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

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

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.

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

1Assigned 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

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

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.

7.1 Methadone

Lofexidine tablet and methadone both prolong the QT interval. ECG monitoring is recommended in patients receiving methadone and lofexidine tablet [seeWarnings 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)].

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.

8.2 Lactation

Risk Summary

There is no information regarding the presence of lofexidine tablet or its metabolites in human milk, the effects on the breastfed infant, or the effects on milk production. Caution should be exercised when lofexidine tablet is administered to a nursing woman.

The developmental and health benefits should be considered along with the mother’s clinical need for lofexidine tablet and any other potential adverse effects on breast-fed children from lofexidine tablet 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 be adequately characterized in animal studies [see Impariment of Fertility (13.1)].

8.4 Pediatric Use

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

8.5 Geriatric Use

No studies have been performed to characterize the pharmacokinetics of lofexidine tablet or establish its safety and effectiveness in geriatric patients. Caution should be exercised when it 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 (8.6)].

8.6 Hepatic Impairment

Hepatic impairment slows the elimination of lofexidine tablet 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 (12.2)]. 
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 lofexidine tablet 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 lofexidine tablet dose is removed during a typical dialysis session, so no additional dose needs to be administered after a dialysis session; lofexidine tablet 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 lofexidine tablet have not been systematically evaluated in patients who do not express the drug metabolizing enzyme CYP2D6, it is likely that the exposure to lofexidine tablet 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 3–8% of Black/African Americans cannot metabolize CYP2D6 substrates and are classified as poor metabolizers (PM) [seeClinical 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

Cardiac Electrophysiology
Single lofexidine doses of 1.44 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 and 1.8 mg respectively in healthy normal volunteers.

In a Phase 3 placebo-controlled, dose-response study in opioid-dependent subjects, lofexidine tablet was associated with a maximum mean prolongation of the QTcF interval 7.3 (8.8)  and 9.3 (10.9) msec at doses of 2.16 and 2.88 mg/day, respectively.

Patients with hepatic impairment 

 
Administration of lofexidine to subjects with hepatic impairment was associated with prolongation of the QTc interval, which was more pronounced in subjects with severe hepatic impairment [seeUse in Specific Populations (8.6)].

Patients with renal impairment 

Administration of lofexidine tablet 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 coadministered with methadone 

Lofexidine tablet (2.88 mg/day) coadministered with methadone in 18 methadone-maintained patients (80-120 mg/day) resulted in a maximum mean increase from methadone-alone baseline in QTcF of 9.1 (14.2) msec.

Lofexidine tablet coadministered with buprenorphine

 
Lofexidine tablet (2.88 mg/day) coadministered with buprenorphine in 21 buprenorphine-maintained patients (16-24 mg/day) resulted in a maximum mean QTcF increase in QTcF of 15 (5.6) msec compared to a buprenorphine-alone baseline.

In Vitro Binding

Lofexidine tablet 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).

12.3 Pharmacokinetics

Absorption
Lofexidine tablet is well absorbed and achieves peak plasma concentration 3 to 5 hours after administration of a single dose.

Lofexidine tablet shows approximately dose-proportional pharmacokinetics. Administration of lofexidine tablet with food does not alter its pharmacokinetics. 

The absolute bioavailability of a single oral lofexidine tablet dose ( 0.36 mg in solution) compared with an intravenous infusion (0.2 mg infused for 200 minutes) was 72%. Mean lofexidine tablet Cmax after the oral dose and intravenous infusion was 0.82 ng/mL (at median Tmax of 3 hours) and 0.64 ng/mL (at median Tmax of 4 hours), respectively. Mean estimates of overall systemic exposure (AUCinf) were 14.9 ng•h/mL and 12.0 ng•h/mL, respectively.

Distribution

Mean lofexidine tablet 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 tablet distribution into body tissue.

Lofexidine tablet protein binding is approximately 55%.

Lofexidine tablet is not preferentially taken up by blood cells. In a study comparing lofexidine tablet concentrations in plasma and whole blood at the time of peak lofexidine tablet concentrations in human volunteers, it was determined that red blood cells contain approximately 27% the lofexidine tablet concentration of the plasma.

Elimination

Metabolism

 
From absolute bioavailability results, approximately 30% of the administered lofexidine tablet dose is converted to inactive metabolites during the first pass effect associated with drug absorption from the gut.

Lofexidine tablet and its major metabolites did not induce or inhibit any CYP450 isoforms, with the exception of a slight inhibition of CYP2D6 by lofexidine tablet, with an IC50 of 4551 nM (approximately 225 times the steady-state Cmax for lofexidine tablet with 0.72 mg 4 times daily dosing). Any lofexidine tablet interaction with CYP2D6 substrates is not expected to be clinically significant.

Lofexidine tablet is metabolized when incubated in vitro with human liver microsomes, the major contributor to the hepatic metabolism of lofexidine tablet is CYP2D6, with CYP1A2 and CYP2C19 also capable of metabolizing lofexidine tablet.

Excretion 

The elimination half-life is approximately 12 hours and mean clearance is 17.6 L/h following an IV infusion. 

Lofexidine tablet 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 tablet 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 tablet but exhibits less effect on the peak plasma concentration following a single dose. In a study comparing the pharmacokinetics of lofexidine tablet (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 Cmax 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

Renal Impairment 
Renal impairment slows the elimination of lofexidine tablet but exhibits less effect on the peak plasma concentration following a single dose. In a study comparing the pharmacokinetics of lofexidine tablet (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 Cmax values were similar for end-stage renal disease and normal renal function subjects, indicating no change in maximum lofexidine tablet exposure with renal impairment as shown in Table 7.

The impact of dialysis on the overall PK of lofexidine tablet during a typical 4-hour dialysis was minimal; the drop in lofexidine tablet 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 (8.6)].

In a study comparing the pharmacokinetics of lofexidine tablet (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 Cmax values in subjects with mild and moderate renal impairment in comparison to subjects with normal renal function with additional increase in mean Cmax values in subjects with severe renal impairment. Mean AUClast, AUC∞, and t1/2 increased with severity of renal impairment as shown in Table 7.

Table 7: Lofexidine tablet Pharmacokinetics in Subjects with Renal Impairment

Drug Interaction Studies

Lofexidine tablet coadministered with methadone

In a double-blind placebo-controlled study of 23 patients maintained on a methadone dose of 80-120 mg/day and concomitantly administered lofexidine tablet up to 2.88 mg/day, lofexidine tablet did not alter the pharmacokinetics of methadone. Lofexidine tablet 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 tablet coadministered with buprenorphine

In a double-blind placebo-controlled study of 30 subjects maintained on buprenorphine (16-24 mg/day) concomitantly administered lofexidine tablet up to 2.88 mg/day, no pharmacokinetic or pharmacodynamic interactions between lofexidine tablet and buprenorphine were seen.

Lofexidine tablet 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 tablet (0.36 mg). The alteration in steady-state pharmacokinetics of oral naltrexone was statistically significant in the presence of lofexidine tablet. The tmax was delayed for both naltrexone and 6ß-naltrexol (2-3 hours), and overall exposure was slightly reduced when naltrexone was administered with lofexidine tablet [see Drug Interactions (7.2)].

Lofexidine tablet coadministered with paroxetine 

In an open-label, single-sequence study of 24 healthy subjects, the strong CYP2D6 inhibitor paroxetine (40 mg/day) increased lofexidine tablet (0.36 mg) Cmax and AUC∞ by approximately 11% and 28%, respectively [see Drug Interactions (7.4)].

13.1 Carcinogenesis , Mutagenesis , Impairment Of Fertility

Carcinogenesis 
No adequate long-term animal studies have been completed to evaluate the carcinogenic potential of lofexidine.

Mutagenesis
Lofexidine tested positive in the in vitro mouse lymphoma assay. Lofexidine 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 to female rabbits 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 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.