otensive disorders, haemorrhage, peripheral vascular disorders
uncommon:
venous thrombosis deep limb, shock, infarction
General disorders and administration site conditions
common:
febrile disorders, pain and discomfort, asthenic conditions, oedema, body temperature perception disturbed, blood alkaline phosphatase increased, weight increased
uncommon:
weight decreased, influenza like illness, blood lactate dehydrogenase increased, feeling jittery, feeling abnormal, multi-organ failure, chest pressure sensation, temperature intolerance
rare:
fall, ulcer, chest tightness, mobility decreased, thirst
very rare:
fat tissue increased
Immune system disorders
Allergic and anaphylactoid reactions have been observed in patients receiving tacrolimus (see section 4.4).
Hepatobiliary disorders
very common:
liver function tests abnormal
common:
bile duct disorders, hepatocellular damage and hepatitis, cholestasis and jaundice
rare:
venoocclusive liver disease, hepatitic artery thrombosis
very rare:
hepatic failure
Reproductive system and breast disorders
uncommon:
dysmenorrhoea and uterine bleeding
Psychiatric disorders
very common:
insomnia
common:
confusion and disorientation, depression, anxiety symptoms, hallucination, mental disorders, depressed mood, mood disorders and disturbances, nightmare
uncommon:
psychotic disorder
4.9 Overdose
Experience with overdose is limited. Several cases of accidental overdose have been reported with tacrolimus; symptoms have included tremor, headache, nausea and vomiting, infections, urticaria, lethargy and increases in blood urea nitrogen, serum creatinine and alanine aminotransferase levels.
No specific antidote to tacrolimus therapy is available. If overdose occurs, general supportive measures and symptomatic treatment should be conducted.
Based on its high molecular weight, poor aqueous solubility, and extensive erythrocyte and plasma protein binding, it is anticipated that tacrolimus will not be dialysable. In isolated patients with very high plasma levels, haemofiltration or -diafiltration have been effective in reducing toxic concentrations. In cases of oral intoxication, gastric lavage and/or the use of adsorbents (such as activated charcoal) may be helpful, if used shortly after intake.
5. PHARMACOLOGICAL PROPERTIES
5.1 Pharmacodynamic properties
Pharmacotherapeutic group: Calcineurin inhibitors, ATC code: L04AD02
Mechanism of action
At the molecular level, the effects of tacrolimus appear to be mediated by binding to a cytosolic protein (FKBP12) which is responsible for the intracellular accumulation of the compound. The FKBP12-tacrolimus complex specifically and competitively binds to and inhibits calcineurin, leading to a calcium-dependent inhibition of T-cell signal transduction pathways, thereby preventing transcription of a discrete set of cytokine genes.
Tacrolimus is a highly potent immunosuppressive agent and has proven activity in both in vitro and in vivo experiments.
In particular, tacrolimus inhibits the formation of cytotoxic lymphocytes, which are mainly responsible for graft rejection. Tacrolimus suppresses T-cell activation and T-helper-cell dependent B-cell prol |
