Buprenorphine (Page 8 of 11)


Buprenorphine sublingual tablets are uncoated oval orange tablets, imprinted with a logo on one side and a numeric imprint on the other side. The tablets contain buprenorphine HCl, USP and are available in two dosage strengths, 2 mg buprenorphine and 8 mg buprenorphine (as the free base). Each tablet also contains citric acid anhydrous, crospovidone, FD&C Yellow #6 HT Aluminum Lake, lactose monohydrate, magnesium stearate, mannitol, pregelatinized starch (maize), povidone, sodium citrate dihydrate.

Chemically, buprenorphine HCl, USP is (2S)-2-[17-Cyclopropylmethyl-4,5α-epoxy-3-hydroxy-6-methoxy-6α,14-ethano-14α-morphinan-7α-yl]-3,3-dimethylbutan-2-ol hydrochloride. It has the following chemical structure:

The following chemical structure for Buprenorphine HCl, USP has the molecular formula C29 H41 NO4 • HCl and the molecular weight is 504.10. It is a white or off-white crystalline powder, sparingly soluble in water, freely soluble in methanol, soluble in alcohol and practically insoluble in cyclohexane.

Buprenorphine HCl, USP has the molecular formula C2 9 H4 1 NO4 •HCl and the molecular weight is 504.10. It is a white or off-white crystalline powder, sparingly soluble in water, freely soluble in methanol, soluble in alcohol and practically insoluble in cyclohexane.


12.1 Mechanism of Action

Buprenorphine sublingual tablets contain buprenorphine, a partial agonist at the mu-opioid receptor and an antagonist at the kappa-opioid receptor.

12.2 Pharmacodynamics

Subjective Effects

Comparisons of buprenorphine to full opioid agonists such as methadone and hydromorphone suggest that sublingual buprenorphine produces typical opioid agonist effects which are limited by a ceiling effect.

Opioid agonist ceiling-effects were also observed in a double-blind, parallel group, dose-ranging comparison of single doses of buprenorphine sublingual solution (1, 2, 4, 8, 16, or 32 mg), placebo and a full agonist control at various doses. The treatments were given in ascending dose order at intervals of at least one week to 16 opioid-experienced subjects who were not physically dependent. Both active drugs produced typical opioid agonist effects. For all measures for which the drugs produced an effect, buprenorphine produced a dose-related response. However, in each case, there was a dose that produced no further effect. In contrast, the highest dose of the full agonist control always produced the greatest effects. Agonist objective rating scores remained elevated for the higher doses of buprenorphine (8-32 mg) longer than for the lower doses and did not return to baseline until 48 hours after drug administration. The onset of effects appeared more rapidly with buprenorphine than with the full agonist control, with most doses nearing peak effect after 100 minutes for buprenorphine compared to 150 minutes for the full agonist control.

Physiologic Effects

Buprenorphine in IV (2, 4, 8, 12 and 16 mg) and sublingual (12 mg) doses has been administered to opioid-experienced subjects who were not physically dependent to examine cardiovascular, respiratory and subjective effects at doses comparable to those used for treatment of opioid dependence. Compared to placebo, there were no statistically significant differences among any of the treatment conditions for blood pressure, heart rate, respiratory rate, O2 saturation, or skin temperature across time. Systolic BP was higher in the 8 mg group than placebo (3-hour AUC values). Minimum and maximum effects were similar across all treatments. Subjects remained responsive to low voice and responded to computer prompts. Some subjects showed irritability, but no other changes were observed.

The respiratory effects of sublingual buprenorphine were compared with the effects of methadone in a double-blind, parallel group, dose ranging comparison 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.

Effects on the Endocrine System

Opioids inhibit the secretion of adrenocorticotropic hormone (ACTH), cortisol, and luteinizing hormone (LH) in humans [see Adverse Reactions (6.2)]. They also stimulate prolactin, growth hormone (GH) secretion, and pancreatic secretion of insulin and glucagon.

Chronic use of opioids may influence the hypothalamic-pituitary-gonadal axis, leading to androgen deficiency that may manifest as low libido, impotence, erectile dysfunction, amenorrhea, or infertility. The causal role of opioids in the clinical syndrome of hypogonadism is unknown because the various medical, physical, lifestyle, and psychological stressors that may influence gonadal hormone levels have not been adequately controlled for in studies conducted to date. Patients presenting with symptoms of androgen deficiency should undergo laboratory evaluation.

12.3 Pharmacokinetics

A bsorption

Plasma levels of buprenorphine increased with the sublingual dose of buprenorphine sublingual tablets (Table 4). There was wide inter-patient variability in the sublingual absorption of buprenorphine, but within subjects the variability was low. Both Cmax and AUC of buprenorphine increased in a linear fashion with the increase in dose (in the range of 4 mg to 16 mg), although the increase was not directly dose-proportional.

Table 4: Pharmacokinetic Parameters of Buprenorphine and Norbuprenorphine After the Sublingual Administration of Buprenorphine Sublingual Tablets
Dose Analyte Mean SD C max (ng/mL) T max (h) AUC inf (h•ng/mL) t 1/2 (h)
2 mg Buprenorphine MeanSD


1.840.62 10.933.945 31.6612.66
Norbuprenorphine MeanSD 0.3010.127 2.362.75 12.394.526 39.2820.85
8 mg Buprenorphine MeanSD 2.881.14 1.280.46 28.3910.22 35.0114.7
Norbuprenorphine MeanSD 1.380.752 1.752.11 50.1822.61 44.3319.27
16 mg Buprenorphine MeanSD 4.702.16 1.420.50 47.0920.03 36.5113.99
Norbuprenorphine MeanSD 2.651.62 1.521.34 92.3134.74 40.3512.07


Buprenorphine is approximately 96% protein bound, primarily to alpha and beta globulin.



Buprenorphine undergoes both N-dealkylation to norbuprenorphine and glucuronidation. The N-dealkylation pathway is mediated primarily by CYP3A4. Norbuprenorphine, the major metabolite, can further undergo glucuronidation. Norbuprenorphine has been found to bind opioid receptors in vitro ; however, it is not known whether norbuprenorphine contributes to the overall effect of buprenorphine sublingual tablets.

E xcretion

A mass balance study of buprenorphine showed complete recovery of radiolabel in urine (30%) and feces (69%) collected up to 11 days after dosing. Almost all of the dose was accounted for in terms of buprenorphine, norbuprenorphine, and two unidentified buprenorphine metabolites. In urine, most of buprenorphine and norbuprenorphine was conjugated (buprenorphine, 1% free and 9.4% conjugated; norbuprenorphine, 2.7% free and 11% conjugated). In feces, almost all of the buprenorphine and norbuprenorphine were free (buprenorphine, 33% free and 5% conjugated; norbuprenorphine, 21% free and 2% conjugated).

When buprenorphine sublingual tablets are administered sublingually, buprenorphine has a mean elimination half-life from plasma ranging from 31 to 35 hours.

Drug Interactions Studies

C YP3A4 Inhibitors and Inducers

Buprenorphine has been found to be a CYP2D6 and CYP3A4 inhibitor and its major metabolite, norbuprenorphine has been found to be a moderate CYP2D6 inhibitor in in vitro studies employing human liver microsomes. However, the relatively low plasma concentrations of buprenorphine and norbuprenorphine resulting from therapeutic doses are not expected to raise significant drug-drug interaction concerns [see Drug Interactions (7)].

S pecific Populations

Hepatic Impairment

In a pharmacokinetic study, the disposition of buprenorphine was determined after administering a 2.0 mg/0.5 mg buprenorphine and naloxone sublingual tablet in subjects with varied degrees of hepatic impairment as indicated by Child-Pugh criteria. The disposition of buprenorphine in patients with hepatic impairment was compared to disposition in subjects with normal hepatic function.

In subjects with mild hepatic impairment, the changes in mean Cmax , AUC0-last , and half-life values of buprenorphine were not clinically significant.

For subjects with moderate and severe hepatic impairment, mean Cmax , AUC0-last , and half-life values of buprenorphine were increased (Table 5) [see Warnings and Precautions (5.12), Use in Specific Populations (8.6)].

Table 5: Changes in Buprenorphine Pharmacokinetic Parameters in Subjects with Moderate and Severe Hepatic Impairment
HepaticImpairment PK Parameters Increase in buprenorphine compared to healthy subjects
Moderate Cmax 8%
AUC0-last 64%
Half-life 35%
Severe Cmax 72%
AUC0-last 181%
Half-life 57%

HCV infection

In subjects with HCV infection but no sign of hepatic impairment, the changes in the mean Cm a x , AUC0 -l a s t , and half-life values of buprenorphine were not clinically significant in comparison to healthy subjects without HCV infection.

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