Download UCSF Nalbuphine monograph July 2013 FINAL

UCSF Pharmacy & Therapeutics Committee
Formulary Consideration: Nalbuphine (Nubain®)
Prepared by: Nicole Nguyen, PharmD
Reviewed by: Candy Tsourounis, PharmD
Medication Outcomes Center
Drug Name:
Manufacturer:
Therapeutic Class:
AHFS Classification:
Similar Agents:
REMS:
Boxed Warning:
Hazardous Drug
Date FDA Approved:
Nalbuphine (Nubain®)
Endo Pharmaceuticals Inc.
Analgesic, Anesthetic Adjunct, Opioid, Opioid Agonist/Antagonist
28:08.12 - Opiate Partial Agonists
Butorphanol, Pentazocine, Buprenorphine
No
No
Not listed as a hazardous drug by NIOSH.
1979 original approval
Indications:
Nalbuphine is approved by the Food and Drug Administration (FDA) for use as an analgesic for moderate
to severe pain and as an adjunct for general anesthesia.
Nalbuphine is used off label for opioid-induced pruritus, post-anesthesia shivering, respiratory depression
and sickle cell anemia with crisis.
Nalbuphine is being requested for formulary consideration for the treatment of opioid-induced pruritus
which is a non-FDA approved indication.
Background:
Pruritus is a common, unpleasant side effect of opioid administration for acute pain from surgery, trauma,
and childbirth. Several options are available to treat opioid-induced pruritus, including nalbuphine,
diphenhydramine, and naloxone.
Treatment Options:
For opioid induced pruritus, typical first line agents include antihistamines given at high doses as they
1
block H1 receptors which inhibit the release of pruritic mediators from mast cells. Since antihistamines
are relative safe, widely available, and affordable, the data on the efficacy of systemic antihistamines for
1
pruritus are limited. First generation antihistamines (diphenhydramine and hydroxyzine) are helpful at
1
night but sedation during the day and use in the elderly may be problematic.
Other partial µ antagonist options such as naloxone and naltrexone appear to be effective against some
1
forms of pruritus, but their use is limited by a high rate of initial adverse effects.
1
Table 1: Similar Products Indicated for the Treatment of Pruritus
Generic name
Brand
Manufacturer
UCSF
Notes
Formulary
Nalbuphine
Nubain®
Endo
No
Useful in nocturnal and intractable
Pharmaceuticals
pruritus; may cause nausea and
Inc.
vomiting as well as drowsiness; may
precipitate acute withdrawal in patients
receiving opioid analgesics; some
potential for abuse due to concomitant
weak µ-opioid receptor agonist activity
Diphenhydramine Benadryl®
Pfizer Inc.
Yes
No direct effect on pruritus except in
urticaria; sedating antihistamines may
be useful through their soporific effects.
Drowsiness, dizziness, anticholinergic
effects, excitability in children.
Naloxone
Narcan®
Endo
Yes
Pure opioid antagonist that competes
Pharmaceuticals
and displaces at receptor sites, reversal
Inc.
of narcotic depression
Pharmacology:
• Nalbuphine is an opioid agonist/antagonist
o Kappa agonistà thought to be itch-suppressive. Activation of kappa opioid receptor in
1,2
the CNS may inhibit itch.
o Partial µ antagonistà activation if µ-opioid receptors in the CNS may contribute to itch
through suppression of the inhibitory effect of pain-transmitting neurons on pruriceptive
1
neurons. Other options naltrexone and naloxone appear to be effective against some
1
forms of pruritus, but limited by high rate of initial adverse effects.
• Nalbuphine is a potent analgesic. Its analgesic potency is essentially equivalent to that of
morphine on a mg basis. Receptor studies show that nalbuphine binds to mu, kappa, and delta
receptors, but not to sigma receptors. Nalbuphine is primarily a kappa agonist/partial µ antagonist
analgesic.
• The opioid antagonism of nalbuphine is 1/4 as potent as nalorphine and 10 times that of
pentazocine.
• Nalbuphine may produce the same degree of respiratory depression as equi-analgesic doses of
morphine. However, nalbuphine exhibits a ceiling effect such that increases in dose >30 mg do
not produce further respiratory depression in the absence of other CNS active medications
affecting respiration.
• Nalbuphine by itself has potent opioid antagonist activity at doses equal to or lower than its
analgesic dose. When nalbuphine is administered following or concurrently with µ agonist opioid
analgesics (e.g., morphine, oxymorphone, fentanyl), nalbuphine may partially reverse or block
opioid-induced respiratory depression from the µ agonist analgesic.
• Nalbuphine may precipitate withdrawal in patients dependent on opioid drugs. Nalbuphine should
2
be used with caution in patients who have been receiving µ opioid analgesics on a regular basis.
2
2,3,12,13
Table 2: Pharmacokinetics
:
Parameters
Nalbuphine
Dose
2.5-5 mg IV, may repeat
dose
Bioavailability
-
Diphenhydramine
25-50 mg IV, IM single
dose, may repeat
42-62%
PO: 65-100%
15 minutes to 1 hour
Naloxone
0.25 mcg/kg/hour IV
infusion
Rapidly inactivated
Onset
IV within 2-3 minutes
IM <15 minutes
SQ <15 minutes
Duration
Analgesia: 3-6 hours
≤10-12 hours
Up to 1.9 days
Time to peak
concentration
IM 0.48-0.63 hour
SQ 0.44-0.48 hour
Epidural 0.14-0.5 hour
not available
3.8 L/kg, the Vd following
epidural administration
ranged from 4.4-8.1 L/kg
Hepatic, extent not reported
with inactive metabolites
none
not available
IV, IM, SQ: Elimination 2.22.6 hours, Epidural: 2.1-3
hours
Plasma ~5 hours
Renal excretion 7% as
unchanged drug and
metabolites
Feces, extensive secondary
to biliary secretion
none
~ 2-4 hours
ET, IM, SQ: 2-15
minutes
Inh via neb:~5 minutes
IV: ~2 minutes
Intranasal:
~8-13
minutes
~30-120
minutes
depending
on
route
IV<IM
not available
not available
17 L/kg
not available
200 L
Extensive hepatic, firstpass effect
none
98.5%
Adults: 9 hours (7-12
hours)
Hepatic via
glucuronidation
Naloxone-3-glucuronide
not available
Adults: 0.5-1.5 hours
Renal as metabolites
and little unchanged
drug
Renal as metabolites
CYP2D6
none
Plasma binding
Volume of
distribution
Metabolism
Active metabolite
Protein binding
Half-life
Excretion
CYP Substrate
3
Clinical Trials:
4,5
Summarized below are a total of 6 trials, 2 are placebo-controlled and 4 are comparative trials. The comparison trials involved nalbuphine vs.
7,10
8,11
dipehnhydramine
and nalbuphine infusion vs. naloxone
Table 3: Summary of Clinical Studies
Design
N
Population
Treatment
7
Liao, et. al
150
Women
NAL 10 mg IM (n=50)
randomized
undergoing
vs.
Caesarean
DIP 30 mg IM (n=50)
section with
vs.
epidural
NS IM (n=50) given after
anesthesia
delivery
10
Alhashemi
prospective,
randomized,
double-blind
80
Treatment of
intrathecal
morphineinduced
pruritus
following
Caesarean
section
NAL (n=24) or DIP (n = 21)
NAL or DIP were given in a
50mL IVPB
NAL doses:
5 mg, 10 mg and 10 mg
DIP doses:
Measure
Occurrence and
severity of pruritus
Caesarian section
wound pain
• Compared both
the efficacy and
cost
• Visual analog
scale (VAS)
• patient
satisfaction
• cost
4
Results
Overall incidence of
pruritus during the
24 hr follow-up
period was:
NS- 72%,
DIP- 68%,
NAL-44%.
Pruritus occurred
less frequently in
group NAL than
group DIP (p =
0.027).
At 4 and 12 hrs
postoperatively, the
pruritus severity was
significantly different
(p =
0.003 and p = 0.002)
and was significantly
less in group NAL
than group DIP in
the intergroup
comparison (p =
0.013 and p =
0.012).
NAL treatment more
likely to achieve a
VAS score of zero
(83% vs. 43%, P <
0.01), had a greater
change in VAS
following treatment
(4 +/- 2 vs. 2+/- 2, P
< 0.003), and
Adverse effects
Pain scores were
less than 5 for
all patients.
Overall efficacy
NAL was superior to DIP in
decreasing the incidence
and severity of pruritis
No significant
differences were
found in pain
scores between the
three groups at the
four time intervals.
10 mg NAL IM was effective
in decreasing incidence and
severity of pruritus and did
not affect analgesia.
No patients were
over-sedated
(Ramsay score ≥5)
and all scores were
in the 2-4 range.
Sedation scores
were not
significantly
different between
groups at the four
time intervals.
No difference in the
proportion of
patients
in each group who
were sedated with
anti-pruritic
therapy; eight
patients reported
being sedated,
NAL was more effective
than DIP in relieving pruritus
caused by intrathecal
morphine and the cost
differences are small
Resolution of pruritus
occurred in 83% of patients
on NAL compared with 43%
Design
N
Population
Treatment
25 mg, 50 mg and 50 mg
Measure
Results
experienced fewer
treatment failures
(4% vs. 29%, P <
0.04), than those
treated with
diphenhydramine).
Each dose was administered
over 15 min with subsequent
doses being given q30
min if symptoms persisted or
recurred.
Subjects receiving
NAL were also more
likely to rate their
pruritus treatment as
being good to
excellent (96% vs
57%, P < 0.004).
Patients who continued to
have pruritus after three doses
of the medication were
considered treatment failures
8
Wang
randomized
double-blind
11
Cohen
randomized
double-blind
75
40
Females
undergoing
epidural
anesthesia
with
morphine for
total
hysterectom
y
Treatment of
side effects
after
1. NAL
60 mcg/kg/h infusion
2. NX
infusion 2 mcg/kg/h
3. NS infusion
Up to 3 IV doses of either
NX 0.2 mg (group 1; n = 20)
Or
Pain relief
Rescue analgesia
Incidence of N/V
Compared NX and
NAL when
administered.
5
Direct drug costs
were higher for NAL
than for DIP ($6.4
+/- 3. I vs $1.7 +/0.7, respectively, P
< 0.0001)
All patients had
adequate
postoperative pain
relief.
Proportion of
patients requiring
rescue analgesia
and the total
consumption of
rescue analgesic
were higher in
naloxone group than
in the other two
groups.
The first dose
of NAL decreased
the incidence of
Adverse effects
three
in group NAL and
five in group DIP
Overall efficacy
of patients treated with DIP
None of these
patients had
respiratory
depression
(respiratory
rate < 10 per min)
nor were they
difficult to arouse.
Postoperative
nausea/vomiting
was observed in
62.5% of NALtreated patients
and 42.9% DIPtreated.
Incidence of
nausea and
vomiting and
pruritus was higher
in placebo group
compared to other
two groups
Coadministration of
either NAL or NX with
epidural morphine reduces
the incidence of morphinerelated side effects.
However, unlike NX,
NAL did not attenuate the
analgesic effect of epidural
morphine
Sedation scores
increased
after nalbuphine (P
NAL is superior to NX for
the treatment of side effects
after epidural morphine.
Design
4
Davies, et al
randomized,
double-blind,
placebocontrolled
trial
N
Population
epidural
morphine, 5
mg, given
for postcesarean
analgesia.
Treatment
NAL 5 mg (group 2; n = 20)
Measure
Incidence of
vomiting, the
severity of nausea
and pruritus, and
the degree of
sedation and pain
were assessed
before and 30 min
after each dose
Results
vomiting (P < 0.005)
and the severity of
nausea
and pruritus (P <
0.01), no change
with NX.
24
Use in
Extracorpor
eal shockwave
lithotripsy
(ESWL),
with
midazolam
used for
sedation,
after 1 does
fentanyl 100
mcg
NAL 10 mg SQ (n=12)
vs.
placebo (n=12)
following epidural fentanyl 100
mcg
Assessment of
pruritus, pain,
sedation,
dysphoria, urinary
retention,
nausea/vomiting
and respiratory
depression at 15
min, 30 min, and
hourly for up to 5
hours if symptoms
continued.
A statistically
significant difference
in the degree of
pruritus was
observed in the NAL
-treated patients, as
determined using a
visual analog
pruritus scoring
system (patient
asked to indicate on
0-10 cm scale, 0=no
pruritus and
10=worst possible
pruritus). Pruritus
remained
unchanged for the
control patients at 1
to 2 hours after the
operation and
pruritus resolved 4
hours
postoperatively in
both groups
Pruritus and pain
assessed on a 010 cm visual
analog scale
Sedation
assessed on a 3point scale (0-3
with 0=
unresponsive,
1=responds/noxio
us,
2=responds/verbal
3=awake)
6
Adverse effects
< 0.05) and
remained
unchanged
after NX, whereas
pain scores
increased
after NX (P < 0.01)
and were
unchanged
after NAL.
Pain scores were
zero until fourth
postoperative hour
when two patients
in each group
developed renal
colic
Patients in both
groups were judged
to be awake (3 on
0-3 scale for
sedation
assessment at all
observed periods
One patient in NS
group developed
urinary retention
Two patients in
control group
developed nausea
No clinically
significant
respiratory
depression in either
group
Overall efficacy
25% of those treated with
NAL achieved relief
compared with none of
those treated with NX
NAL 10 mg SQ was
effective in reducing pruritus
from epidural fentanyl doses
in a controlled study.
A statistically significant
difference in the degree of
pruritus was observed in the
NAL-treated patients.
Design
Penning, et
5
al.
randomized,
prospective,
double-blind,
placebocontrolled
N
20
Population
Elective total
abdominal
hysterectom
y. 0.1 mg/kg
morphine
Treatment
N=14 NAL 0.3 mg/kg-1 IV 6
hours after epidural morphine
Vs.
N=6 placebo/NS
Measure
Pain and pruritus
every two
hours while awake
and immediately
before and ten
minutes after each
administration
Pain scores
determined by the
patients using the
linear analogue
pain scale, graded
from 0 to 10
Pruritus score
attained from the
patient in
response to direct
questioning: “Do
you itch?"
Itching graded
according
to severity: zero
when not present,
one when mild,
two when
moderate and
three when
distressingly
severe.
Were
administered.
7
Results
Eleven patients
needed additional
epidural morphine to
achieve satisfactory
analgesia in the
early postoperative
period. Seven of
these were in the
NAL group, and four
in the NS group. All
patients except one
from the
NS group had
postoperative
analgesia.
The administration
of 0.3 mg/kg NAL
did not diminish
analgesia
The duration of
analgesia after
epidural morphine
(i.e., the time to first
request for
additional
analgesia),
is shown in Table
UI. The duration of
adequate analgesia
in the NAL group
was 5.4 hours
longer than in the
NS group, but this
difference was not
statistically
significant.
Six hours after the
Adverse effects
9 subjects
experienced
greater sedation
Overall efficacy
NAL was effective in
relieving pruritus and there
was no reversal of
analgesia after NAL
administration.
Design
N
Population
Treatment
Measure
Results
administration of
epidural morphine
50% of patients in
both groups
had pruritus
Pruritus was
antagonized by 0.1
mg/kg NAL (p <
0.006).
No reversal of
analgesia.
NAL=nalbuphine, NX=naloxone, NS=normal saline
8
Adverse effects
Overall efficacy
• A quantitative systemic review in 2001 of 22 randomized trials (N=1477) concluded that
naloxone, naltrexone, nalbuphine and droperidol are efficacious in the prevention of opioid6
induced pruritus. Trials with IV naloxone, oral naltrexone, and IV nalbuphine were compared.
Combined data suggested that naloxone infusions were efficacious; the number of patients
requiring rescue analgesia was significantly increased. Oral naltrexone was more efficacious
than control. Nalbuphine as a 40-mg bolus IV injection has a reported efficacy and is not
associated with decreased pain scores, although it is associated with increased drowsiness
compared with control. In this systematic review, the authors were unable to find a dosedependent decrease in the incidence of pruritus with opioid antagonists, possibly because of
1,6
the high doses used in these trials.
• Preliminary data (not yet published) from a meta-analysis reported at the annual meeting of the
American Pain Society assessed treatment efficacy of nalbuphine for opioid-induced pruritus,
concluded that nalbuphine can effectively combat opioid-induced pruritus. Authors concluded
9
that nalbuphine should be used as a first line treatment of opioid-induced pruritus.
o 10 comparison trials (N=1,029 patients), nalbuphine was more effective in treating opioidinduced pruritus than diphenhydramine, naloxone, or propofol, or placebo in patients
receiving opioids for acute pain related to surgery or childbirth.
o The primary outcome was efficacy in reduction of pruritus, while the secondary outcomes
included analgesia and adverse effects
o Low dose nalbuphine offers efficacy in treating pruritus without attenuation of analgesia
or increase in sedation and incidence of adverse outcomes.
o Nalbuphine was also associated with a reduction in nausea or vomiting, and reversal of
respiratory depression. Jannuzzi noted that the incidence of pruritus was higher among
9
patients receiving neuraxial opioids.
2
Adverse Effects :
• Sedation, n= 381 (36%) was the most frequent side effect in (N=1066) patients treated with
nalbuphine
• Less frequent, <10%:
o Feeling sweaty/clamminess, 99 (9%)
o Nausea/vomiting, 68 (6%)
o Dizziness/vertigo, 58 (5%)
o Dry mouth/xerostomia, 44 (4%)
o Headache, 27 (3%)
• Other adverse reactions which may occur (reported incidence of <1%) include:
o CNS effects: Nervousness, depression, restlessness, crying, euphoria, floating, hostility,
unusual dreams, confusion, faintness, hallucinations, dysphoria, feeling of heaviness,
numbness, tingling, unreality. The incidence of psychotomimetic effects, such as unreality,
depersonalization, delusions, dysphoria and hallucinations has been shown to be less than
that which occurs with pentazocine.
o Cardiovascular: Hypertension, hypotension, bradycardia, tachycardia, pulmonary edema.
o Gastrointestinal: Cramps, dyspepsia, bitter taste.
o Respiration: Depression, dyspnea, asthma.
o Dermatological: Itching, burning, urticaria.
o Obstetric: Pseudo-sinusoidal fetal heart rhythm.
• Other possible (rare):
o Speech difficulty
o Urinary urgency
o Blurred vision
o Flushing and warmth
9
2
Post-marketing Experience :
• Reports include abdominal pain, pyrexia, depressed level or loss of consciousness, somnolence,
tremor, anxiety, pulmonary edema, agitation, seizures, and injection site reactions such as pain,
swelling, redness, burning, and hot sensations.
• Death has been reported from severe allergic reactions to nalbuphine treatment.
• Fetal death has been reported where mothers received nalbuphine during labor and delivery.
Safety:
• Sound-alike/look-alike issues: Nubain® may be confused with Navane® (thiothixine) and Nebcin®
(tobramycin)
• The Institute for Safe Medication Practices (ISMP) includes this medication among its list of drug
classes which have a heightened risk of causing significant patient harm when used in error.
• ISMP Medication Safety Alert in April 2013 for nalbuphine-naloxone mix-ups. They appear next to
8
each other in medication profiles and can be mis-stocked, see section on “Potential for Errors”.
• April 2013 ISMP Medication Safety Alert included a warning for nalbuphine and naloxone mix-up.
When bar-coding system was bypassed in two incidents, the patients received nalbuphine instead of
naloxone.
o Patient on epidural infusion had PRN orders for both naloxone and nalbuphine. Rapid
response was called for increased somnolence, naloxone was ordered but the two
medications appeared one after the other in the dispensing cabinet and the nurse
inadvertently selected nalbuphine.
o The second incidence, the pharmacy technician accidently stocked nalbuphine instead of
naloxone.
• In another case, IV nalbuphine instead of naloxone was administered to a patient during anesthesia
reversal. Patient was also on IV diphenhydramine, and had to be re-intubated and transferred to ICU.
The hospital later removed nalbuphine from the OR stock, and further determined that there was no
8
need for it in the OR.
Contraindications:
2
• Severe hypersensitivity to nalbuphine or any of its components
2
Warnings and precautions:
• Boxed Warnings: none
Drug Abuse
• Caution should be observed when prescribing nalbuphine for emotionally unstable patients, or for
individuals with a history of opioid abuse. Such patients should be closely supervised when long-term
therapy is contemplated.
• Reported abuse among body builders due to erroneous expectations of physiological benefit, (i.e.
able to train harder and cope with resulting pain, reduced pain from steroid injections and other illicit
drugs, muscle enhancement). In addition, nalbuphine is associated with a false premise that the drug
lowers cortisol levels. Drug is readily available as it is unscheduled and used recreationally.
Use in Ambulatory Patients
• Nalbuphine may impair the mental or physical abilities required for the performance of potentially
dangerous tasks such as driving a car or operating machinery. Therefore, nalbuphine should be
administered with caution to ambulatory patients who should be warned to avoid such hazards.
Use in Emergency Procedures
• Maintain patient under observation until recovered from nalbuphine effects that would affect driving or
other potentially dangerous tasks.
Use in Pregnancy (Other Than Labor)
• Severe fetal bradycardia has been reported when nalbuphine is administered during labor. Naloxone
may reverse these effects. Although there are no reports of fetal bradycardia earlier in pregnancy, it is
possible that this may occur. This drug should be used in pregnancy only if clearly needed, if the
potential benefit outweighs the risk to the fetus, and if appropriate measures such as fetal monitoring
are used to detect and manage any potential adverse effect on the fetus.
Use During Labor and Delivery
• The placental transfer of nalbuphine is high, rapid, and variable with a maternal to fetal ratio ranging
from 1:0.37 to 1:6. Fetal and neonatal adverse effects that have been reported following the
administration of nalbuphine to the mother during labor include fetal bradycardia, respiratory
10
depression at birth, apnea, cyanosis, and hypotonia. Some of these events have been lifethreatening. Maternal administration of naloxone during labor has normalized these effects in some
cases. Severe and prolonged fetal bradycardia has been reported. Permanent neurological damage
attributed to fetal bradycardia has occurred. A sinusoidal fetal heart rate pattern associated with the
use of nalbuphine has also been reported. nalbuphine should be used during labor and delivery only
if clearly indicated and only if the potential benefit outweighs the risk to the infant. Newborns should
be monitored for respiratory depression, apnea, bradycardia and arrhythmias if nalbuphine has been
used.
Head Injury and Increased Intracranial Pressure
• The possible respiratory depressant effects and the potential of potent analgesics to elevate
cerebrospinal fluid pressure (resulting from vasodilation following CO2 retention) may be markedly
exaggerated in the presence of head injury, intracranial lesions or a preexisting increase in
intracranial pressure. Furthermore, potent analgesics can produce effects which may obscure the
clinical course of patients with head injuries. Therefore, nalbuphine should be used in these
circumstances only when essential, and then should be administered with extreme caution.
Interaction with Other Central Nervous System Depressants
• Although nalbuphine possesses opioid antagonist activity, there is evidence that in nondependent
patients it will not antagonize an opioid analgesic administered just before, concurrently, or just after
an injection of nalbuphine. Therefore, patients receiving an opioid analgesic, general anesthetics,
phenothiazines, or other tranquilizers, sedatives, hypnotics, or other CNS depressants (including
alcohol) concomitantly with nalbuphine may exhibit an additive effect. When such combined therapy
is contemplated, the dose of one or both agents should be reduced.
Precautions
Impaired Respiration:
• At the usual adult dose of 10 mg/70 kg, nalbuphine causes some respiratory depression
approximately equal to that produced by equal doses of morphine. However, in contrast to morphine,
respiratory depression is not appreciably increased with higher doses of nalbuphine. Respiratory
depression induced by nalbuphine can be reversed by naloxone hydrochloride when indicated.
nalbuphine should be administered with caution at low doses to patients with impaired respiration
(e.g., from other medication, uremia, bronchial asthma, severe infection, cyanosis, or respiratory
obstructions).
Impaired Renal or Hepatic Function:
• Because nalbuphine is metabolized in the liver and excreted by the kidneys, nalbuphine should be
used with caution in patients with renal or liver dysfunction and administered in reduced amounts.
Myocardial Infarction:
• As with all potent analgesics, nalbuphine should be used with caution in patients with myocardial
infarction who have nausea or vomiting.
Biliary Tract Surgery:
• As with all opioid analgesics, nalbuphine should be used with caution in patients about to undergo
surgery of the biliary tract since it may cause spasm of the sphincter of Oddi.
Cardiovascular System:
• During evaluation of nalbuphine in anesthesia, a higher incidence of bradycardia has been reported in
patients who did not receive atropine pre-operatively.
Carcinogenesis
• Long term carcinogenicity studies were performed in rats (24 months) and mice (19 months) by oral
administration at doses up to 200 mg/kg (1180 mg/m2) and 200 mg/kg (600 mg/m2) per day,
respectively. There was no evidence of an increase in tumors in either species related to nalbuphine
administration. The maximum recommend human dose (MRHD) in a day is 160 mg subcutaneously,
intramuscularly or intravenously, or approximately 100 mg/m2/day for a 60 kg subject.
Mutagenesis
• Nalbuphine did not have mutagenic activity in the AMES test with four bacterial strains, in the
Chinese Hamster Ovary HGPRT assays or in the Sister Chromatids Exchange Assay. However,
nalbuphine induced an increased frequency of mutation in the mouse lymphoma assay. Clastogenic
activity was not observed in the mouse micronucleus test of the cytogenicity bone marrow assay in
rats.
Impairment of Fertility
11
•
A reproduction study was performed in male and female rats at subcutaneous doses up to 56
mg/kg/day or 330 mg/m2/day. Nalbuphine did not affect either male or female fertility rats.
Special Populations:
1
Pregnancy Category: B
• Reproduction studies have been performed in rats by subcutaneous administration of nalbuphine
up to 100 mg/kg/day, or 590 mg/m2/day which is approximately 6 times the MRHD, and in rabbits
by intravenous administration of nalbuphine up to 32 mg/kg/day, 6 or 378 mg/m2/day which is
approximately 4 times the MRHD. The results did not reveal evidence of developmental toxicity,
including teratogenicity, or harm to the fetus. There are, however, no adequate and wellcontrolled studies in pregnant women. Because animal reproduction studies are not always
predictive of human response, this drug should be used during pregnancy only if clearly needed.
Non-teratogenic Effects:
• Neonatal body weight and survival rates were reduced at birth and during lactation when
nalbuphine was subcutaneously administered to female and male rats prior to mating and
throughout gestation and lactation or to pregnant rats during the last third of gestation and
throughout lactation at doses approximately 4 times the maximum recommended human dose.
Lactation
• Excretion in breast milk is unknown, infant risk and the potential for adverse effects cannot be
ruled out. Until additional data are available, women should be advised against breastfeeding
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while receiving sorafenib.
• Limited data suggest that nalbuphine is excreted in maternal milk but only in a small amount
(<1% of the administered dose) and with a clinically insignificant effect. Caution should be
exercised when nalbuphine is administered to a nursing woman.
Drug Interactions:
• Interaction with Other Central Nervous System Depressants: Although nalbuphine possesses
opioid antagonist activity, there is evidence that in nondependent patients it will not antagonize an
opioid analgesic administered just before, concurrently, or just after an injection of nalbuphine.
• Primarily classes for additive effects include:
o Opioid analgesics
o General anesthetics
o Phenothiazines
o Tranquilizers
o Sedatives
o Hypnotics
o CNS depressants (e.g., alcohol)
• Management is to reduce dose of one or both agents when used in combination
• Caution with mu agonist opioid analgesics (e.g., morphine, oxymorphone, fentanyl); may
precipitate withdrawal
• Total of 699 drugs are known to interact with nalbuphine:
o 27 major
o 666 moderate
o 6 minor
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Dosage and Administration:
Table 6: Product Availability
Drug name
Strength/Form
Nalbuphine
10 mg/ml (1 mL, 10 mL);
20 mg/ml (1 mL, 10 mL)
Diphenhydramine
50mg/ml IV or IM
Naloxone
0.02mg.ml,
0.4mg/ml,
1mg/ml IV, IM or SQ
Usual
Starting
Dose
2.5-5 mg IV,
may repeat
dose
25-50 mg
IV, IM single
dose, may
repeat
0.25
mcg/kg/hour
IV infusion
Compatibility
Stable in D5NS,
D10W, LR, NS
Stable in D5NS,
D5W, D10W, LR, NS,
½ NS, dextran 6% in
NS or dextrose, fat
emulsion 10%
Stable in D5W, NS,
do not mix with
alkaline solutions
Storage:
• Nalbuphine (Nubain®) should be stored at room temperature of 15-30°C (59-86°F)
• Nalbuphine (Nubain®) should be protected from light
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Cost and Utilization:
The following table summarizes the total purchases for diphenhydramine, nalbuphine and naloxone for the last 18 months (1/1/2012 through 7/31/2013)
Generic Name
Trade Name
Strength
Form
DIPHENHYDRAMINE
HCL
DIPHENHYDRAMINE
50MG/ML
CARP
Total
Purchased
10
DIPHENHYDRAMINE
HCL
50MG/ML
MDV
10
SDPF
8050
SDV
17225
Diphenhydramine Total Units Purchased/Spend
NALBUPHINE HCL
NALBUPHINE HCL
25295
10MG/ML*
20MG/ML
AMPS
0
MDV
0
MDV
225
Nalbuphine Total Units Purchased/Spend
NALOXONE HCL
NALOXONE HCL
Spend
285
0.4MG/ML
1MG/ML
MDV
150
SDV
2540
SYRN
115
Naloxone Total Units Purchased/Spend
2805
*Nalbuphine 10mg/mL - 1mL ampules have not been available from the manufacturer since January 2012.
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Conclusion:
• Nalbuphine (Nubain®) is not FDA approved for opioid-induced pruritus and will not be reimbursed.
• The current primary literature supports the use of nalbuphine in reducing opioid-induced pruritus.
• Specifically, nalbuphine has been studied the most for treatment of pruritus from opioid epidural
infusion for Caesarean section surgeries.
• According to one unpublished meta-analysis, nalbuphine was more effective in treating opioidinduced pruritus than diphenhydramine, naloxone, or propofol, or placebo in patients receiving
opioids for acute pain related to surgery or childbirth.
• When compared to naloxone, nalbuphine does not alter pain control or increase the need for more
analgesia but does increase sedation
• Side effects of nalbuphine are minimal, sedation being the most frequent.
• Since nalbuphine is a partial agonist, there is a risk of abuse and subsequently, overdose.
•
•
When compared to diphenhydramine, nalbuphine is less sedating.
Nalbuphine is associated with several look- alike, sound-alike issues that have led to serious mix ups
and patient harm
Recommendation:
Given that there are two other effective formulary alternatives for opioid-induced pruritis and the soundalike, look-alike issues, nalbuphine should not be added to the formulary.
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References:
1. Szarvas S, Harmon D, Murphy D. Neuraxial Opioid-Induced Pruritus: A review. J of Clin
Anesthesia 2003;15:234-239.
2. Product Information: NUBAIN(R) injection, nalbuphine hydrochloride injection. Endo
Pharmaceuticals Inc, Chadds Ford, PA, 2005.
3. Product Information: nalbuphine hydrochloride subcutaneous injection, IM injection, IV injection,
solution, nalbuphine hydrochloride subcutaneous injection, IM injection, IV injection, solution.
Hospira Inc., Lake Forest, IL, 2007.
4. Davies GG & From R: A blinded study using nalbuphine for prevention of pruritus induced by
epidural fentanyl. Anesthesiology 1988; 69:763-765.
5. Penning JP, Samson B, Baxter AD. Reversal of epidural morphine-induced respiratory
depression and pruritus with nalbuphine. Can J Anaesth. 1988;35(6):599.
6. Kjellberg F, Tramer MR. Pharmacological control of opioid-induced pruritus: a quantitative
systemic review of randomized trials. Eur J of Anaesthesiol 2001;18:346-557.
7. Liao C, Chang C, Tseng C, et al. Efficacy of IM nalbuphine versus diphenhydramine for
prevention of epidural morphine-induced pruritus after Cesarean delivery. Chang Gung Med J
2011; 34(2):172-8.
8. Wang JJ, Ho ST, Tzeng JI. Comparison of IV nalbuphine infusion versus naloxone in the
prevention of epidural morphine-related side effects. Reg Anesth Pain Med 1998; 23(5):479-84.
9. Jannuzzi R "Nalbuphine for the treatment of opioid-induced pruritus: a systematic
review" American Pain Society 2013; Abstract 139.
10. Alhashemi J et al. Treatment of intrathecal morphine-induced pruritus following Caesarean
section. Can J Anaeth 1997;44(10):1060-1065.
11. Cohen SE, et al. Nalbuphine is better than naloxone for treatment of side effects after epidural
morphine. Anesth Analg 1992;75(5):747-52.
12. Nalbuphine, Detailed evidence-based information. DRUGDEX®, Micromedex database.
Retrieved April 29, 2013.
13. Nalbuphine drug information. Lexicomp database. Retrieved April 29, 2013.
14. Susman E. Review: Nubain Reduces Opioid-Related Itching. MedPage Today, May 10, 2013.
Accessed June 20, 2013.
15. ISMP Medication Safety Alert! Acute Care: Nalbuphine-naloxone mix-ups. April 4, 2013 Vol. 18
(7).
16. Patel T, Yosipovitch G. Therapy of pruritus. Expert Opin Pharmacother 2010; 11:1673.
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