Mechanism of action
Tacrolimus is a calcineurin inhibitor immunosuppressive agent. By competitively binding to calcineurin, it inhibits T-cell signal transduction pathways, thereby preventing transcription of a discrete set of cytokine genes. Tacrolimus inhibits the formation of cytotoxic lymphocytes, suppresses T-cell activation and T-helper-cell dependent B-cell proliferation, as well as the formation of lymphokines (such as interleukins-2, -3, and γ-interferon) and the expression of the interleukin-2 receptor.
Dosing and administration - considered off-label use in IBD
Tacrolimus can be administered intravenously or orally. Dosing should primarily be based on clinical assessments of tolerability in each patient aided by blood level monitoring. Oral administration appears to be associated with a lower incidence of adverse drug reactions compared with intravenous use.
Trials of tacrolimus in ulcerative colitis have used oral tacrolimus in dosages of 0.025 to 0.075 mg/kg body weight twice daily with target drug levels of 10 to 15 ng/mL during induction of remission phase (2 weeks) and 5 to 10 ng/mL during maintenance.
In perianal/fistulizing Crohn disease Oral Immediate release: Initial: 0.1 mg/kg twice daily; titrate to target concentrations (Sandborn 2003). Note: Due to the toxicity potential, tacrolimus therapy should be limited to short-term use only (ACG [Lichtenstein 2018]).
Capsules should generally be administered on an empty stomach or at least 1 hour before or 2 to 3 hours after a meal, to achieve maximal absorption.
Hypersensitivity to tacrolimus or other macrolides.
As is well known for other potent immunosuppressive agents, patients receiving tacrolimus are at increased risk for infections (viral, bacterial, fungal, protozoal). The course of pre-existing infections may be aggravated.
Patients receiving immunosuppressive therapy are at increased risk of developing malignancies. Benign as well as malignant neoplasms including EBV-associated lymphoproliferative disorders and skin malignancies have been reported in association with tacrolimus treatment.
Gastrointestinal perforation has been reported in patients treated with tacrolimus.
Since levels of tacrolimus in blood may significantly change during diarrhoea episodes, extra monitoring of tacrolimus concentrations is recommended during episodes of diarrhoea.
Common adverse effects
Metabolic: Hyperglycemia, diabetes mellitus, hyperkalemia
Renal: Impaired renal function
Hematologic: Anaemia, leukopenia, thrombocytopenia, leukocytosis, abnormal red blood cell analyses
Cardiovascular: Hypertension, ischemic coronary artery disorders, tachycardia
Psychiatry: Insomnia, mood disorders
Neurology: Tremor, headache, seizures, peripheral neuropathies
Respiratory: Dyspnoea, parenchymal lung disorders, pleural effusion, pharyngitis, cough, nasal congestion
Gastrointestinal: Diarrhoea, nausea, gastrointestinal ulceration and perforation, gastrointestinal haemorrhage
Hepatobiliary: Cholestasis and jaundice, hepatocellular damage and hepatitis, cholangitis, elevated liver function tests
Eye and ear disorders: Visual disturbances, tinnitus
Skin: Pruritus, rash, alopecia, acne, increased perspiration
Musculoskeletal: Arthralgia, muscle spasms, pain in extremity, back pain
Laboratory parameters and monitoring
During the initial treatment period, monitoring of the following parameters should be undertaken on a routine basis: blood pressure, ECG, neurological and visual status, fasting blood glucose levels, electrolytes (particularly potassium), liver and renal function tests, haematology parameters, coagulation values, plasma protein and trough drug levels (in order to follow the decided target and avoid toxicity).
Interactions with other drugs
When substances with a potential for interaction - particularly strong inhibitors of CYP3A4 (such as telaprevir, boceprevir, ritonavir, ketoconazole, voriconazole, itraconazole, telithromycin or clarithromycin) or inducers of CYP3A4 (such as rifampicin, rifabutin) – are being combined with tacrolimus, tacrolimus blood levels should be monitored to adjust the tacrolimus dose as appropriate.
Herbal preparations should be avoided when taking tacrolimus due to the risk of interactions that lead to either a decrease in blood concentrations of tacrolimus and reduced clinical effect of tacrolimus, or an increase in blood concentrations of tacrolimus and risk of toxicity.
The combined administration of ciclosporin and tacrolimus should be avoided, and care should be taken when administering tacrolimus to patients who have previously received ciclosporin due to prolongation of ciclosporin half-life and increased risk of nephrotoxicity.
High potassium intake or potassium-sparing diuretics should be avoided due to risk of hyperkalemia.
Certain combinations of tacrolimus with drugs known to have nephrotoxic or neurotoxic effects may increase the risk of these effects.
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. 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 hyperkalemia in the newborn, which, however, normalizes spontaneously.
In rats and rabbits, tacrolimus caused embryofoetal toxicity at doses which demonstrated maternal toxicity.
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.
A negative effect of tacrolimus on male fertility in the form of reduced sperm counts and motility was observed in rats.
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.