e end of treatment. Additional benefit of using doses of greater than 1,200 mg a day was not demonstrated.
For various degrees of improvement in pain from baseline to end of maintenance treatment, Figure 2 shows the fraction of patients achieving that degree of improvement. The figure is cumulative, so that patients whose change from baseline is, for example, 50%, are also included at every level of improvement below 50%. Patients who did not complete the study were assigned 0% improvement.
Figure 2. Percent of Patients Achieving Various Levels of Improvement in Pain Intensity
14.3 Effects on DrivingDriving performance was assessed in a three way crossover study in healthy volunteers (mean age 36 years). Subjects were dosed at approximately 5 pm with HORIZANT 600 mg (for five days), diphenhydramine 50 mg (1 dose), and placebo (for five days). After the last dose, driving was eva luated on a computer-based simulation for 1 hour in the evening approximately 2 to 4 hours after dosing (7 to 9 pm), in the morning after dosing (7 to 9 am), and at midday the day after dosing (11 am to 1 pm). The primary endpoint of the study was lane position variability. There was no difference in change from baseline in lane position variability for HORIZANT compared to placebo at any of the simulated driving timepoints. Secondary measures included speed variability and the occurrence of simulated crashes. Subjects in this study experienced simulated crashes as described in Table 7. At the times that simulated crashes occurred, there was an increase in average speed variability in the HORIZANT and diphenhydramine treated groups that was most notable in patients who experienced simulated crashes, but no increases in lane position variability. Later time points post-dosing or the effects of driving after more than five days of dosing with HORIZANT were not eva luated.
Table 7. Simulated Crashes at eva luated Timepoints (Secondary Measure) Simulated Driving
Timepoint and Hours
Post Dose
Baseline
N = 36
n (%) Placebo
N = 36
n (%) HORIZANT
600 mg
N = 35
n (%) Diphenhydramine
50 mg
N = 36
n (%)
Day 5
Evening (7 to 9 pm)
2 to 4 hours post dose 0 (0) 0 (0) 0 (0) 3 (9)
Day 6
Morning (7 to 9 am)
14 to 16 hours post dose 2 (6) 1 (3) 1 (3) 0 (0)
Day 6
Midday (11 am to 1 pm)
18 to 20 hours post dose 1 (3) 0 (0) 3 (9) 3 (8)
The results of a separate 2-week driving simulation study in patients (mean age 47 years) with moderate-to-severe primary RLS showed that once daily doses of 1,200 mg and 1,800 mg of HORIZANT significantly impaired simulated driving performance based on lane position variability. An increased number of simulated crashes were reported in patients tested near Tmax after receiving 1,200 mg or 1,800 mg of HORIZANT compared to patients treated with diphenhydramine 50 mg. In addition, patients receiving 1,200 mg of HORIZANT experienced an increased number of simulated crashes at 14 to 16 hours after dosing compared with placebo, diphenhydramine, and 1,800 mg of HORIZANT.
The design limitations of these two studies do not permit inference regarding dose response relationship or the duration of the effect HORIZANT has on driving in patients with RLS.
The results of a separate driving simulation study comparing untreated RLS patients and healthy subjects showed no difference in lane position variability but an increase in speed variability associated with a greater number of simulated crashes in RLS patients relative to healthy subjects, which may indica |
