of single doses of buprenorphine sublingual solution (1, 2, 4, 8, 16, or 32 mg) and oral methadone (15, 30, 45, or 60 mg) in non-dependent, opioid-experienced volunteers. In this study, hypoventilation not requiring medical intervention was reported more frequently after buprenorphine doses of 4 mg and higher than after methadone. Both drugs decreased O2 saturation to the same degree.
Effect of Naloxone:
Physiologic and subjective effects following acute sublingual administration of buprenorphine tablets and buprenorphine/naloxone tablets were similar at equivalent dose levels of buprenorphine. Naloxone had no clinically significant effect when administered by the sublingual route, although blood levels of the drug were measurable. Buprenorphine/naloxone, when administered sublingually to an opioid-dependent cohort, was recognized as an opioid agonist, whereas when administered intramuscularly, combinations of buprenorphine with naloxone produced opioid antagonist actions similar to naloxone. This finding suggests that the naloxone in buprenorphine/naloxone products may deter injection of buprenorphine/naloxone products by persons with active substantial heroin or other full agonist mu-opioid dependence. However, clinicians should be aware that some opioid-dependent persons, particularly those with a low level of full agonist mu-opioid physical dependence or those whose opioid physical dependence is predominantly to buprenorphine, abuse buprenorphine/naloxone combinations by the intravenous or intranasal route. In methadone-maintained patients and heroin-dependent subjects, IV administration of buprenorphine/naloxone combinations precipitated opioid withdrawal signs and symptoms and was perceived as unpleasant and dysphoric. In morphine-stabilized subjects, intravenously administered combinations of buprenorphine with naloxone produced opioid antagonist and withdrawal signs and symptoms that were ratio-dependent; the most intense withdrawal signs and symptoms were produced by 2:1 and 4:1 ratios, less intense by an 8:1 ratio.
12.3 Pharmacokinetics
Absorption:
Plasma levels of buprenorphine and naloxone increased with the buccal dose of BUNAVAIL buccal film. There was wide inter-patient variability in the buccal absorption of buprenorphine and naloxone, but within subjects the variability was low. Both Cmax and AUC of buprenorphine increased with the increase in dose (in the range of 0.875 to 6.3 mg), although the increase was not directly dose-proportional. Naloxone did not affect the pharmacokinetics of buprenorphine.
BUNAVAIL has been shown to have different bioavailability compared to SUBOXONE tablet. The exposure of buprenorphine from one BUNAVAIL 4.2 mg/0.7 mg buccal film was equivalent to one SUBOXONE 8 mg/2 mg sublingual tablet. The naloxone exposure from BUNAVAIL buccal film was 33% less than with SUBOXONE sublingual tablets.
The co-administration of liquids reduced the systemic exposure up to 59% for buprenorphine and up to 76% for naloxone from BUNAVAIL, depending on the pH of the liquid, in comparison to the administration of BUNAVAIL when no liquid was co-administered [see Method of Administration (2.2)].
Distribution:
Buprenorphine is approximately 96% protein bound, primarily to alpha and beta globulin.
Naloxone is approximately 45% protein bound, primarily to albumin.
Metabolism:
Buprenorphine undergoes both N-dealkylation to norbuprenorphine and glucu |
