lofexidine hydrochloride

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)] 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 6.1 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 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%) 6.2 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.