What is the incidence of tremors associated with tacrolimus (FK506) and ursodiol (ursodeoxycholic acid)?

From the Guidelines

Tremors are a known side effect of tacrolimus, but not significantly associated with ursodiol, and the incidence of tremors with tacrolimus and ursodiol is primarily driven by tacrolimus use. When considering the use of tacrolimus and ursodiol together, it is essential to weigh the benefits of these medications against the potential side effects, particularly tremors associated with tacrolimus. The following points are crucial in managing patients on these medications:

• Tacrolimus-induced tremors are typically postural or action tremors that affect the hands and can vary in severity from mild to debilitating.
• These tremors occur due to tacrolimus's effect on the central nervous system and are often dose-dependent, with higher blood levels correlating with increased tremor severity, as observed in a study from 1.
• In contrast, ursodiol (ursodeoxycholic acid), a bile acid used primarily to treat liver conditions, has not been significantly associated with tremors as a side effect, as noted in studies such as 1 and 1.
• When these medications are used together, as they might be in liver transplant patients or those with certain autoimmune liver diseases, there is no known interaction that specifically increases tremor risk beyond what is already expected with tacrolimus alone.
• Management of tacrolimus-induced tremors may include dose reduction when possible, maintaining tacrolimus levels at the lower end of the therapeutic range, as recommended in 1, or in severe cases, considering alternative immunosuppressive regimens.
• Patients experiencing troublesome tremors should not discontinue either medication without medical consultation, as the benefits of these treatments typically outweigh the side effect burden. Key considerations for managing tremors in patients on tacrolimus include:
• Monitoring tacrolimus levels to minimize the risk of tremors, with target trough levels of 6-10 ng/ml during the first month and 4-8 ng/ml thereafter, as recommended in 1.
• Combining tacrolimus with other immunosuppressive drugs to allow for lower tacrolimus trough levels and help preserve renal function, as suggested in 1.
• Adjusting immunosuppression regimens based on individual patient needs and responses to treatment, always prioritizing the minimization of adverse effects like tremors while maintaining therapeutic efficacy.

From the FDA Drug Label

The most common adverse reactions (≥40%) observed in tacrolimus-treated liver transplant patients are: tremor, headache, diarrhea, hypertension, nausea, abnormal renal function, abdominal pain, insomnia, paresthesia, anemia, pain, fever, asthenia, hyperkalemia, hypomagnesemia, and hyperglycemia The most common adverse reactions (≥30%) observed in tacrolimus-treated kidney transplant patients are: infection, tremor, hypertension, abnormal renal function, constipation, diarrhea, headache, abdominal pain, insomnia, nausea, hypomagnesemia, urinary tract infection, hypophosphatemia, peripheral edema, asthenia, pain, hyperlipidemia, hyperkalemia, and anemia The most common adverse reactions (≥15%) observed in tacrolimus-treated heart transplant patients are: abnormal renal function, hypertension, diabetes mellitus, CMV infection, tremor, hyperglycemia, leukopenia, infection, anemia, bronchitis, pericardial effusion, urinary tract infection, and hyperlipemia

• Tremors are a common adverse reaction associated with tacrolimus, with an incidence of:
  • 34% in kidney transplant patients (Study 2) 2
  • 40% or more in liver transplant patients 2
  • 15% or more in heart transplant patients 2
• There is no information in the provided drug labels about the incidence of tremors with ursodiol.
• Tacrolimus and ursodiol may be used together in some clinical settings, but the provided drug labels do not address the specific question of the incidence of tremors with this combination.
• Therefore, based on the available information, the incidence of tremors with tacrolimus and ursodiol cannot be determined.

From the Research

Incidence of Tremors with Tacrolimus

• The incidence of tremors with tacrolimus has been reported in several studies, with varying prevalence rates 3, 4, 5, 6.
• A study published in 2023 found that the incidence of tremor was 21.5% with tacrolimus in patients with transplant indications 5.
• Another study published in 2018 found that tremor was more common and severe in patients taking tacrolimus compared to those taking cyclosporin A or non-calcineurin inhibitors 6.
• The phenomenology and physiology of tacrolimus-induced tremor have been characterized in a study published in 2023, which found that the tremor was mainly postural and kinetic, involving the distal hands, with a frequency of 5-6 Hz 3.

Comparison with Ursodiol

• There is no direct evidence comparing the incidence of tremors with tacrolimus and ursodiol.
• Ursodiol is not mentioned in any of the provided studies as a drug associated with tremors.
• The studies primarily focus on the incidence of tremors with immunosuppressant drugs such as tacrolimus, cyclosporine, sirolimus, and everolimus 3, 4, 5, 6.

Risk Factors and Management

• Risk factors for drug-induced tremor include polypharmacy, male gender, older age, high doses, and immediate-release preparations or reaching toxic levels of the offending drugs 7.
• The management of drug-induced tremor usually involves discontinuing the offending medication, but in some cases, persistent tremor may be observed 7.
• A study published in 2021 found that amantadine monotherapy improved functional independence in a patient with tacrolimus-induced parkinsonism 4.