Lofexidine

1 INDICATIONS AND USAGE Lofexidine tablets are indicated for mitigation of opioid withdrawal symptoms to facilitate abrupt opioid discontinuation in adults. Lofexidine tablets are a central alpha-2 adrenergic agonist indicated for mitigation of opioid withdrawal symptoms to facilitate abrupt opioid discontinuation in adults.

2 DOSAGE AND ADMINISTRATION • The usual lofexidine tablets dosage are three 0.18 mg tablets taken orally 4 times daily at 5-to 6-hour intervals lofexidine tablets treatment may be continued for up to14 days with dosing guided by symptoms. ( 2.1 ) • Discontinue lofexidine tablets 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 lofexidine tablets 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 lofexidine tablets should not exceed 2.88 mg (16 tablets) and no single dose should exceed 0.72 mg (4 tablets). Lofexidine tablets treatment may be continued for up to 14 days with dosing guided by symptoms. Discontinue lofexidine tablets with a gradual dose reduction over a 2- to 4-day period to mitigate lofexidine tablets withdrawal symptoms (e.g., reducing by 1 tablet per dose every 1 to 2 days). [see Warnings & Precautions (5.5) ]. The lofexidine tablets dose should be reduced, held, or discontinued for individuals who demonstrate a greater sensitivity to lofexidine tablets side effects [see Adverse Reactions (6.1), Warnings and Precautions (5.1) ]. Lower doses may be appropriate as opioid withdrawal symptoms wane. Lofexidine tablets 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 (8.5), 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. Lofexidine tablets may be administered without regard to the timing of dialysis [see Use in Specific Populations (8.6), Clinical Pharmacology (12.3) ]. Table 2: Dosage Recommendations in Patients with Renal Impairment Mild or 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)

4 CONTRAINDICATIONS None. None.

5 WARNINGS AND PRECAUTIONS • Risk of Hypotension, Bradycardia, and Syncope: May cause a decrease in blood pressure, a decrease in pulse, and syncope. Monitor vital signs before dosing and advise patients on how to minimize the risk of these cardiovascular effects and manage symptoms, should they occur. Monitor symptoms related to bradycardia and orthostasis. When using in outpatients, ensure that patients are capable of self-monitoring signs and symptoms. Avoid use in patients with severe coronary insufficiency, recent myocardial infarction, cerebrovascular disease, or chronic renal failure, as well as in patients with marked bradycardia. ( 5.1 ) • Risk of QT Prolongation: lofexidine tablets prolongs the QT interval. Avoid use in patients with congenital long QT syndrome. Monitor ECG in patients with electrolyte abnormalities, congestive heart failure, bradyarrhythmias, hepatic or renal impairment, or in patients taking other medicinal products that lead to QT prolongation. ( 5.2 ) • Increased Risk of CNS Depression with Concomitant use of CNS Depressant Drugs: lofexidine tablets potentiates the CNS depressant effects of benzodiazepines and may potentiate the CNS depressant effects of alcohol, barbiturates, and other sedating drugs. ( 5.3 ) • Increased Risk of Opioid Overdose after Opioid Discontinuation: Patients who complete opioid discontinuation are at an increased risk of fatal overdose should they resume opioid use. Use in conjunction with comprehensive management program for treatment of opioid use disorder and inform patients and caregivers of increased risk of overdose. ( 5.4 ) • Risk of Discontiuation Symptoms: Instruct patients not to discontinue therapy without consulting their healthcare provider. When discontinuing therapy, reduce dose gradually. ( 5.5 ) 5.1 Risk of Hypotension, Bradycardia and Syncope Lofexidine tablet 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 lofexidine tablet 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 lofexidine tablet should be reduced in amount, delayed, or skipped. Inform patients that lofexidine tablet 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 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 lofexidine tablet doses when experiencing symptoms of hypotension or bradycardia and to contact their health care provider for guidance on how to adjust dosing. Avoid use lofexidine tablets in patients with severe coronary insufficiency, recent myocardial infarction, cerebrovascular disease, chronic renal failure, and in patients with marked bradycardia. Avoid use lofexidine tablets 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 Lofexidine tablet prolongs the QT interval. Avoid using lofexidine tablet 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 lofexidine tablet [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 Lofexidine tablet 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 lofexidine tablet in an outpatient setting that, until they learn how they respond to lofexidine tablet, 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 Lofexidine tablet 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 lofexidine tablet 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 lofexidine tablet abruptly can cause a marked rise in blood pressure. Symptoms including diarrhea, insomnia, anxiety, chills, hyperhidrosis, and extremity pain have also been observed with lofexidine tablet discontinuation. Instruct patients not to discontinue therapy without consulting their healthcare provider. When discontinuing therapy with lofexidine tablet, gradually reduce the dose [see Dosing and Administration (2.1) ]. Symptoms related to discontinuation can be managed by administration of the previous lofexidine tablet dose and subsequent taper.

7 DRUG INTERACTIONS • Methadone : Methadone and lofexidine tablets both prolong the QT interval. ECG monitoring is recommended when used concomitantly. ( 7.1 ) • Oral Naltrexone : Comcomitant use may reduce efficacy of oral naltrexone. ( 7.2 ) • CYP2D6 Inhibitors : Concomitant use of paroxetine resulted in increased plasma levels of lofexidine tablets. Monitor for symptoms of orthostasis and bradycardia with concomitant use of a CYP2D6 inhibitor. ( 7.4 ) 7.1 Methadone Lofexidine tablet and methadone both prolong the QT interval. ECG monitoring is recommended in patients receiving methadone and lofexidine tablet [see Warnings and Precautions (5.2), Clinical Pharmacology (12.3) ]. 7.2 Oral Naltrexone Coadministration of lofexidine tablet 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 lofexidine tablet.This interaction is not expected if naltrexone is administered by non-oral routes [see Clinical Pharmacology (12.3) ] . 7.3 CNS Depressant Drugs Lofexidine tablet 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 lofexidine tablet and paroxetine resulted in 28% increase in the extent of absorption of lofexidine tablet. Monitor for orthostatic hypotension and bradycardia when an inhibitor of CYP2D6 is used concomitantly with lofexidine tablet [see Clinical Pharmacology (12.3) ].

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 Lambda Therapeutics Research Ltd. at +1-855-642-2594 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 lofexidine was supported by 3 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 3 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 lofexidine and for which the incidence in patients treated with lofexidine was greater than the incidence in subjects treated with placebo in a study that tested two doses of lofexidine, 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 lofexidine tablet than subjects treated with placebo. Table 3: Adverse Reactions Reported by ≥10% of Lofexidine Tablet-Treated Patients and More Frequently than Placebo Adverse Reaction Lofexidine tablet 2.16 mg 1 (%)N=229 Lofexidine tablet 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 * 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 lofexidine tablet but reported in <10% of patients in the lofexidine tablet group included: • Syncope: 0.9%, 1.4% and 0% for lofexidine tablet 2.16 mg/day and 2.88 mg/day and placebo,respectively • Tinnitus: 0.9%, 3.2% and 0% for lofexidine tablet 2.16 mg/day and 2.88 mg/day and placebo,respectively Blood pressure changes and adverse reactions after lofexidine tablet cessation Elevations in blood pressure above normal values (≥ 140 mmHg systolic) and above a subject’s pre-treatment baseline are associated with discontinuing lofexidine tablet, 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 lofexidine tablet 2.88mg/day. Table 4: Blood Pressure Elevations after Stopping Treatment Abrupt lofexidine tablet 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 ≥ 170 mmHg and ≥ 20 mmHg increase from baseline 58 23(39.7) 58 5(8.6) 37 6 (16.2) 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 that were taking lofexidine tablet also had a higher incidence of diarrhea, insomnia anxiety, chills, hyperhidrosis, and extremity pain compared to subjects that were taking placebo. Sex-specific adverse event findings Four out of 101 females (4%) had a serious cardiovascular adverse events compared to 3 out of 289 (1%) of males assigned to receive lofexidine tablet 2.88 mg per day. Discontinuations and dose holds due to bradycardia and orthostatic hypotension, which are the most common adverse reactions associated with lofexidine tablet, occurred with a greater incidence in females assigned to receive the highest studied dose of lofexidine tablet, 2.88 mg per day as shown in Table 5. Table 5: Discontinuations and Dose Holds for Bradycardia and Orthostatic Hypotension by lofexidine tablet Dose and Sex Lofexidine 2.16 mg Lofexidine 2.88 mg Male 22/162 (14%) 29/158 (18%) Female 9/67 (13%) 20/64 (31%) 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 that received lofexidine and three reports of clinically significant QT prolongation in subjects concurrently receiving methadone with lofexidine.

8.1 Pregnancy Risk Summary The safety of lofexidine tablet 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 indicies. 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). 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.