BYFAVO

WARNING: PERSONNEL AND EQUIPMENT FOR MONITORING AND RESUSCITATION AND RISKS FROM CONCOMITANT USE WITH OPIOID ANALGESICS WARNING: PERSONNEL AND EQUIPMENT FOR MONITORING AND RESUSCITATION, AND RISKS FROM CONCOMITANT USE WITH OPIOID ANALGESICS AND OTHER SEDATIVE-HYPNOTICS See full prescribing information for complete boxed warning Only personnel trained in the administration of procedural sedation, and not involved in the conduct of the diagnostic or therapeutic procedure, should administer BYFAVO. ( 2.1 , 5.1 ) Administering personnel must be trained in the detection and management of airway obstruction, hypoventilation, and apnea, including the maintenance of a patent airway, supportive ventilation, and cardiovascular resuscitation. ( 2.1 , 5.1 ) BYFAVO has been associated with hypoxia, bradycardia, and hypotension. Continuously monitor vital signs during sedation and through the recovery period. ( 2.1 , 5.1 ) Resuscitative drugs, and age- and size-appropriate equipment for bag/valve/mask assisted ventilation must be immediately available during administration of BYFAVO. ( 2.1 , 5.1 ) Concomitant use of benzodiazepines with opioid analgesics may result in profound sedation, respiratory depression, coma, and death. The sedative effect of intravenous BYFAVO can be accentuated by concomitantly administered CNS depressant medications, including other benzodiazepines and propofol. Continuously monitor patients for respiratory depression and depth of sedation. ( 5.2 , 7.1 ) Personnel and Equipment for Monitoring and Resuscitation Only personnel trained in the administration of procedural sedation, and not involved in the conduct of the diagnostic or therapeutic procedure, should administer BYFAVO [see Dosage and Administration (2.1) , Warnings and Precautions (5.1) ] . Administering personnel must be trained in the detection and management of airway obstruction, hypoventilation, and apnea, including the maintenance of a patent airway, supportive ventilation, and cardiovascular resuscitation [see Dosage and Administration (2.1) , Warnings and Precautions (5.1) ] . BYFAVO has been associated with hypoxia, bradycardia, and hypotension. Continuously monitor vital signs during sedation and during the recovery period [see Dosage and Administration (2.1) , Warnings and Precautions (5.1) ] . Resuscitative drugs, and age- and size-appropriate equipment for bag/valve/mask assisted ventilation must be immediately available during administration of BYFAVO [see Dosage and Administration (2.1) , Warnings and Precautions (5.1) ]. Risks From Concomitant Use With Opioid Analgesics and Other Sedative-Hypnotics Concomitant use of benzodiazepines, including BYFAVO, and opioid analgesics may result in profound sedation, respiratory depression, coma, and death. The sedative effect of intravenous BYFAVO can be accentuated by concomitantly administered CNS depressant medications, including other benzodiazepines and propofol. Continuously monitor patients for respiratory depression and depth of sedation [see Warnings and Precautions (5.2) , Drug Interactions (7.1) ] .

5 WARNINGS AND PRECAUTIONS Hypersensitivity Reactions : Hypersensitivity reactions including anaphylaxis may occur. ( 5.3 ) Neonatal Sedation and Withdrawal Syndrome : Receiving benzodiazepines during pregnancy can result in neonatal sedation and/or neonatal withdrawal. ( 5.4 , 8.1 ) Pediatric Neurotoxicity : In developing animals, exposures greater than 3 hours cause neurotoxicity. Weigh benefits against potential risks when considering elective procedures in children under 3 years old. ( 5.5 ) 5.1 Personnel and Equipment for Monitoring and Resuscitation Clinically notable hypoxia, bradycardia, and hypotension were observed in Phase 3 studies of BYFAVO. Continuously monitor vital signs during sedation and through the recovery period. Only personnel trained in the administration of procedural sedation, and not involved in the conduct of the diagnostic or therapeutic procedure, should administer BYFAVO. Administering personnel must be trained in the detection and management of airway obstruction, hypoventilation, and apnea, including the maintenance of a patent airway, supportive ventilation, and cardiovascular resuscitation. Resuscitative drugs, and age- and size-appropriate equipment for bag/valve/mask assisted ventilation must be immediately available during administration of BYFAVO [see Dosage and Administration (2.1) ] . Consider the potential for worsened cardiorespiratory depression prior to using BYFAVO concomitantly with other drugs that have the same potential (e.g., opioid analgesics or other sedative-hypnotics) [see Drug Interactions (7.1) ]. Administer supplemental oxygen to sedated patients through the recovery period. A benzodiazepine reversal agent (flumazenil) should be immediately available during administration of BYFAVO [see Overdosage (10) ]. 5.2 Risks from Concomitant Use with Opioid Analgesics and Other Sedative-Hypnotics Concomitant use of benzodiazepines, including BYFAVO, and opioid analgesics may result in profound sedation, respiratory depression, coma, and death [see Drug Interactions (7.1) ]. The sedative effect of intravenous BYFAVO can be accentuated by concomitantly administered CNS depressant medications, including other benzodiazepines and propofol. Titrate the dose of BYFAVO when administered with opioid analgesics and sedative-hypnotics to the desired clinical response. Continuously monitor sedated patients for hypotension, airway obstruction, hypoventilation, apnea, and oxygen desaturation. These cardiorespiratory effects may be more likely to occur in patients with obstructive sleep apnea, the elderly, and ASA III or IV patients. 5.3 Hypersensitivity Reactions BYFAVO contains dextran 40, which can cause hypersensitivity reactions, including rash, urticaria, pruritus, and anaphylaxis. BYFAVO is contraindicated in patients with a history of severe hypersensitivity reaction to dextran 40 or products containing dextran 40 [see Contraindications (4) , Adverse Reactions (6) ]. 5.4 Neonatal Sedation and Withdrawal Syndrome Receiving benzodiazepines late in pregnancy can result in sedation (respiratory depression, lethargy, hypotonia) and/or withdrawal symptoms (hyperreflexia, irritability, restlessness, tremors, inconsolable crying, and feeding difficulties) in the neonate. Monitor neonates exposed to benzodiazepines, including BYFAVO, during pregnancy or labor for signs of sedation and monitor neonates exposed to benzodiazepines during pregnancy for signs of withdrawal and manage these neonates accordingly [see Use in Specific Populations (8.1) ]. 5.5 Pediatric Neurotoxicity Published animal studies demonstrate that the administration of anesthetic and sedation drugs that block NMDA receptors and/or potentiate GABA activity increase neuronal apoptosis in the developing brain and result in long-term cognitive deficits when used for longer than 3 hours. The clinical significance of these findings is not clear. However, based on the available data, the window of vulnerability to these changes is believed to correlate with exposures in the third trimester of gestation through the first several months of life, but may extend out to approximately three years of age in humans [see Use in Specific Populations (8.1 , 8.4) , Nonclinical Pharmacology (13.2) ] . Some published studies in children suggest that similar deficits may occur after repeated or prolonged exposures to anesthetic agents early in life and may result in adverse cognitive or behavioral effects. These studies have substantial limitations, and it is not clear if the observed effects are due to the anesthetic/sedation drug administration or other factors such as the surgery or underlying illness. Anesthetic and sedation drugs are a necessary part of the care of children needing surgery, other procedures, or tests that cannot be delayed, and no specific medications have been shown to be safer than any other. Decisions regarding the timing of any elective procedures requiring anesthesia should take into consideration the benefits of the procedure weighed against the potential risks.

6 ADVERSE REACTIONS The following serious adverse reactions are discussed in greater detail in other sections: Neonatal Sedation and Withdrawal Syndrome [see Warnings and Precautions (5.4) , Use in Specific Populations (8.1) ] The most common adverse reactions (>10%) in patients receiving BYFAVO for procedural sedation are hypotension, hypertension, diastolic hypertension, systolic hypertension, hypoxia, and diastolic hypotension. ( 6 ) To report SUSPECTED ADVERSE REACTIONS, contact Acacia Pharma at 1-877-357-9237 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. The safety of BYFAVO was evaluated in three prospective, randomized, double-blind, multicenter, parallel group clinical studies in 630 patients undergoing colonoscopy (two studies) or bronchoscopy (one study). Colonoscopy Study 1 and the bronchoscopy study evaluated American Society of Anesthesiologists (ASA) physical status I to III patients, and Colonoscopy Study 2 evaluated ASA III and IV patients. All three studies evaluated the safety of BYFAVO compared to placebo with midazolam rescue and an open-label midazolam treatment arm. Patients were administered a total dose ranging from 5 to 30 mg of BYFAVO. In these studies, the most common adverse reactions (incidence greater than 10%) following BYFAVO administration were hypotension, hypertension, diastolic hypertension, systolic hypertension, hypoxia, and diastolic hypotension. There were two patients who experienced an adverse reaction that led to discontinuation of study drug. One patient in the BYFAVO arm in the bronchoscopy study discontinued treatment due to bradycardia, hypertension, hypotension, hypoxia, and respiratory rate increase. One patient in the open-label midazolam arm in Colonoscopy Study 2 discontinued due to respiratory acidosis. No deaths were reported during the studies. Tables 1-3 provide a summary of the common adverse reactions observed in each of the three Phase 3 studies with BYFAVO. Table 1: Common Adverse Reactions in Colonoscopy Study 1 (Incidence >2%), ASA I to III Adverse Reaction BYFAVO N = 296 Placebo (with Midazolam Rescue 57/60 (95%) patients received midazolam rescue. ) N = 60 Midazolam N = 102 n (%) n (%) n (%) Hypotension Hypotension defined as a fall in systolic BP to ≤80 mmHg or in diastolic BP to ≤40 mmHg, or a fall in systolic or diastolic BP of 20% or more below baseline or necessitating medical intervention. 115 (39%) 25 (42%) 63 (62%) Hypertension Hypertension defined as an increase in systolic BP to ≥180 mmHg or in diastolic BP to ≥100 mmHg, or an increase of systolic or diastolic BP of 20% or more over baseline or necessitating medical intervention. 59 (20%) 17 (28%) 18 (18%) Bradycardia 33 (11%) 7 (12%) 16 (16%) Diastolic hypertension 29 (10%) 6 (10%) 9 (9%) Tachycardia 23 (8%) 7 (12%) 13 (13%) Diastolic hypotension 23 (8%) 4 (7%) 9 (9%) Systolic hypertension 16 (5%) 5 (8%) 6 (6%) Table 2: Common Adverse Reactions in Bronchoscopy Study (Incidence >2%) Adverse Reaction BYFAVO N = 303 Placebo (with Midazolam Rescue 57/59 (97%) patients received midazolam rescue. ) N = 59 Midazolam N = 69 n (%) n (%) n (%) Hypotension Hypotension defined as a fall in systolic BP to ≤80 mmHg or in diastolic BP to ≤40 mmHg, or a fall in systolic or diastolic BP of 20% or more below baseline or necessitating medical intervention. 99 (33%) 28 (47%) 23 (33%) Hypertension Hypertension defined as an increase in systolic BP to ≥180 mmHg or in diastolic BP to ≥100 mmHg, or an increase of systolic or diastolic BP of 20% or more over baseline or necessitating medical intervention. 85 (28%) 9 (15%) 19 (28%) Diastolic hypertension 77 (25%) 15 (25%) 16 (23%) Systolic hypertension 67 (22%) 13 (22%) 17 (25%) Hypoxia 66 (22%) 12 (20%) 13 (19%) Respiratory rate increased 43 (14%) 6 (10%) 10 (14%) Diastolic hypotension 41 (14%) 17 (29%) 16 (23%) Nausea 12 (4%) 2 (3%) 2 (3%) Bradycardia 11 (4%) 4 (7%) 4 (6%) Pyrexia 11 (4%) 1 (2%) 1 (1%) Headache 8 (3%) 0 (0%) 3 (4%) Table 3: Common Adverse Reactions in Colonoscopy Study 2 (Incidence >2%), ASA III and IV Adverse Reaction BYFAVO N = 31 Placebo (with Midazolam Rescue 16/16 (100%) patients received midazolam rescue. ) N = 16 Midazolam N = 30 n (%) n (%) n (%) Hypotension Hypotension defined as a fall in systolic BP to ≤80 mmHg or in diastolic BP to ≤40 mmHg, or a fall in systolic or diastolic BP of 20% or more below baseline or necessitating medical intervention. 18 (58%) 11 (69%) 17 (57%) Hypertension Hypertension defined as an increase in systolic BP to ≥180 mmHg or in diastolic BP to ≥100 mmHg, or an increase of systolic or diastolic BP of 20% or more over baseline or necessitating medical intervention. 13 (42%) 6 (38%) 13 (43%) Respiratory acidosis 6 (19%) 2 (13%) 8 (27%) Diastolic hypertension 3 (10%) 0 (0%) 0 (0%) Systolic hypertension 2 (6%) 0 (0%) 0 (0%) Bradycardia 1 (3%) 1 (6%) 4 (13%) Respiratory rate decreased 1 (3%) 1 (6%) 2 (7%) Diastolic hypotension 1 (3%) 1 (6%) 0 (0%) Blood pressure diastolic increased 1 (3%) 0 (0%) 0 (0%) Blood pressure increased 1 (3%) 0 (0%) 0 (0%) Blood pressure systolic increased 1 (3%) 0 (0%) 0 (0%) Upper respiratory tract infection 1 (3%) 0 (0%) 0 (0%) Adverse reaction data from Colonoscopy Study 1 and the bronchoscopy study analyzed according to the cumulative dose of concomitant fentanyl (<100 mcg, 100-150 mcg and >150 mcg) suggest an increase in some adverse reactions with increasing fentanyl dose, such as hypotension, hypertension, bradycardia, hypoxia, and increased respiratory rate (see Table 4 and Table 5 ). There were too few patients in each fentanyl stratum in Colonoscopy Study 2 to perform this analysis. Table 4: Common Adverse Reactions Incidence >2% of patients. in Colonoscopy Study 1 by Cumulative Fentanyl Dose BYFAVO Placebo (with Midazolam Rescue 57/60 (95%) patients received midazolam rescue. ) Midazolam Fentanyl dose (mcg) <100 100-150 >150 <100 100-150 >150 <100 100-150 >150 N = 148 N = 146 N = 2 N = 9 N = 43 N = 8 N = 31 N = 62 N = 9 Adverse Reaction n (%) n (%) n (%) n (%) n (%) n (%) n (%) n (%) n (%) Hypotension Hypotension defined as a fall in systolic BP to ≤80 mmHg or in diastolic BP to ≤40 mmHg, or a fall in systolic or diastolic BP of 20% or more below baseline or necessitating medical intervention. 49 (33%) 64 (44%) 2 (100%) 5 (56%) 17 (40%) 3 (38%) 18 (58%) 36 (58%) 9 (100%) Hypertension Hypertension defined as an increase in systolic BP to ≥180 mmHg or in diastolic BP to ≥100 mmHg, or an increase of systolic or diastolic BP of 20% or more over baseline or necessitating medical intervention. 24 (16%) 35 (24%) 0 (0%) 1 (11%) 14 (33%) 2 (25%) 3 (10%) 12 (19%) 3 (33%) Bradycardia 12 (8%) 20 (14%) 1 (50%) 0 (0%) 5 (12%) 2 (25%) 1 (3%) 13 (21%) 2 (22%) Diastolic hypertension 9 (6%) 20 (14%) 0 (0%) 0 (0%) 3 (7%) 3 (38%) 2 (6%) 7 (11%) 0 (0%) Tachycardia 10 (7%) 12 (8%) 1 (50%) 0 (0%) 6 (14%) 1 (13%) 2 (6%) 8 (13%) 3 (33%) Diastolic hypotension 10 (7%) 13 (9%) 0 (0%) 0 (0%) 3 (7%) 1 (13%) 3 (10%) 4 (6%) 2 (22%) Systolic hypertension 5 (3%) 11 (8%) 0 (0%) 0 (0%) 3 (7%) 2 (25%) 4 (13%) 2 (3%) 0 (0%) Table 5: Common Adverse Reactions Incidence >2% of patients. in Bronchoscopy Study by Cumulative Fentanyl Dose BYFAVO Placebo (with Midazolam Rescue 57/59 (97%) patients received midazolam rescue. ) Midazolam Fentanyl dose (mcg) <100 100-150 >150 <100 100-150 >150 <100 100-150 >150 N = 215 N = 63 N = 25 N = 26 N = 18 N = 15 N = 29 N = 27 N = 13 Adverse Reaction n (%) n (%) n (%) n (%) n (%) n (%) n (%) n (%) n (%) Hypotension Hypotension defined as a fall in systolic BP to ≤ 80 mmHg or in diastolic BP to ≤40 mmHg, or a fall in systolic or diastolic BP of 20% or more below baseline or necessitating medical intervention. 52 (24%) 32 (51%) 16 (64%) 7 (27%) 9 (50%) 12 (80%) 7 (24%) 7 (26%) 9 (69%) Hypertension Hypertension defined as an increase in systolic BP to ≥180 mmHg or in diastolic BP to ≥100 mmHg, or an increase of systolic or diastolic BP of 20% or more over baseline or necessitating medical intervention. 43 (20%) 25 (40%) 18 (72%) 2 (8%) 2 (11%) 5 (33%) 3 (10%) 8 (30%) 8 (62%) Diastolic hypertension 65 (30%) 12 (19%) 0 (0%) 11 (42%) 3 (17%) 1 (7%) 10 (34%) 6 (22%) 0 (0%) Systolic hypertension 55 (26%) 11 (17%) 1 (4%) 10 (38%) 3 (17%) 0 (0%) 9 (31%) 6 (22%) 2 (15%) Hypoxia 35 (16%) 22 (35%) 9 (36%) 6 (23%) 2 (11%) 4 (27%) 2 (7%) 5 (19%) 6 (46%) Respiratory rate increased 22 (10%) 12 (19%) 9 (36%) 1 (4%) 2 (11%) 3 (20%) 2 (7%) 5 (19%) 3 (23%) Diastolic hypotension 28 (13%) 13 (21%) 0 (0%) 8 (31%) 7 (39%) 2 (13%) 7 (24%) 6 (22%) 3 (23%) Nausea 9 (4%) 1 (2%) 2 (8%) 0 (0%) 0 (0%) 2 (13%) 1 (3%) 1 (4%) 0 (0%) Bradycardia 3 (1%) 4 (6%) 4 (16%) 2 (8%) 1 (6%) 1 (7%) 0 (0%) 2 (7%) 2 (15%) Pyrexia 7 (3%) 2 (3%) 2 (8%) 0 (0%) 0 (0%) 1 (7%) 1 (3%) 0 (0%) 0 (0%) Headache 5 (2%) 2 (3%) 1 (4%) 0 (0%) 0 (0%) 0 (0%) 0 (0%) 3 (11%) 0 (0)%

<table width="90%"><caption>Table 1: Common Adverse Reactions in Colonoscopy Study 1 (Incidence &gt;2%), ASA I to III</caption><col width="30%" align="left" valign="middle"/><col width="23%" align="center" valign="middle"/><col width="24%" align="center" valign="middle"/><col width="23%" align="center" valign="middle"/><thead><tr><th styleCode="Lrule Rrule" rowspan="2" align="center">Adverse Reaction</th><th styleCode="Rrule">BYFAVO N = 296</th><th styleCode="Rrule">Placebo (with Midazolam Rescue<footnote>57/60 (95%) patients received midazolam rescue.</footnote>) N = 60</th><th styleCode="Rrule">Midazolam N = 102</th></tr><tr><th styleCode="Rrule" align="center">n (%)</th><th styleCode="Rrule">n (%)</th><th styleCode="Rrule">n (%)</th></tr></thead><tbody><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Hypotension<footnote ID="foot1">Hypotension defined as a fall in systolic BP to &#x2264;80 mmHg or in diastolic BP to &#x2264;40 mmHg, or a fall in systolic or diastolic BP of 20% or more below baseline or necessitating medical intervention.</footnote></td><td styleCode="Rrule">115 (39%)</td><td styleCode="Rrule">25 (42%)</td><td styleCode="Rrule">63 (62%)</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Hypertension<footnote ID="foot2">Hypertension defined as an increase in systolic BP to &#x2265;180 mmHg or in diastolic BP to &#x2265;100 mmHg, or an increase of systolic or diastolic BP of 20% or more over baseline or necessitating medical intervention.</footnote></td><td styleCode="Rrule">59 (20%)</td><td styleCode="Rrule">17 (28%)</td><td styleCode="Rrule">18 (18%)</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Bradycardia</td><td styleCode="Rrule">33 (11%)</td><td styleCode="Rrule">7 (12%)</td><td styleCode="Rrule">16 (16%)</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Diastolic hypertension<footnoteRef IDREF="foot2"/></td><td styleCode="Rrule">29 (10%)</td><td styleCode="Rrule">6 (10%)</td><td styleCode="Rrule">9 (9%)</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Tachycardia</td><td styleCode="Rrule">23 (8%)</td><td styleCode="Rrule">7 (12%)</td><td styleCode="Rrule">13 (13%)</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Diastolic hypotension<footnoteRef IDREF="foot1"/></td><td styleCode="Rrule">23 (8%)</td><td styleCode="Rrule">4 (7%)</td><td styleCode="Rrule">9 (9%)</td></tr><tr><td styleCode="Lrule Rrule">Systolic hypertension<footnoteRef IDREF="foot2"/></td><td styleCode="Rrule">16 (5%)</td><td styleCode="Rrule">5 (8%)</td><td styleCode="Rrule">6 (6%)</td></tr></tbody></table>

<table width="90%"><caption>Table 2: Common Adverse Reactions in Bronchoscopy Study (Incidence &gt;2%)</caption><col width="30%" align="left" valign="middle"/><col width="23%" align="center" valign="middle"/><col width="24%" align="center" valign="middle"/><col width="23%" align="center" valign="middle"/><thead><tr><th styleCode="Lrule Rrule" rowspan="2" align="center">Adverse Reaction</th><th styleCode="Rrule">BYFAVO N = 303</th><th styleCode="Rrule">Placebo (with Midazolam Rescue<footnote>57/59 (97%) patients received midazolam rescue.</footnote>) N = 59</th><th styleCode="Rrule">Midazolam N = 69</th></tr><tr><th styleCode="Rrule" align="center">n (%)</th><th styleCode="Rrule">n (%)</th><th styleCode="Rrule">n (%)</th></tr></thead><tbody><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Hypotension<footnote ID="foot3">Hypotension defined as a fall in systolic BP to &#x2264;80 mmHg or in diastolic BP to &#x2264;40 mmHg, or a fall in systolic or diastolic BP of 20% or more below baseline or necessitating medical intervention.</footnote></td><td styleCode="Rrule">99 (33%)</td><td styleCode="Rrule">28 (47%)</td><td styleCode="Rrule">23 (33%)</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Hypertension<footnote ID="foot4">Hypertension defined as an increase in systolic BP to &#x2265;180 mmHg or in diastolic BP to &#x2265;100 mmHg, or an increase of systolic or diastolic BP of 20% or more over baseline or necessitating medical intervention.</footnote></td><td styleCode="Rrule">85 (28%)</td><td styleCode="Rrule">9 (15%)</td><td styleCode="Rrule">19 (28%)</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Diastolic hypertension<footnoteRef IDREF="foot4"/></td><td styleCode="Rrule">77 (25%)</td><td styleCode="Rrule">15 (25%)</td><td styleCode="Rrule">16 (23%)</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Systolic hypertension<footnoteRef IDREF="foot4"/></td><td styleCode="Rrule">67 (22%)</td><td styleCode="Rrule">13 (22%)</td><td styleCode="Rrule">17 (25%)</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Hypoxia</td><td styleCode="Rrule">66 (22%)</td><td styleCode="Rrule">12 (20%)</td><td styleCode="Rrule">13 (19%)</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Respiratory rate increased</td><td styleCode="Rrule">43 (14%)</td><td styleCode="Rrule">6 (10%)</td><td styleCode="Rrule">10 (14%)</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Diastolic hypotension<footnoteRef IDREF="foot3"/></td><td styleCode="Rrule">41 (14%)</td><td styleCode="Rrule">17 (29%)</td><td styleCode="Rrule">16 (23%)</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Nausea</td><td styleCode="Rrule">12 (4%)</td><td styleCode="Rrule">2 (3%)</td><td styleCode="Rrule">2 (3%)</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Bradycardia</td><td styleCode="Rrule">11 (4%)</td><td styleCode="Rrule">4 (7%)</td><td styleCode="Rrule">4 (6%)</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Pyrexia</td><td styleCode="Rrule">11 (4%)</td><td styleCode="Rrule">1 (2%)</td><td styleCode="Rrule">1 (1%)</td></tr><tr><td styleCode="Lrule Rrule">Headache</td><td styleCode="Rrule">8 (3%)</td><td styleCode="Rrule">0 (0%)</td><td styleCode="Rrule">3 (4%)</td></tr></tbody></table>

<table width="90%"><caption>Table 3: Common Adverse Reactions in Colonoscopy Study 2 (Incidence &gt;2%), ASA III and IV</caption><col width="30%" align="left" valign="middle"/><col width="23%" align="center" valign="middle"/><col width="24%" align="center" valign="middle"/><col width="23%" align="center" valign="middle"/><thead><tr><th styleCode="Lrule Rrule" rowspan="2" align="center">Adverse Reaction</th><th styleCode="Rrule">BYFAVO N = 31</th><th styleCode="Rrule">Placebo (with Midazolam Rescue<footnote>16/16 (100%) patients received midazolam rescue.</footnote>) N = 16</th><th styleCode="Rrule">Midazolam N = 30</th></tr><tr><th styleCode="Rrule" align="center">n (%)</th><th styleCode="Rrule">n (%)</th><th styleCode="Rrule">n (%)</th></tr></thead><tbody><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Hypotension<footnote ID="foot5">Hypotension defined as a fall in systolic BP to &#x2264;80 mmHg or in diastolic BP to &#x2264;40 mmHg, or a fall in systolic or diastolic BP of 20% or more below baseline or necessitating medical intervention.</footnote></td><td styleCode="Rrule">18 (58%)</td><td styleCode="Rrule">11 (69%)</td><td styleCode="Rrule">17 (57%)</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Hypertension<footnote ID="foot6">Hypertension defined as an increase in systolic BP to &#x2265;180 mmHg or in diastolic BP to &#x2265;100 mmHg, or an increase of systolic or diastolic BP of 20% or more over baseline or necessitating medical intervention.</footnote></td><td styleCode="Rrule">13 (42%)</td><td styleCode="Rrule">6 (38%)</td><td styleCode="Rrule">13 (43%)</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Respiratory acidosis</td><td styleCode="Rrule">6 (19%)</td><td styleCode="Rrule">2 (13%)</td><td styleCode="Rrule">8 (27%)</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Diastolic hypertension<footnoteRef IDREF="foot6"/></td><td styleCode="Rrule">3 (10%)</td><td styleCode="Rrule">0 (0%)</td><td styleCode="Rrule">0 (0%)</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Systolic hypertension<footnoteRef IDREF="foot6"/></td><td styleCode="Rrule">2 (6%)</td><td styleCode="Rrule">0 (0%)</td><td styleCode="Rrule">0 (0%)</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Bradycardia</td><td styleCode="Rrule">1 (3%)</td><td styleCode="Rrule">1 (6%)</td><td styleCode="Rrule">4 (13%)</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Respiratory rate decreased</td><td styleCode="Rrule">1 (3%)</td><td styleCode="Rrule">1 (6%)</td><td styleCode="Rrule">2 (7%)</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Diastolic hypotension<footnoteRef IDREF="foot5"/></td><td styleCode="Rrule">1 (3%)</td><td styleCode="Rrule">1 (6%)</td><td styleCode="Rrule">0 (0%)</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Blood pressure diastolic increased</td><td styleCode="Rrule">1 (3%)</td><td styleCode="Rrule">0 (0%)</td><td styleCode="Rrule">0 (0%)</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Blood pressure increased</td><td styleCode="Rrule">1 (3%)</td><td styleCode="Rrule">0 (0%)</td><td styleCode="Rrule">0 (0%)</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Blood pressure systolic increased</td><td styleCode="Rrule">1 (3%)</td><td styleCode="Rrule">0 (0%)</td><td styleCode="Rrule">0 (0%)</td></tr><tr><td styleCode="Lrule Rrule">Upper respiratory tract infection</td><td styleCode="Rrule">1 (3%)</td><td styleCode="Rrule">0 (0%)</td><td styleCode="Rrule">0 (0%)</td></tr></tbody></table>