Opioid Blockade

The opioid blockade study assessed the blockade of subjective opioid drug-liking effects and pharmacokinetics (PK) of BRIXADI (weekly) in 47 patients with moderate or severe opioid dependence. The primary endpoint was the maximum rating (Emax) on the visual analogue scale (VAS) for drug-liking. After stabilization on immediate-release morphine, all patients completed a 3-day qualification/baseline hydromorphone challenge session consisting of 3 intramuscular doses of hydromorphone (0 mg, [placebo], 6 mg, and 18 mg) once daily for 3 consecutive days in a randomized, double-blind, crossover manner. Following the qualification phase, eligible patients received 2 injections of BRIXADI (weekly) for two weeks at either the 24 mg or 32 mg level. Two hydromorphone challenge sessions (3 consecutive days each) were conducted throughout the week after each weekly injection of BRIXADI (weekly).

On average, the subjective effects (e.g., drug liking [Emax]) of 6 mg or 18 mg hydromorphone was blocked following injections of BRIXADI (weekly) at the 24 mg or 32 mg levels. The variability in drug-liking scores was wider for the 18 mg than the 6 mg hydromorphone dose level. In addition, for the 18 mg hydromorphone dose challenge, the drug-liking score variability was wider towards the end of the BRIXADI (weekly) dosing interval compared to earlier in the interval (e.g. Days 4-6 versus Days 1-3; Day 11-13 versus Day 8-10). Drug-liking score variability was wider for the 24 mg BRIXADI (weekly) dose level compared to 32 mg [see Clinical Studies (14.1)].

Figure 14 illustrates the relationship between buprenorphine plasma level and drug liking after 18 mg hydromorphone where data from the 24 mg BRIXADI (weekly) arm is pooled with data from the 32 mg BRIXADI (weekly) arm. The observed plateau for maximal response of drug-liking was reached at buprenorphine concentrations of approximately 1.5-2 ng/mL plasma levels.

Figure 14: Placebo-Corrected Drug Liking VAS vs. Plasma Buprenorphine Concentration Following 18 mg Hydromorphone Challenges for Pooled 24 mg and 32 mg Arms

Androgen Deficiency

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

Thorough QT studies with buprenorphine products have demonstrated modest QT prolongation ≤15 msec. Two categorical analyses of cardiovascular-specific adverse events among patients exposed to buprenorphine demonstrated no proarrhythmic potential. One Holter monitoring study demonstrated no arrhythmia. An analysis of medical literature provided no evidence for causal association between buprenorphine and Torsades de Pointes.

Physiological Effects 

Buprenorphine in IV (2, 4, 8, 12 and 16 mg) and sublingual (12 mg) doses have 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 use disorder. 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.

In clinical studies conducted with BRIXADI at doses ranging from 7.5 to 32 mg for weekly BRIXADI and 64 to 192 mg for monthly BRIXADI, no incidences of temperature elevations, or clinically significant lowering of oxygen saturation were observed.