Adzenys XR-ODT

WARNING: ABUSE, MISUSE AND ADDICTION ADZENYS XR-ODT has a high potential for abuse and misuse, which can lead to the development of a substance use disorder, including addiction. Misuse and abuse of CNS stimulants, including ADZENYS XR-ODT, can result in overdose and death [see Overdosage (10)] , and this risk is increased with higher doses or unapproved methods of administration, such as snorting or injection. Before prescribing ADZENYS XR-ODT, assess each patient’s risk for abuse, misuse, and addiction. Educate patients and their families about these risks, proper storage of the drug, and proper disposal of any unused drug. Throughout ADZENYS XR-ODT treatment, reassess each patient’s risk of abuse, misuse, and addiction and frequently monitor for signs and symptoms of abuse, misuse, and addiction [see Warnings and Precautions (5.1), Drug Abuse and Dependence (9.2)] . See full prescribing information for complete boxed warning. ADZENYS XR-ODT has a high potential for abuse and misuse, which can lead to the development of a substance use disorder, including addiction. Misuse and abuse of CNS stimulants, including ADZENYS XR-ODT, can result in overdose and death (5.1, 9.2, 10): Before prescribing ADZENYS XR-ODT, assess each patient's risk for abuse, misuse, and addiction. Educate patients and their families about these risks, proper storage of the drug, and proper disposal of any unused drug. Throughout treatment, reassess each patient's risk and frequently monitor for signs and symptoms of abuse, misuse, and addiction.

5. WARNINGS AND PRECAUTIONS Risks to Patients with Serious Cardiac Disease: Avoid use in patients with known structural cardiac abnormalities, cardiomyopathy, serious heart arrhythmia, coronary artery disease, or other serious cardiac disease. ( 5.2 ) Increased Blood Pressure and Heart Rate: Monitor blood pressure and pulse. ( 5.3 ) Psychiatric Adverse Reactions: Prior to initiating ADZENYS XR-ODT, screen patients for risk factors for developing a manic episode. If new psychotic or manic symptoms occur, consider discontinuing ADZENYS XR-ODT. ( 5.4 ) Long-Term Suppression of Growth in Pediactric Patients: Closely monitor growth (height and weight) in pediatric patients. Pediatric patients not growing or gaining height or weight as expected may need to have their treatment interrupted. ( 5.5 ) Peripheral Vasculopathy, including Raynaud's phenomenon: Careful observation for digital changes is necessary during ADZENYS XR-ODT treatment. Further clinical evaluation (e.g. rheumatology referral) may be appropriate for patients who develop signs or symptoms of peripheral vasculopathy. ( 5.6 ) Serotonin Syndrome: Increased risk when co-administered with serotonergic agents (e.g., SSRIs, SNRIs, triptans), but also during overdosage situations. If it occurs, discontinue ADZENYS XR-ODT and initiate supportive treatment. ( 5.7 , 17 ) Motor and Verbal Tics, and Worsening of Tourette’s Syndrome: Before initiating ADZENYS XR-ODT, assess the family history and clinically evaluate patients for tics or Tourette’s syndrome. Regularly monitor patients for the emergence or worsening of tics or Tourette’s syndrome. Discontinue treatment if clinically appropriate. ( 5.8 ) 5.1 Abuse, Misuse, and Addiction ADZENYS XR-ODT has a high potential for abuse and misuse. The use of ADZENYS XR-ODT exposes individuals to the risks of abuse and misuse, which can lead to the development of a substance use disorder, including addiction. ADZENYS XR-ODT can be diverted for nonmedical use into illicit channels or distribution [see Drug Abuse and Dependence (9.2)]. Misuse and abuse of CNS stimulants, including ADZENYS XR-ODT, can result in overdose and death [see Overdosage (10)], and this risk is increased with higher doses or unapproved methods of administration, such as snorting or injection. Before prescribing ADZENYS XR-ODT, assess each patient’s risk for abuse, misuse, and addiction. Educate patients and their families about these risks and proper disposal of any unused drug. Advise patients to store ADZENYS XR-ODT in a safe place, preferably locked, and instruct patients to not give ADZENYS XR-ODT to anyone else. Throughout ADZENYS XR-ODT treatment, reassess each patient’s risk of abuse, misuse, and addiction and frequently monitor for signs and symptoms of abuse, misuse, and addiction. 5.2 Risks to Patients with Serious Cardiac Disease Sudden death has been reported in patients with structural cardiac abnormalities or other serious cardiac disease who were treated with CNS stimulants at the recommended ADHD dosage. Avoid ADZENYS XR-ODT use in patients with known structural cardiac abnormalities, cardiomyopathy, serious cardiac arrhythmia, coronary artery disease, or other serious cardiac disease. 5.3 Increased Blood Pressure and Heart Rate CNS stimulants cause an increase in blood pressure (mean increase about 2 to 4 mm Hg) and heart rate (mean increase about 3 to 6 bpm). Some patients may have larger increases. Monitor all ADZENYS XR-ODT-treated patients for potential tachycardia and hypertension. 5.4 Psychiatric Adverse Reactions Exacerbation Pre-existing Psychosis CNS stimulants may exacerbate symptoms of behavior disturbance and thought disorder in patients with a pre-existing psychotic disorder. Induction of a Manic Episode in Patients with Bipolar Disorder CNS stimulants may induce a manic or mixed episode in patients. Prior to initiating ADZENYS XR-ODT treatment, screen patients for risk factors for developing a manic episode (e.g., comorbid or has a history of depressive symptoms or a family history of suicide, bipolar disorder, and depression). New Psychotic or Manic Symptoms CNS stimulants, at the recommended dosages, may cause psychotic or manic symptoms, e.g., hallucinations, delusional thinking, or mania in patients without prior history of psychotic illness or mania. In a pooled analysis of multiple short-term, placebo-controlled studies of CNS stimulants, psychotic or manic symptoms occurred in 0.1% of CNS stimulant-treated patients compared to 0% of placebo-treated patients. If such symptoms occur, conisder discontinuing ADZENYS XR-ODT. 5.5 Long-Term Suppression of Growth in Pediatric Patients ADZENYS XR-ODT is not approved for use and is not recommended in pediatric patients below 6 years of age [see Use in Specific Population (8.4)] . CNS stimulants have been associated with weight loss and slowing of growth rate in pediatric patients. Closely monitor growth (weight and height) in ADZENYS XR-ODT-treated pediatric patients treated with CNS stimulants. Pediatric patients not growing or gaining height or weight as expected may need to have their treatment interrupted. 5.6 Peripheral Vasculopathy, including Raynaud's Phenomenon CNS stimulants, including ADZENYS XR-ODT, used to treat ADHD are associated with peripheral vasculopathy, including Raynaud's phenomenon. Signs and symptoms are usually intermittent and mild; however, sequelae have included digital ulceration and/or soft tissue breakdown. Effects of peripheral vasculopathy, including Raynaud's phenomenon, were observed in post-marketing reports and at the therapeutic dosage of CNS stimulants in all age groups throughout the course of treatment. Signs and symptoms generally improved after dosage reduction or discontinuation of the CNS stimulants. Careful observation for digital changes is necessary during ADZENYS XR-ODT-treatment. Further clinical evaluation (e.g., rheumatology referral) may be appropriate for ADZENYS XRODT-treated patients who develop signs or symptoms of peripheral vasculopathy. 5.7 Serotonin Syndrome Serotonin syndrome, a potentially life-threatening reaction, may occur when amphetamines are used in combination with other drugs that affect the serotonergic neurotransmitter systems such as monoamine oxidase inhibitors (MAOIs), selective serotonin reuptake inhibitors (SSRIs), serotonin norepinephrine reuptake inhibitors (SNRIs), triptans, tricyclic antidepressants, fentanyl, lithium, tramadol, tryptophan, buspirone, and St. John's Wort [see Drug Interactions (7.1) ]. The co-administration with cytochrome P450 2D6 (CYP2D6) inhibitors may also increase the risk with increased exposure to ADZENYS XR-ODT. In these situations, consider an alternative non-serotonergic drug or an alternative drug that does not inhibit CYP2D6 [see Drug Interactions (7.1) ]. Serotonin syndrome symptoms may include mental status changes (e.g., agitation, hallucinations, delirium, and coma), autonomic instability (e.g., tachycardia, labile blood pressure, dizziness, diaphoresis, flushing, hyperthermia), neuromuscular symptoms (e.g., tremor, rigidity, myoclonus, hyperreflexia, incoordination), seizures, and/or gastrointestinal symptoms (e.g., nausea, vomiting, diarrhea). Concomitant use of ADZENYS XR-ODT with MAOI drugs is contraindicated [see Contraindications (4) ]. Discontinue treatment with ADZENYS XR-ODT and any concomitant serotonergic agents immediately if the above symptoms occur, and initiate supportive symptomatic treatment. If concomitant use of ADZENYS XR-ODT with other serotonergic drugs or CYP2D6 inhibitors is clinically warranted, initiate ADZENYS XR-ODT with lower doses, monitor patients for the emergence of serotonin syndrome during drug initiation or titration, and inform patients of the increased risk for serotonin syndrome. 5.8 Motor and Verbal Tics, and Worsening of Tourette’s Syndrome CNS stimulants, including amphetamine, have been associated with the onset or exacerbation of motor and verbal tics. Worsening of Tourette’s syndrome has also been reported [see Adverse Reactions (6.2)]. Before initiating ADZENYS XR-ODT, assess the family history and clinically evaluate patients for tics or Tourette’s syndrome. Regularly monitor ADZENYS XR-ODT-treated patients for the emergence or worsening of tics or Tourette’s syndrome and discontinue treatment if clinically appropriate. 5.9 Potential for Overdose Due to Medication Errors Medication errors, including substitution and dispensing errors, between ADZENYS XR-ODT and other amphetamine products could occur, leading to possible overdosage. To avoid substitution errors and overdosage, do not substitute for other amphetamine products on a milligram-per-milligram basis because of different amphetamine base compositions and differing pharmacokinetic profiles [see Dosage and Administration (2.5)].

6. ADVERSE REACTIONS The following adverse reactions are discussed in greater detail in other sections of the labeling: Abuse, Misuse, and Addiction [see Boxed Warning , Warnings and Precautions (5.1) , and Drug Abuse and Dependence (9.2 , 9.3) ] Hypersensitivity to amphetamine, or other components of ADZENYS XR-ODT [see Contraindications (4) ] Hypertensive Crisis When Used Concomitantly with Monoamine Oxidase Inhibitors [see Contraindications (4) and Drug Interactions (7.1) ] Risks to Patients with Serious Cardiac Disease [see Warnings and Precautions (5.2) ] Increased Blood Pressure and Heart Rate [see Warnings and Precautions (5.3) ] Psychiatric Adverse Reactions [see Warnings and Precautions (5.4) ] Long-Term Suppression of Growth in Pediatric Patients [see Warnings and Precautions (5.5) ] Peripheral Vasculopathy, including Raynaud's phenomenon [see Warnings and Precautions (5.6) ] Serotonin Syndrome [ see Warnings and Precautions (5.7) ] Motor and Verbal Tics, and Worsening of Tourette's Syndrome [ see Warnings and Precautions ( 5.8 ) ] Pediatric patients ages 6 to 12 years: Most common adverse reactions (≥5% and with a higher incidence than on placebo) were loss of appetite, insomnia, abdominal pain, emotional lability, vomiting, nervousness, nausea, and fever. ( 6.1 ) Pediatric patients ages 13 to 17 years: Most common adverse reactions (≥5% and with a higher incidence than on placebo) were loss of appetite, insomnia, abdominal pain, weight loss, and nervousness. ( 6.1 ) Adults: Most common adverse reactions ≥5% and with a higher incidence than on placebo were dry mouth, loss of appetite, insomnia, headache, weight loss, nausea, anxiety, agitation, dizziness, tachycardia, diarrhea, asthenia, and urinary tract infections. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Neos Therapeutics, Inc. at 1-888-319-1789 or http://www.adzenysxrodt.com or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch . 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 to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice. The safety of ADZENYS XR-ODT has been established from adequate and well-controlled studies of single-entity amphetamine product extended-release (MAS ER) capsules [see Clinical Studies (14) ]. The adverse reactions of MAS ER capsules in these adequate and well-controlled studies are described below. The premarketing development program for MAS ER included exposures in a total of 1315 participants in clinical trials (635 pediatric patients, 350 adolescent patients, 248 adult patients, and 82 healthy adult subjects). Of these, 635 patients (ages 6 to 12 years) were evaluated in two controlled clinical studies, one open-label clinical study, and two single-dose clinical pharmacology studies (N= 40). Adverse Reactions Leading to Discontinuation of Treatment The most frequent adverse reactions leading to discontinuation of MAS ER in controlled and uncontrolled, multiple-dose clinical trials of pediatric patients ages 6 to 12 years (N=595) were anorexia (loss of appetite) (2.9%), insomnia (1.5%), weight loss (1.2%), emotional lability (1%), and depression (0.7%). In a separate placebo-controlled 4-week study in pediatric patients ages 13 to 17 years with ADHD, five patients (2.1%) discontinued treatment due to adverse events among MAS ER-treated patients (N=233) compared to 0% who received placebo (N=54). The most frequent adverse event leading to discontinuation and considered to be drug-related (i.e., leading to discontinuation in at least 1% of MAS ER-treated patients and at a rate at least twice that of placebo) was insomnia (1.3%, n=3). In one placebo-controlled 4-week study among adults with ADHD with doses 20 mg to 60 mg, 23 patients (12.0% ) discontinued treatment due to adverse events among MAS ER-treated patients (N=191) compared to one patient (1.6%) who received placebo (N=64). The most frequent adverse events leading to discontinuation and considered to be drug-related (i.e., leading to discontinuation in at least 1% of MAS ER-treated patients and at a rate at least twice that of placebo) were insomnia (5.2%, n=10), anxiety (2.1%, n=4), nervousness (1.6%, n=3), dry mouth (1.6%, n=3), anorexia (1.6%, n=3), tachycardia (1.6%, n=3), headache (1.6%, n=3), and asthenia (1.0%, n=2). Adverse Reactions Occurring in Clinical Trials Adverse reactions reported in a 3-week clinical trial of pediatric patients 6 to 12 years of age and a 4-week clinical trial in pediatric patients 13 to 17 years of age and adults, respectively, treated with MAS ER or placebo are presented in the tables below. Table 2: Adverse Reactions Reported by 2% or More of Pediatric Patients (6-12 years old) Receiving MAS ER with Higher Incidence than on Placebo in a 584-Patient Clinical Study Body System Adverse Reaction MAS ER (n=374) Placebo (n=210) General Abdominal Pain (stomachache) 14% 10% Fever 5% 2% Infection 4% 2% Accidental Injury 3% 2% Asthenia (fatigue) 2% 0% Digestive System Loss of Appetite 22% 2% Vomiting 7% 4% Nausea 5% 3% Dyspepsia 2% 1% Nervous System Insomnia 17% 2% Emotional Lability 9% 2% Nervousness 6% 2% Dizziness 2% 0% Metabolic/Nutritional Weight Loss 4% 0% Table 3: Adverse Reactions Reported by 5% or More of Pediatric Patients (13-17 Years Old) Weighing ≤ 75kg Receiving MAS ER with Higher Incidence than Placebo in a 287 Patient Clinical Forced Weekly-Dose Titration Study Included doses up to 40 mg Body System Preferred Term MAS ER (n=233) Placebo (n=54) Note: The following reactions did not meet the criterion for inclusion in Table 3 but were reported by 2% to 4% of adolescent patients receiving MAS ER with a higher incidence than patients receiving placebo in this study: accidental injury, asthenia (fatigue), dry mouth, dyspepsia, emotional lability, nausea, somnolence, and vomiting. General Abdominal Pain (stomachache) 11% 2% Digestive System Loss of Appetite Dose-related adverse reactions 36% 2% Nervous System Insomnia 12% 4% Metabolic/Nutritional Weight Loss 9% 0% Table 4: Adverse Reactions Reported by 5% or More of Adults Receiving MAS ER with Higher Incidence Than Placebo in a 255 Patient Clinical Forced Weekly-Dose Titration Study Included doses up to 60 mg. Body System Preferred Term MAS ER (n=191) Placebo (n=64) Note: The following reactions did not meet the criterion for inclusion in Table 4 but were reported by 2% to 4% of adult patients receiving MAS ER with a higher incidence than patients receiving placebo in this study: infection, photosensitivity reaction, constipation, tooth disorder (e.g., teeth clenching, tooth infection), emotional lability, libido decreased, somnolence, speech disorder (e.g., stuttering, excessive speech), palpitation, twitching, dyspnea, sweating, dysmenorrhea, and impotence. General Headache 26% 13% Asthenia 6% 5% Digestive System Dry Mouth 35% 5% Loss of Appetite 33% 3% Nausea 8% 3% Diarrhea 6% 0% Nervous System Insomnia 27% 13% Agitation 8% 5% Anxiety 8% 5% Dizziness 7% 0% Cardiovascular System Tachycardia 6% 3% Metabolic/Nutritional Weight Loss 10% 0% Urogenital System Urinary Tract Infection 5% 0% 6.2 Adverse Reactions from Clinical Trials and Spontaneous Postmarketing Reports of Other Amphetamine Products The following adverse reactions are from clinical trials and spontaneous postmarketing reports of other amphetamine products in pediatric patients and adults with ADHD. Because some of these reactions were reported voluntarily from a population of uncertain size, it is not always possible to estimate their frequency reliably or to establish a causal relationship to drug exposure. Cardiovascular: Palpitations, sudden death, myocardial infarction. There have been isolated reports of cardiomyopathy associated with chronic amphetamine use. Central Nervous System: Restlessness, irritability, euphoria, dyskinesia, dysphoria, depression, tremor, aggression, anger, logorrhea, paresthesia (including formication), motor and verbal tics. Eye Disorders: Vision blurred, mydriasis. Gastrointestinal: Unpleasant taste, constipation, intestinal ischemia, other gastrointestinal disturbances. Allergic: Urticaria, rash, hypersensitivity reactions including angioedema and anaphylaxis. Serious skin rashes, including Stevens-Johnson Syndrome and toxic epidermal necrolysis have been reported. Endocrine: Impotence, change in libido, frequent or prolonged erections. Skin: Alopecia. Musculoskeletal, Connective Tissue, and Bone Disorders: rhabdomyolysis. Psychiatric Disorders: dermatillomania, bruxism. Vascular Disorders: Raynaud's phenomenon.

<table width="779px"><caption>Table 2: Adverse Reactions Reported by 2% or More of Pediatric Patients (6-12 years old) Receiving MAS ER with Higher Incidence than on Placebo in a 584-Patient Clinical Study</caption><col/><col/><col/><col/><thead><tr><th styleCode=" Botrule Toprule Lrule Rrule " valign="top"> Body System</th><th styleCode=" Botrule Toprule Lrule Rrule " valign="top"> Adverse Reaction</th><th styleCode=" Botrule Toprule Lrule Rrule " valign="top"> MAS ER (n=374) </th><th styleCode=" Botrule Toprule Lrule Rrule " valign="top"> Placebo (n=210) </th></tr></thead><tbody><tr><td styleCode=" Toprule Lrule Rrule " valign="top"><content styleCode="bold">General</content></td><td styleCode=" Toprule Lrule Rrule " valign="top">Abdominal Pain (stomachache)</td><td styleCode=" Toprule Lrule Rrule " valign="top">14%</td><td styleCode=" Toprule Lrule Rrule " valign="top">10%</td></tr><tr><td styleCode=" Lrule Rrule " valign="top"/><td styleCode=" Lrule Rrule " valign="top">Fever</td><td styleCode=" Lrule Rrule " valign="top">5%</td><td styleCode=" Lrule Rrule " valign="top">2%</td></tr><tr><td styleCode=" Lrule Rrule " valign="top"/><td styleCode=" Lrule Rrule " valign="top">Infection</td><td styleCode=" Lrule Rrule " valign="top">4%</td><td styleCode=" Lrule Rrule " valign="top">2%</td></tr><tr><td styleCode=" Lrule Rrule " valign="top"/><td styleCode=" Lrule Rrule " valign="top">Accidental Injury</td><td styleCode=" Lrule Rrule " valign="top">3%</td><td styleCode=" Lrule Rrule " valign="top">2%</td></tr><tr><td styleCode=" Botrule Lrule Rrule " valign="top"/><td styleCode=" Botrule Lrule Rrule " valign="top">Asthenia (fatigue)</td><td styleCode=" Botrule Lrule Rrule " valign="top">2%</td><td styleCode=" Botrule Lrule Rrule " valign="top">0%</td></tr><tr><td styleCode=" Toprule Lrule Rrule " valign="top"><content styleCode="bold">Digestive System</content></td><td styleCode=" Toprule Lrule Rrule " valign="top">Loss of Appetite</td><td styleCode=" Toprule Lrule Rrule " valign="top">22%</td><td styleCode=" Toprule Lrule Rrule " valign="top">2%</td></tr><tr><td styleCode=" Lrule Rrule " valign="top"/><td styleCode=" Lrule Rrule " valign="top">Vomiting</td><td styleCode=" Lrule Rrule " valign="top">7%</td><td styleCode=" Lrule Rrule " valign="top">4%</td></tr><tr><td styleCode=" Lrule Rrule " valign="top"/><td styleCode=" Lrule Rrule " valign="top">Nausea</td><td styleCode=" Lrule Rrule " valign="top">5%</td><td styleCode=" Lrule Rrule " valign="top">3%</td></tr><tr><td styleCode=" Botrule Lrule Rrule " valign="top"/><td styleCode=" Botrule Lrule Rrule " valign="top">Dyspepsia</td><td styleCode=" Botrule Lrule Rrule " valign="top">2%</td><td styleCode=" Botrule Lrule Rrule " valign="top">1%</td></tr><tr><td styleCode=" Toprule Lrule Rrule " valign="top"><content styleCode="bold">Nervous System</content></td><td styleCode=" Toprule Lrule Rrule " valign="top">Insomnia</td><td styleCode=" Toprule Lrule Rrule " valign="top">17%</td><td styleCode=" Toprule Lrule Rrule " valign="top">2%</td></tr><tr><td styleCode=" Lrule Rrule " valign="top"/><td styleCode=" Lrule Rrule " valign="top">Emotional Lability</td><td styleCode=" Lrule Rrule " valign="top">9%</td><td styleCode=" Lrule Rrule " valign="top">2%</td></tr><tr><td styleCode=" Lrule Rrule " valign="top"/><td styleCode=" Lrule Rrule " valign="top">Nervousness</td><td styleCode=" Lrule Rrule " valign="top">6%</td><td styleCode=" Lrule Rrule " valign="top">2%</td></tr><tr><td styleCode=" Botrule Lrule Rrule " valign="top"/><td styleCode=" Botrule Lrule Rrule " valign="top">Dizziness</td><td styleCode=" Botrule Lrule Rrule " valign="top">2%</td><td styleCode=" Botrule Lrule Rrule " valign="top">0%</td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule " valign="top"><content styleCode="bold">Metabolic/Nutritional</content></td><td styleCode=" Botrule Toprule Lrule Rrule " valign="top">Weight Loss</td><td styleCode=" Botrule Toprule Lrule Rrule " valign="top">4%</td><td styleCode=" Botrule Toprule Lrule Rrule " valign="top">0%</td></tr></tbody></table>

<table><caption>Table 3: Adverse Reactions Reported by 5% or More of Pediatric Patients (13-17 Years Old) Weighing &#x2264; 75kg Receiving MAS ER with Higher Incidence than Placebo in a 287 Patient Clinical Forced Weekly-Dose Titration Study <footnote ID="FOOT_21842">Included doses up to 40 mg</footnote></caption><col/><col/><col/><col/><thead><tr><th styleCode=" Botrule Toprule Lrule Rrule " valign="top"> Body System</th><th styleCode=" Botrule Toprule Lrule Rrule " valign="top"> Preferred Term</th><th styleCode=" Botrule Toprule Lrule Rrule " valign="top"> MAS ER (n=233) </th><th styleCode=" Botrule Toprule Lrule Rrule " valign="top"> Placebo (n=54) </th></tr></thead><tfoot><tr><td colspan="4" valign="top">Note: The following reactions did not meet the criterion for inclusion in Table 3 but were reported by 2% to 4% of adolescent patients receiving MAS ER with a higher incidence than patients receiving placebo in this study: accidental injury, asthenia (fatigue), dry mouth, dyspepsia, emotional lability, nausea, somnolence, and vomiting.</td></tr></tfoot><tbody><tr><td styleCode=" Botrule Toprule Lrule Rrule " valign="top"><content styleCode="bold">General</content></td><td styleCode=" Botrule Toprule Lrule Rrule " valign="top">Abdominal Pain (stomachache)</td><td styleCode=" Botrule Toprule Lrule Rrule " valign="top">11%</td><td styleCode=" Botrule Toprule Lrule Rrule " valign="top">2%</td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule " valign="top"><content styleCode="bold">Digestive System</content></td><td styleCode=" Botrule Toprule Lrule Rrule " valign="top">Loss of Appetite <footnote ID="FOOT_21843">Dose-related adverse reactions</footnote></td><td styleCode=" Botrule Toprule Lrule Rrule " valign="top">36%</td><td styleCode=" Botrule Toprule Lrule Rrule " valign="top">2%</td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule " valign="top"><content styleCode="bold">Nervous System</content></td><td styleCode=" Botrule Toprule Lrule Rrule " valign="top">Insomnia <footnoteRef IDREF="FOOT_21843"/></td><td styleCode=" Botrule Toprule Lrule Rrule " valign="top">12%</td><td styleCode=" Botrule Toprule Lrule Rrule " valign="top">4%</td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule " valign="top"><content styleCode="bold">Metabolic/Nutritional</content></td><td styleCode=" Botrule Toprule Lrule Rrule " valign="top">Weight Loss <footnoteRef IDREF="FOOT_21843"/></td><td styleCode=" Botrule Toprule Lrule Rrule " valign="top">9%</td><td styleCode=" Botrule Toprule Lrule Rrule " valign="top">0%</td></tr></tbody></table>

<table><caption>Table 4: Adverse Reactions Reported by 5% or More of Adults Receiving MAS ER with Higher Incidence Than Placebo in a 255 Patient Clinical Forced Weekly-Dose Titration Study <footnote ID="FOOT_21844">Included doses up to 60 mg.</footnote></caption><col/><col/><col/><col/><thead><tr><th styleCode=" Botrule Toprule Lrule Rrule " valign="top"> Body System</th><th styleCode=" Botrule Toprule Lrule Rrule " valign="top"> Preferred Term</th><th styleCode=" Botrule Toprule Lrule Rrule " valign="top"> MAS ER (n=191) </th><th styleCode=" Botrule Toprule Lrule Rrule " valign="top"> Placebo (n=64) </th></tr></thead><tfoot><tr><td colspan="4" valign="top">Note: The following reactions did not meet the criterion for inclusion in Table 4 but were reported by 2% to 4% of adult patients receiving MAS ER with a higher incidence than patients receiving placebo in this study: infection, photosensitivity reaction, constipation, tooth disorder (e.g., teeth clenching, tooth infection), emotional lability, libido decreased, somnolence, speech disorder (e.g., stuttering, excessive speech), palpitation, twitching, dyspnea, sweating, dysmenorrhea, and impotence.</td></tr></tfoot><tbody><tr><td styleCode=" Toprule Lrule Rrule " valign="top"><content styleCode="bold">General</content></td><td styleCode=" Toprule Lrule Rrule " valign="top">Headache</td><td styleCode=" Toprule Lrule Rrule " valign="top">26%</td><td styleCode=" Toprule Lrule Rrule " valign="top">13%</td></tr><tr><td styleCode=" Botrule Lrule Rrule " valign="top"/><td styleCode=" Botrule Lrule Rrule " valign="top">Asthenia</td><td styleCode=" Botrule Lrule Rrule " valign="top">6%</td><td styleCode=" Botrule Lrule Rrule " valign="top">5%</td></tr><tr><td styleCode=" Toprule Lrule Rrule " valign="top"><content styleCode="bold">Digestive System</content></td><td styleCode=" Toprule Lrule Rrule " valign="top">Dry Mouth</td><td styleCode=" Toprule Lrule Rrule " valign="top">35%</td><td styleCode=" Toprule Lrule Rrule " valign="top">5%</td></tr><tr><td styleCode=" Lrule Rrule " valign="top"/><td styleCode=" Lrule Rrule " valign="top">Loss of Appetite</td><td styleCode=" Lrule Rrule " valign="top">33%</td><td styleCode=" Lrule Rrule " valign="top">3%</td></tr><tr><td styleCode=" Lrule Rrule " valign="top"/><td styleCode=" Lrule Rrule " valign="top">Nausea</td><td styleCode=" Lrule Rrule " valign="top">8%</td><td styleCode=" Lrule Rrule " valign="top">3%</td></tr><tr><td styleCode=" Botrule Lrule Rrule " valign="top"/><td styleCode=" Botrule Lrule Rrule " valign="top">Diarrhea</td><td styleCode=" Botrule Lrule Rrule " valign="top">6%</td><td styleCode=" Botrule Lrule Rrule " valign="top">0%</td></tr><tr><td styleCode=" Toprule Lrule Rrule " valign="top"><content styleCode="bold">Nervous System</content></td><td styleCode=" Toprule Lrule Rrule " valign="top">Insomnia</td><td styleCode=" Toprule Lrule Rrule " valign="top">27%</td><td styleCode=" Toprule Lrule Rrule " valign="top">13%</td></tr><tr><td styleCode=" Lrule Rrule " valign="top"/><td styleCode=" Lrule Rrule " valign="top">Agitation</td><td styleCode=" Lrule Rrule " valign="top">8%</td><td styleCode=" Lrule Rrule " valign="top">5%</td></tr><tr><td styleCode=" Lrule Rrule " valign="top"/><td styleCode=" Lrule Rrule " valign="top">Anxiety</td><td styleCode=" Lrule Rrule " valign="top">8%</td><td styleCode=" Lrule Rrule " valign="top">5%</td></tr><tr><td styleCode=" Botrule Lrule Rrule " valign="top"/><td styleCode=" Botrule Lrule Rrule " valign="top">Dizziness</td><td styleCode=" Botrule Lrule Rrule " valign="top">7%</td><td styleCode=" Botrule Lrule Rrule " valign="top">0%</td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule " valign="top"><content styleCode="bold">Cardiovascular System</content></td><td styleCode=" Botrule Toprule Lrule Rrule " valign="top">Tachycardia</td><td styleCode=" Botrule Toprule Lrule Rrule " valign="top">6%</td><td styleCode=" Botrule Toprule Lrule Rrule " valign="top">3%</td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule " valign="top"><content styleCode="bold">Metabolic/Nutritional</content></td><td styleCode=" Botrule Toprule Lrule Rrule " valign="top">Weight Loss</td><td styleCode=" Botrule Toprule Lrule Rrule " valign="top">10%</td><td styleCode=" Botrule Toprule Lrule Rrule " valign="top">0%</td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule " valign="top"><content styleCode="bold">Urogenital System</content></td><td styleCode=" Botrule Toprule Lrule Rrule " valign="top">Urinary Tract Infection</td><td styleCode=" Botrule Toprule Lrule Rrule " valign="top">5%</td><td styleCode=" Botrule Toprule Lrule Rrule " valign="top">0%</td></tr></tbody></table>