Clinical Pharmacology Corner: FDA Approves LUCEMYRA (Lofexidine)

FDA Approves LUCEMYRA (Lofexidine) for Mitigation of Opioid Withdrawal Symptoms to Facilitate Abrupt Opioid Discontinuation in Adults

On May 16, 2018, the U.S. Food and Drug Administration (FDA) approved LUCEMYRA™ (lofexidine) for mitigation of opioid withdrawal symptoms to facilitate abrupt opioid discontinuation in adults. The approved recommended starting dosage of LUCEMYRA tablets is three 0.18 mg tablets taken orally 4 times daily at 5- to 6-hour intervals during peak withdrawal symptoms, and treatment may be continued for up to14 days with dosing guided by symptoms. The total daily dosage of LUCEMYRA should not exceed 2.88 mg (16 tablets) and no single dose should exceed 0.72 mg (4 tablets).  If clinically significant or symptomatic hypotension and/or bradycardia occur, the next dose of LUCEMYRA should be reduced in amount, delayed, or skipped. To mitigate LUCEMYRA withdrawal symptoms, discontinue LUCEMYRA over a 2- to 4-day period by gradually reducing by 1 tablet per dose every 1-2 days. Lower doses may be appropriate as opioid withdrawal symptoms wane.

The LUCEMYRA dose should be reduced, held, or discontinued for individuals who demonstrate a greater sensitivity to LUCEMYRA side effects.

Monitor ECG in patients with congestive heart failure, bradyarrhythmias, hepatic impairment, renal impairment, or patients taking other drugs that lead to QT prolongation (e.g., methadone). Correct any electrolyte abnormalities (e.g., hypokalemia or hypomagnesemia), and monitor ECG upon initiation of LUCEMYRA. 

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

• MOA: Lofexidine is a central alpha-2 adrenergic agonist that binds to receptors on adrenergic neurons. This reduces the release of norepinephrine and decreases sympathetic tone.
• General PK: LUCEMYRA shows approximately dose-proportional pharmacokinetics.  
• Absorption: Peak plasma concentration was achieved 3 to 5 hours after administration of a single dose. The absolute bioavailability is 72%.  
• Distribution: Mean volume of distribution values following the administration of an oral dose was 480 L. Plasma protein binding is approximately 55%.
• Elimination: The elimination half-life is approximately 12 hours.
• Metabolism: LUCEMYRA is primarily metabolized by CYP2D6, and to a lesser extent by CYP1A2 and CYP2C19 in vitro.
• Excretion: Approximately 93.5% of the radiolabel LUCEMYRA dose was recovered in urine over 144 hours postdose, and 0.92% was recovered in feces over 216 hours postdose. Renal elimination of unchanged drug accounts for approximately 15% to 20% of the administered dose.
• Cardiac Electrophysiology: Single LUCEMYRA doses of 1.44 and 1.8 mg produced a maximum mean change from baseline in QTcF of 14.4 msec (upper two-sided 90% CI: 22.3 msec) and 13.6 msec (17.4 msec), respectively, in healthy normal volunteers. In opioid dependent subjects, the maximum mean prolongation of the QTcF interval was 7.3 (8.8) and 9.3 (10.9) msec at LUCEMYRA doses of 2.16 and 2.88 mg/day, respectively. Maximum mean QTcF increased 9.1 (14.2) msec in methadone-maintained patients (80-120 mg/day) coadministered LUCEMYRA (2.88 mg/day) compared to methadone-alone. See linked full prescribing information for additional information on QTc effects.

Drug Interactions

• CYP2D6 inhibitor: Coadministration with a strong CYP2D6 inhibitor increases LUCEMYRA C_max and AUC. Monitor for orthostatic hypotension and bradycardia when LUCEMYRA is co-administered with CYP2D6 inhibitors or in known CYP2D6 poor metabolizers.  
• Oral naltrexone: Coadministration of LUCEMYRA delays absorption of oral naltrexone. Monitor for reduced efficacy of oral naltrexone when coadministered within 2 hours of LUCEMYRA. 

Use in Specific Populations

• Hepatic impairment: The recommend dosage administered 4 times daily is 3 tablets in patients with mild impairment (Child-Pugh score 5-6), 2 tablets for moderate impairment (Child-Pugh score 7-9), and 1 tablet for several impairment (Child-Pugh score > 9).  
• Renal impairment: The recommended dosage administered 4 times daily is 2 tablets in patients with mild or moderate impairment (eGFR 30-89.9 mL/min/1.73m²), and 1 tablet in patients with severe impairment (eGFR < 30 mL/min/1.73m²), end-stage renal disease, or dialysis. 

Efficacy and Safety

Efficacy of LUCEMYRA was demonstrated in two randomized, double-blind, placebo-controlled trials in patients meeting DSM-IV criteria for opioid dependence who were physically dependent on short-acting opioids (e.g., heroin, hydrocodone, oxycodone). Additional information regarding efficacy trials can be found in the full prescribing information linked below.

Most common adverse reactions (incidence ≥ 10% and notably more frequent than placebo) are orthostatic hypotension, bradycardia, hypotension, dizziness, somnolence, sedation, and dry mouth.

Full prescribing information is available at https://go.usa.gov/xQP3p. 

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 athttp://www.fda.gov/medwatch/report.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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