LOFEXIDINE: 139 Adverse Event Reports & Safety Profile

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-1 H - imidazole monohydrochloride with a molecular formula of C 11 H 12 Cl 2 N 2 O•HCl. Its molecular weight is 295.6 g/mole and its structural formula is: 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 tablet is available as round, concave-shaped, peach-colored, film-coated tablets, debossed with “C” on one side and “71” on other side for oral administration. Each tablet contains 0.18 lofexidine, equivalent to 0.2 mg of lofexidine hydrochloride and the following inactive ingredients: 87 mg lactose monohydrate, 12.3 mg citric acid monohydrate, 5.7 mg microcrystalline cellulose, 1.1 mg povidone K-30, 0.70 mg sodium lauryl sulphate, 5.0 mg sodium starch glycolate, 2.0 mg calcium stearate and Opadry AMB II orange 88A530003 (contains polyvinyl alcohol, talc, titanium dioxide, Glyceryl mono and dicaprylocaprate, sodium lauryl sulfate, FD&C yellow #6/sunset yellow FCF aluminum lake and FD&C blue #2/indigo carmine aluminium lake). lofexidine-structure

AND USAGE 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 )

AND ADMINISTRATION

• The usual lofexidine tablets dosage are three 0.18 mg tablets taken orally 4 times daily at 5-to 6-hour intervals lofexidine tablets treatment may be continued for up to14 days with dosing guided by symptoms. ( 2.1 )
• Discontinue lofexidine tablets with a gradual dose reduction over 2 to 4 days.( 2.1 )
• Hepatic or Renal Impairment: Dosage adjustments are recommended based on degree of impairment. ( 2.2 , 2.3 )

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). <span class="opacity-50 text-xs">[see Warnings &amp; Precautions ( 5.5 )]</span>. The lofexidine tablets dose should be reduced, held, or discontinued for individuals who demonstrate a greater sensitivity to lofexidine tablets side effects <span class="opacity-50 text-xs">[see Adverse Reactions ( 6.1 ), Warnings and Precautions ( 5.1 )]</span>. 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. <span class="opacity-50 text-xs">[see Use in Specific Populations ( 8.5 ), Clinical Pharmacology ( 12.3 )]</span>.

Table

1: Dosage Recommendations in Patients with Hepatic Impairment Mild Impairment Moderate Impairment Severe Impairment Child-Pugh score 5-6 7-9 > 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 <span class="opacity-50 text-xs">[see Use in Specific Populations ( 8.6 ), Clinical Pharmacology ( 12.3 )]</span>.

Table

2: Dosage Recommendations in Patients with Renal Impairment Mild or Moderate Impairment Severe Impairment, End-Stage Renal Disease, or on Dialysis Estimated GFR, mL/min/1.73 m 2 30-89.9 < 30 Recommended dose 2 tablets 4 times daily (1.44 mg per day) 1 tablet 4 times daily (0.72 mg per day)

None. None. ( 4 )

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 ANI Pharmaceuticals, Inc. at 1-855-204-1431 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch

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.

Table

3: Adverse Reactions Reported by ≥ 10% of Lofexidine Tablet-Treated Patients and More Frequently than Placebo Adverse Reaction Lofexidine Tablets 2.16 mg 1 (%) N=229 Lofexidine Tablets 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 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 Blood pressure changes and adverse reactions after lofexidine tablets cessation Elevations in blood pressure above normal values (≥ 140 mmHg systolic) and above a subject’s pre-treatment baseline are associated with discontinuing lofexidine tablets, 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 tablets 2.88 mg/day.

Table

4: Blood Pressure Elevations after Stopping Treatment Abrupt Lofexidine Tablet 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 58 23 (39.7) 37 6 (16.2) ≥ 170 mmHg and ≥ 20 mmHg increase from baseline 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 tablets 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 tablets 2.88 mg/day. Discontinuations and dose holds due to bradycardia and orthostatic hypotension, which are the most common adverse reactions associated with lofexidine tablets, occurred with a greater incidence in females assigned to receive the highest studied dose of lofexidine tablets, 2.88 mg/day as shown in Table 5.

Table

5: Discontinuations and Dose Holds for Bradycardia and Orthostatic Hypotension by Lofexidine Tablets Dose and Sex Lofexidine Tablets 2.16 mg Lofexidine Tablets 2.88 mg Male 22/162 (14%) 29/158 (18%)

Female

9/67 (13%) 20/64 (31%)

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 <span class="opacity-50 text-xs">[see Warnings and Precautions (5.1)]</span> . 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.

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 ) Risk of QT Prolongation : Lofexidine tablets 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 tablets 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 )

5.1 Risk of Hypotension, Bradycardia, and Syncope Lofexidine tablets can cause a decrease in blood pressure, a decrease in pulse, and syncope <span class="opacity-50 text-xs">[see Adverse Reactions (6.1) , Clinical Pharmacology (12.2) ]</span> . 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 <span class="opacity-50 text-xs">[see Dosing and Administration (2.1) , Adverse Reactions (6.1) , Special Populations (8.6 , 8.7) , Clinical Pharmacology (12.2) ]</span> .

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 <span class="opacity-50 text-xs">[see Dosing and Administration (2.1) ]</span> . Symptoms related to discontinuation can be managed by administration of the previous Lofexidine tablet dose and subsequent taper.

INTERACTIONS Methadone : Methadone and Lofexidine tablets both prolong the QT interval. ECG monitoring is recommended when used concomitantly. ( 7.1 )

Oral

Naltrexone : Concomitant use may reduce efficacy of oral naltrexone. ( 7.2 ) CYP2D6 Inhibitors : Concomitant use of paroxetine resulted in increased plasma levels of Lofexidine. Monitor for symptoms of orthostasis and bradycardia with concomitant use of a CYP2D6 inhibitor. ( 7.4 )

7.1 Methadone Lofexidine tablets and methadone both prolong the QT interval. ECG monitoring is recommended in patients receiving methadone and Lofexidine tablets concomitantly <span class="opacity-50 text-xs">[see Warnings and Precautions (5.2) , Clinical Pharmacology (12.3) ]</span> .

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 <span class="opacity-50 text-xs">[see Clinical Pharmacology (12.3) ]</span> .

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 <span class="opacity-50 text-xs">[see Warnings and Precautions (5.3) ]</span> .

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 <span class="opacity-50 text-xs">[see Clinical Pharmacology (12.3) ]</span> .