Lofexidine hydrochloride is a selective central α2-adrenergic agonist.1, 9
Lofexidine hydrochloride is used for mitigation of opiate withdrawal symptoms to facilitate abrupt opiate discontinuance.1, 2, 12, 20
In patients with opiate use disorder, opiate withdrawal management (also referred to as detoxification) generally involves short-term use of tapering dosages of buprenorphine (an opiate partial agonist) or methadone (a full opiate agonist) to reduce withdrawal symptoms.12, 16, 21, 1300, 1301, 1302 However, prescribing restrictions may limit use of these drugs,16, 21 and α2-adrenergic agonists (e.g., lofexidine, clonidine) also have been used for symptomatic relief of noradrenergic-mediated opiate withdrawal symptoms (e.g., lacrimation, sweating, shivering, rhinorrhea) in both inpatient and outpatient settings and may allow for withdrawal over a shorter period of time.1, 5, 6, 12 The α2-adrenergic agonists appear to be less effective than buprenorphine or methadone in the management of opiate withdrawal,16, 1300, 1301, 1302, 1303 and some experts suggest that α2-adrenergic agonists may be most useful in withdrawal management as adjuncts to opiate agonists or partial agonists,16, 1302 to facilitate transition to opiate antagonist (naltrexone) treatment for relapse prevention,12, 13, 14, 1302, 1303 or in settings where therapy with opiate agonists or partial agonists is contraindicated, unacceptable, or unavailable.14, 16, 21, 1300, 1302, 1303 While α2-adrenergic agonists relieve noradrenergic-mediated symptoms of opiate withdrawal, concomitant supportive therapy for other withdrawal symptoms (e.g., abdominal cramping, diarrhea, nausea and vomiting, muscle spasms, anxiety or restlessness, insomnia) may improve patient comfort, particularly in patients treated principally with an α2-adrenergic agonist.5, 12, 16, 1300, 1301, 1303
Although direct comparisons between lofexidine and clonidine are limited, results of several small comparative studies suggest that lofexidine and clonidine have similar efficacy in managing opiate withdrawal symptoms but lofexidine may be associated with less hypotension.5, 6, 9, 12, 13, 17 However, the greater cost of lofexidine compared with off-label clonidine use also must be considered.17, 21
Because of the potential for hypotension and bradycardia, some experts state that α2-adrenergic agonists are not drugs of choice for opiate withdrawal management in geriatric patients or patients with coronary insufficiency, ischemic heart disease, bradycardia, or cerebrovascular disease.12
Lofexidine is not a treatment for opiate use disorder and should be used for mitigation of opiate withdrawal symptoms in patients with opiate use disorder only in conjunction with a comprehensive treatment program.1 Opiate withdrawal without subsequent maintenance treatment is associated with high rates of relapse.14, 16, 1300, 1303 For most patients with opioid use disorder, maintenance treatment with buprenorphine or methadone or treatment with naltrexone for relapse prevention is superior to opiate withdrawal management.14, 1300, 1303
In patients receiving long-term opiate analgesia, withdrawal symptoms generally are managed by slow tapering of the opiate analgesic dosage.14
The current indication for lofexidine is based principally on the results of 2 randomized, double-blind, placebo-controlled, phase 3 studies in a total of 866 adults who were physically dependent on short-acting opiates (e.g., heroin, hydrocodone, oxycodone) and receiving inpatient treatment for withdrawal management.1, 2, 14, 20 In both studies, lofexidine was associated with a reduced severity of opiate withdrawal symptoms (as measured by the Short Opiate Withdrawal Scale of Gossop [SOWS-Gossop]) and higher treatment completion rates compared with placebo.1, 2, 20 The SOWS-Gossop is a patient-reported outcome instrument used to evaluate the severity of 10 specific opiate withdrawal symptoms; each symptom is evaluated on a scale of 0-3 (corresponding to a rating of none, mild, moderate, or severe), and the total score (range: 0-30) is equal to the sum of the individual item scores.1, 14, 20 Patients in these studies could receive other concomitant supportive therapy for opiate withdrawal symptoms (e.g., guaifenesin, antacids, docusate, psyllium hydrocolloid suspension, bismuth sulfate, acetaminophen, zolpidem).1, 2, 20 The studies excluded patients with uncontrolled arrhythmias, corrected QT (QTc) interval prolongation (exceeding 450 msec in males or 470 msec in females), or other clinically important electrocardiographic (ECG) abnormalities; history of myocardial infarction; symptomatic hypotension, systolic blood pressure less than 95 mm Hg (study 1) or 90 mm Hg (study 2), or diastolic blood pressure less than 65 mm Hg (study 1); hypertension with blood pressure exceeding 155/95 mm Hg (study 1) or 160/100 mm Hg (study 2); symptomatic bradycardia or heart rate less than 55 beats/minute (study 1) or 45 beats/minute (study 2); or recent use of antihypertensive or antiarrhythmic agents.14
In study 1, 602 patients were randomized to receive lofexidine 0.54 mg given 4 times daily, lofexidine 0.72 mg given 4 times daily, or placebo for 7 days in an inpatient setting.1, 20 Patients who successfully completed days 1-7 of inpatient treatment were eligible to receive open-label treatment with lofexidine (up to 2.88 mg daily) for an additional 7 days (days 8-14).1, 20 Mean SOWS-Gossop scores for days 1-7 were 6.5, 6.1, or 8.8 for patients receiving lofexidine 2.16 mg daily, lofexidine 2.88 mg daily, or placebo, respectively;1 41, 40, or 28% of patients receiving these respective treatments completed 7 days of treatment.1, 20
In study 2, 264 patients were randomized to receive lofexidine 0.72 mg given 4 times daily or placebo for 5 days in an inpatient setting, followed by 2 additional days of placebo prior to discharge.1, 2 Mean SOWS-Gossop scores for days 1-5 were 7 or 8.9 for patients receiving lofexidine or placebo, respectively;1 49 or 33% of patients receiving these respective treatments completed 5 days of treatment.1, 2
Vital signs should be assessed prior to lofexidine dosing.1 Electrocardiographic (ECG) monitoring is recommended in certain patients at risk for QT interval prolongation.1 (See Hypotension, Bradycardia, and Syncope and also see QT Interval Prolongation under Cautions: Warnings/Precautions.)
Lofexidine is administered orally 4 times daily (i.e., every 5-6 hours) without regard to meals.1
Dosage of lofexidine hydrochloride is expressed in terms of lofexidine.1 Dosage of the drug also has been expressed in terms of the salt; 0.18 mg of lofexidine is equivalent to 0.2 mg of lofexidine hydrochloride.1, 14
The manufacturer states that the usual initial dosage of lofexidine for the mitigation of opiate withdrawal symptoms in adults is 2.16 mg daily administered in 4 divided doses of 0.54 mg every 5-6 hours during the period of peak withdrawal symptoms (generally the first 5-7 days following the last use of opiates), with dosage guided by symptoms and adverse effects.1 Lofexidine may be administered for up to 14 days, with dosage guided by symptoms.1 Single adult doses should not exceed 0.72 mg, and the total daily dosage should not exceed 2.88 mg.1
Some experts recommend an initial lofexidine dosage of 0.36-0.54 mg twice daily and state that dosage may be increased as necessary and tolerated to a maximum of 2.16 mg daily administered in 2-4 divided doses for 7-10 days.12
Dosage of lofexidine should be reduced or therapy with the drug should be interrupted or discontinued in individuals demonstrating greater sensitivity to its adverse effects.1, 12 As opiate withdrawal symptoms wane, lower dosages of lofexidine may be appropriate.1
When lofexidine therapy is discontinued, dosage of the drug should be reduced gradually (e.g., by 0.18 mg per dose every 1-2 days) over 2-4 days to minimize lofexidine withdrawal symptoms and rebound elevations in blood pressure.1 (See Symptoms Resulting from Abrupt Lofexidine Discontinuance under Cautions: Warnings/Precautions.)
In patients with mild hepatic impairment (Child-Pugh score 5-6), the recommended dosage of lofexidine is 0.54 mg 4 times daily.1 In patients with moderate hepatic impairment (Child-Pugh score 7-9), the recommended dosage of lofexidine is 0.36 mg 4 times daily.1 In patients with severe hepatic impairment (Child-Pugh score exceeding 9), the recommended dosage of lofexidine is 0.18 mg 4 times daily.1 (See Hepatic Impairment under Warnings/Precautions: Specific Populations, in Cautions.)
The manufacturer provides no specific dosage recommendations for patients with mild renal impairment.1 In patients with moderate renal impairment (estimated glomerular filtration rate [eGFR] 30-89.9 mL/minute per 1.73 m2), the recommended dosage of lofexidine is 0.36 mg 4 times daily.1 In patients with severe renal impairment or end-stage renal disease (eGFR less than 30 mL/minute per 1.73 m2) or in patients receiving dialysis, the recommended dosage of lofexidine is 0.18 mg 4 times daily.1 Supplemental doses are not required following dialysis.1 Lofexidine may be administered without regard to the timing of dialysis.1 (See Renal Impairment under Warnings/Precautions: Specific Populations, in Cautions.)
Dosage adjustments similar to those recommended in patients with renal impairment should be considered in geriatric patients.1
The manufacturer states there are no known contraindications to the use of lofexidine.1
Hypotension, Bradycardia, and Syncope
Lofexidine can cause hypotension, bradycardia, and syncope.1 In a phase 3 study in patients receiving inpatient treatment for opiate withdrawal (study 1), hypotension, orthostatic hypotension, bradycardia, and syncope were reported in approximately 30, 35, 28, and 1%, respectively, of lofexidine-treated patients.1 The incidence of serious cardiovascular effects was higher in women than in men receiving lofexidine 2.88 mg daily (4 versus 1%); similarly, bradycardia and orthostatic hypotension necessitating drug discontinuance or withholding of doses also occurred more frequently in women than in men receiving lofexidine 2.88 mg daily.1
Vital signs should be assessed prior to lofexidine dosing, and patients receiving the drug should be monitored for symptoms of bradycardia and orthostatic hypotension.1
Patients receiving lofexidine should be informed of the risk of hypotension.1 Those receiving the drug in the outpatient setting should be capable of performing self-monitoring for hypotension, orthostasis, bradycardia, and associated symptoms, and should be instructed on measures for reducing the risk of serious consequences should these adverse effects occur.1 Patients receiving lofexidine in the outpatient setting should be instructed to withhold doses of lofexidine during symptomatic episodes of hypotension or bradycardia and to contact their healthcare provider for guidance on dosage adjustment; following clinically important or symptomatic hypotension and/or bradycardia, the subsequent dose should be reduced in strength, delayed, or omitted.1 (See Advice to Patients.)
Use of lofexidine should be avoided in patients with severe coronary insufficiency, recent myocardial infarction, cerebrovascular disease, chronic renal failure, or marked bradycardia.1, 12 To avoid the risk of excessive bradycardia and hypotension, concomitant use of lofexidine with drugs known to decrease heart rate or blood pressure also should be avoided.1
Lofexidine prolongs the QT interval.1, 3 In healthy individuals, single 1.44- or 1.8-mg doses of lofexidine produced a maximum mean change from baseline in QT interval (corrected for heart rate using Fridericia's formula [QTcF]) of 14.4 or 13.6 msec, respectively.1 In a phase 3, placebo-controlled, dose-response study in opiate-dependent patients, lofexidine 2.16 or 2.88 mg daily was associated with a maximum mean change in QTcF of 7.3 or 9.3 msec, respectively.1 Torsades de pointes with cardiac arrest (with successful resuscitation) has been reported during postmarketing experience.1
Clinically important QT interval prolongation may occur in patients with hepatic or renal impairment.1 Administration of lofexidine in patients with hepatic or renal impairment was associated with prolongation of the corrected QT interval; such effects were more pronounced in those with severe impairment.1
Electrocardiographic (ECG) monitoring is recommended in patients with heart failure, bradyarrhythmias, or hepatic or renal impairment, and in those receiving other drugs known to prolong the QT interval (e.g., methadone).1 (See Drug Interactions: Drugs that Prolong the QT Interval.) In patients with electrolyte abnormalities (e.g., hypokalemia, hypomagnesemia), the electrolyte abnormalities should be corrected prior to initiation of lofexidine therapy, and ECG monitoring should be performed upon initiation of lofexidine.1 Use of lofexidine should be avoided in patients with congenital long QT syndrome.1
Concomitant Use of CNS Depressants
Lofexidine potentiates the CNS depressive effects of benzodiazepines and also is expected to potentiate the CNS depressive effects of alcohol and other sedating drugs (e.g., barbiturates).1 (See Drug Interactions: CNS Depressants.)
Risk of Opiate Overdosage following Relapse to Opiate Use
Patients who complete opiate discontinuance are likely to have a reduced tolerance to opiates and are therefore at an increased risk of fatal opiate overdosage should they resume opiate use.1 Patients and caregivers should be informed of this increased risk of overdosage.1 Lofexidine is not a treatment for opiate use disorder and should be used for mitigation of opiate withdrawal symptoms in patients with opiate use disorder only in conjunction with a comprehensive treatment program.1
Symptoms Resulting from Abrupt Lofexidine Discontinuance
Abrupt discontinuance of lofexidine can result in marked increases in blood pressure, with peak blood pressure values observed on the second day after abrupt discontinuance.1 A 50% reduction in lofexidine dosage one day prior to drug discontinuance resulted in a similar incidence and magnitude of blood pressure elevations as compared with abrupt discontinuance.1 Discontinuance of lofexidine also has been associated with diarrhea, insomnia, anxiety, chills, hyperhydrosis, and extremity pain.1
When lofexidine therapy is discontinued, the dosage should be gradually reduced.1 (See Dosage and Administration: Dosage.) Symptoms related to drug discontinuance can be managed by resuming administration of the previous lofexidine dosage and subsequently tapering the dosage.1
Safety of lofexidine has not been established in pregnant women.1 Oral administration of lofexidine during the period of organogenesis in pregnant rats and rabbits resulted in reduced fetal weights, increased fetal resorption, and loss of litters at exposures less than those achieved in humans.1 When the drug was administered orally from the beginning of organogenesis through lactation, increased stillbirths, loss of litters, and decreased viability and lactation indices resulted, and offspring demonstrated delays in sexual maturation (both males and females), auditory startle, and surface righting.1
Experts state that the recommended treatment of opiate dependence in pregnant women is maintenance treatment with buprenorphine or methadone; this approach is superior to medically supervised withdrawal because withdrawal is associated with high relapse rates and poorer outcomes.18, 19, 1302, 1303
It is not known whether lofexidine or its metabolites are distributed into milk.1 The effects of lofexidine or its metabolites on breast-fed infants or on milk production also are unknown.1 Lofexidine is chemically and pharmacologically related to clonidine, which reaches high concentrations in milk and in breast-fed infants.7 Caution should be exercised if lofexidine is administered to a nursing woman,1 especially while breast-feeding a neonate or preterm infant;7 the developmental and health benefits of breast-feeding and the importance of the drug to the woman should be considered along with the potential adverse effects on the breast-fed child from the drug or from the underlying maternal condition.1
Safety and efficacy of lofexidine have not been established in pediatric patients.1
Safety and efficacy of lofexidine have not been established in geriatric patients.1 Caution should be exercised when lofexidine is used in patients older than 65 years of age.1 (See Geriatric Patients under Dosage and Administration: Special Populations.)
Hepatic impairment decreases elimination of lofexidine but has less effect on peak plasma concentrations than on systemic exposure (i.e., area under the plasma concentration-time curve [AUC]) of the drug following a single dose; dosage adjustment is recommended depending on the degree of hepatic impairment.1 (See Hepatic Impairment under Dosage and Administration: Special Populations.) Following administration of a single 0.36-mg dose of lofexidine, peak plasma concentration in patients with mild (Class-Pugh class A, score 5-6), moderate (Child-Pugh class B, score 7-9), or severe (Child-Pugh class C, score 10-15) hepatic impairment is 114, 117, or 166%, respectively, and systemic exposure is 117, 185, or 260%, respectively, compared with that in individuals with normal hepatic function.1 The half-life of the drug in these respective groups is 139, 281, or 401% of that in individuals with normal hepatic function.1
Clinically important prolongation of the QT interval may occur in patients with hepatic impairment.1 QT interval prolongation was more pronounced in patients with severe hepatic impairment.1 ECG monitoring is recommended in patients with hepatic impairment.1
Renal impairment decreases elimination of lofexidine but has less effect on peak plasma concentrations than on systemic exposure (AUC) of the drug following a single dose; dosage adjustment is recommended depending on the degree of renal impairment.1 (See Renal Impairment under Dosage and Administration: Special Populations.) Following administration of a single 0.36-mg dose of lofexidine, peak plasma concentration in patients with mild (estimated glomerular filtration rate [eGFR] 60-89 mL/minute per 1.73 m2), moderate (eGFR 30-59 mL/minute per 1.732), or severe (eGFR 15-29 mL/minute per 1.73 m2) renal impairment is 124, 117, or 154%, respectively, and systemic exposure is 144, 173, or 243%, respectively, compared with that in individuals with normal renal function (eGFR at least 90 mL/minute per 1.73 m2).1 The half-life of the drug in these respective groups is 111, 145, or 157% of that in individuals with normal renal function.1
In patients with end-stage renal disease receiving hemodialysis 3 times weekly, mean peak plasma concentration was similar to that in individuals with normal renal function matched for sex, age, and body mass index (BMI).1 Only a negligible fraction of a lofexidine dose is removed during a typical dialysis session.1 Decreases in lofexidine plasma concentrations occurring during a 4-hour dialysis session are transient, with a return to near predialysis concentrations within a few hours after completion of the dialysis session.1
Clinically important prolongation of the QT interval may occur in patients with renal impairment.1 QT interval prolongation was more pronounced in patients with severe renal impairment.1 ECG monitoring is recommended in patients with renal impairment.1
Pharmacogenomics and Poor CYP2D6 Metabolizers
Because increased systemic exposure to lofexidine is expected in patients who are poor metabolizers of cytochrome P-450 isoenzyme 2D6 (CYP2D6) substrates, these patients should be monitored for adverse effects (e.g., orthostatic hypotension, bradycardia).1 Lofexidine exposure in patients with the poor CYP2D6 metabolizer phenotype is expected to be similar to that observed in individuals receiving lofexidine concomitantly with a potent CYP2D6 inhibitor.1 (See Drug Interactions: Drugs Affecting Hepatic Microsomal Enzymes.)
Adverse effects reported in clinical studies in 10% or more of opiate-dependent patients receiving lofexidine for mitigation of opiate withdrawal symptoms and occurring more frequently with lofexidine than with placebo include insomnia,1, 2, 20 orthostatic hypotension,1, 20 bradycardia,1, 2, 20 hypotension,1, 2, 20 dizziness,1, 2, 20 somnolence,1, 2, 20 sedation,1, 2, 20 and dry mouth.1, 2, 20
In vitro studies indicate that lofexidine is extensively metabolized, principally by cytochrome P-450 (CYP) isoenzyme 2D6 and to a lesser extent by CYP1A2 and CYP2C19.1, 14, 21 Lofexidine and/or its metabolites cause slight inhibition of CYP2D6, but are unlikely to induce or inhibit major CYP isoenzymes at clinically relevant concentrations.1, 14 Results from an in vitro study suggest that lofexidine is not a substrate of P-glycoprotein (P-gp).14
Drugs Affecting Hepatic Microsomal Enzymes
Use of lofexidine in combination with CYP2D6 inhibitors may increase lofexidine exposure.1 When lofexidine is used concomitantly with CYP2D6 inhibitors, patients should be monitored for adverse effects (e.g., orthostatic hypotension, bradycardia).1
Concomitant administration of lofexidine (single 0.36-mg dose) and the potent CYP2D6 inhibitor paroxetine (40 mg daily) in healthy individuals increased peak plasma concentration and systemic exposure of lofexidine by approximately 11 and 28%, respectively.1
Drugs Metabolized by Hepatic Microsomal Enzymes
Clinically important pharmacokinetic interactions of lofexidine with substrates of CYP2D6 are not expected.1
Concomitant use of lofexidine with drugs that are known to cause hypotension or bradycardia should be avoided.1
Lofexidine enhances the CNS depressive effects of benzodiazepines and also is expected to enhance the effects of other CNS depressants, such as alcohol, barbiturates, opiate agonists or partial agonists, and other sedating drugs.1, 12
Drugs that Prolong the QT Interval
Lofexidine prolongs the QT interval.1, 3 Electrocardiographic (ECG) monitoring is recommended when lofexidine is used concomitantly with other drugs that are known to prolong the QT interval.1, 4
Limited experience suggests that concomitant use of lofexidine with a tricyclic antidepressant may reduce the efficacy of lofexidine, resulting in exacerbation of opiate withdrawal symptoms.8, 9, 15
Addition of desipramine hydrochloride (75 mg daily) to lofexidine therapy in a patient with substance (opiate, alcohol, and stimulant) use disorder resulted in exacerbation of opiate withdrawal symptoms (e.g., marked insomnia, feeling cold, twitching, yawning, runny eyes), which was reflected in increasing Short Opiate Withdrawal Scale of Gossop (SOWS-Gossop) scores.8 Desipramine was discontinued after 2 doses, and opiate withdrawal symptoms abated over the next 24 hours.8
In patients receiving maintenance treatment with buprenorphine (16-24 mg daily), concomitant use of lofexidine (up to 2.88 mg daily) resulted in no pharmacokinetic or pharmacodynamic interaction.1
In patients receiving maintenance treatment with buprenorphine (16-24 mg daily), concomitant use of lofexidine (2.88 mg daily) resulted in a maximum mean increase from baseline in QT interval (corrected for heart rate using Fridericia's formula [QTcF]) of 15 msec.1
Lofexidine and methadone both prolong the QT interval.1, 3, 4 (See Drug Interactions: Drugs that Prolong the QT Interval.) In patients receiving maintenance treatment with methadone hydrochloride (80-120 mg daily), concomitant use of lofexidine (2.88 mg daily) resulted in a maximum mean increase from baseline in QTcF of 9.1 msec.1
In patients receiving maintenance treatment with methadone hydrochloride (80-120 mg daily), concomitant use of lofexidine (up to 2.88 mg daily) did not alter the pharmacokinetics of methadone.1 Lofexidine concentrations may be slightly increased, but the increase in concentration is not expected to be clinically important at recommended dosages.1
Concomitant administration of oral naltrexone hydrochloride (50 mg daily) with lofexidine (single 0.36-mg dose) in healthy individuals did not result in clinically important changes in lofexidine pharmacokinetics; however, at naltrexone steady state, peak plasma naltrexone and 6-β-naltrexol concentrations were delayed by 2-3 hours and overall exposure to the opiate antagonist was reduced slightly.1 Administration of oral naltrexone within 2 hours of lofexidine administration may result in reduced efficacy of naltrexone; however, this interaction is not expected if naltrexone is administered via nonoral routes.1
Lofexidine hydrochloride, a centrally acting α2-adrenergic agonist that is structurally and pharmacologically related to clonidine, binds to receptors on adrenergic neurons, reducing the release of norepinephrine and decreasing sympathetic tone.1, 9, 14 Lofexidine decreases sympathetic neurotransmission from the locus ceruleus, which is responsible for many opiate withdrawal symptoms during acute withdrawal.9, 21 It has been postulated that lofexidine's greater selectivity for the α2A-adrenergic receptor may be responsible for its improved adverse effect profile (e.g., decreased incidence and severity of hypotension and sedation) compared with structurally similar clonidine.5, 6, 9, 12, 13, 15, 21 Lofexidine is not an effective antihypertensive agent and does not suppress psychological cravings.9, 14
Pharmacokinetics of lofexidine are dose proportional over the dosage range of 0.72-2.88 mg daily.1, 10, 14 Absolute oral bioavailability of the drug is approximately 72%; approximately 30% of an orally administered dose is converted to inactive metabolites on first pass through the liver.1 Peak plasma concentrations are achieved 3-5 hours after a single oral dose.1, 10, 14 Administration of lofexidine with a high-fat, high-calorie meal did not alter peak plasma concentration or area under the concentration-time curve (AUC),1, 14 and only slightly delayed the median time to peak plasma concentration (from 5 hours to 6 hours).14 Lofexidine is approximately 55% bound to plasma proteins.1, 14 The volume of distribution of the drug suggests extensive distribution into tissues.1, 14 Lofexidine is extensively metabolized, principally by cytochrome P-450 (CYP) isoenzyme 2D6 and to a lesser extent by CYP1A2 and CYP2C19.1, 14, 21 Lofexidine and its metabolites are eliminated principally by the kidneys;1, 14 93.5% of an administered dose is excreted in urine (15-20% as unchanged drug) and 0.9% is excreted in feces.1 The elimination half-life is approximately 12 hours.1 The terminal half-life is approximately 11-13 hours following the initial dose and approximately 17-22 hours at steady state.1 Pharmacokinetics were similar in opiate-dependent patients and healthy individuals.9, 11
Importance of reading the patient information provided by the manufacturer.1
Importance of informing patients that lofexidine may lessen, but not completely prevent, symptoms associated with opiate withdrawal syndrome (e.g., feeling sick, stomach cramps, muscle spasms or twitching, feeling cold, palpitations, muscular tension, aches and pains, yawning, runny eyes, sleep disturbances).1 Additional supportive measures may be recommended as needed.1
Risk of hypotension and bradycardia.1 Importance of advising patients to be alert for any symptoms of hypotension, orthostasis, or bradycardia (e.g., dizziness, lightheadedness, feelings of faintness at rest or on abrupt standing); to avoid dehydration and overheating; and to rise carefully from a seated or supine position.1 Importance of instructing patients on how to reduce the risk of serious consequences if hypotension occurs (e.g., by sitting or lying down).1 Patients experiencing symptomatic episodes of hypotension, orthostasis, or bradycardia in the outpatient setting should be advised to withhold lofexidine and contact their clinician for instructions.1
Patients receiving lofexidine in the outpatient setting should be advised to avoid driving, operating heavy machinery, or performing other hazardous activities until they know how the drug will affect them.1 Risk of increased CNS depression with concomitant use of benzodiazepines, alcohol, barbiturates, or other drugs with sedative effects.1
Importance of advising patients to avoid abrupt discontinuance of therapy and to consult a clinician prior to discontinuing therapy.1
Risk of opiate overdosage if opiate use is resumed following a period of nonuse (i.e., relapse).1 Importance of informing patients that they may be more sensitive to the effects of opiates and at greater risk of fatal overdosage if they resume opiate use after a period of nonuse.1
Importance of women informing their clinicians if they are or plan to become pregnant or plan to breast-feed.1
Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs and dietary or herbal supplements, as well as any concomitant illnesses (e.g., renal or hepatic impairment; cerebrovascular or cardiovascular disease).1
Importance of informing patients of other important precautionary information.1 (See Cautions.)
Additional Information
Overview® (see Users Guide). For additional information on this drug until a more detailed monograph is developed and published, the manufacturer's labeling should be consulted. It is essential that the manufacturer's labeling be consulted for more detailed information on usual cautions, precautions, contraindications, potential drug interactions, laboratory test interferences, and acute toxicity.
Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.
Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.
Routes | Dosage Forms | Strengths | Brand Names | Manufacturer |
|---|---|---|---|---|
Oral | Tablets, film-coated | 0.18 mg (of lofexidine) |
AHFS® Drug Information. © Copyright, 1959-2025, Selected Revisions October 7, 2019. American Society of Health-System Pharmacists, Inc., 4500 East-West Highway, Suite 900, Bethesda, MD 20814.
1. US WorldMeds. Lucemyra® (lofexidine hydrochloride) tablets prescribing information. Louisville, KY; 2018 May.
2. Gorodetzky CW, Walsh SL, Martin PR et al. A phase III, randomized, multi-center, double blind, placebo controlled study of safety and efficacy of lofexidine for relief of symptoms in individuals undergoing inpatient opioid withdrawal. Drug Alcohol Depend . 2017; 176:79-88. [PubMed 28527421]
3. Schmittner J, Schroeder JR, Epstein DH et al. QT interval increased after single dose of lofexidine. BMJ . 2004; 329:1075. [PubMed 15528619]
4. Schmittner J, Schroeder JR, Epstein DH et al. Electrocardiographic effects of lofexidine and methadone coadministration: secondary findings from a safety study. Pharmacotherapy . 2009; 29:495-502. [PubMed 19397459]
5. National Collaborating Centre for Mental Health (UK), National Institute for Health and Clinical Excellence. Drug misuse: opioid detoxification, national clinical practice guideline number 52. Leicester (UK): The British Psychological Society and The Royal College of Psychiatrists; 2008.
6. Gowing L, Farrell M, Ali R et al. Alpha2-adrenergic agonists for the management of opioid withdrawal. Cochrane Database Syst Rev . 2016; :CD002024. [PubMed 27140827]
7. Lofexidine. Drugs and Lactation Database (LactMed) [Internet]. Bethesda (MD): National Library of Medicine (US); 2006-. Updated 2018 Jun 4. Accessed 2018 Aug 7.
8. Keaney F, Crimlisk H, Bearn J. Lofexidine and desipramine: Interaction results in breakthrough opioid withdrawal symptoms. Int J Psychiatry Clin Pract . 2002; 6:179-81. [PubMed 24945207]
9. Gish EC, Miller JL, Honey BL et al. Lofexidine, an {alpha}2-receptor agonist for opioid detoxification. Ann Pharmacother . 2010; 44:343-51. [PubMed 20040696]
10. Al-Ghananeem AM. Pharmacokinetics of lofexidine hydrochloride in healthy volunteers. J Pharm Sci . 2009; 98:319-26. [PubMed 18393298]
11. Al Ghananeem AM, Herman BH, Abbassi M et al. Urine and plasma pharmacokinetics of lofexidine after oral delivery in opiate-dependent patients. Am J Drug Alcohol Abuse . 2009; 35:311-5. [PubMed 19637105]
12. World Health Organization. Guidelines for the psychosocially assisted pharmacological treatment of opioid dependence. Geneva: World Health Organization; 2009.
13. Kleber HD, Weiss RD, Anton RF et al. Treatment of patients with substance use disorders, second edition. American Psychiatric Association. Am J Psychiatry . 2007; 164(4 Suppl):5-123. [PubMed 17569411]
14. Food and Drug Administration. Center for Drug Evaluation and Research. Application number: 209229Orig1s000: Multi-discipline review. From FDA website. [Web]
15. Britannia Pharmaceuticals. BritLofex 0.2-mg tablets summary of product characteristics. Reading, Berkshire, United Kingdom; 2015 Aug 25. [Web]
16. . Management of opioid withdrawal symptoms. Med Lett Drugs Ther . 2018; 60:137-141. [PubMed 30133420]
17. . Lofexidine (Lucemyra) for opioid withdrawal. Med Lett Drugs Ther . 2018; 60:115-117. [PubMed 30036346]
18. Substance Abuse and Mental Health Services Administration (SAMHSA). Clinical guidance for treating pregnant and parenting women with opioid use disorder and their infants (HHS publication no. [SMA] 18-5054). Rockville, MD: SAMHSA. 2018. From SAMHSA website. [Web]
19. American College of Obstetricians and Gynecologists (ACOG) Committee on Obstetric Practice, in collaboration with the American Society of Addiction Medicine. ACOG committee opinion. No. 711: Opioid use and opioid use disorder in pregnancy. Washington, DC; ACOG: 2017 Aug. From the ACOG website. [Web]
20. Fishman M, Tirado C, Alam D et al. Safety and Efficacy of Lofexidine for Medically Managed Opioid Withdrawal: A Randomized Controlled Clinical Trial. J Addict Med . 2018; [PubMed 30531234]
21. Doughty B, Morgenson D, Brooks T. Lofexidine: A Newly FDA-Approved, Nonopioid Treatment for Opioid Withdrawal. Ann Pharmacother . 2019; :1060028019828954. [PubMed 30724094]
1300. The Management of Substance Use Disorders Work Group, US Department of Veterans Affairs and Department of Defense. VA/DoD clinical practice guideline for the management of substance use disorders. 2015 Dec.
1301. US Department of Health and Human Services, Substance Abuse and Mental Health Services Administration (SAMHSA), Center for Substance Abuse Treatment. Detoxification and substance abuse treatment. Treatment improvement protocol (TIP) series, No. 45. HHS Publication No. (SMA) 15-4131. Rockville, MD; 2006. [Web]
1302. US Department of Health and Human Services, Substance Abuse and Mental Health Services Administration (SAMHSA), Center for Substance Abuse Treatment. Medications for opioid use disorder, for healthcare and addiction professionals, policymakers, patients, and families. Treatment improvement protocol (TIP) series, No. 63. HHS Publication No. (SMA) 18-5063. Rockville, MD; 2018. [Web]
1303. American Society of Addiction Medicine (ASAM). ASAM national practice guideline for the use of medications in the treatment of addiction involving opioid use. Chevy Chase, MD: ASAM. 2015 Jun 1. From ASAM website. [Web]