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 outweighs the risks. Supplemental doses of 0.75 mg OLINVYK can be administered by healthcare providers, beginning 1 hour after the initial dose, and hourly thereafter as needed. Onset of analgesic effect is expected within 2 to 5 minutes after the initial dose [see Clinical Pharmacology ( 12.2 )] . Do not administer single doses greater than 3 mg [see Adverse Reactions ( 6.1 )] . The cumulative total daily dose should not exceed 27 mg. If patients reach a 27 mg cumulative daily dose and analgesia is still required, an alternative analgesic regimen should be administered until OLINVYK can be resumed the next day. Alternative analgesia may include multi-modal therapies. The safety of OLINVYK beyond 48 hours of use was not evaluated in controlled clinical trials [see Warnings and Precautions ( 5.5 )] . Conversion Between Morphine Intravenous Injection and OLINVYK Intravenous Injection Based on data collected in clinical studies, an initial 1 mg dose of OLINVYK is approximately equipotent to morphine 5 mg [see Clinical Pharmacology ( 12.2 )]. As individual patients differ in their response to opioid drugs, this comparison should be used only as a guide. 2.3 Titration and Maintenance of Therapy Titrate the dose based upon the individual patient’s response to their initial dose of OLINVYK. Individually titrate OLINVYK to a dose that provides adequate analgesia and minimizes adverse reactions. Continually reevaluate patients receiving OLINVYK to assess the maintenance of pain control, signs and symptoms of opioid withdrawal, and other adverse reactions, as well as to reassess for the development of addiction, abuse, or misuse [see Warnings and Precautions ( 5.1 , 5.14 )] . Frequent communication is important among the prescriber, other members of the healthcare team, the patient, and the caregiver/family during periods of changing analgesic requirements, including initial titration. If the level of pain increases after dosage stabilization, attempt to identify the source of increased pain before increasing the OLINVYK dosage. If after increasing the dosage, unacceptable opioid-related adverse reactions are observed (including an increase in pain after a dosage increase), consider reducing the dosage [see Warnings and Precautions ( 5 )] . Adjust the dosage to obtain an appropriate balance between management of pain and opioid-related adverse reactions. 2.4 Safe Reduction or Discontinuation of OLINVYK When a patient who has been taking opioids regularly and may be physically dependent no longer requires therapy with OLINVYK, taper the dose gradually while regularly evaluating for signs and symptoms of withdrawal. If the patient develops these signs or symptoms, raise the dose to the previous level and taper more slowly, either by increasing the interval between decreases, decreasing the amount of change in dose, or both. Do not rapidly reduce or abruptly discontinue OLINVYK in patients who may be physically dependent on opioids [see Warnings and Precautions ( 5.1 , 5.14 ), Drug Abuse and Dependence ( 9.3 ); Nonclinical Toxicology ( 13.2 )] .

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 )

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 therapy or following a dose increase. Monitor patients closely for respiratory depression, especially when initiating therapy with OLINVYK and following dosage increases. To reduce the risk of respiratory depression, proper dosing of OLINVYK is essential [see Dosage and Administration ( 2 )] . Overestimating the OLINVYK dosage when converting patients from another opioid product can result in fatal overdose with the first dose. Opioids can cause sleep-related breathing disorders including central sleep apnea (CSA) and sleep-related hypoxemia. Opioid use increases the risk of CSA in a dose-dependent fashion. In patients who present with CSA, consider decreasing the opioid dosage using best practices for opioid taper. 5.3 Risks from Concomitant Use with Benzodiazepines or Other CNS Depressants Profound sedation, respiratory depression, coma, and death may result from the concomitant use of OLINVYK with benzodiazepines and/or other CNS depressants, including alcohol (e.g., non-benzodiazepine sedatives/hypnotics, anxiolytics, tranquilizers, muscle relaxants, general anesthetics, antipsychotics, gabapentinoids [gabapentin or pregabalin], and other opioids, or alcohol). Because of these risks, reserve concomitant prescribing of these drugs for use in patients for whom alternative treatment options are inadequate. Observational studies have demonstrated that concomitant use of opioid analgesics and benzodiazepines increases the risk of drug-related mortality compared to use of opioid analgesics alone. Because of similar pharmacological properties, it is reasonable to expect similar risk with the concomitant use of other CNS depressant drugs with opioid analgesics [see Drug Interactions ( 7 )] . If the decision is made to prescribe a benzodiazepine or other CNS depressant concomitantly with an opioid analgesic, prescribe the lowest effective dosages and minimum durations of concomitant use. In patients already receiving an opioid analgesic, prescribe a lower initial dose of the benzodiazepine or other CNS depressant than indicated in the absence of an opioid, and titrate based on clinical response. If an opioid analgesic is initiated in a patient already taking a benzodiazepine or other CNS depressant, prescribe a lower initial dose of the opioid analgesic, and titrate based on clinical response. Monitor patients closely for signs and symptoms of respiratory depression and sedation. 5.4 Neonatal Opioid Withdrawal Syndrome Use of OLINVYK for an extended period of time during pregnancy can result in withdrawal in the neonate. Neonatal opioid withdrawal syndrome, unlike opioid withdrawal syndrome in adults, may be life‑threatening if not recognized and treated, and requires management according to protocols developed by neonatology experts. Observe newborns for signs of neonatal opioid withdrawal syndrome and manage accordingly. Advise women using opioids for an extended period of time of the risk of neonatal opioid withdrawal syndrome and ensure that management by neonatology experts will be available at delivery [see Use in Specific Populations ( 8.1 )] . 5.5 Potential for QT prolongation with Daily Doses exceeding 27 mg The effect of oliceridine on cardiac physiology was studied in single and multiple-dose thorough QT studies. The multiple-dose study was conducted with a maximum daily cumulative dose of 27 mg. In both studies, there was mild QTc interval prolongation. In the multiple-dose study, the maximum mean ΔΔQTcI was 11.7 ms (two-sided 90% UCI 14.7 ms) at 9 hours. The effect on QT prolongation at total cumulative daily doses >27 mg has not been studied in a thorough QT study [see Clinical Pharmacology ( 12.2 )]. Total cumulative daily doses exceeding 27 mg per day may increase the risk for QTc interval prolongation. Therefore, the cumulative total daily dose of OLINVYK should not exceed 27 mg [see Dosage and Administration ( 2.2 )]. 5.6 Risk of Use in Patients with Decreased Cytochrome P450 2D6 Function or Concomitant Use or Discontinuation with Cytochrome P450 3A4 Inhibitors and Inducers Risk of Increased Oliceridine Plasma Concentrations Increased plasma concentrations of oliceridine, which may result in prolonged opioid adverse reactions and exacerbated respiratory depression, may occur when OLINVYK is used under the following conditions: In patients with decreased Cytochrome P450 (CYP) 2D6 function (poor metabolizers of CYP2D6 or normal metabolizers taking moderate or strong CYP2D6 inhibitors) [See Drug Interactions ( 7 ); Use in Specific Populations ( 8.8 )]. In patients taking a moderate or strong CYP3A4 inhibitor In patients with decreased CYP2D6 function who are also receiving a moderate or strong CYP3A4 inhibitor Discontinuation of a CYP3A4 inducer These patients may require less frequent dosing of OLINVYK. Closely monitor these patients for respiratory depression and sedation at frequent intervals and base subsequent doses of OLINVYK on the patient’s severity of pain and response to treatment. [see Drug Interactions ( 7 ), Use in Specific Populations ( 8.8 ), Clinical Pharmacology ( 12.3 , 12.5 )]. Risk of Lower than Expected Oliceridine Plasma Concentrations Lower than expected concentrations of oliceridine, which may lead to decreased efficacy, may occur under the following conditions: Concomitant use of OLINVYK with CYP3A4 inducers Discontinuation of a moderate or strong CYP3A4 or CYP2D6 inhibitor Closely monitor these patients at frequent intervals and consider supplemental doses of OLINVYK [see Dosage and Administration ( 2.2 ), Drug Interactions ( 7 )] . 5.7 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. This condition differs from tolerance, which is the need for increasing doses of opioids to maintain a defined effect [see Dependence ( 9.3 )] . Symptoms of OIH include (but may not be limited to) increased levels of pain upon opioid dosage increase, decreased levels of pain upon opioid dosage decrease, or pain from ordinarily non-painful stimuli (allodynia). These symptoms may suggest OIH only if there is no evidence of underlying disease progression, opioid tolerance, opioid withdrawal, or addictive behavior. Cases of OIH have been reported, both with short-term and longer-term use of opioid analgesics. Though the mechanism of OIH is not fully understood, multiple biochemical pathways have been implicated. Medical literature suggests a strong biologic plausibility between opioid analgesics and OIH and allodynia. If a patient is suspected to be experiencing OIH, carefully consider appropriately decreasing the dose of the current opioid analgesic or opioid rotation (safely switching the patient to a different opioid moiety) [see Dosage and Administration ( 2.4 ); Warnings and Precautions ( 5.7 )] . 5.8 Life-Threatening Respiratory Depression in Patients with Chronic Pulmonary Disease or in Elderly, Cachectic, or Debilitated Patients The use of OLINVYK in patients with acute or severe bronchial asthma in an unmonitored setting or in the absence of resuscitative equipment is contraindicated. Patients with Chronic Pulmonary Disease : OLINVYK-treated patients with significant chronic obstructive pulmonary disease or cor pulmonale, and those with a substantially decreased respiratory reserve, hypoxia, hypercapnia, or preexisting respiratory depression are at increased risk of decreased respiratory drive including apnea, even at recommended dosages of OLINVYK [see Warnings and Precautions ( 5.2 )]. Elderly, Cachectic, or Debilitated Patients : Life-threatening respiratory depression is more likely to occur in elderly, cachectic, or debilitated patients as they may have altered pharmacokinetics or altered clearance compared to younger, healthier patients [see Warnings and Precautions ( 5.2 )] . Monitor such patients closely, particularly when initiating and titrating OLINVYK and when OLINVYK is given concomitantly with other drugs that depress respiration [see Warnings and Precautions ( 5.2 , 5.3 ); Drug Interactions ( 7 )] . Alternatively, consider the use of non-opioid analgesics in these patients. 5.9 Adrenal Insufficiency Cases of adrenal insufficiency have been reported with opioid use, more often following greater than one month of use. Presentation of adrenal insufficiency may include non-specific symptoms and signs including nausea, vomiting, anorexia, fatigue, weakness, dizziness, and low blood pressure. If adrenal insufficiency is suspected, confirm the diagnosis with diagnostic testing as soon as possible. If adrenal insufficiency is diagnosed, treat with physiologic replacement doses of corticosteroids. Wean the patient off of the opioid to allow adrenal function to recover and continue corticosteroid treatment until adrenal function recovers. Other opioids may be tried as some cases reported use of a different opioid without recurrence of adrenal insufficiency. The information available does not identify any particular opioids as being more likely to be associated with adrenal insufficiency. 5.10 Severe Hypotension OLINVYK may cause severe hypotension, including orthostatic hypotension and syncope in ambulatory patients. There is increased risk in patients whose ability to maintain blood pressure has already been compromised by a reduced blood volume or concurrent administration of certain CNS depressant drugs (e.g., phenothiazines or general anesthetics) [see Drug Interactions ( 7 )] . Monitor these patients for signs of hypotension after initiating or titrating the dosage of OLINVYK. In patients with circulatory shock, OLINVYK may cause vasodilation that can further reduce cardiac output and blood pressure. Avoid the use of OLINVYK in patients with circulatory shock. 5.11 Risks of Use in Patients with Increased Intracranial Pressure, Brain Tumors, Head Injury, or Impaired Consciousness In patients who may be susceptible to the intracranial effects of CO 2 retention (e.g., those with evidence of increased intracranial pressure or brain tumors), OLINVYK may reduce respiratory drive, and the resultant CO 2 retention can further increase intracranial pressure. Monitor such patients for signs of sedation and respiratory depression, particularly when initiating therapy with OLINVYK. Opioids may also obscure the clinical course in a patient with a head injury. Avoid the use of OLINVYK in patients with impaired consciousness or coma. 5.12 Risks of Gastrointestinal Complications OLINVYK is contraindicated in patients with known or suspected gastrointestinal obstruction, including paralytic ileus. The oliceridine in OLINVYK may cause spasm of the sphincter of Oddi. Opioids may cause increases in serum amylase. Monitor patients with biliary tract disease, including acute pancreatitis, for worsening symptoms. Cases of opioid-induced esophageal dysfunction (OIED) have been reported in patients taking opioids. The risk of OIED may increase as the dose and/or duration of opioids increases. Regularly evaluate patients for signs and symptoms of OIED (e.g., dysphagia, regurgitation, non-cardiac chest pain) and, if necessary, adjust opioid therapy as clinically appropriate [see Clinical Pharmacology ( 12.2 )] . 5.13 Increased Risk of Seizures in Patients with Seizure Disorders OLINVYK may increase the frequency of seizures in patients with seizure disorders, and may increase the risk of seizures occurring in other clinical settings associated with seizures. Monitor patients with a history of seizure disorders for worsened seizure control during OLINVYK therapy. 5.14 Withdrawal Do not rapidly reduce or abruptly discontinue OLINVYK in a patient physically dependent on opioids. When discontinuing OLINVYK in a physically-dependent patient, gradually taper the dosage. Rapid tapering of oliceridine in a patient physically dependent on opioids may lead to a withdrawal syndrome and return of pain [see Dosage and Administration ( 2.4 ), Drug Abuse and Dependence ( 9.3 ), Nonclinical Toxicology ( 13.2 )]. Additionally, avoid the use of mixed agonist/antagonist (e.g, pentazocine, nalbuphine, and butorphanol) or partial agonist (e.g., buprenorphine) analgesics in patients who are receiving a full opioid agonist analgesic, including OLINVYK. In these patients, mixed agonist/antagonist and partial agonist analgesics may reduce the analgesic effect and/or precipitate withdrawal symptoms [see Drug Interactions ( 7 )] . 5.15 Risks of Driving and Operating Machinery OLINVYK may impair the mental or physical abilities needed to perform potentially hazardous activities such as driving a car or operating machinery. Warn patients not to drive or operate dangerous machinery unless they are tolerant to the effects of OLINVYK and know how they will react to the medication. 5.16 Patient-Controlled Analgesia (PCA) Although self-administration of opioids by PCA may allow each patient to individually titrate to an acceptable level of analgesia, PCA administration has resulted in adverse outcomes and episodes of respiratory depression. Health care providers and family members monitoring patients receiving PCA analgesia should be instructed in the need for appropriate monitoring for excessive sedation, respiratory depression, or other adverse effects of opioid medications.

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. Intervention: If concomitant use with CYP3A4 inducer is necessary, increase of the OLINVYK dosage may be considered until stable drug effects are achieved. Monitor for signs of opioid withdrawal. If a CYP3A4 inducer is discontinued, consider OLINVYK dosage reduction and monitor for signs of respiratory depression. Examples: Rifampin, carbamazepine, phenytoin Benzodiazepines and Other Central Nervous System (CNS) Depressants Clinical Impact: Due to additive pharmacologic effect, the concomitant use of benzodiazepines or other CNS depressants, including alcohol, increases the risk of hypotension, respiratory depression, profound sedation, coma, and death [see Warnings and Precautions ( 5.3 )]. Intervention: Reserve concomitant prescribing of these drugs for use in patients for whom alternative treatment options are inadequate. Limit dosages and durations to the minimum required. Monitor closely for signs of respiratory depression and sedation [see Warnings and Precautions ( 5.3 )]. Examples: Benzodiazepines and other sedatives/hypnotics, anxiolytics, tranquilizers, muscle relaxants, general anesthetics, antipsychotics, gabapentinoids (gabapentin or pregabalin), other opioids, alcohol Serotonergic Drugs Clinical Impact: The concomitant use of opioids with other drugs that affect the serotonergic neurotransmitter system has resulted in serotonin syndrome. Intervention: If concomitant use is warranted, carefully observe the patient, particularly during treatment initiation and dose adjustment. Discontinue OLINVYK if serotonin syndrome is suspected. Examples: Selective serotonin reuptake inhibitors (SSRIs,) serotonin and norepinephrine reuptake inhibitors (SNRIs), tricyclic antidepressants (TCAs), triptans, 5-HT3 receptor antagonists, drugs that effect the serotonin neurotransmitter system (e.g., mirtazapine, trazodone, tramadol), certain muscle relaxants (i.e., cyclobenzaprine, metaxalone), monoamine oxidase (MAO) inhibitors (those intended to treat psychiatric disorders and also others, such as linezolid and intravenous methylene blue). Mixed Agonist/Antagonist and Partial Agonist Opioid Analgesics Clinical Impact: May reduce the analgesic effect of OLINVYK and/or precipitate withdrawal symptoms. Intervention: Avoid concomitant use. Examples: butorphanol, nalbuphine, pentazocine, buprenorphine Muscle Relaxants Clinical Impact: OLINVYK may enhance the neuromuscular blocking action of skeletal muscle relaxants and produce an increased degree of respiratory depression. Intervention: Monitor patients for signs of respiratory depression that may be greater than otherwise expected and decrease the dosage of OLINVYK and/or the muscle relaxant as necessary. Examples: cyclobenzaprine, metaxalone Diuretics Clinical Impact: Opioids can reduce the efficacy of diuretics by inducing the release of antidiuretic hormone. Intervention: Monitor patients for signs of diminished diuresis and/or effects on blood pressure and increase the dosage of the diuretic as needed. Anticholinergic Drugs Clinical Impact: The concomitant use of anticholinergic drugs may increase risk of urinary retention and/or severe constipation, which may lead to paralytic ileus. Intervention: Monitor patients for signs of urinary retention or reduced gastric motility when OLINVYK is used concomitantly with anticholinergic drugs. Moderate and Strong CYP2D6 and CYP3A4 Inhibitors : Patients may require less frequent dosing. Monitor closely and administer subsequent doses based on severity of pain and patient response. ( 5.6 , 7 ) Serotonergic Drugs : Concomitant use may result in serotonin syndrome. Discontinue OLINVYK if serotonin syndrome is suspected. ( 7 ) Mixed Agonist/Antagonist and Partial Agonist Opioid Analgesics : Avoid use with OLINVYK because they may reduce analgesic effect of OLINVYK or precipitate withdrawal symptoms. ( 7 )

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 demand dose was 1 mg; and supplemental doses of 2 mg were permitted, beginning 1 hour after the loading dose, and hourly thereafter, as needed. A lockout interval of 6 minutes was used for all PCA regimens. In Study 1, a total of 136 patients received OLINVYK ≤27 mg/day, and 98 patients received OLINVYK >27 mg/day during the first 24 hours. In Study 2, a total of 180 patients received OLINVYK ≤27 mg/day, and 56 patients received OLINVYK >27 mg/day during the first 24 hours. Table 1 and Table 2 list adverse drug reactions that were reported in ≥5% of OLINVYK-treated patients in each study, and that occurred at a frequency greater than placebo in at least one of the studies. Table 2 and Table 3 lists adverse drug reactions that were reported in ≥5% of OLINVYK-treated patients for pooled Studies 1 and 2 stratified by total daily dose (≤27 mg/day or >27 mg/day). These data are not an adequate basis for comparison of rates between the OLINVYK treatment group and the morphine treatment group. The OLINVYK and morphine dosing regimens studied are not considered equipotent. Table 1: Adverse Drug Reactions Reported in ≥5% of OLINVYK-Treated Patients Following Orthopedic Surgery-Bunionectomy (Study 1) Adverse Drug Reaction Placebo (N = 79) OLINVYK 0.35 mg a (N = 79) OLINVYK 0.5 mg a (N = 79) Morphine b (N = 76) Patients with any TEAE c (%) 68 86 91 96 Nausea 24 56 63 65 Vomiting 6 39 41 50 Dizziness 10 32 35 34 Somnolence 6 19 13 13 Constipation 11 11 14 17 Pruritus 8 15 4 20 Hypoxia 0 5 9 9 Sedation 1 5 4 3 Oxygen saturation decreased 0 4 5 9 a Each OLINVYK regimen included a loading dose of 1.5 mg, followed by access to demand doses of 0.35 or 0.5 mg, with a 6-minute lockout period between doses, and 0.75-mg supplemental doses, beginning 1 hour after the initial dose, and hourly thereafter, as needed. b The morphine regimen included a loading dose of 4 mg, followed by access to a demand dose of 1 mg, with a 6-minute lockout period between doses, and 2-mg supplemental doses, beginning 1 hour after the initial dose, and hourly thereafter, as needed. c Treatment Emergent Adverse Event Table 2: Adverse Drug Reactions Reported in ≥5% of OLINVYK -Treated Patients Following Plastic Surgery-Abdominoplasty (Study 2) Adverse Drug Reaction Placebo (N = 83) OLINVYK 0.35 mg a (N = 79) OLINVYK 0.5 mg a (N = 80) Morphine b (N = 82) Patients with any TEAE c (%) 78 94 95 98 Nausea 46 62 75 74 Vomiting 13 22 43 54 Hypoxia 5 20 18 23 Constipation 7 17 11 11 Pruritus 5 17 11 18 Dizziness 11 9 9 16 Sedation 8 14 9 23 Back pain 6 13 11 9 Somnolence 1 0 5 7 a Each OLINVYK regimen included a loading dose of 1.5 mg, followed by access to demand doses of 0.35 or 0.5 mg with a 6-minute lockout period between doses, and 0.75-mg supplemental doses beginning 1 hour after the initial dose and hourly thereafter as needed. b The morphine regimen included a loading dose of 4 mg, followed by access to a demand dose of 1 mg with a 6-minute lockout period between doses, and 2-mg supplemental doses beginning 1 hour after the initial dose, and hourly thereafter, as needed. c Treatment Emergent Adverse Event Table 3: Adverse Drug Reactions Reported in ≥5% of OLINVYK-Treated Patients Stratified by Daily Dose (Study 1 and 2 Pooled) Adverse Drug Reaction Placebo (N = 162) OLINVYK ≤ 27 mg (N = 316) OLINVYK > 27 mg (N= 154) Morphine (N =158) Patients with any TEAE a (%) 73 86 92 96 Nausea 35 52 66 70 Vomiting 10 26 42 52 Headache 30 26 26 30 Dizziness 11 18 27 25 Constipation 9 14 12 14 Hypoxia 3 12 6 17 Pruritus 6 9 14 19 Sedation 5 7 7 13 Somnolence 4 6 10 10 Back pain 4 6 4 6 Hot flush 4 4 7 8 Pruritus generalized 1 2 5 10 a Treatment Emergent Adverse Event In an open-label safety study of patients with moderate to severe acute pain following a surgical procedure or due to a medical condition (Study 3), a total of 768 patients received at least one dose of OLINVYK. OLINVYK was administered via clinician-administered bolus dosing, PCA, or a combination of the two. Bolus dosing was initiated at 1 to 2 mg, with supplemental doses of 1 to 3 mg every 1 to 3 hours, as needed, based on individual patient need and previous response to OLINVYK. If OLINVYK was administered via PCA, the loading dose was 1.5 mg, the demand dose was 0.5 mg, and the lockout interval was 6 minutes. Supplemental doses of 1 mg were given as needed, taking into account the patient's utilization of PCA demand doses, individual patient need, and previous response to OLINVYK. In Study 3, for the patients within the highest cumulative dose group (exposure >36 mg), the mean cumulative exposure was 67 mg (range: 37 mg to 224 mg) and the mean cumulative duration of exposure was 54 hours (range: 6 hours to 143 hours). The mean cumulative dose of OLINVYK administered to patients in the Study 3 was 30 mg over a mean cumulative duration of 29 hours. The most frequent condition treated in Study 3 was post-surgical acute pain, and included (in order of decreasing frequency): orthopedic, gynecologic, colorectal, general, plastic, urologic, neurologic (including spinal), bariatric, and cardiothoracic surgical procedures. In Study 3, of the 768 patients treated with OLINVYK, 32% were age 65 years or older and 78% had a Body Mass Index ≥25 kg/m 2 . OLINVYK was administered as needed; 55% of patients received OLINVYK via clinician bolus administration only, and 45% of patients received OLINVYK via PCA self-administration or a combination of clinician bolus- and PCA self-administration. In Study 3 (open-label), a total of 592 patients received OLINVYK ≤27 mg/day and 176 received OLINVYK >27 mg during the first 24 hours. Adverse drug reactions reported in ≥5% of patients receiving OLINVYK in Study 3, stratified by total daily dose (≤27 mg/day or >27 mg/day), are presented in Table 4. Table 4: Adverse Drug Reactions Reported in ≥5% OLINVYK-Treated Patients in Study 3 (Open-Label) Adverse Drug Reaction OLINVYK ≤ 27mg N = 592 OLINVYK > 27mg N = 176 Patients with any TEAE a (%) 62 69 Nausea 29 38 Constipation 10 13 Vomiting 9 15 Headache 4 5 Hypokalaemia 4 7 Pruritus 4 8 Pyrexia 3 5 a Treatment Emergent Adverse Event Adverse Drug Reactions Reported in >1% to <5% of Patients in the controlled and open-label studies (Study 1, Study 2, and Study 3) are listed in descending order of frequency within System Organ Class in Table 5. Table 5: Adverse Drug Reactions Reported in >1% to <5% of Patients in Studies 1-3 System Organ Class Adverse Drug Reaction Preferred Term Blood and lymphatic disorders Anemia Cardiac disorders Tachycardia Gastrointestinal disorders Flatulence, Dry mouth, Dyspepsia, Diarrhea General disorders and administration site conditions Pyrexia, Infusion site extravasation Injury, poisoning and procedural complications Procedural nausea Investigations Oxygen saturation decreased, Alanine aminotransferase increased, Blood pressure increased Metabolism and nutritional disorders Hypokalaemia, Hypocalcaemia, Hypophosphataemia, Hypomagnesaemia Musculoskeletal and connective tissue disorders Muscle spasms Nervous system disorders Headache Psychiatric disorders Anxiety, Insomnia, Restlessness Respiratory, thoracic and mediastinal disorders Cough, Dyspnea Skin and subcutaneous tissue disorders Hyperhidrosis, Rash, Pruritus generalised Vascular disorders Hypotension, Hot flush, Flushing 6.2 Postmarketing Experience Serotonin syndrome : Cases of serotonin syndrome, a potentially life-threatening condition, have been reported during concomitant use of opioids with serotonergic drugs. Adrenal insufficiency : Cases of adrenal insufficiency have been reported with opioid use, more often following greater than one month of use. Anaphylaxis : Anaphylaxis has been reported with ingredients contained in OLINVYK. Androgen deficiency : Cases of androgen deficiency have occurred with use of opioids for an extended period of time [see Clinical Pharmacology ( 12.2 )] . Hyperalgesia and Allodynia : Cases of hyperalgesia and allodynia have been reported with opioid therapy of any duration [see Warnings and Precautions ( 5.7 )]. Hypoglycemia : Cases of hypoglycemia have been reported in patients taking opioids. Most reports were in patients with at least one predisposing risk factor (e.g., diabetes). Opioid-induced esophageal dysfunction (OIED) : Cases of OIED have been reported in patients taking opioids and may occur more frequently in patients taking higher doses of opioid, and/or in patients taking opioids longer term [see Warnings and Precautions ( 5.12 )] . Adverse Reactions from Observational Studies A prospective, observational cohort study estimated the risks of addiction, abuse, and misuse in patients initiating long-term use of Schedule II opioid analgesics between 2017 and 2021. Study participants include in one or more analyses had been enrolled in selected insurance plans or health systems for at least one year, were free of at least one outcome at baseline, completed a minimum number of follow-up assessments, and either: 1) filled multiple extended-release/long-acting opioid analgesic prescriptions during a 90-day period (n=978); or 2) filled any Schedule II opioid analgesic prescriptions covering at least 70 of 90 days (n=1,244). Those included also had no dispensing of the qualifying opioids in the previous 6 months. Over 12 months: approximately 1% to 6% of participants across the two cohorts newly met criteria for addiction, as assessed with two validated interview-based measures of moderate-to-severe opioid use disorder based on Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5) criteria, and approximately 9% and 22% of participants across the two cohorts newly met criteria for prescription opioid abuse and misuse [defined in Drug Abuse and Dependence ( 9.2 )] , respectively, as measured with a validated self-reported instrument. A retrospective, observational cohort study estimated the risk of opioid-involved overdose or opioid overdose-related death in patients with new long-term use of Schedule II opioid analgesics from 2006 through 2016 (n=220,249). Included patients had been enrolled in either one of two commercial insurance programs, one managed care program, or one Medicaid program for at least 9 months. New long-term use was defined as having Schedule II opioid analgesic prescriptions covering at least 70 days’ supply over the 3 months prior to study entry and none during the preceding 6 months. Patients were excluded if they had an opioid-involved overdose in the 9 months prior to study entry. Overdose was measured using a validated medical code-based algorithm with linkage to the National Death Index database. The 5-year cumulative incidence estimates for opioid-involved overdose or opioid overdose-related death ranged from approximately 1.5% to 4% across study sites, counting only the first event during follow-up. Approximately 17% of first opioid overdoses observed over the entire study period (5-11 years, depending on the study site) were fatal. Higher baseline opioid dose was the strongest and most consistent predictor of opioid-involved overdose or opioid overdose-related death. Study exclusion criteria may have selected patients at lower risk of overdose, and substantial loss to follow-up (approximately 80%) also may have biased estimates. The risk estimates from the studies described above may not be generalizable to all patients receiving opioid analgesics, such as those with exposures shorter or longer than the duration evaluated in the studies.

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 an AUC basis.