Source: Health Products and Food Branch (CA) Revision Year: 2018
NUBAIN (nalbuphine hydrochloride) is a synthetic opioid agonist-antagonist analgesic for parenteral use, related chemically to the opioid oxymorphone, and to the opioid antagonist naloxone. Nalbuphine has an analgesic (agonist action) potency equivalent to that of morphine on a milligram for milligram basis. Receptor studies show that nalbuphine binds to mu, kappa, and delta receptors, but not to sigma receptors. Nalbuphine is primarily a kappa agonist/ mu antagonist analgesic. The onset of action of nalbuphine occurs within 2 to 3 minutes after intravenous administration, and in less than 15 minutes following subcutaneous or intramuscular injection. The plasma half-life of nalbuphine is five hours and in clinical studies the duration of analgesic activity has been reported to range from three to six hours. The narcotic antagonist activity of NUBAIN is one-fourth as potent as that of nalorphine and ten times that of pentazocine.
At the usual adult dose of 10 mg/70 kg, nalbuphine may produce respiratory depression equivalent to that of equianalgesic doses of morphine. However, NUBAIN exhibits a ceiling effect such that increases in dose greater than 30 mg do not produce further respiratory depression.
Nalbuphine by itself has potent opioid antagonist activity at doses equal to or lower than its analgesic dose. When administered following or concurrent with mu agonist opioid analgesics (e.g., morphine, oxymorphone, fentanyl), nalbuphine may partially reverse or block opioid-induced respiratory depression from the mu agonist analgesic. Nalbuphine may precipitate withdrawal in patients dependent on opioid drugs. Nalbuphine should be used with caution in patients who have been receiving mu opioid analgesics on a regular basis.
Nalbuphine produces respiratory depression by direct action on brain stem respiratory centres. The respiratory depression involves both a reduction in the responsiveness of the brain stem centres to increases in CO2 tension and to electrical stimulation.
Nalbuphine depresses the cough reflex by direct effect on the cough centre in the medulla. Antitussive effects may occur with doses lower than those usually required for analgesia.
Nalbuphine causes miosis, even in total darkness. Pinpoint pupils are a sign of opioid overdose but are not pathognomonic (e.g., pontine lesions of hemorrhagic or ischemic origin may produce similar findings). Marked mydriasis rather than miosis may be seen with hypoxia in the setting of oxycodone overdose.
Nalbuphine causes a reduction in motility associated with an increase in smooth muscle tone in the antrum of the stomach and duodenum. Digestion of food in the small intestine is delayed and propulsive contractions are decreased. Propulsive peristaltic waves in the colon are decreased, while tone may be increased to the point of spasm resulting in constipation. Other opioidinduced effects may include a reduction in gastric, biliary and pancreatic secretions, spasm of the sphincter of Oddi, and transient elevations in serum amylase.
Nalbuphine by may produce release of histamine with or without associated peripheral vasodilation. Manifestations of histamine release and/or peripheral vasodilatation may include pruritus, flushing, red eyes, hyperhidrosis and/or orthostatic hypotension.
Opioids may influence the hypothalamic-pituitary-adrenal or – gonadal axes. Some changes that can be seen include an increase in serum prolactin, and decreases in plasma cortisol and testosterone. Clinical signs and symptoms may be manifest from these hormonal changes.
In vitro and animal studies indicate that opioids have a variety of effects on immune functions, depending on the context in which they are used. The clinical significance of these findings is unknown.
Acute Toxicology: The animals which died within 14 days of dosing: mouse 1240 mg/kg (S.C.), 775 mg/kg (I.M.), 490 mg/kg (I.V.); rat: >1000 mg/kg (S.C.), 1200-1240 mg/kg (I.M.), 182-218 mg/kg (I.V.); dog: 200 mg/kg (S.C.), ~140 mg/kg (I.V.).
Depending on species and route of administration, the animals died either during clonictonic convulsions, in respiratory failure following clonic-tonic convulsions, or in respiratory failure without prior convulsions. Deaths generally occurred rapidly, and always within 72 hours of dosing. Other signs included cyanosis, depression, emesis, piloerection, ptosis, rapid or laboured respiration, salivation and tremor. Surviving animals generally appeared normal within 24 hours of dosing and most signs had disappeared within 2 to 4 hours. There were no obvious sex differences in response to the drug. Other than skin sores at subcutaneous and intramuscular injection sites, there were no drug-induced abnormalities at autopsy.
Subacute Toxicology: Nalbuphine HCI was administered subcutaneously to groups of 20 male and 20 female young rats for two weeks (14 daily injections in 16 days) at dosage levels of 0, 6.6, 20 and 100 mg/kg/day. The only evidence of toxicity was decreased body weight at high dosage level. Some local irritation was observed at the injection site, but this was apparently due to repeated injections in the same area. Nalbuphine HCI was administered subcutaneously to groups of male and two female young adult beagles for two weeks (14 daily injections in 15 days) at dosage levels of 0, 2, 4, and 50 mg/kg/day. At the high dosage level, the signs of toxicity were slight weight loss, slight tremoring and hind-limb weakness, slight salivation and a few occurrences of emesis. Except for some mild local irritation at the injection sites in the 50 mg/kg/day group, due to large volumes of a 20 mg/ml drug solution, there were no other signs of toxicity. When nalbuphine HCI was administered intravenously to groups of three male and three female young adult beagle dogs once a day, 7 days a week for at least 2 weeks at dosage levels of 4, 8, and 32 mg/kg/day, there were no significant signs of toxicity.
Chronic Toxicology: Nalbuphine HCI was administered subcutaneously to starting groups of 35 male and 35 female young adult rats once a day, seven days a week for up to six months at dosage levels of 0, 7, 14 and 56 mg/kg/day. There was an interim sacrifice of 15 males and 15 females after three months. The drug caused a slight reduction in body weight gain, a slight to moderate increase in food consumption and decrease in food efficiency, a slight to marked but reversible hair loss and a slight normochromic, normocytic anemia, depending on the dosage level, frequency of dosing and animal’s sex. Nalbuphine HCI was administered subcutaneously to groups of four male and four female adult beagle dogs once a day, seven days a week for six months at dosage levels of 0, 4, 8, and 50 mg/kg/day. The drug caused weight loss at all dosage levels.
Carcinogenesis and Mutagenesis: No evidence of carcinogenicity was found in a 24- month carcinogenicity study in rats and an 18-month carcinogenicity study in mice at oral doses as high as the equivalent of approximately three times the maximum recommended therapeutic dose. No evidence of a mutagenic/genotoxic potential to NUBAIN was found in the Ames, Chinese Hamster Ovary HGPRT, and Sister Chromatid Exchange, mouse micronucleus, and rat bone marrow cytogenicity assays. Nalbuphine induces an increased frequency of mutation in mouse lymphoma cells.
Reproduction and Teratology: The reproductive effects of parenterally administered nalbuphine HCI were evaluated in 1) a Segment I fertility and general reproductive performance study in rats at subcutaneous dosage levels of 14, 28 and 56 mg/kg/day, 2) a Segment II teratology study in rats at subcutaneous dosage levels of 7, 14, and 100 mg/kg/day and in rabbits at intravenous dosage levels of 4, 8 and 32 mg/kg/day, and 3) a Segment III perinatal-postnatal study in rats at subcutaneous dosage levels of 14, 28 and 56 mg/kg/day. No adverse effects of compound administration were observed during the evaluation of fertility and general reproductive performance and there was no evidence of compound-induced embryotoxicity or teratogenesis.
Reproduction studies have been performed in rabbits and in rats at dosages as high as approximately 14 and 31 times respectively the maximum recommended daily dose and revealed no evidence of impaired fertility or harm to the fetus due to NUBAIN.
Neonatal body weight and survival was reduced when NUBAIN was subcutaneously administered to female 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 8 to 17 times the maximum recommended therapeutic dose. The clinical significance of this effect is unknown.
Local Irritation Study: A solution of nalbuphine HCI (10 mg/ml) was tested for local irritation by high subcutaneous injection in the shaved abdomen of young mice. Both the 24- and 48-hour readings showed only slight irritation.
Special Studies – Distant Alopecia: The purpose of these studies was to determine the maximum “no-effect” dosage level for distant hair loss in rats and dogs. Nalbuphine hydrochloride was administered subcutaneously to groups of 35 male and 35 female rats at dosages of 0.1 to 56 mg/kg/day. The number of rats exhibiting alopecia increased with increases in dosage, but never exceeded 44 % (at the highest dose level of 56 mg/kg/day). The onset of alopecia was not dose-related or dose-related or dose-dependent (appearing within the first 3 weeks) and the time to peak effect was generally from 3 to 12 weeks. The degree of alopecia ranged from slight to marked and was seen on the abdomen, chest, back, neck, sides, limbs, paw, hip, shoulders and head. The threshold dose was estimated to be 0.16 mg/kg/day.
Dose of 0.1 to 50 mg/kg/day were administered subcutaneously to groups of four male and four female beagle dogs once daily for 1-1/2 to 2-1/2 months. Alopecia was seen at all dosage levels, including the controls, and its incidence increased with dose. All animals in the 4 mg/kg/day group exhibited alopecia. The onset of alopecia was doserelated and generally occurred within eight weeks. The degree of alopecia ranged from slight to marked and was seen on the abdomen, muzzle, chest, ears, limbs, neck, forehead, and tail. The threshold dose for alopecia was estimated to be 0.09 mg/kg/day.
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