Oliceridine Fumarate (Monograph)

Brand name: Olinvyk
Drug class: Opiate Agonists
Chemical name: N-[(3-methoxythiophen-2-yl)methyl]-2-[(9R)-9-pyridin-2-yl-6-oxaspiro[4.5]decan-9-yl]ethanamine
Molecular formula: C₂₂H₃₀N₂O₂S•C₄H₄O₄

Medically reviewed by Drugs.com on Apr 19, 2023. Written by ASHP.

Introduction

Opiate agonist.^{1 2 3 4 8 10}

Uses for Oliceridine Fumarate

Acute Pain

Relief of acute pain that is severe enough to require an IV opiate analgesic; because of the risks of addiction, abuse, and misuse associated with opiates even at recommended dosages, reserve for use in patients for whom alternative treatment options (e.g., nonopiate analgesics, opiate-containing fixed combinations) have not been, or are not expected to be, adequate or tolerated.¹

Pivotal efficacy studies evaluated oliceridine administered as patient-controlled analgesia (PCA) for postoperative pain for periods of ≤48 hours.^{1 3 4}

In symptomatic treatment of acute pain, reserve opiate analgesics for pain resulting from severe injuries, severe medical conditions, or surgical procedures, or when nonopiate alternatives for relieving pain and restoring function are expected to be ineffective or are contraindicated.^{431 432 433 435} Use smallest effective dosage for shortest possible duration since long-term opiate use often begins with treatment of acute pain.^{411 431 434 435} Optimize concomitant use of other appropriate therapies.^{432 434 435} (See Managing Opiate Therapy for Acute Pain under Dosage and Administration.)

Oliceridine Fumarate Dosage and Administration

General

Managing Opiate Therapy for Acute Pain

• Optimize concomitant use of other appropriate therapies.^{432 434 435}

• When opiate analgesia required, use conventional (immediate-release) opiates in smallest effective dosage and for shortest possible duration, since long-term opiate use often begins with treatment of acute pain.^{411 431 434 435}

• Consider prescribing naloxone concomitantly for patients who are at increased risk of opiate overdosage^{411 431 750} or who have household members, including children, or other close contacts who are at risk for accidental ingestion or overdosage.⁷⁵⁰ (See Respiratory Depression under Cautions.)

• When sufficient for pain management, use lower-potency opiate analgesics given in conjunction with acetaminophen or an NSAIA on as-needed (“prn”) basis.⁴³²

• For acute pain not related to trauma or surgery, limit prescribed quantity to amount needed for expected duration of pain severe enough to require opiate analgesia (generally ≤3 days and rarely >7 days).^{411 433 434 435} Do not prescribe larger quantities for use in case pain continues longer than expected;^{411 432} instead, reevaluate patient if severe acute pain does not remit.^{411 431 435}

• For moderate to severe postoperative pain, provide opiate analgesic as part of a multimodal regimen that also includes acetaminophen and/or NSAIAs and other pharmacologic (e.g., certain anticonvulsants, regional local anesthetic techniques) and nonpharmacologic therapy as appropriate.^{430 431 432}

• Oral administration of conventional opiate analgesics generally preferred over IV administration in postoperative patients who can tolerate oral therapy.^{430 431}

• Scheduled (around-the-clock) dosing frequently is required during immediate postoperative period or following major surgery.^{430 432} When repeated parenteral administration is required, IV PCA generally is recommended.^{430 431}

Administration

IV Administration

For IV use only.¹

Vials containing 30 mg of oliceridine are intended for PCA use only; withdraw the oliceridine solution directly from the vial into the PCA syringe or IV bag without dilution.¹

Rate of Administration

PCA: 6-minute lock-out period recommended.¹

Differences in IV infusion times do not appear to alter the drug's pharmacokinetics, with the exception of peak plasma concentration.¹

Dosage

Available as oliceridine fumarate; dosage expressed in terms of oliceridine.¹

Use lowest effective dosage and shortest duration of therapy consistent with treatment goals of the patient.^{1 411 413 431 432 435}

Individualize dosage regimen according to severity of pain, response, prior analgesic use, and risk factors for addiction, abuse, and misuse.¹

When used concomitantly with other CNS depressants, use lowest effective dosages and shortest possible duration of concomitant therapy.^{1 700 703} (See Specific Drugs under Interactions.)

Appropriate dosage selection and titration are essential to reduce the risk of respiratory depression.¹ Monitor closely for respiratory depression, especially during the first 24–48 hours of therapy and following any increase in dosage; adjust dosage accordingly.¹

Frequent communication among the prescriber, other members of the healthcare team, the patient, and the patient's caregiver or family is important during periods of changing analgesic requirements, including the initial dosage titration period.¹

Continually assess adequacy of pain control and reevaluate for adverse effects, as well as for development of addiction, abuse, or misuse.¹

If level of pain increases after dosage stabilization, attempt to identify source of increased pain before increasing dosage.¹

When discontinuing oliceridine in a patient who may be physically dependent on opiates, gradually reduce dosage while carefully monitoring for manifestations of withdrawal.¹ If manifestations of withdrawal occur, increase dosage to the prior level and taper more slowly (increase interval between dosage reductions and/or reduce amount of each incremental change in dose).¹

Adults

Acute Pain

IV

Initial clinician-administered dose of 1.5 mg.¹ For continued administration via PCA, recommended on-demand dose is 0.35 mg with a 6-minute lock-out period; on-demand dose of 0.5 mg may be considered for some patients if potential benefit outweighs the risks.¹ Clinician-administered supplemental doses of 0.75 mg can be given hourly as needed, beginning 1 hour after the initial dose.¹

Titrate dosage to a level that provides adequate analgesia and minimizes adverse effects.¹

Do not exceed cumulative daily dose of 27 mg; if patient still requires analgesia, administer an alternative analgesic regimen (e.g., multimodal therapies) until oliceridine administration can be resumed the following day.¹ Cumulative daily doses >27 mg may increase risk for QT-interval prolongation.¹ (See Prolongation of QT Interval under Cautions.)

Manufacturer states that data from clinical studies suggest that an initial 1-mg dose of oliceridine is approximately equipotent to morphine sulfate 5 mg; however, this estimate of equivalency is only a guide since individual patients differ in their response to opiates.¹

Prescribing Limits

Adults

Acute Pain

IV

Maximum cumulative daily dose is 27 mg.¹ (See Prolongation of QT Interval under Cautions.)

Do not use single doses >3 mg; not evaluated in clinical trials.¹

Safety of >48 hours of use not evaluated in clinical trials.¹

Special Populations

Hepatic Impairment

Mild or moderate hepatic impairment: Adjustment of initial dose not required; longer interval between doses may be required.¹

Severe hepatic impairment: Use caution; consider reducing initial dose, and administer subsequent doses only after carefully reviewing the patient's pain severity and overall clinical status.¹ (See Hepatic Impairment under Cautions.)

Renal Impairment

No dosage adjustment required in patients with renal impairment.¹

Geriatric Patients

In general, select dosage with caution, usually starting at the low end of the dosage range; titrate dosage slowly.¹ (See Geriatric Use under Cautions.)

CYP2D6 Poor Metabolizers

Known or suspected CYP2D6 poor metabolizers: Less frequent dosing may be required.¹ Base subsequent doses on patient's pain severity and response to treatment.¹ (See Pharmacogenomic Considerations under Cautions.)

Cautions for Oliceridine Fumarate

Contraindications

• Substantial respiratory depression.¹

• Acute or severe bronchial asthma in an unmonitored setting or in the absence of resuscitative equipment.¹

• Known or suspected GI obstruction, including paralytic ileus.¹

• Known hypersensitivity (e.g., anaphylaxis) to oliceridine.¹

Warnings/Precautions

Warnings

Addiction, Abuse, and Misuse

Risk of addiction, abuse, and misuse, which can lead to overdosage and death.¹ Addiction can occur at recommended dosages or with misuse or abuse.¹ Concurrent abuse of alcohol and other CNS depressants increases risk of toxicity.¹ Abuse potential similar to that of other potent opiate agonists.¹

Assess each patient’s risk for addiction, abuse, and misuse prior to prescribing; monitor all patients for development of these behaviors or conditions.¹ Personal or family history of substance abuse (drug or alcohol addiction or abuse) or mental illness (e.g., major depression) increases risk.¹

The potential for addiction, abuse, and misuse should not prevent opiate prescribing for appropriate pain management, but does necessitate intensive counseling about risks and proper use and intensive monitoring for signs of addiction, abuse, and misuse.¹

Prescribe only in the smallest appropriate quantity.¹

Respiratory Depression

Serious, life-threatening, or fatal respiratory depression can occur with use of opiates, even when used as recommended; can occur at any time during therapy, but risk is greatest during initiation of therapy and following dosage increases.¹ Monitor for respiratory depression, especially during first 24–48 hours of therapy and following any dosage increase.¹

Carbon dioxide retention from opiate-induced respiratory depression can exacerbate the drug's sedative effects and, in certain patients, can lead to elevated intracranial pressure.¹ (See Increased Intracranial Pressure or Head Injury under Cautions.)

Opiates can cause sleep-related breathing disorders, including central sleep apnea and sleep-related hypoxemia.¹ Risk of central sleep apnea is dose dependent; consider tapering opiate dosage if central sleep apnea occurs.¹

Geriatric, cachectic, or debilitated patients are at increased risk for life-threatening respiratory depression.¹ Closely monitor such patients, particularly following initiation of therapy, during dosage titration, and during concomitant therapy with other respiratory depressants.¹ Consider use of nonopiate analgesics.¹

Even recommended doses of oliceridine may decrease respiratory drive to the point of apnea in patients with COPD or cor pulmonale, substantially decreased respiratory reserve, hypoxia, hypercapnia, or preexisting respiratory depression.¹ Closely monitor such patients, particularly following initiation of therapy, during dosage titration, and during concomitant therapy with other respiratory depressants.¹ Consider use of nonopiate analgesics.¹ (See Contraindications under Cautions.)

Appropriate dosage selection and titration are essential to reduce the risk of respiratory depression.¹ Overestimation of the dosage when transferring patients from another opiate analgesic can result in fatal overdosage with the first dose.¹

If respiratory depression occurs, follow usual guidelines for management of opiate agonist-induced respiratory depression.¹

Concomitant Use with Benzodiazepines or Other CNS Depressants

Concomitant use of opiates and benzodiazepines or other CNS depressants (e.g., anxiolytics, sedatives, hypnotics, tranquilizers, muscle relaxants, general anesthetics, antipsychotics, other opiate agonists, alcohol) may result in profound sedation, respiratory depression, coma, and death.^{1 416 417 418 700 701 702 703} Substantial proportion of fatal opiate overdoses involve concurrent benzodiazepine use.^{416 417 418 435 700 701}

Reserve concomitant use of oliceridine and other CNS depressants for patients in whom alternative treatment options are inadequate.^{1 700 703} (See Specific Drugs under Interactions.)

Other Warnings and Precautions

General Opiate Agonist Precautions

May cause effects similar to those produced by other opiate agonists;¹ observe the usual precautions of opiate agonist therapy.¹

Prolongation of QT Interval

Mild prolongation of QT interval corrected for rate (QT_c) observed in 2 studies in healthy individuals.¹ Dose-dependent prolongation observed in single-dose (3 and 6 mg) study.¹ In multidose study (maximum cumulative dose of 27 mg over 24 hours), maximum prolongation observed at 9 hours; effect on QT_c interval did not increase progressively with repeated dosing and, despite continued dosing, began to diminish after 12 hours.¹ Mechanism and clinical importance not established.¹

Carefully consider these findings in situations associated with QT-interval prolongation (e.g., patients receiving drugs known to prolong the QT interval, those with underlying conditions associated with QT-interval prolongation).¹

Avoid cumulative daily doses >27 mg.¹ Cumulative daily doses >27 mg not systematically evaluated and may increase risk for QT_c-interval prolongation.¹ (See Dosage under Dosage and Administration.)

CYP-mediated Interactions

Concomitant use of moderate or potent CYP2D6 or CYP3A4 inhibitors or discontinuance of a CYP3A4 inducer may increase plasma concentrations of oliceridine, which may exacerbate respiratory depression and prolong opiate-related adverse effects; conversely, concomitant use of CYP3A4 inducers or discontinuance of moderate or potent CYP2D6 or CYP3A4 inhibitors may decrease plasma concentrations of oliceridine, which may reduce analgesic efficacy and/or precipitate opiate withdrawal.¹ Close monitoring at frequent intervals required.¹ (See Interactions.)

Pharmacogenomic Considerations

CYP2D6 poor metabolizers may have increased plasma concentrations of oliceridine, which may exacerbate respiratory depression and prolong opiate-related adverse effects.¹ (See Absorption: Special Populations, under Pharmacokinetics.)

Inhibition of both the CYP2D6 and CYP3A4 pathways can result in greater increases in plasma oliceridine concentrations compared with inhibition of either metabolic pathway alone.¹ CYP2D6 poor metabolizers who are receiving a moderate or potent CYP3A4 inhibitor may have greater increases in plasma oliceridine concentrations and may require less frequent dosing of oliceridine.¹

Closely monitor CYP2D6 poor metabolizers at frequent intervals for respiratory depression and sedation.¹ Dosage adjustments may be required.¹ (See CYP2D6 Poor Metabolizers under Dosage and Administration and also see Combined Moderate to Potent CYP3A4 and CYP2D6 Inhibition under Interactions.)

Adrenal Insufficiency

Adrenal insufficiency reported in patients receiving opiate agonists or opiate partial agonists.^{1 400} Manifestations are nonspecific and may include nausea, vomiting, anorexia, fatigue, weakness, dizziness, and hypotension.^{1 400} Variable onset, but often after ≥1 month of use.¹

If adrenal insufficiency is suspected, perform appropriate laboratory testing promptly and, if confirmed, provide physiologic (replacement) dosages of corticosteroids; taper and discontinue the opiate agonist or partial agonist to allow recovery of adrenal function.^{1 400} If the opiate agonist or partial agonist can be discontinued, perform follow-up assessment of adrenal function to determine if corticosteroid replacement therapy can be discontinued.⁴⁰⁰ In some patients, switching to a different opiate improved symptoms.^{1 400}

Hypotension

May cause severe hypotension, including orthostatic hypotension and syncope, in ambulatory patients, especially in individuals whose ability to maintain their BP is compromised by depleted blood volume or concomitant use of certain CNS depressants (e.g., phenothiazines, general anesthetics).¹ Monitor BP following initiation of therapy and dosage increases in such patients.¹ (See Specific Drugs under Interactions.)

Vasodilation produced by the drug may further reduce cardiac output and BP in patients with circulatory shock.¹ Avoid use in such patients.¹

Increased Intracranial Pressure or Head Injury

Potential for increased carbon dioxide retention and secondary elevation of intracranial pressure; in patients particularly susceptible to these effects (e.g., those with evidence of elevated intracranial pressure or brain tumors), monitor closely for sedation and respiratory depression, particularly during initiation of therapy.¹

Opiates may obscure the clinical course in patients with head injuries.¹

Avoid use in patients with impaired consciousness or coma.¹

GI Conditions

May cause spasm of the sphincter of Oddi and increase serum amylase concentrations; monitor patients with biliary disease, including acute pancreatitis, for worsening symptoms.¹

Contraindicated in patients with known or suspected GI obstruction, including paralytic ileus.¹

Seizures

May aggravate preexisting seizure disorder.¹ Monitor for worsened seizure control.¹

May increase risk of seizures in other settings associated with seizures.¹

Dependence and Tolerance

Physical dependence and tolerance can develop during prolonged opiate therapy.¹ Abrupt discontinuance or substantial dosage reduction may result in symptoms of withdrawal (e.g., restlessness, lacrimation, rhinorrhea, yawning, sweating, chills, myalgia, mydriasis, irritability, anxiety, backache, joint pain, weakness, abdominal cramps, insomnia, nausea, anorexia, vomiting, diarrhea, increased BP, respiratory rate, or heart rate).¹ Symptoms may be avoided by tapering the dosage when the drug is discontinued.¹

Avoid concomitant use of opiate partial agonists.¹ (See Specific Drugs under Interactions.)

Infants born to women who are physically dependent on opiates also will be physically dependent and may exhibit respiratory difficulties and manifestations of opiate withdrawal.¹ (See Pregnancy under Cautions.)

CNS Depression

Performance of activities requiring mental alertness and/or physical coordination (e.g., driving, operating machinery) may be impaired.¹

Concurrent use with other CNS depressants may result in profound sedation, respiratory depression, coma, or death.^{1 700 703} (See Concomitant Use with Benzodiazepines or Other CNS Depressants under Cautions.)

Patient-controlled Analgesia

Although PCA may allow patients to individually titrate opiate dosage to an acceptable level of analgesia, such administration has resulted in adverse outcomes and episodes of respiratory depression.¹

Instruct clinicians and family members monitoring patients receiving opiate analgesics via PCA in the need for appropriate monitoring for excessive sedation, respiratory depression, and other opiate-related adverse effects.¹

Hypogonadism

Hypogonadism or androgen deficiency reported in patients receiving long-term opiate agonist or opiate partial agonist therapy;^{1 400 401 402 403 404} causality not established.^{1 400} Manifestations may include decreased libido, impotence, erectile dysfunction, amenorrhea, or infertility.^{1 400} Not known whether effects on fertility are reversible.¹ Perform appropriate laboratory testing in patients with manifestations of hypogonadism.⁴⁰⁰

In animal studies, oliceridine prolonged estrous cycle lengths and decreased number of implantations and viable embryos in female rats; did not alter male fertility.¹

Specific Populations

Pregnancy

Analysis of data from the National Birth Defects Prevention Study (large population-based, case-control study) suggests therapeutic use of opiates in pregnant women during organogenesis is associated with a low absolute risk of birth defects, including heart defects, spina bifida, and gastroschisis.⁶ Manufacturer states that data not available for establishing risk of major birth defects and spontaneous abortion with oliceridine.¹

In animal studies, oliceridine reduced live litter size at birth and increased postnatal pup mortality in rats at clinically relevant concentrations; no effects on embryofetal development observed.¹

Use of opiates in pregnant women during labor can result in neonatal respiratory depression.¹ Use of oliceridine immediately before or during labor and delivery is not recommended.¹ Monitor neonates exposed to opiates during labor for respiratory depression and excessive sedation; an opiate antagonist should be readily available for reversal of opiate-induced respiratory depression.¹

Prolonged maternal use of opiates during pregnancy can result in neonatal opiate withdrawal syndrome; in contrast to adults, withdrawal syndrome in neonates may be life-threatening and requires management according to protocols developed by neonatology experts.¹ Syndrome presents with irritability, hyperactivity and abnormal sleep pattern, high-pitched cry, tremor, vomiting, diarrhea, and failure to gain weight.¹ Onset, duration, and severity vary depending on the specific opiate used, duration of use, timing and amount of last maternal use, and rate of drug elimination by the neonate.¹ Monitor neonates for opiate withdrawal and provide appropriate management as needed.¹

Lactation

Not known whether oliceridine distributes into milk, affects breast-fed infants, or affects milk production.¹

Consider developmental and health benefits of breast-feeding along with the mother's clinical need for oliceridine and any potential adverse effects on the breast-fed infant from the drug or underlying maternal condition.¹

Monitor infants exposed to oliceridine through breast milk for excessive sedation and respiratory depression.¹ Symptoms of withdrawal can occur in opiate-dependent infants when maternal administration of opiates is discontinued or breast-feeding is stopped.¹

Pediatric Use

Safety and efficacy in pediatric patients not established.¹

Geriatric Use

Controlled clinical studies did not include sufficient numbers of patients ≥65 years of age to determine whether geriatric patients respond differently than younger adults.¹

Respiratory depression is the chief risk; monitor closely for CNS and respiratory depression.¹

Geriatric patients may be more sensitive to the effects of the drug.¹ Consider the greater frequency of decreased hepatic, renal, and/or cardiac function and of concomitant disease or other drug therapy in the elderly.¹

Dosage selection should be cautious.¹ (See Geriatric Patients under Dosage and Administration.)

Hepatic Impairment

Some pharmacokinetic parameters may be altered.^{1 5} (See Elimination: Special Populations, under Pharmacokinetics.) Dosage adjustments may be required.¹ (See Hepatic Impairment under Dosage and Administration.)

Use with caution in patients with severe hepatic impairment.¹

Renal Impairment

End-stage renal disease does not substantially alter clearance; no dosage adjustment required in patients with renal impairment.^{1 5}

Common Adverse Effects

Nausea, vomiting, dizziness, headache, constipation, pruritus, hypoxia.¹ Pivotal trials did not allow for comparison of the frequency of adverse effects following administration of equipotent dosages of oliceridine and morphine sulfate.¹ (See Actions.)

Drug Interactions

Metabolized mainly by CYP3A4 and CYP2D6, with minor contributions from CYP2C9 and CYP2C19.¹ Does not inhibit CYP enzymes at clinically relevant concentrations.¹

Does not inhibit major transporters, including breast cancer resistance protein (BCRP) and P-glycoprotein (P-gp) in vitro at clinically relevant concentrations.¹

Moderate to Potent CYP2D6 Inhibitors

Concomitant use can increase plasma oliceridine concentrations; may increase or prolong opiate effects (e.g., respiratory depression).¹ Drug interaction studies lacking, but effect may be similar to that of CYP2D6 poor metabolizer phenotype (i.e., approximately 50% reduction in plasma clearance and twofold increase in AUC).¹ If concomitant therapy is required, closely monitor for respiratory depression and sedation at frequent intervals and adjust oliceridine dosage according to severity of pain and response to treatment; reduced dosing frequency may be required.¹

If the moderate or potent CYP2D6 inhibitor is discontinued, oliceridine concentrations may decrease, resulting in decreased analgesic efficacy and/or opiate withdrawal; monitor for opiate withdrawal and consider increasing oliceridine dosage until drug effects are stable.¹

Examples of moderate to potent CYP2D6 inhibitors include but are not limited to bupropion, fluoxetine, paroxetine, and quinidine.¹

Moderate to Potent CYP3A4 Inhibitors

Concomitant use can increase plasma oliceridine concentrations; may increase or prolong opiate effects (e.g., respiratory depression).¹ If concomitant therapy is required, closely monitor for respiratory depression and sedation at frequent intervals and adjust oliceridine dosage according to severity of pain and response to treatment; reduced dosing frequency may be required.¹

If the moderate or potent CYP3A4 inhibitor is discontinued, oliceridine concentrations may decrease, resulting in decreased analgesic efficacy and/or opiate withdrawal; monitor for opiate withdrawal and consider increasing oliceridine dosage until drug effects are stable.¹

Examples of moderate to potent CYP3A4 inhibitors include but are not limited to macrolide antibiotics (e.g., erythromycin), azole antifungals (e.g., itraconazole, ketoconazole), HIV protease inhibitors (e.g., ritonavir), and SSRIs.¹

Combined Moderate to Potent CYP3A4 and CYP2D6 Inhibition

Increase in plasma oliceridine concentrations may exceed that resulting from inhibition of either metabolic pathway alone.¹ (See Specific Drugs under Interactions.)

If oliceridine is used concomitantly with a CYP2D6 inhibitor and a potent CYP3A4 inhibitor, closely monitor for respiratory depression and sedation at frequent intervals and adjust oliceridine dosage according to severity of pain and response to treatment; reduced dosing frequency may be required.¹

CYP3A4 Inducers

Concomitant use can decrease plasma oliceridine concentrations; may reduce analgesic efficacy and/or precipitate opiate withdrawal.¹ If concomitant therapy is required, monitor for opiate withdrawal and consider adjusting oliceridine dosage until drug effects are stable.¹

If the CYP3A4 inducer is discontinued, oliceridine concentrations may increase, resulting in increased or prolonged therapeutic or adverse effects; monitor for respiratory depression; reduced oliceridine dosing frequency may be required.¹

Examples of CYP3A4 inducers include but are not limited to carbamazepine, phenytoin, and rifampin.¹

Serotonergic Drugs

Risk of serotonin syndrome when opiates used with other serotonergic agents.^{1 400} Examples include serotonin type 1 (5-HT₁) receptor agonists (“triptans”), SSRIs, SNRIs, tricyclic antidepressants, antiemetics that are 5-HT₃ receptor antagonists, buspirone, cyclobenzaprine, dextromethorphan, lithium, St. John’s wort (Hypericum perforatum), tryptophan, other serotonin modulators (e.g., mirtazapine, nefazodone, trazodone, vilazodone), and MAO inhibitors (those used to treat psychiatric disorders and others [e.g., linezolid, methylene blue, selegiline]).^{1 400}

Serotonin syndrome may occur at usual dosages.⁴⁰⁰ Symptom onset generally occurs within several hours to a few days of concomitant use, but may occur later, particularly after dosage increases.^{1 400} (See Advice to Patients.)

If concomitant use is warranted, monitor for serotonin syndrome, particularly during initiation of therapy and dosage increases.^{1 400}

If serotonin syndrome is suspected, discontinue oliceridine, other opiates, and/or any concurrently administered serotonergic agents.^{1 400}

Specific Drugs

Oliceridine Fumarate Pharmacokinetics

Absorption

Bioavailability

Differences in IV infusion time do not appear to alter the drug's pharmacokinetics, with the exception of peak plasma concentration.¹

Clearance decreases slightly with increasing dose, resulting in greater than proportional exposure, particularly at doses >2 mg.¹

Onset

Following IV administration, onset is rapid (median: 1–3 minutes); most patients experience perceptible pain relief within 5 minutes after first dose.¹

Special Populations

CYP2D6 poor metabolizers: Systemic exposure approximately twofold higher than in individuals who are not poor metabolizers.¹

Mild to severe hepatic impairment: Total systemic exposure not substantially altered.^{1 5} (See Elimination: Special Populations, under Pharmacokinetics.)

Distribution

Extent

Extensively distributes into tissues.¹

Plasma Protein Binding

77% bound to plasma proteins.¹

Special Populations

Moderate or severe hepatic impairment: Estimated volume of distribution is substantially increased.^{1 5} (See Elimination: Special Populations, under Pharmacokinetics.)

Elimination

Metabolism

Extensively metabolized, mainly by oxidation with subsequent glucuronidation and to a lesser extent by N-dealkylation, glucuronidation, and dehydrogenation.¹ Metabolism mediated mainly by CYP3A4 and CYP2D6, with minor contributions from CYP2C9 and CYP2C19.¹ Known metabolites have no appreciable activity at μ-opiate receptor.¹

Elimination Route

Metabolites are eliminated mainly (70%) in urine; remainder eliminated in feces.¹ Approximately 1–7% of administered dose is recovered as unchanged drug in urine.¹

Half-life

1.3–3 hours.¹

Special Populations

CYP2D6 poor metabolizers: Plasma clearance decreased by approximately 50%.¹

Hepatic impairment: Mean half-life is increased in individuals with moderate (4.3 hours) or severe (5.8 hours) hepatic impairment, compared with healthy individuals (2.1 hours) or those with mild hepatic impairment (2.6 hours).^{1 5} While moderate or severe hepatic impairment substantially increases estimated volume of distribution, clearance and total systemic exposure are not substantially altered in individuals with mild to severe hepatic impairment.^{1 5}

End-stage renal disease: Does not substantially alter clearance.^{1 5}

Stability

Storage

Parenteral

Injection

20–25°C (may be exposed to 15–30°C).¹ Protect from light and freezing.¹

Actions

• Full opiate agonist; relatively selective for the μ-opiate receptor.^{1 2 3 4 8 10} Structurally unrelated to morphine or other μ-opiate receptor agonists.¹⁰

• Precise mechanism of analgesic action is unknown; however, specific opiate receptors for endogenous compounds with opiate-like activity have been identified throughout the brain and spinal cord and are thought to play a role in the drug's analgesic effects.¹

• Oliceridine preferentially activates signaling through the G-protein-coupled pathway (which has been associated with antinociceptive activity) as compared with the β-arrestin pathway (which has been associated with certain opiate-related adverse effects).^{7 9 10} Hypothesized that this preferential effect may result in less sedation, respiratory depression, and slowing of GI motility as compared with conventional opiate analgesics that are not selective (or “biased”) toward the G-protein-coupled pathway; however, additional study required to establish clinical relevance of this differential effect.^{2 7 8 9 10}

Advice to Patients

• Potential risk of serotonin syndrome with concurrent use of opiates and serotonergic agents.^{1 400} Importance of immediately informing clinician if manifestations of serotonin syndrome (e.g., agitation, hallucinations, tachycardia, labile BP, fever, excessive sweating, shivering, shaking, muscle stiffness, twitching, loss of coordination, nausea, vomiting, diarrhea) develop.^{1 400}

• Importance of informing patients that severe constipation may develop and advising patients on appropriate management.¹

• Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs, as well as any concomitant illnesses.¹

• Importance of women informing clinicians if they are or plan to become pregnant or plan to breast-feed.¹

• Importance of informing patients of other important precautionary information.¹ (See Cautions.)

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.

Subject to control under the Federal Controlled Substances Act of 1970 as a schedule II (C-II) drug.

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