1 INDICATIONS AND USAGE Remifentanil hydrochloride (HCl) for injection is indicated for intravenous (IV) administration: • As an analgesic agent for use during the induction and maintenance of general anesthesia for inpatient and outpatient procedures.

• For continuation as an analgesic into the immediate postoperative period in adult patients under the direct supervision of an anesthesia practitioner in a postoperative anesthesia care unit or intensive care setting.

• As an analgesic component of monitored anesthesia care in adult patients.

Remifentanil hydrochloride for injection is an opioid agonist indicated for intravenous administration: • As an analgesic agent for use during the induction and maintenance of general anesthesia for inpatient and outpatient procedures.

( 1 ) • For continuation as an analgesic into the immediate postoperative period in adult patients under the direct supervision of an anesthesia practitioner in a postoperative anesthesia care unit or intensive care setting.

( 1 ) • As an analgesic component of monitored anesthesia care in adult patients.

( 1 )

6 ADVERSE REACTIONS The following serious adverse reactions are described, or described in greater detail, in other sections: • Addiction, Abuse, and Misuse [see Warnings and Precautions ( 5.1 )] • Respiratory Depression in Spontaneously Breathing Patients [see Warnings and Precautions ( 5.2 )] • Interactions with Benzodiazepines or other CNS Depressants [see Warnings and Precautions ( 5.3 )] • Serotonin Syndrome [see Warnings and Precautions ( 5.4 )] • Skeletal Muscle Rigidity [see Warnings and Precautions ( 5.6 )] • Bradycardia [see Warnings and Precautions ( 5.8 )] • Hypotension [see Warnings and Precautions ( 5.9 )] • Biliary Tract Disease [see Warnings and Precautions ( 5.12 )] • Seizures [see Warnings and Precautions ( 5.13 )] Most common adverse reactions (incidence ≥ 1%) were respiratory depression, bradycardia, hypotension, and skeletal muscle rigidity.

( 6 ) To report SUSPECTED ADVERSE REACTIONS, contact Fresenius Kabi USA, LLC at 1-800-551-7176 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.

Adverse event information is derived from controlled clinical studies that were conducted in a variety of surgical procedures of varying duration, using a variety of premedications and other anesthetics, and in patient populations with diverse characteristics including underlying disease.

Adults Approximately 2,770 adult patients were exposed to remifentanil HCl in controlled clinical studies.

The frequencies of adverse events during general anesthesia with the recommended doses of remifentanil HCl are given in Table 11.

Each patient was counted once for each type of adverse event.

Table 11: Adverse Events Reported in ≥ 1% of Adult Patients in General Anesthesia Studies a at the Recommended Doses b of Remifentanil HCl Adverse Event Induction/Maintenance Postoperative Analgesia After Discontinuation Remifentanil HCl (n = 921) Alfentanil/ Fentanyl (n = 466) Remifentanil HCl (n = 281) Morphine (n = 98) Remifentanil HCl (n = 929) Alfentanil/ Fentanyl (n = 466) Nausea 8 (< 1%) 0 61 (22%) 15 (15%) 339 (36%) 202 (43%) Hypotension 178 (19%) 30 (6%) 0 0 16 (2%) 9 (2%) Vomiting 4 (< 1%) 1 (< 1%) 22 (8%) 5 (5%) 150 (16%) 91 (20%) Muscle rigidity 98 (11%) c 37 (8%) 7 (2%) 0 2 (< 1%) 1 (< 1%) Bradycardia 62 (7%) 24 (5%) 3 (1%) 3 (3%) 11 (1%) 6 (1%) Shivering 3 (< 1%) 0 15 (5%) 9 (9%) 49 (5%) 10 (2%) Fever 1 (< 1%) 0 2 (< 1%) 0 44 (5%) 9 (2%) Dizziness 0 0 1 (< 1%) 0 27 (3%) 9 (2%) Visual disturbance 0 0 0 0 24 (3%) 14 (3%) Headache 0 0 1 (< 1%) 1 (1%) 21 (2%) 8 (2%) Respiratory depression 1 (< 1%) 0 19 (7%) 4 (4%) 17 (2%) 20 (4%) Apnea 0 1 (< 1%) 9 (3%) 2 (2%) 2 (< 1%) 1 (< 1%) Pruritus 2 (< 1%) 0 7 (2%) 1 (1%) 22 (2%) 7 (2%) Tachycardia 6 (< 1%) 7 (2%) 0 0 10 (1%) 8 (2%) Postoperative pain 0 0 7 (2%) 0 4 (< 1%) 5 (1%) Hypertension 10 (1%) 7 (2%) 5 (2%) 3 (3%) 12 (1%) 8 (2%) Agitation 2 (< 1%) 0 3 (1%) 1 (1%) 6 (< 1%) 1 (< 1%) Hypoxia 0 0 1 (< 1%) 0 10 (1%) 7 (2%) a Does not include adverse events from cardiac studies or the neonatal study.

See Tables 14, 15, and 16 for cardiac information.

b See Table 1 for recommended doses.

Not all doses of remifentanil HCl were equipotent to the comparator opioid.

Administration of remifentanil HCl in excess of the recommended dose (i.e., doses > 1 and up to 20 mcg/kg) resulted in a higher incidence of some adverse events: muscle rigidity (37%), bradycardia (12%), hypertension (4%), and tachycardia (4%).

c Included in the muscle rigidity incidence is chest wall rigidity (5%).

The overall muscle rigidity incidence is < 1% when remifentanil is administered concurrently or after a hypnotic induction agent.

In the elderly population (> 65 years), the incidence of hypotension is higher, whereas the incidence of nausea and vomiting is lower.

Table 12: Incidence (%) of Most Common Adverse Events by Gender in General Anesthesia Studies a at the Recommended Doses b of Remifentanil HCl Adverse Event n Induction/Maintenance Postoperative Analgesia After Discontinuation Remifentanil HCl Alfentanil/Fentanyl Remifentanil HCl Morphine Remifentanil HCl Alfentanil/Fentanyl Male 326 Female 595 Male 183 Female 283 Male 85 Female 196 Male 36 Female 62 Male 332 Female 597 Male 183 Female 283 Nausea 2% < 1% 0 0 12% 26% 8% 19% 22% 45% 30% 52% Hypotension 29% 14% 7% 6% 0 0 0 0 2% 2% 2% 2% Vomiting < 1% < 1% 0 < 1% 4% 10% 0 8% 5% 22% 8% 27% Muscle rigidity 17% 7% 14% 4% 6% 1% 0 0 < 1% < 1% 0 < 1% a Does not include adverse events from cardiac studies or the neonatal study.

b See Table 1 for recommended doses.

Not all doses of remifentanil HCl were equipotent to the comparator opioid.

The frequencies of adverse events from the clinical studies at the recommended doses of remifentanil HCl in monitored anesthesia care are given in Table 13.

Table 13: Adverse Events Reported in ≥ 1% of Adult Patients in Monitored Anesthesia Care Studies at the Recommended Doses a of Remifentanil HCl Adverse Event Remifentanil HCl (n = 159) Remifentanil HCl + 2 mg Midazolam b (n = 103) Propofol (0.5 mg/kg then 50 mcg/kg/min) (n = 63) Nausea 70 (44%) 19 (18%) 20 (32%) Vomiting 35 (22%) 5 (5%) 13 (21%) Pruritus 28 (18%) 16 (16%) 0 Headache 28 (18%) 12 (12%) 6 (10%) Sweating 10 (6%) 0 1 (2%) Shivering 8 (5%) 1 (< 1%) 1 (2%) Dizziness 8 (5%) 5 (5%) 1 (2%) Hypotension 7 (4%) 0 6 (10%) Bradycardia 6 (4%) 0 7 (11%) Respiratory depression 4 (3%) 1 (< 1%) a 0 Muscle rigidity 4 (3%) 0 1 (2%) Chills 2 (1%) 0 2 (3%) Flushing 2 (1%) 0 0 Warm sensation 2 (1%) 0 0 Pain at study IV site 2 (1%) 0 11 (17%) a See Table 3 for recommended doses.

Administration of remifentanil HCl in excess of the recommended infusion rate (i.e., starting doses > 0.1 mcg/kg/min) resulted in a higher incidence of some adverse events: nausea (60%), apnea (8%), and muscle rigidity (5%).

b With higher midazolam doses, higher incidences of respiratory depression and apnea were observed.

Other Adverse Events in Adult Patients The frequencies of less commonly reported adverse clinical events from all controlled general anesthesia and monitored anesthesia care studies are presented below.

Event frequencies are calculated as the number of patients who were administered remifentanil HCl and reported an event divided by the total number of patients exposed to remifentanil HCl in all controlled studies including cardiac dose-ranging and neurosurgery studies (n = 1,883 general anesthesia, n = 609 monitored anesthesia care).

Incidence Less than 1% Digestive: constipation, abdominal discomfort, xerostomia, gastro-esophageal reflux, dysphagia, diarrhea, ileus.

Cardiovascular: various atrial and ventricular arrhythmias, heart block, ECG change consistent with myocardial ischemia, elevated CPK-MB level, syncope.

Musculoskeletal: muscle stiffness, musculoskeletal chest pain.

Respiratory: cough, dyspnea, bronchospasm, laryngospasm, rhonchi, stridor, nasal congestion, pharyngitis, pleural effusion, hiccup(s), pulmonary edema, rales, bronchitis, rhinorrhea.

Nervous: anxiety, involuntary movement, prolonged emergence from anesthesia, confusion, awareness under anesthesia without pain, rapid awakening from anesthesia, tremors, disorientation, dysphoria, nightmare(s), hallucinations, paresthesia, nystagmus, twitch, seizure, amnesia.

Body as a Whole: decreased body temperature, anaphylactic reaction, delayed recovery from neuromuscular block.

Skin: rash, urticaria.

Urogenital: urine retention, oliguria, dysuria, urine incontinence.

Infusion Site Reaction: erythema, pruritus, rash.

Metabolic and Nutrition: abnormal liver function, hyperglycemia, electrolyte disorders, increased CPK level.

Hematologic and Lymphatic: anemia, lymphopenia, leukocytosis, thrombocytopenia.

The frequencies of adverse events from the clinical studies at the recommended doses of remifentanil HCl in cardiac surgery are given in Tables 14, 15, and 16.

These tables represent adverse events collected during discrete phases of cardiac surgery.

Any event should be viewed as temporally associated with drug administration and the phase indicated should not be perceived as the only time the event might occur.

Table 14: Adverse Events Reported in ≥ 1% of Patients in the Induction/Intubation and Maintenance Phases of Cardiac Surgery Studies at the Recommended Doses a of Remifentanil HCl Induction/Intubation Maintenance Adverse Event Remifentanil HCl (n = 227) Fentanyl (n = 176) Sufentanil (n = 41) Remifentanil HCl (n = 227) Fentanyl (n = 176) Sufentanil (n = 41) Hypotension 18 (8%) 6 (3%) 7 (17%) 26 (11%) 6 (3%) 1 (2%) Bradycardia 9 (4%) 5 (3%) 0 3 (1%) 1 (< 1%) 1 (2%) Hypertension 3 (1%) 2 (1%) 2 (5%) 8 (4%) 6 (3%) 1 (2%) Constipation 9 (4%) 1 (< 1%) 3 (7%) 0 0 1 (2%) Muscle rigidity 2 (< 1%) 2 (1%) 0 5 (2%) 8 (5%) 0 Premature ventricular beats 1 (< 1%) 0 0 3 (1%) 1 (< 1%) 0 Myocardial ischemia 0 0 0 7 (3%) 8 (5%) 1 (2%) Atrial fibrillation 0 0 0 7 (3%) 3 (2%) 1 (2%) Decreased cardiac output 0 0 0 5 (2%) 1 (< 1%) 1 (2%) Tachycardia 0 1 (< 1%) 0 4 (2%) 2 (1%) 0 Coagulation disorder 0 0 0 4 (2%) 0 1 (2%) Arrhythmia 0 0 0 3 (1%) 0 0 Ventricular fibrillation 0 0 0 3 (1%) 1 (< 1%) 1 (2%) Postoperative complication 0 0 0 3 (1%) 0 0 Third degree heart block 0 0 0 2 (< 1%) 0 1 (2%) Hemorrhage 0 0 0 2 (< 1%) 0 1 (2%) Perioperative complication 0 0 0 2 (< 1%) 1 (< 1%) 1 (2%) Involuntary movement(s) 0 0 0 2 (< 1%) 3 (2%) 0 Thrombocytopenia 0 0 1 (2%) 0 0 0 Oliguria 0 0 0 0 3 (2%) 0 Anemia 0 0 0 2 (< 1%) 2 (1%) 0 a See Table 4 for recommended doses.

Table 15: Adverse Events Reported in ≥ 1% of Patients in the ICU Phase of Cardiac Surgery Studies at the Recommended Doses a of Remifentanil HCl Adverse Event Remifentanil HCl n = 227 Fentanyl n = 176 Sufentanil n = 41 Hypertension 14 (6%) 8 (5%) 2 (5%) Hypotension 12 (5%) 3 (2%) 1 (2%) Tachycardia 9 (4%) 5 (3%) 0 Shivering 8 (4%) 3 (2%) 1 (2%) Nausea 8 (4%) 3 (2%) 0 Hemorrhage 4 (2%) 1 (< 1%) 1 (2%) Postoperative complication 4 (2%) 5 (3%) 2 (5%) Agitation 4 (2%) 1 (< 1%) 1 (2%) Ache 4 (2%) 0 0 Decreased cardiac output 3 (1%) 0 0 Arrhythmia 3 (1%) 0 0 Muscle rigidity 2 (< 1%) 1 (< 1%) 2 (5%) Bradycardia 2 (< 1%) 2 (1%) 0 Vomiting 1 (< 1%) 2 (1%) 0 Premature ventricular beats 1 (< 1%) 2 (1%) 0 Anemia 0 3 (2%) 0 Somnolence 0 0 1 (2%) Fever 0 2 (1%) 0 a See Table 4 for recommended doses.

Table 16: Adverse Events Reported in ≥ 1% of Patients in the Post-Study Drug Phase of Cardiac Surgery Studies at the Recommended Doses a of Remifentanil HCl Adverse Event Remifentanil HCl n = 227 Fentanyl n = 176 Sufentanil n = 41 Nausea 90 (40%) 63 (36%) 16 (39%) Vomiting 33 (15%) 26 (15%) 3 (7%) Fever 30 (13%) 15 (9%) 0 Atrial fibrillation 27 (12%) 33 (19%) 4 (10%) Constipation 20 (9%) 35 (20%) 3 (7%) Pleural effusion 11 (5%) 2 (1%) 2 (5%) Hypotension 8 (4%) 8 (5%) 1 (2%) Tachycardia 9 (4%) 15 (9%) 0 Postoperative complication 10 (4%) 6 (3%) 2 (5%) Oliguria 7 (3%) 7 (4%) 1 (2%) Confusion 7 (3%) 10 (6%) 5 (12%) Ache 6 (3%) 2 (1%) 0 Anxiety 6 (3%) 6 (3%) 0 Headache 6 (3%) 2 (1%) 0 Perioperative complication 5 (2%) 7 (4%) 1 (2%) Anemia 5 (2%) 5 (3%) 1 (2%) Agitation 5 (2%) 3 (2%) 1 (2%) Diarrhea 5 (2%) 1 (< 1%) 1 (2%) Edema 4 (2%) 6 (3%) 0 Dizziness 4 (2%) 3 (2%) 1 (2%) Postoperative infection 5 (2%) 7 (4%) 0 Hypoxia 4 (2%) 5 (3%) 0 Apnea 4 (2%) 1 (< 1%) 1 (2%) Hypertension 3 (1%) 3 (2%) 0 Shivering 3 (1%) 1 (< 1%) 0 Heartburn 3 (1%) 3 (2%) 0 Atrial flutter 3 (1%) 1 (< 1%) 0 Arrhythmia 3 (1%) 5 (3%) 0 Hallucinations 3 (1%) 3 (2%) 0 Pneumonia 3 (1%) 3 (2%) 1 (2%) Pharyngitis 3 (1%) 1 (< 1%) 1 (2%) Decreased mental acuity 3 (1%) 1 (< 1%) 0 Dyspnea 3 (1%) 1 (< 1%) 0 Cough 3 (1%) 0 0 Decreased cardiac output 1 (< 1%) 0 3 (7%) Renal insufficiency 1 (< 1%) 5 (3%) 0 Bradycardia 1 (< 1%) 1 (< 1%) 1 (2%) Urine retention 2 (< 1%) 3 (2%) 0 Cerebral infarction 2 (< 1%) 2 (1%) 1 (2%) Premature ventricular beats 2 (< 1%) 3 (2%) 0 Cerebral ischemia 1 (< 1%) 1 (< 1%) 1 (2%) Paresthesia 2 (< 1%) 2 (1%) 0 Seizure 2 (< 1%) 1 (< 1%) 1 (2%) Sleep disorder 1 (< 1%) 1 (< 1%) 1 (2%) Bronchospasm 1 (< 1%) 6 (3%) 0 Atelectasis 2 (< 1%) 3 (2%) 0 Respiratory depression 2 (< 1%) 3 (2%) 0 Pulmonary edema 1 (< 1%) 2 (1%) 0 Respiratory distress 2 (< 1%) 0 1 (2%) Hyperkalemia 2 (< 1%) 3 (2%) 0 Electrolyte disorder 0 3 (2%) 0 Chest congestion 0 3 (2%) 0 Hemoptysis 0 2 (1%) 0 Facial ptosis 0 2 (1%) 0 Hemorrhage 0 2 (1%) 0 Hematuria 0 1 (< 1%) 1 (2%) Visual disturbance(s) 0 1 (< 1%) 1 (2%) Hypokalemia 0 2 (1%) 0 Exacerbation of renal failure 0 0 1 (2%) Blood in stool 0 0 1 (2%) First degree heart block 0 0 1 (2%) Pericarditis 0 0 1 (2%) a See Table 4 for recommended doses.

Pediatrics Remifentanil HCl has been studied in 342 pediatric patients in controlled clinical studies for maintenance of general anesthesia.

In the pediatric population (birth to 12 years), the most commonly reported events were nausea, vomiting, and shivering.

The frequencies of adverse events during general anesthesia with the recommended doses of remifentanil HCl are given in Table 17.

Each patient was counted once for each type of adverse event.

There were no adverse events ≥ 1% for any treatment group during the maintenance period in the pediatric patient general anesthesia studies.

Table 17: Adverse Events Reported in ≥ 1% of Pediatric Patients Receiving remifentanil HCl in General Anesthesia Studies at the Recommended Doses a of Remifentanil HCl Recovery Follow-up b Adverse Event Remifentanil HCl (n = 342) Fentanyl (n = 103) Bupivacaine (n = 86) Remifentanil HCl (n = 342) Fentanyl (n = 103) Bupivacaine (n = 86) Vomiting 40 (12%) 9 (9%) 10 (12%) 56 (16%) 8 (8%) 12 (14%) Nausea 23 (8%) 7 (7%) 1 (1%) 17 (6%) 6 (6%) 5 (6%) Shivering 9 (3%) 0 0 0 0 0 Rhonchi 8 (3%) 2 (2%) 0 0 0 0 Postoperative complication 5 (2%) 2 (2%) 0 4 (1%) 0 0 Stridor 4 (1%) 2 (2%) 0 0 0 0 Cough 4 (1%) 1 (< 1%) 0 0 0 0 a See Table 2 for recommended doses.

b In subjects receiving halothane (n = 22), 10 (45%) experienced vomiting.

6.2 Postmarketing Experience The following adverse reactions have been identified during post approval use of remifentanil.

Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

Cardiovascular : Asystole Serotonin syndrome : Cases of serotonin syndrome, a potentially life-threatening condition, have been reported during concomitant use of opioids with serotonergic drugs.

Anaphylaxis : Anaphylaxis has been reported with ingredients contained in remifentanil HCl.