A1,
A2,
B,
C1,
C2,
D,
E,
F,
G-H,
I-K,
L,
M,
N,
O,
P1,
P2,
Q-R,
S,
T,
U-V,
W-Z
Ultiva Indications, Dosage, Storage, Stability - Remifentanil
Ultiva Indications, Dosage, Storage, Stability - Remifentanil
INDICATIONS
ULTIVA is indicated for IV
administration:
1. as an analgesic
agent for use during
the induction and
maintenance of general anesthesia
for inpatient and
outpatient procedures,
and for continuation as an analgesic
into the immediate
postoperative period
under the direct supervision of an anesthesia
practitioner
in a postoperative anesthesia care unit
or intensive care
setting.
2. as an analgesic
component of monitored
anesthesia care.
DOSAGE AND ADMINISTRATION
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.
During 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 and doses of thiopental, propofol, isoflurane,
and midazolam have been reduced by up to 75% with the coadministration
of ULTIVA. The administration of ULTIVA must be individualized based
on the patient's response. Table 6 summarizes the recommended doses
in adult patients, predominately
ASA physical status
I, II, or III. Recommendations for maintenance anesthesia with nitrous
oxide also apply to pediatric
patients ³2 years.
Table 6: Dosing Guidelines — General Anesthesia
and Continuing as an Analgesic into the Postoperative Care Unit
or Intensive Care Setting*
|
Phase
|
Continuous IV
Infusion of ULTIVA
(mcg/kg/min)
|
Infusion Dose
Range of 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%)
Isoflurane (0.4 to 1.5 M.C.
Propofol (100 to 200 mcg/kg/min)
|
0.4
0.25
0.25
|
0.1 - 2
0.05 - 2
0.05 - 2
|
1
1
1
|
| Continuation as
an analgesic into the immediate
postoperative period |
0.1
|
0.025 - 0.2
|
not recommended
|
| * An
initial dose
of 1 mcg/kg may be administered over 30 to 60 seconds. |
During 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.
During Maintenance of Anesthesia
After endotracheal intubation,
the infusion rate
of ULTIVA should be decreased in accordance with the dosing guidelines
in Table 6. 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 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.
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. 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).
Guidelines for Discontinuation: Upon discontinuation
of ULTIVA, the IV tubing should be cleared to prevent the inadvertent
administration
of ULTIVA at a later time.
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 PHARMACOLOGY:
CLINICAL TRIALS).
Analgesic Component of Monitored Anesthesia Care
It is strongly recommended that supplemental
oxygen be supplied to
the patient whenever ULTIVA is administered.
Table 7 summarizes the recommended doses for monitored anesthesia
care in adult patients,
predominately ASA physical
status I, II, or III.
Table 7: Dosing Guidelines — 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 - 0.2
mcg/ kg/ min)
|
0.025 mcg/kg/min
(Range: 0.025 - 0.2
mcg/kg/min)
|
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 PRECAUTIONS).
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.
Individualization of Dosage
Use in Elderly Patients: The starting doses of ULTIVA
should be decreased by 50% in elderly patients (> 65 years).
ULTIVA should then be cautiously titrated to effect.
Use in Pediatric Patients: No
data are available on the use of ULTIVA in pediatric
patients under 2 years of age. The same doses (per kg) as adults
are recommended for pediatric
patients 2 years of age and older.
Use 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).
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 dilutent 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 25, 50, or 250 mcg/mL prior to administration
(see Table 8). ULTIVA should not be administered without dilution.
Table 8: Reconstitution and Dilution of ULTIVA
|
Final
Concentration
|
Amount of ULTIVA
in Each Vial
|
Final Volume After
Reconstitution and Dilution
|
|
25 mcg/mL
|
1 mg
2 mg
5 mg
|
40 mL
80 mL
200 mL
|
|
50 mcg/mL
|
1 mg
2 mg
5 mg
|
20 mL
40 mL
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
9:
Table 9: IV
Infusion Rates of ULTIVA (mL/kg/h)
|
Drug Delivery Rate
(mcg/kg/min)
|
Infusion Delivery Rate (mL/kg/h)
|
|
25 mcg/mL
|
50 mcg/mL
|
250 mcg/mL
|
|
0.0125
0.025
0.05
0.075
0.1
0.15
0.2
0.25
0.5
0.75
1.0
1.25
1.5
1.75
2.0
|
0.03
0.06
0.12
0.18
0.24
0.36
0.48
0.6
1.2
1.8
2.4
3.0
3.6
4.2
4.8
|
0.015
0.03
0.06
0.09
0.12
0.18
0.24
0.3
0.6
0.9
1.2
1.5
1.8
2.1
2.4
|
not recommended
not recommended
0.012
0.018
0.024
0.036
0.048
0.06
0.12
0.18
0.24
0.3
0.36
0.42
0.48
|
When ULTIVA is used as an analgesic
component of monitored
analgesia care or for pediatric
patients ³2 years of age, a final
concentration
of 25 mcg/mL is recommended. Table 10 is a guideline
for milliliter-per-hour delivery
for a solution of 25
mcg/mL with an infusion
device.
Table 10: 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
0.025
0.05
0.075
0.1
0.15
0.2
|
0.3
0.6
1.2
1.8
2.4
3.6
4.8
|
0.6
1.2
2.4
3.6
4.8
7.2
9.6
|
0.9
1.8
3.6
5.4
7.2
10.8
14.4
|
1.2
2.4
4.8
7.2
9.6
14.4
19.2
|
1.5
3.0
6.0
9.0
12.0
18.0
24.0
|
1.8
3.6
7.2
10.8
14.4
21.6
28.8
|
2.1
4.2
8.4
12.6
16.8
25.2
33.6
|
2.4
4.8
9.6
14.4
19.2
28.8
38.4
|
2.7
5.4
10.8
16.2
21.6
32.4
43.2
|
3.0
6.0
12.0
18.0
24.0
36.0
48.0
|
Table 11 is a guideline
for milliliter-per-hour delivery
for a solution of 50 mcg/mL with an infusion
device.
Table 11: 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
0.05
0.075
0.1
0.15
0.2
0.25
|
2.7
3.6
5.4
7.2
9.0
|
2.4
3.6
4.8
7.2
9.6
12.0
|
3.0
4.5
6.0
9.0
12.0
15.0
|
3.6
5.4
7.2
10.8
14.4
18.0
|
2.1
4.2
6.3
8.4
12.6
16.8
21.0
|
2.4
4.8
7.2
9.6
14.4
19.2
24.0
|
2.7
5.4
8.1
10.8
16.2
21.6
27.0
|
3.0
6.0
9.0
12.0
18.0
24.0
30.0
|
|
0.5
0.75
1.0
1.25
1.5
1.75
2.0
|
18.0
27.0
36.0
45.0
54.0
63.0
72.0
|
24.0
36.0
48.0
60.0
72.0
84.0
96.0
|
30.0
45.0
60.0
75.0
90.0
105.0
120.0
|
36.0
54.0
72.0
90.0
108.0
126.0
144.0
|
42.0
63.0
84.0
105.0
126.0
147.0
168.0
|
48.0
72.0
96.0
120.0
144.0
168.0
192.0
|
54.0
81.0
108.0
135.0
162.0
189.0
216.0
|
60.0
90.0
120.0
150.0
180.0
210.0
240.0
|
Table 12 is a guideline
for milliliter-per-hour delivery
for a solution of 250 mcg/mL with an infusion
device.
Table 12: 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
0.15
0.2
0.25
0.5
0.75
1.0
1.25
1.5
1.75
2.0
|
0.72
1.08
1.44
1.80
3.60
5.40
7.20
9.00
10.80
12.60
14.40
|
0.96
1.44
1.92
2.40
4.80
7.20
9.60
12.00
14.40
16.80
19.20
|
1.20
1.80
2.40
3.00
6.00
9.00
12.00
15.00
18.00
21.00
24.00
|
1.44
2.16
2.88
3.60
7.20
10.80
14.40
18.00
21.60
25.20
28.80
|
1.68
2.52
3.36
4.20
8.40
12.60
16.80
21.00
25.20
29.40
33.60
|
1.92
2.88
3.84
4.80
9.60
14.40
19.20
24.00
28.80
33.60
38.40
|
2.16
3.24
4.32
5.40
10.80
16.20
21.60
27.00
32.40
37.80
43.20
|
2.40
3.60
4.80
6.00
12.00
18.00
24.00
30.00
36.00
42.00
48.00
|
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.
HOW SUPPLIED
ULTIVA should be stored at 2° to 25° C (36° to 77°
F). ULTIVA for IV use is
supplied as follows:
NDC 0173-0483-00 1 mg of
remifentanil base lyophilized
powder, 3-mL Vial (Carton of 10)
NDC 0173-0484-00 2 mg of
remifentanil base lyophilized
powder, 5-mL Vial (Carton of 10)
NDC 0173-0485-00 5 mg of
remifentanil base lyophilized
powder, 10-mL Vial (Carton of 10)
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