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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 1 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 12 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 13 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. 14 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. 15 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. 16