2.1 Dosing Information

The usual LUCEMYRA starting dosage is three 0.18 mg tablets taken orally 4 times daily during the period of peak withdrawal symptoms (generally the first 5 to 7 days following last use of opioid) with dosing guided by symptoms and side effects. There should be 5 to 6 hours between each dose. 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).

LUCEMYRA treatment may be continued for up to 14 days with dosing guided by symptoms.

Discontinue LUCEMYRA with a gradual dose reduction over a 2- to 4-day period to mitigate LUCEMYRA withdrawal symptoms (e.g., reducing by 1 tablet per dose every 1 to 2 days) [see Warnings & Precautions (5.5)]. The LUCEMYRA dose should be reduced, held, or discontinued for individuals who demonstrate a greater sensitivity to LUCEMYRA side effects [see Warnings and Precautions (5.1), Adverse Reactions (6.1)]. Lower doses may be appropriate as opioid withdrawal symptoms wane.

LUCEMYRA can be administered in the presence or absence of food.

2.2 Dosage Recommendations for Patients with Hepatic Impairment

Recommended dosage adjustments based on the degree of hepatic impairment are shown in Table 1. [see Use in Specific Populations (8.6), Clinical Pharmacology (12.3)].

2.3 Dosage Recommendations for Patients with Renal Impairment

Recommended dosage adjustments based on the degree of renal impairment are shown in Table 2. LUCEMYRA may be administered without regard to the timing of dialysis [see Use in Specific Populations (8.7), Clinical Pharmacology (12.3)].

5.1 Risk of Hypotension, Bradycardia, and Syncope

LUCEMYRA can cause a decrease in blood pressure, a decrease in pulse, and syncope [see Adverse Reactions (6.1), Clinical Pharmacology (12.2)]. Monitor vital signs before dosing. Monitor symptoms related to bradycardia and orthostasis.

Patients being given LUCEMYRA in an outpatient setting should be capable of and instructed on self-monitoring for hypotension, orthostasis, bradycardia, and associated symptoms. If clinically significant or symptomatic hypotension and/or bradycardia occur, the next dose of LUCEMYRA should be reduced in amount, delayed, or skipped.

Inform patients that LUCEMYRA may cause hypotension and that patients moving from a supine to an upright position may be at increased risk for hypotension and orthostatic effects. Instruct patients to stay hydrated, on how to recognize symptoms of low blood pressure, and on how to reduce the risk of serious consequences should hypotension occur (e.g., sit or lie down, carefully rise from a sitting or lying position). Instruct outpatients to withhold LUCEMYRA doses when experiencing symptoms of hypotension or bradycardia and to contact their healthcare provider for guidance on how to adjust dosing.

Avoid using LUCEMYRA in patients with severe coronary insufficiency, recent myocardial infarction, cerebrovascular disease, chronic renal failure, and in patients with marked bradycardia.

Avoid using LUCEMYRA in combination with medications that decrease pulse or blood pressure to avoid the risk of excessive bradycardia and hypotension.

5.2 Risk of QT Prolongation

LUCEMYRA prolongs the QT interval.

Avoid using LUCEMYRA in patients with congenital long QT syndrome.

Monitor ECG in patients with congestive heart failure, bradyarrhythmias, hepatic impairment, renal impairment, or patients taking other medicinal products that lead to QT prolongation (e.g., methadone). In patients with electrolyte abnormalities (e.g., hypokalemia or hypomagnesemia), correct these abnormalities first, and monitor ECG upon initiation of LUCEMYRA [see Dosing and Administration (2.1), Adverse Reactions (6.1), Special Populations (8.6, 8.7), Clinical Pharmacology (12.2)].

5.3 Increased Risk of Central Nervous System Depression with Concomitant use of CNS Depressant Drugs

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

Advise patients using LUCEMYRA in an outpatient setting that, until they learn how they respond to LUCEMYRA, they should be careful or avoid doing activities such as driving or operating heavy machinery.

5.4 Increased Risk of Opioid Overdose after Opioid Discontinuation

LUCEMYRA is not a treatment for opioid use disorder. Patients who complete opioid discontinuation are likely to have a reduced tolerance to opioids and are at increased risk of fatal overdose should they resume opioid use. Use LUCEMYRA in patients with opioid use disorder only in conjunction with a comprehensive management program for the treatment of opioid use disorder and inform patients and caregivers of this increased risk of overdose.

5.5 Risk of Discontinuation Symptoms

Stopping LUCEMYRA abruptly can cause a marked rise in blood pressure. Symptoms including diarrhea, insomnia, anxiety, chills, hyperhidrosis, and extremity pain have also been observed with LUCEMYRA discontinuation. Instruct patients not to discontinue therapy without consulting their healthcare provider. When discontinuing therapy with LUCEMYRA, gradually reduce the dose [see Dosing and Administration (2.1)].

Symptoms related to discontinuation can be managed by administration of the previous LUCEMYRA dose and subsequent taper.

6.1 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.

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

6.2 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 [see Warnings and Precautions (5.1)]. 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.

7.1 Methadone

LUCEMYRA and methadone both prolong the QT interval. ECG monitoring is recommended in patients receiving methadone and LUCEMYRA concomitantly [see Warnings and Precautions (5.2), Clinical Pharmacology (12.3)].

7.2 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 [see Clinical Pharmacology (12.3)].

7.3 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 [see Warnings and Precautions (5.3)].

7.4 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 [see Clinical Pharmacology (12.3)].

8.1 Pregnancy

8.2 Lactation

8.3 Females and Males of Reproductive Potential

In animal studies that included some fertility endpoints, lofexidine decreased breeding rate and increased resorptions at exposures below human exposures. The impact of lofexidine on male fertility has not been adequately characterized in animal studies [see Impairment of Fertility (13.1)].

8.4 Pediatric Use

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

8.5 Geriatric Use

No studies have been performed to characterize the pharmacokinetics of LUCEMYRA or to establish its safety and effectiveness in geriatric patients. Caution should be exercised when LUCEMYRA is administered to patients over 65 years of age. Dosing adjustments similar to those recommended in patients with renal impairment should be considered [see Dosage and Administration (2.3), Use in Specific Populations (8.7)].

8.6 Hepatic Impairment

Hepatic impairment slows the elimination of LUCEMYRA but exhibits less effect on the peak plasma concentration than on AUC values following a single dose. Dosage adjustments are recommended based on the degree of hepatic impairment. [see Dosage and Administration (2.2), Clinical Pharmacology (12.3)].

Clinically relevant QT prolongation may occur in subjects with hepatic impairment [see Warnings and Precautions (5.2), Clinical Pharmacology (12.2)].

8.7 Renal Impairment

Renal impairment slows the elimination of LUCEMYRA but exhibits less effect on the peak plasma concentration than on AUC values following a single dose. Dosage adjustments are recommended based on the degree of renal impairment [see Dosage and Administration (2.3), Clinical Pharmacology (12.3)].

Only a negligible fraction of the LUCEMYRA dose is removed during a typical dialysis session, so no additional dose needs to be administered after a dialysis session; LUCEMYRA may be administered without regard to the timing of dialysis [see Dosage and Administration (2.3), Clinical Pharmacology (12.3)].

Clinically relevant QT prolongation may occur in subjects with renal impairment [see Warnings and Precautions (5.2), Clinical Pharmacology (12.2)].

8.8 CYP2D6 Poor Metabolizers

Although the pharmacokinetics of LUCEMYRA have not been systematically evaluated in patients who do not express the drug metabolizing enzyme CYP2D6, it is likely that the exposure to LUCEMYRA would be increased similarly to taking strong CYP2D6 inhibitors (approximately 28%). Monitor adverse events such as orthostatic hypotension and bradycardia in known CYP2D6 poor metabolizers. Approximately 8% of Caucasians and 3 to 8% of Black/African Americans cannot metabolize CYP2D6 substrates and are classified as poor metabolizers (PM) [see Clinical Pharmacology (12.3)].

12.1 Mechanism of Action

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.

12.2 Pharmacodynamics

12.3 Pharmacokinetics

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

Study 1, NCT01863186

Study 1 was a 2-part efficacy, safety, and dose-response study conducted in the United States in patients meeting DSM-IV criteria for opioid dependence who were physically dependent on short-acting opioids (e.g., heroin, hydrocodone, oxycodone). The first part of the study was an inpatient, randomized, double-blind, placebo-controlled design consisting of 7 days of inpatient treatment (Days 1 – 7) with LUCEMYRA 2.16 mg total daily dose (0.54 mg 4 times daily) (n=229), LUCEMYRA 2.88 mg total daily dose (0.72 mg 4 times daily) (n=222), or matching placebo (n=151). Patients also had access to a variety of support medications for withdrawal symptoms (guaifenesin, antacids, dioctyl sodium sulfosuccinate, psyllium hydrocolloid suspension, bismuth sulfate, acetaminophen, and zolpidem). The second part of the study (Days 8 – 14) was an open-label design where all patients who successfully completed Days 1 – 7 were eligible to receive open-label treatment with variable dose LUCEMYRA treatment (as determined by the investigator, but not to exceed 2.88 mg total daily dose) for up to an additional 7 days (Days 8 – 14) in either an inpatient or outpatient setting as determined by the investigator and the patient. No patient received LUCEMYRA for more than 14 days.

The two endpoints to support efficacy were the mean Short Opiate Withdrawal Scale of Gossop (SOWS-Gossop) total score on Days 1 – 7 of treatment and the proportion of patients who completed 7 days of treatment. The SOWS-Gossop, a patient-reported outcome (PRO) instrument, evaluates the following opioid withdrawal symptoms: feeling sick, stomach cramps, muscle spasms/twitching, feeling of coldness, heart pounding, muscular tension, aches and pains, yawning, runny eyes and insomnia/problems sleeping. For each opioid withdrawal symptom, patients are asked to rate their symptom severity using four response options (none, mild, moderate, and severe). The SOWS-Gossop total score ranges from 0 to 30, where a higher score indicates greater withdrawal symptom severity. The SOWS-Gossop was administered at baseline and once daily 3.5 hours after the first morning dose on Days 1 – 7.

Of the randomized and treated patients, 28% of placebo patients, 41% of LUCEMYRA 2.16 mg and 40% of LUCEMYRA 2.88 mg patients completed 7 days of treatment. The difference in proportion in both LUCEMYRA groups was significant compared to placebo. See Figure 1. Patients in the placebo group were more likely to drop out of the study prematurely due to lack of efficacy than patients treated with LUCEMYRA.

The mean SOWS-Gossop scores for Days 1 – 7 were 8.8, 6.5, and 6.1 for placebo, LUCEMYRA 2.16 mg and LUCEMYRA 2.88 mg, respectively. Results are shown in Figure 2. The mean difference between LUCEMYRA 2.16 mg and placebo was -2.3 with a 95% CI of (-3.4, -1.2). The mean difference between LUCEMYRA 2.88 mg and placebo was -2.7 with a 95% CI of (-3.9, -1.6). They were both significant. Symptoms assessed on the SOWS-Gossop were recorded as absent or mild for almost all patients remaining to the end of the assessment period.

Figure 2: Mean SOWS-Gossop Scores for Days 1 – 7 in Study 1

Study 2, NCT00235729

Study 2 was an inpatient, randomized, multicenter, double-blind, placebo-controlled study carried out in the United States in patients meeting DSM-IV criteria for opioid dependence who were physically dependent on short-acting opioids (e.g., heroin, hydrocodone, oxycodone). Patients were treated with LUCEMYRA tablets (2.88 mg/day [0.72 mg 4 times daily]) or matching placebo for 5 days (Days 1 – 5). Patients also had access to a variety of support medications for withdrawal symptoms (guaifenesin, antacids, dioctyl sodium sulfosuccinate, psyllium hydrocolloid suspension, bismuth sulfate, acetaminophen, and zolpidem). All patients then received placebo on Days 6 and 7 and were discharged on Day 8.

The two endpoints to support efficacy were the mean SOWS-Gossop total score on Days 1 – 5 of treatment and the proportion of patients who completed 5 days of treatment. The SOWS-Gossop was administered at baseline and once daily 3.5 hours after the first morning dose on Days 1 – 5.

A total of 264 patients were randomized into the study. Of these, 134 patients were randomized to LUCEMYRA 2.88 mg/day and 130 patients to placebo.

Of the randomized and treated patients, 33% of placebo patients and 49% of LUCEMYRA patients completed 5 days of treatment. The difference in proportion between the two groups was significant. See Figure 3. Patients in the placebo group were more likely to drop out of the study prematurely due to lack of efficacy than patients treated with LUCEMYRA.

The mean SOWS-Gossop scores for Days 1 – 5 were 8.9 and 7.0 for placebo and LUCEMYRA 2.88 mg, respectively. Results are shown in Figure 4. The mean difference was -1.9 with a 95% CI of (-3.2, -0.6) and was statistically significant.

Figure 4: Mean SOWS-Gossop Scores for Days 1 – 5 in Study 2

How Supplied

Available as 0.18 mg round, convex-shaped, peach colored, film-coated tablets, imprinted with "LFX" on one side and "18" on the other side; approximately 7 mm in diameter.

Storage

Store in original container at controlled room temperature, 25°C (77°F); with excursions permitted between 15°C to 30°C (59°F to 86°F) [see USP Controlled Room Temperature]. Keep LUCEMYRA away from excess heat and moisture both in the pharmacy and after dispensing. Do not remove desiccant packs from bottles until all tablets are used. Keep LUCEMYRA and all medicines out of the reach of children.

Hypotension and Bradycardia

Inform patients to be alert for any symptoms of low blood pressure or pulse (e.g., dizziness, lightheadedness, or feelings of faintness at rest or upon abruptly standing). Advise patients on how to reduce the risk of serious consequences should hypotension occur (sit or lie down, carefully rise from a sitting or lying position).

Patients being given LUCEMYRA in an outpatient setting should be capable of and instructed on self-monitoring for hypotension, orthostasis, and bradycardia and advised to withhold LUCEMYRA doses and contact their healthcare provider for instructions if they experience these signs or related symptoms [see Warnings and Precautions (5.1)].

Advise patients to avoid becoming dehydrated or overheated, which may potentially increase the risks of hypotension and syncope [see Warnings and Precautions (5.1)].

Concomitant Medications

Review with patients all concomitant medications being taken and request that they immediately inform their healthcare provider of any changes in concomitant medications, including any other medications that may be used to treat individual symptoms of withdrawal.

Increased Risk of CNS Depression with Concomitant use of CNS Depressant Drugs

Inform patients of the increased risk of CNS depression with concomitant use of benzodiazepines, alcohol, barbiturates, or other sedating drugs [see Warnings and Precautions (5.3)].

Advise patients using LUCEMYRA in an outpatient setting that, until they learn how they respond to LUCEMYRA, they should be careful or avoid doing activities such as driving or operating heavy machinery.

Sudden Discontinuation of LUCEMYRA

Inform patients not to discontinue LUCEMYRA without consulting their healthcare provider [see Warnings and Precautions (5.5)].

Risk of Opioid Overdose After Discontinuation of Opioids

Advise patients that after a period of not using opioid drugs, they may be more sensitive to the effects of opioids and at greater risk of overdosing [see Warnings and Precautions (5.4)].