Lucemyra Drug Information

is indicated for mitigation of opioid withdrawal symptoms to facilitate abrupt opioid discontinuation in adults. LUCEMYRA is a central alpha-2 adrenergic agonist indicated for mitigation of opioid withdrawal symptoms to facilitate abrupt opioid discontinuation in adults.

Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to adverse reaction rates observed for another drug and may not reflect the rates observed in practice. The safety of LUCEMYRA was supported by three randomized, double-blind, placebo-controlled clinical trials, an open-label study, and clinical pharmacology studies with concomitant administration of either methadone, buprenorphine, or naltrexone. The three randomized, double-blind, placebo-controlled clinical trials enrolled 935 subjects dependent on short-acting opioids undergoing abrupt opioid withdrawal.

Patients were monitored before each dose in an inpatient setting. Table 3 presents the incidence, rounded to the nearest percent, of adverse events that occurred in at least 10% of subjects treated with LUCEMYRA and for which the incidence in patients treated with LUCEMYRA was greater than the incidence in subjects treated with placebo in a study that tested two doses of LUCEMYRA, 2.16 mg per day and 2.88 mg per day, and placebo. The overall safety profile in the combined dataset was similar.

Orthostatic hypotension, bradycardia, hypotension, dizziness, somnolence, sedation, and dry mouth were notably more common in subjects treated with LUCEMYRA than subjects treated with placebo. Table 3: Adverse Reactions Reported by ≥10% of LUCEMYRA-Treated Patients and More Frequently than Placebo Adverse Reaction LUCEMYRA 2.16 mg Assigned dose; mean average daily dose received was 79% of assigned dose due to dose-holds for out-of-range vital signs. (%) N=229 LUCEMYRA 2.88 mg (%) N=222 Placebo (%) N=151 Insomnia 51 55 48 Orthostatic Hypotension 29 42 5 Bradycardia 24 32 5 Hypotension 30 30 1 Dizziness 19 23 3 Somnolence 11 13 5 Sedation 13 12 5 Dry Mouth 10 11 0 Other notable adverse reactions associated with the use of LUCEMYRA but reported in <10% of patients in the LUCEMYRA group included: Syncope: 0.9%, 1.4% and 0% for LUCEMYRA 2.16 mg/day and 2.88 mg/day and placebo, respectively Tinnitus: 0.9%, 3.2% and 0% for LUCEMYRA 2.16 mg/day and 2.88 mg/day and placebo, respectively Blood pressure changes and adverse reactions after LUCEMYRA cessation Elevations in blood pressure above normal values (≥140 mmHg systolic) and above a subject's pre-treatment baseline are associated with discontinuing LUCEMYRA, and peaked on the second day after discontinuation, as shown in Table 4. Blood pressure values were evaluated for 3 days following the last dose of a 5-day course of LUCEMYRA 2.88 mg/day. Table 4: Blood Pressure Elevations after Stopping Treatment Abrupt LUCEMYRA Discontinuation 2.88 mg (N = 134) Placebo (N = 129) N at risk n (%) N at risk n (%) Systolic Blood Pressure on Day 2 after Discontinuation ≥ 140 mmHg and ≥ 20 mmHg increase from baseline 58 23 37 6 ≥ 170 mmHg and ≥ 20 mmHg increase from baseline 58 5 37 0 Blood pressure elevations of a similar magnitude and incidence were observed in a small number of patients (N=10) that had a one-day, 50% dose reduction prior to discontinuation.

After stopping treatment, subjects who were taking LUCEMYRA also had a higher incidence of diarrhea, insomnia, anxiety, chills, hyperhidrosis, and extremity pain compared to subjects who were taking placebo. Sex-specific adverse event findings Four out of 101 females (4%) had serious cardiovascular adverse events compared to 3 out of 289 (1%) males assigned to receive LUCEMYRA 2.88 mg/day. Discontinuations and dose-holds due to bradycardia and orthostatic hypotension, which are the most common adverse reactions associated with LUCEMYRA, occurred with a greater incidence in females assigned to receive the highest studied dose of LUCEMYRA, 2.88 mg/day as shown in Table 5. Table 5: Discontinuations and Dose-Holds for Bradycardia and Orthostatic Hypotension by LUCEMYRA Dose and Sex LUCEMYRA 2.16 mg LUCEMYRA 2.88 mg Male 22/162 (14%) 29/158 (18%) Female 9/67 (13%) 20/64 (31%)

Postmarketing Experience Lofexidine is marketed in other countries for relief of opioid

withdrawal symptoms. The following events have been identified during postmarketing use of lofexidine. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

Since lofexidine's initial market introduction in 1992, the most frequently reported postmarketing adverse event with lofexidine has been hypotension . There has been one report of QT prolongation, bradycardia, torsades de pointes, and cardiac arrest with successful resuscitation in a patient who received lofexidine, and three reports of clinically significant QT prolongation in subjects concurrently receiving methadone with lofexidine.

Methadone

LUCEMYRA and methadone both prolong the QT interval. ECG monitoring is recommended in patients receiving methadone and LUCEMYRA concomitantly .

Oral Naltrexone Coadministration of

LUCEMYRA and oral naltrexone resulted in statistically significant differences in the steady-state pharmacokinetics of naltrexone. It is possible that oral naltrexone efficacy may be reduced if used concomitantly within 2 hours of LUCEMYRA. This interaction is not expected if naltrexone is administered by non-oral routes .

CNS Depressant Drugs

LUCEMYRA potentiates the CNS depressant effects of benzodiazepines and may potentiate the CNS depressant effects of alcohol, barbiturates, and other sedating drugs. Advise patients to inform their healthcare provider of other medications they are taking, including alcohol .

CYP2D6 Inhibitor - Paroxetine Coadministration of

LUCEMYRA and paroxetine resulted in a 28% increase in the extent of absorption of LUCEMYRA. Monitor for orthostatic hypotension and bradycardia when an inhibitor of CYP2D6 is used concomitantly with LUCEMYRA .

Pregnancy Risk Summary The safety of LUCEMYRA in pregnant women has not been established. In animal reproduction studies, oral administration of lofexidine during organogenesis to pregnant rats and rabbits caused a reduction in fetal weights, increases in fetal resorptions, and litter loss at exposures below that in humans. When oral lofexidine was administered from the beginning of organogenesis through lactation, increased stillbirths and litter loss were noted along with decreased viability and lactation indices.

The offspring exhibited delays in sexual maturation, auditory startle, and surface righting. These effects occurred at exposures below that in humans . The background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies carry some risk of birth defect, loss, or other adverse outcomes.

The background risk of major birth defects in the U.S. general population is 2% to 4% and of miscarriage is 15% to 20% of clinically recognized pregnancies. Data Animal Data Increased incidence of resorptions, decreased number of implantations, and a concomitant reduction in the number of fetuses were observed when pregnant rabbits were orally administered lofexidine hydrochloride during organogenesis (from gestation day 7 to 19) at a daily dose of 5.0 mg/kg/day (approximately 0.08 times the maximum recommended human dose of 2.88 mg lofexidine base on an AUC basis). Maternal toxicity evidenced by increased mortality was noted at the highest tested dose of 15 mg/kg/day (approximately 0.4 times the MRHD on an AUC basis). Decreased implantations per dam and decreased mean fetal weights were noted in a study in which pregnant rats were treated with oral lofexidine hydrochloride during organogenesis (from GD 7 to 16) at a daily dose of 3.0 mg/kg/day (approximately 0.9 times the MRHD on an AUC basis). This dose was associated with maternal toxicity (decreased body weight gain and mortality). No malformations or evidence of developmental toxicity were evident at 1.0 mg/kg/day (approximately 0.2 times the MRHD on an AUC basis). A dose-dependent increase in pup mortality was noted in all doses of lofexidine hydrochloride administered orally to pregnant rats from GD 6 through lactation at an exposure less than the human exposure based on AUC comparisons. Doses higher than 1.0 mg/kg/day (approximately 0.2 times the MRHD on an AUC basis) resulted in incidences of total litter loss and maternal toxicity (piloerection and decreased body weight gain). At the highest dose tested of 2.0 mg/kg/day (approximately 0.6 times the MRHD on an AUC basis), increased stillbirths as well as decreased viability and lactation indices were reported.

Surviving offspring exhibited lower body weights, developmental delays, and increased delays in auditory startle at doses of 1.0 mg/kg/ day or higher. Sexual maturation was delayed in male offspring (preputial separation) at 2.0 mg/kg/day and in female offspring (vaginal opening) at 1.0 mg/kg/day or higher.

Pediatric Use The safety and effectiveness of LUCEMYRA have not been established in pediatric patients.

Overdose with LUCEMYRA may manifest as hypotension, bradycardia, and sedation. In the event of acute overdose, perform gastric lavage where appropriate. Dialysis will not remove a substantial portion of the drug.

Initiate general symptomatic and supportive measures in cases of overdosage.