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adverse reactions
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.