6 ADVERSE REACTIONS

The following clinically significant adverse reactions are described in more detail in the Warnings and Precautions section of the label:

Effects on Driving [see Warnings and Precautions (5.1)]
Somnolence/Sedation and Dizziness [see Warnings and Precautions (5.2)]
Suicidal Behavior and Ideation [see Warnings and Precautions (5.4)]
Drug Reaction With Eosinophilia and Systemic Symptoms (DRESS)/Multiorgan Hypersensitivity[see Warnings and Precautions (5.5)]
Respiratory Depression [see Warnings and Precautions (5.5)]

6.1 Clinical Trials Experience

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

In all controlled and uncontrolled trials across various patient populations, more than 2,300 patients have received HORIZANT orally in daily doses ranging from 600 to 3,600 mg.

Restless Legs Syndrome

The exposure to HORIZANT in 1,201 patients with RLS included 613 exposed for at least 6 months and 371 exposed for at least 1 year. HORIZANT in the treatment of RLS was studied primarily in placebo-controlled trials (n = 642), and in long- term follow-up studies. The population with RLS ranged from 18 to 82 years of age, with 60% being female and 95% being Caucasian.

The safety of HORIZANT in doses ranging from 600 to 2,400 mg has been evaluated in 515 patients with RLS in 3 double-blind, placebo-controlled, 12-week clinical trials. The 600-mg dose was studied in 2 of the 3 studies. Eleven out of 163 (7%) patients treated with 600 mg of HORIZANT discontinued treatment due to adverse reactions compared with 10 of the 245 (4%) patients who received placebo.

The most commonly observed adverse reactions (≥5% and at least 2 times the rate of placebo) in these trials for the 600-mg dose of HORIZANT were somnolence/sedation and dizziness (see Table 4). Table 4 lists treatment-emergent adverse reactions that occurred in ≥2% of patients with RLS treated with HORIZANT and numerically greater than placebo.

Table 4. Incidence of Adverse Reactions in 12-Week RLS Studies Reported in ≥2% of Patients Treated With 600 or 1,200 mg of HORIZANT and Numerically Greater Than Placebo
Body System/Adverse Reaction	Placebo* (N = 245) %	HORIZANT 600 mg/day† (N = 163) %	HORIZANT 1,200 mg/day‡ (N = 269) %
* Placebo was a treatment arm in each of the 3 double-blind, placebo-controlled, 12-week clinical trials. † The 600-mg dose of HORIZANT was a treatment arm in 2 of the 3 double-blind, placebo- controlled, 12-week clinical trials. ‡ The 1,200-mg dose of HORIZANT was a treatment arm in each of the 3 double-blind, placebo-controlled, 12-week clinical trials.
Nervous system disorders
Somnolence/sedation	6	20	27
Dizziness	4	13	22
Headache	11	12	15
Gastrointestinal disorders
Nausea	5	6	7
Dry mouth	2	3	4
Flatulence	<1	3	2
General disorders and administration site conditions
Fatigue	4	6	7
Irritability	1	4	4
Feeling drunk	0	1	3
Feeling abnormal	<1	<1	3
Peripheral edema	1	<1	3
Metabolism and nutritional disorders
Weight increased	2	2	3
Increased appetite	<1	2	2
Ear and labyrinth disorders
Vertigo	0	1	3
Psychiatric disorders
Depression	<1	<1	3
Libido decreased	<1	<1	2

Adverse reactions reported in these three 12-week studies in <2% of patients treated with 600 mg of HORIZANT and numerically greater than placebo were balance disorder, blurred vision, disorientation, feeling drunk, lethargy, and vertigo.

The following adverse reactions were dose-related: somnolence/sedation, dizziness, feeling drunk, libido decreased, depression, headache, peripheral edema, and vertigo.

Postherpetic Neuralgia

The exposure to HORIZANT in 417 patients with PHN included 207 patients exposed for at least 3 months. Overall, the mean age of patients in the PHN studies ranged from 61 to 64 years of age across dose groups; the majority of patients were male (45% to 61%) and Caucasian (80% to 98%).

The safety of HORIZANT in doses ranging from 1,200 to 3,600 mg has been evaluated in 417 patients with PHN in 3 clinical studies. The principal efficacy study evaluating the efficacy and safety of HORIZANT in the management of PHN was a 12-week, double-blind, multicenter study comparing 1,200 mg/day, 2,400 mg/day and 3,600 mg/day to placebo. Six out of 107 (6%) patients treated with 1,200 mg of HORIZANT discontinued treatment due to adverse events compared with 12 of the 95 (13%) patients who received placebo.

The most commonly observed adverse reactions (≥10% and greater than placebo) in this trial for the 1,200 mg dose of HORIZANT were dizziness, somnolence, and headache (see Table 5). Table 5 lists treatment-emergent adverse reactions that occurred in ≥2% of patients with PHN treated with HORIZANT 1,200 mg/day and numerically greater than placebo.

Table 5. Incidence of Adverse Reactions (in At Least 2% of Patients Treated With 1,200 mg/day of HORIZANT and Numerically Greater Than the Placebo Rate) Reported in All Patients in the 12-Week PHN Study
Body System/Adverse Reaction	Placebo (N = 95) %	HORIZANT 1,200 mg/day (N = 107) %	HORIZANT 2,400 mg/day (N = 82) %	HORIZANT 3,600 mg/day (N = 87) %
Nervous System
Dizziness	15	17	26	30
Somnolence	8	10	11	14
Headache	9	10	10	7
Gastrointestinal disorders
Nausea	5	8	4	9
General disorders and administration site conditions
Fatigue/Asthenia	1	6	4	10
Peripheral edema	0	6	7	6
Psychiatric disorders
Insomnia	2	3	5	7
Metabolism and nutritional disorders
Weight increased	1	3	5	5
Eye disorders
Blurred vision	0	2	5	2

The following adverse reactions were also reported as ≥2% at 2,400 mg/day and/or 3,600 mg/day and appeared to be dose-related but were <2% at 1,200 mg/day: balance disorder, confusional state, depression, dry mouth, flatulence, increased appetite, irritability, and vertigo. Dizziness, somnolence, fatigue, and insomnia appeared to show a dose relationship.

6.2 Postmarketing Experience

The following adverse reactions have been reported in patients receiving gabapentin and have been identified during postapproval use of HORIZANT. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure: breast enlargement, gynecomastia, elevated creatine kinase, bullous pemphigoid.

There are postmarketing reports of life-threatening or fatal respiratory depression in patients taking gabapentin with opioids or other CNS depressants, or in the setting of underlying respiratory impairment [see Warnings and Precautions (5.5)].