OLINVYK OLICERIDINE 30 mg/30mL Injection, Solution — NDC 71308-301-10 (Billing 71308-0301-10)

12 CLINICAL PHARMACOLOGY

12.1Mechanism of Action Oliceridine is a full opioid agonist and is relatively selective for the mu-opioid receptor. The principal therapeutic action of oliceridine is analgesia. Like all full opioid agonists, there is no ceiling effect to analgesia for oliceridine.

Clinically, dosage is titrated to provide adequate analgesia and may be limited by adverse reactions, including respiratory, and CNS depression. The precise mechanism of the analgesic action is unknown. However, specific CNS opioid receptors for endogenous compounds with opioid-like activity have been identified throughout the brain and spinal cord and are thought to play a role in the analgesic effects of this drug.

12.2Pharmacodynamics In nonclinical models, the antinociceptive effect of oliceridine can be antagonized by the opioid antagonist naloxone. Effects on the Central Nervous System Opioids produces respiratory depression by direct action on brain stem respiratory centers. The respiratory depression involves a reduction in the responsiveness of the brain stem respiratory centers to both increases in carbon dioxide tension and electrical stimulation.

Opioids causes miosis, even in total darkness. Pinpoint pupils are a sign of opioid overdose but are not pathognomonic (e.g., pontine lesions of hemorrhagic or ischemic origins may produce similar findings). Marked mydriasis rather than miosis may be seen due to hypoxia in overdose situations.

Effects on the Gastrointestinal Tract and Other Smooth Muscle Opioids causes a reduction in motility associated with an increase in smooth muscle tone in the antrum of the stomach and duodenum. Digestion of food in the small intestine is delayed and propulsive contractions are decreased. Propulsive peristaltic waves in the colon are decreased, while tone may be increased to the point of spasm, resulting in constipation.

Other opioid-induced effects may include a reduction in biliary and pancreatic secretions, spasm of sphincter of Oddi, transient elevations in serum amylase, and opioid-induced esophageal dysfunction (OIED). Effects on the Cardiovascular System Opioids produces peripheral vasodilation, which may result in orthostatic hypotension or syncope. Manifestations of histamine release and/or peripheral vasodilation may include pruritus, flushing, red eyes, sweating, and/or orthostatic hypotension.

Effects on the Endocrine System Opioids inhibit the secretion of adrenocorticotropic hormone (ACTH), cortisol, and luteinizing hormone (LH) in humans [see Adverse Reactions ( 6.1 )] . They also stimulate prolactin, growth hormone (GH) secretion, and pancreatic secretion of insulin and glucagon. Use of opioids for an extended period of time 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 [see Adverse Reactions ( 6.1 )] . Effects on the Immune System Opioids have been shown to have a variety of effects on components of the immune system in in vitro and animal models. The clinical significance of these findings is unknown.

Overall, the effects of opioids appear to be modestly immunosuppressive. Concentration-Analgesia Relationships In a fixed-dose bunionectomy trial (N=192), the onset of action of OLINVYK (as measured by the two-stopwatch method) was almost immediate (median 1-3 minutes) upon administration of the first dose. Perceptible pain relief was achieved in the majority of patients within 5 minutes after the first dose of OLINVYK.

The minimum effective analgesic concentration will vary widely among patients, especially among patients who have been previously treated with opioid agonists. The minimu… [Excerpted — this section continues on DailyMed.]

12.1Mechanism of Action Oliceridine is a full opioid agonist and is relatively selective for the mu-opioid receptor. The principal therapeutic action of oliceridine is analgesia. Like all full opioid agonists, there is no ceiling effect to analgesia for oliceridine.

Clinically, dosage is titrated to provide adequate analgesia and may be limited by adverse reactions, including respiratory, and CNS depression. The precise mechanism of the analgesic action is unknown. However, specific CNS opioid receptors for endogenous compounds with opioid-like activity have been identified throughout the brain and spinal cord and are thought to play a role in the analgesic effects of this drug.

12.3Pharmacokinetics Distribution The mean steady-state volume of distribution of oliceridine ranges between 90-120 L indicating extensive tissue distribution. The plasma protein binding of oliceridine is 77%. In vitro data indicate that oliceridine is not an inhibitor of any of the major transporters, including breast cancer resistance protein (BCRP) and MDR1, at clinically relevant concentrations.

Elimination Metabolism In vitro studies suggest that oliceridine is metabolized primarily by CYP3A4 and CYP2D6 P450 hepatic enzymes, with minor contributions from CYP2C9 and CYP2C19 into inactive metabolites. The mean clearance of oliceridine decreases slightly with increasing dose, resulting in greater-than-proportional exposure, particularly at doses greater than 2 mg. The percent of unchanged oliceridine excreted in the urine is low (0.97-6.75% of dose), reflecting its low renal clearance.

The pharmacokinetics of oliceridine were not changed substantially (except for peak concentrations) when administered over different infusion times. Excretion Metabolic clearance is the major route of elimination of oliceridine, primarily by oxidation with subsequent glucuronidation. Additional biotransformation pathways included N −dealkylation, glucuronidation, and dehydrogenation.

The majority of the metabolites (approximately 70%) are eliminated in the urine, with the remainder eliminated in the feces. Only a small amount of unchanged drug (0.97-6.75% of a dose) is found in the urine. The half-life of these metabolites (~44 hours) is much longer than that of unchanged oliceridine (1.3-3 hours).

In vitro binding studies have demonstrated that none of these metabolites has any appreciable activity at the mu-opioid receptor. Specific Populations Renal Impairment In a study comparing subjects with end stage renal disease (N=8) to healthy age and sex−matched healthy subjects (N=8), no significant difference in oliceridine clearance was observed. OLINVYK doses do not need to be adjusted in patients with renal impairment.

Hepatic Impairment In a study of mild (N=8), moderate (N=8), or severe hepatic impairment (N=6), both clearance and total exposure were similar to age and sex-matched healthy controls (N=8). The mean half-life of oliceridine was increased in subjects with moderate (4.3 hours) or severe (5.8 hours) hepatic impairment, as compared with healthy subjects (2.1 hours), or patients with mild hepatic impairment (2.6 hours). The estimated volume of distribution of oliceridine was significantly higher in subjects with moderate or severe hepatic impairment (212 and 348 L, respectively), as compared to healthy subjects (126 L) or patients with mild hepatic impairment (167 L).

Based on these data, the initial dose of OLINVYK does not need to be reduced in patients with mild or moderate hepatic impairment, but these patients may require less frequent dosing. Use caution when dosing OLINVYK in patients with severe hepatic impairment. Consider reducing the initial dose, and administer subsequent doses only after a careful review of the patient’s severity of pain and overall clinical status.

Drug Interaction Studies In vitro studies suggest that oliceridine is metabolized primarily by the CYP3A4 and CYP2D6 P450 hepatic enzymes, with minor contributions from CYP2C9 and CYP2C19. Inhibition studies using selective inhibitors of all the major CYP enzymes show that only the inhibition of CYP3A4 and CYP2D6 significantly affects the metabolism of oliceridine in these assays, suggesting that the contribution of CYP2C9 and CYP2C19 to the metabolism of oliceridine is minor. The effect of concomitant administration of a CYP2D6 inhibitor on the pharmacokinetics of OLINVYK, although not studied, may be similar to that noted in subjects who are CYP2D6 poor metabolizers.

The plasma clearance of oliceridine in CYP2D6 poor metabolizers is approximately 50% of plasma clearance in subjects who are nonpoor CYP2D6 metabolizers [See Pharmacogenomics ( 12.5 )]. In he… [Excerpted — this section continues on DailyMed.]

12.2Pharmacodynamics In nonclinical models, the antinociceptive effect of oliceridine can be antagonized by the opioid antagonist naloxone. Effects on the Central Nervous System Opioids produces respiratory depression by direct action on brain stem respiratory centers. The respiratory depression involves a reduction in the responsiveness of the brain stem respiratory centers to both increases in carbon dioxide tension and electrical stimulation.

Opioids causes miosis, even in total darkness. Pinpoint pupils are a sign of opioid overdose but are not pathognomonic (e.g., pontine lesions of hemorrhagic or ischemic origins may produce similar findings). Marked mydriasis rather than miosis may be seen due to hypoxia in overdose situations.

Effects on the Gastrointestinal Tract and Other Smooth Muscle Opioids causes a reduction in motility associated with an increase in smooth muscle tone in the antrum of the stomach and duodenum. Digestion of food in the small intestine is delayed and propulsive contractions are decreased. Propulsive peristaltic waves in the colon are decreased, while tone may be increased to the point of spasm, resulting in constipation.

Other opioid-induced effects may include a reduction in biliary and pancreatic secretions, spasm of sphincter of Oddi, transient elevations in serum amylase, and opioid-induced esophageal dysfunction (OIED). Effects on the Cardiovascular System Opioids produces peripheral vasodilation, which may result in orthostatic hypotension or syncope. Manifestations of histamine release and/or peripheral vasodilation may include pruritus, flushing, red eyes, sweating, and/or orthostatic hypotension.

Effects on the Endocrine System Opioids inhibit the secretion of adrenocorticotropic hormone (ACTH), cortisol, and luteinizing hormone (LH) in humans [see Adverse Reactions ( 6.1 )] . They also stimulate prolactin, growth hormone (GH) secretion, and pancreatic secretion of insulin and glucagon. Use of opioids for an extended period of time 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 [see Adverse Reactions ( 6.1 )] . Effects on the Immune System Opioids have been shown to have a variety of effects on components of the immune system in in vitro and animal models. The clinical significance of these findings is unknown.

Overall, the effects of opioids appear to be modestly immunosuppressive. Concentration-Analgesia Relationships In a fixed-dose bunionectomy trial (N=192), the onset of action of OLINVYK (as measured by the two-stopwatch method) was almost immediate (median 1-3 minutes) upon administration of the first dose. Perceptible pain relief was achieved in the majority of patients within 5 minutes after the first dose of OLINVYK.

The minimum effective analgesic concentration will vary widely among patients, especially among patients who have been previously treated with opioid agonists. The minimum effective analgesic concentration of oliceridine for any individual patient may increase over time due to an increase in pain, the development of a new pain syndrome, and/or the development of analgesic tolerance [see Dosage and Administration ( 2.1 , 2.3 )] . Concentration-Adverse Experience Relationships There is a general relationship between increasing oliceridine doses and increasing frequency of dose-related opioid adverse reactions such as nausea, vomiting, CNS effects, and respiratory depression.

In opioid-tolerant patients, the situation may be altered by the development of tolerance to opioid-related adverse reactions [see Dosage and Administration ( 2.1 , 2.2 , 2.3 )] . Cardiac Electrophysiol… [Excerpted — this section continues on DailyMed.]

14 CLINICAL STUDIES The efficacy of OLINVYK was established in two randomized, double-blind, placebo- and morphine-controlled studies of patients with moderate to severe acute pain following orthopedic surgery-bunionectomy or plastic surgery-abdominoplasty. In each study, pain intensity was measured using a patient-reported numeric rating scale (11-point numerical scale ranging from 0-10, where zero corresponds to no pain and 10 corresponds to worst pain imaginable). In each study, patients were randomized to one of three OLINVYK treatment regimens, a placebo-control regimen, or a morphine-control regimen.

Each blinded treatment regimen consisted of a loading dose, incremental doses delivered as needed via patient-controlled analgesia (PCA) device, and supplemental doses, beginning 1 hour after the initial dose, and hourly thereafter, as needed. The loading dose for all OLINVYK treatment regimens was 1.5 mg; demand doses were 0.1, 0.35 or 0.5 mg, according to the assigned treatment group; supplemental doses were 0.75 mg. The loading dose for the morphine treatment regimen was 4 mg; the demand dose was 1 mg; supplemental doses were 2 mg.

The placebo-control regimen was volume-matched. A lockout interval of 6 minutes was used for all PCA regimens. For Studies 1 and 2, patients may have received rescue pain medication (pre-defined in the protocols as etodolac 200 mg every 6 hours, as needed) if the patient requested rescue pain medication and reported a Numeric Rating Scale score ≥4.

14.1Study 1 – Orthopedic Surgery - Bunionectomy A total of 389 patients (placebo n=79, OLINVYK 0.1 mg n=76, OLINVYK 0.35 mg n=79, OLINVYK 0.5 mg n=79, and morphine n=76), 19-74 years of age, with moderate to severe acute pain following orthopedic surgery-bunionectomy, were treated for up to 48 hours in Study 1 (NCT02815709). Treatment began after discontinuation of regional anesthesia in patients with pain intensity of ≥4 on a 0-10 numeric rating scale [NRS] within 9 hours after discontinuation of regional anesthesia.

The analgesic effects were measured using the Summed Pain Intensity Differences over 48 hours (SPID-48). The SPID-48 is calculated by multiplying the Pain Intensity Difference (calculated by subtracting the pain intensity at a particular timepoint from the pain intensity at baseline) scores at each post-baseline timepoint by the duration (in hours) since the preceding timepoint, and then summing the values, over 48 hours. The majority of the study population was female (85%), and the mean age was 45 years.

Patients were 69% White, 24% Black or African American, 4% Asian, 1% Native Hawaiian or Other Pacific Islander, 1% American Indian or Alaska Native and 1% other races. Twenty-five (25%) of patients were Hispanic or Latino. The majority of patients treated with OLINVYK (0.1 mg treatment group: 83%; 0.35 mg treatment group 87%; 0.5 mg treatment group 84%) completed the randomized treatment period (compared to 60% of patients treated with placebo).

Nine percent (9%), 4%, and 5% of patients in the 0.1 mg, 0.35 mg and 0.5 mg OLINVYK treatment groups, respectively, discontinued study medication due to lack of efficacy (compared to 34% of patients treated with placebo). In the 0.1 mg, 0.35 mg and 0.5 mg OLINVYK treatment groups, 41%, 20%, and 17% of patients, respectively, used the protocol-specified rescue medication etodolac, compared to 77% of patients treated with placebo. The mean (SD) baseline pain intensity score was 6.7 (1.7).

A statistically significantly greater analgesic effect was observed in both 0.35 mg and 0.5 mg OLINVYK treatment groups, compared to the placebo group (see Table 7). The mean pain intensities over time for placebo, 0.35 mg and 0.5 mg oliceridine and morphine treatment arms are shown in Figure 1. Table 7: SPID-48 (Efficacy Endpoint) Results in Study 1 (Orthopedic Surgery - Bunionectomy) Efficacy Measure Placebo regimen (N=79) OLINVYK Morphine regimen (N=76) 0.35 mg regimen (N=79) 0.5 mg regimen (N=79) SPID-48 A… [Excerpted — this section continues on DailyMed.]

13 NONCLINICAL TOXICOLOGY

13.1Carcinogenesis, Mutagenesis, Impairment of Fertility Carcinogenesis : Long-term animal studies have not been completed to evaluate the carcinogenic potential of oliceridine. Mutagenesis: Oliceridine was negative in an in vitro Ames bacterial reverse mutation assay, the in vitro chromosomal aberration assay using human peripheral blood lymphocytes, and the in vivo rat micronucleus assay. Impairment of Fertility: In a fertility and early embryonic development study, oliceridine administered to female rats via continuous intravenous infusion at 6, 12, or 24 mg/kg/day for 14 days prior to cohabitation and through GD 15 for a total of 29-42 days resulted in prolonged estrous cycle lengths and decreased number of implantations and viable embryos at doses ≥12 mg/kg/day (≥3 times the estimated plasma exposure at the MRHD of 27 mg/day on an AUC basis).

Oliceridine did not alter male fertility at any dose tested. Males were dosed at 6, 12, or 24 mg/kg/day, producing plasma exposures up to 8 times the estimated plasma exposure at the MRHD, for 28 days prior to cohabitation, throughout the mating period and up to the time of scheduled necropsy for a total of 64-65 days of dosing.

13.2Animal Toxicology and/or Pharmacology Continuous intravenous infusion of oliceridine to rats for 14 days followed by one-day withdrawal from the treatment resulted in opioid withdrawal stress-related gastric lesions including erosions/ulcers in the glandular stomach, mucosal congestion/hemorrhage and degeneration/necrosis in the nonglandular stomach at all doses tested including the low dose producing plasma exposure 2 times the estimated human exposure at the MRHD on an AUC basis. The effect is believed to be due to acute withdrawal stress, as similar findings were not noted in rats sacrificed immediately after the last dose of oliceridine.