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warnings and cautions
5 WARNINGS AND PRECAUTIONS A person trained in the administration of general anesthesia and not involved in the conduct of the diagnostic/therapeutic procedure should manage treatment of patients with LUSEDRA. ( 5.1 ) Respiratory depression ( 5.2 ) Hypoxemia ( 5.3 ) Hypotension ( 5.5 ) 5.1 Monitoring LUSEDRA should be administered only by persons trained in the administration of general anesthesia and not involved in the conduct of the diagnostic or therapeutic procedure. Sedated patients should be continuously monitored, and facilities for maintenance of a patent airway, providing artificial ventilation, administering supplemental oxygen, and instituting cardiovascular resuscitation must be immediately available. Patients should be continuously monitored during sedation and through the recovery process for early signs of hypotension, apnea, airway obstruction, and/or oxygen desaturation. 5.2 Respiratory Depression LUSEDRA may cause loss of spontaneous respiration. Apnea was reported in 1/455 (< 1%) patients treated with LUSEDRA using the standard or modified dosing regimen [see Dosage and Administration ( 2.2 , 2.3 ) ]. In patients treated with greater than the recommended LUSEDRA dose, apnea was reported in 14/556 (3%). Supplemental oxygen is recommended for all patients receiving LUSEDRA. Dosages of LUSEDRA must be individualized for each patient and titrated to effect [see Dosage and Administration ( 2.1 ) and Clinical Pharmacology ( 12.2 ) ] . Use lower doses of LUSEDRA in patients who are ≥65 years of age or who have severe systemic disease [see Dosage and Administration ( 2.3 ) ]. The additive cardiorespiratory effects of narcotic analgesics and sedative-hypnotic agents should be considered when administered concomitantly with LUSEDRA. Patients should be assessed for their ability to demonstrate purposeful response while sedated with LUSEDRA as patients who are unable to do so may lose protective reflexes. Airway assistance maneuvers may be required in the management of respiratory depression (see Table 4). 5.3 Hypoxemia LUSEDRA may cause hypoxemia detectable by pulse oximetry. Hypoxemia was reported in 20/455 (4%) patients treated with LUSEDRA using the standard or modified dosing regimen [see Dosage and Administration ( 2.2 , 2.3 ) ]. Hypoxemia was reported among patients who retained the ability to respond purposefully to their health care provider following administration of LUSEDRA. Therefore, retention of purposeful responsiveness did not prevent patients from becoming hypoxemic following administration of LUSEDRA. In patients treated with greater than the recommended LUSEDRA dose , hypoxemia was reported in 151/556 (27%). The risk of hypoxemia is reduced by appropriate positioning of the patient and the use of supplemental oxygen in all patients receiving LUSEDRA. Airway assistance maneuvers may be required in the management of hypoxemia (see Table 4). The additive cardiorespiratory effects of narcotic analgesics and other sedative-hypnotic agents should be considered when administered concomitantly with LUSEDRA. 5.4 Patient Unresponsiveness to Vigorous Tactile or Painful Stimulation LUSEDRA has not been studied for use in general anesthesia. However, administration of LUSEDRA may inadvertently cause patients to become unresponsive or minimally responsive to vigorous tactile or painful stimulation. The incidence of patients sedated for colonoscopy who became minimally responsive or unresponsive to vigorous tactile or painful stimulation was 7/183 (4%). The duration of minimal or complete unresponsiveness in colonoscopy patients ranged from 2 to 16 minutes. Among patients sedated for bronchoscopy, the incidence of patients who became minimally or completely unresponsive to vigorous tactile or painful stimulation was 24/149 (16%). The duration of minimal to complete unresponsiveness in bronchoscopy patients ranged from 2 to 20 minutes. 5.5 Hypotension Hypotension following the use of LUSEDRA may occur. Hypotension was reported in 18/455 (4%) patients treated with LUSEDRA using the standard or modified dosing regimen [see Dosage and Administration ( 2.2 , 2.3 ) ]. In patients treated with greater than the recommended LUSEDRA dose, hypotension was reported in 31/556 (6%). Patients with compromised myocardial function, reduced vascular tone, or who have reduced intravascular volume may be at an increased risk for hypotension. A secure intravenous access catheter and supplemental volume replacement fluids should be readily available during the procedure. Additional pharmacological management may be necessary.
6 ADVERSE REACTIONS The following serious adverse reactions are discussed elsewhere in the labeling: Respiratory depression [see Warnings and Precautions ( 5.2 ) ] Hypoxemia [see Warnings and Precautions ( 5.3 ) ] Loss of purposeful responsiveness [see Warnings and Precautions ( 5.4 ) ] Hypotension [see Warnings and Precautions ( 5.5 ) ] The most common adverse reactions (reported in greater than 20%) are paresthesia and pruritus. The most commonly reported reasons for discontinuation are paresthesia and cough. Most common adverse reactions (> 20%) are paresthesia and pruritus. ( 6 ) To report SUSPECTED ADVERSE REACTIONS, contact Eisai Inc. at 1-888-422-4743 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch . 6.1 Clinical Trials Experience Adverse reactions presented in this section are derived from 332 patients in 3 controlled clinical trials in patients undergoing colonoscopy or flexible bronchoscopy and 123 patients in one open-label study in patients undergoing minor procedures. Patients enrolled in the studies who received the standard or modified dosing regimen included males and females, ≥18 years of age and ranging from healthy (359/455 [79%] ASA P1 or P2) to those with severe systemic disease (96/455 [21%] ASA P3 or P4). Of the 455 patients enrolled, 345 (76%) were ≥18 to <65 years of age and 110 (24%) were ≥65 years of age. Adverse reactions are reported for patients who received the standard or the modified dosing regimen [see Dosage and Administration ( 2 ) ]. The majority of procedures were less than thirty minutes in duration. All patients in these studies received 50 mcg fentanyl citrate intravenously as premedication, and some of the patients received additional 25 mcg fentanyl citrate supplemental doses. Adverse reactions occurring in ≥2% of patients in these studies are presented in Table 3. 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 accurately reflect the rates observed in practice. Table 3. Common Adverse Reactions for Patients Receiving the Standard or Modified Dosing Regimen (Reactions Occurring at a Rate ≥ 2%) Reaction Term Colonoscopy (N=183) n (%) Minor Surgical Procedures (N=123) n (%) Bronchoscopy (N=149) n (%) a Paresthesia includes the following terms: Paresthesia genital male; Burning sensation; Genital burning sensation; Vaginal burning sensation; Skin burning sensation; Genital pain (reported as burning); Perineal pain (reported as burning); Anal discomfort (reported as burning); Chest pain (reported as burning); Ear discomfort (reported as burning); Nasal discomfort (reported as burning); Buttock pain (reported as stinging); Groin pain (reported as stinging); Pain (reported as stinging); Sensory disturbance (reported as non-specific sensation in pubic area). b Pruritus includes the following terms: Genital pruritus female; Genital pruritus male; Pruritus genital; Pruritus ani; Pruritus generalized. Gastrointestinal disorders Nausea Vomiting 0 0 5 (4) 4 (3) 2 (1) 0 Injury, poisoning, and procedural complications Procedural Pain 0 0 3 (2) Nervous system disorders Paresthesia a Headache 135 (74) 1 (1) 77 (63) 3 (2) 78 (52) 1 (1) Respiratory, thoracic, and mediastinal disorders Hypoxemia 3 (2) 1 (1) 16 (11) Skin and subcutaneous tissue disorders Pruritus b 30 (16) 34 (28) 24 (16) Vascular disorders Hypotension 4 (2) 4 (3) 10 (7) Paresthesias (including burning, tingling, stinging) and/or pruritus, usually manifested in the perineal region, were the most frequently recorded adverse reactions in clinical trials. Paresthesias and pruritus generally occurred within 5 minutes after administration of the initial dose of LUSEDRA and were generally transient and mild to moderate in intensity. The pharmacologic basis of these sensory phenomena is unknown. No pretreatments, including the use of nonsteroidal anti-inflammatory drugs, opioids, or lidocaine, are known to have an effect on or to reduce the incidence of these sensations. Sedation-related adverse reactions were experienced at the following rates for subjects receiving the standard or modified LUSEDRA dosing regimen: 20/455 (4%) hypoxemia, 18/455 (4%) hypotension, 1/455 (< 1%) apnea. A greater rate of sedation-related adverse reactions necessitating intervention was observed in patients undergoing bronchoscopy compared with colonoscopy and minor surgical procedures. In the colonoscopy studies, 5/183 (3%) patients were ASA P3. In the minor surgical procedures study, 23/123 (19%) patients were ASA P3 or P4. In the flexible bronchoscopy study, 68/150 (46%) patients were ASA P3 or P4. The type and incidence of airway assistance interventions required for patients who experienced sedation-related adverse reactions are presented in Table 4. Table 4. Patient Incidence of Airway Management Events Healthy Subjects a 6 mg/kg Colonoscopy b 6.5 mg/kg (or modified dosing regimen) Minor Procedures b 6.5 mg/kg (or modified dosing regimen) Flexible Bronchoscopy b 6.5 mg/kg (or modified dosing regimen) N=69 n (%) N=183 n (%) N=123 n (%) N=149 n (%) a No concomitant medications administered. All subjects were healthy volunteers. b All patients premedicated with 50 mcg fentanyl citrate. Subjects ranged from healthy to those with severe systemic disease that is a constant threat to life (ASA P1 to P4). Increased O 2 0 0 0 21 (14) Patient Repositioning 0 0 0 2 (1) Verbal Stimulation 0 2 (1) 1 (1) 5 (3) Tactile Stimulation 0 0 0 3 (2) Face Mask (100% O 2 ) 0 0 0 1 (1) Jaw Thrust 0 0 0 2 (1) Chin Lift 0 0 1 (1) 3 (2) Nasal Trumpet 0 0 0 0 Oral Airway 0 0 0 0 Suction 0 0 0 2 (1) Manual Ventilation (bag valve mask) 0 0 0 1 (1) Mechanical Ventilation 0 0 0 0 6.2 Adverse Reactions in Prolonged Exposure in Adults The safety of LUSEDRA for continuous sedation has not been established and therefore its use is not recommended. LUSEDRA was administered to 38 intubated and mechanically ventilated patients in postoperative and intensive care settings. An occurrence of nonsustained ventricular tachycardia was observed as a serious adverse reaction in one patient in the study. Another patient with acute myeloid leukemia with renal and hepatic insufficiency experienced a further increase in plasma formate concentration from a baseline of 66 mcg/mL to a post-dose level of 212 mcg/mL after a 12-hour infusion. The clinical significance of these findings is unknown.