Important 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.

General 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).

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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.

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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.

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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 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.

Continuation 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.

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ULTIVA has not been studied in pediatric patients for use in the immediate postoperative period.

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The use of bolus injections of ULTIVA to treat pain during the postoperative period is not recommended.

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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.

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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.

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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)].

Analgesic Component of Monitored Anesthesia Care

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

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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 (5.6)].

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.

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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.

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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.

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Rates greater than 0.2 mcg/kg/min are generally associated with respiratory depression (respiratory rates less than 8 breaths/min).

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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.

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)].

Dosage 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)].

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.

Dosage 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).]

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)].

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.

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.

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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.

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:

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

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

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

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 listed below.

Sterile Water for Injection, USP
5% Dextrose Injection, USP
5% Dextrose and 0.9% Sodium Chloride Injection, USP
0.9% Sodium Chloride Injection, USP
0.45% Sodium Chloride Injection, USP
Lactated 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.