FDA

Lofexidine Hydrochloride

Approved 24 Feb 2025OralTablet

The FDA lists this product in 3 strengths and forms.

Indications

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 )

Contraindications

None. None. ( 4 )

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 for 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 ) Ri sk of QT Prolongation: Lofexidine prolong 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 potentiate 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 a comprehensive management program for treatment of opioid use disorder and inform patients and caregivers of increased risk of overdose. ( 5.4 ) Risk of Discontinuation Symptoms: Instruct patients not to discontinue therapy without consulting their healthcare provider. When discontinuing therapy, reduce dose gradually. ( 5.5 )

5.1Risk of Hypotension, Bradycardia, and Syncope

Lofexidine 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 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 should be reduced in amount, delayed, or skipped.

At a glance

Brand name: Lofexidine Hydrochloride
Route: Oral
Dosage form: Tablet
Applicant: MSN
Status: Prescription
FDA approval: 24 Feb 2025
Application: ANDA218699-001

Indications

Warnings and precautions

5.1Risk of Hypotension, Bradycardia, and Syncope

Pregnancy and breastfeeding

8.1Pregnancy 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). At 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.

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

6.1Clinical 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%)

6.2Postmarketing 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.

Lofexidine Hydrochloride

Indications

Contraindications

Warnings and precautions

5.1Risk of Hypotension, Bradycardia, and Syncope

At a glance

Two medicines in one question?

Lofexidine Hydrochloride

Indications

Contraindications

Warnings and precautions

5.1Risk of Hypotension, Bradycardia, and Syncope

At a glance

Two medicines in one question?

5.2Risk of QT Prolongation

5.4Increased Risk of Opioid Overdose after Opioid Discontinuation

5.5Risk of Discontinuation Symptoms

Interactions

7.1Methadone Lofexidine

7.2Oral Naltrexone Coadministration

7.3CNS Depressant Drugs

7.4CYP2D6

Pregnancy and breastfeeding

8.1Pregnancy Risk Summary

Adverse reactions

6.1Clinical Trials Experience

6.2Postmarketing Experience

Composition

Strengths and forms

Official product information