6 ADVERSE REACTIONS

The following adverse reactions are discussed in greater detail in other sections of the label:

Blood Pressure and Heart Rate Increases [see Warnings and Precautions (5.1)]
Psychiatric Symptoms [see Warnings and Precautions (5.2)]

6.1 Clinical Trials Experience

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

The safety of SUNOSI has been evaluated in 930 patients (ages 18 to 75 years) with narcolepsy or OSA. Among these patients, 396 were treated with SUNOSI in the 12-week placebo-controlled trials at doses of 37.5 mg (OSA only), 75 mg, and 150 mg once daily. Information provided below is based on the pooled 12-week placebo-controlled studies in patients with narcolepsy or OSA.

Most Common Adverse Reactions

The most common adverse reactions (incidence ≥ 5% and greater than placebo) reported more frequently with the use of SUNOSI than placebo in either the narcolepsy or OSA populations were headache, nausea, decreased appetite, anxiety, and insomnia.

Table 1 presents the adverse reactions that occurred at a rate of ≥ 2% and more frequently in SUNOSI-treated patients than in placebo-treated patients in the narcolepsy population.

Table 1: Adverse Reactions ≥ 2% in Patients Treated with SUNOSI and Greater than Placebo in Pooled 12-Week Placebo-Controlled Clinical Trials in Narcolepsy (75 mg and 150 mg)
* “Insomnia” includes insomnia, initial insomnia, middle insomnia, and terminal insomnia. “Anxiety” includes anxiety, nervousness, and panic attack. “Headache” includes headache, tension headache, and head discomfort. “Nausea” includes nausea and vomiting.
	Narcolepsy
System Organ Class	Placebo N = 108 (%)	SUNOSI N = 161 (%)
Metabolism and Nutrition Disorders Decreased appetite	1	9
Psychiatric Disorders Insomnia* Anxiety*	4 1	5 6
Nervous System Disorders Headache*	7	16
Cardiac Disorders Palpitations	1	2
Gastrointestinal Disorders Nausea* Dry mouth Constipation	4 2 1	7 4 3

Table 2 presents the adverse reactions that occurred at a rate of ≥ 2% and more frequently in SUNOSI-treated patients than in placebo-treated patients in the OSA population.

Table 2: Adverse Reactions ≥ 2% in Patients Treated with SUNOSI and Greater than Placebo in Pooled 12-Week Placebo-Controlled Clinical Trials in OSA (37.5 mg, 75 mg, and 150 mg)
* “Anxiety” includes anxiety, nervousness, and panic attack. “Nausea” includes nausea and vomiting. “Abdominal pain” includes abdominal pain, abdominal pain upper, and abdominal discomfort.
	OSA
System Organ Class	Placebo N = 118 (%)	SUNOSI N = 235 (%)
Metabolism and Nutrition Disorders Decreased appetite	1	6
Psychiatric Disorders Anxiety* Irritability	1 0	4 3
Nervous System Disorders Dizziness	1	2
Cardiac Disorders Palpitations	0	3
Gastrointestinal Disorders Nausea* Diarrhea Abdominal pain* Dry mouth	6 1 2 2	8 4 3 3
General Disorders and Administration Site Conditions Feeling jittery Chest discomfort	0 0	3 2
Skin and Subcutaneous Tissue Disorders Hyperhidrosis	0	2

Other Adverse Reactions Observed During the Premarketing Evaluation of SUNOSI

Other adverse reactions of < 2% incidence but greater than placebo are shown below. The following list does not include adverse reactions: 1) already listed in previous tables or elsewhere in the labeling, 2) for which a drug cause was remote, 3) which were so general as to be uninformative, or 4) which were not considered to have clinically significant implications.

Narcolepsy population:

Psychiatric disorders: agitation, bruxism, irritability

Respiratory, thoracic and mediastinal disorders: cough

Skin and subcutaneous tissue disorders: hyperhidrosis

General disorders and administration site conditions: feeling jittery, thirst, chest discomfort, chest pain

Investigations: weight decreased

OSA population:

Psychiatric disorders: bruxism, restlessness

Nervous system disorders: disturbance in attention, tremor

Respiratory, thoracic and mediastinal disorders: cough, dyspnea

Gastrointestinal disorders: constipation, vomiting

Investigations: weight decreased

Dose-Dependent Adverse Reactions

In the 12-week placebo-controlled clinical trials that compared doses of 37.5 mg, 75 mg, and 150 mg daily of SUNOSI to placebo, the following adverse reactions were dose-related: headache, nausea, decreased appetite, anxiety, diarrhea, and dry mouth (Table 3).

Table 3: Dose-Dependent Adverse Reactions ≥ 2% in Patients Treated with SUNOSI and Greater than Placebo in Pooled 12-Week Placebo-Controlled Clinical Trials in Narcolepsy and OSA
* In OSA only. ** “Headache” includes headache, tension headache, and head discomfort. “Nausea” includes nausea and vomiting.
	Placebo N = 226 (%)	SUNOSI 37.5 mg N = 58* (%)	SUNOSI 75 mg N = 120 (%)	SUNOSI 150 mg N = 218 (%)
Headache**	8	7	9	13
Nausea**	5	7	5	9
Decreased appetite	1	2	7	8
Anxiety	1	2	3	7
Dry mouth	2	2	3	4
Diarrhea	2	2	4	5

Adverse Reactions Resulting in Discontinuation of Treatment

In the 12-week placebo-controlled clinical trials, 11 of the 396 patients (3%) who received SUNOSI discontinued because of an adverse reaction compared to 1 of the 226 patients (< 1%) who received placebo. The adverse reactions resulting in discontinuation that occurred in more than one SUNOSI-treated patient and at a higher rate than placebo were: anxiety (2/396; < 1%), palpitations (2/396; < 1%), and restlessness (2/396; < 1%).

Increases in Blood Pressure and Heart Rate

SUNOSI’s effects on blood pressure and heart rate are summarized below. Table 4 shows maximum mean changes in blood pressure and heart rate recorded at sessions where the Maintenance of Wakefulness Test (MWT) was administered [see Clinical Studies (14)]. Table 5 summarizes 24-hour ambulatory blood pressure monitoring (ABPM) and ambulatory heart rate monitoring performed in the outpatient setting.

Table 4: Maximal Mean Changes in Blood Pressure and Heart Rate Assessed at MWT Sessions from Baseline through Week 12: Mean (95% CI)*
SBP = systolic blood pressure; DBP = diastolic blood pressure; HR = heart rate * For study weeks 1, 4, and 12, SBP, DBP, and HR were assessed pre-dose and every 1-2 hours for 10 hours after test drug administration. For all time points at all visits, the mean change from baseline was calculated, by indication and dose, for all patients with a valid assessment. The table shows, by indication and dose, the mean changes from baseline for the week and time point with the maximal change in SBP, DBP, and HR. ** The maximum recommended daily dose is 150 mg. Dosages above 150 mg daily do not confer increased effectiveness sufficient to outweigh dose-related adverse reactions.
		Placebo	SUNOSI 37.5 mg	SUNOSI 75 mg	SUNOSI 150 mg	SUNOSI 300 mg**
Narcolepsy STUDY 1	n	52	-	51	49	53
	SBP	3.5 (0.7, 6.4)	-	3.1 (0.1, 6.0)	4.9 (1.7, 8.2)	6.8 (3.2, 10.3)
	n	23	-	47	49	53
	DBP	1.8 (-1.8, 5.5)	-	2.2 (0.2, 4.1)	4.2 (2.0, 6.5)	4.2 (1.5, 6.9)
	n	48	-	26	49	53
	HR	2.3 (-0.1, 4.7)	-	3.7 (0.4, 6.9)	4.9 (2.3, 7.6)	6.5 (3.9, 9.0)
OSA STUDY 2	n	35	17	54	103	35
	SBP	1.7 (-1.4, 4.9)	4.6 (-1.1, 10.2)	3.8 (1.2, 6.4)	2.4 (0.4, 4.4)	4.5 (1.1, 7.9)
	n	99	17	17	107	91
	DBP	1.4 (-0.1, 2.9)	1.9 (-2.3, 6.0)	3.2 (-0.9, 7.3)	1.8 (0.4, 3.2)	3.3 (1.8, 4.8)
	n	106	17	51	102	91
	HR	1.7 (0.1, 3.3)	1.9 (-1.9, 5.7)	3.3 (0.6, 6.0)	2.9 (1.4, 4.4)	4.5 (3.0, 6.0)

Table 5: Blood Pressure and Heart Rate by 24-hour Ambulatory Monitoring: Mean Change (95% CI) from Baseline at Week 8
SBP = systolic blood pressure; DBP = diastolic blood pressure; HR = heart rate * Number of patients who had at least 50% valid ABPM readings. ** The maximum recommended daily dose is 150 mg. Dosages above 150 mg daily do not confer increased effectiveness sufficient to outweigh dose-related adverse reactions.
		Placebo	SUNOSI 37.5 mg	SUNOSI 75 mg	SUNOSI 150 mg	SUNOSI 300 mg**
Narcolepsy STUDY 1	n*	46		44	44	40
	SBP	-0.4 (-3.1, 2.4)	-	1.6 (-0.4, 3.5)	-0.5 (-2.1, 1.1)	2.4 (0.5, 4.3)
	DBP	-0.2 (-1.9, 1.6)	-	1.0 (-0.4, 2.5)	0.8 (-0.4, 2.0)	3.0 (1.4, 4.5)
	HR	0.0 (-1.9, 2.0)	-	0.2 (-2.1, 2.4)	1.0 (-1.2, 3.2)	4.8 (2.3, 7.2)
OSA STUDY 2	n*	92	43	49	96	84
	SBP	-0.2 (-1.8, 1.4)	1.8 (-1.1, 4.6)	2.6 (0.02, 5.3)	-0.2 (-2.0, 1.6)	2.8 (-0.1, 5.8)
	DBP	0.2 (-0.9, 1.3)	1.4 (-0.4, 3.2)	1.5 (-0.04, 3.1)	-0.1 (-1.1, 1.0)	2.4 (0.5, 4.4)
	HR	-0.4 (-1.7, 0.9)	0.4 (-1.4, 2.2)	1.0 (-0.9, 2.81)	1.7 (0.5, 2.9)	1.6 (0.3, 2.9)

6.2 Postmarketing Experience

The following adverse reactions have been reported during post-approval use of SUNOSI. 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:

Immune system disorders: Hypersensitivity (rash erythematous, rash [unspecified], and urticaria).