OLINVYK

1 INDICATIONS AND USAGE OLINVYK is indicated in adults for the management of acute pain severe enough to require an intravenous opioid analgesic and for whom alternative treatments are inadequate. Limitations of Use Because of the risks of addiction, abuse, misuse, overdose, and death, which can occur at any dosage or duration [see Warnings and Precautions ( 5.1 )] , and persist over the course of therapy, reserve opioid analgesics, including OLINVYK, for use in patients for whom alternative treatment options are ineffective, not management of pain. The cumulative total daily dose should not exceed 27 mg, as total daily doses greater than 27 mg may increase the risk for QTc interval prolongation [see Warnings and Precautions ( 5.5 ] . OLINVYK is an opioid agonist indicated in adults for the management of acute pain severe enough to require an intravenous opioid analgesic and for whom alternative treatments are inadequate. ( 1 ) Limitations of Use ( 1 ) Because of the risks of addiction, abuse, misuse, overdose, and death, which can occur at any dosage or duration and persist over the course of therapy, reserve opioid analgesics, including OLINVYK, for use in patients for whom alternative treatment options are ineffective, not tolerated, or would be otherwise inadequate to provide sufficient management of pain.( 1 , 5.1 ) The cumulative total daily dose should not exceed 27 mg. ( 2.1 , 2.2 , 5.5 ).

2 DOSAGE AND ADMINISTRATION For intravenous administration only. OLINVYK should be prescribed only by healthcare professionals who are knowledgeable about the use of opioids and how to mitigate the associated risks. ( 2.1 ) Use the lowest effective dosage for the shortest duration consistent with individual patient treatment goals. Reserve titration to higher doses of OLINVYK for patients in whom lower doses are insufficiently effective and in whom the expected benefits of using a higher dose opioid clearly outweigh the substantial risks. ( 2.1 , 5 ) Initiate the dosing regimen for each patient individually, taking into account the patient’s underlying cause and severity of pain, prior analgesic treatment and response, and risk factors for addiction, abuse and misuse. ( 2.1 , 5.1 ) Respiratory depression can occur at any time during opioid therapy, especially when initiating and following dosage increases with OLINVYK. Consider this risk when selecting an initial dose and when making dose adjustments. ( 2.1 , 5.2 ) Initiate treatment with a 1.5 mg dose. ( 2.2 ) For patient controlled analgesia (PCA), recommended demand dose is 0.35 mg, with a 6-minute lock-out. A demand dose of 0.5 mg may be considered. ( 2.2 ) Supplemental doses of 0.75 mg can be administered, beginning 1 hour after the initial dose, and hourly thereafter, as needed. ( 2.2 ) Periodically reassess patients receiving OLINVYK to evaluate the continued need for opioid analgesics to maintain pain control, for the signs or symptoms of adverse reactions, and for the development of addiction, abuse, or misuse. ( 2.3 ) Do not rapidly reduce or abruptly discontinue OLINVYK in a physically-dependent patient. ( 2.4 , 5.14 ) 2.1 Important Dosage and Administration Instructions For intravenous administration only. OLINVYK should be prescribed only by healthcare professionals who are knowledgeable about the use of opioids and how to mitigate the associated risks. Individual single doses greater than 3 mg have not been evaluated. The cumulative daily dose should not exceed 27 mg. OLINVYK 30 mg/30 mL (1mg/mL) vial is intended for patient-controlled analgesia (PCA) use only. Draw OLINVYK directly from the vial into the PCA syringe or IV bag without diluting. Use the lowest effective dose for the shortest duration consistent with individual patient treatment goals [see Warnings and Precautions ( 5 )] . Because the risk of overdose increases as opioid doses increase, reserve titration to higher doses of OLINVYK for patients in whom lower doses are insufficiently effective and in whom the expected benefits of using a higher dose opioid clearly outweigh the substantial risks. Use of OLINVYK beyond 48 hours has not been studied in controlled clinical trials. There is variability in opioid analgesic dose and duration needed to adequately manage pain due both to the cause of pain and to individual patient factors. Initiate the dosing regimen for each patient individually, taking into account the patient's underlying cause and severity of pain, prior analgesic treatment and response, and risk factors for addiction, abuse, and misuse ( 5.1 )] . Respiratory depression can occur at any time during opioid therapy, especially when initiating and following dosage increases with OLINVYK. Consider this risk when selecting an initial dose and when making dose adjustments [see Warnings and Precautions ( 5 ) ] . Inspect OLINVYK for particulate matter and discoloration prior to administration. The solution is a clear, colorless, preservative free solution for intravenous use. If visibly opaque particles, discoloration, or other foreign particles are observed, do not use. 2.2 Initial Dosage OLINVYK can be administered by a healthcare provider with an initial dose of 1.5 mg. For PCA, the initial dose can be followed by access to patient demand doses with a 6-minute lock-out. The recommended demand dose is 0.35 mg. A demand dose of 0.5 mg may be considered for some patients if the potential benefit …

5 WARNINGS AND PRECAUTIONS Opioid-Induced Hyperalgesia and Allodynia: Opioid-Induced Hyperalgesia (OIH) occurs when an opioid analgesic paradoxically causes an increase in pain, or an increase in sensitivity to pain. If OIH is suspected, carefully consider appropriately decreasing the dose of the current opioid analgesic or opioid rotation. ( 5.7 ) Potential for QT Prolongation with Daily Doses Exceeding 27 mg : May increase risk for QT interval prolongation. Do not exceed a cumulative daily dose of 27 mg. ( 5.5 ) Life-Threatening Respiratory Depression in Patients with Chronic Pulmonary Disease or in Elderly, Cachectic, or Debilitated Patients : Monitor closely, particularly during initiation and titration. ( 5.8 ) Adrenal Insufficiency : If diagnosed, treat with physiologic replacement corticosteroids and wean the patient off the opioid. ( 5.9 ) Severe Hypotension : Monitor patients during initiation or titration. Avoid use of OLINVYK in patients with circulatory shock. ( 5.10 ) Risks of Use in Patients with Increased Intracranial Pressure, Brain Tumors, Head Injury, or Impaired Consciousness : Monitor for signs of sedation and respiratory depression. Avoid the use of OLINVYK in patients with impaired consciousness or coma. ( 5.11 ) 5.1 Addiction, Abuse, and Misuse OLINVYK contains oliceridine, a Schedule II controlled substance. As an opioid, OLINVYK exposes users to the risks of addiction, abuse, and misuse [see Drug Abuse and Dependence ( 9 )] . Although the risk of addiction in any individual is unknown, it can occur in patients appropriately prescribed OLINVYK. Addiction can occur at recommended dosages and if the drug is misused or abused [see Drug Abuse and Dependence ( 9 )] . The risk of opioid-related overdose or overdose-related death is increased with higher opioid doses, and this risk persists over the course of therapy. In postmarketing studies, addiction, abuse, misuse, and fatal and non-fatal opioid overdose were observed in patients with long-term opioid use [see Adverse Reactions ( 6.2 )] . Assess each patient’s risk for opioid addiction, abuse, or misuse prior to prescribing OLINVYK, and monitor all patients receiving OLINVYK for the development of these behaviors or conditions. Risks are increased in patients with a personal or family history of substance abuse (including drug or alcohol abuse or addiction) or mental illness (e.g., major depression). The potential for these risks should not, however, prevent the proper management of pain in any given patient. Patients at increased risk may be prescribed opioids such as OLINVYK, but use in such patients necessitates intensive counseling about the risks and proper use of OLINVYK along with intensive monitoring for signs of addiction, abuse, and misuse. Opioids are sought for nonmedical use and are subject to diversion from legitimate prescribed use. Consider these risks when prescribing or dispensing OLINVYK. Strategies to reduce these risks include prescribing the drug in the smallest appropriate quantity. Contact local state professional licensing board or state-controlled substances authority for information on how to prevent and detect abuse or diversion of this product. 5.2 Life-Threatening Respiratory Depression Serious, life-threatening respiratory depression has been reported with the use of opioids, even when used as recommended. Respiratory depression, if not immediately recognized and treated, may lead to respiratory arrest and death. Management of respiratory depression may include close observation, supportive measures, and use of opioid opioid overdose reversal agents (e.g., naloxone, nalmefene), depending on the patient’s clinical status [see Overdosage ( 10.2 )] . Carbon dioxide (CO 2 ) retention from opioid-induced respiratory depression can exacerbate the sedating effects of opioids. While serious, life-threatening, or fatal respiratory depression can occur at any time during the use of opioids, the risk is greatest during initiation of the…

4 CONTRAINDICATIONS OLINVYK is contraindicated in patients with: Significant respiratory depression [see Warnings and Precautions ( 5.2 )] Acute or severe bronchial asthma in an unmonitored setting or in the absence of resuscitative equipment [see Warnings and Precautions ( 5.8 )] Known or suspected gastrointestinal obstruction, including paralytic ileus [see Warnings and Precautions ( 5.12 )] Known hypersensitivity to oliceridine (e.g., anaphylaxis) Significant respiratory depression ( 4 ) Acute or severe bronchial asthma in an unmonitored setting or in absence of resuscitative equipment ( 4 ) Known or suspected gastrointestinal obstruction, including paralytic ileus ( 4 ) Known hypersensitivity to oliceridine ( 4 )

7 DRUG INTERACTIONS Table 6 includes clinically significant drug interactions with OLINVYK. Table 6: Clinically Significant Drug Interactions with OLINVYK Moderate to Strong Inhibitors of CYP2D6 Clinical Impact: Concomitant administration of a moderate to strong CYP2D6 inhibitor can increase the plasma concentration of oliceridine [see Clinical Pharmacology ( 12.3 )] , resulting in increased or prolonged opioid effects. Intervention: If concomitant use is necessary, patients taking a moderate to strong CYP2D6 inhibitor may require less frequent dosing of OLINVYK. Monitor closely for respiratory depression and sedation at frequent intervals and base subsequent doses on the patient’s severity of pain and response to treatment. If a CYP2D6 inhibitor is discontinued, increase of the OLINVYK dosage may be considered until stable drug effects are achieved. Monitor for signs of opioid withdrawal. Examples: Paroxetine, fluoxetine, quinidine, bupropion Moderate to Strong Inhibitors of CYP3A4 Clinical Impact: The concomitant administration of moderate to strong CYP3A4 inhibitors can increase the plasma concentration of oliceridine, resulting in increased or prolonged opioid adverse reactions. After stopping a CYP3A4 inhibitor, as the effects of the inhibitor decline, the oliceridine concentration may decrease, resulting in decreased opioid efficacy or a withdrawal syndrome in patients who had developed physical dependence to oliceridine [see Warnings and Precautions ( 5.14 )] . Intervention: Caution should be used when administering OLINVYK to patients taking inhibitors of the CYP3A4 enzyme. If concomitant use is necessary, patients taking a CYP3A4 inhibitor may require less frequent dosing. Monitor patients for respiratory depression and sedation at frequent intervals. If a CYP3A4 inhibitor is discontinued, increase of the OLINVYK dosage may be considered until stable drug effects are achieved. Monitor for signs of opioid withdrawal. Examples: Macrolide antibiotics (e.g., erythromycin), azole-antifungal agents (e.g. ketoconazole), protease inhibitors (e.g., ritonavir). Strong and Moderate CYP3A4 Inhibitors and CYP2D6 Inhibitors Clinical Impact: OLINVYK is primarily metabolized by both CYP3A4 and CYP2D6. Compared to inhibition of either metabolic pathway, inhibition of both pathways can result in a greater increase of the plasma concentrations of oliceridine and prolong opioid adverse reactions [See Clinical Pharmacology ( 12.3 )]. Intervention: Patients who are CYP2D6 normal metabolizers taking a CYP2D6 inhibitor, and a strong CYP3A4 inhibitor (or discontinuation of CYP3A4 inducers) may require less frequent dosing. Patients who are known CYP2D6 poor metabolizers and taking a CYP3A4 inhibitor (or discontinuation of CYP3A4 inducers) may require less frequent dosing. These patients should be closely monitored for respiratory depression and sedation at frequent intervals, and subsequent doses should be based on the patient’s severity of pain and response to treatment. Examples: Inhibitors of CYP3A4: Macrolide antibiotics (e.g., erythromycin), azole-antifungal agents (e.g., ketoconazole, itraconazole), anti-retroviral agents, selective serotonin re-uptake inhibitors (SSRIs), protease inhibitors (e.g., ritonavir), NS3/4A inhibitors. Inhibitors of CYP2D6: Paroxetine, fluoxetine, quinidine, bupropion Inducers of CYP3A4 Clinical Impact: The concomitant use of OLINVYK and CYP3A4 inducers can decrease the plasma concentration of oliceridine [see Clinical Pharmacology ( 12.3 )] , resulting in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence to oliceridine. [see Warnings and Precautions ( 5.14 )] . After stopping a CYP3A4 inducer, as the effects of the inducer decline, the oliceridine plasma concentration may increase [see Clinical Pharmacology ( 12.3 )] , which could increase or prolong both the therapeutic effects and adverse reactions, and may cause serious respiratory depression. Intervent…

8.1 Pregnancy Risk Summary Use of opioid analgesics for an extended period of time during pregnancy may result in neonatal opioid withdrawal syndrome [see Warnings and Precautions ( 5.4 )] . There are no available data on OLINVYK use in pregnant women to evaluate for a drug-associated risk of major birth defects and miscarriage or adverse maternal outcomes. There are adverse outcomes reported within detal exposure to opioid analgesics (see Clinical Considerations) . In animal reproductive studies, oliceridine reduced live litter size at birth and increased postnatal pup mortality between birth and Postnatal Day 4 when administered intravenously to rats from organogenesis through weaning at doses producing clinically relevant plasma exposure. Oliceridine had no effect on embryo-fetal development in rats and rabbits when administered intravenously during organogenesis at doses producing plasma exposures 7 and 8 times the estimated plasma exposure at the maximum recommended human dose (MRHD) on an AUC basis, respectively (see Data) . The background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively. Clinical Considerations Fetal/Neonatal Adverse Reactions Use of opioid analgesics for an extended period of time during pregnancy for medical or nonmedical purposes can result in physical dependence in the neonate and neonatal opioid withdrawal syndrome shortly after birth. Neonatal opioid withdrawal syndrome presents as irritability, hyperactivity and abnormal sleep pattern, high-pitched cry, tremor, vomiting, diarrhea, and failure to gain weight. The onset, duration, and severity of neonatal opioid withdrawal syndrome vary based on the specific opioid used, duration of use, timing and amount of last maternal use, and rate of elimination of the drug by the newborn. Observe newborns for symptoms of neonatal opioid withdrawal syndrome and manage accordingly [see Warnings and Precautions ( 5.4 )] . Labor or Delivery Opioids cross the placenta and may produce respiratory depression and psycho-physiologic effects in neonates. An opioid overdose reversal agent, such as naloxone or nalmefene, should be available for reversal of opioid induced respiratory depression in the neonate. OLINVYK is not recommended for use in pregnant women during and immediately prior to labor, when other analgesic techniques are more appropriate. Opioid analgesics can prolong labor through actions that temporarily reduce the strength, duration, and frequency of uterine contractions. However, this effect is not consistent and may be offset by an increased rate of cervical dilatation, which tends to shorten labor. Monitor neonates exposed to OLINVYK during labor for signs of excess sedation and respiratory depression. Data Animal Data Oliceridine administered via continuous intravenous infusion during the period of embryofetal organogenesis at doses of 6, 12, or 24 mg/kg/day to pregnant rats from Gestation Day (GD) 6 to 20 and 1.5, 3, or 6 mg/kg/day to pregnant rabbits from GD 7 to 29 had no effect on embryonic development at exposures 7 (rats) to 8 times (rabbits) the estimated plasma exposure at the MRHD of 27 mg/day on an AUC basis. Maternal toxicity (reduced body weight gain) was observed at ≥12 mg/kg/day in rats and at 6 mg/kg/day in rabbits. In a pre−and post−natal development study in rats, oliceridine administered via continuous intravenous infusion at doses of 0.6, 2.4, and 6.0 mg/kg/day from Gestation Day 6 through Lactation Day 21 resulted in reduced live litter size at birth at 1.5 times the estimated plasma exposure at the MRHD on an AUC basis and lower pup survival between birth and Postnatal Day 4 at 0.6 times the estimated plasma exposure at the MRHD on a…

6 ADVERSE REACTIONS The following adverse reactions are described, or described in greater detail, in other sections: Addiction, Abuse, and Misuse [see Warnings and Precautions ( 5.1 )] Life-threatening Respiratory Depression [see Warnings and Precautions ( 5.2 )] Interactions with Benzodiazepines or Other CNS Depressants [see Warnings and Precautions ( 5.3 )] Neonatal Opioid Withdrawal Syndrome [see Warnings and Precautions ( 5.4 )] Opioid-Induced Hyperalgesia and Allodynia [see Warnings and Precautions ( 5.7 )] Adrenal Insufficiency [see Warnings and Precautions ( 5.9 )] Severe Hypotension [see Warnings and Precautions ( 5.10 )] Gastrointestinal Adverse Reactions [see Warnings and Precautions ( 5.12 )] Seizures [see Warnings and Precautions ( 5.13 )] Withdrawal [see Warnings and Precautions ( 5.14 )] The most common (incidence ≥10%) adverse reactions in controlled clinical trials (Studies 1 and 2) were nausea, vomiting, dizziness, headache, constipation, pruritus, and hypoxia. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Trevena, Inc. at 1-844-465-4686 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch 6.1 Clinical Studies Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice. A total of 1535 patients were treated with OLINVYK in controlled and open-label trials in patients with moderate to severe acute pain. Of these, 1181 patients received a total daily dose ≤27 mg and 354 patients received a total daily dose >27 mg during the first 24-hour treatment period. Among patients who received a daily dose of >27 mg, 198 patients received a daily dose between 27 mg and 40 mg, and 142 patients received a daily dose >40 mg. The most common adverse drug reactions (≥10%) in controlled efficacy trials (Study 1 and Study 2) were nausea, vomiting, dizziness, headache, constipation, pruritus and hypoxia. Adverse reactions leading to discontinuation of OLINVYK were hypotension, hypoxia, nausea, hypoventilation, oxygen saturation decreased, alanine aminotransferase increased, aspartate aminotransferase increased, electrocardiogram QT prolongation, and urticaria. In two randomized, double-blind, placebo- and morphine-controlled studies, when stratified by 27 mg daily dosing limit, discontinuation of OLINVYK due to adverse reactions occurred in 4% of patients who received a daily dose ≤ 27 mg, and less than 1% of patients who received a daily dose >27 mg. In these same studies, discontinuation due to adverse reactions occurred in 5% of morphine-treated patients, and no placebo-treated patients. In an open-label safety study, discontinuation of OLINVYK due to adverse drug reactions occurred in 3% of patients who received a daily dose ≤ 27 mg, and 1% of patients who received a daily dose >27 mg. In two randomized, double-blind, placebo- and morphine-controlled studies in patients with moderate to severe acute pain following either orthopedic surgery-bunionectomy (Study 1), or plastic surgery-abdominoplasty (Study 2), patients received one of three OLINVYK dosing regimens, a morphine- control regimen, or a volume‑matched placebo-control regimen. All dosing regimens were administered via patient-controlled analgesia (PCA), allowing patients to individually titrate the dose available to an acceptable level of analgesia. Patients were treated for up to 48 hours in the bunionectomy study (Study 1), and for up to 24 hours in the abdominoplasty study(Study 2) [see Clinical Studies ( 14 )]. 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 assigned treatment group; supplemental doses of 0.75 mg were permitted, beginning 1 hour after the loading dose, and hourly thereafter, as needed. The loading dose for the morphine treatment regimen was 4 mg; the deman…