Ultiva Dailymed

1 Indications And Usage

ULTIVA 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.

ULTIVA 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)

2 Dosage And Administration

• •Monitor patients closely for respiratory depression when initiating therapy and following dosage increases and adjust the dosage accordingly. (2.1)
• • Initial Dosage in Adults: See full prescribing information for recommended doses in adult patients. (2.2, 2.3)
• • Initial Dosage in Pediatric Patients: See full prescribing information for recommended doses in pediatric patients. (2.2)
• • Geriatric Patients: The starting doses should be decreased by 50% in elderly patients (> 65 years). (2.6)

2.1Important Dosage and Administration Instructions

Monitor patients closely for respiratory depression when initiating therapy and following dosage increases with ULTIVA and adjust the dosage accordingly [see Warnings and Precautions (5.2)].

ULTIVA is for IV use only. Continuous infusions of ULTIVA should be administered only by an infusion device. The injection site should be close to the venous cannula and all IV tubing should be cleared at the time of discontinuation of infusion.

ULTIVA should not be administered without dilution.

Consider an alternative to ULTIVA for patients taking mixed agonist/antagonist and partial agonist opioid analgesics due to reduced analgesic effect or potential withdrawal symptoms. If concomitant use is warranted, carefully observe the patient, particularly during treatment initiation and dose adjustment. Discontinue ULTIVA if patient is not responding appropriately to treatment.

Discard unused portion.

2.2General Anesthesia

ULTIVA is not recommended as the sole agent in general anesthesia because loss of consciousness cannot be assured and because of a high incidence of apnea, muscle rigidity, and tachycardia. ULTIVA is synergistic with other anesthetics; therefore, clinicians may need to reduce doses of thiopental, propofol, isoflurane, and midazolam by up to 75% with the coadministration of ULTIVA. The administration of ULTIVA must be individualized based on the patient's response.

Induction of Anesthesia

ULTIVA should be administered at an infusion rate of 0.5 to 1 mcg/kg/min with a hypnotic or volatile agent for the induction of anesthesia. If endotracheal intubation is to occur less than 8 minutes after the start of the infusion of ULTIVA, then an initial dose of 1 mcg/kg may be administered over 30 to 60 seconds.

ULTIVA should not be used as a sole agent for induction of anesthesia because loss of consciousness cannot be assured and because of a high incidence of apnea, muscle rigidity, and tachycardia.

Maintenance of Anesthesia

After endotracheal intubation, the infusion rate of ULTIVA should be decreased in accordance with the dosing guidelines in Tables 1 (adults, predominately ASA physical status I, II, or III) and 2 (pediatric patients).

• •Due to the fast onset and short duration of action of ULTIVA, the rate of administration during anesthesia can be titrated upward in 25% to 100% increments in adult patients or up to 50% increments in pediatric patients, or downward in 25% to 50% decrements every 2 to 5 minutes to attain the desired level of µ-opioid effect.
• •In response to light anesthesia or transient episodes of intense surgical stress, supplemental bolus doses of 1 mcg/kg may be administered every 2 to 5 minutes.
• •At infusion rates > 1 mcg/kg/min, increases in the concomitant anesthetic agents should be considered to increase the depth of anesthesia. [See Clinical Pharmacology: Specific Populations: Pediatric Population (12.3) and Dosage and Administration, Table 2 (2.2).]

Table 1: Dosing Guidelines in Adults – General Anesthesia and Continuing as an Analgesic into the Postoperative Care Unit or Intensive Care Setting An initial dose of 1 mcg/kg may be administered over 30 to 60 seconds.

Phase	Continuous IV Infusion of ULTIVA (mcg/kg/min)	Range of Infusion Dose ULTIVA (mcg/kg/min)	Supplemental IV Bolus Dose of ULTIVA (mcg/kg)
Induction of Anesthesia (through intubation)	0.5 – 1
Maintenance of anesthesia with:
Nitrous oxide (66%)	0.4	0.1 – 2	1
Isoflurane (0.4 to 1.5 MAC)	0.25	0.05 – 2	1
Propofol (100 to 200 mcg/kg/min)	0.25	0.05 – 2	1
Continuation as an analgesic into the immediate postoperative period	0.1	0.025 – 0.2	not recommended

 

Table 2 summarizes the recommended doses in pediatric patients, predominantly ASA physical status I, II, or III. In pediatric patients, remifentanil was administered with nitrous oxide or nitrous oxide in combination with halothane, sevoflurane, or isoflurane. The use of atropine may blunt the potential for bradycardia that can occur upon administration of ULTIVA.

Table 2: Dosing Guidelines in Pediatric Patients – Maintenance of Anesthesia

Phase	Continuous IV Infusion of ULTIVA (mcg/kg/min)	Range of Infusion Dose ULTIVA (mcg/kg/min)	Supplemental IV Bolus Dose of ULTIVA (mcg/kg)
Maintenance of anesthesia in patients aged 1 to 12 years old with An initial dose of 1 mcg/kg may be administered over 30 to 60 seconds. :
Halothane (0.3 to 1.5 MAC)	0.25	0.05 – 1.3	1
Sevoflurane (0.3 to 1.5 MAC)	0.25	0.05 – 1.3	1
Isoflurane (0.4 to 1.5 MAC)	0.25	0.05 – 1.3	1
Maintenance of anesthesia for patients from birth to 2 months of age with:
Nitrous oxide (70%)The clearance rate in neonates is highly variable, on average two times higher than in the young healthy adult population. Therefore, an increased infusion rate may be necessary to maintain adequate surgical anesthesia, and additional bolus doses may be required. The use of atropine may blunt the potential for bradycardia that can occur upon administration of ULTIVA. [See Clinical Pharmacology: Specific Populations: Pediatric Population (12.3) and Clinical Studies (14.4).]	0.4	0.4 – 1.0	1Boluses of 1 mcg/kg were studied in ASA 1 and 2, full-term patients weighing at least 2500 gm, undergoing pyloromyotomy who received pretreatment with atropine. Neonates receiving supplementation with potent inhalation agents or neuraxial anesthesia, those with significant co-morbidities or undergoing significant fluid shifts, or those who have not been pretreated with atropine, may require smaller bolus doses to avoid hypotension and/or bradycardia.

 

2.3Continuation as an Analgesic into the Immediate Postoperative Period Under the Direct Supervision of an Anesthesia Practitioner

Infusions of ULTIVA may be continued into the immediate postoperative period for select patients for whom later transition to longer acting analgesics may be desired.

• • ULTIVA has not been studied in pediatric patients for use in the immediate postoperative period.
• •The use of bolus injections of ULTIVA to treat pain during the postoperative period is not recommended.
• •When used as an IV analgesic in the immediate postoperative period, ULTIVA should be initially administered by continuous infusion at a rate of 0.1 mcg/kg/min.
• •The infusion rate may be adjusted every 5 minutes in 0.025 mcg/kg/min increments to balance the patient's level of analgesia and respiratory rate.
• •Infusion rates greater than 0.2 mcg/kg/min are associated with respiratory depression (respiratory rate less than 8 breaths/min).

Due to the rapid offset of action of ULTIVA, no residual analgesic activity will be present within 5 to 10 minutes after discontinuation. For patients undergoing surgical procedures where postoperative pain is generally anticipated, alternative analgesics should be administered prior to discontinuation of ULTIVA. The choice of analgesic should be appropriate for the patient's surgical procedure and the level of follow-up care [see Clinical Studies (14)].

2.4 Analgesic Component of Monitored Anesthesia Care

It is strongly recommended that supplemental oxygen be supplied to the patient whenever ULTIVA is administered.

• • ULTIVA has not been studied for use in children in monitored anesthesia care.

Single Dose

A single IV dose of 0.5 to 1 mcg/kg over 30 to 60 seconds of ULTIVA may be given 90 seconds before the placement of the local or regional anesthetic block [see Warnings and Precautions (5.7) ].

Continuous Infusion

When used alone as an IV analgesic component of monitored anesthesia care, ULTIVA should be initially administered by continuous infusion at a rate of 0.1 mcg/kg/min beginning 5 minutes before placement of the local or regional anesthetic block.

• •Because of the risk for hypoventilation, the infusion rate of ULTIVA should be decreased to 0.05 mcg/kg/min following placement of the block.
• •Thereafter, rate adjustments of 0.025 mcg/kg/min at 5 minute intervals may be used to balance the patient's level of analgesia and respiratory rate.
• •Rates greater than 0.2 mcg/kg/min are generally associated with respiratory depression (respiratory rates less than 8 breaths/min).
• •Bolus doses of ULTIVA administered simultaneously with a continuous infusion of ULTIVA to spontaneously breathing patients are not recommended.

Table 3 summarizes the recommended doses for monitored anesthesia care in adult patients, predominately ASA physical status I, II, or III.

Table 3: Dosing Guidelines in Adults – Monitored Anesthesia Care

Method	Timing	ULTIVA Alone	ULTIVA + 2 mg Midazolam
Single IV Dose	Given 90 seconds before local anesthetic	1 mcg/kg over 30 to 60 seconds	0.5 mcg/kg over 30 to 60 seconds
Continuous IV Infusion	Beginning 5 minutes before local anesthetic	0.1 mcg/kg/min	0.05 mcg/kg/min
	After local anesthetic	0.05 mcg/kg/min (Range: 0.025 to 0.2 mcg/kg/min)	0.025 mcg/kg/min (Range: 0.025 to 0.2 mcg/kg/min)

 

2.5 Discontinuation

Upon discontinuation of ULTIVA, the IV tubing should be cleared to prevent the inadvertent administration of ULTIVA at a later time.

For patients undergoing surgical procedures where postoperative pain is generally anticipated, alternative analgesics should be administered prior to discontinuation of ULTIVA. The choice of analgesic should be appropriate for the patient's surgical procedure and the level of follow-up care [see Clinical Studies (14)].

2.6Dosage Modifications in Geriatric Patients

The starting doses of ULTIVA should be decreased by 50% in elderly patients (> 65 years). ULTIVA should then be cautiously titrated to effect [see Use in Specific Populations (8.5)].

2.7 Dosage Modifications in Pediatric Patients

See Table 2 for dosing recommendations for use of ULTIVA in pediatric patients from birth to 12 years of age for maintenance of anesthesia. [See Clinical Pharmacology: Specific Populations: Pediatric Population (12.3) and Dosage and Administration, Table 2 and Maintenance of Anesthesia (2.2).]

ULTIVA has not been studied in pediatric patients for use in the immediate postoperative period or for use as a component of monitored anesthesia care.

2.8Dosage Modifications in Coronary Artery Bypass Surgery

Table 4 summarizes the recommended doses for induction, maintenance, and continuation as an analgesic into the ICU in adult patients, predominantly ASA physical status III or IV. To avoid hypotension during the induction phase, it is important to consider the concomitant medication regimens. [See Clinical Studies: Coronary Artery Bypass Surgery (14.5).]

Table 4: Dosing RecommendationsSee Clinical Studies: Coronary Artery Bypass Surgery subsection (14.5) for concomitant medication regimens. – Coronary Artery Bypass Surgery

Phase	Continuous IV Infusion of ULTIVA (mcg/kg/min)	Range of Infusion Dose ULTIVA (mcg/kg/min)	Supplemental IV Bolus Dose of ULTIVA (mcg/kg)
Induction of Anesthesia (through intubation)	1
Maintenance of Anesthesia	1	0.125 to 4	0.5 to 1
Continuation as an analgesic into ICU	1	0.05 to 1

 

2.9 Dosage Modifications in Obese Patients

The starting doses of ULTIVA should be based on ideal body weight (IBW) in obese patients (greater than 30% over their IBW) [see Use in Specific Populations (8.6)].

2.10 Dosage Modifications in Preanesthetic Medication

The need for premedication and the choice of anesthetic agents must be individualized. In clinical studies, patients who received ULTIVA frequently received a benzodiazepine premedication.

2.11 Preparation for Administration

To reconstitute solution, add 1 mL of diluent per mg of remifentanil. Shake well to dissolve. When reconstituted as directed, the solution contains approximately 1 mg of remifentanil activity per 1 mL.

• • ULTIVA should be diluted to a recommended final concentration of 20, 25, 50, or 250 mcg/mL prior to administration (see Table 5). ULTIVA should not be administered without dilution.

Table 5: Reconstitution and Dilution of ULTIVA

Final Concentration	Amount of ULTIVA in Each Vial	Final Volume After Reconstitution and Dilution
20 mcg/mL	1 mg	50 mL
	2 mg	100 mL
	5 mg	250 mL
25 mcg/mL	1 mg	40 mL
	2 mg	80 mL
	5 mg	200 mL
50 mcg/mL	1 mg	20 mL
	2 mg	40 mL
	5 mg	100 mL
250 mcg/mL	5 mg	20 mL

 

Continuous IV infusions of ULTIVA should be administered only by an infusion device. Infusion rates of ULTIVA can be individualized for each patient using Table 6:

Table 6: IV Infusion Rates of ULTIVA (mL/kg/h)

Drug Delivery Rate (mcg/kg/min)	Infusion Delivery Rate (mL/kg/h)
	20 mcg/mL	25 mcg/mL	50 mcg/mL	250 mcg/mL
0.0125	0.038	0.03	0.015	not recommended
0.025	0.075	0.06	0.03	not recommended
0.05	0.15	0.12	0.06	0.012
0.075	0.23	0.18	0.09	0.018
0.1	0.3	0.24	0.12	0.024
0.15	0.45	0.36	0.18	0.036
0.2	0.6	0.48	0.24	0.048
0.25	0.75	0.6	0.3	0.06
0.5	1.5	1.2	0.6	0.12
0.75	2.25	1.8	0.9	0.18
1.0	3.0	2.4	1.2	0.24
1.25	3.75	3.0	1.5	0.3
1.5	4.5	3.6	1.8	0.36
1.75	5.25	4.2	2.1	0.42
2.0	6.0	4.8	2.4	0.48

 

When ULTIVA is used as an analgesic component of monitored analgesia care, a final concentration of 25 mcg/mL is recommended. When ULTIVA is used for pediatric patients 1 year of age and older, a final concentration of 20 or 25 mcg/mL is recommended. Table 7 is a guideline for milliliter-per-hour delivery for a solution of 20 mcg/mL with an infusion device.

Table 7: IV Infusion Rates of ULTIVA (mL/h) for a 20 mcg/mL Solution

Infusion Rate(mcg/kg/min)	Patient Weight (kg)
	5	10	20	30	40	50	60
0.0125	0.188	0.375	0.75	1.125	1.5	1.875	2.25
0.025	0.375	0.75	1.5	2.25	3.0	3.75	4.5
0.05	0.75	1.5	3.0	4.5	6.0	7.5	9.0
0.075	1.125	2.25	4.5	6.75	9.0	11.25	13.5
0.1	1.5	3.0	6.0	9.0	12.0	15.0	18.0
0.15	2.25	4.5	9.0	13.5	18.0	22.5	27.0
0.2	3.0	6.0	12.0	18.0	24.0	30.0	36.0
0.25	3.75	7.5	15.0	22.5	30.0	37.5	45.0
0.3	4.5	9.0	18.0	27.0	36.0	45.0	54.0
0.35	5.25	10.5	21.0	31.5	42.0	52.5	63.0
0.4	6.0	12.0	24.0	36.0	48.0	60.0	72.0

 

Table 8 is a guideline for milliliter-per-hour delivery for a solution of 25 mcg/mL with an infusion device.

Table 8: IV Infusion Rates of ULTIVA (mL/h) for a 25 mcg/mL Solution

Infusion Rate(mcg/kg/min)	Patient Weight (kg)
	10	20	30	40	50	60	70	80	90	100
0.0125	0.3	0.6	0.9	1.2	1.5	1.8	2.1	2.4	2.7	3.0
0.025	0.6	1.2	1.8	2.4	3.0	3.6	4.2	4.8	5.4	6.0
0.05	1.2	2.4	3.6	4.8	6.0	7.2	8.4	9.6	10.8	12.0
0.075	1.8	3.6	5.4	7.2	9.0	10.8	12.6	14.4	16.2	18.0
0.1	2.4	4.8	7.2	9.6	12.0	14.4	16.8	19.2	21.6	24.0
0.15	3.6	7.2	10.8	14.4	18.0	21.6	25.2	28.8	32.4	36.0
0.2	4.8	9.6	14.4	19.2	24.0	28.8	33.6	38.4	43.2	48.0

 

Table 9 is a guideline for milliliter-per-hour delivery for a solution of 50 mcg/mL with an infusion device.

Table 9: IV Infusion Rates of ULTIVA (mL/h) for a 50 mcg/mL Solution

Infusion Rate (mcg/kg/min)	Patient Weight (kg)
	30	40	50	60	70	80	90	100
0.025					2.1	2.4	2.7	3.0
0.05		2.4	3.0	3.6	4.2	4.8	5.4	6.0
0.075	2.7	3.6	4.5	5.4	6.3	7.2	8.1	9.0
0.1	3.6	4.8	6.0	7.2	8.4	9.6	10.8	12.0
0.15	5.4	7.2	9.0	10.8	12.6	14.4	16.2	18.0
0.2	7.2	9.6	12.0	14.4	16.8	19.2	21.6	24.0
0.25	9.0	12.0	15.0	18.0	21.0	24.0	27.0	30.0
0.5	18.0	24.0	30.0	36.0	42.0	48.0	54.0	60.0
0.75	27.0	36.0	45.0	54.0	63.0	72.0	81.0	90.0
1.0	36.0	48.0	60.0	72.0	84.0	96.0	108.0	120.0
1.25	45.0	60.0	75.0	90.0	105.0	120.0	135.0	150.0
1.5	54.0	72.0	90.0	108.0	126.0	144.0	162.0	180.0
1.75	63.0	84.0	105.0	126.0	147.0	168.0	189.0	210.0
2.0	72.0	96.0	120.0	144.0	168.0	192.0	216.0	240.0

 

Table 10 is a guideline for milliliter-per-hour delivery for a solution of 250 mcg/mL with an infusion device.

Table 10: IV Infusion Rates of ULTIVA (mL/h) for a 250 mcg/mL Solution

Infusion Rate (mcg/kg/min)	Patient Weight (kg)
	30	40	50	60	70	80	90	100
0.1	0.72	0.96	1.20	1.44	1.68	1.92	2.16	2.40
0.15	1.08	1.44	1.80	2.16	2.52	2.88	3.24	3.60
0.2	1.44	1.92	2.40	2.88	3.36	3.84	4.32	4.80
0.25	1.80	2.40	3.00	3.60	4.20	4.80	5.40	6.00
0.5	3.60	4.80	6.00	7.20	8.40	9.60	10.80	12.00
0.75	5.40	7.20	9.00	10.80	12.60	14.40	16.20	18.00
1.0	7.20	9.60	12.00	14.40	16.80	19.20	21.60	24.00
1.25	9.00	12.00	15.00	18.00	21.00	24.00	27.00	30.00
1.5	10.80	14.40	18.00	21.60	25.20	28.80	32.40	36.00
1.75	12.60	16.80	21.00	25.20	29.40	33.60	37.80	42.00
2.0	14.40	19.20	24.00	28.80	33.60	38.40	43.20	48.00

 

2.12 Compatibility and Stability

Reconstitution and Dilution Prior to Administration

ULTIVA is stable for 24 hours at room temperature after reconstitution and further dilution to concentrations of 20 to 250 mcg/mL with the IV fluids uled below.

Sterile Water for Injection, USP5% Dextrose Injection, USP5% Dextrose and 0.9% Sodium Chloride Injection, USP0.9% Sodium Chloride Injection, USP0.45% Sodium Chloride Injection, USPLactated Ringer's and 5% Dextrose Injection, USP

ULTIVA is stable for 4 hours at room temperature after reconstitution and further dilution to concentrations of 20 to 250 mcg/mL with Lactated Ringer's Injection, USP.

ULTIVA has been shown to be compatible with these IV fluids when coadministered into a running IV administration set.

Compatibility with Other Therapeutic Agents

ULTIVA has been shown to be compatible with Diprivan^® (propofol) Injection when coadministered into a running IV administration set. The compatibility of ULTIVA with other therapeutic agents has not been evaluated.

Incompatibilities

Nonspecific esterases in blood products may lead to the hydrolysis of remifentanil to its carboxylic acid metabolite. Therefore, administration of ULTIVA into the same IV tubing with blood is not recommended.

Note: Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration whenever solution and container permit. Product should be a clear, colorless liquid after reconstitution and free of visible particulate matter.

ULTIVA does not contain any antimicrobial preservative and thus care must be taken to assure the sterility of prepared solutions.

• • Life-Threatening Respiratory Depression: Monitor closely, particularly during initiation and titration. (5.2)
• • Risks from Use as Postoperative Analgesia with Concomitant Benzodiazepines or other CNS Depressants: Hypotension, profound sedation, respiratory depression, coma, and death may result from the concomitant use of ULTIVA with benzodiazepines or other CNS depressants (5.3)
• • Opioid-Induced Hyperalgesia and Allodynia: Opioid-Induced Hyperalgesia (OIH) occurs when an opioid analgesic paradoxically causes an increase in pain, or an increase in sensitivity to pain. If OIH is suspected, carefully consider appropriately decreasing the dose of the current opioid analgesic or opioid rotation. (5.4)
• • Serotonin Syndrome: Potentially life-threatening condition could result from concomitant serotonergic drug administration. Discontinue ULTIVA if serotonin syndrome is suspected. (5.5)
• • Administration: Continuous infusions of ULTIVA should be administered only by an infusion device. (5.6)
• • Skeletal Muscle Rigidity: is related to the dose and speed of administration. Muscle rigidity induced by ULTIVA should be managed in the context of the patient's clinical condition. (5.7)
• • Potential Inactivation by Nonspecific Esterases in Blood Products: ULTIVA should not be administered into the same IV tubing with blood due to potential inactivation by nonspecific esterases in blood products. (5.8)
• • Bradycardia: Monitor heart rate during dosage initiation and titration. It is responsive to ephedrine or anticholinergic drugs (5.9)
• • Hypotension: Monitor blood pressure during dosage initiation and titration. It is responsive to decreases in the administration of ULTIVA or to IV fluids or catecholamine administration (5.10)
• • Intraoperative Awareness: Inoperative awareness has been reported in patients under 55 years of age when ULTIVA has been administered with propofol infusion rates of ≤ 75 mcg/kg/min (5.11)
• • Risks of Use in Spontaneously Breathing Patients with Increased Intracranial Pressure, Brain Tumors, Head Injury, or Impaired Consciousness: Monitor for sedation and respiratory depression. (5.12)
• • Risks of Use in Patients with Biliary Tract Disease: Monitor patients with biliary tract disease, including acute pancreatitis, for worsening symptoms. (5.13)
• • Increased Risk of Seizures in Patients with Seizure Disorders: Monitor patients with a history of seizure disorders for worsened seizure control during ULTIVA therapy. (5.14)
• • Rapid Offset of Action: Standard monitoring should be maintained in the postoperative period to ensure adequate recovery without stimulation. (5.15)

5.1 Addiction, Abuse, and Misuse

ULTIVA contains remifentanil, a Schedule II controlled substance. As an opioid, ULTIVA exposes users to the risks of addiction, abuse, and misuse [see Drug Abuse and Dependence (9)].

Opioids are sought for nonmedical use and are subject to diversion from legitimate prescribed use. Consider these risks when handling ULTIVA. Strategies to reduce these risks include proper product storage and control practices for a C-II drug. Contact local state professional licensing board or state-controlled substances authority for information on how to prevent and detect abuse or diversion of this product.

5.2Life-Threatening Respiratory Depression

Serious, life-threatening, or fatal respiratory depression has been reported with the use of opioids, even when used as recommended. Respiratory depression, if not immediately recognized and treated, may lead to respiratory arrest and death.

ULTIVA should be administered only by persons specifically trained in the use of anesthetic drugs and the management of the respiratory effects of potent opioids, including respiration and cardiac resuscitation of patients in the age group being treated. Such training must include the establishment and maintenance of a patent airway and assisted ventilation. Resuscitative and intubation equipment, oxygen, and opioid antagonists must be readily available.

Respiratory depression in spontaneously breathing patients is generally managed by decreasing the rate of the infusion of ULTIVA by 50% or by temporarily discontinuing the infusion [see Overdosage (10)].

Carbon dioxide (CO₂) retention from opioid-induced respiratory depression can exacerbate the sedating effects of opioids. While serious, life-threatening, or fatal respiratory depression can occur at any time during the use of ULTIVA, the risk is greatest during the initiation of therapy or following a dosage increase. Monitor patients closely for respiratory depression, especially when initiating therapy with and following dosage increases of ULTIVA.

ULTIVA should not be used in diagnostic or therapeutic procedures outside the monitored anesthesia care setting. Patients receiving monitored anesthesia care should be continuously monitored by persons not involved in the conduct of the surgical or diagnostic procedure. Oxygen saturation should be monitored on a continuous basis.

Patients with significant chronic obstructive pulmonary disease or cor pulmonale, and those with a substantially decreased respiratory reserve, hypoxia, hypercapnia, or pre-existing respiratory depression are at increased risk of decreased respiratory drive including apnea, even at recommended dosages of ULTIVA. Elderly, cachectic, or debilitated patients may have altered pharmacokinetics or altered clearance compared to younger, healthier patients resulting in greater risk for respiratory depression. Monitor such patients closely including vital signs, particularly when initiating and titrating ULTIVA and when ULTIVA is given concomitantly with other drugs that depress respiration. To reduce the risk of respiratory depression, proper dosing and titration of ULTIVA are essential [see Dosage and Administration (2.11)].

5.3Risks from Use as Postoperative Analgesia with Concomitant Benzodiazepines or Other CNS Depressants

When benzodiazepines or other CNS depressants are used with ULTIVA, pulmonary arterial pressure may be decreased. This fact should be considered by those who conduct diagnostic and surgical procedures where interpretation of pulmonary arterial pressure measurements might determine final management of the patient. When high dose or anesthetic dosages of ULTIVA are employed, even relatively small dosages of diazepam may cause cardiovascular depression.

When ULTIVA is used with CNS depressants, hypotension can occur. If it occurs, consider the possibility of hypovolemia and manage with appropriate parenteral fluid therapy. When operative conditions permit, consider repositioning the patient to improve venous return to the heart. Exercise care in moving and repositioning of patients because of the possibility of orthostatic hypotension. If volume expansion with fluids plus other countermeasures do not correct hypotension, consider administration of pressor agents other than epinephrine. Epinephrine may paradoxically decrease blood pressure in patients treated with a neuroleptic that blocks alpha adrenergic activity.

Hypotension, profound sedation, respiratory depression, coma, and death may result from the concomitant use of ULTIVA with benzodiazepines and/or other CNS depressants, including alcohol (e.g., non-benzodiazepine sedatives/hypnotics, anxiolytics, tranquilizers, muscle relaxants, general anesthetics, antipsychotics, other opioids). Patients should be advised to avoid alcohol for 24 hours after surgery [see Drug Interactions (7) ].

Observational studies have demonstrated that concomitant use of opioid analgesics and benzodiazepines increases the risk of drug-related mortality compared to use of opioid analgesics alone. Because of similar pharmacological properties, it is reasonable to expect similar risk with the concomitant use of other CNS depressant drugs with opioid analgesics [see Drug Interactions (7) ].

If the decision is made to manage postoperative pain with ULTIVA concomitantly with a benzodiazepine or other CNS depressant, start dosing with the lowest effective dosage and titrate based on clinical response. Monitor patients closely for signs and symptoms of respiratory depression, sedation, and hypotension. Fluids or other measures to counter hypotension should be available [see Drug Interactions (7) ].

5.4 Opioid-Induced Hyperalgesia and Allodynia

Opioid-Induced Hyperalgesia (OIH) occurs when an opioid analgesic paradoxically causes an increase in pain, or an increase in sensitivity to pain. This condition differs from tolerance, which is the need for increasing doses of opioids to maintain a defined effect [see Dependence (9.3)]. Symptoms of OIH include (but may not be limited to) increased levels of pain upon opioid dosage increase, decreased levels of pain upon opioid dosage decrease, or pain from ordinarily non-painful stimuli (allodynia). These symptoms may suggest OIH only if there is no evidence of underlying disease progression, opioid tolerance, opioid withdrawal, or addictive behavior.

Cases of OIH have been reported, both with short-term and longer-term use of opioid analgesics. Though the mechanism of OIH is not fully understood, multiple biochemical pathways have been implicated. Medical literature suggests a strong biologic plausibility between opioid analgesics and OIH and allodynia. If a patient is suspected to be experiencing OIH, carefully consider appropriately decreasing the dose of the current opioid analgesic or opioid rotation (safely switching the patient to a different opioid moiety) [see Dosage and Administration (2), Warnings and Precautions (5.2)] .

5.5Serotonin Syndrome with Concomitant Use of Serotonergic Drugs

Cases of serotonin syndrome, a potentially life-threatening condition, have been reported during concomitant use of ULTIVA with serotonergic drugs. Serotonergic drugs include selective serotonin reuptake inhibitors (SSRIs), serotonin and norepinephrine reuptake inhibitors (SNRIs), tricyclic antidepressants (TCAs), triptans, 5-HT3 receptor antagonists, drugs that affect the serotonergic neurotransmitter system (e.g., mirtazapine, trazodone, tramadol), certain muscle relaxants (i.e., cyclobenzaprine, metaxalone), and drugs that impair metabolism of serotonin (including MAO inhibitors, both those intended to treat psychiatric disorders and also others, such as linezolid and intravenous methylene blue) [see Drug Interactions (7)]. This may occur within the recommended dosage range.

Serotonin syndrome symptoms may include mental status changes (e.g., agitation, hallucinations, coma), autonomic instability (e.g., tachycardia, labile blood pressure, hyperthermia), neuromuscular aberrations (e.g., hyperreflexia, incoordination, rigidity), and/or gastrointestinal symptoms (e.g., nausea, vomiting, diarrhea) and can be fatal. The onset of symptoms generally occurs within several hours to a few days of concomitant use, but may occur later than that. Discontinue ULTIVA if serotonin syndrome is suspected.

5.6Administration

Continuous infusions of ULTIVA should be administered only by an infusion device. IV bolus administration of ULTIVA should be used only during the maintenance of general anesthesia. In nonintubated patients, single doses of ULTIVA should be administered over 30 to 60 seconds.

Interruption of an infusion of ULTIVA will result in rapid offset of effect. Rapid clearance and lack of drug accumulation result in rapid dissipation of respiratory depressant and analgesic effects upon discontinuation of ULTIVA at recommended doses. Discontinuation of an infusion of ULTIVA should be preceded by the establishment of adequate postoperative analgesia.

Injections of ULTIVA should be made into IV tubing at or close to the venous cannula. Upon discontinuation of ULTIVA, the IV tubing should be cleared to prevent the inadvertent administration of ULTIVA at a later point in time. Failure to adequately clear the IV tubing to remove residual ULTIVA has been associated with the appearance of respiratory depression, apnea, and muscle rigidity upon the administration of additional fluids or medications through the same IV tubing.

5.7Skeletal Muscle Rigidity

Skeletal muscle rigidity can be caused by ULTIVA and is related to the dose and speed of administration. ULTIVA may cause chest wall rigidity (inability to ventilate) after single doses of > 1 mcg/kg administered over 30 to 60 seconds, or after infusion rates > 0.1 mcg/kg/min. Single doses < 1 mcg/kg may cause chest wall rigidity when given concurrently with a continuous infusion of ULTIVA.

Muscle rigidity induced by ULTIVA should be managed in the context of the patient's clinical condition. Muscle rigidity occurring during the induction of anesthesia should be treated by the administration of a neuromuscular blocking agent and the concurrent induction medications and can be treated by decreasing the rate or discontinuing the infusion of ULTIVA or by administering a neuromuscular blocking agent. The neuromuscular blocking agents used should be compatible with the patient's cardiovascular status.

Muscle rigidity seen during the use of ULTIVA in spontaneously breathing patients may be treated by stopping or decreasing the rate of administration of ULTIVA. Resolution of muscle rigidity after discontinuing the infusion of ULTIVA occurs within minutes. In the case of life-threatening muscle rigidity, a rapid onset neuromuscular blocker or naloxone may be administered.

5.8Potential Inactivation by Nonspecific Esterases in Blood Products

ULTIVA should not be administered into the same IV tubing with blood due to potential inactivation by nonspecific esterases in blood products.

5.9Bradycardia

Bradycardia has been reported with ULTIVA and is responsive to ephedrine or anticholinergic drugs, such as atropine and glycopyrrolate.

5.10Hypotension

Hypotension has been reported with ULTIVA and is responsive to decreases in the administration of ULTIVA or to IV fluids or catecholamine (ephedrine, epinephrine, norepinephrine, etc.) administration.

5.11 Intraoperative Awareness

Intraoperative awareness has been reported in patients under 55 years of age when ULTIVA has been administered with propofol infusion rates of ≤ 75 mcg/kg/min.

5.12 Risks of Use in Spontaneously Breathing Patients with Increased Intracranial Pressure, Brain Tumors, Head Injury, or Impaired Consciousness

In patients who may be susceptible to the intracranial effects of CO₂ retention (e.g., those with evidence of increased intracranial pressure or brain tumors), ULTIVA may reduce respiratory drive, and the resultant CO₂ retention can further increase intracranial pressure in spontaneously breathing patients. Monitor such patients for signs of sedation and respiratory depression, particularly when initiating therapy with ULTIVA.

Opioids may also obscure the clinical course in a patient with a head injury.

5.13 Risks of Use in Patients with Biliary Tract Disease

The remifentanil in ULTIVA may cause spasm of the sphincter of Oddi. Opioids may cause increases in serum amylase. Monitor patients with biliary tract disease, including acute pancreatitis, for worsening symptoms.

5.14 Increased Risk of Seizures in Patients with Seizure Disorders

The remifentanil in ULTIVA may increase the frequency of seizures in patients with seizure disorders, and may increase the risk of seizures occurring in other clinical settings associated with seizures. Monitor patients with a history of seizure disorders for worsened seizure control during ULTIVA therapy.

5.15 Rapid Offset of Action

Analgesic activity will subside within 5 to 10 minutes after discontinuation of administration of ULTIVA. However, respiratory depression may continue in some patients for up to 30 minutes after termination of infusion due to residual effects of concomitant anesthetics. Standard monitoring should be maintained in the postoperative period to ensure adequate recovery without stimulation. For patients undergoing surgical procedures where postoperative pain is generally anticipated, other analgesics should be administered prior to the discontinuation of ULTIVA.

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)]
• •Life-Threatening Respiratory Depression [see Warnings and Precautions (5.2)]
• •Interactions with Benzodiazepines or other CNS Depressants [see Warnings and Precautions (5.3)]
• •Opioid-Induced Hyperalgesia and Allodynia [see Warnings and Precautions (5.4)]
• •Serotonin Syndrome [see Warnings and Precautions (5.5) ]
• •Skeletal Muscle Rigidity [see Warnings and Precautions (5.7) ]
• •Bradycardia [see Warnings and Precautions (5.9) ]
• •Hypotension [see Warnings and Precautions (5.10) ]
• •Biliary Tract Disease [see Warnings and Precautions (5.13) ]
• •Seizures [see Warnings and Precautions (5.14) ]

Most common adverse reactions (incidence ≥ 1%) were respiratory depression, bradycardia, hypotension, and skeletal muscle rigidity. (6)

 

To report SUSPECTED ADVERSE REACTIONS, contact Mylan at 1-877-446-3679 (1-877-4-INFO-RX) or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

6.1Clinical 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.

Approximately 2,770 adult patients were exposed to ULTIVA in controlled clinical studies. The frequencies of adverse events during general anesthesia with the recommended doses of ULTIVA 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 StudiesDoes not include adverse events from cardiac studies or the neonatal study. See Tables 14, 15, and 16 for cardiac information. at the Recommended DosesSee Table 1 for recommended doses. Not all doses of ULTIVA were equipotent to the comparator opioid. Administration of ULTIVA 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%). of ULTIVA

Adverse Event	Induction/Maintenance		Postoperative Analgesia		After Discontinuation
	ULTIVA(n = 921)	Alfentanil/ Fentanyl(n = 466)	ULTIVA(n = 281)	Morphine(n = 98)	ULTIVA(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%)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.	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%)

 

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 StudiesDoes not include adverse events from cardiac studies or the neonatal study. at the Recommended DosesSee Table 1 for recommended doses. Not all doses of ULTIVA were equipotent to the comparator opioid. of ULTIVA

Adverse Event n	Induction Maintenance				Postoperative Analgesia				After Discontinuation
	ULTIVA		Alfentanil/Fentanyl		ULTIVA		Morphine		ULTIVA		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%

The frequencies of adverse events from the clinical studies at the recommended doses of ULTIVA 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 DosesSee Table 3 for recommended doses. Administration of ULTIVA 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%). of ULTIVA

Adverse Event	ULTIVA(n = 159)	ULTIVA + 2 mg Midazolam With higher midazolam doses, higher incidences of respiratory depression and apnea were observed. (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%)	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%)

 

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 ULTIVA and reported an event divided by the total number of patients exposed to ULTIVA 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 ULTIVA 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 DosesSee Table 4 for recommended doses. of ULTIVA

	Induction/Intubation			Maintenance
Adverse Event	ULTIVA(n = 227)	Fentanyl(n = 176)	Sufentanil(n = 41)	ULTIVA(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

 

Table 15: Adverse Events Reported in ≥ 1% of Patients in the ICU Phase of Cardiac Surgery Studies at the Recommended DosesSee Table 4 for recommended doses. of ULTIVA

Adverse Event	ULTIVAn = 227	Fentanyln = 176	Sufentaniln = 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

 

Table 16: Adverse Events Reported in ≥ 1% of Patients in the Post-Study Drug Phase of Cardiac Surgery Studies at the Recommended DosesSee Table 4 for recommended doses. of ULTIVA

Adverse Event	ULTIVAn = 227	Fentanyln = 176	Sufentaniln = 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%)

 

ULTIVA 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 ULTIVA 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 ULTIVA in General Anesthesia Studies at the Recommended DosesSee Table 2 for recommended doses. of ULTIVA

	Recovery			Follow-up In subjects receiving halothane (n = 22), 10 (45%) experienced vomiting.
Adverse Event	ULTIVA(n = 342)	Fentanyl(n = 103)	Bupivacaine(n = 86)	ULTIVA(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

 

6.2Postmarketing 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 ULTIVA.

Hyperalgesia and Allodynia: Cases of hyperalgesia and allodynia have been reported with opioid therapy of any duration [see Warnings and Precautions (5.4)].

Hypoglycemia: Cases of hypoglycemia have been reported in patients taking opioids. Most reports were in patients with at least one predisposing risk factor (e.g., diabetes).