Lofexidine .2 mg Tablet, Film Coated, 36-count — NDC 85789-901-36 (Billing 85789-0901-36)

12 CLINICAL PHARMACOLOGY

12.1Mechanism of Action Lofexidine tablets are a central alpha-2 adrenergic agonist that binds to receptors on adrenergic neurons. This reduces the release of norepinephrine and decreases sympathetic tone.

12.2Pharmacodynamics Cardiac Electrophysiology Single Lofexidine tablets doses of 1.44 mg to 1.8 mg produced maximum mean change from baseline in QTcF (ΔQTcF) of 14.4 msec (upper two-sided 90% CI: 22.3 msec) and 13.6 msec (17.4 msec) for 1.44 mg and 1.8 mg respectively in healthy normal volunteers. In a Phase 3 placebo-controlled, dose response study in opioid dependent subjects, Lofexidine tablets were associated with a maximum mean prolongation of the QTcF interval 7.3 (8.8) msec and 9.3 (10.9) msec at doses of 2.16 mg/day and 2.88 mg/ day, respectively.

Patients with hepatic impairment Administration of Lofexidine tablets to subjects with hepatic impairment was associated with prolongation of the QTc interval, which was more pronounced in subjects with severe hepatic impairment [see Use in Specific Populations (8.6) ] . Patients with renal impairment Administration of Lofexidine tablets to subjects with renal impairment was associated with prolongation of the QTc interval, which was more pronounced in subjects with severe renal impairment [see Use in Specific Populations (8.7) ] .

Lofexidine tablets coadministered with methadone Lofexidine tablets (2.88 mg/day) coadministered with methadone in 18 methadone-maintained patients (80 to 120 mg/day) resulted in a maximum mean increase from methadone-alone baseline in QTcF of 9.1 (14.2) msec. Lofexidine tablets coadministered with buprenorphine Lofexidine tablets (2.88 mg/day) coadministered with buprenorphine in 21 buprenorphine-maintained patients (16 to 24 mg/ day) resulted in a maximum mean QTcF increase of 1.5 (5.6) msec compared to a buprenorphine-alone baseline.

In Vitro Binding Lofexidine tablets exhibits in vitro binding affinity and functional agonist activity with alpha-2A and alpha-2C adrenoreceptors at concentrations within clinical exposure plasma levels (Ki values of approximately 7.2 nM and 12 nM, and EC50 values of 4.9 nM and 0.9 nM, respectively).

12.3Pharmacokinetics Absorption Lofexidine tablets are well absorbed and achieves peak plasma concentration 3 to 5 hours after administration of a single dose. Lofexidine tablets show approximately dose-proportional pharmacokinetics. Administration of Lofexidine tablets with food does not alter its pharmacokinetics.

The absolute bioavailability of a single oral Lofexidine tablets dose (0.36 mg in solution) compared with an intravenous infusion (0.2 mg infused for 200 minutes) was 72%. Mean Lofexidine tablets 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 tablets 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 tablets distribution into body tissue. Lofexidine tablets protein binding is approximately 55%. Lofexidine tablets are not preferentially taken up by blood cells.

In a study comparing Lofexidine tablets concentrations in plasma and whole blood at the time of peak Lofexidine tablets concentrations in human volunteers, it was determined that red blood cells contain approximately 27% the Lofexidine tablets concentration of the plasma. Elimination Metabolism From absolute bioavailability results, approximately 30% of the administered Lofexidine tablets dose is converted to inactive metabolites during the first pass effect associated with drug absorption from the gut. Lofexidine tablets and its major metabolites did not induce or inhibit any CY… [Excerpted — this section continues on DailyMed.]

12.1Mechanism of Action Lofexidine tablets are a central alpha-2 adrenergic agonist that binds to receptors on adrenergic neurons. This reduces the release of norepinephrine and decreases sympathetic tone.

12.3Pharmacokinetics Absorption Lofexidine tablets are well absorbed and achieves peak plasma concentration 3 to 5 hours after administration of a single dose. Lofexidine tablets show approximately dose-proportional pharmacokinetics. Administration of Lofexidine tablets with food does not alter its pharmacokinetics.

The absolute bioavailability of a single oral Lofexidine tablets dose (0.36 mg in solution) compared with an intravenous infusion (0.2 mg infused for 200 minutes) was 72%. Mean Lofexidine tablets 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 tablets 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 tablets distribution into body tissue. Lofexidine tablets protein binding is approximately 55%. Lofexidine tablets are not preferentially taken up by blood cells.

In a study comparing Lofexidine tablets concentrations in plasma and whole blood at the time of peak Lofexidine tablets concentrations in human volunteers, it was determined that red blood cells contain approximately 27% the Lofexidine tablets concentration of the plasma. Elimination Metabolism From absolute bioavailability results, approximately 30% of the administered Lofexidine tablets dose is converted to inactive metabolites during the first pass effect associated with drug absorption from the gut. Lofexidine tablets and its major metabolites did not induce or inhibit any CYP450 isoforms, with the exception of a slight inhibition of CYP2D6 by Lofexidine tablets, with an IC50 of 4551 nM (approximately 225 times the steady-state C max for Lofexidine tablets with 0.72 mg 4 times daily dosing).

Any Lofexidine tablets interaction with CYP2D6 substrates is not expected to be clinically significant Lofexidine tablets are metabolized when incubated in vitro with human liver microsomes, the major contributor to the hepatic metabolism of Lofexidine tablets is CYP2D6, with CYP1A2 and CYP2C19 also capable of metabolizing Lofexidine tablets. Excretion The elimination half-life is approximately 12 hours and mean clearance is

17.6L/h following an IV infusion. Lofexidine tablets have 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 tablets 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 tablets but exhibits less effect on the peak plasma concentration following a single dose. In a study comparing the pharmacokinetics of Lofexidine tablets (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 tablets Pharmacokinetics in Subjects with Hepatic Impairment Normal Mild Impairment Moderate Impairment Severe Impairment Child-Pugh Class & Score Normal Function Class A 5-6 Class B 7-9 Class C 10-15 C max… [Excerpted — this section continues on DailyMed.]

12.2Pharmacodynamics Cardiac Electrophysiology Single Lofexidine tablets doses of 1.44 mg to 1.8 mg produced maximum mean change from baseline in QTcF (ΔQTcF) of 14.4 msec (upper two-sided 90% CI: 22.3 msec) and 13.6 msec (17.4 msec) for 1.44 mg and 1.8 mg respectively in healthy normal volunteers. In a Phase 3 placebo-controlled, dose response study in opioid dependent subjects, Lofexidine tablets were associated with a maximum mean prolongation of the QTcF interval 7.3 (8.8) msec and 9.3 (10.9) msec at doses of 2.16 mg/day and 2.88 mg/ day, respectively.

Patients with hepatic impairment Administration of Lofexidine tablets to subjects with hepatic impairment was associated with prolongation of the QTc interval, which was more pronounced in subjects with severe hepatic impairment [see Use in Specific Populations (8.6) ] . Patients with renal impairment Administration of Lofexidine tablets to subjects with renal impairment was associated with prolongation of the QTc interval, which was more pronounced in subjects with severe renal impairment [see Use in Specific Populations (8.7) ] .

Lofexidine tablets coadministered with methadone Lofexidine tablets (2.88 mg/day) coadministered with methadone in 18 methadone-maintained patients (80 to 120 mg/day) resulted in a maximum mean increase from methadone-alone baseline in QTcF of 9.1 (14.2) msec. Lofexidine tablets coadministered with buprenorphine Lofexidine tablets (2.88 mg/day) coadministered with buprenorphine in 21 buprenorphine-maintained patients (16 to 24 mg/ day) resulted in a maximum mean QTcF increase of 1.5 (5.6) msec compared to a buprenorphine-alone baseline.

In Vitro Binding Lofexidine tablets exhibits in vitro binding affinity and functional agonist activity with alpha-2A and alpha-2C adrenoreceptors at concentrations within clinical exposure plasma levels (Ki values of approximately 7.2 nM and 12 nM, and EC50 values of 4.9 nM and 0.9 nM, respectively).

14 CLINICAL STUDIES Two randomized, double-blind, placebo-controlled trials supported the efficacy of Lofexidine tablets. 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 Lofexidine tablets 2.16 mg total daily dose (0.54 mg 4 times daily) (n=229), Lofexidine tablets 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 Lofexidine tablets 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 Lofexidine tablets 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 Lofexidine tablets 2.16 mg and 40% of Lofexidine tablets 2.88 mg patients completed 7 days of treatment. The difference in proportion in both Lofexidine tablets 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 Lofexidine tablets. The mean SOWS-Gossop scores for Days 1 – 7 were 8.8, 6.5, and 6.1 for placebo, Lofexidine tablets 2.16 mg and Lofexidine tablets 2.88 mg, respectively. Results are shown in Figure 2 .

The mean difference between Lofexidine tablets 2.16 mg and placebo was -2.3 with a 95% CI of (-3.4, -1.2). The mean difference between Lofexidine tablets 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. 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 Lofexidine 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). A… [Excerpted — this section continues on DailyMed.]

13 NONCLINICAL TOXICOLOGY

13.1Carcinogenesis, Mutagenesis, Impairment of Fertility Carcinogenesis No adequate long-term animal studies have been completed to evaluate the carcinogenic potential of lofexidine tablets. Mutagenesis Lofexidine tablets tested positive in the in vitro mouse lymphoma assay. Lofexidine tablets tested negative in the in vitro bacterial reverse mutation assay (Ames assay) and in the in vivo rat micronucleus assay.

Impairment of Fertility In a female fertility study in rabbits, fertility was not adversely impacted by administration of lofexidine hydrochloride up to 6.4 mg/ kg/day (approximately 0.1 times the MRHD of 2.88 mg on an AUC basis) when administered orally starting 2 weeks prior to mating and through gestation and lactation. However, decreased breeding rate and higher post- implantation loss was observed at this dose, which correlated with higher resorptions and reduced litter size. Maternal toxicity, which included increased mortality rate, reduced body weight gain, and moderate sedation was observed at 6.4 mg/kg/day.

The NOAEL for female fertility was 6.4 mg/kg/ day and the NOAEL for female-mediated developmental parameters was 0.4 mg/kg/day (approximately 0.005 times the MRHD on an AUC basis). In a fertility study in rats, fertility was unaffected by administration of lofexidine tablets up to 0.88 mg/kg/day (approximately 0.2 times the MRHD on an AUC basis) via diet to male and female rats prior to mating and to the dams through gestation and lactation. No evidence of maternal toxicity was observed.

However, no assessment of sperm or reproductive organs were performed in this study. Reduced testes, epididymis, and seminiferous tubule weights, as well as delayed sexual maturation of males and females and decreases in the number of corpora lutea and implantations after mating, were noted in offspring of pregnant rats administered lofexidine hydrochloride orally from GD 6 through lactation at exposures less than the human exposure based on AUC comparisons.