Lofexidine Hydrochloride

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. ( 1 )

2 DOSAGE AND ADMINISTRATION The usual lofexidine tablet dosage is three 0.18 mg tablets taken orally 4 times daily at 5- to 6-hour intervals. Lofexidine tablet treatment may be continued for up to 14 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 tablet 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 tablet 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 tablet withdrawal symptoms (e.g., reducing by 1 tablet per dose every 1 to 2 days) [see Warnings & Precautions (5.5)] .The lofexidine tablet dose should be reduced, held, or discontinued for individuals who demonstrate a greater sensitivity to lofexidine tablets side effects [see Warnings and Precautions (5.1) , Adverse Reactions (6.1) ] . 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 (8.6), Clinical Pharmacology (12.3)] . Table 1: Dosage Recommendations in Patients with Hepatic Impairment Mild Impairment Moderate Impairment Severe Impairment Child-Pugh score 5 to 6 7 to 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 (8.7) , 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 to 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)

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 Novadoz Pharmaceuticals LLC at 1-855-668-2369 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 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 lofexidine and for which the incidence in patients treated with lofexidine were 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 than subjects treated with placebo. Table 3: Adverse Reactions Reported by ≥10% of Lofexidine-Treated Patients and More Frequently than Placebo Adverse Reaction Lofexidine 2.16 mg 1 (%) N=229 Lofexidine 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 lofexidine but reported in <10% of patients in the lofexidine group included: Syncope: 0.9%, 1.4% and 0% for lofexidine 2.16 mg/day and 2.88 mg/day and placebo, respectively Tinnitus: 0.9%, 3.2% and 0% for lofexidine 2.16 mg/day and 2.88 mg/day and placebo, respectively Blood pressure changes and adverse reactions after lofexidine cessation Elevations in blood pressure above normal values (≥ 140 mmHg systolic) and above a subject’s pre-treatment baseline are associated with discontinuing lofexidine, 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 2.88 mg/day. Table 4: Blood Pressure Elevations after Stopping Treatment Abrupt Lofexidine 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) 37 6 (16.2) 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 lofexidine 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 lofexidine 2.88 mg/day. Discontinuations and dose-holds due to bradycardia and orthostatic hypotension, which are the most common adverse reactions associated with lofexidine, occurred with a greater incidence in females assigned to receive the highest studied dose of lofexidine, 2.88 mg/day as shown in Table 5. Table 5: Discontinuations and Dose-Holds for Bradycardia and Orthostatic Hypotension by Lofexidine 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 who received lofexidine, and three reports of clinically significant QT prolongation in subjects concurrently receiving methadone with lofexidine.

12.3 Pharmacokinetics Absorption Lofexidine is well absorbed and achieves peak plasma concentration 3 to 5 hours after administration of a single dose. Lofexidine shows approximately dose-proportional pharmacokinetics. Administration of lofexidine with food does not alter its pharmacokinetics. The absolute bioavailability of a single oral lofexidine dose (0.36 mg in solution) compared with an intravenous infusion (0.2 mg infused for 200 minutes) was 72%. Mean lofexidine C max after the oral dose and intravenous infusion was 0.82 ng/mL (at median T max of 3 hours) and 0.64 ng/mL (at median T max of 4 hours), respectively. Mean estimates of overall systemic exposure (AUC inf ) were 14.9 ng•h/mL and 12.0 ng•h/mL, respectively. Distribution Mean lofexidine apparent volume of distribution and volume of distribution values following the administration of an oral dose and an intravenous dose were 480.0 L and 297.9 L, respectively, which are appreciably greater than total body volume, suggesting extensive lofexidine distribution into body tissue. Lofexidine protein binding is approximately 55%. Lofexidine is not preferentially taken up by blood cells. In a study comparing lofexidine concentrations in plasma and whole blood at the time of peak lofexidine concentrations in human volunteers, it was determined that red blood cells contain approximately 27% the lofexidine concentration of the plasma. Elimination Metabolism From absolute bioavailability results, approximately 30% of the administered lofexidine dose is converted to inactive metabolites during the first pass effect associated with drug absorption from the gut. Lofexidine and its major metabolites did not induce or inhibit any CYP450 isoforms, with the exception of a slight inhibition of CYP2D6 by lofexidine, with an IC 50 of 4551 nM (approximately 225 times the steady-state C max for lofexidine with 0.72 mg 4 times daily dosing). Any lofexidine interaction with CYP2D6 substrates is not expected to be clinically significant. Lofexidine is metabolized when incubated in vitro with human liver microsomes, the major contributor to the hepatic metabolism of lofexidine is CYP2D6, with CYP1A2 and CYP2C19 also capable of metabolizing lofexidine. Excretion The elimination half-life is approximately 12 hours and mean clearance is 17.6 L/h following an IV infusion. Lofexidine has a terminal half-life of approximately 11 to 13 hours following the first dose. At steady-state, the terminal half-life is approximately 17 to 22 hours. Accumulation occurs up to 4 days with repeat dosing, following the recommended dosing regimen. A mass balance study of lofexidine showed nearly complete recovery of radiolabel in urine (93.5%) over 144 hours postdose, with an additional 0.92% recovered in the feces over 216 hours postdose. Thus, it appears that all, or nearly all, of the dose was absorbed, and that the primary route of elimination of the parent drug and its metabolites is via the kidney. Renal elimination of unchanged drug accounts for approximately 15% to 20% of the administered dose. Specific Populations Hepatic Impairment Hepatic impairment slows the elimination of lofexidine but exhibits less effect on the peak plasma concentration following a single dose. In a study comparing the pharmacokinetics of lofexidine (0.36 mg) in mild, moderate, and severe hepatically impaired subjects to subjects with normal hepatic function (6 subjects in each hepatic function group), mean C max values were similar for subjects with normal, mild, and moderate hepatic impairment as shown in Table 6. Table 6: Lofexidine Pharmacokinetics in Subjects with Hepatic Impairment Normal Mild Impairment Moderate Impairment Severe Impairment Child-Pugh Class & Score Normal Function Class A 5 to 6 Class B 7 to 9 Class C 10 to 15 C max % of normal 100 114 117 166 AUC last % of normal 100 127 190 304 AUC ∞ % of normal 100 117 185 260 t 1/2 % of normal 100 139 281 401 Renal Impairment Renal impairment slows the elimination of lofexidine but exhibits less effect on the peak plasma concentration following a single dose. In a study comparing the pharmacokinetics of lofexidine (0.36 mg) in 8 end-stage renal disease subjects on 3 times weekly hemodialysis to 8 subjects with normal renal function matched for sex, age, and body mass index, mean C max values were similar for end-stage renal disease and normal renal function subjects, indicating no change in maximum lofexidine exposure with renal impairment as shown in Table 7. The impact of dialysis on the overall pharmacokinetics of lofexidine during a typical 4-hour dialysis was minimal; the drop in lofexidine plasma concentrations produced during the dialysis session was transient, with a rebound to nearly predialysis concentrations after re-equilibration within a few hours following completion of the dialysis cycle [see Dosage and Administration (2.3) , Use in Specific Populations (8.7)] . In a study comparing the pharmacokinetics of lofexidine (0.36 mg) in 6 subjects each with normal renal function, mild renal impairment, and moderate renal impairment as well as 5 subjects with severe renal impairment but not requiring dialysis, there were similar increases in mean C max values in subjects with mild and moderate renal impairment in comparison to subjects with normal renal function with additional increases in mean C max values in subjects with severe renal impairment. Mean AUC last , AUC ∞ , and t 1/2 increased with severity of renal impairment as shown in Table 7. Table 7: Lofexidine Pharmacokinetics in Subjects with Renal Impairment Normal Mild Impairment Moderate Impairment Severe Impairment ESRD or on dialysis eGFR (mL/min/1.73 m 2 ) ≥ 90 60 to 89 30 to 59 15 to 29 < 15 C max % of normal 100 124 117 154 104 AUC last % of normal 100 157 187 272 181 AUC ∞ % of normal 100 144 173 243 171 t 1/2 % of normal 100 111 145 157 137 Drug Interaction Studies Lofexidine coadministered with methadone In a double-blind placebo-controlled study of 23 patients maintained on methadone (80 to 120 mg/day) concomitantly administered lofexidine up to 2.88 mg/day, lofexidine did not alter the pharmacokinetics of methadone. Lofexidine concentrations may be slightly increased when coadministered with methadone; however, the increase at concentrations expected with recommended dosing is not clinically meaningful [see Drug Interactions (7.1)]. Lofexidine coadministered with buprenorphine In a double-blind placebo-controlled study of 30 subjects maintained on buprenorphine (16 to 24 mg/day) concomitantly administered lofexidine up to 2.88 mg/day, no pharmacokinetic or pharmacodynamic interactions between lofexidine and buprenorphine were seen. Lofexidine coadministered with oral naltrexone In an open-label, single-arm study of 24 healthy subjects, oral naltrexone (50 mg/day) did not significantly alter the single-dose pharmacokinetics of lofexidine (0.36 mg). The alteration in steady-state pharmacokinetics of oral naltrexone was statistically significant in the presence of lofexidine. The T max was delayed for both naltrexone and 6ß-naltrexol (2 to 3 hours), and overall exposure was slightly reduced when naltrexone was administered with lofexidine [see Drug Interactions (7.2)]. Lofexidine coadministered with paroxetine In an open-label, single-sequence study of 24 healthy subjects, the strong CYP2D6 inhibitor paroxetine (40 mg/day) increased lofexidine (0.36 mg) C max and AUC ∞ by approximately 11% and 28%, respectively [see Drug Interactions (7.4)] .