Xcopri Titration Pack (Page 6 of 9)

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

Carcinogenesis

Oral administration of cenobamate (0, 5, 15, or 35 mg/kg/day) to Tg.rasH2 mice for up to 26 weeks did not result in an increase in tumors. Oral administration of cenobamate (0, 4, 8, or 20 mg/kg/day) to male and female rats for up to 87 or 90 weeks, respectively, did not result in an increase in tumors. Plasma exposure at the highest dose tested in rats was less than that in humans at the maximum recommended human dose (MRHD) of 400 mg/day.

Mutagenesis

Cenobamate was negative for genotoxicity in in vitro (Ames, mouse lymphoma) and in vivo (rat bone marrow micronucleus) assays.

Impairment of Fertility

Oral administration of cenobamate (0, 11, 22, or 44 mg/kg/day) to male and female rats prior to and throughout mating and continuing in females to Gestation Day 6 did not produce adverse effects on fertility, general reproductive performance, or early embryonic development. Plasma exposure (AUC) at the highest dose tested in rats was less than that in humans at the MRHD.

14 CLINICAL STUDIES

The efficacy of XCOPRI for the treatment of partial-onset seizures was established in two multicenter, randomized, double-blind, placebo-controlled studies in adult patients (Study 1 and Study 2). Patients enrolled in the studies had partial-onset seizures with or without secondary generalization and were not adequately controlled with 1 to 3 concomitant AEDs. During an 8-week baseline period, patients were required to have at least 3 or 4 partial-onset seizures per 28 days on average with no seizure-free period exceeding 3 to 4 weeks. In these studies, patients had a mean duration of epilepsy of approximately 24 years and median baseline seizure frequency of 8.5 seizures per 28 days. More than 80% of patients were taking 2 or more concomitant AEDs.

Study 1 (NCT01397968) compared doses of XCOPRI 200 mg/day with placebo. Study 2 (NCT01866111) compared doses of XCOPRI 100 mg/day, 200 mg/day, and 400 mg/day with placebo. Both studies had an 8-week baseline period to establish a baseline seizure frequency, following which patients were randomized to a treatment arm. Patients entered a treatment period consisting of an initial titration phase (6 weeks), and a subsequent maintenance phase (6 weeks for Study 1 and 12 weeks for Study 2). In Study 1, patients were started on a daily dose of 50 mg (a higher starting dose than currently recommended) and subsequently increased by 50 mg/day every two weeks, until the final daily target dose of 200 mg/day was achieved. In Study 2, patients were started on a daily dose of 50 mg (a higher starting dose than currently recommended) and subsequently increased by 50 mg/day every week (a faster titration than currently recommended) until 100 mg/day or 200 mg/day was reached and then increased by 100 mg/day every week in patients randomized to 400 mg/day [see Dosage and Administration (2.2), Warnings and Precautions (5.1), and Adverse Reactions (6.1)].

The primary efficacy outcome in Study 1 and Study 2 was the percent change from baseline in seizure frequency per 28 days in the treatment period. Table 6 summarizes the results of the primary endpoint for XCOPRI in each study.

Table 6: Percent Change from Baseline in Seizure Frequency per 28 Days in the Treatment Period (Study 1 and Study 2)

* A negative percent change from baseline in seizure frequency indicates reduction in seizure frequency from baseline. ** Statistically significant compared to placebo
	N	Median Percent Change from Baseline in Seizure Frequency per 28 Days (%)*	p-value(Compared to Placebo)
Study 1
Placebo	108	-21.5	—
XCOPRI 200 mg/day	113	-55.6	<0.0001**
Study 2
Placebo	106	-24.3	—
XCOPRI 100 mg/day	108	-36.3	0.006**
XCOPRI 200 mg/day	109	-55.2	<0.001**
XCOPRI 400 mg/day	111	-55.3	<0.001**

Figure 1 and Figure 2 show the proportion of patients with different percent reductions during the maintenance phase over baseline in Study 1 and Study 2, respectively. Patients in whom the seizure frequency increased are shown in the left-most column as “worse.” Patients in whom the seizure frequency decreased are shown in the remaining four categories.

Figure 1: Proportion of Patients Exhibiting Different Percent Reductions During the Maintenance Phase over Baseline in Study 1

Figure 2: Proportion of Patients Exhibiting Different Percent Reductions During the Maintenance Phase over Baseline in Study 2

In Study 2, 4 of 102 (4%) patients in the XCOPRI 100 mg/day group, 11 of 98 (11%) patients in the XCOPRI 200 mg/day group, and 20 of 95 (21%) patients in the XCOPRI 400 mg/day group and 1 of 102 (1%) of patients in the placebo group reported no partial seizures during the maintenance phase.

16 HOW SUPPLIED/STORAGE AND HANDLING

16.1 How Supplied

XCOPRI tablets are supplied in the following configurations:

Bottles; 30 count

Strength	NDC Number	Tablet Description (Color, Shape, Markings)
50 mg	71699-050-30	Film coated round yellow tablets with SK on one side and 50 on the other side
100 mg	71699-100-30	Film coated round brown tablets with SK on one side and 100 on the other side
150 mg	71699-150-30	Film coated round light orange tablets with SK on one side and 150 on the other side
200 mg	71699-200-30	Film coated modified oval light orange tablets with SK on one side and 200 on the other side

Titration Blister Packs; 28-Day

Daily Dose	NDC Number	Supplied As [strength(quantity)]	Tablet Description (Color, Shape, Markings)
12.5 mg per day for 14 days, then 25 mg per day for 14 days	71699-201-28	12.5 mg (14-count)	Uncoated round white to off-white tablets with SK on one side and 12 on the other side
		25 mg (14-count)	Film coated round brown tablets with SK on one side and 25 on the other side
50 mg per day for 14 days, then 100 mg per day for 14 days	71699-202-28	50 mg (14-count)	Film coated round yellow tablets with SK on one side and 50 on the other side
		100 mg (14-count)	Film coated round brown tablets with SK on one side and 100 on the other side
150 mg per day for 14 days, then 200 mg per day for 14 days	71699-203-28	150 mg (14-count)	Film coated round light orange tablets with SK on one side and 150 on the other side
		200 mg (14-count)	Film coated modified oval light orange tablets with SK on one side and 200 on the other side

Maintenance Blister Packs; 28-Day

Daily Dose	NDC Number	Supplied As [strength(quantity)]	Tablet Description (Color, Shape, Markings)
250 mg per day	71699-104-56	100 mg (28-count)	Film coated round brown tablets with SK on one side and 100 on the other side
		150 mg (28-count)	Film coated round light orange tablets with SK on one side and 150 on the other side
350 mg per day	71699-103-56	150 mg (28-count)	Film coated round light orange tablets with SK on one side and 150 on the other side
		200 mg (28-count)	Film coated modified oval light orange tablets with SK on one side and 200 on the other side