OLINVYK™ (oliceridine) injection

Postoperative oliceridine use in patients with advanced age and/or increased BMI was not associated with increased risk of OIRD

Low Incidence of Opioid-Induced Respiratory Depression Observed with Oliceridine Regardless of Age or Body Mass Index: Exploratory Analysis from a Phase 3 Open-Label Trial in Postsurgical Pain

Marek Brzezinski, Gregory B. Hammer, Keith A. Candiotti, Sergio D. Bergese, Peter H. Pan, Michael H. Bourne, Cathy Michalsky, Linda Wase, Mark A. Demitrack, Ashraf S. Habib. Pain & Therapy 2021.

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Review of the efficacy and safety of intravenous oliceridine in the treatment of moderate to severe acute pain

Oliceridine in the treatment of moderate to severe acute pain

Sarada S Eleswarpu & Ashraf S Habib. Future Medicine 2021.

DOI: 10.2217/pmt-2020-0087

Oliceridine significantly reduced risk of vomiting and rescue antiemetic use compared to IV morphine in a retrospective analysis

Oliceridine is Associated with Reduced Risk of Vomiting and Need for Rescue Antiemetics Compared to Morphine: Exploratory Analysis from Two Phase 3 Randomized Placebo and Active Controlled Trials

Timothy L. Beard,  Cathy Michalsky, Keith A. Candiotti, Paul Rider, Linda Wase, Ashraf S. Habib, Mark A. Demitrack, Michael J. Fossler, Eugene R. Viscusi

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Benefit and Risk Evaluation of Biased μ-Receptor Agonist Oliceridine versus Morphine.

Benefit and Risk Evaluation of Biased μ-Receptor Agonist Oliceridine versus Morphine.

Albert Dahan, C. Jan van Dam, Marieke Niesters, Monique van Velzen, Michael J. Fossler, Mark A. Demitrack, Erik Olofsen. Anesthesiology 2020. doi:

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Incidence of Opioid-Induced Respiratory Depression Associated with Oliceridine and Morphine as Measured by the Frequency and Average Cumulative Duration of Dosing Interruption in Patients Treated for Acute Postoperative Pain: Findings indicate improved safety with oliceridine.

Evaluating the Incidence of Opioid-Induced Respiratory Depression Associated with Oliceridine and Morphine as Measured by the Frequency and Average Cumulative Duration of Dosing Interruption in Patients Treated for Acute Postoperative Pain.

Sabry Ayad, Mark A. Demitrack, David A. Burt, Cathy Michalsky, Linda Wase, Michael J. Fossler & Ashish K. Khanna. Clin Drug Investig (2020).

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Oliceridine Monograph

Oliceridine, a G protein-selective ligand at the μ-opioid receptor, for the management of moderate to severe acute pain

Gan TJ & Wase L. Drugs Today (Barc). 2020 Apr;56(4):269-286. doi: 10.1358/dot.2020.56.4.3107707.

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Phase 3 “Real World” Safety Study for Oliceridine

ATHENA: A Phase 3, Open-Label Study Of The Safety And Effectiveness Of Oliceridine (TRV130), A G-Protein Selective Agonist At The μ-Opioid Receptor, In Patients With Moderate To Severe Acute Pain Requiring Parenteral Opioid Therapy

Bergese SD, Brzezinski M, Hammer GB, Beard TL, Pan PH, Mace SE, Berkowitz RD, Cochrane K, Wase L, Minkowitz HS, Habib AS. J Pain Research. 2019, 12: 3113-3126.

DOI: 10.2147/JPR.S217563 [open access]

Pharmacokinetics of IV oliceridine in patients with renal impairment or patients with mild/moderate hepatic impairment- No dose adjustments required

The Influence of Renal or Hepatic Impairment on the Pharmacokinetics, Safety, and Tolerability of Oliceridine

Nafziger AN, Arscott KA, Cochrane K, Skobieranda F, Burt DA, Fossler MJ. Clin Pharmacol Drug Dev. 2019 Nov 7. doi:10.1002/cpdd.750.[open access]

Oliceridine (TRV130) Phase-3 Pivotal trial in soft-tissue (abdominoplasty) acute pain

APOLLO-2: A Randomized, Placebo and Active-Controlled Phase III Study Investigating Oliceridine (TRV130), a G Protein-Biased Ligand at the μ-Opioid Receptor, for Management of Moderate to Severe Acute Pain Following Abdominoplasty

Neil K. Singla, Franck Skobieranda, David G. Soergel, Monica Salamea, David A. Burt, Mark A. Demitrack, Eugene R. Viscusi Pain Pract. 2019 Sep;19(7):715-731

Oliceridine (TRV130) Phase-3 Pivotal trial in hard-tissue (bunionectomy) acute pain

APOLLO-1: a randomized placebo and active-controlled phase III study investigating oliceridine (TRV130), a G protein-biased ligand at the µ-opioid receptor, for management of moderate-to-severe acute pain following bunionectomy

Eugene R Viscusi, Franck Skobieranda, David G Soergel,Emily Cook, David A Burt, and Neil Singla. J Pain Res. 2019; 12: 927–943.

Oliceridine (TRV130) Phase 2b trial in soft-tissue (abdominoplasty) acute pain

A randomized, Phase IIb study investigating oliceridine (TRV130), a novel µ-receptor G-protein pathway selective (μ-GPS) modulator, for the management of moderate to severe acute pain following abdominoplasty

Neil Singla, Harold S Minkowitz, David G Soergel, David A Burt, Ruth Ann Subach, Monica Y Salamea, Michael J Fossler, and Franck Skobieranda. J Pain Res. 2017; 10: 2413–2424

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Oliceridine (TRV130) Phase 2 trial in hard-tissue (bunionectomy) acute pain

A randomized, phase 2 study investigating TRV130, a biased ligand of the μ-opioid receptor, for the intravenous treatment of acute pain.

Viscusi ER, Webster L, Kuss M, Daniels S, Bolognese JA, Zuckerman S, Soergel DG, Subach RA, Cook E, Skobieranda F. Pain. 2016 Jan;157(1):264-72.

TRV130- phase I study in healthy volunteers

Biased agonism of the μ-opioid receptor by TRV130 increases analgesia and reduces on-target adverse effects versus morphine: A randomized, double-blind, placebo-controlled, crossover study in healthy volunteers

Soergel D, Subach RA, Burnham N, Lark MW, James IE, Sadler BM, Skobieranda F, Violin JD, Webster LR. Pain. 2014 Sep;155(9):1829-35

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TRV130 – analgesia and ventilatory response to hypercapnia vs. morphine in healthy volunteers

Biased agonism of the μ-opioid receptor by TRV130 increases analgesia and reduces on-target adverse effects versus morphine: A randomized, double-blind, placebo-controlled, crossover study in healthy volunteers

Soergel DG, Subach RA, Burnham N, et al. Pain. 2014;155(9):1829-1835. doi:10.1016/j.pain.2014.06.011

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TRV130- First clinical experience, pharmacokinetics and pharmacodynamics

First clinical experience with TRV130: pharmacokinetics and pharmacodynamics in healthy volunteers

Soergel DG, Subach RA, Sadler B, Connell J, Marion AS, Cowan CL, Violin JD, Lark MW. J Clin Pharmacol. 2014 Mar;54(3):351-7.

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TRV130-Concept of biased ligand

Structure-activity relationships and discovery of a G protein biased μ opioid receptor ligand, [(3-methoxythiophen-2-yl)methyl]({2-[(9R)-9-(pyridin-2-yl)-6-oxaspiro-[4.5]decan-9-yl]ethyl})amine (TRV130), for the treatment of acute severe pain

Chen XT, Pitis P, Liu G, Yuan C, Gotchev D, Cowan CL, Rominger DH, Koblish M, Dewire SM, Crombie AL, Violin JD, Yamashita DS. J Med Chem. 2013 Oct 24;56(20):8019-31.

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TRV-130 preclinical safety results

A G protein-biased ligand at the μ-opioid receptor is potently analgesic with reduced gastrointestinal and respiratory dysfunction compared with morphine

DeWire SM, Yamashita DS, Rominger DH, Liu G, Cowan CL, Graczyk TM, Chen XT, Pitis PM, Gotchev D, Yuan C, Koblish M, Lark MW, Violin JD. J Pharmacol Exp Ther. 2013 Mar;344(3):708-17.

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Reduced Incidence of Postoperative Vomiting with Oliceridine than with Morphine at Equianalgesic Conditions

Timothy L Beard, Cathy Michalsky, Keith A Candiotti, Paul Rider, Linda Wase, Ashraf S Habib, Mark A Demitrack, Michael J Fossler, Eugene R Viscusi

Annual Meeting of the American Society of Anesthesiologists (ASA); 2020

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Evaluating Predictive Value of Postoperative O2 Saturation Levels to Rate of Respiratory Safety Events In Oliceridine Trials

Sabry Ayad, Ashish K Khanna, Cathy Michalsky, Linda Wase, Mark A Demitrack, Michael J Fossler, Kit N Simpson

Annual Meeting of the American Society of Anesthesiologists (ASA); 2020

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Improved Tolerability with Oliceridine Compared to Morphine at Equianalgesic Conditions

Gregory B Hammer, Cathy Michalsky, Linda Wase, Mark A Demitrack, Roderick Little, Sabry Ayad, Ashish K Khanna, Michael J Fossler

Annual Meeting of the American Society of Anesthesiologists (ASA); 2020

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Improved Safety of Opioid Analgesic Oliceridine Compared to Morphine Assessed by Utility Function Analysis

Albert Dahan, Marieke Niesters, Michael J. Fossler, Mark A. Demitrack, Erik Olofsen.

Annual Meeting of the American Society of Anesthesiologists (ASA); 2019

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Discovery Innovations

Biased ligands at G-protein-coupled receptors: promise and progress

Violin JD, Crombie AL, Soergel DG, Lark MW. Trends Pharmacol Sci. 2014 Jul;35(7):308-16.

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Signalling bias in new drug discovery: detection, quantification and therapeutic impact

Kenakin T, Christopoulos A. Nat Rev Drug Discov. 2013 Mar;12(3):205-16.

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Discovery of β-arrestin-biased dopamine D2 ligands for probing signal transduction pathways essential for antipsychotic efficacy

Allen JA, Yost JM, Setola V, Chen X, Sassano MF, Chen M, Peterson S, Yadav PN, Huang XP, Feng B, Jensen NH, Che X, Bai X, Frye SV, Wetsel WC, Caron MG, Javitch JA, Roth BL, Jin J. Proc Natl Acad Sci U S A. 2011 Nov 8;108(45):18488-93.

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Structural features for functional selectivity at serotonin receptors

Wacker D, Wang C, Katritch V, Han GW, Huang XP, Vardy E, McCorvy JD, Jiang Y, Chu M, Siu FY, Liu W, Xu HE, Cherezov V, Roth BL, Stevens RC. Science. 2013 May 3;340(6132):615-9.

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Quantifying ligand bias at seven-transmembrane receptors

Rajagopal S, Ahn S, Rominger DH, Gowen-MacDonald W, Lam CM, Dewire SM, Violin JD, Lefkowitz RJ. Mol Pharmacol. 2011 Sep;80(3):367-77.

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Beta-arrestin-biased ligands at seven-transmembrane receptors

Violin JD, Lefkowitz RJ. Trends Pharmacol Sci. 2007 Aug;28(8):416-22.

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Beta-arrestins and cell signaling

DeWire SM, Ahn S, Lefkowitz RJ, Shenoy SK. Annu Rev Physiol. 2007;69:483-510.

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Biased ligands: pathway validation for novel GPCR therapeutics

Rominger DH, Cowan CL, Gowen-MacDonald W, Violin JD. Curr Opin Pharmacol. 2014 Jun;16:108-15

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TRV250

TRV250 – Phase 1 Study in Healthy Volunteers

A Phase I, Randomized, Single Blind, Placebo Controlled, Single Ascending Dose Study of the Safety, Tolerability, and Pharmacokinetics of Subcutaneous and Oral TRV250, a G Protein-Selective Delta Receptor Agonist, in Healthy Subjects.

Fossler MJ, Schmith V, Greene SA, et al. CNS Drugs. 2020;34(8):853-865. doi:10.1007/s40263-020-00738-0

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TRV734

A First-in-Human Clinical Study With TRV734, an Orally Bioavailable G-Protein-Biased Ligand at the μ-Opioid Receptor

James IE, Skobieranda F, Soergel DG, Ramos KA, Ruff D, Fossler MJ. Clin Pharmacol Drug Dev. 2019 Jul 8.

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Formulation and Food Effect Studies of TRV734, an Oral, G Protein-biased Ligand of the μ-opioid Receptor

Franck Skobieranda, Ian E. James, Michael J. Fossler, Gregory Alcorn, David G. Soergel.

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An orally available µ-opioid receptor biased ligand is analgesic with reduced constipation in rodents

Jonathan D. Violin, Scott M. DeWire, Mike Koblish, Daniel Chen, Aimee L. Crombie, Dennis Yamashita, Ruth Ann Subach, David G. Soergel, Michael W. Lark.

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TRV027

β-Arrestin-Biased Angiotensin II Receptor Agonists for COVID-19

Manglik A, Wingler LM, Rockman HA, Lefkowitz RJ. Circulation. 15 May 2020.

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TRV045

TRV045, a novel, selective S1PR1 modulator, is efficacious in reversing neuropathic pain without affecting lymphocyte trafficking

Michael S. Kramer, Stefania Risso, Michael J.Fossler, Mark A. Demitrack.

American College of Neuropsychopharmacology 59th Annual Meeting; 2020

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TRV045, a novel, selective S1P1 receptor modulator that is not an immunosuppressant, is efficacious in rodent models of epilepsy

Stefania Risso, Michael S. Kramer, Michael J.Fossler, Mark A. Demitrack

American College of Neuropsychopharmacology 59th Annual Meeting; 2020

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For medical inquiries, please contact Medical Affairs at MedInfo@trevena.com.

IMPORTANT SAFETY INFORMATION

WARNING:  ADDICTION, ABUSE, AND MISUSE; LIFE-THREATENING RESPIRATORY DEPRESSION; NEONATAL OPIOID WITHDRAWAL SYNDROME; and RISKS FROM CONCOMITANT USE WITH BENZODIAZEPINES OR OTHER CENTRAL NERVOUS SYSTEM (CNS) DEPRESSANTS

Addiction, Abuse, and Misuse
OLINVYK exposes patients and other users to the risks of opioid addiction, abuse, and misuse, which can lead to overdose and death. Assess each patient’s risk before prescribing OLINVYK, and monitor all patients regularly for the development of behaviors or conditions.

Life-Threatening Respiratory Depression
Serious, life-threatening, or fatal respiratory depression may occur with use of OLINVYK.  Monitor for respiratory depression, especially during initiation of OLINVYK or following a dose increase.

Neonatal Opioid Withdrawal Syndrome
Prolonged use of OLINVYK during pregnancy can result in neonatal opioid withdrawal syndrome, which may be life-threatening if not recognized and treated, and requires management according to protocols developed by neonatology experts. If opioid use is required for a prolonged period in a pregnant woman, advise the patient of the risk of neonatal opioid withdrawal syndrome and ensure that appropriate treatment will be available.

Risk From Concomitant Use With Benzodiazepines or Other CNS Depressants
Concomitant use of opioids with benzodiazepines or other CNS depressants, including alcohol, may result in profound sedation, respiratory depression, coma, and death. Reserve concomitant prescribing for use in patients for whom alternative treatment options are inadequate; limit dosages and durations to the minimum required; and follow patients for signs and symptoms of respiratory depression and sedation.

INDICATIONS AND USAGE
OLINVYK is a new chemical entity 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, and misuse with opioids, even at recommended doses, reserve OLINVYK for use in patients for whom alternative treatment options [e.g., non-opioid analgesics or opioid combination products]:

  • Have not been tolerated, or are not expected to be tolerated
  • Have not provided adequate analgesia, or are not expected to provide adequate analgesia.

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.

CONTRAINDICATIONS
OLINVYK is contraindicated in patients with:

WARNINGS AND PRECAUTIONS

  • Significant respiratory depression
  • Acute or severe bronchial asthma in an unmonitored setting or in the absence of resuscitative equipment
  • Known or suspected gastrointestinal obstruction, including paralytic ileus
  • Known hypersensitivity to oliceridine (e.g., anaphylaxis)
  • OLINVYK contains oliceridine, a Schedule II controlled substance, that exposes users to the risks of addiction, abuse, and misuse. Although the risk of addiction in any individual is unknown, it can occur in patients appropriately prescribed OLINVYK. Assess risk, counsel, and monitor all patients receiving opioids.
  • Serious, life-threatening respiratory depression has been reported with the use of opioids, even when used as recommended, especially in patients with chronic pulmonary disease, or in elderly, cachectic and debilitated patients. The risk is greatest during initiation of OLINVYK therapy, following a dose increase, or when used with other drugs that depress respiration. Proper dosing of OLINVYK is essential, especially when converting patients from another opioid product to avoid overdose. Management of respiratory depression may include close observation, supportive measures, and use of opioid antagonists, depending on the patient’s clinical status.
  • Opioids can cause sleep-related breathing disorders including central sleep apnea (CSA) and sleep-related hypoxemia with risk increasing in a dose-dependent fashion. In patients who present with CSA, consider decreasing the dose of opioid using best practices for opioid taper.
  • Prolonged use of opioids during pregnancy can result in withdrawal in the neonate that may be life‑threatening. Observe newborns for signs of neonatal opioid withdrawal syndrome and manage accordingly. Advise pregnant women using OLINVYK for a prolonged period of the risk of neonatal opioid withdrawal syndrome and ensure that appropriate treatment will be available.
  • Profound sedation, respiratory depression, coma, and death may result from the concomitant use of OLINVYK with benzodiazepines or other CNS depressants (e.g., non-benzodiazepine sedatives/hypnotics, anxiolytics, tranquilizers, muscle relaxants, general anesthetics, antipsychotics, 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, prescribe the lowest effective dose, and minimize the duration.
  • OLINVYK was shown to have mild QTc interval prolongation in thorough QT studies where patients were dosed up to 27 mg. Total cumulative daily doses exceeding 27 mg per day were not studied and may increase the risk for QTc interval prolongation. Therefore, the cumulative total daily dose of OLINVYK should not exceed 27 mg
  • Increased plasma concentrations of OLINVYK may occur in patients with decreased Cytochrome P450 (CYP) 2D6 function or normal metabolizers taking moderate or strong CYP2D6 inhibitors; also 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, or with discontinuation of a CYP3A4 inducer. These patients may require less frequent dosing and should be closely monitored for respiratory depression and sedation at frequent intervals. Concomitant use of OLINVYK with CYP3A4 inducers or discontinuation of a moderate or strong CYP3A4 inhibitor can lower the expected concentration, which may decrease efficacy, and may require supplemental doses.
  • Cases of adrenal insufficiency have been reported with opioid use (usually greater than one month). Presentation and symptoms may be nonspecific and include nausea, vomiting, anorexia, fatigue, weakness, dizziness, and low blood pressure. If confirmed, treat with physiologic replacement doses of corticosteroids and wean patient from the opioid.
  • 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). Monitor these patients for signs of hypotension. In patients with circulatory shock, avoid the use of OLINVYK as it may cause vasodilation that can further reduce cardiac output and blood pressure.
  • Avoid the use of OLINVYK in patients with impaired consciousness or coma. OLINVYK should be used with caution in patients who may be susceptible to the intracranial effects of CO2 retention, such as those with evidence of increased intracranial pressure or brain tumors, as a reduction in respiratory drive and the resultant CO2 retention can further increase intracranial pressure. Monitor such patients for signs of sedation and respiratory depression, particularly when initiating therapy.
  • As with all opioids, OLINVYK may cause spasm of the sphincter of Oddi, and may cause increases in serum amylase. Monitor patients with biliary tract disease, including acute pancreatitis, for worsening symptoms.
  • 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). Monitor these patients for signs of hypotension. In patients with circulatory shock, avoid the use of OLINVYK as it may cause vasodilation that can further reduce cardiac output and blood pressure.
  • Avoid the use of OLINVYK in patients with impaired consciousness or coma. OLINVYK should be used with caution in patients who may be susceptible to the intracranial effects of CO2 retention, such as those with evidence of increased intracranial pressure or brain tumors, as a reduction in respiratory drive and the resultant CO2 retention can further increase intracranial pressure. Monitor such patients for signs of sedation and respiratory depression, particularly when initiating therapy.
  • As with all opioids, OLINVYK may cause spasm of the sphincter of Oddi, and may cause increases in serum amylase. Monitor patients with biliary tract disease, including acute pancreatitis, for worsening symptoms.
  • 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). Monitor these patients for signs of hypotension. In patients with circulatory shock, avoid the use of OLINVYK as it may cause vasodilation that can further reduce cardiac output and blood pressure.
  • Avoid the use of OLINVYK in patients with impaired consciousness or coma. OLINVYK should be used with caution in patients who may be susceptible to the intracranial effects of CO2 retention, such as those with evidence of increased intracranial pressure or brain tumors, as a reduction in respiratory drive and the resultant CO2 retention can further increase intracranial pressure. Monitor such patients for signs of sedation and respiratory depression, particularly when initiating therapy.
  • As with all opioids, OLINVYK may cause spasm of the sphincter of Oddi, and may cause increases in serum amylase. Monitor patients with biliary tract disease, including acute pancreatitis, for worsening symptoms.
  • OLINVYK may increase the frequency of seizures in patients with seizure disorders and may increase the risk of seizures in vulnerable patients. Monitor patients with a history of seizure disorders for worsened seizure control.
  • Do not abruptly discontinue OLINVYK in a patient physically dependent on opioids. Gradually taper the dosage to avoid a withdrawal syndrome and return of pain. 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 OLINVYK, as they may reduce the analgesic effect and/or precipitate withdrawal symptoms.
  • OLINVYK may impair the mental or physical abilities needed to perform potentially hazardous activities such as driving a car or operating machinery.
  • Although self-administration of opioids by patient-controlled analgesia (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.

ADVERSE REACTIONS
Adverse reactions are described in greater detail in the Prescribing Information.
The most common (incidence ≥10%) adverse reactions in Phase 3 controlled clinical trials were nausea, vomiting, dizziness, headache, constipation, pruritus, and hypoxia.

MEDICAL INFORMATION
For medical inquiries or to report an adverse event, other safety-related information or product complaints for a company product, please contact the Trevena Medical Information Contact Center at 1-844-465-4686 or email MedInfo@Trevena.com.

You are encouraged to report negative side effects of prescription drugs to the FDA. Visit www.fda.gov/medwatch or call 1-800-FDA-1088. Please see Full Prescribing Information, including Boxed Warning.