Clinical Pharmacology Corner: FDA Approves OLINVYK (Oliceridine)

FDA Approves OLINVYK (Oliceridine) in Adults for Acute Pain Severe Enough to Require an Intravenous Opioid Analgesic and for Whom Alternative Treatments are Inadequate

On August 7, 2020, the U.S. Food and Drug Administration (FDA) approved OLINVYK (oliceridine) in adults for the management of acute pain severe enough to require an intravenous opioid analgesic and for whom alternative treatments are inadequate. Because of the risks of addiction, abuse, and misuse with opioids, even at recommended doses, reserve OLINVYK for use in patients for whom alternative treatment options [e.g., non-opioid analgesics or opioid combination products]: (1) have not been tolerated, or are not expected to be tolerated, or (2) have not provided adequate analgesia, or are not expected to provide adequate analgesia. 

OLINVYK can be administered intravenously by a healthcare provider with an initial dose of 1.5 mg. For patient-controlled analgesia (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 a healthcare provider, beginning 1 hour after the initial dose, and hourly thereafter as needed. Use the lowest effective dose for the shortest duration consistent with individual patient treatment goals. Do not administer single doses greater than 3 mg. The cumulative total daily dose should not exceed 27 mg, as this may increase the risk for QTc interval prolongation.

There is a boxed warning regarding addiction, abuse, and misuse; life threatening respiratory depression neonatal opioid withdrawal syndrome; and risks from concomitant use with benzodiazepines or other CNS depressants that states: 

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 before prescribing OLINVYK, and monitor all patients regularly for the development of behaviors or conditions. 

Serious, life-threatening, or fatal respiratory depression may occur with use of OLINVYK. Monitor for respiratory depression, especially during initiation of OLINVYK or following a dose increase. 

Prolonged use of OLINVYK during pregnancy can result in neonatal opioid withdrawal syndrome, which may be life-threatening if not recognized and treated, and requires management according to protocols developed by neonatology experts. If opioid use is required for a prolonged period in a pregnant woman, advise the patient of the risk of neonatal opioid withdrawal syndrome and ensure that appropriate treatment will be available.

Concomitant use of opioids with benzodiazepines or other CNS depressants, including alcohol, may result in profound sedation, respiratory depression, coma, and death. 

• Reserve concomitant prescribing of OLINVYK and benzodiazepines or other CNS depressants for use in patients for whom alternative treatment options are inadequate. 
• Limit dosages and durations to the minimum required. 
• Follow patients for signs and symptoms of respiratory depression and sedation.

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, and known hypersensitivity to oliceridine (e.g., anaphylaxis).  

Additional information regarding dosage and administration as well as warnings and precautions about addiction, abuse, and misuse, life-threatening respiratory depression, neonatal opioid withdrawal syndrome, life-threatening respiratory depression in patients with chronic pulmonary disease or in elderly, cachectic, or debilitated patients, adrenal insufficiency, severe hypotension, risks of use in patients with increased intracranial pressure, brain tumors, head injury, or impaired consciousness, gastrointestinal adverse reactions, increased risk of seizures, withdrawal, and risk of impaired mental or physical abilities can be found in the full prescribing information linked below.

Mechanism of Action (MOA), Pharmacokinetics (PK), and Pharmacodynamics (PD) 

MOA: Oliceridine is an opioid agonist. 

Distribution: The mean steady-state volume of distribution of oliceridine ranges between 90-120 L. Plasma protein binding of oliceridine is 77%.

Elimination: The half-life of oliceridine ranges between 1.3-3 hours.

Metabolism: Oliceridine is primarily metabolized by CYP3A4 and CYP2D6, with minor contributions from CYP2C9 and CYP2C19 into inactive metabolites, in vitro.  

Excretion: The percent of unchanged oliceridine excreted in the urine is 0.97-6.75% of the dose.  

PD: Perceptible pain relief was achieved in the majority of patients within 5 minutes after the first dose of OLINVYK. 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: Up to a 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.

Drug Interactions

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. 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.

• In patients with decreased CYP2D6 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

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. Closely monitor these patients at frequent intervals and consider supplemental doses of OLINVYK. 

• Concomitant use of OLINVYK with CYP3A4 inducers
• Discontinuation of a moderate or strong CYP3A4 or CYP2D6 inhibitor

Benzodiazepines and Other CNS Depressants: Concomitant use of benzodiazepines or other CNS depressants, including alcohol, increases the risk of hypotension, respiratory depression, profound sedation, coma, and death. Reserve concomitant prescribing of these drugs for use in patients for whom alternative treatment options are inadequate. Limit dosages and durations to the minimum required. Monitor for signs of respiratory depression and sedation. 

Serotonergic Drugs: Concomitant use of opioids with other drugs that affect the serotonergic neurotransmitter system has resulted in serotonin syndrome. If concomitant use is warranted, carefully observe the patient, particularly during treatment initiation and dose adjustment. Discontinue OLINVYK if serotonin syndrome is suspected.

Mixed Agonist/Antagonist and Partial Agonist Opioid Analgesics: Avoid concomitant use as it may reduce the analgesic effect of OLINVYK and/or precipitate withdrawal symptoms.  

Muscle Relaxants: OLINVYK may enhance the neuromuscular blocking action of skeletal muscle relaxants and produce an increased degree of respiratory depression. Monitor for signs of respiratory depression that may be greater than otherwise expected and decrease the dosage of OLINVYK and/or the muscle relaxant as necessary.

Diuretics: Opioids can reduce the efficacy of diuretics by inducing the release of antidiuretic hormone. Monitor for signs of diminished diuresis and/or effects on blood pressure and increase the dosage of the diuretic as needed.

Anticholinergic Drugs: Concomitant use of anticholinergic drugs may increase risk of urinary retention and/or severe constipation, which may lead to paralytic ileus. Monitor for signs of urinary retention or reduced gastric motility when OLINVYK is used concomitantly with anticholinergic drugs.

Use in Specific Populations

Renal Impairment: In patients with end-stage renal disease, there was no clinically significant change in oliceridine clearance. No dosage adjustment of OLINVYK in patients with renal impairment is recommended. 

Hepatic Impairment: Patients with mild or moderate hepatic impairment may require less frequent dosing, however, no adjustment of the initial dose is recommended. In patients with severe hepatic impairment, consider reducing the initial OLINVYK dose, and administer subsequent doses only after a careful review of the patient’s severity of pain and overall clinical status. 

Poor CYP2D6 Metabolizers: 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 base subsequent doses on the patient’s severity of pain and response to treatment.

Efficacy and Safety

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. Additional information regarding the efficacy trials can be found in the full prescribing information linked below.

The most common (incidence ≥10%) adverse reactions were nausea, vomiting, dizziness, hypoxia, pruritus, somnolence, headache, constipation, and hypoxia.  

Full prescribing information is available at https://go.usa.gov/xfsc4.

Visit Drugs@FDA at http://go.usa.gov/cMsjT for prescribing and patient information, approval letters, reviews and other information for FDA-approved drug products, which are often available shortly following approval.

A non-comprehensive list of examples of clinical substrates, inhibitors and inducers for metabolic and transporter system related interactions may be found at https://go.usa.gov/xXY9C.

Healthcare professionals should report all serious adverse events suspected to be associated with the use of any medicine and device to FDA’s MedWatch Reporting System by completing a form online at https://www.fda.gov/safety/medwatch/default.htm, by faxing (1-800-FDA-0178), or by mailing the postage-paid address form provided online, or by telephone (1-800-FDA-1088).

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This communication was prepared by Office of Clinical Pharmacology, Office of Translational Sciences, CDER, FDA.