Oliceridine
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Alara Ece Dagsali, M.D.
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Black Box Warning
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SERIOUS AND LIFE-THREATENING RISKS FROM USE OF OLINVYK
See full prescribing information for complete Boxed Warning.
Addiction, Abuse, and Misuse: (Because the use of OLINVYK exposes patients and other users to the risks of opioid addiction, abuse, and misuse, which can lead to overdose and death, assess each patient’s risk prior to prescribing and reassess all patients regularly for the development of these behaviors and conditions)
Life-Threatening Respiratory Depression: (Serious, life-threatening, or fatal respiratory depression may occur with use of OLINVYK, especially during initiation or following a dosage increase. To reduce the risk of respiratory depression, proper dosing and titration of OLINVYK are essential) Risks From Concomitant Use With Benzodiazepines Or Other CNS Depressants: (Concomitant use of opioids with benzodiazepines or other central nervous system (CNS) depressants, including alcohol, may result in profound sedation, respiratory depression, coma, and death. Reserve concomitant prescribing of OLINVYK and benzodiazepines or other CNS depressants for use in patients for whom alternative treatment options are inadequate) Neonatal Opioid Withdrawal Syndrome: (If opioid use is required for an extended period of time in a pregnant woman, advise the patient of the risk of NOWS, which may be life-threatening if not recognized and treated. Ensure that management by neonatology experts will be available at delivery) |
Overview
Oliceridine is an μ opioid agonist that is FDA approved for the {{{indicationType}}} of OLINVYK is indicated in adults for the management of acute pain severe enough to require an intravenous opioid analgesic and for whom alternative treatments are inadequate.. There is a Black Box Warning for this drug as shown here. Common adverse reactions include The following adverse reactions are described, or described in greater detail, in other sections:
- Addiction, Abuse, and Misuse
- Life-threatening Respiratory Depression
- Interactions with Benzodiazepines or Other CNS Depressants.
- Neonatal Opioid Withdrawal Syndrome.
- Opioid-Induced Hyperalgesia and Allodynia.
- Adrenal Insufficiency.
- Severe Hypotension.
- Gastrointestinal Adverse Reactions.
- Seizures.
- Withdrawal..
Adult Indications and Dosage
FDA-Labeled Indications and Dosage (Adult)
OLINVYK is indicated in adults for the management of acute pain severe enough to require an intravenous opioid analgesic and for whom alternative treatments are inadequate. DOSAGE For intravenous administration only.
OLINVYK should be prescribed only by healthcare professionals who are knowledgeable about the use of opioids and how to mitigate the associated risks.
Individual single doses greater than 3 mg have not been evaluated.
The cumulative daily dose should not exceed 27 mg.
OLINVYK 30 mg/30 mL (1mg/mL) vial is intended for patient-controlled analgesia (PCA) use only. Draw OLINVYK directly from the vial into the PCA syringe or IV bag without diluting.
Use the lowest effective dose for the shortest duration consistent with individual patient treatment goals. Because the risk of overdose increases as opioid doses increase, reserve titration to higher doses of OLINVYK for patients in whom lower doses are insufficiently effective and in whom the expected benefits of using a higher dose opioid clearly outweigh the substantial risks.
Use of OLINVYK beyond 48 hours has not been studied in controlled clinical trials.
There is variability in opioid analgesic dose and duration needed to adequately manage pain due both to the cause of pain and to individual patient factors. Initiate the dosing regimen for each patient individually, taking into account the patient's underlying cause and severity of pain, prior analgesic treatment and response, and risk factors for addiction, abuse.
Respiratory depression can occur at any time during opioid therapy, especially when initiating and following dosage increases with OLINVYK. Consider this risk when selecting an initial dose and when making dose adjustments.
Inspect OLINVYK for particulate matter and discoloration prior to administration. The solution is a clear, colorless, preservative free solution for intravenous use. If visibly opaque particles, discoloration, or other foreign particles are observed, do not use.
Off-Label Use and Dosage (Adult)
Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Oliceridine in adult patients.
Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Oliceridine in adult patients.
Pediatric Indications and Dosage
FDA-Labeled Indications and Dosage (Pediatric)
There is limited information regarding Oliceridine FDA-Labeled Indications and Dosage (Pediatric) in the drug label.
Off-Label Use and Dosage (Pediatric)
Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Oliceridine in pediatric patients.
Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Oliceridine in pediatric patients.
Contraindications
OLINVYK is contraindicated in patients with:
- Significant respiratory depression
- Acute or severe bronchial asthma in an unmonitored setting or in the absence of resuscitative equipment
- Known or suspected gastrointestinal obstruction, including paralytic ileus
- Known hypersensitivity to oliceridine (e.g., anaphylaxis)
Warnings
|
SERIOUS AND LIFE-THREATENING RISKS FROM USE OF OLINVYK
See full prescribing information for complete Boxed Warning.
Addiction, Abuse, and Misuse: (Because the use of OLINVYK exposes patients and other users to the risks of opioid addiction, abuse, and misuse, which can lead to overdose and death, assess each patient’s risk prior to prescribing and reassess all patients regularly for the development of these behaviors and conditions)
Life-Threatening Respiratory Depression: (Serious, life-threatening, or fatal respiratory depression may occur with use of OLINVYK, especially during initiation or following a dosage increase. To reduce the risk of respiratory depression, proper dosing and titration of OLINVYK are essential) Risks From Concomitant Use With Benzodiazepines Or Other CNS Depressants: (Concomitant use of opioids with benzodiazepines or other central nervous system (CNS) depressants, including alcohol, may result in profound sedation, respiratory depression, coma, and death. Reserve concomitant prescribing of OLINVYK and benzodiazepines or other CNS depressants for use in patients for whom alternative treatment options are inadequate) Neonatal Opioid Withdrawal Syndrome: (If opioid use is required for an extended period of time in a pregnant woman, advise the patient of the risk of NOWS, which may be life-threatening if not recognized and treated. Ensure that management by neonatology experts will be available at delivery) |
Addiction, Abuse, and Misuse’’’ OLINVYK contains oliceridine, a Schedule II controlled substance. As an opioid, OLINVYK exposes users to the risks of addiction, abuse, and misuse Although the risk of addiction in any individual is unknown, it can occur in patients appropriately prescribed OLINVYK. Addiction can occur at recommended dosages and if the drug is misused or abused Assess each patient’s risk for opioid addiction, abuse, or misuse prior to prescribing OLINVYK, and monitor all patients receiving OLINVYK for the development of these behaviors or conditions. Risks are increased in patients with a personal or family history of substance abuse (including drug or alcohol abuse or addiction) or mental illness (e.g., major depression). The potential for these risks should not, however, prevent the proper management of pain in any given patient. Patients at increased risk may be prescribed opioids such as OLINVYK, but use in such patients necessitates intensive counseling about the risks and proper use of OLINVYK along with intensive monitoring for signs of addiction, abuse, and misuse. Opioids are sought for nonmedical use and are subject to diversion from legitimate prescribed use. Consider these risks when prescribing or dispensing OLINVYK. Strategies to reduce these risks include prescribing the drug in the smallest appropriate quantity. Contact local state professional licensing board or state-controlled substances authority for information on how to prevent and detect abuse or diversion of this product. Life-Threatening Respiratory Depression Serious, life-threatening respiratory depression has been reported with the use of opioids, even when used as recommended. Respiratory depression, if not immediately recognized and treated, may lead to respiratory arrest and death. Management of respiratory depression may include close observation, supportive measures, and use of opioid antagonists, depending on the patient’s clinical status. Carbon dioxide (CO2) retention from opioid-induced respiratory depression can exacerbate the sedating effects of opioids. While serious, life-threatening, or fatal respiratory depression can occur at any time during the use of opioids, the risk is greatest during initiation of therapy or following a dose increase. Monitor patients closely for respiratory depression, especially when initiating therapy with OLINVYK and following dosage increases. To reduce the risk of respiratory depression, proper dosing of OLINVYK is essential. Overestimating the OLINVYK dosage when converting patients from another opioid product can result in fatal overdose with the first dose. Opioids can cause sleep-related breathing disorders including central sleep apnea (CSA) and sleep-related hypoxemia. Opioid use increases the risk of CSA in a dose-dependent fashion. In patients who present with CSA, consider decreasing the opioid dosage using best practices for opioid taper. Risks from Concomitant Use with Benzodiazepines or Other CNS Depressants Profound sedation, respiratory depression, coma, and death may result from the concomitant use of OLINVYK with benzodiazepines and/or other CNS depressants, including alcohol (e.g., non-benzodiazepine sedatives/hypnotics, anxiolytics, tranquilizers, muscle relaxants, general anesthetics, antipsychotics, other opioids, or alcohol). Because of these risks, reserve concomitant prescribing of these drugs for use in patients for whom alternative treatment options are inadequate. Observational studies have demonstrated that concomitant use of opioid analgesics and benzodiazepines increases the risk of drug-related mortality compared to use of opioid analgesics alone. Because of similar pharmacological properties, it is reasonable to expect similar risk with the concomitant use of other CNS depressant drugs with opioid analgesics. If the decision is made to prescribe a benzodiazepine or other CNS depressant concomitantly with an opioid analgesic, prescribe the lowest effective dosages and minimum durations of concomitant use. In patients already receiving an opioid analgesic, prescribe a lower initial dose of the benzodiazepine or other CNS depressant than indicated in the absence of an opioid, and titrate based on clinical response. If an opioid analgesic is initiated in a patient already taking a benzodiazepine or other CNS depressant, prescribe a lower initial dose of the opioid analgesic, and titrate based on clinical response. Monitor patients closely for signs and symptoms of respiratory depression and sedation. Neonatal Opioid Withdrawal Syndrome Use of OLINVYK for an extended period of time during pregnancy can result in withdrawal in the neonate. Neonatal opioid withdrawal syndrome, unlike opioid withdrawal syndrome in adults, may be life threatening if not recognized and treated, and requires management according to protocols developed by neonatology experts. Observe newborns for signs of neonatal opioid withdrawal syndrome and manage accordingly. Advise women using opioids for an extended period of time of the risk of neonatal opioid withdrawal syndrome and ensure that management by neonatology experts will be available at delivery. Potential for QT prolongation with Daily Doses exceeding 27 mg The effect of oliceridine on cardiac physiology was studied in single and multiple-dose thorough QT studies. The multiple-dose study was conducted with a maximum daily cumulative dose of 27 mg. In both studies, there was mild QTc interval prolongation. In the multiple-dose study, the maximum mean ΔΔQTcI was 11.7 ms (two-sided 90% UCI 14.7 ms) at 9 hours. The effect on QT prolongation at total cumulative daily doses >27 mg has not been studied in a thorough QT study. Total cumulative daily doses exceeding 27 mg per day may increase the risk for QTc interval prolongation. Therefore, the cumulative total daily dose of OLINVYK should not exceed 27 mg. Risk of Use in Patients with Decreased Cytochrome P450 2D6 Function or Concomitant Use or Discontinuation with Cytochrome P450 3A4 Inhibitors and Inducers Risk of Increased Oliceridine Plasma Concentrations Increased plasma concentrations of oliceridine, which may result in prolonged opioid adverse reactions and exacerbated respiratory depression, may occur when OLINVYK is used under the following conditions:
- In patients with decreased Cytochrome P450 (CYP) 2D6 function (poor metabolizers of CYP2D6 or normal metabolizers taking moderate or strong CYP2D6 inhibitors.
- In patients taking a moderate or strong CYP3A4 inhibitor
- In patients with decreased CYP2D6 function who are also receiving a moderate or strong CYP3A4 inhibitor
- Discontinuation of a CYP3A4 inducer
These patients may require less frequent dosing of OLINVYK. Closely monitor these patients for respiratory depression and sedation at frequent intervals and base subsequent doses of OLINVYK on the patient’s severity of pain and response to treatment.
Risk of Lower than Expected Oliceridine Plasma Concentrations
Lower than expected concentrations of oliceridine, which may lead to decreased efficacy, may occur under the following conditions:
- Concomitant use of OLINVYK with CYP3A4 inducers
- Discontinuation of a moderate or strong CYP3A4 or CYP2D6 inhibitor
Closely monitor these patients at frequent intervals and consider supplemental doses of OLINVYK. Opioid-Induced Hyperalgesia and Allodynia Opioid-Induced Hyperalgesia (OIH) occurs when an opioid analgesic paradoxically causes an increase in pain, or an increase in sensitivity to pain. This condition differs from tolerance, which is the need for increasing doses of opioids to maintain a defined effect. Symptoms of OIH include (but may not be limited to) increased levels of pain upon opioid dosage increase, decreased levels of pain upon opioid dosage decrease, or pain from ordinarily non-painful stimuli (allodynia). These symptoms may suggest OIH only if there is no evidence of underlying disease progression, opioid tolerance, opioid withdrawal, or addictive behavior. Cases of OIH have been reported, both with short-term and longer-term use of opioid analgesics. Though the mechanism of OIH is not fully understood, multiple biochemical pathways have been implicated. Medical literature suggests a strong biologic plausibility between opioid analgesics and OIH and allodynia. If a patient is suspected to be experiencing OIH, carefully consider appropriately decreasing the dose of the current opioid analgesic or opioid rotation (safely switching the patient to a different opioid moiety). Life-Threatening Respiratory Depression in Patients with Chronic Pulmonary Disease or in Elderly, Cachectic, or Debilitated Patients The use of OLINVYK in patients with acute or severe bronchial asthma in an unmonitored setting or in the absence of resuscitative equipment is contraindicated. Patients with Chronic Pulmonary Disease: OLINVYK-treated patients with significant chronic obstructive pulmonary disease or cor pulmonale, and those with a substantially decreased respiratory reserve, hypoxia, hypercapnia, or preexisting respiratory depression are at increased risk of decreased respiratory drive including apnea, even at recommended dosages of OLINVYK. Elderly, Cachectic, or Debilitated Patients: Life-threatening respiratory depression is more likely to occur in elderly, cachectic, or debilitated patients as they may have altered pharmacokinetics or altered clearance compared to younger, healthier patients. Monitor such patients closely, particularly when initiating and titrating OLINVYK and when OLINVYK is given concomitantly with other drugs that depress respiration. Alternatively, consider the use of non-opioid analgesics in these patients. Adrenal Insufficiency Cases of adrenal insufficiency have been reported with opioid use, more often following greater than one month of use. Presentation of adrenal insufficiency may include non-specific symptoms and signs including nausea, vomiting, anorexia, fatigue, weakness, dizziness, and low blood pressure. If adrenal insufficiency is suspected, confirm the diagnosis with diagnostic testing as soon as possible. If adrenal insufficiency is diagnosed, treat with physiologic replacement doses of corticosteroids. Wean the patient off of the opioid to allow adrenal function to recover and continue corticosteroid treatment until adrenal function recovers. Other opioids may be tried as some cases reported use of a different opioid without recurrence of adrenal insufficiency. The information available does not identify any particular opioids as being more likely to be associated with adrenal insufficiency. Severe Hypotension OLINVYK may cause severe hypotension, including orthostatic hypotension and syncope in ambulatory patients. There is increased risk in patients whose ability to maintain blood pressure has already been compromised by a reduced blood volume or concurrent administration of certain CNS depressant drugs (e.g., phenothiazines or general anesthetics. Monitor these patients for signs of hypotension after initiating or titrating the dosage of OLINVYK. In patients with circulatory shock, OLINVYK may cause vasodilation that can further reduce cardiac output and blood pressure. Avoid the use of OLINVYK in patients with circulatory shock. Risks of Use in Patients with Increased Intracranial Pressure, Brain Tumors, Head Injury, or Impaired Consciousness In patients who may be susceptible to the intracranial effects of CO2 retention (e.g., those with evidence of increased intracranial pressure or brain tumors), OLINVYK may reduce respiratory drive, and the resultant CO2 retention can further increase intracranial pressure. Monitor such patients for signs of sedation and respiratory depression, particularly when initiating therapy with OLINVYK. Opioids may also obscure the clinical course in a patient with a head injury. Avoid the use of OLINVYK in patients with impaired consciousness or coma. Risks of Use in Patients with Gastrointestinal Conditions OLINVYK is contraindicated in patients with known or suspected gastrointestinal obstruction, including paralytic ileus. OLINVYK may cause spasm of the sphincter of Oddi. Opioids may cause increases in serum amylase. Monitor patients with biliary tract disease, including acute pancreatitis, for worsening symptoms. Increased Risk of Seizures in Patients with Seizure Disorders OLINVYK may increase the frequency of seizures in patients with seizure disorders, and may increase the risk of seizures occurring in other clinical settings associated with seizures. Monitor patients with a history of seizure disorders for worsened seizure control during OLINVYK therapy. Withdrawal Do not abruptly discontinue OLINVYK in a patient physically dependent on opioids. When discontinuing OLINVYK in a physically-dependent patient, gradually taper the dosage. Rapid tapering of oliceridine in a patient physically dependent on opioids may lead to a withdrawal syndrome and return of pain. Additionally, avoid the use of mixed agonist/antagonist (e.g, pentazocine, nalbuphine, and butorphanol) or partial agonist (e.g., buprenorphine) analgesics in patients who are receiving a full opioid agonist analgesic, including OLINVYK. In these patients, mixed agonist/antagonist and partial agonist analgesics may reduce the analgesic effect and/or precipitate withdrawal symptoms. Risks of Driving and Operating Machinery OLINVYK may impair the mental or physical abilities needed to perform potentially hazardous activities such as driving a car or operating machinery. Warn patients not to drive or operate dangerous machinery unless they are tolerant to the effects of OLINVYK and know how they will react to the medication. Patient-Controlled Analgesia (PCA) Although self-administration of opioids by PCA may allow each patient to individually titrate to an acceptable level of analgesia, PCA administration has resulted in adverse outcomes and episodes of respiratory depression. Health care providers and family members monitoring patients receiving PCA analgesia should be instructed in the need for appropriate monitoring for excessive sedation, respiratory depression, or other adverse effects of opioid medications.
Adverse Reactions
Clinical Trials Experience
in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice.
A total of 1535 patients were treated with OLINVYK in controlled and open-label trials in patients with moderate to severe acute pain. Of these, 1181 patients received a total daily dose ≤27 mg and 354 patients received a total daily dose >27 mg during the first 24-hour treatment period. Among patients who received a daily dose of >27 mg, 198 patients received a daily dose between 27 mg and 40 mg, and 142 patients received a daily dose >40 mg.
The most common adverse drug reactions (≥10%) in controlled efficacy trials (Study 1 and Study 2) were nausea, vomiting, dizziness, headache, constipation, pruritus and hypoxia. Adverse reactions leading to discontinuation of OLINVYK were hypotension, hypoxia, nausea, hypoventilation, oxygen saturation decreased, alanine aminotransferase increased, aspartate aminotransferase increased, electrocardiogram QT prolongation, and urticaria. In two randomized, double-blind, placebo- and morphine-controlled studies, when stratified by 27 mg daily dosing limit, discontinuation of OLINVYK due to adverse reactions occurred in 4% of patients who received a daily dose ≤ 27 mg, and less than 1% of patients who received a daily dose >27 mg. In these same studies, discontinuation due to adverse reactions occurred in 5% of morphine-treated patients, and no placebo-treated patients. In an open-label safety study, discontinuation of OLINVYK due to adverse drug reactions occurred in 3% of patients who received a daily dose ≤ 27 mg, and 1% of patients who received a daily dose >27 mg.
In two randomized, double-blind, placebo- and morphine-controlled studies in patients with moderate to severe acute pain following either orthopedic surgery-bunionectomy (Study 1), or plastic surgery-abdominoplasty (Study 2), patients received one of three OLINVYK dosing regimens, a morphine- control regimen, or a volume‑matched placebo-control regimen. All dosing regimens were administered via patient-controlled analgesia (PCA), allowing patients to individually titrate the dose available to an acceptable level of analgesia. Patients were treated for up to 48 hours in the bunionectomy study (Study 1), and for up to 24 hours in the abdominoplasty study(Study 2). The loading dose for all OLINVYK treatment regimens was 1.5 mg; demand doses were 0.1, 0.35, or 0.5 mg, according to assigned treatment group; supplemental doses of 0.75 mg were permitted, beginning 1 hour after the loading dose, and hourly thereafter, as needed. The loading dose for the morphine treatment regimen was 4 mg; the demand dose was 1 mg; and supplemental doses of 2 mg were permitted, beginning 1 hour after the loading dose, and hourly thereafter, as needed. A lockout interval of 6 minutes was used for all PCA regimens.
In Study 1, a total of 136 patients received OLINVYK ≤27 mg/day, and 98 patients received OLINVYK >27 mg/day during the first 24 hours. In Study 2, a total of 180 patients received OLINVYK ≤27 mg/day, and 56 patients received OLINVYK >27 mg/day during the first 24 hours.
Table 1 and Table 2 list adverse drug reactions that were reported in ≥5% of OLINVYK-treated patients in each study, and that occurred at a frequency greater than placebo in at least one of the studies. Table 2 and Table 3 lists adverse drug reactions that were reported in ≥5% of OLINVYK-treated patients for pooled Studies 1 and 2 stratified by total daily dose (≤27 mg/day or >27 mg/day).
These data are not an adequate basis for comparison of rates between the OLINVYK treatment group and the morphine treatment group. The OLINVYK and morphine dosing regimens studied are not considered equipotent.
Postmarketing Experience
Serotonin syndrome: Cases of serotonin syndrome, a potentially life-threatening condition, have been reported during concomitant use of opioids with serotonergic drugs.
Adrenal insufficiency: Cases of adrenal insufficiency have been reported with opioid use, more often following greater than one month of use.
Anaphylaxis: Anaphylaxis has been reported with ingredients contained in OLINVYK.
Androgen deficiency: Cases of androgen deficiency have occurred with use of opioids for an extended period of time.
Hyperalgesia and Allodynia: Cases of hyperalgesia and allodynia have been reported with opioid therapy of any duration.
Hypoglycemia: Cases of hypoglycemia have been reported in patients taking opioids. Most reports were in patients with at least one predisposing risk factor (e.g., diabetes).
Drug Interactions
- Clinically Significant Drug Interactions with OLINVYK
Moderate to Strong Inhibitors of CYP2D6
- Moderate to Strong Inhibitors of CYP3A4
- Strong and Moderate CYP3A4 Inhibitors and CYP2D6 Inhibitors
- Inducers of CYP3A4
- Benzodiazepines and Other Central Nervous System (CNS) Depressants
- Serotonergic Drugs
- Mixed Agonist/Antagonist and Partial Agonist Opioid Analgesics
- Muscle Relaxants
- Diuretics
- Anticholinergic Drugs
Use in Specific Populations
Pregnancy
Pregnancy Category (FDA):
There is no FDA guidance on usage of Oliceridine in women who are pregnant.
Pregnancy Category (AUS):
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Oliceridine in women who are pregnant.
Labor and Delivery
Use of opioid analgesics for an extended period of time during pregnancy may result in neonatal opioid withdrawal syndrome. There are no available data on OLINVYK use in pregnant women to evaluate for a drug-associated risk of major birth defects and miscarriage or adverse maternal outcomes. There are adverse outcomes reported within detal exposure to opioid analgesics.
In animal reproductive studies, oliceridine reduced live litter size at birth and increased postnatal pup mortality between birth and Postnatal Day 4 when administered intravenously to rats from organogenesis through weaning at doses producing clinically relevant plasma exposure. Oliceridine had no effect on embryo-fetal development in rats and rabbits when administered intravenously during organogenesis at doses producing plasma exposures 7 and 8 times the estimated plasma exposure at the maximum recommended human dose (MRHD) on an AUC basis, respectively.
The background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively.
Nursing Mothers
It is not known whether oliceridine is present in human milk. The effects of oliceridine on a breastfeeding infant and on milk production have not been evaluated.
The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for OLINVYK and any potential adverse effects on the breastfed infant from OLINVYK or from the underlying maternal condition.
Pediatric Use
The safety and effectiveness of OLINVYK in pediatric patients has not been established.
Geriatic Use
Controlled clinical studies of OLINVYK did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.
Elderly patients (aged 65 years or older) may have increased sensitivity to OLINVYK. In general, use caution when selecting a dosage for an elderly patient, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function and of concomitant disease or other drug therapy.
Respiratory depression is the chief risk for elderly patients treated with opioids, and has occurred after large initial doses were administered to patients who were not opioid-tolerant or when opioids were co-administered with other agents that depress respiration. Titrate the dosage of OLINVYK slowly in geriatric patients and monitor for signs of central nervous system and respiratory depression
Gender
Human Data
Use of opioids for an extended period of time may cause reduced fertility in females and males of reproductive potential. It is not known whether these effects on fertility are reversible.
Animal Data
Oliceridine administered intravenously for 14 days prior to cohabitation and administered through GD15 caused prolonged estrous cycle lengths and decreased the number of implantations and viable embryos in female rats at doses producing plasma exposures ≥ 3 times the MRHD on an AUC basis.
Race
There is no FDA guidance on the use of Oliceridine with respect to specific racial populations.
Renal Impairment
In patients with end-stage renal disease, there was no clinically significant change in oliceridine clearance. Therefore, dosage adjustment of OLINVYK in patients with renal impairment is not required
Hepatic Impairment
In patients with mild or moderate hepatic impairment, no adjustment of the initial dose is needed; however, these patients may require less frequent dosing. When using OLINVYK in patients with severe hepatic impairment, consider reducing the initial dose, and administer subsequent doses only after a careful review of the patient’s severity of pain and overall clinical status
Females of Reproductive Potential and Males
There is no FDA guidance on the use of Oliceridine in women of reproductive potentials and males.
Immunocompromised Patients
There is no FDA guidance one the use of Oliceridine in patients who are immunocompromised.
Poor Metabolizers of CYP2D6 Substrates
In patients who are known or suspected to be poor CYP2D6 metabolizers, based on genotype or previous history/experience with other CYP2D6 substrates, less frequent dosing of OLINVYK may be required. These patients should be closely monitored, and subsequent doses should be based on the patient’s severity of pain and response to treatment.
Administration and Monitoring
Administration
OLINVYK can be administered by a healthcare provider with an initial dose of 1.5 mg. For PCA, the initial dose can be followed by access to patient demand doses with a 6-minute lock-out. The recommended demand dose is 0.35 mg. A demand dose of 0.5 mg may be considered for some patients if the potential benefit outweighs the risks. Supplemental doses of 0.75 mg OLINVYK can be administered by healthcare providers, beginning 1 hour after the initial dose, and hourly thereafter as needed.
Monitoring
Although self-administration of opioids by PCA may allow each patient to individually titrate to an acceptable level of analgesia, PCA administration has resulted in adverse outcomes and episodes of respiratory depression. Health care providers and family members monitoring patients receiving PCA analgesia should be instructed in the need for appropriate monitoring for excessive sedation, respiratory depression, or other adverse effects of opioid medications.
IV Compatibility
OLINVYK 30 mg/30 mL (1mg/mL) vial is intended for patient-controlled analgesia (PCA) use only. Draw OLINVYK directly from the vial into the PCA syringe or IV bag without diluting. For intravenous administration only.
Overdosage
Acute overdose with OLINVYK can be manifested by respiratory depression, somnolence progressing to stupor or coma, skeletal muscle flaccidity, cold and clammy skin, constricted pupils, and, in some cases, pulmonary edema, bradycardia, hypotension, hypoglycemia, partial or complete airway obstruction, atypical snoring, and death. Marked mydriasis rather than miosis may be seen due to severe hypoxia in overdose situations
Treatment of Overdose In case of overdose, priorities are the reestablishment of a patent and protected airway and institution of assisted or controlled ventilation, if needed. Employ other supportive measures (including oxygen and vasopressors) in the management of circulatory shock and pulmonary edema as indicated. Cardiac arrest or arrhythmias will require advanced life-support measures.
The opioid antagonist, naloxone, is a specific antidote for respiratory depression resulting from opioid overdose. While naloxone reversal of OLINVYK’s effects has not been established in humans, some pharmacological effects (analgesia) of oliceridine have been shown to be reversed by naloxone in animals. For clinically significant respiratory or circulatory depression secondary to oliceridine overdose, administer an opioid antagonist.
Because the duration of opioid reversal is expected to be less than the duration of oliceridine in OLINVYK injection, carefully monitor the patient until spontaneous respiration is reliably reestablished. If the response to an opioid antagonist is suboptimal or only brief in nature, administer additional antagonist as directed by the product’s prescribing information.
In an individual physically dependent on opioids, administration of the recommended usual dosage of the antagonist will precipitate an acute withdrawal syndrome. The severity of the withdrawal symptoms experienced will depend on the degree of physical dependence and the dose of the antagonist administered. If a decision is made to treat serious respiratory depression in the physically dependent patient, administration of the antagonist should be initiated with care and by titration with smaller than usual doses of the antagonist.
Pharmacology
There is limited information regarding Oliceridine Pharmacology in the drug label.
Mechanism of Action
Oliceridine is a full opioid agonist and is relatively selective for the mu-opioid receptor. The principal therapeutic action of oliceridine is analgesia. Like all full opioid agonists, there is no ceiling effect to analgesia for oliceridine. Clinically, dosage is titrated to provide adequate analgesia and may be limited by adverse reactions, including respiratory, and CNS depression.
The precise mechanism of the analgesic action is unknown. However, specific CNS opioid receptors for endogenous compounds with opioid-like activity have been identified throughout the brain and spinal cord and are thought to play a role in the analgesic effects of this drug.
Structure
There is limited information regarding Oliceridine Structure in the drug label.
Pharmacodynamics
In nonclinical models, the antinociceptive effect of oliceridine can be antagonized by the opioid antagonist naloxone.
Effects on the Central Nervous System
Opioids produces respiratory depression by direct action on brain stem respiratory centers. The respiratory depression involves a reduction in the responsiveness of the brain stem respiratory centers to both increases in carbon dioxide tension and electrical stimulation.
Opioids causes miosis, even in total darkness. Pinpoint pupils are a sign of opioid overdose but are not pathognomonic (e.g., pontine lesions of hemorrhagic or ischemic origins may produce similar findings). Marked mydriasis rather than miosis may be seen due to hypoxia in overdose situations.
Effects on the Gastrointestinal Tract and Other Smooth Muscle
Opioids causes a reduction in motility associated with an increase in smooth muscle tone in the antrum of the stomach and duodenum. Digestion of food in the small intestine is delayed and propulsive contractions are decreased. Propulsive peristaltic waves in the colon are decreased, while tone may be increased to the point of spasm, resulting in constipation. Other opioid-induced effects may include a reduction in biliary and pancreatic secretions, spasm of sphincter of Oddi, and transient elevations in serum amylase.
Effects on the Cardiovascular System
Opioids produces peripheral vasodilation, which may result in orthostatic hypotension or syncope. Manifestations of histamine release and/or peripheral vasodilation may include pruritus, flushing, red eyes, sweating, and/or orthostatic hypotension.
Effects on the Endocrine System
Opioids inhibit the secretion of adrenocorticotropic hormone (ACTH), cortisol, and luteinizing hormone (LH) in humans. They also stimulate prolactin, growth hormone (GH) secretion, and pancreatic secretion of insulin and glucagon.
Use of opioids for an extended period of time may influence the hypothalamic-pituitary-gonadal axis, leading to androgen deficiency that may manifest as low libido, impotence, erectile dysfunction, amenorrhea, or infertility. The causal role of opioids in the clinical syndrome of hypogonadism is unknown because the various medical, physical, lifestyle, and psychological stressors that may influence gonadal hormone levels have not been adequately controlled for in studies conducted to date.
Effects on the Immune System
Opioids have been shown to have a variety of effects on components of the immune system in in vitro and animal models. The clinical significance of these findings is unknown. Overall, the effects of opioids appear to be modestly immunosuppressive.
Concentration-Analgesia Relationships
In a fixed-dose bunionectomy trial (N=192), the onset of action of OLINVYK (as measured by the two-stopwatch method) was almost immediate (median 1-3 minutes) upon administration of the first dose. Perceptible pain relief was achieved in the majority of patients within 5 minutes after the first dose of OLINVYK.
The minimum effective analgesic concentration will vary widely among patients, especially among patients who have been previously treated with opioid agonists. The minimum effective analgesic concentration of oliceridine for any individual patient may increase over time due to an increase in pain, the development of a new pain syndrome, and/or the development of analgesic tolerance [see Dosage and Administration.
Concentration-Adverse Experience Relationships
There is a general relationship between increasing oliceridine doses and increasing frequency of dose-related opioid adverse reactions such as nausea, vomiting, CNS effects, and respiratory depression. In opioid-tolerant patients, the situation may be altered by the development of tolerance to opioid-related adverse reactions.
Cardiac Electrophysiology
The effect of oliceridine on the QTc interval was evaluated in 2 dedicated Thorough QT/QTc studies. A single-dose, randomized, positive- (moxifloxacin) and placebo-controlled 4 period crossover study evaluated the ECG effects of oliceridine at a therapeutic (3 mg IV infusion) and a supratherapeutic (6 mg IV infusion) dose in 62 healthy volunteers. Dose-dependent QTc prolongation (3 mg: 7 ms [upper 90% CI: 9 ms]; 6 mg: 12 ms [14 ms]), which occurred after peak oliceridine plasma concentration, was observed in this study.
A multi-dose, randomized, positive- (moxifloxacin) and placebo-controlled 3-way crossover study in 65 healthy volunteers evaluated intermittent dosing over 24 hours to the maximum daily cumulative dose of 27 mg. The maximum mean ΔΔQTcI was 11.7 ms (two-sided 90% UCI 14.7 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.
The underlying mechanism and clinical significance of the transient QT changes seen in the single-dose and multiple-dose studies in healthy volunteers are unknown. These findings should be carefully considered when OLINVYK is administered in clinical settings where prolongation of the QT interval has been observed either due to the use of concomitant medications known to prolong the QT interval or to underlying medical conditions associated with QT interval prolongation.
Pharmacokinetics
Distribution
The mean steady-state volume of distribution of oliceridine ranges between 90-120 L indicating extensive tissue distribution. The plasma protein binding of oliceridine is 77%. In vitro data indicate that oliceridine is not an inhibitor of any of the major transporters, including breast cancer resistance protein (BCRP) and MDR1, at clinically relevant concentrations.
Elimination
Metabolism
In vitro studies suggest that oliceridine is metabolized primarily by CYP3A4 and CYP2D6 P450 hepatic enzymes, with minor contributions from CYP2C9 and CYP2C19 into inactive metabolites.
The mean clearance of oliceridine decreases slightly with increasing dose, resulting in greater-than-proportional exposure, particularly at doses greater than 2 mg. The percent of unchanged oliceridine excreted in the urine is low (0.97-6.75% of dose), reflecting its low renal clearance. The pharmacokinetics of oliceridine were not changed substantially (except for peak concentrations) when administered over different infusion times.
Excretion
Metabolic clearance is the major route of elimination of oliceridine, primarily by oxidation with subsequent glucuronidation. Additional biotransformation pathways included N−dealkylation, glucuronidation, and dehydrogenation. The majority of the metabolites (approximately 70%) are eliminated in the urine, with the remainder eliminated in the feces. Only a small amount of unchanged drug (0.97-6.75% of a dose) is found in the urine. The half-life of these metabolites (~44 hours) is much longer than that of unchanged oliceridine (1.3-3 hours). In vitro binding studies have demonstrated that none of these metabolites has any appreciable activity at the mu-opioid receptor.
Specific Populations
Renal Impairment
In a study comparing subjects with end stage renal disease (N=8) to healthy age and sex−matched healthy subjects (N=8), no significant difference in oliceridine clearance was observed. OLINVYK doses do not need to be adjusted in patients with renal impairment.
Hepatic Impairment
In a study of mild (N=8), moderate (N=8), or severe hepatic impairment (N=6), both clearance and total exposure were similar to age and sex-matched healthy controls (N=8). The mean half-life of oliceridine was increased in subjects with moderate (4.3 hours) or severe (5.8 hours) hepatic impairment, as compared with healthy subjects (2.1 hours), or patients with mild hepatic impairment (2.6 hours). The estimated volume of distribution of oliceridine was significantly higher in subjects with moderate or severe hepatic impairment (212 and 348 L, respectively), as compared to healthy subjects (126 L) or patients with mild hepatic impairment (167 L).
Based on these data, the initial dose of OLINVYK does not need to be reduced in patients with mild or moderate hepatic impairment, but these patients may require less frequent dosing. Use caution when dosing OLINVYK in patients with severe hepatic impairment. Consider reducing the initial dose, and administer subsequent doses only after a careful review of the patient’s severity of pain and overall clinical status.
Drug Interaction Studies
In vitro studies suggest that oliceridine is metabolized primarily by the CYP3A4 and CYP2D6 P450 hepatic enzymes, with minor contributions from CYP2C9 and CYP2C19. Inhibition studies using selective inhibitors of all the major CYP enzymes show that only the inhibition of CYP3A4 and CYP2D6 significantly affects the metabolism of oliceridine in these assays, suggesting that the contribution of CYP2C9 and CYP2C19 to the metabolism of oliceridine is minor.
The effect of concomitant administration of a CYP2D6 inhibitor on the pharmacokinetics of OLINVYK, although not studied, may be similar to that noted in subjects who are CYP2D6 poor metabolizers. The plasma clearance of oliceridine in CYP2D6 poor metabolizers is approximately 50% of plasma clearance in subjects who are nonpoor CYP2D6 metabolizers.
In healthy subjects CYP2D6 poor metabolizers (n=4) given a single 0.25 mg dose of OLINVYK after 5 days of itraconazole 200 mg QD (a strong CYP3A4 inhibitor), the total exposure (AUC) of OLINVYK was increased by approximately 80%; however, the peak concentration was not significantly affected. The mean clearance of oliceridine was reduced to approximately 30% of that observed in nonpoor metabolizers of CYP2D6.
Oliceridine does not inhibit any P450 enzymes at clinically relevant concentrations.
Nonclinical Toxicology
Carcinogenesis, Mutagenesis, Impairment of Fertility Carcinogenesis:
Long-term animal studies have not been completed to evaluate the carcinogenic potential of oliceridine.
Mutagenesis:
Oliceridine was negative in an in vitro Ames bacterial reverse mutation assay, the in vitro chromosomal aberration assay using human peripheral blood lymphocytes, and the in vivo rat micronucleus assay.
Impairment of Fertility:
In a fertility and early embryonic development study, oliceridine administered to female rats via continuous intravenous infusion at 6, 12, or 24 mg/kg/day for 14 days prior to cohabitation and through GD 15 for a total of 29-42 days resulted in prolonged estrous cycle lengths and decreased number of implantations and viable embryos at doses ≥12 mg/kg/day (≥3 times the estimated plasma exposure at the MRHD of 27 mg/day on an AUC basis).
Oliceridine did not alter male fertility at any dose tested. Males were dosed at 6, 12, or 24 mg/kg/day, producing plasma exposures up to 8 times the estimated plasma exposure at the MRHD, for 28 days prior to cohabitation, throughout the mating period and up to the time of scheduled necropsy for a total of 64-65 days of dosing.
Animal Toxicology and/or Pharmacology Continuous intravenous infusion of oliceridine to rats for 14 days followed by one-day withdrawal from the treatment resulted in opioid withdrawal stress-related gastric lesions including erosions/ulcers in the glandular stomach, mucosal congestion/hemorrhage and degeneration/necrosis in the nonglandular stomach at all doses tested including the low dose producing plasma exposure 2 times the estimated human exposure at the MRHD on an AUC basis. The effect is believed to be due to acute withdrawal stress, as similar findings were not noted in rats sacrificed immediately after the last dose of oliceridine.
Clinical Studies
The efficacy of OLINVYK was established in two randomized, double-blind, placebo- and morphine-controlled studies of patients with moderate to severe acute pain following orthopedic surgery-bunionectomy or plastic surgery-abdominoplasty. In each study, pain intensity was measured using a patient-reported numeric rating scale (11-point numerical scale ranging from 0-10, where zero corresponds to no pain and 10 corresponds to worst pain imaginable).
In each study, patients were randomized to one of three OLINVYK treatment regimens, a placebo-control regimen, or a morphine-control regimen. Each blinded treatment regimen consisted of a loading dose, incremental doses delivered as needed via patient-controlled analgesia (PCA) device, and supplemental doses, beginning 1 hour after the initial dose, and hourly thereafter, as needed. The loading dose for all OLINVYK treatment regimens was 1.5 mg; demand doses were 0.1, 0.35 or 0.5 mg, according to the assigned treatment group; supplemental doses were 0.75 mg. The loading dose for the morphine treatment regimen was 4 mg; the demand dose was 1 mg; supplemental doses were 2 mg. The placebo-control regimen was volume-matched. A lockout interval of 6 minutes was used for all PCA regimens. For Studies 1 and 2, patients may have received rescue pain medication (pre-defined in the protocols as etodolac 200 mg every 6 hours, as needed) if the patient requested rescue pain medication and reported a Numeric Rating Scale score ≥4.
How Supplied
OLINVYK (oliceridine) injection is a clear, colorless, preservative free solution for intravenous use supplied as follows:
NDC# 71308-011-10: 1 mg/mL, sterile solution in single-dose, 2 mL clear glass vials with gray stoppers topped with overseals with gray plastic flip-off caps (carton of 10 vials)
NDC# 71308-021-10: 2 mg/2 mL (1 mg/mL), sterile solution in single-dose, 2 mL clear glass vials with gray stoppers topped with overseals with orange plastic flip-off caps (carton of 10 vials)
NDC# 71308-301-10: 30 mg/30 mL (1 mg/mL), sterile solution in single-patient-use, 30 mL clear glass vials with gray stoppers topped with overseals with purple plastic flip-off caps (carton of 10 vials). For PCA Use Only.
Storage
Store at controlled room temperature 20°-25°C (68°-77°F); excursions permitted to 15°-30°C (59°-86°F)
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Patient Counseling Information
Addiction, Abuse, and Misuse
Inform patients that the use of OLINVYK, even when taken as recommended, can result in addiction, abuse, and misuse, which can lead to overdose and death.
Life-Threatening Respiratory Depression
Inform patients of the risk of life-threatening respiratory depression, including information that the risk is greatest when starting OLINVYK or when the dosage is increased, and that it can occur even at recommended dosages.
Hyperalgesia and Allodynia
Advise patients to inform their healthcare provider if they experience symptoms of hyperalgesia, including worsening pain, increased sensitivity to pain, or new pain.
Serotonin Syndrome
Inform patients that opioids could cause a rare but potentially life-threatening condition called serotonin syndrome resulting from concomitant administration of serotonergic drugs. Warn patients of the symptoms of serotonin syndrome and to seek medical attention right away if symptoms develop after discharge from the hospital. Instruct patients to inform their healthcare provider if they are taking or plan to take serotonergic medications.
Constipation
Advise patients of the potential for severe constipation, including management instructions and when to seek medical attention
Precautions with Alcohol
Alcohol-Oliceridine interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
Brand Names
Olinvyk
Look-Alike Drug Names
There is limited information regarding Oliceridine Look-Alike Drug Names in the drug label.
Drug Shortage Status
Price
References
The contents of this FDA label are provided by the National Library of Medicine.