FDA label fbf8d37d-1626-47b9-9871-0b90dd6d7cad

5 WARNINGS AND PRECAUTIONS • Serious Rash, including Stevens-Johnson Syndrome: Discontinue NUVIGIL at the first sign of rash, unless the rash is clearly not drug-related. ( 5.1 ) • Pediatric Patients: NUVIGIL is not approved for use in pediatric patients for any indication. (5.1, 8.4) • Angioedema and Anaphylactoid Reactions: If suspected, discontinue NUVIGIL. ( 5.2 ) • Multi-organ Hypersensitivity Reactions: If suspected, discontinue NUVIGIL. ( 5.3 ) • Persistent Sleepiness: Assess patients frequently for degree of sleepiness and, if appropriate, advise patients to avoid driving or engaging in any other potentially dangerous activity. ( 5.4 ) • Psychiatric Symptoms: Use particular caution in treating patients with a history of psychosis, depression, or mania. Consider discontinuing NUVIGIL if psychiatric symptoms develop. ( 5.5 ) • OSA: use only in setting of optimized treatment for underlying obstruction ( 5.7 ) • Known Cardiovascular Disease: Increased monitoring may be necessary. ( 5.9 ) 5.1 Serious Rash, including Stevens-Johnson Syndrome Serious rash requiring hospitalization and discontinuation of treatment has been reported in association with the use of NUVIGIL (armodafinil) or modafinil (the racemic mixture of S- and R-enantiomers). NUVIGIL has not been studied in pediatric patients in any setting and is not approved for use in pediatric patients for any indication. In clinical trials of modafinil, the incidence of rash resulting in discontinuation was approximately 0.8% (13 per 1,585) in pediatric patients (age <17 years); these rashes included 1 case of possible Stevens-Johnson Syndrome (SJS) and 1 case of apparent multi-organ hypersensitivity reaction. Several of the cases were associated with fever and other abnormalities (e.g., vomiting, leukopenia). The median time to rash that resulted in discontinuation was 13 days. No such cases were observed among 380 pediatric patients who received placebo. No serious skin rashes have been reported in adult clinical trials (0 per 4,264) of modafinil. Rare cases of serious or life-threatening rash, including SJS, Toxic Epidermal Necrolysis (TEN), and Drug Rash with Eosinophilia and Systemic Symptoms (DRESS) have been reported in adults and children in worldwide post-marketing experience. The reporting rate of TEN and SJS associated with modafinil use, which is generally accepted to be an underestimate due to underreporting, exceeds the background incidence rate. Estimates of the background incidence rate for these serious skin reactions in the general population range between 1 to 2 cases per million-person years. Cases of serious rash similar to those observed with modafinil including skin and mouth blistering have been reported in adults in postmarketing experience with NUVIGIL. There are no factors that are known to predict the risk of occurrence or the severity of rash associated with modafinil or armodafinil. Nearly all cases of serious rash associated with these drugs occurred within 1 to 5 weeks after treatment initiation. However, isolated cases have been reported after prolonged treatment (e.g., 3 months). Accordingly, duration of therapy cannot be relied upon as a means to predict the potential risk heralded by the first appearance of a rash. Although benign rashes also occur with NUVIGIL, it is not possible to reliably predict which rashes will prove to be serious. Accordingly, NUVIGIL should be discontinued at the first sign of rash, unless the rash is clearly not drug-related. Discontinuation of treatment may not prevent a rash from becoming life-threatening or permanently disabling or disfiguring. 5.2 Angioedema and Anaphylactoid Reactions Angioedema and hypersensitivity (with rash, dysphagia, and bronchospasm), were observed with NUVIGIL. Patients should be advised to discontinue therapy and immediately report to their physician any signs or symptoms suggesting angioedema or anaphylaxis (e.g., swelling of face, eyes, lips, tongue or larynx; difficulty in swallowing or breathing; hoarseness). 5.3 Multi-organ Hypersensitivity Reactions Multi-organ hypersensitivity reactions, including at least one fatality in post-marketing experience, have occurred in close temporal association (median time to detection 13 days: range 4-33) to the initiation of modafinil. A similar risk of multi-organ hypersensitivity reactions with armodafinil cannot be ruled out. Although there have been a limited number of reports, multi-organ hypersensitivity reactions may result in hospitalization or be life-threatening. There are no factors that are known to predict the risk of occurrence or the severity of multi-organ hypersensitivity reactions. Signs and symptoms of this disorder were diverse; however, patients typically, although not exclusively, presented with fever and rash associated with other organ system involvement. Other associated manifestations included myocarditis, hepatitis, liver function test abnormalities, hematological abnormalities (e.g., eosinophilia, leukopenia, thrombocytopenia), pruritus, and asthenia. Because multi-organ hypersensitivity is variable in its expression, other organ system symptoms and signs, not noted here, may occur. If a multi-organ hypersensitivity reaction is suspected, NUVIGIL should be discontinued. Although there are no case reports to indicate cross-sensitivity with other drugs that produce this syndrome, the experience with drugs associated with multi-organ hypersensitivity would indicate this to be a possibility. 5.4 Persistent Sleepiness Patients with abnormal levels of sleepiness who take NUVIGIL should be advised that their level of wakefulness may not return to normal. Patients with excessive sleepiness, including those taking NUVIGIL, should be frequently reassessed for their degree of sleepiness and, if appropriate, advised to avoid driving or any other potentially dangerous activity. Prescribers should also be aware that patients may not acknowledge sleepiness or drowsiness until directly questioned about drowsiness or sleepiness during specific activities. 5.5 Psychiatric Symptoms In pre-approval narcolepsy, OSA and SWD controlled trials of NUVIGIL, anxiety, agitation, nervousness, and irritability were reasons for treatment discontinuation more often in patients on NUVIGIL compared to placebo (NUVIGIL 1.2% and placebo 0.3%). Depression was also a reason for treatment discontinuation more often in patients on NUVIGIL compared to placebo (NUVIGIL 0.6% and placebo 0.2%). Cases of suicide ideation were observed in clinical trials. Caution should be exercised when NUVIGIL is given to patients with a history of psychosis, depression, or mania. If psychiatric symptoms develop in association with NUVIGIL administration, consider discontinuing NUVIGIL. Psychiatric adverse experiences have been reported in patients treated with modafinil. Modafinil and armodafinil (NUVIGIL) are very closely related. Therefore, the incidence and type of psychiatric symptoms associated with NUVIGIL are expected to be similar to the incidence and type of these events with modafinil. Post-marketing adverse events associated with the use of modafinil have included mania, delusions, hallucinations, suicidal ideation, and aggression, some resulting in hospitalization. Many, but not all, patients had a prior psychiatric history. One healthy male volunteer developed ideas of reference, paranoid delusions, and auditory hallucinations in association with multiple daily 600 mg doses of modafinil and sleep deprivation. There was no evidence of psychosis 36 hours after drug discontinuation. 5.6 Diagnosis of Sleep Disorders NUVIGIL should be used only in patients who have had a complete evaluation of their excessive sleepiness, and in whom a diagnosis of narcolepsy, OSA, or SWD has been made in accordance with International Classification of Sleep Disorders (ICSD) or Diagnostic and Statistical Manual of Mental Disorders (DSM) diagnostic criteria. [see Clinical Studies (14.1)] . Such an evaluation usually consists of a complete history and physical examination, and it may be supplemented with testing in a laboratory setting. Some patients may have more than one sleep disorder contributing to their excessive sleepiness (e.g., OSA and SWD coincident in the same patient). 5.7 CPAP Use in Patients with OSA In OSA, NUVIGIL is not indicated as treatment for the underlying obstruction. If continuous positive airway pressure (CPAP) is the treatment of choice for a patient, a maximal effort to treat with CPAP for an adequate period of time should be made prior to initiating NUVIGIL for excessive sleepiness. If NUVIGIL is used adjunctively with CPAP, the encouragement of and periodic assessment of CPAP compliance is necessary. There was a slight trend for reduced CPAP use over time (mean reduction of 18 minutes for patients treated with NUVIGIL and a 6-minute reduction for placebo-treated patients from a mean baseline use of 6.9 hours per night) in NUVIGIL trials. 5.8 Effects on Ability to Drive and Use Machinery Although NUVIGIL has not been shown to produce functional impairment, any drug affecting the CNS may alter judgment, thinking or motor skills. Patients should be cautioned about operating an automobile or other hazardous machinery until it is reasonably certain that NUVIGIL therapy will not adversely affect their ability to engage in such activities. 5.9 Cardiovascular System NUVIGIL has not been evaluated or used to any appreciable extent in patients with a recent history of myocardial infarction or unstable angina, and such patients should be treated with caution. In clinical studies of modafinil, cardiovascular adverse events, including chest pain, palpitations, dyspnea and transient ischemic T-wave changes on ECG were observed in three subjects in association with mitral valve prolapse or left ventricular hypertrophy. It is recommended that NUVIGIL tablets not be used in patients with a history of left ventricular hypertrophy or in patients with mitral valve prolapse who have experienced the mitral valve prolapse syndrome when previously receiving CNS stimulants. Findings suggestive of mitral valve prolapse syndrome include but are not limited to ischemic ECG changes, chest pain, or arrhythmia. If new onset of any of these findings occurs, consider cardiac evaluation. Blood pressure monitoring in short term (≤ 3 months) pre-approval controlled trials of OSA, SWD, and narcolepsy showed small average increases in mean systolic and diastolic blood pressure in patients receiving NUVIGIL as compared to placebo (1.2 to 4.3 mmHg in the various experimental groups). There was also a slightly greater proportion of patients on NUVIGIL requiring new or increased use of antihypertensive medications (2.9%) compared to patients on placebo (1.8%). There was a small, but consistent, average increase in pulse rate over placebo in pre-approval controlled trials. This increase varied from 0.9 to 3.5 BPM. Increased monitoring of heart rate and blood pressure may be appropriate in patients on NUVIGIL. Caution should be exercised when prescribing NUVIGIL to patients with known cardiovascular disease.

5.1 Serious Rash, including Stevens-Johnson Syndrome Serious rash requiring hospitalization and discontinuation of treatment has been reported in association with the use of NUVIGIL (armodafinil) or modafinil (the racemic mixture of S- and R-enantiomers). NUVIGIL has not been studied in pediatric patients in any setting and is not approved for use in pediatric patients for any indication. In clinical trials of modafinil, the incidence of rash resulting in discontinuation was approximately 0.8% (13 per 1,585) in pediatric patients (age <17 years); these rashes included 1 case of possible Stevens-Johnson Syndrome (SJS) and 1 case of apparent multi-organ hypersensitivity reaction. Several of the cases were associated with fever and other abnormalities (e.g., vomiting, leukopenia). The median time to rash that resulted in discontinuation was 13 days. No such cases were observed among 380 pediatric patients who received placebo. No serious skin rashes have been reported in adult clinical trials (0 per 4,264) of modafinil. Rare cases of serious or life-threatening rash, including SJS, Toxic Epidermal Necrolysis (TEN), and Drug Rash with Eosinophilia and Systemic Symptoms (DRESS) have been reported in adults and children in worldwide post-marketing experience. The reporting rate of TEN and SJS associated with modafinil use, which is generally accepted to be an underestimate due to underreporting, exceeds the background incidence rate. Estimates of the background incidence rate for these serious skin reactions in the general population range between 1 to 2 cases per million-person years. Cases of serious rash similar to those observed with modafinil including skin and mouth blistering have been reported in adults in postmarketing experience with NUVIGIL. There are no factors that are known to predict the risk of occurrence or the severity of rash associated with modafinil or armodafinil. Nearly all cases of serious rash associated with these drugs occurred within 1 to 5 weeks after treatment initiation. However, isolated cases have been reported after prolonged treatment (e.g., 3 months). Accordingly, duration of therapy cannot be relied upon as a means to predict the potential risk heralded by the first appearance of a rash. Although benign rashes also occur with NUVIGIL, it is not possible to reliably predict which rashes will prove to be serious. Accordingly, NUVIGIL should be discontinued at the first sign of rash, unless the rash is clearly not drug-related. Discontinuation of treatment may not prevent a rash from becoming life-threatening or permanently disabling or disfiguring.

5.2 Angioedema and Anaphylactoid Reactions Angioedema and hypersensitivity (with rash, dysphagia, and bronchospasm), were observed with NUVIGIL. Patients should be advised to discontinue therapy and immediately report to their physician any signs or symptoms suggesting angioedema or anaphylaxis (e.g., swelling of face, eyes, lips, tongue or larynx; difficulty in swallowing or breathing; hoarseness).

5.3 Multi-organ Hypersensitivity Reactions Multi-organ hypersensitivity reactions, including at least one fatality in post-marketing experience, have occurred in close temporal association (median time to detection 13 days: range 4-33) to the initiation of modafinil. A similar risk of multi-organ hypersensitivity reactions with armodafinil cannot be ruled out. Although there have been a limited number of reports, multi-organ hypersensitivity reactions may result in hospitalization or be life-threatening. There are no factors that are known to predict the risk of occurrence or the severity of multi-organ hypersensitivity reactions. Signs and symptoms of this disorder were diverse; however, patients typically, although not exclusively, presented with fever and rash associated with other organ system involvement. Other associated manifestations included myocarditis, hepatitis, liver function test abnormalities, hematological abnormalities (e.g., eosinophilia, leukopenia, thrombocytopenia), pruritus, and asthenia. Because multi-organ hypersensitivity is variable in its expression, other organ system symptoms and signs, not noted here, may occur. If a multi-organ hypersensitivity reaction is suspected, NUVIGIL should be discontinued. Although there are no case reports to indicate cross-sensitivity with other drugs that produce this syndrome, the experience with drugs associated with multi-organ hypersensitivity would indicate this to be a possibility.

6 ADVERSE REACTIONS The following serious adverse reactions are described below and elsewhere in the labeling: • Serious Rash, including Stevens-Johnson Syndrome [see Warnings and Precautions (5.1)] • Angioedema and Anaphylactoid Reactions [ see Warnings and Precautions (5.2)] • Multi-organ Hypersensitivity Reactions [see Warnings and Precautions (5.3)] • Persistent Sleepiness [see Warnings and Precautions (5.4)] • Psychiatric Symptoms [see Warnings and Precautions (5.5)] • Diagnosis of Sleep Disorders [see Warnings and Precautions (5.6)] • CPAP Use in Patients with OSA [see Warnings and Precautions (5.7)] • Effects on Ability to Drive and Use Machinery [see Warnings and Precautions (5.8)] • Cardiovascular System [see Warnings and Precautions (5.9)] • Most common adverse reactions (≥5%): headache, nausea, dizziness, and insomnia. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Teva Pharmaceuticals at 1-800-896-5855 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 practice. OSA, SWD, and Narcolepsy NUVIGIL has been evaluated for safety in over 1100 patients with excessive sleepiness associated with OSA, SWD, and narcolepsy. In the pre-approval controlled clinical trials, the most commonly observed adverse events (≥ 5%) associated with the use of NUVIGIL occurring more frequently than in the placebo-treated patients were headache, nausea, dizziness, and insomnia. The adverse event profile was similar across the studies. In the pre-approval controlled clinical trials, 44 of the 645 patients (7%) who received NUVIGIL discontinued due to an adverse experience compared to 16 of the 445 (4%) of patients that received placebo. The most frequent reason for discontinuation was headache (1%). Incidence in Controlled Trials The following table (Table 1) presents the adverse experiences that occurred at a rate of 1% or more and were more frequent in patients treated with NUVIGIL than in placebo group patients in the pre-approval controlled clinical trials. The prescriber should be aware that the figures provided below cannot be used to predict the frequency of adverse experiences in the course of usual medical practice, where patient characteristics and other factors may differ from those occurring during clinical studies. Similarly, the cited frequencies cannot be directly compared with figures obtained from other clinical investigations involving different treatments, uses, or investigators. Review of these frequencies, however, provides prescribers with a basis to estimate the relative contribution of drug and non-drug factors to the incidence of adverse events in the population studied. Table 1. Incidence 1% or Greater Of Treatment-Emergent Adverse Experiences In Parallel-Group, Placebo-Controlled Clinical Trials* In OSA, Narcolepsy, and SWD With NUVIGIL (150 mg and 250 mg) *Four double-blind, placebo-controlled clinical studies in SWD, OSA, and narcolepsy; incidence is rounded to the nearest whole percent. Included are only those events for which NUVIGIL incidence is greater than that of placebo. System Organ Class MedDRA preferred term NUVIGIL (%) N=645 Placebo (%) N=445 Cardiac Disorders Palpitations 2 1 Gastrointestinal Disorders Nausea 7 3 Diarrhea 4 2 Dry Mouth 4 1 Dyspepsia 2 0 Abdominal Pain Upper 2 1 Constipation 1 0 Vomiting 1 0 Loose Stools 1 0 General Disorders And Administration Site Conditions Fatigue 2 1 Thirst 1 0 Influenza-Like Illness 1 0 Pain 1 0 Pyrexia 1 0 Immune System Disorders Seasonal Allergy 1 0 Investigations Gamma-Glutamyltransferase Increased 1 0 Heart Rate Increased 1 0 Metabolism And Nutrition Disorders Anorexia 1 0 Decreased Appetite 1 0 Nervous System Disorders Headache 17 9 Dizziness 5 2 Disturbance In Attention 1 0 Tremor 1 0 Migraine 1 0 Paresthesia 1 0 Psychiatric Disorders Insomnia 5 1 Anxiety 4 1 Depression 2 0 Agitation 1 0 Nervousness 1 0 Depressed Mood 1 0 Renal And Urinary Disorders Polyuria 1 0 Respiratory, Thoracic And Mediastinal Disorders Dyspnea 1 0 Skin And Subcutaneous Tissue Disorders Rash 2 0 Contact Dermatitis 1 0 Hyperhydrosis 1 0 Dose Dependency of Adverse Events In the pre-approval controlled clinical trials which compared doses of 150 mg/day and 250 mg/day of NUVIGIL and placebo, the only adverse events that appeared to be dose-related were headache, rash, depression, dry mouth, insomnia, and nausea. See Table 2 for additional information. Table 2. Incidence of Dose-Dependent, Treatment-Emergent Adverse Experiences By Dose and By Treatment In Parallel-Group, Placebo-Controlled Clinical Trials* In OSA, Narcolepsy and SWD With NUVIGIL (150 mg and 250 mg) *Four double-blind, placebo-controlled clinical studies in SWD, OSA, and narcolepsy. System Organ Class MedDRA preferred term NUVIGIL 250 mg (%) N=198 NUVIGIL 150 mg (%) N=447 NUVIGIL Combined (%) N=645 Placebo (%) N=445 Gastrointestinal Disorders Nausea 9 6 7 3 Dry Mouth 7 2 4 <1 Nervous System Disorders Headache 23 14 17 9 Psychiatric Disorders Insomnia 6 4 5 1 Depression 3 1 2 <1 Skin And Subcutaneous Tissue Disorders Rash 4 1 2 <1 Laboratory Changes Clinical chemistry, hematology, and urinalysis parameters were monitored in the studies. Mean plasma levels of gamma glutamyltransferase (GGT) and alkaline phosphatase (AP) were found to be higher following administration of NUVIGIL, but not placebo. Few subjects, however, had GGT or AP elevations outside of the normal range. No differences were apparent in alanine aminotransferase (ALT), aspartate aminotransferase (AST), total protein, albumin, or total bilirubin, although there were rare cases of isolated elevations of AST and/or ALT. A single case of mild pancytopenia was observed after 35 days of treatment and resolved with drug discontinuation. A small mean decrease from baseline in serum uric acid compared to placebo was seen in clinical trials. The clinical significance of this finding is unknown. Vital Sign Changes Blood pressure monitoring in pre-approval controlled trials of OSA, SWD, and narcolepsy showed small average increases in mean systolic and diastolic blood pressure in patients receiving NUVIGIL as compared to placebo (1.2 to 4.3 mmHg in the various experimental groups). There was also a slightly greater proportion of patients on NUVIGIL requiring new or increased use of antihypertensive medications (2.9%) compared to patients on placebo (1.8%). There was a small, but consistent, average increase in pulse rate over placebo in pre-approval controlled trials. This increase varied from 0.9 to 3.5 BPM. [see Warnings and Precautions (5.9)]

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 practice. OSA, SWD, and Narcolepsy NUVIGIL has been evaluated for safety in over 1100 patients with excessive sleepiness associated with OSA, SWD, and narcolepsy. In the pre-approval controlled clinical trials, the most commonly observed adverse events (≥ 5%) associated with the use of NUVIGIL occurring more frequently than in the placebo-treated patients were headache, nausea, dizziness, and insomnia. The adverse event profile was similar across the studies. In the pre-approval controlled clinical trials, 44 of the 645 patients (7%) who received NUVIGIL discontinued due to an adverse experience compared to 16 of the 445 (4%) of patients that received placebo. The most frequent reason for discontinuation was headache (1%). Incidence in Controlled Trials The following table (Table 1) presents the adverse experiences that occurred at a rate of 1% or more and were more frequent in patients treated with NUVIGIL than in placebo group patients in the pre-approval controlled clinical trials. The prescriber should be aware that the figures provided below cannot be used to predict the frequency of adverse experiences in the course of usual medical practice, where patient characteristics and other factors may differ from those occurring during clinical studies. Similarly, the cited frequencies cannot be directly compared with figures obtained from other clinical investigations involving different treatments, uses, or investigators. Review of these frequencies, however, provides prescribers with a basis to estimate the relative contribution of drug and non-drug factors to the incidence of adverse events in the population studied. Table 1. Incidence 1% or Greater Of Treatment-Emergent Adverse Experiences In Parallel-Group, Placebo-Controlled Clinical Trials* In OSA, Narcolepsy, and SWD With NUVIGIL (150 mg and 250 mg) *Four double-blind, placebo-controlled clinical studies in SWD, OSA, and narcolepsy; incidence is rounded to the nearest whole percent. Included are only those events for which NUVIGIL incidence is greater than that of placebo. System Organ Class MedDRA preferred term NUVIGIL (%) N=645 Placebo (%) N=445 Cardiac Disorders Palpitations 2 1 Gastrointestinal Disorders Nausea 7 3 Diarrhea 4 2 Dry Mouth 4 1 Dyspepsia 2 0 Abdominal Pain Upper 2 1 Constipation 1 0 Vomiting 1 0 Loose Stools 1 0 General Disorders And Administration Site Conditions Fatigue 2 1 Thirst 1 0 Influenza-Like Illness 1 0 Pain 1 0 Pyrexia 1 0 Immune System Disorders Seasonal Allergy 1 0 Investigations Gamma-Glutamyltransferase Increased 1 0 Heart Rate Increased 1 0 Metabolism And Nutrition Disorders Anorexia 1 0 Decreased Appetite 1 0 Nervous System Disorders Headache 17 9 Dizziness 5 2 Disturbance In Attention 1 0 Tremor 1 0 Migraine 1 0 Paresthesia 1 0 Psychiatric Disorders Insomnia 5 1 Anxiety 4 1 Depression 2 0 Agitation 1 0 Nervousness 1 0 Depressed Mood 1 0 Renal And Urinary Disorders Polyuria 1 0 Respiratory, Thoracic And Mediastinal Disorders Dyspnea 1 0 Skin And Subcutaneous Tissue Disorders Rash 2 0 Contact Dermatitis 1 0 Hyperhydrosis 1 0 Dose Dependency of Adverse Events In the pre-approval controlled clinical trials which compared doses of 150 mg/day and 250 mg/day of NUVIGIL and placebo, the only adverse events that appeared to be dose-related were headache, rash, depression, dry mouth, insomnia, and nausea. See Table 2 for additional information. Table 2. Incidence of Dose-Dependent, Treatment-Emergent Adverse Experiences By Dose and By Treatment In Parallel-Group, Placebo-Controlled Clinical Trials* In OSA, Narcolepsy and SWD With NUVIGIL (150 mg and 250 mg) *Four double-blind, placebo-controlled clinical studies in SWD, OSA, and narcolepsy. System Organ Class MedDRA preferred term NUVIGIL 250 mg (%) N=198 NUVIGIL 150 mg (%) N=447 NUVIGIL Combined (%) N=645 Placebo (%) N=445 Gastrointestinal Disorders Nausea 9 6 7 3 Dry Mouth 7 2 4 <1 Nervous System Disorders Headache 23 14 17 9 Psychiatric Disorders Insomnia 6 4 5 1 Depression 3 1 2 <1 Skin And Subcutaneous Tissue Disorders Rash 4 1 2 <1 Laboratory Changes Clinical chemistry, hematology, and urinalysis parameters were monitored in the studies. Mean plasma levels of gamma glutamyltransferase (GGT) and alkaline phosphatase (AP) were found to be higher following administration of NUVIGIL, but not placebo. Few subjects, however, had GGT or AP elevations outside of the normal range. No differences were apparent in alanine aminotransferase (ALT), aspartate aminotransferase (AST), total protein, albumin, or total bilirubin, although there were rare cases of isolated elevations of AST and/or ALT. A single case of mild pancytopenia was observed after 35 days of treatment and resolved with drug discontinuation. A small mean decrease from baseline in serum uric acid compared to placebo was seen in clinical trials. The clinical significance of this finding is unknown. Vital Sign Changes Blood pressure monitoring in pre-approval controlled trials of OSA, SWD, and narcolepsy showed small average increases in mean systolic and diastolic blood pressure in patients receiving NUVIGIL as compared to placebo (1.2 to 4.3 mmHg in the various experimental groups). There was also a slightly greater proportion of patients on NUVIGIL requiring new or increased use of antihypertensive medications (2.9%) compared to patients on placebo (1.8%). There was a small, but consistent, average increase in pulse rate over placebo in pre-approval controlled trials. This increase varied from 0.9 to 3.5 BPM. [see Warnings and Precautions (5.9)]

<table ID="_Refid_1056a336-2c72-4e81-a7ea-709cc1870" width="100%"> <caption>Table 1. Incidence 1% or Greater Of Treatment-Emergent Adverse Experiences In Parallel-Group, Placebo-Controlled Clinical Trials* In OSA, Narcolepsy, and SWD With NUVIGIL (150 mg and 250 mg)</caption> <col width="32%"/> <col width="14%"/> <col width="11%"/> <tfoot> <tr> <td align="left" colspan="3" styleCode="Botrule" valign="top">*Four double-blind, placebo-controlled clinical studies in SWD, OSA, and narcolepsy; incidence is rounded to the nearest whole percent. Included are only those events for which NUVIGIL incidence is greater than that of placebo.</td> </tr> </tfoot> <tbody> <tr> <td styleCode="Rrule Botrule Lrule Toprule "> <paragraph> <content styleCode="bold">System Organ Class</content> <content styleCode="bold"> MedDRA preferred term</content> </paragraph> </td> <td align="center" styleCode="Rrule Botrule Toprule "> <paragraph> <content styleCode="bold">NUVIGIL</content> <content styleCode="bold">(%)</content> </paragraph> <paragraph> <content styleCode="bold">N=645</content> </paragraph> </td> <td align="center" styleCode="Rrule Botrule Toprule "> <paragraph> <content styleCode="bold">Placebo</content> <content styleCode="bold">(%)</content> </paragraph> <paragraph> <content styleCode="bold"> N=445</content> </paragraph> </td> </tr> <tr> <td colspan="3" styleCode="Rrule Lrule Botrule "> <paragraph> <content styleCode="bold">Cardiac Disorders</content> </paragraph> </td> </tr> <tr> <td styleCode="Rrule Lrule Botrule "> <paragraph>Palpitations</paragraph> </td> <td align="center" styleCode="Rrule Botrule "> <paragraph>2</paragraph> </td> <td align="center" styleCode="Rrule Botrule "> <paragraph>1</paragraph> </td> </tr> <tr> <td colspan="3" styleCode="Rrule Lrule Botrule "> <paragraph> <content styleCode="bold">Gastrointestinal Disorders</content> </paragraph> </td> </tr> <tr> <td styleCode="Rrule Lrule Botrule "> <paragraph>Nausea</paragraph> </td> <td align="center" styleCode="Rrule Botrule "> <paragraph>7</paragraph> </td> <td align="center" styleCode="Rrule Botrule "> <paragraph>3</paragraph> </td> </tr> <tr> <td styleCode="Rrule Lrule Botrule "> <paragraph>Diarrhea</paragraph> </td> <td align="center" styleCode="Rrule Botrule "> <paragraph>4</paragraph> </td> <td align="center" styleCode="Rrule Botrule "> <paragraph>2</paragraph> </td> </tr> <tr> <td styleCode="Rrule Lrule Botrule "> <paragraph>Dry Mouth</paragraph> </td> <td align="center" styleCode="Rrule Botrule "> <paragraph>4</paragraph> </td> <td align="center" styleCode="Rrule Botrule "> <paragraph>1</paragraph> </td> </tr> <tr> <td styleCode="Rrule Lrule Botrule "> <paragraph>Dyspepsia</paragraph> </td> <td align="center" styleCode="Rrule Botrule "> <paragraph>2</paragraph> </td> <td align="center" styleCode="Rrule Botrule "> <paragraph>0</paragraph> </td> </tr> <tr> <td styleCode="Rrule Lrule Botrule "> <paragraph>Abdominal Pain Upper</paragraph> </td> <td align="center" styleCode="Rrule Botrule "> <paragraph>2</paragraph> </td> <td align="center" styleCode="Rrule Botrule "> <paragraph>1</paragraph> </td> </tr> <tr> <td styleCode="Rrule Lrule Botrule "> <paragraph>Constipation</paragraph> </td> <td align="center" styleCode="Rrule Botrule "> <paragraph>1</paragraph> </td> <td align="center" styleCode="Rrule Botrule "> <paragraph>0</paragraph> </td> </tr> <tr> <td styleCode="Rrule Lrule Botrule "> <paragraph>Vomiting</paragraph> </td> <td align="center" styleCode="Rrule Botrule "> <paragraph>1</paragraph> </td> <td align="center" styleCode="Rrule Botrule "> <paragraph>0</paragraph> </td> </tr> <tr> <td styleCode="Rrule Lrule Botrule "> <paragraph>Loose Stools</paragraph> </td> <td align="center" styleCode="Rrule Botrule "> <paragraph>1</paragraph> </td> <td align="center" styleCode="Rrule Botrule "> <paragraph>0</paragraph> </td> </tr> <tr> <td colspan="3" styleCode="Rrule Lrule Botrule "> <paragraph> <content styleCode="bold">General Disorders And Administration Site Conditions</content> </paragraph> </td> </tr> <tr> <td styleCode="Rrule Lrule Botrule "> <paragraph>Fatigue</paragraph> </td> <td align="center" styleCode="Rrule Botrule "> <paragraph>2</paragraph> </td> <td align="center" styleCode="Rrule Botrule "> <paragraph>1</paragraph> </td> </tr> <tr> <td styleCode="Rrule Lrule Botrule "> <paragraph>Thirst</paragraph> </td> <td align="center" styleCode="Rrule Botrule "> <paragraph>1</paragraph> </td> <td align="center" styleCode="Rrule Botrule "> <paragraph>0</paragraph> </td> </tr> <tr> <td styleCode="Rrule Lrule Botrule "> <paragraph>Influenza-Like Illness</paragraph> </td> <td align="center" styleCode="Rrule Botrule "> <paragraph>1</paragraph> </td> <td align="center" styleCode="Rrule Botrule "> <paragraph>0</paragraph> </td> </tr> <tr> <td styleCode="Rrule Lrule Botrule "> <paragraph>Pain</paragraph> </td> <td align="center" styleCode="Rrule Botrule "> <paragraph>1</paragraph> </td> <td align="center" styleCode="Rrule Botrule "> <paragraph>0</paragraph> </td> </tr> <tr> <td styleCode="Rrule Lrule Botrule "> <paragraph>Pyrexia</paragraph> </td> <td align="center" styleCode="Rrule Botrule "> <paragraph>1</paragraph> </td> <td align="center" styleCode="Rrule Botrule "> <paragraph>0</paragraph> </td> </tr> <tr> <td colspan="3" styleCode="Rrule Lrule Botrule "> <paragraph> <content styleCode="bold">Immune System Disorders</content> </paragraph> </td> </tr> <tr> <td styleCode="Rrule Lrule Botrule "> <paragraph>Seasonal Allergy</paragraph> </td> <td align="center" styleCode="Rrule Botrule "> <paragraph>1</paragraph> </td> <td align="center" styleCode="Rrule Botrule "> <paragraph>0</paragraph> </td> </tr> <tr> <td colspan="3" styleCode="Rrule Lrule Botrule "> <paragraph> <content styleCode="bold">Investigations</content> </paragraph> </td> </tr> <tr> <td styleCode="Rrule Lrule Botrule "> <paragraph>Gamma-Glutamyltransferase Increased</paragraph> </td> <td align="center" styleCode="Rrule Botrule "> <paragraph>1</paragraph> </td> <td align="center" styleCode="Rrule Botrule "> <paragraph>0</paragraph> </td> </tr> <tr> <td styleCode="Rrule Lrule Botrule "> <paragraph> Heart Rate Increased</paragraph> </td> <td align="center" styleCode="Rrule Botrule "> <paragraph>1</paragraph> </td> <td align="center" styleCode="Rrule Botrule "> <paragraph>0</paragraph> </td> </tr> <tr> <td colspan="3" styleCode="Rrule Lrule Botrule "> <paragraph> <content styleCode="bold">Metabolism And Nutrition Disorders</content> </paragraph> </td> </tr> <tr> <td styleCode="Rrule Lrule Botrule "> <paragraph>Anorexia</paragraph> </td> <td align="center" styleCode="Rrule Botrule "> <paragraph>1</paragraph> </td> <td align="center" styleCode="Rrule Botrule "> <paragraph>0</paragraph> </td> </tr> <tr> <td styleCode="Rrule Lrule Botrule "> <paragraph>Decreased Appetite</paragraph> </td> <td align="center" styleCode="Rrule Botrule "> <paragraph>1</paragraph> </td> <td align="center" styleCode="Rrule Botrule "> <paragraph>0</paragraph> </td> </tr> <tr> <td colspan="3" styleCode="Rrule Lrule Botrule "> <paragraph> <content styleCode="bold">Nervous System Disorders</content> </paragraph> </td> </tr> <tr> <td styleCode="Rrule Lrule Botrule "> <paragraph>Headache</paragraph> </td> <td align="center" styleCode="Rrule Botrule "> <paragraph>17</paragraph> </td> <td align="center" styleCode="Rrule Botrule "> <paragraph>9</paragraph> </td> </tr> <tr> <td styleCode="Rrule Lrule Botrule "> <paragraph>Dizziness</paragraph> </td> <td align="center" styleCode="Rrule Botrule "> <paragraph>5</paragraph> </td> <td align="center" styleCode="Rrule Botrule "> <paragraph>2</paragraph> </td> </tr> <tr> <td styleCode="Rrule Lrule Botrule "> <paragraph>Disturbance In Attention</paragraph> </td> <td align="center" styleCode="Rrule Botrule "> <paragraph>1</paragraph> </td> <td align="center" styleCode="Rrule Botrule "> <paragraph>0</paragraph> </td> </tr> <tr> <td styleCode="Rrule Lrule Botrule "> <paragraph>Tremor</paragraph> </td> <td align="center" styleCode="Rrule Botrule "> <paragraph>1</paragraph> </td> <td align="center" styleCode="Rrule Botrule "> <paragraph>0</paragraph> </td> </tr> <tr> <td styleCode="Rrule Lrule Botrule "> <paragraph>Migraine</paragraph> </td> <td align="center" styleCode="Rrule Botrule "> <paragraph>1</paragraph> </td> <td align="center" styleCode="Rrule Botrule "> <paragraph>0</paragraph> </td> </tr> <tr> <td styleCode="Rrule Lrule Botrule "> <paragraph>Paresthesia</paragraph> </td> <td align="center" styleCode="Rrule Botrule "> <paragraph>1</paragraph> </td> <td align="center" styleCode="Rrule Botrule "> <paragraph>0</paragraph> </td> </tr> <tr> <td colspan="3" styleCode="Rrule Lrule Botrule "> <paragraph> <content styleCode="bold">Psychiatric Disorders </content> </paragraph> </td> </tr> <tr> <td styleCode="Rrule Lrule Botrule "> <paragraph>Insomnia</paragraph> </td> <td align="center" styleCode="Rrule Botrule "> <paragraph>5</paragraph> </td> <td align="center" styleCode="Rrule Botrule "> <paragraph>1</paragraph> </td> </tr> <tr> <td styleCode="Rrule Lrule Botrule "> <paragraph>Anxiety</paragraph> </td> <td align="center" styleCode="Rrule Botrule "> <paragraph>4</paragraph> </td> <td align="center" styleCode="Rrule Botrule "> <paragraph>1</paragraph> </td> </tr> <tr> <td styleCode="Rrule Lrule Botrule "> <paragraph>Depression</paragraph> </td> <td align="center" styleCode="Rrule Botrule "> <paragraph>2</paragraph> </td> <td align="center" styleCode="Rrule Botrule "> <paragraph>0</paragraph> </td> </tr> <tr> <td styleCode="Rrule Lrule Botrule "> <paragraph>Agitation</paragraph> </td> <td align="center" styleCode="Rrule Botrule "> <paragraph>1</paragraph> </td> <td align="center" styleCode="Rrule Botrule "> <paragraph>0</paragraph> </td> </tr> <tr> <td styleCode="Rrule Lrule Botrule "> <paragraph>Nervousness</paragraph> </td> <td align="center" styleCode="Rrule Botrule "> <paragraph>1</paragraph> </td> <td align="center" styleCode="Rrule Botrule "> <paragraph>0</paragraph> </td> </tr> <tr> <td styleCode="Rrule Lrule Botrule "> <paragraph>Depressed Mood</paragraph> </td> <td align="center" styleCode="Rrule Botrule "> <paragraph>1</paragraph> </td> <td align="center" styleCode="Rrule Botrule "> <paragraph>0</paragraph> </td> </tr> <tr> <td colspan="3" styleCode="Rrule Lrule Botrule "> <paragraph> <content styleCode="bold">Renal And Urinary Disorders</content> </paragraph> </td> </tr> <tr> <td styleCode="Rrule Lrule Botrule "> <paragraph>Polyuria</paragraph> </td> <td align="center" styleCode="Rrule Botrule "> <paragraph>1</paragraph> </td> <td align="center" styleCode="Rrule Botrule "> <paragraph>0</paragraph> </td> </tr> <tr> <td colspan="3" styleCode="Rrule Lrule Botrule "> <paragraph> <content styleCode="bold">Respiratory, Thoracic And Mediastinal Disorders</content> </paragraph> </td> </tr> <tr> <td styleCode="Rrule Lrule Botrule "> <paragraph>Dyspnea</paragraph> </td> <td align="center" styleCode="Rrule Botrule "> <paragraph>1</paragraph> </td> <td align="center" styleCode="Rrule Botrule "> <paragraph>0</paragraph> </td> </tr> <tr> <td colspan="3" styleCode="Rrule Lrule Botrule "> <paragraph> <content styleCode="bold">Skin And Subcutaneous Tissue Disorders</content> </paragraph> </td> </tr> <tr> <td styleCode="Rrule Lrule Botrule "> <paragraph>Rash</paragraph> </td> <td align="center" styleCode="Rrule Botrule "> <paragraph>2</paragraph> </td> <td align="center" styleCode="Rrule Botrule "> <paragraph>0</paragraph> </td> </tr> <tr> <td styleCode="Rrule Lrule Botrule "> <paragraph>Contact Dermatitis </paragraph> </td> <td align="center" styleCode="Rrule Botrule "> <paragraph>1</paragraph> </td> <td align="center" styleCode="Rrule Botrule "> <paragraph>0</paragraph> </td> </tr> <tr> <td styleCode="Rrule Botrule Lrule "> <paragraph>Hyperhydrosis</paragraph> </td> <td align="center" styleCode="Rrule Botrule "> <paragraph>1</paragraph> </td> <td align="center" styleCode="Rrule Botrule "> <paragraph>0</paragraph> </td> </tr> </tbody> </table>

<table ID="_Refid_b5fcb86a-634c-43b1-a249-be8a3a1ef" width="100%"> <caption>Table 2. Incidence of Dose-Dependent, Treatment-Emergent Adverse Experiences By Dose and By Treatment In Parallel-Group, Placebo-Controlled Clinical Trials* In OSA, Narcolepsy and SWD With NUVIGIL (150 mg and 250 mg)</caption> <col width="28%"/> <col width="12%"/> <col width="12%"/> <col width="23%"/> <col width="10%"/> <tfoot> <tr> <td align="left" colspan="8" styleCode="Botrule" valign="top">*Four double-blind, placebo-controlled clinical studies in SWD, OSA, and narcolepsy.</td> </tr> </tfoot> <tbody> <tr> <td styleCode="Rrule Botrule Lrule Toprule "> <paragraph> <content styleCode="bold">System Organ Class</content> <content styleCode="bold"> MedDRA preferred term</content> </paragraph> </td> <td align="center" styleCode="Rrule Botrule Toprule " valign="middle"> <paragraph> <content styleCode="bold">NUVIGIL </content> <content styleCode="bold">250 mg</content> <content styleCode="bold">(%)</content> <content styleCode="bold">N=198</content> </paragraph> </td> <td align="center" styleCode="Rrule Botrule Toprule " valign="middle"> <paragraph> <content styleCode="bold">NUVIGIL </content> <content styleCode="bold">150 mg</content> <content styleCode="bold">(%) N=447</content> </paragraph> </td> <td align="center" styleCode="Rrule Botrule Toprule " valign="middle"> <paragraph> <content styleCode="bold">NUVIGIL Combined</content> <content styleCode="bold">(%)</content> <content styleCode="bold">N=645</content> </paragraph> </td> <td align="center" styleCode="Rrule Botrule Toprule "> <paragraph> <content styleCode="bold">Placebo</content> <content styleCode="bold">(%)</content> <content styleCode="bold">N=445</content> </paragraph> </td> </tr> <tr> <td colspan="5" styleCode="Rrule Lrule Botrule "> <paragraph> <content styleCode="bold">Gastrointestinal Disorders</content> </paragraph> </td> </tr> <tr> <td styleCode="Rrule Lrule Botrule "> <paragraph>Nausea</paragraph> </td> <td align="center" styleCode="Rrule Botrule "> <paragraph>9</paragraph> </td> <td align="center" styleCode="Rrule Botrule "> <paragraph>6</paragraph> </td> <td align="center" styleCode="Rrule Botrule "> <paragraph>7</paragraph> </td> <td align="center" styleCode="Rrule Botrule "> <paragraph>3</paragraph> </td> </tr> <tr> <td styleCode="Rrule Lrule Botrule "> <paragraph>Dry Mouth</paragraph> </td> <td align="center" styleCode="Rrule Botrule "> <paragraph>7</paragraph> </td> <td align="center" styleCode="Rrule Botrule "> <paragraph>2</paragraph> </td> <td align="center" styleCode="Rrule Botrule "> <paragraph>4</paragraph> </td> <td align="center" styleCode="Rrule Botrule "> <paragraph>&lt;1</paragraph> </td> </tr> <tr> <td colspan="5" styleCode="Rrule Lrule Botrule "> <paragraph> <content styleCode="bold">Nervous System Disorders</content> </paragraph> </td> </tr> <tr> <td styleCode="Rrule Lrule Botrule "> <paragraph>Headache</paragraph> </td> <td align="center" styleCode="Rrule Botrule "> <paragraph>23</paragraph> </td> <td align="center" styleCode="Rrule Botrule "> <paragraph>14</paragraph> </td> <td align="center" styleCode="Rrule Botrule "> <paragraph>17</paragraph> </td> <td align="center" styleCode="Rrule Botrule "> <paragraph>9</paragraph> </td> </tr> <tr> <td colspan="5" styleCode="Rrule Lrule Botrule "> <paragraph> <content styleCode="bold">Psychiatric Disorders</content> </paragraph> </td> </tr> <tr> <td styleCode="Rrule Lrule Botrule "> <paragraph>Insomnia</paragraph> </td> <td align="center" styleCode="Rrule Botrule "> <paragraph>6</paragraph> </td> <td align="center" styleCode="Rrule Botrule "> <paragraph>4</paragraph> </td> <td align="center" styleCode="Rrule Botrule "> <paragraph>5</paragraph> </td> <td align="center" styleCode="Rrule Botrule "> <paragraph>1</paragraph> </td> </tr> <tr> <td styleCode="Rrule Lrule Botrule "> <paragraph>Depression</paragraph> </td> <td align="center" styleCode="Rrule Botrule "> <paragraph>3</paragraph> </td> <td align="center" styleCode="Rrule Botrule "> <paragraph>1</paragraph> </td> <td align="center" styleCode="Rrule Botrule "> <paragraph>2</paragraph> </td> <td align="center" styleCode="Rrule Botrule "> <paragraph>&lt;1</paragraph> </td> </tr> <tr> <td colspan="5" styleCode="Rrule Lrule Botrule "> <paragraph> <content styleCode="bold">Skin And Subcutaneous Tissue Disorders</content> </paragraph> </td> </tr> <tr> <td styleCode="Rrule Botrule Lrule "> <paragraph>Rash</paragraph> </td> <td align="center" styleCode="Rrule Botrule "> <paragraph>4</paragraph> </td> <td align="center" styleCode="Rrule Botrule "> <paragraph>1</paragraph> </td> <td align="center" styleCode="Rrule Botrule "> <paragraph>2</paragraph> </td> <td align="center" styleCode="Rrule Botrule "> <paragraph>&lt;1</paragraph> </td> </tr> </tbody> </table>