LUCEMYRA

1 INDICATIONS AND USAGE LUCEMYRA 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. ( 1 )

2 DOSAGE AND ADMINISTRATION The usual LUCEMYRA dosage is three 0.18 mg tablets taken orally 4 times daily at 5- to 6-hour intervals. LUCEMYRA treatment may be continued for up to 14 days with dosing guided by symptoms. ( 2.1 ) Discontinue LUCEMYRA with a gradual dose reduction over 2 to 4 days. ( 2.1 ) Hepatic or Renal Impairment : Dosage adjustments are recommended based on degree of impairment. ( 2.2 , 2.3 ) 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) ] . Table 1: Dosage Recommendations in Patients with Hepatic Impairment Mild Impairment Moderate Impairment Severe Impairment Child-Pugh score 5-6 7-9 > 9 Recommended dose 3 tablets 4 times daily (2.16 mg per day) 2 tablets 4 times daily (1.44 mg per day) 1 tablet 4 times daily (0.72 mg per day) 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) ] . Table 2: Dosage Recommendations in Patients with Renal Impairment Moderate Impairment Severe Impairment, End-Stage Renal Disease, or on Dialysis Estimated GFR, mL/min/1.73 m 2 30-89.9 < 30 Recommended dose 2 tablets 4 times daily (1.44 mg per day) 1 tablet 4 times daily (0.72 mg per day)

3 DOSAGE FORMS AND STRENGTHS LUCEMYRA is available as round, peach-colored, film-coated tablets, imprinted with "LFX" on one side and "18" on the other side. Each tablet contains 0.18 mg lofexidine (equivalent to 0.2 mg of lofexidine hydrochloride). Tablets: 0.18 mg. ( 3 )

4 CONTRAINDICATIONS None. None. ( 4 )

6 ADVERSE REACTIONS The following serious adverse reactions are described elsewhere in labeling: Hypotension, Bradycardia, and Syncope [see Warnings and Precautions (5.1) ] QT Prolongation [see Warnings and Precautions (5.2) ] Central Nervous System Depression [see Warnings and Precautions (5.3) ] Opioid Overdose [see Warnings and Precautions (5.4) ] Discontinuation Symptoms [see Warnings and Precautions (5.5) ] Most common adverse reactions (incidence ≥ 10% and notably more frequent than placebo) are orthostatic hypotension, bradycardia, hypotension, dizziness, somnolence, sedation, and dry mouth. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact BioCorRx Pharmaceuticals Inc at 1-833-LUCEMYRA or FDA at 1-800-FDA-1088 or www.fda.gov/ medwatch 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. Table 3: Adverse Reactions Reported by ≥10% of LUCEMYRA-Treated Patients and More Frequently than Placebo Adverse Reaction LUCEMYRA 2.16 mg 1 (%) N=229 LUCEMYRA 2.88 mg 1 (%) 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 1 Assigned dose; mean average daily dose received was 79% of assigned dose due to dose-holds for out-of-range vital signs. 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 (39.7) 37 6 (16.2) ≥ 170 mmHg and ≥ 20 mmHg increase from baseline 58 5 (8.6) 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 …

7 DRUG INTERACTIONS Methadone : Methadone and LUCEMYRA both prolong the QT interval. ECG monitoring is recommended when used concomitantly. ( 7.1 ) Oral Naltrexone : Concomitant use may reduce efficacy of oral naltrexone. ( 7.2 ) CYP2D6 Inhibitors : Concomitant use of paroxetine resulted in increased plasma levels of LUCEMYRA. Monitor for symptoms of orthostasis and bradycardia with concomitant use of a CYP2D6 inhibitor. ( 7.4 ) 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 USE IN SPECIFIC POPULATIONS 8.1 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 [see Animal Data ] . 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 [GD] 7 to 19) at a daily dose of 5.0 mg/kg/day (approximately 0.08 times the maximum recommended human dose [MRHD] 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. 8.2 Lactation Risk Summary There is no information regarding the presence of LUCEMYRA or its metabolites in human milk, the effects on the breastfed infant, or the effects on milk production. Caution should be exercised when LUCEMYRA is administered to a nursing woman. The developmental and health benefits should be considered along with the mother's clinical need for LUCEMYRA and any other potential adverse effects on breastfed children from LUCEMYRA or from the underlying maternal condition. 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 estab …

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.

11 DESCRIPTION LUCEMYRA tablets contain lofexidine, a central alpha-2 adrenergic agonist, as the hydrochloride salt. Lofexidine hydrochloride is chemically designated as 2-[1-(2,6-dichlorophenoxy)ethyl]-4,5 dihydro-1 H - imidazole monohydrochloride with a molecular formula of C 11 H 12 Cl 2 N 2 O∙HCl. Its molecular weight is 295.6 g/mole and its structural formula is: Lofexidine hydrochloride is a white to off-white crystalline powder freely soluble in water, methanol, and ethanol. It is slightly soluble in chloroform and practically insoluble in n-hexane and benzene. LUCEMYRA is available as round, convex-shaped, peach-colored, film-coated tablets for oral administration. Each tablet contains 0.18 lofexidine, equivalent to 0.2 mg of lofexidine hydrochloride, and the following inactive ingredients: 92.6 mg lactose, 12.3 mg citric acid, 1.1 mg povidone, 5.7 mg microcrystalline cellulose, 1.4 mg calcium stearate, 0.7 mg sodium lauryl sulphate, and Opadry OY S 9480 (contains indigo carmine and sunset yellow). Chemical Structure

10 OVERDOSAGE 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.

16 HOW SUPPLIED/STORAGE AND HANDLING 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. Bottles of 36 tablets................................................................................................................................... NDC 85789-801-36 Bottles of 96 tablets................................................................................................................................... NDC 85789-801-96 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.