was started on omeprazole.6
1. Takahashi K, et al. Lansoprazole-tacrolimus interaction in Japanese transplant recipient with CYP2C19 polymorphism. Ann Pharmacother 2004; 38: 791–4
2. Homma M, et al. Effects of lansoprazole and rabeprazole on tacrolimus blood concentration: case of a renal transplant recipient with CYP2C19 gene mutation. Transplantation 2002; 73: 303–4
3. Itagaki F, et al. Effect of lansoprazole and rabeprazole on tacrolimus pharmacokinetics in healthy volunteers with CYP2C19 mutations. J Pharm Pharmacol 2004; 56: 1055–9
4. Christians U, et al. Identification of drugs inhibiting the in vitro metabolism of tacrolimus by human liver microsomes. Br J Clin Pharmacol 1996; 41: 187–90
5. Pascual J, et al. Interaction between omeprazole and tacrolimus in renal allograft recipients: a clinical-analytical study. Transplant Proc 2005; 37: 3752–3
6. Moreau C, et al. Interaction between tacrolimus and omeprazole in a pediatric liver transplant recipient. Transplantation 2006; 81: 487–8.

Immunosuppressants.

Sirolimus may decrease blood concentrations of tacrolimus; in stable renal transplant recipients given both drugs, mean exposure and trough concentrations of tacrolimus decreased by about 30% relative to tacrolimus alone. Tacrolimus may inhibit ciclosporin metabolism in vitro, with the possibility of increased nephrotoxicity. Tacrolimus may also increase concentrations of mycophenolic acid, a metabolite of mycophenolate mofetil, and the risk of infection may be increased if used together.

💊 Pharmacokinetics

Absorption of tacrolimus after oral doses is reported to be erratic. Oral bioavailability varies very widely; the mean value is in the range of 20 to 25%. The rate and extent of absorption of tacrolimus is decreased by the presence of food, with the effect most pronounced after a high-fat meal. There is little or no systemic exposure to tacrolimus after topical use (but see Absorption, below). After intravenous doses it is widely distributed to the tissues; it is extensively bound to erythrocytes in the blood, and variations in red cell binding account for much of the variability in pharmacokinetics. The portion in plasma is about 99% bound to plasma proteins. Tacrolimus is extensively metabolised in the liver, principally by cytochrome P450 isoenzyme CYP3A4, and excreted, primarily in bile, almost entirely as metabolites. Considerable metabolism also occurs in the intestinal wall. Whole-blood elimination half-life has been reported to average 43 hours in healthy subjects, and to range from about 12 to 16 hours in transplant patients.
1. Gruber SA, et al. Pharmacokinetics of FK506 after intravenous and oral administration in patients awaiting renal transplantation. J Clin Pharmacol 1994; 34: 859–64
2. Jusko WJ, et al. Pharmacokinetics of tacrolimus in liver transplant patients. Clin Pharmacol Ther 1995; 57: 281–90
3. Venkataramanan R, et al. Clinical pharmacokinetics of tacrolimus. Clin Pharmacokinet 1995; 29: 404–30
4. Wallemacq PE, Verbeeck RK. Comparative clinical pharmacokinetics of tacrolimus in paediatric and adult patients. Clin Pharmacokinet 2001; 40: 283–95
5. Bekersky I, et al. Comparative tacrolimus pharmacokinetics: normal versus mildly hepatically impaired subjects. J Clin Pharmacol 2001; 41: 628–35
6. Reding R, et al. Efficacy and pharmacokinetics of tacrolimus oral suspension in pediatric liver transplant recipients. Pediatr Transplant 2002; 6: 124–6
7. Staatz CE, Tett SE. Clinical pharmacokinetics and pharmacodynamics of tacrolimus in solid organ transplantation. Clin Pharmacokinet 2004; 43: 623–53
8. Kuypers DRJ, et al. Time-related clinical determinants of longterm tacrolimus pharmacokinetics in combination therapy with mycophenolic acid and corticosteroids: a prospective study in one hundred de novo renal transplant recipients. Clin Pharmacokinet 2004; 43: 741–62
9. Iwasaki K. Metabolism of tacrolimus (FK506) and recent topics in clinical pharmacokinetics. Drug Metab Pharmacokinet 2007; 22: 328–35
10. Antignac M, et al. Population pharmacokinetics and bioavailability of tacrolimus in kidney transplant patients. Br J Clin Pharmacol 2007; 64: 750–7.

Absorption.

A single topical application of a 0.1% tacrolimus ointment to an infant for the treatment of chronic dermatitis, resulted in high serum-tacrolimus concentrations (24 nanograms/mL). Tacrolimus levels decreased over 7 days, after which another smaller, single application of 0.03% tacrolimus ointment again resulted in high serum concentrations. The authors cautioned against its use in young children and diseases with decreased skin barrier function.1 In another report,2elevated blood tacrolimus concentrations were seen after application of 0.1% tacrolimus ointment to a large area of the body of a patient with erythroderma; again, caution in conditions where the skin barrier is disrupted was advised.
1. Kameda G, et al. Unexpected high serum levels of tacrolimus after a single topical application in an infant. J Pediatr 2003; 143: 280. Correction. ibid.; 462
2. Teshima D, et al. Increased topical tacrolimus absorption in generalized leukemic erythroderma. Ann Pharmacother 2003; 37: 1444–7.

Bioavailability.

Bioavailability of tacrolimus appears to be influenced by the type and timing of meals. Food, particularly high-fat meals, significantly reduced bioavailability, compared with the fasting state.1 Ingestion of tacrolimus up to 1.5 hours after a meal also considerably reduced absorption.2 UK licensed product information states that tacrolimus should be taken on an empty stomach, or at least 1 hour before or 2 to 3 hours after a meal, to achieve maximal absorption. Gastrointestinal metabolism of tacrolimus is thought to be extensive, significantly affecting its bioavailability,3 and differences in this metabolism may account for apparent differences in availability according to ethnic origin.4
1. Bekersky I, et al. Effect of low- and high-fat meals on tacrolimus absorption following 5 mg single oral doses to healthy human subjects. J Clin Pharmacol 2001; 41: 176–82
2. Bekersky I, et al. Effect of time of meal consumption on bioavailability of a single oral 5 mg tacrolimus dose. J Clin Pharmacol 2001; 41: 289–97
3. Tuteja S, et al. The effect of gut metabolism on tacrolimus bioavailability in renal transplant recipients. Transplantation 2001; 71: 1301–7
4. Mancinelli LM, et al. The pharmacokinetics and metabolic disposition of tacrolimus: a comparison across ethnic groups. Clin Pharmacol Ther 2001; 69: 24–31.

Genetic factors.

Renal transplant recipients homozygous for CYP3A5*3 required lower doses to reach target trough concentrations of tacrolimus compared with CYP3A5*1 allele carriers;1the latter group can be expected to have a tacrolimus clearance 25 to 45% greater than that of homozygotes.2 Determination of the cytochrome P450 isoenzyme genotype before transplantation may identify patients at risk for underimmunosuppression or toxicity.
1. Hesselink DA, et al. Genetic polymorphisms of the CYP3A4, CYP3A5, and MDR-1 genes and pharmacokinetics of the calcineurin inhibitors cyclosporine and tacrolimus. Clin Pharmacol Ther 2003; 74: 245–54
2. Utecht KN, et al. Effects of genetic polymorphisms on the pharmacokinetics of calcineurin inhibitors. Am J Health-Syst Pharm 2006; 63: 2340–8.

Therapeutic drug monitoring.

There is a good correlation between tacrolimus trough concentrations and systemic exposure, and analysis at other time points is not considered to offer any advantage.1 However, since tacrolimus concentrations appear to be generally higher in the morning than the evening, some have suggested that the morning might be the best time for therapeutic drug monitoring.2 Microparticle enzyme immunoassay (MEIA) and enzymelinked immunosorbent assay (ELISA) have both been used to measure tacrolimus whole blood concentrations. A study3 of liver transplant recipients found that increasing trough tacrolimus concentrations, as measured by the ELISA, correlated with decreasing risk of acute rejection, but increasing risk of nephrotoxicity. The authors suggested a trough blood concentration of less than 15 nanograms/mL to minimise nephrotoxicity. While several studies have shown that adverse effects are more closely correlated with tacrolimus concentrations than with dose, the correlation between concentrations and allograft rejection has not been established. There is some suggestion that measuring the unbound concentration of tacrolimus may be a better correlate for rejection than whole blood concentrations.4 Licensed product information states that blood trough concentrations of tacrolimus should be monitored during the post-transplantation period; blood should be drawn about 12 hours after dosing, just before the next dose. Samples which are not analysed immediately should be stored at room temperature or in a refrigerator and assayed within 7 days; if samples are to be kept longer they may be frozen at −20° for up to 12 months. The frequency of monitoring is based on clinical need; about twiceweekly during the early post-transplant period is recommended, followed by periodic monitoring during maintenance therapy. Trough concentrations should also be monitored after dose adjustment, although it may take several days before changes become apparent. Monitoring is also recommended after changes in the immunosuppressive regimen, or when other drugs are given which may alter tacrolimus blood concentrations. The majority of patients can be successfully managed if blood concentrations are maintained below 20 nanograms/mL. In practice, in the early post-transplant period, whole blood trough concentrations have generally been in the range of 5 to 20 nanograms/mL in liver transplant recipients, and 10 to 20 nanograms/mL in kidney and heart transplant recipients. During maintenance therapy, blood concentrations have generally been between 5 to 15 nanograms/mL in liver, kidney, and heart transplant patients. Bayesian forecasting has also been used.5 UK licensed product information states that the relationship between tacrolimus trough concentrations and systemic exposure is similar for the standard formulation (Prograf, Astellas) and the prolonged-release formulation (Advagraf, Astellas).
1. Oellerich M, Armstrong VW. The role of therapeutic drug monitoring in individualizing immunosuppressive drug therapy: recent developments. Ther Drug Monit 2006; 28: 720–5
2. Baraldo M, Furlanut M. Chronopharmacokinetics of ciclosporin and tacrolimus. Clin Pharmacokinet 2006; 45: 775–88
3. Venkataramanan R, et al. Clinical utility of monitoring tacrolimus blood concentrations in liver transplant patients. J Clin Pharmacol 2001; 41: 542–51
4. Zahir H, et al. Factors affecting variability in distribution of tacrolimus in liver transplant recipients. Br J Clin Pharmacol 2004; 57: 298–309
5. Fukudo M, et al. Forecasting of blood tacrolimus concentrations based on the Bayesian method in adult patients receiving livingdonor liver transplantation. Clin Pharmacokinet 2003; 42: 1161–78.

💊 Uses and Administration

Tacrolimus is a potent macrolide (macrolactam) immunosuppressant derived from Streptomyces tsukubaensis, and has actions similar to those of ciclosporin. Tacrolimus binds to an intracellular protein, FKBP-12, and then forms a complex with calcium, calmodulin, and calcineurin, which inhibits the activity of calcineurin. This interferes with the production of lymphokines such as interleukin-2 and inhibits T-lymphocyte activation, resulting in immunosuppression. Tacrolimus is used to prevent or manage rejection in patients receiving organ transplants, as indicated by the cross-references given in Organ and Tissue Transplantation, below. Tacrolimus has been tried in a few patients with refractory auto-immune or immune-mediated disorders; in some countries it is licensed for use in myasthenia gravis, in rheumatoid arthritis that is unresponsive to conventional therapy, and in lupus nephritis where corticosteroids are ineffective or contra-indicated. Tacrolimus is also applied topically in the management of moderate to severe atopic eczema. Tacrolimus-releasing stents have been developed to reduce restenosis after coronary artery stent placement. UK licensed product information recommends that oral tacrolimus should be taken on an empty stomach or at least 1 hour before or 2 to 3 hours after a meal, to achieve maximum absorption.
For transplantation, in adult patients in the UK, the
Published November 14, 2018.