Safety profile of upadacitinib in patients at risk of cardiovascular disease: integrated post hoc analysis of the SELECT phase III rheumatoid arthritis clinical programme.

OBJECTIVE: Increased risk of serious adverse events (AEs) was reported for tofacitinib relative to tumour necrosis factor inhibitor therapy in patients with rheumatoid arthritis (RA) aged ≥50 years enriched for cardiovascular (CV) risk (ORAL Surveillance). We assessed post hoc the potential risk of upadacitinib in a similar RA population. METHODS: Pooled safety data from six phase III trials were evaluated post hoc for AEs in patients receiving upadacitinib 15 mg once a day (with or without conventional synthetic disease-modifying antirheumatic drugs), adalimumab 40 mg every other week with concomitant methotrexate (MTX), or MTX monotherapy in the overall trial population and in a subset of patients with higher CV risk (aged ≥50 years, ≥1 CV risk factor). Higher-risk patients from a head-to-head study of upadacitinib 15 mg versus adalimumab (SELECT-COMPARE) were assessed in parallel. Exposure-adjusted incidence rates for treatment-emergent AEs were summarised based on exposure to upadacitinib or comparators. RESULTS: A total of 3209 patients received upadacitinib 15 mg, 579 received adalimumab and 314 received MTX monotherapy; ~54% of the patients were included in the overall and SELECT-COMPARE higher-risk populations. Major adverse cardiovascular events (MACE), malignancy (excluding non-melanoma skin cancer (NMSC)) and venous thromboembolism (VTE) were more frequent in the higher-risk cohorts versus the overall population but were generally similar across treatment groups. Rates of serious infections in higher-risk populations and herpes zoster (HZ) and NMSC in all populations were higher with upadacitinib 15 mg than comparators. CONCLUSIONS: An increased risk of MACE, malignancy (excluding NMSC) and VTE was observed in higher-risk populations with RA, yet risk was comparable between upadacitinib-treated and adalimumab-treated patients. Higher rates of NMSC and HZ were observed with upadacitinib versus comparators across all populations, and increased rates of serious infections were detected in upadacitinib-treated patients at higher CV risk. TRIAL REGISTRATION NUMBERS: NCT02706873, NCT02675426, NCT02629159, NCT02706951, NCT02706847 and NCT03086343.

Safety of upadacitinib in moderate-to-severe atopic dermatitis: An integrated analysis of phase 3 studies.

BACKGROUND: Upadacitinib is a selective reversible Janus kinase (JAK) inhibitor with established efficacy in moderate-to-severe atopic dermatitis (AD). OBJECTIVE: We evaluated the safety of upadacitinib in patients with moderate-to-severe AD. METHODS: Integrated safety data from the 16-week placebo-controlled periods of 1 phase 2b and 3 ongoing phase 3 studies (16 weeks) and longer-term safety data from patients receiving upadacitinib during the blinded extension periods of the three phase 3 studies were analyzed (all upadacitinib exposure). Treatment-emergent adverse events (TEAEs) were presented as exposure-adjusted rates per 100 patient-years (PY). RESULTS: Safety results were similar between the 16-week and all upadacitinib exposure groups. The latter group included 2485 patients (333 adolescents), receiving upadacitinib 15 mg (n = 1239) or 30 mg (n = 1246) for a mean duration of approximately 1 year. Upadacitinib was well tolerated by both adults and adolescents. TEAEs and discontinuation due to AEs were reported more frequently in patients receiving 30 mg upadacitinib (respectively, 311.9 and 5.7 events per 100 PY) versus 15 mg (respectively, 274.6 and 4.4 events per 100 PY). Serious adverse event rates (15/30 mg, 7.1/7.7 events per 100 PY) were similar in both groups. Acne was the most frequently reported adverse event (15/30 mg, 13.3/20.2 events per 100 PY). Serious infection rates were similar across treatment groups. Adjudicated major adverse cardiovascular event and venous thromboembolic event rates were ≤0.1 events per 100 PY. Rates of malignant neoplasms were within the expected range for the general population. CONCLUSIONS: Upadacitinib was well tolerated, and no new important safety risks were observed among adults and adolescents with moderate-to-severe AD treated for approximately 1 year compared to the known safety profile of upadacitinib.

Safety and tolerability of adjunctive lacosamide in a pediatric population with focal seizures - An open-label trial.

PURPOSE: To evaluate safety and tolerability of adjunctive lacosamide in children with focal seizures. METHODS: Patients were eligible for this open-label, fixed-titration trial (SP0847; NCT00938431) if aged 1 month-17 years with focal seizures taking 1-3 antiepileptic drugs. Findings from Cohort 1, aged 5-11 years, who received lacosamide ≤8 mg/kg/day, informed dosing for age-based cohorts 2-5, who then received ≤12 mg/kg/day (≤600 mg/day). Oral lacosamide was initiated at 2 mg/kg/day (1 mg/kg bid) and uptitrated by 2 mg/kg/day/week to the maximum cohort-defined dose (maximum trial duration: 13 weeks). Patients who did not achieve the maximum cohort-defined dose were discontinued. RESULTS: Forty-seven patients (aged 6 months-≤17 years) enrolled (≥1 month-<4 years: n = 15; ≥4-<12 years: n = 23; ≥12-≤17 years: n = 9). 24/47 (51.1%) patients completed the trial at the maximum cohort-defined dose and 40/47 (85.1%) continued lacosamide in the extension trial. Treatment-emergent adverse events (TEAEs) were reported by 42/47 (89.4%) patients. The most common TEAEs (≥10% of patients) were vomiting (21.3%), diarrhea (14.9%), somnolence (12.8%), irritability, dizziness, and pyrexia (10.6% each). Twenty (42.6%) patients discontinued due to TEAEs, most commonly vomiting (8.5%), gait disturbance, dizziness, and somnolence (6.4% each). Six (12.8%) patients reported serious TEAEs, most commonly status epilepticus (3/47; 6.4%). CONCLUSION: This fixed-titration trial supports the safety of adjunctive lacosamide in children (aged 6 months-≤17 years) with focal seizures. The TEAE profile was generally consistent with that observed in trials in adults, and no new safety concerns were identified.

Safety and Tolerability of Adjunctive Brivaracetam in Pediatric Patients < 16 Years with Epilepsy: An Open-Label Trial.

OBJECTIVE: This trial evaluated the short-term safety and tolerability, steady-state pharmacokinetics, and preliminary efficacy of brivaracetam oral solution in children aged 1 month to < 16 years with epilepsy. METHODS: This was a phase IIa, open-label, single-arm, fixed three-step dose escalation trial of 3-weeks duration (N01263; NCT00422422). Patients were taking one to three concomitant antiepileptic drugs. Brivaracetam oral solution dosage, in two divided daily doses, was increased each week: approximately 0.8, 1.6, and 3.2 mg/kg/day for patients aged ≥ 8 years, and 1.0, 2.0, and 4.0 mg/kg/day for patients aged < 8 years. RESULTS: Of the 100 patients enrolled, 90 (90.0%) completed the trial. The safety population comprised 99 patients. Treatment-emergent adverse events (TEAEs) considered drug related by the investigator were reported by 32/99 (32.3%) patients, most commonly (≥ 5%) somnolence (7.1%) and decreased appetite (6.1%). TEAEs were reported by 66/99 (66.7%) patients, most commonly (≥ 5%) convulsion, irritability, pyrexia, somnolence, and decreased appetite. In patients with a history of focal seizures with or without secondary generalization and no primary generalized seizures aged 4 to < 16 years (n = 34), drug-related TEAEs and TEAE incidences were 47.1% and 67.6%, respectively. Steady-state trough brivaracetam and brivaracetam metabolite plasma concentrations increased proportionally with dose. The ≥ 50% responder rates (all seizure types) were 21.3% (all patients, n = 80) and 36.4% (patients with focal seizures, aged 4 to < 16 years, n = 22). CONCLUSIONS: This open-label trial in pediatric patients with epilepsy provides preliminary information that short-term, adjunctive brivaracetam treatment is well tolerated and effective. Plasma concentrations of brivaracetam and metabolites increased with increasing dose.

Randomized double-blind comparison of cognitive and EEG effects of lacosamide and carbamazepine.

Differential effectiveness of antiepileptic drugs (AEDs) is more commonly determined by tolerability than efficacy. Cognitive effects of AEDs can adversely affect tolerability and quality of life. This study evaluated cognitive and EEG effects of lacosamide (LCM) compared with carbamazepine immediate-release (CBZ-IR). A randomized, double-blind, double-dummy, two-period crossover, fixed-dose study in healthy subjects compared neuropsychological and EEG effects of LCM (150mg, b.i.d.) and CBZ-IR (200mg, t.i.d.). Testing was conducted at screening, predrug baseline, the end of each treatment period (3-week titration; 3-week maintenance), and the end of each washout period (4weeks after treatment). A composite Z-score was derived for the primary outcome variable (computerized cognitive tests and traditional neuropsychological measures) and separately for the EEG measures. Other variables included individual computer, neuropsychological, and EEG scores and adverse events (AEs). Subjects included 60 healthy adults (57% female; mean age: 34.4years [SD: 10.5]); 44 completed both treatments; 41 were per protocol subjects. Carbamazepine immediate-release had worse scores compared with LCM for the primary composite neuropsychological outcome (mean difference=0.33 [SD: 1.36], p=0.011) and for the composite EEG score (mean difference=0.92 [SD: 1.77], p=0.003). Secondary analyses across the individual variables revealed that CBZ-IR was statistically worse than LCM on 36% (4/11) of the neuropsychological tests (computerized and noncomputerized) and 0% of the four EEG measures; none favored CBZ-IR. Drug-related AEs occurred more with CBZ-IR (49%) than LCM (22%). Lacosamide had fewer untoward neuropsychological and EEG effects and fewer AEs and AE-related discontinuations than CBZ-IR in healthy subjects. Lacosamide exhibits a favorable cognitive profile.

Safety and tolerability of adjunctive brivaracetam as intravenous infusion or bolus in patients with epilepsy.

OBJECTIVES: An intravenous (IV) formulation of brivaracetam (BRV), a selective, high-affinity ligand for synaptic vesicle protein 2A, has been developed. We investigated the safety, tolerability, and pharmacokinetics of adjunctive IV BRV administered as a bolus or infusion to adults with epilepsy. METHODS: A phase III, multicenter, randomized, four-arm, parallel-group study (NCT01405508) of patients aged 16-70 years with focal or generalized epilepsy uncontrolled by 1-2 antiepileptic drugs was undertaken. The study comprised a 7-day baseline period, a 7-day double-blind run-in period (oral BRV 200 mg/day or placebo [PBO] twice daily [BID]), and 4.5-day open-label evaluation period (IV BRV 200 mg/day BID; 2-min bolus or 15-min infusion, total nine doses). Patients were randomized 1:1:1:1 PBO/BRV bolus; PBO/BRV infusion; BRV/BRV bolus; BRV/BRV infusion. Safety and tolerability were assessed using adverse events, electrocardiography, vital signs, and laboratory assessments. BRV plasma concentrations were measured before and 15 min after the first and last IV doses. RESULTS: Of the 105 patients randomized (53.3% women; 77.1% white; mean [standard deviation; SD] age 41.6 [12.2] years), 103 (98.1%) completed the study. Treatment-emergent adverse event (TEAE) incidence during IV BRV was similar whether IV BRV was initiated first (70.6%) or followed oral BRV (66.0%), and whether it was administered as a bolus (71.2%) or infusion (65.4%). Injection-related TEAEs were reported by 9.6% of patients following bolus and 11.5% following infusion. No serious TEAEs were reported. IV BRV plasma concentrations were higher after the first dose in the conversion groups than initiation groups, and slightly higher in the bolus arm than the infusion arm; concentrations were similar in all patients after the last IV dose. SIGNIFICANCE: IV BRV was generally well tolerated, with similar tolerability as a bolus or infusion and independent of de novo administration or as conversion from oral BRV tablets. IV BRV may be an option for patients who are unable to receive oral BRV.

Prospective Open-Label, Single-Arm, Multicenter, Safety, Tolerability, and Pharmacokinetic Studies of Intravenous Levetiracetam in Children With Epilepsy.

Levetiracetam given via intravenous administration has been shown to be an effective alternative in adults with epilepsy when oral administration is not feasible. This study was a prospective single-arm, multicenter study to assess tolerability, safety, and pharmacokinetics of intravenous levetiracetam in children with epilepsy. Children with epilepsy ages 1 month to 16 years requiring intravenous levetiracetam were enrolled. Assessments included vital signs, electrocardiogram, hematology, chemistry, plasma concentrations of antiepileptic medications, weight, physical/neurological examinations, and pharmacokinetics. A total of 52 patients were enrolled. Mild to moderate treatment-emergent adverse events occurred in 63%, the most frequent being pyrexia and dry mouth. Most other treatment-emergent adverse events were considered unrelated to intravenous levetiracetam administration. Therefore, intravenous levetiracetam in the acute setting was overall well tolerated in children 1 month to 16 years.

Safety and tolerability of adjunctive lacosamide intravenous loading dose in lacosamide-naive patients with partial-onset seizures.

PURPOSE: To examine the safety and tolerability of rapidly initiating adjunctive lacosamide via a single intravenous loading dose followed by twice-daily oral lacosamide in lacosamide-naive adults with partial-onset seizures. METHODS: This open-label, multicenter trial, enrolled patients with epilepsy who were taking 1-2 antiepileptic drugs (AEDs) in one of four sequential cohorts containing 25 subjects each. An intravenous lacosamide loading dose (200, 300, or 400 mg) was administered over 15 min followed 12 h later by initiation of oral dosing consisting of one-half of the loading dose administered twice daily for 6.5 days. The first cohort was administered lacosamide 200 mg/day, followed by a cohort at 300 mg/day, and then a cohort at 400 mg/day. The results from each cohort were evaluated before enrolling the next highest dose level. The fourth cohort enrolled patients at the highest dose with clinically acceptable safety and tolerability results. Safety evaluations included treatment-emergent adverse events (TEAEs), patient withdrawals due to TEAEs, and changes in vital signs, 12-lead electrocardiography (ECG) studies, laboratory parameters, and clinical examinations. Postinfusion lacosamide plasma concentrations were also evaluated. KEY FINDINGS: A total of 100 patients were enrolled, 25 in each cohort. The loading dose for the repeat cohort was 300 mg; therefore, 25 patients were enrolled at 200 mg/day, 50 at 300 mg/day, and 25 at 400 mg/day. Most TEAEs occurred within the first 4 h following infusion; dose-related TEAEs (incidence ≥10%) during this timeframe included dizziness, somnolence, and nausea. Seven patients withdrew, all due to TEAEs: three (6%) from the combined 300 mg group and four (16%) from the 400 mg group; four of these patients discontinued within 4 h following infusion. The most common TEAEs leading to discontinuation (overall incidence >1%) were dizziness (6%), nausea (5%), and vomiting (3%). No clinically relevant pattern of changes from baseline ECG, clinical laboratory parameters, or vital signs were observed. Trough plasma concentrations suggested that near steady-state lacosamide concentrations were achieved with a single intravenous loading dose. SIGNIFICANCE: Intravenous loading doses of 200 and 300 mg lacosamide administered over 15 min followed by oral lacosamide were well tolerated in lacosamide-naive patients. The 400-mg loading dose was less well tolerated due to a higher frequency of dose-related TEAEs. These results support the feasibility of rapid initiation of adjunctive lacosamide treatment.