Lofexidine Hydrochloride

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Lofexidine Hydrochloride Prescribing Information

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 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.

)
Discontinue lofexidine tablets with a gradual dose reduction over 2 to 4 days. (
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.

)

Hepatic or Renal Impairment:

Dosage adjustments are recommended based on degree of impairment. (

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 m²	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)

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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.

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 Risk 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.

Inform patients that lofexidine 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 on 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 doses when experiencing symptoms of hypotension or bradycardia and to contact their health care provider for guidance on how to adjust dosing.

Avoid using lofexidine in patients with severe coronary insufficiency, recent myocardial infarction, cerebrovascular disease, chronic renal failure, and in patients with marked bradycardia.

Avoid using lofexidine in combination with medications that decrease pulse or blood pressure to avoid the risk of excessive bradycardia and hypotension.

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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 Risk of QT Prolongation

Lofexidine prolong the QT interval.

Avoid using lofexidine 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
[see Dosing and Administration (2.1), Adverse Reactions (6.1), Special Populations (8.6, 8.7), Clinical Pharmacology (12.2)].

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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 Central Nervous System Depression with Concomitant use of CNS Depressant Drugs

Lofexidine potentiate 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 in an outpatient setting that, until they learn how they respond to Lofexidine, they should be careful or avoid doing activities such as driving or operating heavy machinery.

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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 Increased Risk of Opioid Overdose after Opioid Discontinuation

Lofexidine 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 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.
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Risk of Discontinuation Symptoms:
Instruct patients not to discontinue therapy without consulting their healthcare provider. When discontinuing therapy, reduce dose gradually. (
5.5 Risk of Discontinuation Symptoms

Stopping lofexidine 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 discontinuation. Instruct patients not to discontinue therapy without consulting their healthcare provider. When discontinuing therapy with lofexidine tablets, gradually reduce the dose
[see Dosing and Administration (2.1)].

Symptoms related to discontinuation can be managed by administration of the previous lofexidine dose and subsequent taper.

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Lofexidine Hydrochloride

Lofexidine Hydrochloride Prescribing Information

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