AHFS Class:

• Opioid Agonists 28:08.08

Generic Name(s):

• Oliceridine

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

Oliceridine fumarate is an opiate agonist.1,2,3,4,8,10

Acute Pain

Oliceridine fumarate is used for the 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, oliceridine should be reserved 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

Efficacy and safety of oliceridine for the relief of acute pain have been established in 2 phase 3 randomized, double-blind, placebo- and active-controlled clinical studies in adults with moderate to severe pain following orthopedic or plastic surgery.1,3,4 In each study, patients were randomized to receive oliceridine (1 of 3 regimens), morphine sulfate, or placebo.1,3,4 Each treatment regimen included a clinician-administered IV loading dose of the assigned treatment followed by incremental doses delivered via patient-controlled analgesia (PCA) as needed (with a lock-out interval of 6 minutes); clinician-administered supplemental IV doses of the assigned treatment were allowed on an hourly basis as needed, beginning 1 hour after the initial dose.1,3,4 The oliceridine regimens consisted of a 1.5-mg loading dose, on-demand doses of 0.1, 0.35, or 0.5 mg (depending on the assigned regimen), and supplemental doses of 0.75 mg.1,3,4 The morphine sulfate regimen consisted of a 4-mg loading dose, on-demand doses of 1 mg, and supplemental doses of 2 mg.1,3,4 Rescue therapy with etodolac was available upon request for pain resulting in an intensity score of 4 or greater on an 11-point numeric scale.1,3,4

The first study (Apollo-1; NCT02815709) included 389 adults with moderate to severe acute pain (mean baseline pain intensity score of 6.7) following bunionectomy.1,3 Treatment was initiated in patients with a pain intensity score of 4 or greater within 9 hours following discontinuance of regional anesthesia, and efficacy was evaluated over a 48-hour treatment period.1,3 In this study, 83-87% of patients receiving oliceridine and 60% of those receiving placebo completed the randomized treatment period; 41, 20, or 17% of patients receiving on-demand oliceridine doses of 0.1, 0.35, or 0.5 mg received etodolac rescue therapy, compared with 77% of those receiving placebo.1 All 3 doses of oliceridine provided superior analgesia compared with placebo;2 a difference in the summed pain intensity difference (i.e., the difference between current pain and pain at baseline, multiplied by the interval between ratings and adjusted to account for any rescue analgesics1,2 ) over 48 hours was observed between all 3 oliceridine regimens and placebo.2 A substantial number of patients receiving on-demand oliceridine doses of 0.35 or 0.5 mg (60 or 63% of patients, respectively) exceeded the maximum recommended cumulative daily dose of 27 mg; the median time to reach this dosage level was 15.8 or 13.6 hours for patients receiving doses of 0.35 or 0.5 mg, respectively.1,2

The second study (Apollo-2; NCT02820324) included 401 adults with moderate to severe acute pain (mean baseline pain intensity score of 7.3) following abdominoplasty.1,4 Treatment was initiated following discontinuance of general anesthesia in patients with a pain intensity score of 5 or greater within 4 hours after the end of surgery.1,4 Efficacy was evaluated over 24 hours.1,4 In this study, 86-90% of patients receiving oliceridine and 74% of those receiving placebo completed the randomized treatment period without discontinuing the assigned treatment; 31, 21, or 18% of patients receiving on-demand oliceridine doses of 0.1, 0.35, or 0.5 mg, respectively, received etodolac rescue therapy, compared with 49% of those receiving placebo.1 The 0.35- and 0.5-mg on-demand doses of oliceridine provided superior analgesia, as measured by the summed pain intensity difference over 24 hours, compared with placebo; the 0.1-mg dose was not superior to placebo on this measure of efficacy.1,2 A number of patients receiving on-demand oliceridine doses of 0.35 or 0.5 mg (28 or 43%, respectively) exceeded the maximum recommended cumulative daily dose of 27 mg; the median time to reach this dosage level was 19.4 or 14.1 hours for patients receiving doses of 0.35 or 0.5 mg, respectively.1,2

For further information on the role of opiate analgesics in the management of acute pain, see Uses: Pain, in the Opiate Agonists General Statement 28:08.08.

Administration

Oliceridine fumarate is intended for IV use only.1

Vials containing 30 mg of oliceridine are intended for patient-controlled analgesia (PCA) use only; the oliceridine solution should be withdrawn directly from the vial into the PCA syringe or IV bag without dilution.1

Oliceridine injection should be inspected visually for particulate matter and discoloration prior to administration; the solution should appear clear and colorless, and should be discarded if opaque particles, discoloration, or other foreign particles are visible.1

Dosage

Dosage of oliceridine fumarate is expressed in terms of oliceridine.1

Opiate analgesics should be given at the lowest effective dosage and for the shortest duration of therapy consistent with the treatment goals of the patient.1,411,413,431,432,435 The dosage regimen should be individualized according to severity of pain, response, prior analgesic use, and risk factors for addiction, abuse, and misuse.1 If concomitant therapy with other CNS depressants is required, the lowest effective dosages and shortest possible duration of concomitant therapy should be used.1,700,703 (See Benzodiazepines and Other CNS Depressants under Drug Interactions.)

Appropriate dosage selection and titration are essential to reduce the risk of respiratory depression.1 Patients should be monitored closely for respiratory depression, especially during the first 24-48 hours of therapy and following any increase in dosage, and dosage should be adjusted accordingly.1

Patients receiving opiate analgesia should be reevaluated continually for adequacy of pain control and for adverse effects, as well for the development of addiction, abuse, or misuse.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 If the level of pain increases after dosage stabilization, an attempt should be made to identify the source of increased pain before increasing the oliceridine dosage.1

For further information on the management of opiate analgesic therapy, see Dosage and Administration: Dosage, in the Opiate Agonists General Statement 28:08.08.

Adult Dosage

For the relief of acute pain that is severe enough to require an IV opiate analgesic, the recommended initial adult dosage of oliceridine is 1.5 mg administered by a clinician.1 Onset of analgesic effect is expected within 2-5 minutes after the initial dose.1 For continued administration via PCA, an on-demand dose of 0.35 mg with a 6-minute lock-out period is recommended; an on-demand dose of 0.5 mg may be considered for some patients if the 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 of the drug.1

The cumulative daily dose of oliceridine should not exceed 27 mg since use of higher cumulative daily doses may increase the risk for QT-interval prolongation.1 (See Prolongation of QT Interval under Cautions.) Patients who reach a 27-mg cumulative daily dose and still require analgesia should receive an alternative analgesic regimen (e.g., multimodal therapies) until oliceridine administration can be resumed the following day.1

Individual single doses of oliceridine exceeding 3 mg have not been evaluated and should not be used.1 The safety of oliceridine use beyond 48 hours has not been evaluated in clinical trials.1

The 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 should be used only as a guide since individual patients differ in their response to opiates.1

Dosage of oliceridine should be individually titrated to a level that provides adequate analgesia and minimizes adverse effects.1 When oliceridine therapy is discontinued in a patient who may be physically dependent on opiates, the dosage should be reduced gradually while carefully monitoring for manifestations of withdrawal.1 If manifestations of withdrawal occur, the dosage should be increased to the prior level and tapered more slowly (i.e., by increasing the interval between dosage reductions and/or reducing the amount of each incremental change in dose).1

Special Populations

Hepatic Impairment

No adjustment of the initial dose of oliceridine is needed in patients with mild or moderate hepatic impairment, but a longer interval between doses may be required.1 In patients with severe hepatic impairment, the drug should be dosed with caution; reduction of the initial dose should be considered, and subsequent doses should be administered only after careful review of the patient's pain severity and overall clinical status.1 (See Hepatic Impairment under Cautions.)

Renal Impairment

No dosage adjustment is required in patients with renal impairment.1

Geriatric Patients

In general, dosage selection for geriatric patients should be cautious, usually starting at the low end of the dosage range, and dosage should be titrated slowly.1 (See Geriatric Use under Cautions.)

CYP2D6 Poor Metabolizers

Less frequent dosing may be required in patients who are known or suspected poor metabolizers of cytochrome P-450 (CYP) 2D6 substrates (based on genotype or experience with other CYP2D6 substrates).1 Subsequent doses should be based on the patient's pain severity and response to treatment.1 (See Pharmacogenomic Considerations under Cautions.)

Contraindications

Oliceridine is contraindicated in patients with substantial 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; or known hypersensitivity (e.g., anaphylaxis) to the drug.1

Warnings/Precautions

Warnings

Addiction, Abuse, and Misuse

Oliceridine exposes patients and other users to the risks of opiate addiction, abuse, and misuse, which can lead to overdosage and death.1 Oliceridine has an abuse potential similar to that of other potent opiate agonists (e.g., fentanyl, hydrocodone, hydromorphone, methadone, morphine, oxycodone, oxymorphone, tapentadol).1 Addiction can occur at recommended dosages or may be associated with misuse or abuse.1 Concurrent abuse of alcohol and other CNS depressants increases the risk of toxicity.1 Each patient's risk for addiction, abuse, or misuse should be assessed prior to initiating oliceridine therapy, and all patients receiving the drug should be monitored for the development of these behaviors or conditions.1 Personal or family history of substance abuse (including drug or alcohol addiction or abuse) or mental illness (e.g., major depression) increases risk.1 The potential for addiction, abuse, or 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 Oliceridine should be prescribed in the smallest appropriate quantity.1

Respiratory Depression

Serious, life-threatening, or fatal respiratory depression can occur in patients receiving opiates, including oliceridine, even when the drugs are used as recommended.1 Carbon dioxide retention as a result of opiate-induced respiratory depression can exacerbate sedation and, in certain patients, can lead to elevated intracranial pressure.1 (See Increased Intracranial Pressure or Head Injury under Cautions.) Although respiratory depression can occur at any time during therapy, the risk is greatest during initiation of therapy or following an increase in dosa therefore, patients receiving oliceridine should be monitored closely for respiratory depression, especially during the first 24-48 hours of therapy and following any increase in dosage.1

Opiates also can cause sleep-related breathing disorders, including central sleep apnea and sleep-related hypoxemia.1 The risk of central sleep apnea is dose dependent; tapering of the opiate dosage should be considered in patients who present with central sleep apnea.1

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

Geriatric, cachectic, or debilitated patients are at increased risk for life-threatening respiratory depression since pharmacokinetics of opiate agonists may be altered in these patients.1 In patients with chronic obstructive pulmonary disease or cor pulmonale, substantially decreased respiratory reserve, hypoxia, hypercapnia, or preexisting respiratory depression, even recommended doses of oliceridine may decrease respiratory drive to the point of apnea.1 Such patients should be monitored closely, particularly during initiation of oliceridine therapy and dosage titration and when other drugs with respiratory depressant effects are used concomitantly.1 Alternatively, use of nonopiate analgesics should be considered in such patients.1 Use of oliceridine in patients with substantial respiratory depression or in those with acute or severe bronchial asthma in unmonitored settings or in the absence of resuscitative equipment is contraindicated.1

For usual guidelines for management of opiate agonist-induced respiratory depression, see Acute Toxicity: Treatment, in the Opiate Agonists General Statement 28:08.08.

Neonatal Opiate Withdrawal Syndrome

Prolonged maternal use of opiates, including oliceridine, during pregnancy can result in neonatal opiate withdrawal syndrome.1 (See Pregnancy under Cautions.)

Concomitant Use with Benzodiazepines or Other CNS Depressants

Profound sedation, respiratory depression, coma, and death may occur when opiate agonists are used concomitantly with benzodiazepines or other CNS depressants.1,700,701,702 Concomitant use of such drugs should be reserved for patients in whom alternative treatment options are inadequate.1,700,703 (See Benzodiazepines and Other CNS Depressants under Drug Interactions.)

Other Warnings and Precautions

General Opiate Agonist Precautions

Administration of oliceridine may cause effects similar to those produced by other opiate agonist drugs,1 and the usual precautions of opiate agonist therapy should be observed.1 (See the Opiate Agonists General Statement 28:08.08.)

Prolongation of QT Interval

Mild prolongation of the QT interval corrected for rate (QT_c) was observed in healthy individuals in studies evaluating the effect of oliceridine on cardiac physiology.1 In one study, dose-dependent prolongation of the QT_c interval was observed following single 3- and 6-mg IV doses of oliceridine (i.e., prolongation of 7 and 12 msec, respectively, following attainment of peak plasma concentrations of the drug).1 In another study, repeated doses of oliceridine over a 24-hour period (maximum cumulative dose of 27 mg) resulted in a maximum mean placebo-corrected change in QT_c interval from baseline (ΔΔQT_cI) of 11.7 msec at 9 hours; thereafter, the effect on the QT_c interval did not increase progressively with repeated dosing and, despite continued dosing, began to diminish after 12 hours.1 The mechanism and clinical importance of the transient QT-interval changes observed in these studies in healthy individuals are unknown.1

The findings of these studies should be carefully considered when oliceridine is used in situations associated with QT-interval prolongation (e.g., patients receiving concomitant drugs known to prolong the QT interval, those with underlying conditions associated with QT-interval prolongation).1 Cumulative daily doses exceeding 27 mg may increase the risk for QT_c-interval prolongation and should be avoided; the effect of such doses on the QT interval has not been systematically evaluated.1 (See Adult Dosage under Dosage and Administration.)

Cytochrome P-450-mediated Interactions

Because oliceridine is metabolized extensively, mainly by cytochrome P-450 (CYP) isoenzymes 2D6 and 3A4, 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 Patients receiving or discontinuing such concomitant therapy should be monitored closely at frequent intervals.1 (See Drugs Affecting or Metabolized by Hepatic Microsomal Enzymes under Drug Interactions.)

Pharmacogenomic Considerations

Patients who are poor metabolizers of CYP2D6 substrates may have increased plasma concentrations of oliceridine, which may exacerbate respiratory depression and prolong opiate-related adverse effects.1 In healthy individuals, systemic exposure to the drug was approximately twofold higher in CYP2D6 poor metabolizers compared with individuals who were not poor metabolizers.1 Because inhibition of both the CYP2D6 and CYP3A4 pathways can result in greater increases in plasma concentrations of oliceridine compared with inhibition of either metabolic pathway alone, 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 Patients receiving oliceridine who are known to be CYP2D6 poor metabolizers should be monitored closely 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 Drugs Affecting or Metabolized by Hepatic Microsomal Enzymes under Drug Interactions.)

Adrenal Insufficiency

Adrenal insufficiency has been reported in patients receiving opiate agonists or opiate partial agonists.1,400 Manifestations of adrenal insufficiency are nonspecific and may include nausea, vomiting, anorexia, fatigue, weakness, dizziness, and hypotension.1,400 In many of the reported cases, onset of adrenal insufficiency occurred after at least 1 month of opiate agonist or partial agonist use,1,400 although the time to onset has ranged from within 1 day to more than 1 year.400

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

Hypotension

Oliceridine may cause severe hypotension, including orthostatic hypotension and syncope, in ambulatory patients.1 Because the risk is increased in patients whose ability to maintain blood pressure has been compromised by blood volume depletion or concomitant use of certain CNS depressants (e.g., general anesthetics, phenothiazines), such patients should be monitored for hypotension following initiation of oliceridine therapy or an increase in dosage.1 Use of oliceridine should be avoided in patients with circulatory shock since the drug may cause vasodilation that can further reduce cardiac output and blood pressure.1

Increased Intracranial Pressure or Head Injury

The respiratory depressant effects of oliceridine promote carbon dioxide retention, which can result in elevation of intracranial pressure.1 Patients who may be particularly susceptible to these effects (e.g., those with evidence of increased intracranial pressure or brain tumors) should be monitored for sedation and respiratory depression, particularly during initiation of therapy.1 Opiates also may obscure the clinical course in patients with head injuries.1 Use of oliceridine should be avoided in patients with impaired consciousness or coma.1

GI Conditions

Oliceridine may increase serum amylase concentrations and cause spasm of the sphincter of Oddi.1 Patients with biliary tract disease, including those with acute pancreatitis, should be monitored for worsening symptoms during therapy with oliceridine.1

Oliceridine is contraindicated in patients with known or suspected GI obstruction, including paralytic ileus.1

Seizures

Oliceridine may increase the frequency of seizures in patients with seizure disorders and may increase the risk of seizures in some clinical settings associated with seizures.1 Patients with seizure disorders should be monitored for worsening of seizure control during oliceridine therapy.1

Dependence and Tolerance

Both physical dependence and tolerance can develop during long-term opiate therapy.1

In patients who are physically dependent on opiates, abrupt discontinuance of oliceridine or a substantial reduction in dosage may result in manifestations 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, increases in blood pressure, respiratory rate, or heart rate) and recurrence of pain.1 Withdrawal also may be precipitated by concomitant administration of an opiate partial agonist.1 (See Opiate Partial Agonists under Drug Interactions.) When oliceridine therapy is discontinued in a patient who may be physically dependent on opiates, the dosage should be tapered gradually.1

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

Oliceridine may impair mental alertness and/or physical coordination required to perform potentially hazardous tasks such as driving or operating machinery.1

Concurrent use of oliceridine and other CNS depressants may result in profound sedation, respiratory depression, coma, or death.1,700,703 (See Benzodiazepines and Other CNS Depressants under Drug Interactions.)

Patient-controlled Analgesia

Although self-administration of opiates via a patient-controlled analgesia (PCA) device may allow the patient to individually titrate dosage to an acceptable level of analgesia, PCA administration of opiates has resulted in adverse outcomes and episodes of respiratory depression.1 Clinicians and family members monitoring patients receiving opiate analgesics via PCA should be instructed in the need for appropriate monitoring for excessive sedation, respiratory depression, and other opiate-related adverse effects.1

Hypogonadism

Long-term use of opiates may reduce fertility in females and males of reproductive potential.1 It is not known whether these effects on fertility are reversible.1 Hypogonadism or androgen deficiency has been reported in patients receiving long-term opiate agonist or opiate partial agonist therapy,1,400,401,402,403,404 although a causal relationship has not been established.1,400 Patients receiving long-term opiate agonist or partial agonist therapy who present with manifestations of hypogonadism (e.g., decreased libido, impotence, erectile dysfunction, amenorrhea, infertility1 ) should undergo laboratory evaluation.400

In animal studies, oliceridine prolonged estrous cycle lengths and decreased the number of implantations and viable embryos in female rats at exposure levels of 3 or more times that achieved at the maximum recommended human dosage, but did not alter male fertility at any dosage tested.1

Specific Populations

Pregnancy

Analysis of data from the National Birth Defects Prevention Study, a large population-based, case-control study, suggests that therapeutic use of opiate agonists in pregnant women during the period of organogenesis is associated with a low absolute risk of birth defects, including heart defects, spina bifida, and gastroschisis.6 The manufacturer states that there are no available data regarding use of oliceridine in pregnant women by which to establish the risk of major birth defects and spontaneous abortion with the drug.1 In animal studies, no effects on embryofetal development were observed in rats or rabbits at oliceridine exposure levels of 7 or 8 times, respectively, the estimated plasma exposure at the maximum recommended human dosage.1 Oliceridine reduced live litter size at birth and increased postnatal pup mortality in rats at clinically relevant plasma concentrations.1

Use of opiates in pregnant women during labor can result in neonatal respiratory depression.1 Oliceridine is not recommended for use during or immediately prior to labor and delivery, when other analgesic techniques are more appropriate.1 Opiate analgesics can prolong labor by temporarily reducing the strength, duration, and frequency of uterine contractions; however, this effect is not consistent and may be offset by an increased rate of cervical dilatation, which tends to shorten labor.1 Neonates exposed to opiates during labor should be monitored for respiratory depression and excessive sedation; an opiate antagonist (e.g., naloxone) should be available to reverse opiate-induced respiratory depression in the neonate.1

Prolonged maternal use of opiates during pregnancy can result in neonatal opiate withdrawal syndrome with manifestations of irritability, hyperactivity and abnormal sleep pattern, high-pitched cry, tremor, vomiting, diarrhea, and failure to gain weight.1 In contrast to adults, the withdrawal syndrome in neonates may be life-threatening if not recognized and treated, and requires management according to protocols developed by neonatology experts.1 Women who require prolonged opiate agonist therapy during pregnancy should be advised of the risk of neonatal opiate withdrawal syndrome, and availability of appropriate treatment should be ensured.1 The onset, duration, and severity of the syndrome vary depending on the specific opiate agonist used, duration of use, timing and amount of last maternal use, and rate of drug elimination by the neonate.1 Neonates should be monitored for manifestations of opiate withdrawal and receive appropriate management as needed. 1

Lactation

It is not known whether oliceridine is distributed into human milk, affects breast-fed infants, or affects milk production.1 The developmental and health benefits of breast-feeding should be considered along with the mother's clinical need for oliceridine and any potential adverse effects on the breast-fed infant from the drug or from the underlying maternal condition.1

Infants exposed to oliceridine through breast milk should be monitored 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 of oliceridine in pediatric patients have not been established.1

Geriatric Use

Controlled clinical studies of oliceridine did not include sufficient numbers of patients 65 years of age and older to determine whether geriatric patients respond differently than younger adults.1 While other clinical experience has not revealed differences in response, dosage selection should be cautious, usually initiating therapy at the low end of the dosage range, since geriatric patients may be more sensitive to the effects of the drug.1 The greater frequency of decreased hepatic, renal, and/or cardiac function and of concomitant disease or other drug therapy in the elderly also should be considered.1

Respiratory depression is the chief risk for geriatric patients receiving opiate analgesics and has occurred following large initial doses in patients who were not opiate tolerant or when opiates were used concomitantly with other respiratory depressants.1 Geriatric patients receiving oliceridine therapy should be monitored for CNS and respiratory depression; dosage of the drug should be titrated slowly.1

Hepatic Impairment

Some pharmacokinetic parameters of oliceridine may be altered in patients with hepatic impairment.1,5 While clearance and total systemic exposure are not substantially altered in individuals with mild to severe hepatic impairment, estimated volume of distribution is substantially higher in those with moderate or severe impairment.1,5 The mean half-life of oliceridine also is increased in individuals with moderate (4.3 hours) or severe (5.8 hours) hepatic impairment, compared with healthy individuals (2.1 hours) or individuals with mild hepatic impairment (2.6 hours).1,5 Dosage adjustments may be required in patients with hepatic impairment.1 (See Hepatic Impairment under Dosage and Administration.) The drug should be used with caution in those with severe hepatic impairment.1

Renal Impairment

End-stage renal disease does not substantially alter the clearance of oliceridine; no dosage adjustment is required in patients with renal impairment.1,5

Common Adverse Effects

Adverse effects reported in 10% or more of patients receiving oliceridine in phase 3 controlled clinical trials include nausea, vomiting, dizziness, headache, constipation, pruritus, and hypoxia.1 These studies did not allow for comparison of the frequency of adverse effects following administration of equipotent dosages of oliceridine and morphine sulfate.1 (See Description.)

Drugs Affecting or Metabolized by Hepatic Microsomal Enzymes

In vitro studies suggest that oliceridine is metabolized mainly by cytochrome P-450 (CYP) isoenzymes 3A4 and 2D6, with minor contributions from CYP isoenzymes 2C9 and 2C19.1 Oliceridine does not inhibit CYP enzymes at clinically relevant concentrations.1

Moderate to Potent CYP2D6 Inhibitors

Concomitant use of oliceridine and moderate to potent CYP2D6 inhibitors (e.g., bupropion, fluoxetine, paroxetine, quinidine) can increase plasma concentrations of oliceridine, resulting in increased or prolonged opiate effects (e.g., exacerbated respiratory depression).1 Although drug interaction studies involving oliceridine and CYP2D6 inhibitors are lacking, the effect of CYP2D6 inhibitors on the pharmacokinetics of oliceridine may be similar to the pharmacokinetic changes observed in CYP2D6 poor metabolizers (i.e., approximately 50% reduction in plasma clearance and twofold increase in systemic exposure of oliceridine compared with individuals who are not CYP2D6 poor metabolizers).1 If concomitant use of oliceridine and moderate to potent CYP2D6 inhibitors is required, a reduction in the frequency of oliceridine dosing may be needed.1 Patients receiving such concomitant therapy should be monitored closely for respiratory depression and sedation at frequent intervals, and dosage should be adjusted according to the patient's severity of pain and response to treatment.1

If a moderate or potent CYP2D6 inhibitor is discontinued, oliceridine concentrations may decrease as the effects of the CYP2D6 inhibitor abate, resulting in decreased analgesic efficacy and/or development of opiate withdrawal syndrome.1 Patients should be monitored for opiate withdrawal; an increase in oliceridine dosage may be considered until stable drug effects are achieved.1

Moderate to Potent CYP3A4 Inhibitors

Concomitant use of oliceridine and moderate to potent CYP3A4 inhibitors (e.g., macrolide antibiotics [e.g., erythromycin], azole antifungals [e.g., itraconazole, ketoconazole], protease inhibitors [e.g., ritonavir], selective serotonin-reuptake inhibitors [SSRIs]) can increase plasma concentrations of oliceridine, resulting in increased or prolonged opiate effects (e.g., exacerbated respiratory depression).1 Oliceridine should be used with caution in patients receiving CYP3A4 inhibitors.1 If concomitant use of oliceridine and moderate to potent CYP3A4 inhibitors is required, a reduction in the frequency of oliceridine dosing may be needed.1 Patients receiving such concomitant therapy should be monitored closely for respiratory depression and sedation at frequent intervals, and dosage should be adjusted according to the patient's severity of pain and response to treatment.1

If a moderate or potent CYP3A4 inhibitor is discontinued, oliceridine concentrations may decrease as the effects of the CYP3A4 inhibitor abate, resulting in decreased analgesic efficacy and/or development of opiate withdrawal syndrome.1 Patients should be monitored for opiate withdrawal; an increase in oliceridine dosage may be considered until stable drug effects are achieved.1

Combined Moderate to Potent CYP3A4 and CYP2D6 Inhibition

Inhibition of both the CYP3A4 and CYP2D6 metabolic pathways can result in a greater increase in plasma oliceridine concentrations than inhibition of either metabolic pathway alone.1 A reduction in the frequency of oliceridine dosing may be required in patients receiving therapy with both a CYP2D6 inhibitor and a potent CYP3A4 inhibitor.1 These patients should be monitored closely for respiratory depression and sedation at frequent intervals, and dosage should be adjusted according to the patient's severity of pain and response to treatment.1

In healthy CYP2D6 poor metabolizers, concomitant administration of oliceridine (single 0.25-mg dose) and the potent CYP3A4 inhibitor itraconazole (200 mg daily) increased systemic exposure to oliceridine by approximately 80% compared with administration of oliceridine alone, but did not substantially alter the peak concentration of the drug.1,2 In CYP2D6 poor metabolizers receiving oliceridine and itraconazole, mean clearance of oliceridine was reduced to approximately 30% of that observed in individuals who were not CYP2D6 poor metabolizers.1

CYP3A4 Inducers

Concomitant use of oliceridine and CYP3A4 inducers (e.g., carbamazepine, phenytoin, rifampin) can decrease plasma concentrations of oliceridine, resulting in decreased analgesic efficacy and/or development of opiate withdrawal.1 Patients should be monitored for opiate withdrawal, and dosage adjustments should be considered until stable drug effects are achieved.1

If a CYP3A4 inducer is discontinued, oliceridine concentrations may increase as the effects of the CYP3A4 inducer abate, possibly resulting in increased or prolonged therapeutic or adverse effects, including serious respiratory depression.1 A reduction in the frequency of oliceridine dosing may be required; the patient should be monitored for signs of respiratory depression.1

Drugs Affected by Transport Systems

In vitro data indicate that oliceridine does not inhibit major transporters, including breast cancer resistance protein (BCRP) and P-glycoprotein (P-gp), at clinically relevant concentrations.1

Anticholinergic Agents

Concomitant use of oliceridine and drugs with anticholinergic activity may increase the risk of urinary retention and/or severe constipation, which can lead to paralytic ileus.1 Patients receiving such concomitant therapy should be monitored for signs or symptoms of urinary retention and reduced GI motility.1

Benzodiazepines and Other CNS Depressants

Concomitant use of opiate agonists and benzodiazepines or other CNS depressants, including other opiate agonists, anxiolytics, sedatives, hypnotics, tranquilizers, muscle relaxants, general anesthetics, antipsychotics, and alcohol, may result in hypotension, profound sedation, respiratory depression, coma, and death.1,416,417,418,700,701,702,703 A substantial proportion of fatal opiate overdoses involve concurrent benzodiazepine use.416,417,418,435,700,701 Whenever possible, concomitant use of opiate agonists and benzodiazepines should be avoided.410,411,415,435 Concomitant use of opiate analgesics and benzodiazepines or other CNS depressants should be reserved for patients in whom alternative treatment options are inadequate; the lowest effective dosages and shortest possible duration of concomitant therapy should be used, and the patient should be monitored closely for respiratory depression and sedation.1,700,703 (See Drug Interactions: Benzodiazepines and Other CNS Depressants, in the Opiate Agonists General Statement 28:08.08.)

If a benzodiazepine or other CNS depressant is required for any indication other than epilepsy in a patient receiving an opiate analgesic, the drug should be initiated at a lower dosage than indicated in the absence of opiate therapy and titrated based on clinical response.1,700,703 In patients receiving a CNS depressant, opiate analgesics, if required, should be initiated at a reduced dosage and titrated based on clinical response.1,700,703 Patients receiving such concomitant therapy should be monitored closely for respiratory depression and sedation.1 Clinicians should consider prescribing the opiate antagonist naloxone for patients receiving opiates who are at increased risk of opiate overdosage, including those receiving benzodiazepines or other CNS depressants concomitantly.411,431,750

Diuretics

Opiate agonists may decrease the effects of diuretics by inducing the release of vasopressin (antidiuretic hormone).1 Patients receiving such concomitant therapy should be monitored for decreased diuretic or hypotensive effects; dosage of the diuretic may be increased if clinically indicated.1

Neuromuscular Blocking Agents

Oliceridine may enhance the neuromuscular blocking action and increase the respiratory depressant effect of neuromuscular blocking agents.1 Patients receiving such concomitant therapy should be monitored for a greater than expected degree of respiratory depression; dosage of one or both drugs should be decreased as needed.1

Opiate Partial Agonists

Use of opiate partial agonists (e.g., buprenorphine, butorphanol, nalbuphine, pentazocine) should be avoided in patients receiving oliceridine, since the partial agonist may reduce the analgesic effect of oliceridine, a full opiate agonist, and/or precipitate withdrawal symptoms.1

Serotonergic Drugs

Serotonin syndrome has occurred in patients receiving opiate agonists in conjunction with other serotonergic drugs, including serotonin (5-hydroxytryptamine; 5-HT) type 1 receptor agonists (“triptans”), selective serotonin-reuptake inhibitors (SSRIs), selective serotonin- and norepinephrine-reuptake inhibitors (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 monoamine oxidase (MAO) inhibitors (both those used to treat psychiatric disorders and others, such as linezolid, methylene blue, and selegiline).1,400 Serotonin syndrome may occur within the recommended dosage ranges for these drugs.400 Manifestations of serotonin syndrome may include mental status changes (e.g., agitation, hallucinations, coma), autonomic instability (e.g., tachycardia, labile blood pressure, hyperthermia), neuromuscular aberrations (e.g., hyperreflexia, incoordination, rigidity), and/or GI symptoms (e.g., nausea, vomiting, diarrhea).400 Symptom onset generally occurs within several hours to a few days of concomitant use, but may occur later, particularly after dosage increases.400

If concurrent therapy with opiate agonists and serotonergic drugs is warranted, patients should be monitored for serotonin syndrome, particularly during initiation of therapy and dosage increases.1,400 If serotonin syndrome is suspected, treatment with oliceridine, other opiate therapy, and/or any concurrently administered serotonergic agents should be discontinued.1,400

For further information on serotonin syndrome, including manifestations and treatment, see Drug Interactions: Serotonergic Drugs, in Fluoxetine Hydrochloride 28:16.04.20.

Description

Oliceridine is a full opiate agonist that is relatively selective for the µ-opiate receptor.1,2,3,4,8,10 Oliceridine is structurally unrelated to morphine or other µ-opiate receptor agonists.10 The 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 analgesic effects of the drug.1 Binding of agonists to opiate receptors results in activation of various signaling pathways, including G-protein-coupled and β-arrestin pathways.7,9,10 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 It is hypothesized that this preferential effect of oliceridine 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 is required to establish the clinical relevance of this differential effect.2,7,8,9,10

Following IV administration of oliceridine, the onset of action is rapid (median: 1-3 minutes), with most patients experiencing perceptible pain relief within 5 minutes after the initial dose.1 Differences in the IV infusion time do not appear to alter the drug's pharmacokinetics, with the exception of peak plasma concentration.1 Oliceridine is extensively distributed into tissues and is 77% bound to plasma proteins.1 The drug is extensively metabolized, mainly by oxidation with subsequent glucuronidation and to a lesser extent by N -dealkylation, glucuronidation, and dehydrogenation.1 Metabolism is mediated mainly by cytochrome P-450 (CYP) isoenzymes 3A4 and 2D6, with minor contributions from CYP isoenzymes 2C9 and 2C19.1 None of the identified metabolites have appreciable activity at the µ-opiate receptor.1 The metabolites are eliminated mainly (70%) in urine, with the remainder eliminated in feces; approximately 1-7% of an administered dose is recovered as unchanged drug in urine.1 Mean clearance of oliceridine decreases slightly with increasing dose, resulting in greater than proportional exposure, particularly at doses exceeding 2 mg.1 Oliceridine has a half-life of 1.3-3 hours.1

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 blood pressure, 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.)

Additional Information

Overview^® (see Users Guide). For additional information on this drug until a more detailed monograph is developed and published, the manufacturer's labeling should be consulted. It is essential that the manufacturer's labeling be consulted for more detailed information on usual cautions, precautions, contraindications, potential drug interactions, laboratory test interferences, and acute toxicity.

1. Trevena, Inc. Olinvyk^® (oliceridine fumarate) injection prescribing information. Chesterbrook, PA; 2021 Mar.

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