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 Side Effects, and Drug Interactions - Remifentanil
Ultiva Side Effects, and Drug Interactions - Remifentanil
SIDE EFFECTS
ULTIVA produces adverse events that are characteristic
of µ-opioids, such as respiratory
depression, bradycardia,
hypotension, and
skeletal muscle rigidity. These adverse events dissipate within
minutes of discontinuing or decreasing the infusion
rate of ULTIVA. (See CLINICAL
PHARMACOLOGY, WARNINGS,
and PRECAUTIONS on the management
of these events.)
Adverse event information is derived from controlled clinical
trials 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 2492 patients were exposed to ULTIVA in controlled
clinical trials. The frequencies of adverse events during general
anesthesia with the
recommended doses of ULTIVA are given in Table 3. Each patient
was counted once for each type
of adverse event.
Table 3: Adverse Events Reported in ³1%
of Patients in General Anesthesia Studies at the Recommended Doses
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%) †
|
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%)
|
| * See Table
6 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%). |
| † 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 4: Incidence (%) of Most Common Adverse
Events by Gender in General Anesthesia Studies at the Recommended
Dose* of ULTIVA
|
Adverse
Event
|
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
Hypotension
Vomiting
Muscle rigidity
|
2%
29%
<1%
17%
|
<1%
14%
<1%
7%
|
0
7%
0
14%
|
0
6%
<1%
4%
|
12%
0
4%
6%
|
26%
0
10%
1%
|
8%
0
0
0
|
19%
0
8%
0
|
22%
2%
5%
<1%
|
45%
2%
22%
<1%
|
30%
2%
8%
0
|
52%
2%
27%
<1%
|
| * See Table 6 for
recommended doses. Not all doses of ULTIVA were equipotent
to the comparator opioid. |
The frequencies of adverse events from the clinical
studies at the recommended doses of ULTIVA in monitored anesthesia
care are given in Table 5.
Table 5: Adverse Events Reported in ³
1% of Patients in Monitored Anesthesia Care Studies at the Recommended
Doses of ULTIVA*
|
Adverse Event
|
ULTIVA (n = 159)
|
ULTIVA + 2 mg
Midazolam †
(n = 103)
|
Propofol (0.5 mg/kg
then 50
mcg/kg/min)
(n = 63)
|
| Nausea
Vomiting
Pruritus
Headache
Sweating
Shivering
Dizziness
Hypotension
Bradycardia
Respiratory depression
Muscle rigidity
Chills
Flushing
Warm sensation
Pain at study IV
site
|
70 (44%)
35 (22%)
28 (18%)
28 (18%)
10 (6%)
8 (5%)
8 (5%)
7 (4%)
6 (4%)
4 (3%)
4 (3%)
2 (1%)
2 (1%)
2 (1%)
2 (1%)
|
19 (18%)
5 (5%)
16 (16%)
12 (12%)
0
1 (< 1%)
5 (5%)
0
0
1 (< 1%)*
0
0
0
0
0
|
20 (32%)
13 (21%)
0
6 (10%)
1 (2%)
1 (2%)
1 (2%)
6 (10%)
7 (11%)
0
1 (2%)
2 (3%)
0
0
11 (17%)
|
| * See Table 7 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%). |
| † With higher midazolam
doses, higher incidences of respiratory
depression
and apnea were observed |
Other Adverse Events
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
and neurosurgery
studies (n = 1883 general anesthesia,
n = 609 monitored anesthesia care).
Incidence Less than 1%
Digestive: constipation,
abdominal discomfort,
xerostomia, gastro-esophageal reflux,
dysphagia, diarrhea,
heartburn, 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,
sleep disorder, 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.
DRUG ABUSE AND DEPENDENCE
ULTIVA is a Schedule II controlled drug
substance that can
produce drug dependence of the morphine
type and has the potential
for being abused.
DRUG INTERACTIONS
In animals the duration
of muscle paralysis
from succinylcholine is not prolonged by remifentanil.
Remifentanil clearance
is not altered by concomitant
administration of thiopental, isoflurane, propofol, or temazepam
during anesthesia. In vitro studies with atracurium, mivacurium,
esmolol, echothiophate, neostigmine, physostigmine, and midazolam
revealed no inhibition
of remifentanil hydrolysis in whole human
blood by these drugs.
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