Lofexidine

Risk Summary

The safety of lofexidine 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). 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.

Risk Summary

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

The developmental and health benefits should be considered along with the mother’s clinical need for lofexidine and any other potential adverse effects on breastfed children from lofexidine or from the underlying maternal condition.

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.

• Hypotension, Bradycardia, and Syncope
• QT Prolongation
• Central Nervous System Depression
• Opioid Overdose
• Discontinuation Symptoms

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 1 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 than subjects treated with placebo.

Table 1. Adverse Reactions Reported by ≥10% of Lofexidine-Treated Patients and More Frequently than Placebo:

* 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 2. Blood pressure values were evaluated for 3 days following the last dose of a 5-day course of lofexidine 2.88 mg/day.

Table 2. 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 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%) of males assigned to receive lofexidine 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, occurred with a greater incidence in females assigned to receive the highest studied dose of lofexidine, 2.88 mg per day as shown in Table 3.

Table 3. Discontinuations and Dose Holds for Bradycardia and Orthostatic Hypotension by Lofexidine Dose and Sex:

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. 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.