Tacrolimus

Tacrolimus is extensively bound to plasma proteins. Possible interactions with other medicinal products known to have high affinity for plasma proteins should be considered (e.g. NSAIDs, oral anticoagulants, or oral antidiabetics).

Systemically available tacrolimus is metabolised by hepatic CYP3A4. There is also evidence of gastrointestinal metabolism by CYP3A4 in the intestinal wall. Concomitant use of medicinal products or herbal remedies known to inhibit or induce CYP3A4 may affect the metabolism of tacrolimus and thereby increase or decrease tacrolimus blood levels.

It is therefore strongly recommended to closely monitor tacrolimus blood levels, as well as, QT prolongation (with ECG), renal function and other side effects, whenever substances which have the potential to alter CYP3A4 metabolism are used concomitantly and to interrupt or adjust the tacrolimus dose as appropriate in order to maintain similar tacrolimus exposure.

Tacrolimus is a known CYP3A4 inhibitor; thus concomitant use of tacrolimus with medicinal products known to be metabolised by CYP3A4 may affect the metabolism of such medicinal products.

Grapefruit juice has been reported to increase the blood level of tacrolimus and should therefore be avoided.

Dose reduction may be necessary in patients with severe liver impairment in order to maintain the blood trough levels within the recommended target range.

As tacrolimus treatment may be associated with hyperkalaemia, or may increase pre-existing hyperkalaemia, high potassium intake, or potassium-sparing diuretics (e.g. amiloride, triamterene, or spironolactone) should be avoided.

As tacrolimus may reduce the clearance of steroid-based contraceptives leading to increased hormone exposure, particular care should be exercised when deciding upon contraceptive measures.

Concurrent use of tacrolimus with medicinal products known to have nephrotoxic or neurotoxic effects may increase these effects (e.g. aminoglycosides, gyrase inhibitors, vancomycin, sulfamethoxazole+trimethoprim, NSAIDs, ganciclovir or aciclovir).

Immunosuppressants may affect the response to vaccination and vaccination during treatment with tacrolimus may be less effective. The use of live attenuated vaccines should be avoided.

Enhanced nephrotoxicity has been observed following the administration of amphotericin B and ibuprofen in conjunction with tacrolimus.

In vitro the following substances have been shown to be potential inhibitors of tacrolimus metabolism: bromocriptine, cortisone, dapsone, ergotamine, gestodene, lidocaine, mephenytoin, miconazole, midazolam, nilvadipine, norethisterone, quinidine, tamoxifen, troleandomycin.

Carbamazepine, metamizole and isoniazid have the potential to decrease tacrolimus concentrations.

The half-life of ciclosporin is prolonged when tacrolimus is given concomitantly. In addition, synergistic/additive nephrotoxic effects can occur. For these reasons, the combined administration of ciclosporin and tacrolimus is not recommended and care should be taken when administering tacrolimus to patients who have previously received ciclosporin.

Caution should be exercised when switching combination therapy from ciclosporin, which interferes with enterohepatic recirculation of mycophenolic acid, to tacrolimus, which is devoid of this effect, as this might result in changes of mycophenolic acid exposure. Drugs which interfere with mycophenolic acid’s enterohepatic cycle have potential to reduce the plasma level and efficacy of mycophenolic acid. Therapeutic drug monitoring of mycophenolic acid may be appropriate when switching from ciclosporin to tacrolimus or vice versa.

Clinically the following substances have been shown to increase tacrolimus blood levels:

Weak interactions have been observed with clotrimazole, clarithromycin, josamycin, nifedipine, nicardipine, diltiazem, verapamil, amiodarone, danazol, ethinylestradiol, omeprazole, nefazodone and (Chinese) herbal remedies containing extracts of Schisandra sphenanthera.

Clinically the following substances have been shown to increase tacrolimus blood levels:

Strong interactions have been observed with antifungal agents such as ketoconazole, fluconazole, itraconazole voriconazole and isavuconalzole, the macrolide antibiotic erythromycin, HIV protease inhibitors (e.g. ritonavir, nelfinavir, saquinavir), HCV protease inhibitors (e.g. telaprevir, boceprevir, and the combination of ombitasvir and paritaprevir with ritonavir, when used with and without dasabuvir), or the CMV antiviral letermovir, the pharmacokinetic enhancer cobicistat, and the tyrosine kinase inhibitors nilotinib and imatinib. Concomitant use of these substances may require decreased tacrolimus doses in nearly all patients.

Lansoprazole and ciclosporin may potentially inhibit CYP3A4-mediated metabolism of tacrolimus and thereby increase tacrolimus whole blood concentrations.

Potential interactions that may increase systemic exposure of tacrolimus include the prokinetic agent metoclopramide, cimetidine and magnesium-aluminium-hydroxide.

Animal data have shown that tacrolimus could potentially decrease the clearance and increase the half-life of pentobarbital and phenazone.

Tacrolimus has been shown to increase the blood level of phenytoin.

High dose prednisolone or methylprednisolone administered for the treatment of acute rejection have the potential to increase or decrease tacrolimus blood levels.

Clinically the following substances have been shown to decrease tacrolimus blood levels:

Strong interactions have been observed with rifampicin, phenytoin or St. John’s Wort (Hypericum perforatum) which may require increased tacrolimus doses in almost all patients. Clinically significant interactions have also been observed with phenobarbital. Maintenance doses of corticosteroids have been shown to reduce tacrolimus blood levels.

Ventricular hypertrophy or hypertrophy of the septum, reported as cardiomyopathies, have been observed on rare occasions. Most cases have been reversible, occurring primarily in children with tacrolimus blood trough concentrations much higher than the recommended maximum levels.

Other factors observed to increase the risk of these clinical conditions included pre-existing heart disease, corticosteroid usage, hypertension, renal or hepatic dysfunction, infections, fluid overload, and oedema. Accordingly, high-risk patients, particularly young children and those receiving substantial immunosuppression should be monitored, using such procedures as echocardiography or ECG pre- and post-transplant (e.g. initially at three months and then at 9-12 months). If abnormalities develop, dose reduction of tacrolimus therapy, or change of treatment to another immunosuppressive agent should be considered.

Tacrolimus may prolong the QT interval and may cause Torsades de Pointes. Caution should be exercised in patients with risk factors for QT prolongation, including patients with a personal or family history of QT prolongation, congestive heart failure, bradyarrhythmias and electrolyte abnormalities.

Caution should also be exercised in patients diagnosed or suspected to have Congenital Long QT Syndrome or acquired QT prolongation or patients on concomitant medications known to prolong the QT interval, induce electrolyte abnormalities or known to increase tacrolimus exposure

Patients treated with immunosuppressants, including tacrolimus are at increased risk for infections including opportunistic infections (bacterial, fungal, viral and protozoal) such as BK virus associated nephropathy and JC virus associated progressive multifocal leukoencephalopathy (PML). Patients are also at an increased risk of infections with viral hepatitis (for example, hepatitis B and C reactivation and de novo infection, as well as hepatitis E, which may become chronic). These infections are often related to a high total immunosuppressive burden and may lead to serious or fatal conditions that physicians should consider in the differential diagnosis in immunosuppressed patients with deteriorating hepatic or renal function or neurological symptoms.

Prevention and management should be in accordance with appropriate clinical guidance.

Patients treated with tacrolimus have been reported to develop posterior reversible encephalopathy syndrome (PRES). If patients taking tacrolimus present with symptoms indicating PRES such as headache, altered mental status, seizures, and visual disturbances, a radiological procedure (e.g. MRI) should be performed. If PRES is diagnosed, adequate blood pressure control and immediate discontinuation of systemic tacrolimus is advised. Most patients completely recover after appropriate measures are taken.

Cases of pure red cell aplasia (PRCA) have been reported in patients treated with tacrolimus. All patients reported risk factors for PRCA such as parvovirus B19 infection, underlying disease or concomitant medications associated with PRCA.

Gastrointestinal perforation has been reported in patients treated with tacrolimus. As gastrointestinal perforation is a medically important event that may lead to a life-threatening or serious condition, adequate treatments should be considered immediately after suspected symptoms or signs occur.

Since levels of tacrolimus in blood may significantly change during diarrhoea episodes, extra monitoring of tacrolimus concentrations is recommended during episodes of diarrhoea.

Patients treated with tacrolimus have been reported to develop Epstein-Barr virus (EBV)-associated lymphoproliferative disorders. Patients switched to tacrolimus therapy should not receive anti-lymphocyte treatment concomitantly. Very young (<2 years), EBV-VCA-negative children have been reported to have an increased risk of developing lymphoproliferative disorders. Therefore, in this patient group, EBV-VCA serology should be ascertained before starting treatment with tacrolimus. During treatment, careful monitoring with EBV-PCR is recommended. Positive EBV-PCR may persist for months and is per se not indicative of lymphoproliferative disease or lymphoma.

As with other immunosuppressive agents, owing to the potential risk of malignant skin changes, exposure to sunlight and UV light should be limited by wearing protective clothing and using a sunscreen with a high protection factor.

As with other potent immunosuppressive compounds, the risk of secondary cancer is unknown.

Human data show that tacrolimus is able to cross the placenta. Limited data from organ transplant recipients show no evidence of an increased risk of adverse effects on the course and outcome of pregnancy under tacrolimus treatment compared with other immunosuppressive medicinal products. However, cases of spontaneous abortion have been reported. To date, no other relevant epidemiological data are available. Due to the need of treatment, tacrolimus can be considered in pregnant women when there is no safer alternative and when the perceived benefit justifies the potential risk to the foetus. In case of in utero exposure, monitoring of the newborn for the potential adverse effects of tacrolimus is recommended (in particular the effects on the kidneys). There is a risk for premature delivery (<37 week) as well as for hyperkalaemia in the newborn, which, however, normalizes spontaneously.

In rats and rabbits, tacrolimus caused embryofoetal toxicity at doses which demonstrated maternal toxicity.

There are no adequate data from the use of tacrolimus ointment in pregnant women. Studies in animals have shown reproductive toxicity following systemic administration. The potential risk for humans is unknown.

Tacrolimus ointment should not be used during pregnancy unless clearly necessary.

Human data demonstrate that tacrolimus is excreted into breast milk. As detrimental effects on the newborn cannot be excluded, women should not breast-feed whilst receiving tacrolimus.

Although clinical data have shown that systemic exposure from application of tacrolimus ointment is low, breast-feeding during treatment with tacrolimus ointment is not recommended.

Fertility

A negative effect of tacrolimus on male fertility in the form of reduced sperm counts and motility was observed in rats.

Tacrolimus may cause visual and neurological disturbances. This effect may be enhanced if tacrolimus is administered in association with alcohol.

Tacrolimus ointment has no or negligible influence on the ability to drive and use machines.