Xcopri Titration Pack (Page 3 of 9)

6 ADVERSE REACTIONS

The following serious adverse reactions are described in more detail in the Warnings and Precautions section of the labeling:

• Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS)/Multiorgan Hypersensitivity [see Warnings and Precautions (5.1)]
• QT Shortening [see Warnings and Precautions (5.2)]
• Suicidal Behavior and Ideation [see Warnings and Precautions (5.3)]
• Neurological Adverse Reactions [see Warnings and Precautions (5.4)]
• Withdrawal of Antiepileptic Drugs [see Warnings and Precautions (5.5)]

6.1 Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions and for varying durations, adverse reaction frequencies observed in the clinical trials of a drug cannot be directly compared with frequencies in the clinical trials of another drug and may not reflect the frequencies observed in practice.

In all controlled and uncontrolled trials performed in adult partial-onset seizure patients, XCOPRI was administered as adjunctive therapy to 1944 patients. Of these patients, 1575 were treated for at least 6 months, 710 for at least 12 months, 349 for at least 24 months, and 320 for at least 36 months. A total of 658 patients (442 patients treated with XCOPRI and 216 patients treated with placebo) constituted the safety population in the pooled analysis of placebo-controlled studies in patients with partial-onset seizures (Studies 1 and 2) [see Clinical Studies (14)]. The adverse reactions presented in Table 4 are based on this safety population; the median length of treatment in these studies was 18 weeks. Of the patients in those studies, approximately 49% were male, 76% were Caucasian, and the mean age was 39 years.

In Study 1 and Study 2, adverse events occurred in 77% of patients treated with XCOPRI and 68% treated with placebo. Table 4 gives the incidence of adverse reactions that occurred in subjects with partial-onset seizures in any XCOPRI treatment group and for which the incidence was greater than placebo during the controlled clinical trials. The most common adverse reactions that occurred in XCOPRI-treated patients (incidence at least 10% and greater than placebo) were somnolence, dizziness, fatigue, diplopia, and headache.

The discontinuation rates because of adverse events were 11%, 9%, and 21% for patients randomized to receive XCOPRI at doses of 100 mg/day, 200 mg/day, and 400 mg/day, respectively, compared to 4% in patients randomized to receive placebo. The adverse reactions most commonly (1% or greater in any XCOPRI treatment group, and greater than placebo) leading to discontinuation, in descending order of frequency, were ataxia, dizziness, somnolence, diplopia, nystagmus, and vertigo.

Table 4: Adverse Reactions in Pooled Placebo-Controlled Adjunctive Therapy Studies in Patients with Partial-Onset Seizures with XCOPRI Frequency in Any Treatment Arm Greater Than 1% Over Placebo

* Reported as an adverse reaction; see Laboratory Abnormalities for ALT changes from collected laboratory values
Adverse Reaction	XCOPRI			Placebo
	100mg	200mg	400mg
	n = 108%	n= 223%	n=111%	n=216%
Cardiac Disorders
Palpitations	0	0	2	0
Ear and Labyrinth Disorders
Vertigo	1	1	6	1
Eye Disorders
Diplopia	6	7	15	2
Vision Blurred	2	2	4	0
Gastrointestinal Disorders
Nausea	6	6	9	3
Constipation	2	4	8	0
Diarrhea	1	3	5	0
Vomiting	2	4	5	0
Dry Mouth	1	1	3	0
Abdominal Pain	2	2	1	0
Dyspepsia	2	2	0	0
Infections and Infestations
Nasopharyngitis	2	4	5	3
Pharyngitis	1	2	0	0
Urinary Tract Infection	2	5	0	2
Injury, Poisoning and Procedural Complications
Head Injury	1	0	2	0
Investigations
Alanine Aminotransferase Increased*	1	1	4	0
Aspartate Aminotransferase Increased	1	1	3	0
Weight Decreased	2	0	1	0
Metabolism and Nutrition Disorders
Decreased Appetite	3	1	5	1
Musculoskeletal and Connective Tissue Disorders
Back Pain	4	2	5	3
Musculoskeletal Chest Pain	2	1	0	0
Nervous System Disorders
Somnolence	19	22	37	11
Dizziness	18	22	33	15
Fatigue	12	14	24	7
Headache	10	12	10	9
Balance Disorder	3	5	9	1
Gait Disturbance	1	3	8	1
Dysarthria	2	1	7	0
Nystagmus	3	7	6	0
Ataxia	2	3	6	2
Aphasia	2	1	4	0
Asthenia	0	1	3	1
Dysgeusia	2	0	2	0
Memory Impairment	2	1	2	0
Migraine	0	0	2	0
Sedation	1	1	2	0
Tremor	0	3	1	1
Psychiatric Disorders
Confusional State	2	2	3	0
Euphoric Mood	0	0	2	0
Irritability	1	0	2	0
Suicidal Ideation	2	1	0	0
Renal and Urinary Disorders
Pollakiuria	0	1	0	0
Reproductive System and Breast Disorders
Dysmenorrhea	1	2	1	0
Respiratory, Thoracic and Mediastinal Disorders
Hiccups	0	1	1	0
Dyspnea	0	3	0	0
Skin and Subcutaneous Tissue Disorders
Pruritus	2	1	0	0
Rash Papular	2	0	0	0

Laboratory Abnormalities

Hepatic Transaminases

In Study 2, there was a post-baseline elevation of alanine aminotransferase (ALT) to greater than 3 times the upper limit of normal (ULN) in 1 (0.9%) patient treated with 100 mg XCOPRI, 2 (1.8%) patients treated with 200 mg, and 3 (2.7%) patients treated with 400 mg, compared to no patients who took placebo. The maximum ALT elevation was 7.6 times ULN in patients treated with 400 mg XCOPRI.

Potassium

In clinical studies, there was a post-baseline elevation of potassium values greater than 5 meq/L (upper reference range) in patients treated with XCOPRI. In Study 1, there were 17 (17%) patients treated with XCOPRI 200 mg compared to 8 (7%) patients who took placebo with normal baseline potassium values who had at least one post-baseline maximum value greater than 5 meq/L. In Study 2, there was a dose-related distribution where at least one post-baseline potassium value was greater than 5 meq/L, occurring in 8.3%, 9.1%, and 10.8% of the patients treated with XCOPRI 100 mg, 200 mg, and 400 mg, respectively, compared to 5.6% of patients who took placebo. Two patients had a maximum potassium value of 5.9 meq/L.

Other Adverse Reactions

Gastrointestinal disorders: There was an incidence of appendicitis in the overall clinical trial safety population of 2.9 cases of appendicitis/1000 patient-years of exposure that is in excess of the expected background rate in the general population.

Adverse Reactions Based on Gender

No significant gender differences were noted in the incidence of adverse reactions.