FDA Label for Lofexidine Hydrochloride

1 Indications And Usage

Lofexidine tablets are indicated for mitigation of opioid withdrawal symptoms to facilitate abrupt opioid discontinuation in adults.

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.

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)].

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)].

3 Dosage Forms And Strengths

Lofexidine tablets are available as round, peach-colored, film-coated tablets, imprinted with "LFX" on one side and "18" on the other side. Each tablet contains 0.18 mg lofexidine (equivalent to 0.2 mg of lofexidine hydrochloride).

4 Contraindications

None.

5.1 Risk Of Hypotension, Bradycardia, And Syncope

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

Inform patients that Lofexidine tablets 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 tablets doses when experiencing symptoms of hypotension or bradycardia and to contact their healthcare provider for guidance on how to adjust dosing.

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

Avoid using 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 tablets prolong the QT interval.

Avoid using Lofexidine tablets 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 tablets [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 tablets 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 tablets in an outpatient setting that, until they learn how they respond to Lofexidine tablets, 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 tablets are 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 tablets 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 tablets 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 tablets 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 tablet dose and subsequent taper.

6 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)]

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 tablets 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 tablets and for which the incidence in patients treated with Lofexidine tablets were greater than the incidence in subjects treated with placebo in a study that tested two doses of Lofexidine tablets, 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 tablets than subjects treated with placebo.

Other notable adverse reactions associated with the use of Lofexidine tablets but reported in <10% of patients in the Lofexidine tablets group included:

• Syncope: 0.9%, 1.4% and 0% for Lofexidine tablets 2.16 mg/day and 2.88 mg/day and placebo, respectively
• Tinnitus: 0.9%, 3.2% and 0% for Lofexidine tablets 2.16 mg/day and 2.88 mg/day and placebo, respectively

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 who received lofexidine, and three reports of clinically significant QT prolongation in subjects concurrently receiving methadone with lofexidine.

7.1 Methadone

Lofexidine tablets and methadone both prolong the QT interval. ECG monitoring is recommended in patients receiving methadone and Lofexidine tablets concomitantly [see Warnings and Precautions (5.2), Clinical Pharmacology (12.3)].

7.2 Oral Naltrexone

Coadministration of Lofexidine tablets 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 tablets. This interaction is not expected if naltrexone is administered by non-oral routes [see Clinical Pharmacology (12.3)].

7.3 Cns Depressant Drugs

Lofexidine tablets potentiate 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 tablets and paroxetine resulted in a 28% increase in the extent of absorption of Lofexidine. Monitor for orthostatic hypotension and bradycardia when an inhibitor of CYP2D6 is used concomitantly with Lofexidine tablets [see Clinical Pharmacology (12.3)].

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 been adequately characterized in animal studies [see Impairment of Fertility (13.1)].

8.4 Pediatric Use

The safety and effectiveness of Lofexidine tablets have not been established in pediatric patients.

8.5 Geriatric Use

No studies have been performed to characterize the pharmacokinetics of Lofexidine tablets or to establish its safety and effectiveness in geriatric patients. Caution should be exercised when Lofexidine tablets are 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 (8.7)].

8.6 Hepatic Impairment

Hepatic impairment slows the elimination of lofexidine 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 (12.3)].

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 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 tablets 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 tablets have not been systematically evaluated in patients who do not express the drug metabolizing enzyme CYP2D6, it is likely that the exposure to Lofexidine tablets 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 to 8% of Black/African Americans cannot metabolize CYP2D6 substrates and are classified as poor metabolizers (PM) [see Clinical Pharmacology (12.3)].

10 Overdosage

Overdose with Lofexidine tablets may manifest as hypotension, bradycardia, and sedation. In the event of acute overdose, perform gastric lavage where appropriate. Dialysis will not remove a substantial portion of the drug. Initiate general symptomatic and supportive measures in cases of overdosage.

11 Description

Lofexidine tablets contain lofexidine, a central alpha-2 adrenergic agonist, as the hydrochloride salt. Lofexidine hydrochloride is chemically designated as 2-[1-(2,6-dichlorophenoxy)ethyl]-4,5 dihydro-1H- imidazole monohydrochloride with a molecular formula of C₁₁H₁₂Cl₂N₂O∙HCl. Its molecular weight is 295.6 g/mole and its structural formula is:

Chemical Structure - lofexidine tablets 1

Lofexidine hydrochloride is a white to off-white crystalline powder freely soluble in water, methanol, and ethanol. It is slightly soluble in chloroform and practically insoluble in n-hexane and benzene.

Lofexidine tablets are available as round, convex-shaped, peach-colored, film-coated tablets for oral administration. Each tablet contains 0.18 lofexidine, equivalent to 0.2 mg of lofexidine hydrochloride, and the following inactive ingredients: 92.6 mg lactose, 12.3 mg citric acid, 1.1 mg povidone, 5.7 mg microcrystalline cellulose, 1.4 mg calcium stearate, 0.7 mg sodium lauryl sulphate, and Opadry OY S 9480 (contains indigo carmine and sunset yellow).

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.

14 Clinical Studies

Two randomized, double-blind, placebo-controlled trials supported the efficacy of lofexidine.

17 Patient Counseling Information

Advise patients to read the FDA-approved patient labeling (Patient Information).

Lofexidine tablets may mitigate, but not completely prevent, the symptoms associated with opioid withdrawal syndrome, which may include feeling sick, stomach cramps, muscle spasms or twitching, feeling of cold, heart pounding, muscular tension, aches and pains, yawning, runny eyes and sleep problems (insomnia). Patients should be advised that withdrawal will not be easy. Additional supportive measures should be clearly advised, as needed.

Principal Display Panel - 0.18 Mg Tablet Carton 36 Count

NDC 66993-345-37
36 Tablets

Lofexidine Tablets
0.18 mg

Store and dispense
in original container. 

Protect from heat and moisture.
Do not remove desiccants.
Keep the bottle tightly closed.

Rx Only

Keep out of reach of children.

36 ct - lofexidine tablets 6

Principal Display Panel - 0.18 Mg Tablet Carton 96 Count

NDC 66993-345-76
96 Tablets

Lofexidine Tablets
0.18 mg

Store and dispense
in original container. 

Protect from heat and moisture.
Do not remove desiccants.
Keep the bottle tightly closed.

Rx Only

Keep out of reach of children.

96 count - lofexidine tablets 7