Version May 2024
The FDA has issued a drug safety communication to announce safety-related updates to the prescribing information for immediate-release (IR) and extended-release (ER)/long-acting (LA) opioid analgesics, including updates to Boxed Warnings, Indications and Usage, Dosage and Administration, Warnings and Precautions, and the Medication Guide. These safety labeling changes are intended to provide clarity on appropriate patient populations for opioid treatment, appropriate dosage and administration, and updated information on the risks associated with opioid use. The required safety labeling changes include stating:
the risk of overdose increases as the dosage increases for all opioid pain medicines;
IR opioids should not be used for an extended period of time unless a patient's pain remains severe enough to require them and alternative treatment options continue to be inadequate;
many acute pain conditions treated in the outpatient setting require no more than a few days of an opioid pain medicine;
it is recommended to reserve ER/LA opioid pain medicines for severe and persistent pain that requires an extended treatment period with a daily opioid pain medicine and for which alternative treatment options are inadequate; and
a warning about opioid-induced hyperalgesia (OIH), including information on differentiating OIH symptoms from those of opioid tolerance and withdrawal.
Further information may be found at https://www.fda.gov/drugs/drug-safety-and-availability/fda-updates-prescribing-information-all-opioid-pain-medicines-provide-additional-guidance-safe-use.
Because the use of oliceridine 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 prior to prescribing and reassess all patients regularly for the development of these behaviors and conditions.
Serious, life-threatening, or fatal respiratory depression may occur with use of oliceridine, especially during initiation or following a dosage increase. To reduce the risk of respiratory depression, proper dosing and titration of oliceridine are essential.
If opioid use is required for an extended period in a pregnant woman, advise the patient of the risk of neonatal opioid withdrawal syndrome (NOWS), which may be life-threatening if not recognized and treated. Ensure that management by neonatology experts will be available at delivery.
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 of oliceridine and benzodiazepines or other CNS depressants for use in patients for whom alternative treatment options are inadequate.
Dosage guidance:
Dosing: Dosing provided is based on typical doses; some patients may require higher or lower doses. Dosing should be individualized based on patient-specific factors (eg, comorbidities, severity of pain, degree of opioid experience/tolerance) and titrated to patient-specific treatment goals (eg, improvement in function and quality of life, decrease in pain using a validated pain rating scale). Use the lowest effective dose for the shortest period of time.
Clinical considerations: Opioids may be part of a comprehensive, multimodal, patient-specific treatment plan for managing moderate to severe pain. Maximize nonopioid analgesia (when appropriate) prior to initiation of opioid analgesia (Ref).
Pain management, acute:
Note: Administration beyond 48 hours has not been studied. An alternative analgesic may be administered if patient reaches total daily cumulative dose and analgesia is still required. The 30 mg per 30 mL vial is for patient-controlled analgesia use only.
IV:
Intermittent bolus dosing: Initial: 1.5 mg; a supplemental dose of 0.75 mg may be administered 1 hour after initial dose; subsequent supplemental doses may be repeated no more frequently than hourly and titrated based on tolerability and response; maximum single supplemental dose: 3 mg. Maximum total cumulative daily dose: 27 mg.
Patient-controlled analgesia:
Initial dose (administered by health care provider): 1.5 mg.
Demand dose: Range: 0.35 to 0.5 mg.
Lockout interval: 6 minutes.
Supplemental dose (administered by health care provider): 0.75 mg; may be administered beginning 1 hour after the initial dose and repeated hourly as needed; may be used in addition to the demand dose if needed for adequate analgesia.
Maximum total cumulative daily dose: 27 mg.
Conversion between morphine injection and oliceridine: An initial dose of oliceridine 1 mg is approximately equipotent to morphine 5 mg.
Discontinuation of therapy: When reducing the dose, discontinuing, or tapering long-term opioid therapy, the dose should be gradually tapered. An optimal tapering schedule has not been established. Individualize tapering based on discussions with patient to minimize withdrawal, while considering patient-specific goals and concerns and the opioid's pharmacokinetics. Proposed initial schedules range from slow (eg, 10% reduction per week or 10% reduction per month depending on duration of long-term therapy) to rapid (eg, 25% to 50% reduction every few days) (CDC 2015; CDC [Dowell 2022]). Slower tapers may be appropriate after long-term use (eg, >1 year), whereas more rapid tapers may be appropriate in patients experiencing severe adverse effects. During tapering, patients may be at an increased risk of overdose if they return to their original (or higher) opioid dose or use illicit opioids, due to rapid loss of tolerance; consider prescribing naloxone. Monitor carefully for signs/symptoms of withdrawal. If the patient displays withdrawal symptoms, consider slowing the taper schedule; alterations may include increasing the interval between dose reductions, decreasing amount of daily dose reduction, pausing the taper and restarting when the patient is ready, and/or coadministration of an alpha-2 agonist (eg, clonidine) to blunt autonomic withdrawal symptoms and other adjunctive agents to treat GI symptoms and muscle spasms, as needed. Continue to offer nonopioid analgesics as needed for pain management during the taper (CDC [Dowell 2022]).
Dosage adjustment for concomitant therapy: Significant drug interactions exist, requiring dose/frequency adjustment or avoidance. Consult drug interactions database for more information.
No dosage adjustment necessary.
Mild to moderate impairment: No dosage adjustment necessary; may require less frequent dosing.
Severe impairment: There are no specific dosage adjustments provided in the manufacturer's labeling; use with caution; an initial dosage reduction is recommended.
Note: Minimize opioid use in older adults unless for the management of severe acute pain. Opioids are associated with an increased risk of falls and inducing or worsening delirium in older adults (Beers Criteria [AGS 2023]).
Refer to adult dosing. Use with caution; may require reduced dosage; titrate slowly.
Opioids, including oliceridine, cause dizziness and CNS depression, which may result in significant drowsiness and a sedated state.
Mechanism: Dose-related; related to the pharmacologic action of the drug (ie, G protein-selective agonist at mu opioid receptors within the CNS).
Risk factors:
• High dosage (Ref)
• Duration of therapy
• Coadministration with benzodiazepines or other CNS depressants (eg, nonbenzodiazepine sedatives/hypnotics, anxiolytics, tranquilizers, muscle relaxants, general anesthetics, antipsychotics, other opioids, alcohol)
Oliceridine use results in nausea, vomiting, and constipation.
Mechanism: Opioids decrease gastric emptying and stimulate pyloric tone, resulting in nausea and vomiting. Opioid-induced constipation is caused by decreased GI motility and increased fluid absorption in the small and large intestine (Ref). Oliceridine, a G protein-selective agonist at the mu-opioid receptor, has less activation of the beta-arrestin pathway compared to nonselective mu receptor agonists (eg, morphine) which activate both G protein and beta-arrestin pathways; reduced beta-arrestin pathway activation by oliceridine is hypothesized to result in a decreased incidence of GI-related adverse effects compared to nonselective opioids (Ref).
Oliceridine may cause severe hypotension, including orthostatic hypotension and syncope, especially during initiation of therapy or following a dosage increase.
Mechanism: Opioids produce peripheral vasodilation, which may result in orthostatic hypotension or syncope.
Risk factors:
• Hypovolemia
• Coadministration with medications that may exaggerate hypotensive effects (including phenothiazines or general anesthetics)
Oliceridine may increase the risk for prolonged QT interval on ECG with total cumulative daily doses >27 mg, which is dosing that exceeds the maximum recommended dose. In a single dose (using a supratherapeutic dose) and multiple-dose studies (using a maximum daily cumulative dose of 27 mg) in healthy volunteers, a transient QTc change has been observed, although the clinical significance is unknown. In one open label trial, not adequately powered to assess safety, QT prolongation was observed in a few patients; however, patients were allowed to receive concomitant medications known to increase the QT interval (Ref). In a clinical trial evaluating the efficacy and safety of oliceridine, a clinically meaningful change in the QTc interval was not observed; those with a QTcF interval, at screening, of >450 ms in males and >470 ms in females were excluded (Ref). According to an FDA advisory committee briefing document, no meaningful differences in the incidence of potentially clinically significant ECG results were observed for any of the oliceridine groups in controlled phase 3 studies, suggesting that oliceridine does not present a clinically meaningful risk on the cardiac safety of patients when used under the recommended use and dosing (Ref).
Mechanism: Dose-related (observed in a single-dose study using a supratherapeutic dose); per the manufacturer's labeling, the underlying mechanism (and clinical significance) of the transient QT changes observed is unknown.
Onset: According to the manufacturer's labeling, in a multiple-dose study using a maximum daily cumulative dose of 27 mg in healthy volunteers, the maximum mean double delta QTc interval was 11.7 ms at 9 hours. Thereafter, the QTc effect did not progressively increase with repeat dosing, and despite continued dosing began to diminish after 12 hours.
Life-threatening or fatal respiratory depression has occurred with opioids, including oliceridine. Carbon dioxide retention from opioid-induced respiratory depression can exacerbate the sedating effects of opioids. Oliceridine can also cause hypoxia and sleep-related breathing disorders, including central sleep apnea (CSA).
Mechanism:
• Respiratory depression: Opioids produce respiratory depression by direct action on brain stem respiratory centers, reducing the responsiveness of the brain stem respiratory centers to both increases in carbon dioxide tension and electrical stimulation.
• CSA: Dose-related; related to the pharmacologic action of the drug. Oliceridine, a G protein-selective agonist at the mu-opioid receptor, has less activation of the beta-arrestin pathway compared to nonselective mu receptor agonists (eg, morphine) which activate both G protein and beta-arrestin pathways; reduced beta-arrestin pathway activation by oliceridine is hypothesized to result in a decreased respiratory depression compared to nonselective opioids (Ref).
Risk factors:
• Initiation of therapy or following a dose increase
• Older age
• Cachexia
• Debilitation
• Chronic pulmonary disease or cor pulmonale; substantially decreased respiratory reserve, hypoxia, hypercapnia; or preexisting respiratory depression
• CYP2D6 poor metabolizers
• Coadministration with benzodiazepines or other CNS depressants (eg, nonbenzodiazepine sedatives/hypnotics, anxiolytics, tranquilizers, muscle relaxants, general anesthetics, antipsychotics, other opioids, alcohol)
• Coadministration with a moderate or strong CYP3A4 inhibitor
Physical dependence, manifesting as a withdrawal syndrome, has been observed after abrupt discontinuation of opioids.
Mechanism: Withdrawal; autonomic hyperexcitability in the absence of opioid agonist suppressive effects (Ref).
Risk factors:
• Abrupt discontinuation in physically dependent patients
• Coadministration of drugs with opioid antagonist activity (eg, naloxone); mixed agonist/antagonist analgesics (eg, pentazocine, butorphanol, nalbuphine); or partial agonists (eg, buprenorphine)
The following adverse drug reactions and incidences are derived from product labeling unless otherwise specified. Adverse reactions reported in adults.
>10%:
Dermatologic: Pruritus (11% to 17%)
Gastrointestinal: Constipation (11% to 17%) (table 1), nausea (56% to 75%) (table 2), vomiting (22% to 43%) (table 3)
|
Drug (Oliceridine) |
Placebo |
Dose |
Indication |
Number of Patients (Oliceridine) |
Number of Patients (Placebo) |
|---|---|---|---|---|---|
|
17% |
7% |
0.35 mg |
Abdominoplasty |
79 |
79 |
|
11% |
7% |
0.5 mg |
Abdominoplasty |
79 |
79 |
|
14% |
11% |
0.5 mg |
Bunionectomy |
79 |
79 |
|
11% |
11% |
0.35 mg |
Bunionectomy |
79 |
79 |
|
Drug (Oliceridine) |
Placebo |
Dose |
Indication |
Number of Patients (Oliceridine) |
Number of Patients (Placebo) |
|---|---|---|---|---|---|
|
75% |
46% |
0.5 mg |
Abdominoplasty |
79 |
79 |
|
62% |
46% |
0.35 mg |
Abdominoplasty |
79 |
79 |
|
63% |
24% |
0.5 mg |
Bunionectomy |
79 |
79 |
|
56% |
24% |
0.35 mg |
Bunionectomy |
79 |
79 |
|
Drug (Oliceridine) |
Placebo |
Dose |
Indication |
Number of Patients (Oliceridine) |
Number of Patients (Placebo) |
|---|---|---|---|---|---|
|
43% |
13% |
0.5 mg |
Abdominoplasty |
79 |
79 |
|
22% |
13% |
0.35 mg |
Abdominoplasty |
79 |
79 |
|
41% |
6% |
0.5 mg |
Bunionectomy |
79 |
79 |
|
39% |
6% |
0.35 mg |
Bunionectomy |
79 |
79 |
Nervous system: Dizziness (9% to 35%) (table 4), drowsiness (≤19%) (table 5), sedated state (4% to 14%) (table 6)
|
Drug (Oliceridine) |
Placebo |
Dose |
Indication |
Number of Patients (Oliceridine) |
Number of Patients (Placebo) |
|---|---|---|---|---|---|
|
9% |
11% |
0.5 mg |
Abdominoplasty |
79 |
79 |
|
9% |
11% |
0.35 mg |
Abdominoplasty |
79 |
79 |
|
35% |
10% |
0.5 mg |
Bunionectomy |
79 |
79 |
|
32% |
10% |
0.35 mg |
Bunionectomy |
79 |
79 |
|
Drug (Oliceridine) |
Placebo |
Dose |
Indication |
Number of Patients (Oliceridine) |
Number of Patients (Placebo) |
|---|---|---|---|---|---|
|
5% |
1% |
0.5 mg |
Abdominoplasty |
79 |
79 |
|
0% |
1% |
0.35 mg |
Abdominoplasty |
79 |
79 |
|
19% |
6% |
0.35 mg |
Bunionectomy |
79 |
79 |
|
13% |
6% |
0.5 mg |
Bunionectomy |
79 |
79 |
|
Drug (Oliceridine) |
Placebo |
Dose |
Indication |
Number of Patients (Oliceridine) |
Number of Patients (Placebo) |
|---|---|---|---|---|---|
|
14% |
8% |
0.35 mg |
Abdominoplasty |
79 |
79 |
|
9% |
8% |
0.5 mg |
Abdominoplasty |
79 |
79 |
|
5% |
1% |
0.35 mg |
Bunionectomy |
79 |
79 |
|
4% |
1% |
0.5 mg |
Bunionectomy |
79 |
79 |
Neuromuscular & skeletal: Back pain (11% to 13%)
Respiratory: Hypoxia (5% to 20%) (table 7)
|
Drug (Oliceridine) |
Placebo |
Dose |
Indication |
Number of Patients (Oliceridine) |
Number of Patients (Placebo) |
|---|---|---|---|---|---|
|
20% |
5% |
0.35 mg |
Abdominoplasty |
79 |
79 |
|
18% |
5% |
0.5 mg |
Abdominoplasty |
79 |
79 |
|
9% |
0% |
0.5 mg |
Bunionectomy |
79 |
79 |
|
5% |
0% |
0.35 mg |
Bunionectomy |
79 |
79 |
1% to 10%:
Cardiovascular: Flushing, hypotension, increased blood pressure, oxygen saturation decreased (4% to 5%), tachycardia
Dermatologic: Hyperhidrosis, skin rash
Endocrine & metabolic: Hot flash, hypocalcemia, hypokalemia, hypomagnesemia, hypophosphatemia
Gastrointestinal: Diarrhea, dyspepsia, flatulence, xerostomia
Hematologic & oncologic: Anemia
Hepatic: Increased serum alanine aminotransferase
Nervous system: Anxiety, headache, insomnia, restlessness
Neuromuscular & skeletal: Muscle spasm
Respiratory: Cough, dyspnea
Miscellaneous: Fever
Frequency not defined:
Dermatologic: Urticaria
Hepatic: Increased serum aspartate aminotransferase
Nervous system: Drug abuse, opioid dependence, neonatal withdrawal
Respiratory: Hypoventilation, respiratory depression
Postmarketing:
Cardiovascular: Prolonged QT interval on ECG (Bergese 2019)
Nervous system: Allodynia (opioid-induced hyperalgesia) (FDA Safety Communication 2023)
Hypersensitivity (eg, anaphylaxis) to oliceridine or any component of the formulation; significant respiratory depression; acute or severe bronchial asthma in an unmonitored setting or in the absence of resuscitative equipment; known or suspected GI obstruction, including paralytic ileus.
Concerns related to adverse effects:
• CNS depression: May cause CNS depression, which may impair physical or mental abilities; patients must be cautioned about performing tasks that require mental alertness (eg, operating machinery, driving).
• Constipation: May cause constipation; consider preventive measures to reduce the potential for constipation.
• Hyperalgesia: Opioid-induced hyperalgesia (OIH) has occurred with short-term and prolonged use of opioid analgesics. Symptoms may include increased levels of pain upon opioid dosage increase, decreased levels of pain upon opioid dosage decrease, or pain from ordinarily nonpainful stimuli; symptoms may be suggestive of OIH if there is no evidence of underlying disease progression, opioid tolerance, opioid withdrawal, or addictive behavior. Consider decreasing the current opioid dose or opioid rotation in patients who experience OIH.
• Hypotension: May cause severe hypotension (including orthostatic hypotension and syncope); use with caution in patients with hypovolemia, cardiovascular disease (including acute myocardial infarction), or drugs that may exaggerate hypotensive effects (including phenothiazines or general anesthetics). Monitor for symptoms of hypotension following initiation or dose titration. Avoid use in patients with circulatory shock.
• Respiratory depression: Fatal respiratory depression may occur. Carbon dioxide retention from opioid-induced respiratory depression can exacerbate the sedating effects of opioids. Patients and caregivers should be educated on how to recognize respiratory depression and the importance of getting emergency assistance immediately (eg, calling 911) in the event of known or suspected overdose.
• QT prolongation: May increase risk for QT interval prolongation; use with caution in patients with conditions that may increase the risk of QT prolongation or in patients receiving medications known to prolong the QT interval. Do not exceed a cumulative oliceridine daily dose of 27 mg.
Disease-related concerns:
• Abdominal conditions: May obscure diagnosis or clinical course of patients with acute abdominal conditions.
• Adrenocortical insufficiency: Use with caution in patients with adrenal insufficiency, including Addison disease. Long-term opioid use may cause secondary hypogonadism, which may lead to mood disorders and osteoporosis (Brennan 2013).
• Biliary tract impairment: Use with caution in patients with biliary tract dysfunction, including acute pancreatitis; opioids may cause constriction of sphincter of Oddi.
• CNS depression/coma: Avoid use in patients with impaired consciousness or coma, as these patients are susceptible to intracranial effects of CO2 retention.
• Delirium tremens: Use with caution in patients with delirium tremens.
• Head trauma: Use with extreme caution in patients with head injury, intracranial lesions, or elevated intracranial pressure (ICP); exaggerated elevation of ICP may occur.
• Hepatic impairment: Use with caution in patients with severe hepatic impairment; an initial dosage reduction is recommended.
• Mental health conditions: Use opioids with caution for chronic pain in patients with mental health conditions (eg, depression, anxiety disorders, post-traumatic stress disorder) due to potential increased risk for opioid use disorder and overdose; more frequent monitoring is recommended (CDC [Dowell 2022]).
• Obesity: Use with caution in patients who are morbidly obese.
• Prostatic hyperplasia/urinary stricture: Use with caution in patients with prostatic hyperplasia and/or urinary stricture.
• Psychosis: Use with caution in patients with toxic psychosis.
• Respiratory disease: Use with caution and monitor for respiratory depression in patients with significant chronic obstructive pulmonary disease or cor pulmonale and those with a substantially decreased respiratory reserve, hypoxia, hypercapnia, or preexisting respiratory depression, particularly when initiating and titrating therapy; critical respiratory depression may occur, even at therapeutic dosages. Consider the use of alternative nonopioid analgesics in these patients.
• Seizures: Use with caution in patients with a history of seizure disorders; may cause or exacerbate preexisting seizures.
• Sleep-related disorders: Use with caution in patients with sleep-related disorders, including sleep apnea, due to increased risk for respiratory and CNS depression. Monitor carefully and titrate dosage cautiously in patients with mild sleep-disordered breathing. Avoid opioids in patients with moderate to severe sleep-disordered breathing (CDC [Dowell 2022]).
• Thyroid dysfunction: Use with caution in patients with thyroid dysfunction.
Concurrent drug therapy issues:
• Benzodiazepines or other CNS depressants: Concomitant use may result in respiratory depression and sedation, which may be fatal. Consider prescribing naloxone for emergency treatment of opioid overdose in patients taking benzodiazepines or other CNS depressants concomitantly with opioids.
Special populations:
• Cachectic or debilitated patients: Use with caution in cachectic or debilitated patients; there is a greater potential for critical respiratory depression, even at therapeutic dosages. Consider the use of alternative nonopioid analgesics in these patients.
• CYP2D6 poor metabolizers: Less frequent dosing may be needed in known or suspected poor CYP2D6 metabolizers; monitor closely.
• Older adult: Use opioids with caution in older adults; may be more sensitive to adverse effects. Clearance may also be reduced in older adults (with or without renal impairment) resulting in a narrow therapeutic window and increased adverse effects. Monitor closely for adverse effects associated with opioid therapy (eg, respiratory and CNS depression, falls, cognitive impairment, constipation) (CDC [Dowell 2022]). Consider the use of alternative nonopioid analgesics in these patients when possible.
• Neonates: Neonatal withdrawal syndrome: Signs and symptoms include irritability, hyperactivity and abnormal sleep pattern, high-pitched cry, tremor, vomiting, diarrhea, and failure to gain weight. Onset, duration, and severity depend on the drug used, duration of use, maternal dose, and rate of drug elimination by the newborn.
Other warnings/precautions:
• Abrupt discontinuation/withdrawal: Abrupt discontinuation in patients who are physically dependent on opioids has been associated with serious withdrawal symptoms, uncontrolled pain, attempts to find other opioids (including illicit), and suicide. Use a collaborative, patient-specific taper schedule that minimizes the risk of withdrawal, considering factors such as current opioid dose, duration of use, type of pain, and physical and psychological factors. Monitor pain control, withdrawal symptoms, mood changes, suicidal ideation, and for use of other substances and provide care as needed. Concurrent use of mixed agonist/antagonist analgesics (eg, pentazocine, nalbuphine, butorphanol) or partial-agonist (eg, buprenorphine) analgesics may also precipitate withdrawal symptoms and/or reduced analgesic efficacy in patients following prolonged therapy with mu opioid agonists.
• Abuse/misuse/diversion: Use with caution in patients with a history of substance abuse disorder; potential for drug dependency exists. Other factors associated with increased risk for misuse include concomitant depression or other mental health conditions, higher opioid dosages, or taking other CNS depressants. Consider offering naloxone prescriptions in patients with an increased risk for overdose, such as history of overdose or substance use disorder, higher opioid dosages (≥50 morphine milligram equivalents [MME]/day orally), concomitant benzodiazepine use, and patients at risk for returning to a high dose after losing tolerance (CDC [Dowell 2022]).
• Naloxone access: Discuss the availability of naloxone with all patients who are prescribed opioid analgesics, as well as their caregivers, and consider prescribing it to patients who are at increased risk of opioid overdose. These include patients who are also taking benzodiazepines or other CNS depressants, have an opioid use disorder (OUD) (current or history of), or have experienced opioid-induced respiratory depression/opioid overdose. Additionally, health care providers should consider prescribing naloxone to patients prescribed medications to treat OUD; patients at risk of opioid overdose even if they are not taking an opioid analgesic or medication to treat OUD; and patients taking opioids, including methadone or buprenorphine for OUD, if they have household members, including children, or other close contacts at risk for accidental ingestion or opioid overdose. Inform patients and caregivers on options for obtaining naloxone (eg, by prescription, directly from a pharmacist, a community-based program) as permitted by state dispensing and prescribing guidelines. Educate patients and caregivers on how to recognize respiratory depression, proper administration of naloxone, and getting emergency help (FDA 2020).
• Optimal regimen: An opioid-containing analgesic regimen should be tailored to each patient's needs and based upon the type of pain being treated (acute versus chronic), the route of administration, degree of tolerance for opioids (naive versus chronic user), age, weight, and medical condition. The optimal analgesic dose varies widely among patients; doses should be titrated to pain relief/prevention.
• Surgery: Opioids decrease bowel motility; monitor for decreased bowel motility in post-operative patients receiving opioids. Use with caution in the perioperative setting; individualize treatment when transitioning from parenteral to oral analgesics.
Excipient information presented when available (limited, particularly for generics); consult specific product labeling.
Solution, Intravenous, as fumarate [preservative free]:
Olinvyk: 1 mg/mL (1 mL); 2 mg/2 mL (2 mL); 30 mg/30 mL (30 mL)
No
Solution (Olinvyk Intravenous)
1 mg/mL (per mL): $21.00
2 mg/2 mL (per mL): $15.45
30 mg/30 mL (per mL): $4.40
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C-II
IV: For IV administration only; no dilution necessary. Administration beyond 48 hours has not been studied. The 1 mg per 1 mL and 2 mg per 2 mL single-dose vials should be used for intermittent bolus dosing (ie, health care provider administered initial and supplemental doses). The 30 mg per 30 mL vial is for patient-controlled analgesia use only.
Pain management: 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 substance use disorder, abuse, and misuse with opioids, which may occur at any dosage or duration, reserve oliceridine for use in patients for whom alternative treatment options (eg, 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 >27 mg may increase the risk for QTc interval prolongation.
The Institute for Safe Medication Practices (ISMP) includes this medication among its list of drug classes that have a heightened risk of causing significant patient harm when used in error.
Substrate of CYP2C19 (minor), CYP2C9 (minor), CYP2D6 (major), CYP3A4 (major); Note: Assignment of Major/Minor substrate status based on clinically relevant drug interaction potential
Note: Interacting drugs may not be individually listed below if they are part of a group interaction (eg, individual drugs within “CYP3A4 Inducers [Strong]” are NOT listed). For a complete list of drug interactions by individual drug name and detailed management recommendations, use the Lexicomp drug interactions program by clicking on the “Launch drug interactions program” link above.
Ajmaline: May increase the serum concentration of CYP2D6 Substrates (High risk with Inhibitors). Risk C: Monitor therapy
Alizapride: May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy
Alvimopan: Opioid Agonists may enhance the adverse/toxic effect of Alvimopan. This is most notable for patients receiving long-term (i.e., more than 7 days) opiates prior to alvimopan initiation. Management: Alvimopan is contraindicated in patients receiving therapeutic doses of opioids for more than 7 consecutive days immediately prior to alvimopan initiation. Risk D: Consider therapy modification
Amphetamines: May enhance the analgesic effect of Opioid Agonists. Risk C: Monitor therapy
Anticholinergic Agents: May enhance the adverse/toxic effect of Opioid Agonists. Specifically, the risk for constipation and urinary retention may be increased with this combination. Risk C: Monitor therapy
Artemether and Lumefantrine: May increase the serum concentration of CYP2D6 Substrates (High risk with Inhibitors). Risk C: Monitor therapy
Azelastine (Nasal): May enhance the CNS depressant effect of CNS Depressants. Risk X: Avoid combination
Blonanserin: CNS Depressants may enhance the CNS depressant effect of Blonanserin. Management: Use caution if coadministering blonanserin and CNS depressants; dose reduction of the other CNS depressant may be required. Strong CNS depressants should not be coadministered with blonanserin. Risk D: Consider therapy modification
Brimonidine (Topical): May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy
Bromopride: May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy
Bromperidol: May enhance the CNS depressant effect of CNS Depressants. Risk X: Avoid combination
Cannabinoid-Containing Products: CNS Depressants may enhance the CNS depressant effect of Cannabinoid-Containing Products. Risk C: Monitor therapy
Chlormethiazole: May enhance the CNS depressant effect of CNS Depressants. Management: Monitor closely for evidence of excessive CNS depression. The chlormethiazole labeling states that an appropriately reduced dose should be used if such a combination must be used. Risk D: Consider therapy modification
Chlorphenesin Carbamate: May enhance the adverse/toxic effect of CNS Depressants. Risk C: Monitor therapy
Clofazimine: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Risk C: Monitor therapy
CNS Depressants: May enhance the CNS depressant effect of Opioid Agonists. Management: Avoid concomitant use of opioid agonists and benzodiazepines or other CNS depressants when possible. These agents should only be combined if alternative treatment options are inadequate. If combined, limit the dosages and duration of each drug. Risk D: Consider therapy modification
CYP2D6 Inhibitors (Moderate): May increase the serum concentration of Oliceridine. Risk C: Monitor therapy
CYP2D6 Inhibitors (Strong): May increase the serum concentration of Oliceridine. Risk C: Monitor therapy
CYP3A4 Inducers (Moderate): May decrease the serum concentration of Oliceridine. Risk C: Monitor therapy
CYP3A4 Inducers (Strong): May decrease the serum concentration of Oliceridine. Risk C: Monitor therapy
CYP3A4 Inhibitors (Moderate): May increase the serum concentration of Oliceridine. Risk C: Monitor therapy
CYP3A4 Inhibitors (Strong): May increase the serum concentration of Oliceridine. Risk C: Monitor therapy
Daridorexant: May enhance the CNS depressant effect of CNS Depressants. Management: Dose reduction of daridorexant and/or any other CNS depressant may be necessary. Use of daridorexant with alcohol is not recommended, and the use of daridorexant with any other drug to treat insomnia is not recommended. Risk D: Consider therapy modification
Desmopressin: Opioid Agonists may enhance the hyponatremic effect of Desmopressin. Risk C: Monitor therapy
DexmedeTOMIDine: CNS Depressants may enhance the CNS depressant effect of DexmedeTOMIDine. Management: Monitor for increased CNS depression during coadministration of dexmedetomidine and CNS depressants, and consider dose reductions of either agent to avoid excessive CNS depression. Risk D: Consider therapy modification
Difelikefalin: May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy
Dimethindene (Topical): May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy
Diuretics: Opioid Agonists may enhance the adverse/toxic effect of Diuretics. Opioid Agonists may diminish the therapeutic effect of Diuretics. Risk C: Monitor therapy
DroPERidol: May enhance the CNS depressant effect of CNS Depressants. Management: Consider dose reductions of droperidol or of other CNS agents (eg, opioids, barbiturates) with concomitant use. Risk D: Consider therapy modification
Eluxadoline: Opioid Agonists may enhance the constipating effect of Eluxadoline. Risk X: Avoid combination
Fexinidazole: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Risk X: Avoid combination
Flunarizine: CNS Depressants may enhance the CNS depressant effect of Flunarizine. Risk X: Avoid combination
Flunitrazepam: CNS Depressants may enhance the CNS depressant effect of Flunitrazepam. Management: Reduce the dose of CNS depressants when combined with flunitrazepam and monitor patients for evidence of CNS depression (eg, sedation, respiratory depression). Use non-CNS depressant alternatives when available. Risk D: Consider therapy modification
Fusidic Acid (Systemic): May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Risk X: Avoid combination
Gastrointestinal Agents (Prokinetic): Opioid Agonists may diminish the therapeutic effect of Gastrointestinal Agents (Prokinetic). Risk C: Monitor therapy
HydrOXYzine: May enhance the CNS depressant effect of CNS Depressants. Management: Consider a decrease in the CNS depressant dose, as appropriate, when used together with hydroxyzine. Increase monitoring of signs/symptoms of CNS depression in any patient receiving hydroxyzine together with another CNS depressant. Risk D: Consider therapy modification
Ixabepilone: May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy
Kava Kava: May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy
Kratom: May enhance the CNS depressant effect of CNS Depressants. Risk X: Avoid combination
Lemborexant: May enhance the CNS depressant effect of CNS Depressants. Management: Dosage adjustments of lemborexant and of concomitant CNS depressants may be necessary when administered together because of potentially additive CNS depressant effects. Close monitoring for CNS depressant effects is necessary. Risk D: Consider therapy modification
Lisuride: May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy
Lofexidine: May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy
Magnesium Sulfate: May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy
Methotrimeprazine: CNS Depressants may enhance the CNS depressant effect of Methotrimeprazine. Methotrimeprazine may enhance the CNS depressant effect of CNS Depressants. Management: Reduce the usual dose of CNS depressants by 50% if starting methotrimeprazine until the dose of methotrimeprazine is stable. Monitor patient closely for evidence of CNS depression. Risk D: Consider therapy modification
Metoclopramide: May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy
MetyroSINE: CNS Depressants may enhance the sedative effect of MetyroSINE. Risk C: Monitor therapy
Minocycline (Systemic): May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy
Monoamine Oxidase Inhibitors: Opioid Agonists may enhance the serotonergic effect of Monoamine Oxidase Inhibitors. This could result in serotonin syndrome. Management: Monitor for signs and symptoms of serotonin syndrome/serotonin toxicity (eg, hyperreflexia, clonus, hyperthermia, diaphoresis, tremor, autonomic instability, mental status changes) when these agents are combined. Risk C: Monitor therapy
Nabilone: May enhance the CNS depressant effect of CNS Depressants. Risk X: Avoid combination
Nalfurafine: Opioid Agonists may enhance the adverse/toxic effect of Nalfurafine. Opioid Agonists may diminish the therapeutic effect of Nalfurafine. Risk C: Monitor therapy
Nalmefene: May diminish the therapeutic effect of Opioid Agonists. Management: Avoid the concomitant use of oral nalmefene and opioid agonists. Discontinue oral nalmefene 1 week prior to any anticipated use of opioid agonists. If combined, larger doses of opioid agonists will likely be required. Risk D: Consider therapy modification
Naltrexone: May diminish the therapeutic effect of Opioid Agonists. Management: Seek therapeutic alternatives to opioids. See full drug interaction monograph for detailed recommendations. Risk X: Avoid combination
Nefazodone: Opioid Agonists (metabolized by CYP3A4 and CYP2D6) may enhance the serotonergic effect of Nefazodone. This could result in serotonin syndrome. Nefazodone may increase the serum concentration of Opioid Agonists (metabolized by CYP3A4 and CYP2D6). Management: Monitor for increased opioid effects, including fatal respiratory depression, when these agents are combined and consider opioid dose reductions until stable drug effects are achieved. Additionally, monitor for serotonin syndrome/serotonin toxicity. Risk C: Monitor therapy
Olopatadine (Nasal): May enhance the CNS depressant effect of CNS Depressants. Risk X: Avoid combination
Opioid Agonists: CNS Depressants may enhance the CNS depressant effect of Opioid Agonists. Management: Avoid concomitant use of opioid agonists and benzodiazepines or other CNS depressants when possible. These agents should only be combined if alternative treatment options are inadequate. If combined, limit the dosages and duration of each drug. Risk D: Consider therapy modification
Opioids (Mixed Agonist / Antagonist): May diminish the analgesic effect of Opioid Agonists. Management: Seek alternatives to mixed agonist/antagonist opioids in patients receiving pure opioid agonists, and monitor for symptoms of therapeutic failure/high dose requirements (or withdrawal in opioid-dependent patients) if patients receive these combinations. Risk X: Avoid combination
Orphenadrine: CNS Depressants may enhance the CNS depressant effect of Orphenadrine. Risk X: Avoid combination
Oxomemazine: May enhance the CNS depressant effect of CNS Depressants. Risk X: Avoid combination
Oxybate Salt Products: CNS Depressants may enhance the CNS depressant effect of Oxybate Salt Products. Management: Consider alternatives to this combination when possible. If combined, dose reduction or discontinuation of one or more CNS depressants (including the oxybate salt product) should be considered. Interrupt oxybate salt treatment during short-term opioid use Risk D: Consider therapy modification
OxyCODONE: CNS Depressants may enhance the CNS depressant effect of OxyCODONE. Management: Avoid concomitant use of oxycodone and benzodiazepines or other CNS depressants when possible. These agents should only be combined if alternative treatment options are inadequate. If combined, limit the dosages and duration of each drug. Risk D: Consider therapy modification
Paraldehyde: CNS Depressants may enhance the CNS depressant effect of Paraldehyde. Risk X: Avoid combination
Peginterferon Alfa-2b: May decrease the serum concentration of CYP2D6 Substrates (High risk with Inhibitors). Peginterferon Alfa-2b may increase the serum concentration of CYP2D6 Substrates (High risk with Inhibitors). Risk C: Monitor therapy
Pegvisomant: Opioid Agonists may diminish the therapeutic effect of Pegvisomant. Risk C: Monitor therapy
Piribedil: CNS Depressants may enhance the CNS depressant effect of Piribedil. Risk C: Monitor therapy
Pramipexole: CNS Depressants may enhance the sedative effect of Pramipexole. Risk C: Monitor therapy
Procarbazine: May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy
Ramosetron: Opioid Agonists may enhance the constipating effect of Ramosetron. Risk C: Monitor therapy
Ropeginterferon Alfa-2b: CNS Depressants may enhance the adverse/toxic effect of Ropeginterferon Alfa-2b. Specifically, the risk of neuropsychiatric adverse effects may be increased. Management: Avoid coadministration of ropeginterferon alfa-2b and other CNS depressants. If this combination cannot be avoided, monitor patients for neuropsychiatric adverse effects (eg, depression, suicidal ideation, aggression, mania). Risk D: Consider therapy modification
ROPINIRole: CNS Depressants may enhance the sedative effect of ROPINIRole. Risk C: Monitor therapy
Rotigotine: CNS Depressants may enhance the sedative effect of Rotigotine. Risk C: Monitor therapy
Rufinamide: May enhance the adverse/toxic effect of CNS Depressants. Specifically, sleepiness and dizziness may be enhanced. Risk C: Monitor therapy
Samidorphan: May diminish the therapeutic effect of Opioid Agonists. Risk X: Avoid combination
Selective Serotonin Reuptake Inhibitors (Strong CYP2D6 Inhibitors): Oliceridine may enhance the serotonergic effect of Selective Serotonin Reuptake Inhibitors (Strong CYP2D6 Inhibitors). This could result in serotonin syndrome. Selective Serotonin Reuptake Inhibitors (Strong CYP2D6 Inhibitors) may increase the serum concentration of Oliceridine. Management: Monitor for increased opioid effects (eg, respiratory depression, sedation) and for serotonin syndrome/serotonin toxicity when these agents are combined. Risk C: Monitor therapy
Serotonergic Agents (High Risk): Opioid Agonists (metabolized by CYP3A4 and CYP2D6) may enhance the serotonergic effect of Serotonergic Agents (High Risk). This could result in serotonin syndrome. Management: Monitor for signs and symptoms of serotonin syndrome/serotonin toxicity (eg, hyperreflexia, clonus, hyperthermia, diaphoresis, tremor, autonomic instability, mental status changes) when these agents are combined. Risk C: Monitor therapy
Sincalide: Drugs that Affect Gallbladder Function may diminish the therapeutic effect of Sincalide. Management: Consider discontinuing drugs that may affect gallbladder motility prior to the use of sincalide to stimulate gallbladder contraction. Risk D: Consider therapy modification
Somatostatin Analogs: Opioid Agonists may diminish the analgesic effect of Somatostatin Analogs. Opioid Agonists may enhance the analgesic effect of Somatostatin Analogs. Risk C: Monitor therapy
Succinylcholine: May enhance the bradycardic effect of Opioid Agonists. Risk C: Monitor therapy
Suvorexant: CNS Depressants may enhance the CNS depressant effect of Suvorexant. Management: Dose reduction of suvorexant and/or any other CNS depressant may be necessary. Use of suvorexant with alcohol is not recommended, and the use of suvorexant with any other drug to treat insomnia is not recommended. Risk D: Consider therapy modification
Thalidomide: CNS Depressants may enhance the CNS depressant effect of Thalidomide. Risk X: Avoid combination
Valerian: May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy
Zolpidem: CNS Depressants may enhance the CNS depressant effect of Zolpidem. Management: Reduce the Intermezzo brand sublingual zolpidem adult dose to 1.75 mg for men who are also receiving other CNS depressants. No such dose change is recommended for women. Avoid use with other CNS depressants at bedtime; avoid use with alcohol. Risk D: Consider therapy modification
Zuranolone: May enhance the CNS depressant effect of CNS Depressants. Management: Consider alternatives to the use of zuranolone with other CNS depressants or alcohol. If combined, consider a zuranolone dose reduction and monitor patients closely for increased CNS depressant effects. Risk D: Consider therapy modification
Chronic opioid use may cause hypogonadism and hyperprolactinemia which may decrease fertility in patients of reproductive potential. Menstrual cycle disorders (including amenorrhea), erectile dysfunction, and impotence have been reported. The incidence of hypogonadism may be increased with the use of opioids in high doses or long-acting opioid formulations. It is not known if the effects on fertility are reversible. Monitor patients on long-term therapy (de Vries 2020; Gadelha 2022).
Consider family planning, contraception, and the effects on fertility prior to prescribing opioids for chronic pain to patients who could become pregnant (ACOG 2017; CDC [Dowell 2022]).
Opioids cross the placenta.
Maternal use of opioids may be associated with poor fetal growth, stillbirth, and preterm delivery (CDC [Dowell 2022]). Opioids used as part of obstetric analgesia/anesthesia during labor and delivery may temporarily affect the fetal heart rate (ACOG 2019).
Neonatal abstinence syndrome (NAS)/neonatal opioid withdrawal syndrome (NOWS) may occur following prolonged in utero exposure to opioids (CDC [Dowell 2022]). NAS/NOWS may be life-threatening if not recognized and treated and requires management according to protocols developed by neonatology experts. Presentation of symptoms varies by opioid characteristics (eg, immediate release, sustained release), time of last dose prior to delivery, drug metabolism (maternal, placental, and infant), net placental transfer, as well as other factors (AAP [Hudak 2012]; AAP [Patrick 2020]). Clinical signs characteristic of withdrawal following in utero opioid exposure include excessive crying or easily irritable, fragmented sleep (<2 to 3 hours after feeding), tremors, increased muscle tone, or GI dysfunction (hyperphagia, poor feeding, feeding intolerance, watery or loose stools) (Jilani 2022). NAS/NOWS occurs following chronic opioid exposure and would not be expected following the use of opioids at delivery (AAP [Patrick 2020]).
Monitor infants of mothers on long-term/chronic opioid therapy for symptoms of withdrawal. Symptom onset reflects the half-life of the opioid used. Monitor infants for at least 3 days following exposure to immediate-release opioids; monitor for at least 4 to 7 days following exposure to sustained-release opioids (AAP [Patrick 2020]; CDC [Dowell 2022]). Monitor newborns for excess sedation and respiratory depression when opioids are used during labor.
When opioids are needed to treat acute pain in pregnant patients, the lowest effective dose for only the expected duration of pain should be prescribed (CDC [Dowell 2022]).
Opioid use for pain following vaginal or cesarean delivery should be made as part of a shared decision-making process. A stepwise multimodal approach to managing postpartum pain is recommended. A low-dose, low-potency, short-acting opioid can be used to treat acute pain associated with delivery when needed (ACOG 2021).
Opioids are not preferred for the treatment of chronic noncancer pain during pregnancy; consider strategies to minimize or avoid opioid use. Advise pregnant patients requiring long-term opioid use of the risk of NAS/NOWS and provide appropriate treatment for the neonate after delivery. NAS/NOWS is an expected and treatable condition following chronic opioid use during pregnancy and should not be the only reason to avoid treating pain with an opioid in pregnant patients (ACOG 2017; CDC [Dowell 2022]). Do not abruptly discontinue opioids during pregnancy; taper prior to discontinuation when appropriate, considering the risks to the pregnant patient and fetus if maternal withdrawal occurs (CDC [Dowell 2022]).
It is not known if oliceridine is present in breast milk.
According to the manufacturer, the decision to breastfeed during therapy should consider the risk of infant exposure, the benefits of breastfeeding to the infant, and the benefits of treatment to the mother. Nonopioid analgesics are preferred for lactating patients who require pain control peripartum or for surgery outside of the postpartum period. When opioids are needed for lactating patients, use the lowest effective dose for the shortest duration of time to limit adverse events in the mother and breastfeeding infant. When an opioid is needed to treat maternal pain, agents other than oliceridine may be preferred (AAP [Sachs 2013]; ABM [Martin 2018]; ABM [Reece-Stremtan 2017]; WHO 2002).
When chronic opioids are prescribed prenatally and continued postpartum, breastfeeding may be initiated to help mitigate potential newborn withdrawal; monitor both the mother and the infant (AAP [Meek 2022]; AAP [Patrick 2020]).
Monitor infants exposed to opioids via breast milk for drowsiness, sedation, feeding difficulties, or limpness (ACOG 2019). Withdrawal symptoms may occur when maternal use is discontinued, or breastfeeding is stopped.
Pain relief, respiratory depression (especially within the first 24 to 48 hours after initiation); mental status, BP, heart rate; bowel function; signs/symptoms of misuse, abuse, and substance use disorder; signs or symptoms of hypogonadism or hypoadrenalism (Brennan 2013).
Selectively binds to the G-protein section of the opioid mu receptor to induce analgesia. Reduced activation of the beta-arrestin pathway associated with opioid-related adverse events (eg, respiratory depression, GI effects) (Dahan 2020; Gan 2020).
Onset: ≤5 minutes.
Distribution: Vdss: 90 to 120 L.
Protein binding: 77%.
Metabolism: Hepatic, primarily via CYP3A4 and 2D6 (major pathways) and 2C9 and 2C19 (minor pathways) to inactive metabolites.
Half-life elimination: 1.3 to 3 hours (oliceridine); ~44 hours (metabolites).
Excretion: Urine (~70% as metabolites; ≤6.75% as unchanged drug); feces (~30% as metabolites).
Altered kidney function: No significant differences in oliceridine clearance were observed in patients with end-stage renal disease compared to healthy subjects.
Hepatic function impairment: In patients with moderate to severe impairment, half-life increased to 4.3 and 5.8 hours, and volume of distribution increased to 212 and 348 L, respectively, compared to healthy subjects.
CYP2D6 poor metabolizers: AUC ~2-fold higher than in patients who are non-poor CYP2D6 metabolizers.
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