Pharmacological properties : תכונות פרמקולוגיות

Pharmacodynamic Properties

14.2    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.
In opioid-experienced subjects who were not physically dependent, acute sublingual doses of buprenorphine/naloxone tablets produced opioid agonist effects which reached a maximum between doses of 8 mg/2 mg and 16 mg/4 mg buprenorphine/naloxone.
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 mg to 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.
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 tablets may deter injection of buprenorphine/naloxone tablets by persons with active substantial heroin or other full mu-opioid dependence. However, clinicians should be aware that some opioid-dependent persons, particularly those with a low level of full 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.
Effects on the Endocrine System
Opioids inhibit the secretion of adrenocorticotropic hormone (ACTH), cortisol, and luteinizing hormone (LH) in humans [see Adverse Reactions (8.2)]. 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.
Cardiac Electrophysiology
Through QT studies with buprenorphine products have demonstrated QT prolongation ≤ 15 msec.

Pharmacokinetic Properties

14.3    Pharmacokinetics
Absorption
In several pharmacokinetic studies following the administration of different dosages, a dose of one or two of the 2 mg/0.5 mg SUBOXONE films administered sublingually or buccally showed comparable relative bioavailability to the same total dose of SUBOXONE sublingual tablets. In contrast, one 8 mg/2 mg and one 12 mg/3 mg SUBOXONE films administered sublingually or buccally showed higher relative bioavailability for both buprenorphine and naloxone compared to the same total dose of SUBOXONE sublingual tablets. A combination of one 8 mg/2 mg and two 2 mg/0.5 mg SUBOXONE films (total dose of 12 mg/ 3 mg) administered sublingually showed comparable relative bioavailability to the same total dose of SUBOXONE sublingual tablets, while buccally administered SUBOXONE films showed higher relative bioavailability. Table 5, below, illustrates the relative increase in exposure to buprenorphine and naloxone associated with SUBOXONE films compared to SUBOXONE sublingual tablets, and shows the effect of route of administration [see Dosage and Administration (5.9, 5.10)].
Across relevant pharmacokinetic studies, the pharmacokinetic parameters and exposures derived from the buccal and sublingual administrations of SUBOXONE film were comparable to one another.
Table 5. Changes in Pharmacokinetic Parameters for SUBOXONE Film Administered Sublingually or Buccally in Comparison to SUBOXONE Sublingual Tablet



Dosage           PK           Increase in Buprenorphine              PK            Increase in Naloxone Parameter                                           Parameter
Film         Film         Film                       Film         Film         Film Sublingual   Buccal       Buccal                     Sublingual   Buccal       Buccal Compared     Compared     Compared                   Compared     Compared     Compared to Tablet    to Tablet    to Film                    to Tablet    to Tablet    to Film Sublingual   Sublingual   Sublingual                 Sublingual   Sublingual   Sublingual 
1x2              Cmax         22%          25%          -            Cmax          -            -            - 3mg/0.5 mg
AUC0-last    -            19%          -            AUC0-last     -            -            - 
2 x 2 mg/0.5     Cmax         -            21%          21%          Cmax          -            17%          21% mg
AUC0-last    -            23%          16%          AUC0-last     -            22%          24% 
1 x 8 mg/2 mg    Cmax         28%          34%          -            Cmax          41%          54%          - 
AUC0-last    20%          25%          -            AUC0-last     30%          43%          - 
1 x 12 mg/3      Cmax         37%          47%          -            Cmax          57%          72%          9% mg
AUC0-last    21%          29%          -            AUC0-last     45%          57%          - 
1 x 8 mg/2 mg    Cmax         -            27%          13%          Cmax          17%          38%          19% plus
2 x 2 mg/0.5     AUC0-last    -            23%          -            AUC0-last     -            30%          19% mg

1 x 16 mg/4      Cmax         34%          29%          7%           Cmax          44%          46%          9% mg film
AUC0-last    32%          -            -            AUC0-last     49%          36%          3% 
Note: 1. the 16 mg/4 mg strength film is not marketed; it is compositionally proportional to the 8 mg/2 mg strength film and has the same size of 2 x 8 mg/2 mg film. 2. – represents no change when the 90% confidence intervals for the geometric mean ratios of the Cmax and AUC0-last values are within the 80% to 125% limit. 3. There are no data for the 4 mg/1 mg strength film; it is compositionally proportional to 2 mg/0.5 mg strength film and has the same size of 2 x 2 mg/0.5 mg film strength.
Distribution
Buprenorphine is approximately 96% protein bound, primarily to alpha and beta globulin.
Naloxone is approximately 45% protein bound, primarily to albumin.
Elimination
Buprenorphine is metabolized and eliminated in urine and feces. Naloxone undergoes metabolism as well.
When SUBOXONE film is administered sublingually or buccally, buprenorphine has a mean elimination half-life ranging from 24 to 42 hours and naloxone has a mean elimination half-life ranging from 2 to 12 hours.
Metabolism
Buprenorphine undergoes both N-dealkylation to norbuprenorphine and glucuronidation. The N-dealkylation pathway is mediated primarily by the CYP3A4. Norbuprenorphine, the major metabolite, can further undergo glucuronidation. Norbuprenorphine has been found to bind opioid receptors in vitro; however, it has not been 
studied clinically for opioid-like activity. Naloxone undergoes direct glucuronidation to naloxone-3-glucuronide as well as N-dealkylation, and reduction of the 6-oxo group.
Excretion
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). Based on all studies performed with sublingually and buccally administered SUBOXONE film, buprenorphine has a mean elimination half-life from plasma ranging from 24 to 42 hours and naloxone has a mean elimination half-life from plasma ranging from 2 to 12 hours.
Drug Interactions Studies
CYP3A4 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 (9)].
Specific Populations
Hepatic Impairment
In a pharmacokinetic study, the disposition of buprenorphine and naloxone were determined after administering a 2.0/0.5 mg SUBOXONE sublingual tablet in subjects with varied degrees of hepatic impairment as indicated by Child-Pugh criteria. The disposition of buprenorphine and naloxone in patients with hepatic impairment were 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 both buprenorphine and naloxone were not clinically significant. No dosing adjustment is needed in patients with mild hepatic impairment.
For subjects with moderate and severe hepatic impairment, mean Cmax, AUC0-last, and half-life values of both buprenorphine and naloxone were increased; the effects on naloxone are greater than that on buprenorphine (Table 6).
Table 6. Changes in Pharmacokinetic Parameters in Subjects With Moderate and Severe Hepatic Impairment 
Hepatic Impairment     PK Parameters         Increase in buprenorphine           Increase in naloxone compared to healthy subjects        compared to healthy subjects

Moderate               Cmax                  8%                                  170% 
AUC0-last             64%                                 218%

Half-life             35%                                 165%
Severe                 Cmax                  72%                                 1030% 

AUC0-last               181%                                 1302%
Half-life               57%                                  122%


The difference in magnitude of the effects on naloxone and buprenorphine are greater in subjects with severe hepatic impairment than subjects with moderate hepatic impairment [see Warnings and Precautions (7.12), Use in Specific Populations (10.6)].
HCV infection
In subjects with HCV infection but no sign of hepatic impairment, the changes in the mean Cmax, AUC0-last, and half-life values of buprenorphine and naloxone were not clinically significant in comparison to healthy subjects without HCV infection.