Sublocade buprenorphine 300 mg Solution, 1 pouch — NDC 12496-0300-1 (Billing 12496-0300-01)

12 CLINICAL PHARMACOLOGY

12.1Mechanism of Action SUBLOCADE Injection contains buprenorphine. Buprenorphine is a partial agonist at the mu- opioid receptor and an antagonist at the kappa-opioid receptor.

12.2Pharmacodynamics Mu-Opioid Receptor Occupancy and Association With Opioid Blockade In a Positron Emission Tomography (PET) study with SUBLOCADE in 2 subjects (one subject receiving 200 mg subcutaneous injections and one subject receiving 300 mg subcutaneous injections) with opioid use disorder, 75 to 92% occupancy of the mu-opioid receptors in the brain was maintained for 28 days following the last dose under steady-state conditions. The opioid blockade study evaluated the blockade of subjective opioid effects, pharmacokinetics (PK) and safety of subcutaneous injections of SUBLOCADE.

Stabilization doses of SL buprenorphine prior to injection of SUBLOCADE failed to provide full blockade of subjective effects of hydromorphone 18 mg IM. After SUBLOCADE injections at Weeks 0 and 4, on average, subjective effects of both 6 mg and 18 mg doses of hydromorphone were blocked; however, wide variability was seen across subjects. Complete blockade continued throughout the 8 weeks of observation that followed the 2 nd SUBLOCADE injection [see Clinical Studies ( 14.1 )] .

Figure 10 illustrates the relationship between buprenorphine plasma level and drug liking after 18 mg hydromorphone IM. Figure 10 Drug Liking VAS vs. Plasma Buprenorphine Concentration Following 18 mg Hydromorphone Challenges Exposure-response relationships were assessed for illicit opioid use, based on urine samples negative for illicit opioids combined with self-reports negative for illicit opioid use, and withdrawal symptoms using data obtained from 489 opioid dependent patients in the double-blind Phase 3 Study (13-0001).

The observed plateau for maximal response was reached at buprenorphine plasma concentrations of approximately 2-3 ng/mL for illicit opioid use and 4 ng/mL for opioid withdrawal symptoms. Population PK/PD modeling indicated that patients using opioids by the injectable route at baseline may require higher buprenorphine exposure compared to patients not using opioids by the injectable route at baseline. Figure 10 Cardiac Electrophysiology Serial ECGs were collected following a single dose and at steady-state to evaluate the effect of SUBLOCADE on the QT interval in five clinical studies including the Phase 3 study.

In a Phase 3 study, seven patients had an increase from baseline QTc greater than 60 msec at any time [2/203 patients (1.0%) in the 300 mg/100 mg group and 5/201 patients (2.0%) in the 300 mg/300 mg group] and one patient in the 300 mg/300 mg group was found to have a QTc greater than 500 msec. These QTc findings were all sporadic and transient and none led to aberrant ventricular rhythm. Review of ECG and adverse event data provided no evidence for syncope, seizure, or ventricular tachycardia or fibrillation.

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 dependence. Compared to placebo, there were no statistically significant differences among any of the treatment conditions for blood pressure, heart rate, respiratory rate, O 2 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)… [Excerpted — this section continues on DailyMed.]

12.1Mechanism of Action SUBLOCADE Injection contains buprenorphine. Buprenorphine is a partial agonist at the mu- opioid receptor and an antagonist at the kappa-opioid receptor.

12.3Pharmacokinetics Absorption The pharmacokinetics (PK) of buprenorphine following subcutaneous injection of SUBLOCADE was evaluated in subjects with opioid use disorder after single doses (50 mg to 200 mg) and repeated doses (50 to 300 mg) separated by 28 days for up to 12 injections. After SUBLOCADE injection, an initial buprenorphine peak was observed and the median T max occurred at 24 hours after injection. After the initial buprenorphine peak, the plasma buprenorphine concentrations decreased slowly to a plateau.

Steady-state was achieved at 4-6 months. Mean buprenorphine plasma concentrations levels for C avg , C max and C trough at steady-state are presented in Table 7 for SUBLOCADE in comparison to daily transmucosal buprenorphine. Table 7 Comparison of Steady-state Buprenorphine Plasma Exposure Between Daily Transmucosal Buprenorphine and Once Monthly SUBLOCADE at Trough (C trough ), Average (C avg ) and Peak (C max ) Levels (Geometric Mean (CV%)) Pharmacokinetic parameters Transmucosal Buprenorphine SUBLOCADE 8 mg 12 mg 16 mg 24 mg 100 mg 300 mg C avg,ss (ng/mL) 1.37 (40) 1.79 (40) 2.16 (40) 2.84 (40) 2.87 (32) 6.32 (32) C max,ss (ng/mL) 4.27 (45) 5.60 (45) 6.77 (45) 8.86 (45) 5.10 (33) 11.81 (35) C trough,ss (ng/mL) 0.66 (63) 0.87 (63) 1.04 (61) 1.37 (62) 2.46 (40) 5.47 (39) At steady state, buprenorphine plasma concentrations achieved with 100 mg monthly dosing are contained within the range obtained with transmucosal treatment; peak concentrations with SUBLOCADE may be lower, while average and trough concentrations may be higher.

Potential differences in steady state levels need to be taken into consideration when transitioning a patient established on long term treatment with transmucosal buprenorphine to SUBLOCADE. Distribution Buprenorphine is approximately 96% protein bound, primarily to alpha and beta globulin. Elimination Buprenorphine is metabolized and eliminated in urine and feces.

The apparent terminal plasma half-life of buprenorphine following subcutaneous injection of SUBLOCADE ranged between 43 to 60 days as a result of the slow release of buprenorphine from the subcutaneous depot. A study assessing buprenorphine exposure 22 to 38 months following the last SUBLOCADE injection indicated that buprenorphine could potentially be detected in plasma and urine over that time period. Concentrations in urine were more variable than in plasma and generally higher depending on the test used.

Hence, it is expected that buprenorphine will be detected in patients for a longer time in urine than in plasma. Metabolism Buprenorphine is metabolized to its major metabolite, norbuprenorphine, primarily by CYP3A4. Norbuprenorphine 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. Norbuprenorphine steady-state plasma concentrations in humans after subcutaneous injection of SUBLOCADE are low compared to buprenorphine (AUC norbuprenorphine/buprenorphine ratio of 0.20 to 0.40). Excretion A mass balance study of buprenorphine administered by IV infusion in humans 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 were 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).

Drug Interaction Studies CYP3A4 Inhibitors and Inducers The effects of co-administered CYP3A4 inhibitors and inducers on buprenorphine exposure in subjects treated with SUBLOCADE have not been studied; however, such interactions have been established in studies using transmucosal bu… [Excerpted — this section continues on DailyMed.]

12.2Pharmacodynamics Mu-Opioid Receptor Occupancy and Association With Opioid Blockade In a Positron Emission Tomography (PET) study with SUBLOCADE in 2 subjects (one subject receiving 200 mg subcutaneous injections and one subject receiving 300 mg subcutaneous injections) with opioid use disorder, 75 to 92% occupancy of the mu-opioid receptors in the brain was maintained for 28 days following the last dose under steady-state conditions. The opioid blockade study evaluated the blockade of subjective opioid effects, pharmacokinetics (PK) and safety of subcutaneous injections of SUBLOCADE.

Stabilization doses of SL buprenorphine prior to injection of SUBLOCADE failed to provide full blockade of subjective effects of hydromorphone 18 mg IM. After SUBLOCADE injections at Weeks 0 and 4, on average, subjective effects of both 6 mg and 18 mg doses of hydromorphone were blocked; however, wide variability was seen across subjects. Complete blockade continued throughout the 8 weeks of observation that followed the 2 nd SUBLOCADE injection [see Clinical Studies ( 14.1 )] .

Figure 10 illustrates the relationship between buprenorphine plasma level and drug liking after 18 mg hydromorphone IM. Figure 10 Drug Liking VAS vs. Plasma Buprenorphine Concentration Following 18 mg Hydromorphone Challenges Exposure-response relationships were assessed for illicit opioid use, based on urine samples negative for illicit opioids combined with self-reports negative for illicit opioid use, and withdrawal symptoms using data obtained from 489 opioid dependent patients in the double-blind Phase 3 Study (13-0001).

The observed plateau for maximal response was reached at buprenorphine plasma concentrations of approximately 2-3 ng/mL for illicit opioid use and 4 ng/mL for opioid withdrawal symptoms. Population PK/PD modeling indicated that patients using opioids by the injectable route at baseline may require higher buprenorphine exposure compared to patients not using opioids by the injectable route at baseline. Figure 10 Cardiac Electrophysiology Serial ECGs were collected following a single dose and at steady-state to evaluate the effect of SUBLOCADE on the QT interval in five clinical studies including the Phase 3 study.

In a Phase 3 study, seven patients had an increase from baseline QTc greater than 60 msec at any time [2/203 patients (1.0%) in the 300 mg/100 mg group and 5/201 patients (2.0%) in the 300 mg/300 mg group] and one patient in the 300 mg/300 mg group was found to have a QTc greater than 500 msec. These QTc findings were all sporadic and transient and none led to aberrant ventricular rhythm. Review of ECG and adverse event data provided no evidence for syncope, seizure, or ventricular tachycardia or fibrillation.

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 dependence. Compared to placebo, there were no statistically significant differences among any of the treatment conditions for blood pressure, heart rate, respiratory rate, O 2 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 buprenorphi… [Excerpted — this section continues on DailyMed.]

14 CLINICAL STUDIES The key studies from the SUBLOCADE clinical development program that support its use in moderate to severe OUD are a Phase 3 double-blind efficacy and safety study (13-0001, NCT02357901), an opioid blockade study (13-0002, NCT02044094), and a study evaluating rapid induction of SUBLOCADE after an initial dose of transmucosal buprenorphine (Rapid Induction Substudy INDV-6000-401, NCT04995029).

14.1Study 13-0002, NCT02044094 The opioid blockade study evaluated the blockade of subjective opioid effects, PK and safety of subcutaneous injections of SUBLOCADE in 39 subjects with OUD (not treatment-seeking). The peak (E max ) effect of “Drug Liking” Visual Analog Scale (VAS) measurement after challenge with IM injections of 6 mg and 18 mg hydromorphone (HM) was not inferior (i.e., shown to be not substantially more likeable) compared to the E max of “Drug Liking” VAS measured after challenge with placebo (at weeks 1 through 4 following the first injection of 300 mg SUBLOCADE).

The noninferiority (NI) margin, the largest difference allowed for the 6 or 18 mg HM VAS to exceed the placebo VAS (the maximum VAS recorded following IM injection of 0 mg HM) before being considered significant, was set at 20. Based on comparison to the historical response to opioid agonists in unblocked subjects, a difference of less than 20 points (on a unipolar scale) between the mean maximum response to hydromorphone and the mean maximum placebo response for the same challenge was considered to indicate near-complete blockade.

All 12 weeks of the treatment period demonstrated blockade for both 6 mg and 18 mg following SUBLOCADE injections. However, wide variation can be seen in isolated measurements from individual subjects, shown in the figure below. For comparison, stabilization doses of SL buprenorphine in Week 0 failed to provide full blockade to 18 mg of HM.

Complete blockade continued throughout the 8 weeks of observation that followed the 2 nd SUBLOCADE injection. Figure 12 Median (95% Confidence Interval) of Placebo-Corrected Drug-Liking Scores by Hydromorphone Dose and by Week Key to Figure: The grey shaded area indicates the period where subjects were stabilized with 8 to 24 mg/day sublingual (SL) buprenorphine; the two vertical arrows represent treatment injections of SUBLOCADE, with 300 mg of buprenorphine. The light grey and dark grey squares represent the median E max drug-liking scores, placebo-corrected (VAS drug liking for that week's 0 mg dose subtracted) during the hydromorphone challenge of 6 and 18 mg, respectively.

This median Placebo-Corrected E max is shown by treatment week, together with its 95% confidence interval (CI; vertical line). In some cases, 95% CI are not visible as the median was equal to the confidence limit. The horizontal line at 20 mm delineates the non-inferiority margin for opioid blockade.

Next to median estimates, individual data are summarized by circles, the area of which is proportional to the number of subjects at that location. The X axis shows how many weeks following injection #1 that each weeks' Placebo-Corrected Drug-Liking Score was measured. Beneath that treatment week indicator, is the number of subjects (N) who provided those VAS measurements for all three challenges with placebo, 6 and 18 mg hydromorphone.

Figure 12

14.2Study 13-0001, NCT02357901 The efficacy of SUBLOCADE for the treatment of opioid use disorder was evaluated in a Phase 3, 24- week, randomized, double-blind, placebo-controlled, multicenter trial in treatment-seeking patients who met the DSM-5 criteria for moderate or severe opioid use disorder. Patients were randomized to one of following dosing regimens: 6 once-monthly 300 mg doses, 2 once-monthly 300 mg doses followed by 4 once-monthly 100 mg doses, or 6 once-monthly subcutaneous injections of placebo. All doses were administered by a physician or suitably qualified designee and were separated by 28 ± 2 days.

In addition to study medication, all subjects rec… [Excerpted — this section continues on DailyMed.]

13 NONCLINICAL TOXICOLOGY

13.1Carcinogenesis, Mutagenesis, Impairment of Fertility Carcinogenicity Long-term studies in animals performed to evaluate carcinogenic potential of SUBLOCADE have not been conducted. However, the carcinogenic potential of the active drug substance in SUBLOCADE, buprenorphine, has been evaluated in Sprague-Dawley rats and CD-1 mice. In the carcinogenicity study conducted in Sprague-Dawley rats, buprenorphine was administered in the diet at doses of 0.6, 5.5, and 56 mg/kg/day (approximately 0.5, 5, and 50 times the recommended human monthly subcutaneous dose of 300 mg of buprenorphine) for 27 months.

A statistically significant dose-related increase in Leydig cell tumors occurred. In an 86 week study in CD-1 mice, buprenorphine was not carcinogenic at dietary doses up to 100 mg/kg/day (approximately 45 times the recommended human monthly subcutaneous dose of 300 mg of buprenorphine). N-methyl-2-pyrrolidone [NMP], an excipient in SUBLOCADE, produced an increase in hepatocellular adenomas and carcinomas in male and female mice at 6 and 8 times the maximum daily dose (MDD) of NMP via SUBLOCADE.

The clinical significance of these findings is unclear. No tumors were noted at 1 and 1.3 times the MDD. In 2-year inhalation and dietary studies in rats, NMP did not result in evidence of carcinogenicity.

Mutagenicity No evidence of mutagenic potential for subcutaneous SUBLOCADE was found in in vivo subcutaneous micronucleus test using rats' marrow. Mutagenic potential for buprenorphine was studied in a series of tests utilizing gene, chromosome, and DNA interactions in both prokaryotic and eukaryotic systems. Results were negative in yeast ( S. cerevisiae ) for recombinant, gene convertant, or forward mutations; negative in Bacillus subtilis “rec” assay, negative for clastogenicity in CHO cells, Chinese hamster bone marrow and spermatogonia cells, and negative in the mouse lymphoma L5178Y assay.

Results were equivocal in the Ames test: negative in studies in two laboratories, but positive for frame shift mutation at a high dose (5 mg/plate) in a third study. Results were positive in the Green-Tweets ( E. coli ) survival test, positive in a DNA synthesis inhibition (DSI) test with testicular tissue from mice, for both in vivo and in vitro incorporation of [3H]thymidine, and positive in unscheduled DNA synthesis test using testicular cells from mice. Impairment of Fertility In a fertility study in rats, SUBLOCADE or ATRIGEL ® was administered every 28 days for 3 months (males) or once before mating and once on GD 7; female mating, fertility, and fecundity indices were unaffected by the subcutaneous administration of SUBLOCADE up to 900 mg/kg buprenorphine (approximately 38 times the maximum recommended human dose [MRHD] of 300 mg on an AUC basis).

However, higher mean post-implantation loss was observed with SUBLOCADE at 900 mg/kg buprenorphine and at an equivalent level of ATRIGEL ® alone, which correlated with higher mean number of resorptions and reduced mean number of viable fetuses/litter size. Mean gravid uterine weight and mean final body weight were lower with SUBLOCADE at 900 mg/kg buprenorphine and an equivalent level of the ATRIGEL ® alone, and correlated with higher mean number of resorptions and lower fetal body weights. The NOAEL for female fertility was 900 mg/kg and the NOAEL for female-mediated developmental parameters was 600 mg/kg (approximately 25 times the MRHD on an AUC basis).

Male fertility and reproduction indices were lower as evidenced by abnormal sperm parameters (low motility, low mean number of sperm, and higher percentage of abnormal sperm) with SUBLOCADE at 600 mg/kg and with an equivalent level of ATRIGEL ® . The NOAEL for male fertility parameters, including sperm analysis, and male-mediated developmental parameters was 300 mg/kg (approximately 32 times the MRHD on an AUC basis).