A fifth of patients receiving cyclosporine and tacrolimus for treating transplant and nontransplant indications can potentially develop a tremor. |
Sirolimus and everolimus have a substantially lower risk of neurological toxicity, especially the risk of tremors. |
Tacrolimus formulations do not seem to impact the risk of tremors. |
1 Introduction
2 Methods
2.1 Statistical Analyses
3 Results
3.1 Cyclosporine and Tremor
Author(s) | Country | Study design | Study duration | Grafted organ/etiology | Cohort size (n) | Dosing protocol (mg/kg/day) | Target or mean trough in ng/mL | Tremor prevalence, n (%) | Early vs late | Treatment method/outcome | Other neurologic side effects |
---|---|---|---|---|---|---|---|---|---|---|---|
Asćerić et al. [8] | Bosnia | Observational | 18 mo | Kidney | 30 | Oral: 2–5 mg/kg/day | 122.5–280.5 | 4 (7.5) | NS | NR | NR |
Briggs et al. [9] | UK, Norway, Finland, Sweden, Germany | Prospective, open, multicenter, parallel-group | 3 mo | Kidney | 58 | Changed if blood trough concentrations >300 ng/mL. | 150–300 | 1 (1.7) | NS | NR | NR |
Caccavo et al. [10] | Italy | Prospective, non-randomized | 24 mo | SLE | 30 | Oral 2.5–5 mg/kg/day reduced by 0.5 mg/kg/day if cr level increased by >30% baseline value | NR | 2 (7) | Late | Therapy withdrawn after 5 mo, ONR | Paresthesia, fatigue |
Conti et al. [11] | Italy | Retrospective | N/A | SLE | 56 | Initial: oral 5 mg/kg/day maintenance: oral 3 mg/kg/day; dose reduction when tremor present | NR | 6 (5.4) | Early | Discontinuation (n = 3), resolved | Headache, paresthesia, insomnia, dizziness |
David-Neto et al. [12] | Brazil | Observational | 4 h | Kidney | 46 | Mean dose: oral 6 ± 1.9 mg/kg/day; reduction of dose in 10 children with highest AUC values: 7.5 ± 2.5 to 4.8 ± 2.3 mg/kg per day; Cmax positively correlated with intensity of tremor | 203 ± 75 | 20 (43.5) | NS | Reduction of dosage; intensity of tremor diminished | NR |
Dehghani et al. [13] | Turkey | Prospective | ~30 mo | Liver | 4 | Convulsions on CSA, converted to tacrolimus | NR | 1 (25) | NS | NR | Convulsions, insomnia, headache, muscle cramps, paresthesia, weakness |
Erro et al. [14] | Italy | Observational | NR | Kidney | 32 | NR | Therapeutic range | 20 (62) | NS | NR | NR |
Frank et al. [15] | USA | Prospective | NR | Liver | 29 | Continuous IV: 2–8 mg/mL adjusted to 250–350 mg/mL; changed to FK506 rescue therapy | 250–350 | 1 (3.4) | NS | NR | Headaches, seizures, sleep disorders |
Hami et al. [16] | Iran | Observational | 6 mo | Kidney | 50 | Day 1 post-transplant: oral ~10 mg/kg subsequently: 5-mg/kg/day dose adjustment according to trough concentration | ~250–350 | 18 (36) | Early | NR | Headache |
Kahan et al. [17] | USA | Clinical | 72 mo | Kidney | 402 | Living related donor: 5-day loading continuous IV cadaveric renal graft: pre-operation oral 14 mg/kg, IV 2.5 mg/kg | 100–250 | 79 (20) | Early and late | NR | Seizure, paresthesia |
Mahdi et al. [18] | Canada | Prospective | NR | IBD | 10 | Initial: IV 4 mg/kg in two divided doses maintenance: 250–400 ug/L trough concentrations | 250–400 | 1 (0.1) | NS | Withdrawal resolved | NR |
Martin et al. [19] | UK | Open-label | 18 mo | HTLV-1 Spastic paraparesis | 7 | Oral 2.5–5 mg/kg/day; dose adjusted trough concentrations | 80–100 | 1 (0.14) | Early | Treatment cessation; resolved | NR |
Menegaux et al. [20] | USA | Retrospective | NR | Liver | 27 | Induction: 2–3 mg/kg/day, IV continuous infusion, moved to oral administration after digestive reactivation | 300–500 | 2 (7) | Early | Unclear | Encephalopathy seizure, stroke, brachial plexopathy, neuropathy headache, tremor, facial paralysis, spinal cord deficit, Parkinson’s disease |
Miller et al. [21] | USA | Prospective | 40 mo | Bone marrow | 45 | Induction (day 1–22): IV 2.5 mg/kg/day maintenance: oral 6.0 mg/kg/day; modified to maintain therapeutic concentrations | 325–375 (RIA) | 16 (35) | NS | NR | Paresthesia, seizures, somnolence |
Minuk et al. [22] | Canada | Prospective | 12 mo | Liver | 12 | Induction: oral 2.5 mg/kg/day maintenance: oral adjusted to fit therapeutic concentrations | Serum: 100–200 | 2 (16.7) | Late | No treatment; ONR | Headaches, paresthesia |
Munhoz et al. [23] | Brazil | Observational | 7 mo | Bone marrow | 60 | Maintenance oral 5 mg/kg/day | NR | 13 (21.7) | Early | NR | NR |
Navazo et al. [24] | Spain | Non-randomized | ~12–36 mo | IBD | 11 | Induction: oral 7–7.5 mg/kg/day | Plasma induction: 250–300 ng/mL | 7 (63.6) | Early | Oral magnesium supplement control of tremor | Headache |
Neuhaus et al. [25] | Germany, UK, France, Sweden | Open, randomized, parallel-group | 22 mo | Liver | 273 | Induction: IV 1–6 mg/kg⋅BW/day Maintenance: oral 8–15 mg/kg⋅BW/day | NR | 27 (9.9) | Early | NR | Coma, somnolence, encephalopathy, convulsion, dysarthria, psychosis, confusion, delirium, paranoid reaction, insomnia, depression, headache, neuropathy |
Pescovitz et al. [26] | USA | Randomized, prospective, open-label, multicenter | 6 mo | Kidney | 15 | Baseline oral 487.5 mg/month: 3–6 mo ~300 mg | 224–347 ng/mL | 7 (46.7) | Late | NR | Headache, insomnia |
Pirsch et al. [27] | USA | Randomized, open-label | 21 mo | Kidney | 207 | Induction: oral 5.0 mg/kg BW/day maintenance: dependent on target trough | Induction blood: 150–400 Maintenance blood: 100–300 | 70 (33.8) | Early | Dose reduction, ONR | Headache, insomnia, paresthesia, dizziness, anxiety |
Pistoia et al. [28] | Italy | Prospective | NR | Connective tissue, disorder | 9 | 3–10 mg/kg/day maintenance: 3–5 mg/kg/day tapering to maintenance dosage | NR | 1 (11.1) | NS | Temporary tapering; control of tremor | NR |
Schmidt et al. [29] | NR | Retrospective | NR | Bone marrow | 51 | 2–5 mg/kg/day 30% dose reduction if bilirubin or cr started to rise | Plasma concentration >250 ng/mL to reduce dose severity | 51 (NR) | Early | NR | NR |
Sheth et al. [30] | Canada | Prospective | 3 mo | Liver, kidney | 10 | NR | NR | 3 (30) | Early | NR | Headache |
Sood et al. [31] | India | Retrospective, cross-sectional | 12–62 mo | IBD | 24 | Induction: IV 4 mg/kg/day Maintenance: oral, microemulsion 4 mg/kg/day | NR | 9 (37.5) | Early | NR | Paresthesia, headache, peripheral neuropathy |
Stack et al. [32] | UK | Clinical | ~60 mo | IBD | 22 | Induction: 4 mg/kg/day Maintenance: 6 mg/kg/day | Serum: 100–200 | 4 (18) | Early | NR | Headaches, paresthesia |
Stange et al. [33] | Germany | Clinical | 10 wk | IBD | 13 | Maintenance: oral 25–600 mg, twice daily | Blood: 200–800 | 4 (30.8) | Early | NR | Hyperesthesia |
Steinsson et al. [34] | Iceland | Controlled, multicenter | 18 mo | Psoriatic arthritis | 8 | induction: oral 3.5 mg/kg/day | Blood: <500 | 1 (12.5) | Early | Discontinue | NR |
Thompson et al. [35] | USA | Retrospective | NR | Bone marrow | 12 | IV 3 mg/kg/day or oral 12.5 mg/kg/day; dosage held or reduced with seizure | 200–400 | 2 (18.2) | Mid | Withholding drug and replacing magnesium | Seizures, ataxia, depression, transient aphasia |
Tolou-Ghamari et al. [36] | Iran | Population-based | NR | Kidney | 75 | Dose unspecified, but oral and twice daily | 16.5–1261 | 35 (46.7) | NS | NR | Headache, anxiety |
Trocha et al. [37] | Germany | Prospective | NR | Liver | 14 | Group 1: oral 100–325 mg group 2: unspecified | NR | 7 (50) | Early | NR | Anarthria, dysarthria, seizures, confusion, coma, polyneuropathy |
Wakefield and McCluskey [38] | Australia | Open, uncontrolled | 48 mo | SLE | 22 | Initial: oral 10 mg/kg/day modified to reach 5 mg/kg/day dosage below led to relapse | NR | 6 (27.3) | Early and late | NR | NR |
Wakefield and McCluskey [39] | Australia | Open, uncontrolled | NR | SLE | 7 | Induction, oral 10 mg/kg/day; maintenance oral 5 mg/kg/day | NR | 5 (71.4) | Late | NR | Facial pain |
Wijdicks et al. [40] | USA | Retrospective | NR | Liver | 227 | Induction: 10-mg/kg/day IV emulsion maintenance: oral dose modified to therapeutic goal timeline | NR | 13 (5.7) | Early and late | Dose reduction, persistence (n = 1) Amelioration (n = 12) | Pain, headaches, paresthesia, seizures, sleep difficulty, leg cramps |
3.2 Tacrolimus and Tremor
Author(s) | Country/continent | Design | Study duration | Graft organ/etiology | Cohort size (n) | Dosing protocol | Target or mean trough in ng/mL | Tremor (n) | Treatment method and outcome | Other neurological side effects |
---|---|---|---|---|---|---|---|---|---|---|
Alissa et al. [41] | Saudi Arabia | Retrospective | NS | Liver | 338 | Day 1: 0.05– 0.1 mg/kg/day every 12 h; maintenance: 7–10 ng/mL within first 3 mo; dose reduction or switch to CSA if intolerance | 10 July | 6 (10%) | Switching to CSA (n = 4); reduction in dose (n = 2) | Seizures, psychosis, agitation, tremors, confusion, twitching, behavioral changes |
Alloway et al. [42] | USA | Prospective, 3-sequence, open-label, multicenter | 12 mo | Liver | Immediate release: 59; ER-Tac: 59; extension phase ER-Tac: 49 | Tacrolimus: oral, twice daily, fixed-dose at investigator discretion; ER-Tac: oral, once daily, fixed-dose at investigator discretion; extension phase ER-Tac: oral, remained on Tac for an additional 50 wk | Blood: 5–15 ER-Tac and Tac | Tac: 1 (1.7%); ER-Tac: 4 (6.8%); extension phase; ER-Tac: 1 (2%) | NR | Dizziness, fatigue, headache, insomnia, back pain |
Baumgart et al. [43] | Germany | Retrospective, observational single-center | 12 mo | IBD | 31 | Oral 0.1 mg/kg/day, divided into two doses (n = 37) IV 0.01 mg/kg/day (n = 1) | Serum: 4–6 | 3 (9.7%) | Dose tapering ONR | Paresthesia |
Baumgart et al. [44] | Germany | Retrospective observational single-center | ~2 y | IBD | 53 | Oral 0.1 mg/kg⋅ BW/day, in 2 divided doses (n = 51); induction IV 0.01 mg/kg BW/day (n = 2) | Serum: 4–8 | 5 (9.4%) | NR | Paresthesia |
Boschetti et al. [45] | France | Retrospective | 12 mo | IBD | 30 | Induction (12 wk) oral 0.15–0.15 mg/kg BW, 2× day; maintenance: adjusted to achieve target trough concentrations | Induction serum: 10–15; maintenance serum: 5–10 | 6 (20%) | Med stopped (n = 3), ONR | Headache |
Briggs et al. [9] | Europe | Prospective, open, multicenter, parallel-group | 3 mo | Kidney | 61 | Induction: oral 0.2 mg/kg, divided into two doses; maintenance: oral, adjusted to achieve target trough concentrations | Blood: 10–20 | 10 (16.4%) | NR | NR |
Bulatova et al. [46] | Jordan | Multicenter, cross-sectional, observational | 16 mo | Kidney | 154 | Oral and personalized doses to achieve therapeutic concentrations | Blood: 4–7 | 61 (40%) | NR | Seizures, headache, paresthesia, sleep disturbance, asthenia, dizziness |
Burkhalter et al. [47] | USA | Prospective | 5.6 mo | Liver | 100 | Induction IV 0.075–1 mg/kg BW; maintenance: oral 0.3 mg/kg/day; modified to achieve target concentrations or prevent graft rejection and hepatic or renal dysfunction | Serum: 0.5–1.5 | 1 (1%) | Discontinuation but tremor persisted | Central pontine myelinolysis coma, delirium, dysarthria, brain abscess, TIA |
Chand et al. [48] | USA | Retrospective | 39 mo | Kidney, heart | 22 | Total: oral 0.1–0.3 mg/kg/day, in two doses; maintain therapeutic concentrations or in response to complications such as post-transplant lymphoproliferative disease | Induction: 15–25; maintenance: 5–15 | 1 (9%) | NR, remission of symptoms | Headache |
Chen et al. [49] | China | Prospective, multicenter clinical | 24 mo | Kidney | 14 | Induction: oral 0.05 mg/kg/day mean dose; (1–6 mo): oral 5.4 ± 1.7 mg/day mean dose; (6–12 mo): oral 3.8 ± 1.3 mg/day | Induction blood: 5–10 maintenance blood: 4–6 | 1 (7.1%) | Reduction in dosage, remission | NR |
Choi et al. [50] | USA | Retrospective | 10.9 mo | Liver | 25 | IR-Tac: oral 4 mg, daily; LCP-Tac: oral 3 mg, daily; modified according to target level designations | Monotherapy: month 0–1 blood: 8–10; month 1– 6 blood: 5–8; maintenance blood: 3–5 | 6 (32%) | Switch to LCP-Tac formulation, 88% tremor improved | NR |
De Simone et al. [51] | Italy | Single-center, retrospective | ~45 mo | Liver | 178 | Oral, dose not reported; adjusted for participant needs and to attain desired trough concentrations | Blood: 6–15 | 32 (17.9%) | NS | Headache |
Dehghani et al. [13] | Turkey | Single-center, observational | ~36 mo | Liver | 44 | NR | Mean trough: 12.4 ± 6.3 | 6 (13.6%) | Dose reduction, ONR | Headache, insomnia, weakness, convulsion paresthesia, muscle cramps, dizziness |
DuBay et al. [52] | USA | Open-label, multicenter, randomized phase II | 12 mo | Liver | ER-Tac: 29; IR-Tac: 29 | ER-Tac: oral 0.07–0.13 mg/kg/day, once daily; IR-Tac: oral 0.10–0.15, divided 2× day | Induction blood: 5–20; maintenance blood: 5–15 | ER-Tac: 8 (27.6%); IR-Tac: 10 (34.5%) | NS | Headache, back pain, nausea, insomnia |
Eidelman et al. [53] | USA | Group 1: retrospective chart review; Group 2: prospective; Group 3: surveillance | 2 mo | Liver, lungs, heart, kidney | Group 1: 23; group 2: 294; group 3: 83 | Induction (IV 0.075 mg/kg 4-h infusion per 12 h; modified to IV 0.15-mg/kg continuous infusion; maintenance: oral, 0.15 mg/kg per 12 h | Plasma: 2.5 Plasma mean: 3.4 ± 3 | Group 1: 2; group 2: reported, NS; group 3: NR (overall, 8.7%) | Resolved following treatment discontinuation | Akinetic mutism, aphasia, dysarthria, dysesthesia, encephalopathy, headache, mood disturbances, seizures, sleep and visual disturbances |
Erro et al. [14] | Italy | Prospective | transplant patients between February 1988 and August 2016; clinical exam day | Kidney | 67 | Oral, dose NR | Within therapeutic range; NR observed those with tremor did show higher plasma concentrations than those without | 55 (82%) | NS | Mild cerebellar and neuropathic symptoms |
Fan et al. [54] | China | Prospective, multicenter clinical | 24 mo | Kidney | 24 | Induction: oral 0.05 mg/kg/d, 2× day at 12-h intervals | Induction blood: 5–10; maintenance blood: 4–6 | 2 (8.3%) | Reduction in dosage, remission | NR |
Frank et al. [15] | USA | Prospective | NS | Liver | Group 1 (rescue): 20; group 2 (prophy):7 | Oral, 0.3 mg/kg/day, in 2 divided doses; based on renal function or possible rejection | NR, plasma was utilized | Group 1: 4 (20%) group 2: 2 (28%) | Dose reduction, remission | Headache, seizures, sleep disorders, focal white and gray matter lesions, necrotizing angiopathy |
January et al. [55] | USA | Single-center, retrospective | ~24 mo | Kidney | LCP-Tac: 84; IR-Tac: 42 | LCP-Tac: oral 0.08 mg/kg, once daily; IR-Tac: oral 0.1 mg/kg once daily; maintain therapeutic concentrations | Induction blood: 7–10; maintenance blood: 3–7 | 9 (7%) | NS | NS |
Karasawa et al. [56] | Japan | Retrospective | 60 mo | Kidney | 26 | Induction: oral 3 mg/day, evening administration | Blood: <8 ng/mL | 3 (11.5%) | Reduction in dosage, remission | Facial nerve paralysis, trigeminal neuralgia |
Katari et al. [57] | USA | Observational | 48 mo | Kidney | 22 | Induction: IV 0.075–0.1 mg/kg/day; maintenance: oral 0.30 mg/kg/day | Blood: 5–20; plasma: 0.5–1.5 | 2 (9%) | NS | NS |
Langone et al. [58] | USA | 2-sequence, open-label, prospective phase IIIb, multicenter, clinical | ~15 mo | Kidney | 38 | Dose personalized, conversion to once-daily ER-Tac from twice-daily capsule therapy, used 0.70 conversion for non-black and 0.85 for black participants | Blood: 3–12 | All had tremor prior to conversion | Formulation adjustment (capsule to ER-Tac), amelioration of tremor severity | NS |
Menegaux,et al. [20] | USA | Retrospective | Unclear | Liver | 64 adult 10 peds | NS | Whole blood: <20 | 4 adults 1 peds (7%) | Dosage reduction or remission | Encephalopathy, seizure, stroke, peripheral neuropathy headache, facial paralysis, spinal cord deficit, Parkinson's disease |
Mok et al. [59] | China | Prospective | 12 mo | Kidney | 21 | Oral 4 mg/day, in two divided doses | NR | 1 (3%) | NS | Facial twitching, dyspepsia, cramps |
Neu et al. [60] | USA | Retrospective | ~27 mo | Kidney | 14 | Initial: oral 0.03 mg/kg/d; modified to achieve target trough concentrations | Blood: 5–12 | 7 (50%) | NS | Seizures myalgias, fatigue, hyperesthesia, headache, insomnia |
Neuhaus et al. [25] | Europe | Open, randomized, parallel-group | 22 mo | Liver | 267 | Induction: 0.075 mg/kg BW IV infusion over 4 h, repeated every 12 h; maintenance: oral 0.3 mg/kg BW/day | NS | 43 (16.1%) | NR | Coma, somnolence, encephalopathy, convulsion, aphasia, psychosis, confusion, delirium, insomnia, depression, headache, neuropathy |
Pirsch et al. [27] | USA | Randomized, open-label | 21 mo | Kidney | 205 | Induction: oral 0.1 mg/kg BW/day; maintenance: oral and dependent on individual | Induction blood: 1 0–25; maintenance blood: 5–15 | 111 (54.1) | Dose reduction, ONR | Headache, insomnia, paresthesia, dizziness, anxiety |
Reding et al. [61] | Belgium | Prospective, clinical | 23.9 mo | Liver | 23 | Postoperative (n = 3): 0.14–0.16 mg/kg/day for 4–19 days, transitioned to 0.2–0.33 mg/kg/day postoperative maintenance (n = 20): 0.2–0.33 mg/kg/day | Plasma: 0.1–1 | 1 (4.4%) | NR | Myalgia, coma, depression seizures |
Riva et al. [62] | Argentina | Retrospective, single-center cohort | 30 mo | Liver | 72 | Oral 0.1 mg/kg/day, adjusted for trough concentrations | Month (1–6), blood: 7–8; month (6–12), blood: 5–7; maintenance blood: 5 | 1 (1.4%) | NR | NR |
Rostaing et al. [63] | USA | Randomized, double-blind, double-dummy, multicenter phase III | 24 mo | Kidney | ER-Tac: 268; IR-Tac: 275 | ER-Tac: oral 0.17 mg/kg/day, once daily; IR-Tac: oral 0.1 mg/kg/day, 2× day; modified to maintain target trough concentrations | Induction blood: 6–11; maintenance blood: 4–11 | ER-Tac: 59 (22%); IR-Tac: 51 (18.5%) | Discontinuation and ONS | NR |
Sánchez Fructuoso et al. [64] | Spain | Multicenter, retrospective, single-cohort conversion | 5 mo | Kidney | 365 | NS | Blood: 7–8.4 | Pre-conversion: 76 (23%); post-conversion: 43 (11.8%) | Switch to ER formulation, improvement in symptoms | Headache, concentration issues, insomnia |
Tamaki et al. [65] | Japan | Clinical | 3.9 mo | IBD | 14 | 0.01–0.02 mg/kg/day (n = 3), days 1–14: IV, oral for remaining; oral 0.1–0.2 mg/kg/day (n = 11) | Induction serum: 10–15; maintenance serum: 5–10 | 1 (7%) | Dose reduction, remission | Paresthesia |
Thorp et al. [66] | USA | Prospective clinical | 12 mo | Kidney | 16 | Oral 0.1 mg/kg, 2× day adjusted based on blood trough concentrations taken during first week; considered stable following 3 measurements in target range | Blood: 5–20 | 1 (6.25%) | No treatment, tremor reported as well tolerated | Headaches |
Trocha et al. [37] | Germany | Prospective cohort | ~30 mo | Liver | 23 | Group 1 + 2 induction: 0.05–0.30 mg/kg BW 2× day; group 1 maintenance: 6–9 mg/day; group 2 maintenance: altered to maintain target plasma concentrations at investigator discretion | Plasma 0.3–3.0 | 14 (77.8%) | Dose reduction, amelioration of tremor | Anarthria, dysarthria, confusion apathy, coma, polyneuropathy |
Truffinet et al. [67] | France | Retrospective | NS | IBD | 8 | Induction: oral 0.05–0.2 mg/kg, 12 h; maintenance: oral, NR | Induction blood: 8–15; maintenance blood: 5–10 | 1 (12.5%) | Discontinuation of treatment, ONR | Paresthesia |
Turunc et al. [68] | Turkey | Single-center, retrospective | 6 mo | Kidney | ER-Tac: 52; IR-Tac 63 | Day 2 (pre-transplantation) ER-Tac: oral 0.2 mg/kg/day; day 2 (pre-transplantation) IR-Tac: oral 0.15 mg/kg/day; lowered over the first month following achievement of target concentrations | Blood (day 1–30): 8–12; blood (day 31–180): 4–11; blood (day 180–end): 6–8 | ER-Tac: 4 (7.6%); IR-Tac: 9 (14.3%) | NS | NR |
Uemoto et al. [5] | Japan | Prospective, clinical | ~33 mo | Liver | 61 | Postoperative: IV 0.06-mg/kg infusion, postoperative: concurrent oral 0.15 mg/kg per 12 h and above infusion | Blood: 10–20 | 12 (23%) | NR | Convulsions |
Uemoto et al. [69] | Japan | Prospective, clinical | ~30 mo | Liver | 22 | Postoperative (when using a rescue immunosuppressant drug, n = 14): IV 0.075-mg/kg infusion per 12 h, overlapping oral 0.15 mg/kg during transition from IV to oral, postoperative (n = 8): 0.03 mg/kg per 12 h | Plasma: 0.15–0.50, blood: 10–30 | 8 (36%) | Considered manageable; no treatment required, ONR | Insomnia |
Watson et al. [70] | USA | Retrospective chart review | NS | IBD | 46 | Oral 0.1 mg twice/day; adjusted to yield target trough concentrations | Induction blood: 10–15; maintenance blood: 5–10 | 21 (46%) | Weaning/cessation of treatment, spontaneously resolved/resolved with other treatments | Headache, seizure |
Wijdicks et al. [4] | USA | Group 1: comparative; Group 2: open-label, multicenter, randomized parallel comparison | 44 mo | Liver | Group 1: 21; group 2: 23 | Postoperative (group 1): 0.075 mg/kg/6 h continuous IV infusion; maintenance (group 1): oral 0.15 mg/kg/12 h; maintenance (group 2, high dose): 0.03 mg/kg/12 h IV; continuous infusion or oral 0.075 mg/kg/12 h | Blood: <60, Plasma: <5 | 10 (4.4%) | Dose reduction, remission (n = 7), persistence (n = 3) | Psychosis temporary apraxia, pseudobulbar affect, suicidal behavior, tonic-clonic generalized seizures |
Yamamoto et al. [71] | Japan | Retrospective, observational, single-center | Unclear | IBD | 27 | Induction (n = 4): 0.01 mg/kg BW IV infusion then moved to oral formulation, maintenance (n = 23): oral 0.1 mg/kg BW | Induction blood: 10–15; maintenance blood: 5–10 | 7 (25.9%) | NR | Headache |
Yanik et al. [72] | USA | Retrospective chart review | ~6 mo | BM | Related: 11; unrelated: 20 | Inpatient: 0.03 mg/kg/day continuous IV infusion; outpatient: oral, quadruple IV-calculated dose until no evidence of GVHD, tapered by 25% per month until discontinued | Serum: 5–15 | 13 (32%) | Magnesium supplementation, remission attributed to hypomagnesemia development (n = 7), tremor persistence (n = 6) | Focal complex seizure |
Yocum et al. [73] | USA | Open-label, long-term safety | ~12 mo | RA | 896 | Oral, 3 mg/day | Blood: 2–3 | 81 (9%) | Withdrawal from study (n = 14), ONS | Asthenia, back pain, dizziness, headache |
3.3 Sirolimus and Everolimus, and Tremor
Author(s) | Country | Study design | Study duration | Grafted organ/etiology | Cohort size (n) | Dosing protocol | Target or mean trough in ng/mL | Tremor prevalence n (%) | Treatment method/outcome | Other neurologic side effects |
---|---|---|---|---|---|---|---|---|---|---|
Jeon et al. [74] | Korea | Prospective, open-label, non-comparative, observational post-marketing surveillance | 6 mo | Kidney | 209 | 1.8 ± 0.7 | Immunoassay: 5.5 ± 2.6, HPLC: 7.8 ± 4.2 | 1 (0.48%) | No treatment, defined as self-limited | NR |
Chinnock et al. [75] | USA | Retrospective | NS | Kidney | 20 | NR | 8 May | 1 (5%) | No treatment, self-limited, symptoms resolved at conclusion of study | NR |
Erro et al. [14] | Italy | Prospective | NS | Kidney | 27 | NR | Assumed to be within therapeutic range | 12 (44%) | NR | NR |
Pescovitz et al. [26] | USA | Prospective, randomized, open-label, multicenter | 0.5 mo | Kidney | 30 | Induction (days 1–3): 15 mg/day, oral solution; maintenance (day 4–end): oral 10-mg/day tablets; to reduce drug-related toxicity while maintaining immunosuppression, at investigator discretion | Induction blood: 10–25; maintenance blood: 8–15 | 3 (10%) | NR | Headache, insomnia, fatigue |
Van de Beek et al. [76] | USA | Retrospective | NS follow-up was ~6 y | Heart, liver, kidney | 313 | NR | NR | 5 (5%) | No treatment, ONR | Depression, polyneuropathy TIAs, seizures, stroke |
Tedesco-Silva et al. [77] | 42 countries | Randomized open-label, 2-arm | 1 y | Kidney | 1014 | Adjusted for target trough concentrations | Blood: 3–8 | 98 (9.7%) | Dose adjustment, ONR | Insomnia |