Safety evaluation of perampanel as monotherapy or first adjunctive therapy in patients with epilepsy

Figures & data

Figure 1. Mechanism of action of perampanel.

AMPA, α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid

Table 1. Summary of study length, TEAEs, and most common TEAEs (occurring in ≥5% of patients) across studies that included patients treated with perampanel monotherapy or early adjunctive therapy (Safety Analysis Sets, where specified).

	Monotherapy						Early adjunctive therapy
	Study 342 (FREEDOM; prospective)^a,b [12]
	Perampanel 4 mg/day (N = 89)	Perampanel 4 and/or 8 mg/day (N = 89)	Study 504 (retrospective)^a,c,d [15] (N = 60)	Study 506 (PROVE; retrospective)^a,c,d [16,17] (n = 47)	Toledano Delgado retrospective study^c,d [18] (N = 98)	Chinvarun retrospective study^d [19] (N = 39)	Study 412 (prospective)^b,e [20] (N = 102)	PERADON (prospective)^f [22] (N = 113)	Santamarina retrospective study^d,e [23] (N = 149)	Rea retrospective study^d,e [24] (N = 27)	COM-PER study (retrospective)^d,e [25] (n = 21)
Study length	32 weeks^g		Up to 38 months^h	2 years	>1 year^i	1 year	36 weeks	1 year	1 year	6 months	1 year
TEAEs, n (%)	57 (64.0)	67 (75.3)	12 (20.0)	17 (36.2)	45 (45.9)	16 (41.0)	77 (75.5)	NR	72 (48.3)	18 (66.7)	8 (38.1)
Treatment-related TEAEs, n (%)	38 (42.7)	47 (52.8)	NR	NR	NR	NR	NR	34 (30.1)	NR	NR	NR
Serious TEAEs, n (%)	9 (10.1)	9 (10.1)	0 (0.0)	2 (4.3)	NR	0 (0.0)	8 (7.8)	0 (0.0)^j	NR	NR	NR
Most common TEAEs reported in ≥5% patients in any group, n (%)
Dizziness	20 (22.5)	28 (31.5)	3 (5.0)	6 (12.8)	8 (8.1)	11 (28.2)	51 (50.0)	8 (7.1)^j	23 (15.4)	0 (0.0)	5 (23.8)
Nasopharyngitis	11 (12.4)	13 (14.6)	NR	0 (0.0)	NR	0 (0.0)	1 (1.0)	0 (0.0)^j	NR	0 (0.0)	NR
Somnolence	11 (12.4)	12 (13.5)	1 (1.7)	2 (4.3)	10 (10.2)	4 (10.3)	10 (9.8)	2 (1.8)^j	21 (14.1)	0 (0.0)	0 (0.0)
Headache	10 (11.2)	10 (11.2)	1 (1.7)	1 (2.1)	NR	0 (0.0)	9 (8.8)	0 (0.0)^j	6 (4.0)	0 (0.0)	NR
Epilepsy	5 (5.6)	5 (5.6)	NR	0 (0.0)	NR	0 (0.0)	NR^k	0 (0.0)^j	NR	0 (0.0)	NR
Irritability	2 (2.2)	3 (3.4)	2 (3.3)	0 (0.0)	17 (17.3)	0 (0.0)	2 (2.0)	9 (8.0)^j	21 (14.1)	4 (14.8)	3 (14.3)
Gait disturbance	NR	NR	NR	3 (6.4)	NR	0 (0.0)	1 (1.0)	0 (0.0)^j	NR	0 (0.0)	NR
Depression	NR	NR	NR	1 (2.1)	10 (10.2)	1 (2.6)	1 (1.0)	1 (0.9)^j	NR	0 (0.0)	NR
Anxiety	0 (0.0)	2 (2.2)	NR	NR	1 (1.0)	0 (0.0)	0 (0.0)	2 (1.8)^j	10 (6.7)	2 (7.4)	NR
Ataxia	NR	NR	NR	NR	NR	6 (15.4)	0 (0.0)	0 (0.0)^j	4 (2.7)	4 (14.8)	NR
Fatigue	NR	NR	NR	NR	NR	0 (0.0)	2 (2.0)	NR^j,l	9 (6.0)	0 (0.0)	NR
Vertigo	NR	NR	NR	NR	NR	0 (0.0)	0 (0.0)	0 (0.0)^j	NR	5 (18.5)	NR
Aggression	0 (0.0)	0 (0.0)	NR	NR	NR	0 (0.0)	0 (0.0)	4 (3.5)^j	NR	4 (14.8)	NR
Suicidal thoughts	NR	NR	NR	NR	NR	0 (0.0)	1 (1.0)	0 (0.0)^j	NR	2 (7.4)	NR

Note that there is a possibility that patients may have been included in more than one of the studies presented here

^aA patient with ≥2 TEAEs is counted only once for that event; ^bIncludes the core study data only; ^cIncludes patients receiving primary or secondary monotherapy; ^dNote that not all TEAEs that occurred during perampanel treatment may have been recorded in retrospective studies due to the nature of these studies; ^eIncludes patients receiving perampanel as first adjunctive therapy; ^fIncludes patients receiving perampanel as first or second adjunctive therapy; ^gFor patients who were up-titrated to 8 mg/day, study length was 30 weeks plus the time in which they received 4 mg/day; ^hMedian duration of perampanel monotherapy of 6.1 months at cutoff; ⁱMedian duration of exposure to perampanel monotherapy of 14 months; ^jTreatment-related TEAEs; ^kSeizure TEAEs were reported in 3.9% of patients; ^lTiredness was reported in 0.9% of patients

NR, not reported; TEAE, treatment-emergent adverse event

Table 2. Summary of the most common TEAEs (in ≥10% of patients for any ASM and at a higher frequency in the treatment group vs placebo) reported in clinical trials of adjunctive oral^a PER, BRV, CNB, ESL, LCM, LMT, and LEV in adults^b with FOS,^c as described in the US prescribing information for each ASM.

Most common TEAEs, %	PER [5]		BRV^d [47]		CNB [48]		ESL [49]		LCM [50]		LMT [51]		LEV [52]
	PER 4, 8, or 12 mg/day (n = 858)	Placebo (n = 442)	BRV 50, 100, or 200 mg/day (n = 803)	Placebo (n = 459)	CNB 100, 200, or 400 mg/day (n = 442)	Placebo (n = 216)	ESL 800 or 1200 mg/day (n = 825)	Placebo (n = 426)	LCM 200, 400, or 600 mg/day^e (n = 944)	Placebo (n = 364)	LMT 150–500 mg/day (n = 711)	Placebo (n = 419)	LEV 1000, 2000, or 3000 mg/day (n = 769)	Placebo (n = 439)
Dizziness	16–43	9	12	7	18–33	15	20–28	9	31	8	38	13	9	4
Somnolence	9–18	7	16^f	8^f	19–37	11	11–18	8	7	5	14	7	15	8
Headache	11–13	11	–	–	10–12	9	13–15	9	13	9	29	19	14	13
Irritability	4–12	3	3	1	0–2	0	–	–	–	–	3	2	–	–
Fatigue	8–12	5	9	4	12–24	7	4–7	4	9	6	–	–	–	–
Falls	2–10	3	–	–	–	–	1–3	1	–	–	–	–	–	–
Ataxia	1–8	0	≤3^g	≤1^g	2–6	2	4–6	2	8	2	22	6	1	3
Nausea	3–8	5	≤5^h	≤3^h	6–9	3	10–16	5	11	4	19	10	–	–
Blurred vision	1–4	1	–	–	2–4	0	5–6	1	8	3	16	5	–	–
Infection	≥3–4^i	≥3^i	–	–	≥2–5^j	≥0–3^j	≥2^k	≥1^k	–	–	–	–	13	8
Vomiting	2–4	3	≤5^h	≤3^h	2–5	0	6–10	3	9	3	9	4	–	–
Diplopia	1–3	1	–	–	6–15	2	9–11	2	11	2	28	7	2	1
Asthenia	1–2	1	–	–	0–3	1	2–3	2	2	1	–	–	15	9
Rhinitis	–	–	–	–	–	–	–	–	–	–	14	9	4	3
Pharyngitis	–	–	–	–	0–2	0	–	–	–	–	10	9	6	4
Rash	–	–	–	–	≥0–2^l	≥0^l	1–3	1	–	–	10	5	–	–

^aOral administration not specified for BRV in the prescribing information; ^bIncluded adults and adolescents ≥12 years of age for trials of perampanel; ^cPatients were described as having epilepsy in trials of LMT; ^dOnly TEAEs with a frequency that was >2% higher with BRV than with placebo were listed; ^e600 mg/day is 1.5-times greater than the maximum recommended dose; ^fReported as somnolence and sedation; ^gReported as cerebellar coordination and balance disturbances, which include ataxia, balance disorder, coordination abnormal, and nystagmus; ^hReported as nausea or vomiting; ⁱReported as upper respiratory tract infection; ^jReported as nasopharyngitis, pharyngitis, or urinary tract infection; ^kReported as urinary tract infection; ^lReported as rash papular

ASM, anti-seizure medication; BRV, brivaracetam; CNB, cenobamate; ESL, eslicarbazepine acetate; FOS, focal-onset seizures; LCM, lacosamide; LMT, lamotrigine; LEV, levetiracetam; PER, perampanel; TEAE, treatment-emergent adverse event

Table

Box 1. Drug summary
Drug name	Perampanel
Development status	Approved by the US Food and Drug Administration and European Medicines Agency for focal-onset seizures and generalized tonic-clonic seizures [5,6]
Indications	In the US, perampanel is approved for the treatment of focal-onset seizures (adjunctive and monotherapy), with or without focal to bilateral tonic-clonic seizures, in patients with epilepsy aged ≥4 years, and as adjunctive treatment of generalized tonic-clonic seizures in patients with epilepsy aged ≥12 years [5] In the European Union, perampanel is approved as adjunctive treatment of focal-onset seizures, with or without focal to bilateral tonic-clonic seizures, in patients aged ≥4 years, and as adjunctive treatment of generalized tonic-clonic seizures in patients aged ≥7 years with idiopathic generalized epilepsy [6]
Mechanism of action	Selective, noncompetitive α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor antagonist [5,7]
Route of administration	Oral [5,6]
Chemical structure	[5]
Pivotal trials	Three randomized, double-blind, placebo-controlled Phase III trials in patients with treatment-resistant focal-onset seizures (Studies 304 [NCT00699972], 305 [NCT00699582], and 306 [NCT00700310]) and one randomized, double-blind, placebo-controlled Phase III trial in patients with treatment-resistant generalized tonic-clonic seizures (Study 332 [NCT01393743]) [8–11]

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