Tacrolimus adverse effects

In 14 patients with renal transplants, there was a closed relation between individual tacrolimus whole blood trough concentrations and the occurrence of adverse effects (124). The incidence of tacrolimus adverse effects was 76% with tacrolimus concentrations above 30 ng/ml and only 5.3% with concentrations below 10 ng/ml. This relation was found in all separate groups of adverse effects analysed, that is nephrotoxicity, neurotoxicity, infections, and others. In contrast, there was no relation between tacrolimus concentrations and rejection episodes. Accordingly, the authors stressed that tacrolimus whole blood trough concentrations should be strictly kept under 20 ng/ml. 

Tacrolimus, an immunosuppressant that inhibits T-cell activation, is a useful alternative in severe recalcitrant psoriasis. Although it is not FDA approved for this indication, patients have received oral doses of 0.05 mg/kg daily, with increases up to 0.15 mg/kg daily, depending on results. Adverse effects include diarrhea, nausea, paresthesias, hypertension, tremor, and insomnia. 

The topical immunomodulators tacrolimus (Protopic) and pimecrolimus (Elidel) inhibit calcineurin, which normally initiatives T-cell activation. These agents can be used on all parts of the body for prolonged periods without producing corticosteroid-induced adverse effects. Tacrolimus ointment 0.03% and 0.1% is applied twice daily the lower strength is preferred in children with moderate to severe atopic dermatitis. The most common adverse effect is transient itching and burning at the site of application. Pimecrolimus cream 1% is applied twice daily for mild to moderate atopic dermatitis in adults and children older than age 2. 

Monitoring Regularly assess serum creatinine and potassium. Perform routine monitoring of metabolic and hematologic systems as clinically warranted. Hypertension Hypertension is a common adverse effect of tacrolimus therapy. Mild or moderate hypertension is reported more frequently than severe hypertension. Hyperglycemia Hyperglycemia was associated with the use of tacrolimus in 29% to... 

Lohmann T, List C, Lamesch P, Kohlhaw K, Wenzke M, Schwarz C, Richter O, Hauss J, Seissler J. Diabetes mellitus and islet cell specific autoimmunity as adverse effects of immunsuppressive therapy by FK506/tacrolimus. Exp Clin Endocrinol Diabetes 2000 108(5) 347-52. 

Adverse Effects. Common side effects of tacrolimus include gastrointestinal disturbances (cramps, nausea, diarrhea, constipation), weakness, fever, and skin rashes and itching. More serious problems include renal and central nervous system (CNS) toxicity (headache, anxiety, nervousness, seizures).41 Tacrolimus is also associated with problems with glucose metabolism (hyperglycemia, glucose intolerance), and can cause diabetes mellitus in certain individuals.73... 

After kidney transplantation, 15 of 20 children tolerated tacrolimus after switching from ciclosporin for immunological reasons or adverse effects (609). The most frequent adverse effects were neuropsychological and behavioral symptoms in three children, ranging from anorexia nervosa-like symptoms, with weight loss, amenorrhea, depression, and school problems, to severe insomnia and in one child aggressive and anxious behavior. Only the last child was exposed to toxic tacrolimus blood concentrations. All the adverse effects were fully reversible after withdrawal. 

Tacrolimus, an immunosuppressant that inhibits T-cell activation, is a useful alternative in severe recalcitrant psoriasis. Although it is not FDA approved for this indication, patients have received oral doses of 0.05 mg/kg daily, with increases up to 0.15 mg/kg daily, depending on results. Adverse effects include diarrhea, nausea, paresthesias, hypertension, tremor, and insomnia. Methotrexate, an antimetabolite, is indicated for moderate to severe psoriasis. It is particularly beneficial for psoriatic arthritis. It is also indicated for patients refractory to topical or UV therapy. Methotrexate can he administered orally, subcutaneously, or intramuscularly. The starting dose is 7.5 to 15 mg per week, increased incrementally by 2.5 mg every 2 to 4 weeks until response maximal doses are approximately 25 mg/wk. Adverse effects include nausea, vomiting, mucosal ulceration, stomatitis, malaise, headache, macrocytic anemia, and hepatic and pulmonary toxicity. Nausea and macrocytic anemia can be ameliorated by giving oral fohc acid 1 to 5 mg/day. Methotrexate should be avoided in patients with active infections and in those with liver disease. It is contraindicated in pregnancy because it is teratogenic. 

TACROLIMUS CHLORAMPHENICOL Toxic blood levels of tacrolimus, usually on the second day of starting chloramphenicol Attributed to impaired clearance of tacrolimus by chloramphenicol. Dose i of nearly 80% of tacrolimus may be required to prevent toxicity. Watch for adverse effects. Monitor tacrolimus plasma concentrations... 

TACROLIMUS GRAPEFRUIT JUICE t efficacy and t adverse effects of tacrolimus Unclear but probably due to inhibition of metabolism Avoid concomitant use. Measure levels if toxicity is suspected, l dose as necessary and monitor levels closely... 

TACROLIMUS OESTROGENS May T plasma tacrolimus concentrations Due to inhibition of CYP3A4 Be aware. Monitor plasma tacrolimus concentrations and watch for adverse effects... 

TACROLIMUS PROTON PUMP INHIBITORS Possible t efficacy and adverse effects of immunosuppression Altered metabolism from CYP2C19 to CYP3A4 in patients with low CYP2C19 levels Monitor levels more closely... 

GRAPEFRUIT JUICE SIROLIMUS, TACROLIMUS Possibly T efficacy and T adverse effects of sirolimus Possibly t bioavailability via inhibition of intestinal CYP3A4 and effects of P-gp Avoid concomitant use... 

Pratschke, J., Neuhaus, R., Tullius, S.G., Haller, G.W., Jonas, S., Stein-mueller, T., Bechstein, W.O., Neuhaus, P. Treatment of cyclosporine-related adverse effects by conversion to tacrolimus after liver transplantation. Transplantation 1997 64 938-940... 

Tacrolimus (FK 506), a macrolide immunosuppressant, has adverse effects similar to those of ciclosporin, including nephrotoxicity. Increased nephrotoxicity can be expected when it is given with amphotericin (156). 

Although the pattern of long-term toxicity of ciclosporin and tacrohmus is remarkably similar for most serious adverse effects (particularly nephrotoxicity), a higher incidence of several minor adverse effects with ciclosporin, namely hirsutism, gingivitis or gum hyperplasia, has been thought to underlie a moderate but significant decrease in the quahty of life with ciclosporin compared with tacrolimus (2). 

In 11 patients with orthotopic hver transplants who had adverse effects from ciclosporin or tacrolimus, mycophenolate mofetil monotherapy for 1 year was successful. This was followed by a randomized, controlled trial in 18 patients, of whom nine were given mycophenolate mofetil (23). Five patients completed the 3 month trial. Of these, two had an episode of acute rejection, one after 2 months and one after 3 months, which did not respond to the reintroduction of tacrohmus and intravenous glucocorticoids. One had a glucocorticoid-responsive episode of severe acute rejection after 3 weeks. The other two patients had normal liver function tests after 2 weeks and 2 months respectively, when the trial was stopped. Mycophenolate mofetil allows a reduction of the dose of... 

An interaction of nelfinavir with the macrolide immunosuppressant tacrolimus has been reported in a patient co-infected with HIV and hepatitis C virus who had undergone orthotopic liver transplantation (18). The dose of tacrolimus had to be reduced to a 70th of the normal dose to avoid adverse effects. Nelfinavir serum concentrations were not affected by tacrolimus. The authors suggested that this effect had resulted from inhibition of the metabolism of tacrolimus, because both compounds are substrates of CYP3A4. 

Combination of sirolimus with tacrolimus virtually eliminates acute rejection. However, the adverse effects of both drugs are potentiated, increasing the nephrotoxicity of tacrolimus (11). 

Tacrolimus, a macrolide derivative, has similar immunosuppressive properties to ciclosporin and has effects on T lymphocytes by inhibiting interleukin-2 production. On a weight basis, tacrolimus is about 100 times more potent than ciclosporin. In view of the outcome of several multicenter trials, it has been used as an alternative to ciclosporin as a baseline regimen for the prophylaxis of renal and liver transplant rejection and in the treatment of acute rejection (SED-13,1130) (SEDA-21, 390) (1). The clinical pharmacology, clinical use, and adverse effects profile of tacrolimus in organ transplantation have been extensively reviewed (2). 

The incidence of adverse effects (for example neurotoxicity, nephrotoxicity, and hyperglycemia), particularly those requiring drug withdrawal, was initially found to be higher in tacroUmus-treated Uver transplant patients, but subsequently fell after the initial tacrolimus dose was reduced. This was in accordance with the results of very early trials, which showed that the initially proposed dose of tacrolimus was too high (3). In subsequent studies, tacrolimus and ciclosporin had a similar spectrum of adverse effects for nephrotoxicity, infectious complications, and lymphoproliferative disorders, and long-term adverse effects occurred at comparable rates, that is less than 2% (SED-13,1130) (SEDA-21, 390). 

Long-term follow-up (mean of 93 months) of tacroU-mus-based immunosuppression has been reported in 121 adult patients with liver transplants (10). Infections were the most common causes of deaths (17 patients out of 42), and half of them occurred during the first year after transplantation. Cardiovascular events (seven patients) or de novo malignancies (three patients) were also important causes of death. End-stage renal disease related to tacrolimus nephrotoxicity was noted in two patients who required renal transplantation At 7 years, other important adverse effects included hyperkalemia (30%) or... 

When neurological symptoms occur in patients taking tacrolimus they are very similar to those seen in patients taking ciclosporin, with more frequent insomnia, tremor, and headaches, but a similar rate of severe neurological adverse effects, such as acute psychosis, peripheral neuropathy, seizures, encephalopathy, coma, and paralysis. Persistent speech disorders (dysarthria, apraxia, expressive aphasia, akinetic mutism), and visual blurring can also occur (SEDA-21, 391) (SEDA-22, 420) (24). 

In children 0.1% tacrolimus ointment has been used daily without major adverse effects. 

The long-term safety of topical tacrolimus ointment 0.1% for 6-12 months has been assessed in 316 patients with atopic dermatitis (82). The most common adverse effects clearly attributed to tacrolimus were a local burning sensation (47%), pruritus (24%), and erythema (12%) the incidences fell with time. The observed incidence of infections did not exceed the expected incidence in patients with atopic dermatitis, and there were no effects on circulating cell-mediated immunity. 

In a randomized, double-blind, placebo-controlled study at 23 centers in the USA, children with moderate to severe atopic dermatitis applied the vehicle, tacrolimus ointment 0.03%, or tacrolimus ointment 0.1% for 12 weeks (94). Burning and pruritus were the main adverse effects. Varicella infection and vesiculobullous rashes on non-application areas occurred, but with a low incidence (below 5%). Since they occurred in those who used tacrolimus 0.03%, it is likely that they were random events rather than drug-related. Regardless of dose, there were some age-related differences in the incidence of individual adverse events. For example, otitis media was more common in younger children (2-6 years). Tacrolimus ointment had no age-selective effect that was not also observed with the vehicle. Each of the adverse events resolved without sequelae. 

Cantarovich D, Renou M, Megnigheto A, Giral-Class M, Hourmant M, Dantal J, Blancho G, Karam G, Soulillou JP. Switching from cyclosporine to tacrolimus in patients with chronic transplant dysfunction or cyclosporine-induced adverse effects.Transplan-tation 2005 79 72-78. 

Cyclosporine and tacrolimus have dramatically enhanced the success of solid organ transplantation. Nephrotoxicity, however, remains a major dose-limiting adverse effect of both drugs. " Early acute hemodynamically-mediated renal insufficiency and delayed chronic interstitial nephritis have been observed (see section on chronic interstitial nephritis later in this chapter). ... 

Calcineurin inhibitors (CIs), such as cyclosporine and tacrolimus, block T-cell activity by inhibiting the production of IL-2. They are associated with significant adverse effects, namely, nephrotoxicity and neurotoxicity. 

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