Lofexidine is an oral, selective alpha 2-adrenergic receptor agonist indicated for the mitigation of withdrawal symptoms to facilitate abrupt discontinuation of opioids in adults. Lofexidine represents the first non-opioid medication to receive FDA approval for opioid agonist withdrawal. Central alpha-2 agonists are particularly beneficial in treating opiate withdrawal symptoms related to autonomic hyperactivity such as tachycardia, increased blood pressure, anxiety, chills, and sweating. Because lofexidine is associated with QT prolongation, ECG monitoring is recommended in patient populations receiving the drug who are at increased risk for developing QT prolongation. Due to the central alpha-2 agonist properties of lofexidine, hypotension, orthostasis, and syncope can occur. Patients receiving lofexidine on an outpatient basis should be instructed on recognizing and managing the symptoms of orthostasis. Available data indicate that lofexidine is associated with less significant hypotension than clonidine, another central alpha-2 agonist used for the treatment of opioid agonist withdrawal. Lofexidine is not a treatment for opioid use disorder (OUD), but can be used as part of a broader, long-term treatment plan for managing OUD. Lofexidine was FDA-approved in May 2018.
General Administration Information
For storage information, see the specific product information within the How Supplied section.
Route-Specific Administration
Oral Administration
Oral Solid Formulations
-May administer orally without regard to meals.
-There should be 5 to 6 hours between each dose.
In a dose-ranging study of oral lofexidine 2.16 mg/day and 2.88 mg/day in adults, the following centrally-mediated effects occurred in at least 10% of lofexidine-treated patients and more frequently than in placebo-treated patients: insomnia (51% to 55%), dizziness (19% to 23%), somnolence (11% to 13%), sedation/drowsiness (12% to 13%), and xerostomia (10% to 11%). Tinnitus occurred in 0.9% of patients receiving lofexidine 2.16 mg/day and 3.2% of patients receiving lofexidine 2.88 mg/day compared to no patients receiving placebo. Somnolence and sedation may result in impairment of cognitive and motor skills. Patients receiving lofexidine on an outpatient basis should be advised to use caution or avoid performing activities that require mental alertness, such as driving or operating machinery, until they know lofexidine affects them. It is expected that the CNS depressive effects of lofexidine may be increased during coadministration with other CNS depressant medications and alcohol. Advise patients to inform their healthcare provider of other medications they are taking and any alcohol use.
Lofexidine can cause adverse cardiac effects related to central alpha-2 agonist activity including hypotension, orthostatic hypotension, bradycardia, and syncope. Patients receiving lofexidine on an outpatient basis should be instructed on recognizing and managing hypotension, orthostasis, and bradycardia. In one dose-ranging study of oral lofexidine 2.16 mg/day and 2.88 mg/day in adults, the following cardiovascular effects occurred in at least 10% of lofexidine-treated patients and more frequently than in placebo-treated patients: hypotension (30%), orthostatic hypotension (29% to 42%), and bradycardia (24% to 32%). Syncope occurred in 0.9% of patients receiving lofexidine 2.16 mg/day and 1.4% of patients receiving lofexidine 2.88 mg/day compared to no patients receiving placebo. In the 2.88 mg/day group, 4 of 101 females (4%) had a serious cardiac adverse effect compared to 3 of 289 (1%) males, and more females (13% to 31%) than males (14% to 18%) discontinued treatment or had doses withheld due to bradycardia and orthostatic hypotension. During postmarketing use, the most frequently reported effect has been hypotension. There have been postmarketing reports of QT prolongation and torsade de pointes during lofexidine administration. One patient experienced QT prolongation, bradycardia, torsade de pointes, and cardiac arrest with successful resuscitation. There are 3 reports of clinically significant QT prolongation during concurrent use of lofexidine and methadone. In a cardiac electrophysiology study, single doses of lofexidine of 1.44 mg to 1.8 mg resulted in maximum mean changes from baseline QTcF of 14.4 msec and 13.6 msec, respectively, in healthy normal volunteers. In a dose response study in opioid-dependent subjects, doses of lofexidine of 2.16 mg and 2.88 mg were associated with maximum mean prolongations of the QTcF interval of 7.3 msec and 9.3 msec, respectively.
Abrupt discontinuation of lofexidine can cause a significant increase in blood pressure and potential drug-discontinuation symptoms (withdrawal). Patients should be instructed not to discontinue lofexidine without consulting their healthcare provider. When discontinuing the drug, a gradual reduction in dose is recommended. During clinical trial evaluation, elevations in blood pressure above normal values (systolic 140 mmHg or higher) and above baseline values peaked on the second day after abrupt discontinuation of lofexidine. On day 2 of abrupt discontinuation, 39.7% of patients receiving 2.88 mg/day of lofexidine experienced an increase in systolic blood pressure to 140 mmHg or more and a 20 mmHg or more increase from baseline compared to 16.2% of patients receiving placebo. In addition, 8.6% of patients in the 2.88 mg/day group experienced an increase in systolic blood pressure to 170 mmHg or more and a 20 mmHg or more increase from baseline compared to no patients receiving placebo. Blood pressure elevations of a similar magnitude and incidence were observed in a small number of patients that had a 1 day, 50% dose reduction prior to discontinuation. After stopping treatment, the lofexidine-treated group also had a higher incidence of diarrhea, insomnia, anxiety, chills, hyperhidrosis, and extremity pain than the placebo-treated group.
Lofexidine can cause QT prolongation and should be avoided in patients with congenital long QT syndrome. The manufacturer of lofexidine recommends ECG monitoring and cautious use in patients with congestive heart failure, bradyarrhythmias, liver or kidney impairment, or in patients receiving medications that lead to QT prolongation. Correct any electrolyte imbalance (e.g., hypokalemia, hypomagnesemia, hypocalcemia) prior to initiation of lofexidine and ECG monitoring is recommended upon lofexidine initiation. Use lofexidine with caution in patients with conditions that may increase the risk of QT prolongation including bradycardia, AV block, stress-related cardiomyopathy, myocardial infarction, stroke, or in patients receiving medications known to prolong the QT interval or cause electrolyte imbalances. Females, people 65 years and older, patients with sleep deprivation, pheochromocytoma, sickle cell disease, hypothyroidism, hyperparathyroidism, hypothermia, systemic inflammation (e.g., human immunodeficiency virus (HIV) infection, fever, and some autoimmune diseases including rheumatoid arthritis, systemic lupus erythematosus (SLE), and celiac disease) and patients undergoing apheresis procedures (e.g., plasmapheresis [plasma exchange], cytapheresis) may also be at increased risk for QT prolongation. Because lofexidine is a central alpha-2 adrenergic agonist, hypotension, orthostatic hypotension, bradycardia, and syncope can occur. Avoid use in patients with severe coronary insufficiency, recent or acute myocardial infarction, cerebrovascular disease, or marked bradycardia. Patients receiving lofexidine on an outpatient basis should be instructed on and be capable of self-monitoring for hypotension, orthostasis, bradycardia, and related symptoms. If clinically significant hypotension and/or bradycardia occur, the next dose of lofexidine should be reduced, delayed, or withheld. Instruct patients that moving from a supine to upright position may increase the risk for hypotension or orthostatic effects. Instruct patients to stay hydrated (avoid dehydration), to recognize symptoms of hypotension, and to know how to minimize the risk of serious consequences if hypotension occurs (e.g., sit or lie down, carefully rise from a sitting or lying position). Instruct patients to withhold doses when experiencing hypotension or bradycardia and to contact their healthcare provider for guidance on dose adjustments. Although the pharmacokinetics of lofexidine have not been formally evaluated in patients who do not express CYP2D6, it is likely that exposure to the drug would be increased similarly to taking a strong CYP2D6 inhibitor (about 28%). Monitor for adverse effects such as orthostatic hypotension and bradycardia in known CYP2D6 poor metabolizers.
Somnolence and sedation are among the most commonly reported adverse effects with lofexidine and these effects may result in impairment of cognitive and motor skills. Patients receiving lofexidine on an outpatient basis should be advised to use caution or avoid performing activities that require mental alertness, such as driving or operating machinery, until they know lofexidine affects them. It is expected that the CNS depressive effects of lofexidine may be increased during coadministration with other CNS depressants such as benzodiazepines, ethanol, and barbiturates. Advise patients to inform their healthcare provider of other medications they are taking, including ethanol ingestion. Patients who complete opioid discontinuation are at an increased risk of fatal overdose should they resume opioid use. Use lofexidine in conjunction with comprehensive management program for treatment of opioid use disorder and inform patients and caregivers of increased risk of overdose.
Abrupt discontinuation of lofexidine can cause a significant increase in blood pressure. Other discontinuation symptoms include diarrhea, insomnia, anxiety, chills, hyperhidrosis, and extremity pain. Patients should be instructed not to discontinue lofexidine therapy without consulting their healthcare provider. When discontinuing the drug, a gradual reduction in dose is recommended.
The use of lofexidine in patient with hepatic disease may reduce the clearance of the drug. Dosage reductions are recommended based upon the degree of hepatic impairment. Lofexidine is associated with QT prolongation and clinically relevant QT prolongation may occur in patients with hepatic impairment; therefore, the manufacturer of lofexidine recommends ECG monitoring in this population. Administration of lofexidine to subjects with hepatic impairment was associated with QT prolongation, which was more pronounced in subjects with severe hepatic impairment.
The use of lofexidine in patient with renal impairment may reduce the clearance of the drug. Dosage reductions are recommended based upon the degree of renal impairment, including renal failure (end-stage renal disease, patients on dialysis). Because only a negligible amount of lofexidine is removed by dialysis, the drug may be administered without regard to the timing of dialysis. Lofexidine is associated with QT prolongation and clinically relevant QT prolongation may occur in patients with renal impairment; therefore, the manufacturer of lofexidine recommends ECG monitoring in this population. Administration of lofexidine to subjects with renal impairment was associated with QT prolongation, which was more pronounced in subjects with severe renal impairment.
Caution is recommended when administering lofexidine to geriatric patients over 65 years of age. No studies have been performed to determine the kinetics of lofexidine or the safety and effectiveness of the drug in geriatric adults. Dose adjustments similar to those recommended in patients with renal impairment should be considered. Geriatric patients may be at increased risk for QT prolongation when using lofexidine.
The safety of lofexidine during human pregnancy has not been established. In animal studies, oral administration of lofexidine during the period of organogenesis resulted in a reduction in fetal weights, increases in fetal resorptions, and litter loss at exposures below human exposure. Lofexidine administration from organogenesis through lactation in animal studies was associated with increased stillbirths, litter loss, and decreased viability and lactation indices. The offspring exhibited delays in sexual maturation, auditory startle, and surface righting. These effects occurred at exposures below those in humans.
Caution is recommended when lofexidine is administered during breast-feeding. There is no information regarding the presence of lofexidine or its metabolites in human milk, the effects on the breast-fed infant, or the effects on milk production. Consider the benefits of breast-feeding, the risk of potential infant drug exposure, and the risk of an untreated or inadequately treated condition. If a breast-feeding infant experiences an adverse effect related to a maternally administered drug, healthcare providers are encouraged to report the adverse effect to the FDA.
The safety and effectiveness of lofexidine in infants, children, and adolescents less than 18 years of age have not been established.
The impact of lofexidine on human fertility is not known; infertility potential has been noted in some animal studies. In animal studies that included fertility endpoints, fertility was not adversely impacted; however, lofexidine decreased breeding rate and increased resorptions in females at exposures below human exposures. The impact of lofexidine on male fertility has not been adequately determined in animal studies. Reduced testes, epididymis, and seminiferous tubule weights, as well as delayed sexual maturation of males and females and decreases in the number of corpora lutea and implantations after mating, were noted in offspring of pregnant rats administered lofexidine orally from gestation day 6 through lactation at exposures less than the human exposure based on AUC comparisons.
For the treatment of opiate agonist withdrawal symptoms to facilitate abrupt opioid discontinuation:
Oral dosage:
Adults: 0.54 mg PO 4 times daily during the period of peak withdrawal symptoms (generally the first 5 to 7 days after last use of opioid) with dosing guided by symptoms and tolerance for up to 14 days. Max: 0.72 mg/dose and 2.88 mg/day. To discontinue, gradually taper the dose over 2 to 4 days to reduce drug withdrawal symptoms (e.g., reduce dose by 0.18 mg/dose every 1 to 2 days). Reduce or hold the dose or discontinue therapy in persons who display a greater sensitivity to lofexidine adverse reactions. Lower doses may be appropriate as opioid withdrawal symptoms wane.
Maximum Dosage Limits:
-Adults
2.88 mg/day PO.
-Geriatric
2.88 mg/day PO.
-Adolescents
Safety and efficacy have not been established.
-Children
Safety and efficacy have not been established.
-Infants
Safety and efficacy have not been established.
Patients with Hepatic Impairment Dosing
Mild hepatic impairment (i.e., Child-Pugh score 5 to 6): 3 tablets (0.54 mg) PO 4 times per day (2.16 mg/day).
Moderate hepatic impairment (i.e., Child-Pugh score 7 to 9): 2 tablets (0.36 mg) PO 4 times per day (1.44 mg/day).
Severe hepatic impairment (i.e., Child-Pugh score greater than 9): 1 tablet (0.18 mg) PO 4 times per day (0.72 mg/day).
Patients with Renal Impairment Dosing
Mild to moderate renal impairment (i.e., eGFR 30 to 89.9 mL/min/1.73 m2): 2 tablets (0.36 mg) PO 4 times per day (1.44 mg/day).
Severe renal impairment, including end-stage renal disease (i.e., eGFR less than 30 mL/min/1.73 m2): 1 tablet (0.18 mg) PO 4 times per day (0.72 mg/day).
Intermittent hemodialysis
The recommended dose is 1 tablet (0.18 mg) PO 4 times per day (0.72 mg/day).
*non-FDA-approved indication
Acebutolol: (Major) Because both lofexidine and acebutolol can cause hypotension and bradycardia, concurrent use should be avoided if possible. 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.
Acetaminophen; Aspirin; Diphenhydramine: (Major) Monitor for excessive sedation during coadministration of diphenhydramine and lofexidine due to the potential for additive CNS depressant effects. Patients should be advised to avoid driving or performing any other tasks requiring mental alertness until the effects of the combination are known.
Acetaminophen; Caffeine; Dihydrocodeine: (Moderate) Monitor for excessive hypotension and sedation during coadministration of lofexidine and dihydrocodeine. Lofexidine can potentiate the effects of CNS depressants.
Acetaminophen; Chlorpheniramine: (Moderate) Monitor for additive sedation during coadministration of lofexidine and chlorpheniramine. Lofexidine can potentiate the effects of CNS depressants. Patients should be advised to avoid driving or performing any other tasks requiring mental alertness until the effects of the combination are known.
Acetaminophen; Chlorpheniramine; Dextromethorphan: (Moderate) Monitor for additive sedation during coadministration of lofexidine and chlorpheniramine. Lofexidine can potentiate the effects of CNS depressants. Patients should be advised to avoid driving or performing any other tasks requiring mental alertness until the effects of the combination are known.
Acetaminophen; Chlorpheniramine; Dextromethorphan; Phenylephrine: (Moderate) Monitor for additive sedation during coadministration of lofexidine and chlorpheniramine. Lofexidine can potentiate the effects of CNS depressants. Patients should be advised to avoid driving or performing any other tasks requiring mental alertness until the effects of the combination are known.
Acetaminophen; Chlorpheniramine; Dextromethorphan; Pseudoephedrine: (Moderate) Monitor for additive sedation during coadministration of lofexidine and chlorpheniramine. Lofexidine can potentiate the effects of CNS depressants. Patients should be advised to avoid driving or performing any other tasks requiring mental alertness until the effects of the combination are known.
Acetaminophen; Chlorpheniramine; Phenylephrine : (Moderate) Monitor for additive sedation during coadministration of lofexidine and chlorpheniramine. Lofexidine can potentiate the effects of CNS depressants. Patients should be advised to avoid driving or performing any other tasks requiring mental alertness until the effects of the combination are known.
Acetaminophen; Codeine: (Moderate) Monitor for excessive hypotension and sedation during coadministration of lofexidine and codeine. Lofexidine can potentiate the effects of CNS depressants.
Acetaminophen; Dextromethorphan; Doxylamine: (Moderate) Monitor for additive sedation during coadministration of lofexidine and doxylamine. Lofexidine can potentiate the effects of CNS depressants. Patients should be advised to avoid driving or performing any other tasks requiring mental alertness until the effects of the combination are known.
Acetaminophen; Diphenhydramine: (Major) Monitor for excessive sedation during coadministration of diphenhydramine and lofexidine due to the potential for additive CNS depressant effects. Patients should be advised to avoid driving or performing any other tasks requiring mental alertness until the effects of the combination are known.
Acetaminophen; Hydrocodone: (Moderate) Monitor for excessive hypotension and sedation during coadministration of lofexidine and hydrocodone. Lofexidine can potentiate the effects of CNS depressants.
Acetaminophen; Oxycodone: (Moderate) Monitor for excessive hypotension and sedation during coadministration of lofexidine and oxycodone. Lofexidine can potentiate the effects of CNS depressants.
Adagrasib: (Major) Avoid concomitant use of adagrasib and lofexidine due to the potential for increased lofexidine exposure and additive risk for QT/QTc prolongation and torsade de pointes (TdP). If use is necessary, monitor for lofexidine-related adverse effects, such as orthostatic hypotension and bradycardia, and consider taking additional steps to minimize the risk for QT prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring. Lofexidine is a CYP2D6 substrate, adagrasib is a moderate CYP2D6 inhibitor, and both medications have been associated with QT interval prolongation. Coadministration with a strong CYP2D6 inhibitor increased the lofexidine AUC by 28%.
Alfentanil: (Moderate) Monitor for excessive hypotension and sedation during coadministration of lofexidine and alfentanil. Lofexidine can potentiate the effects of CNS depressants.
Alfuzosin: (Major) Monitor ECG if lofexidine is coadministered with alfuzosin due to the potential for additive QT prolongation. Lofexidine prolongs the QT interval. In addition, there are postmarketing reports of torsade de pointes. Based on electrophysiology studies performed by the manufacturer, alfuzosin may prolong the QT interval in a dose-dependent manner. Alfuzosin is an alpha-blocker that does not commonly result in a drop in blood pressure, however, additive effects on blood pressure may also occur.
Alpha-blockers: (Major) Because the central alpha-2 agonist effects of lofexidine can cause hypotension and orthostasis, the drug should be avoided, if possible, in combination with other medications that can significantly decrease blood pressure such as the antihypertensive alpha-blockers. If coadministration is required, blood pressure should be monitored, particularly after dose changes of either agent. Adjustments should be made as clinically indicated. 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.
Alprazolam: (Moderate) Monitor for excessive hypotension and sedation during coadministration of lofexidine and benzodiazepines. Lofexidine can potentiate the effects of CNS depressants such as benzodiazepines.
Amiodarone: (Major) Avoid coadministration of lofexidine and amiodarone if possible, due to the potential for additive QT prolongation and torsade de pointes (TdP) and other serious adverse effects. Monitor ECG for QT prolongation and monitor for orthostatic hypotension and bradycardia if coadministration is required. Coadministration may increase lofexidine exposure. Lofexidine is a CYP2D6 substrate that prolongs the QT interval. In addition, there are postmarketing reports of TdP. Amiodarone, a CYP2D6 inhibitor and Class III antiarrhythmic agent, is associated with a well established risk of QT prolongation and TdP. Although the frequency of TdP is less with amiodarone than with other Class III agents, amiodarone is still associated with a risk of TdP. Due to the extremely long half-life of amiodarone, a drug interaction is possible for days to weeks after discontinuation of amiodarone. Coadministration with a strong CYP2D6 inhibitor increased the lofexidine AUC by 28%.
Amisulpride: (Major) Monitor ECGs for QT prolongation when amisulpride is administered with lofexidine. Amisulpride causes dose- and concentration- dependent QT prolongation. Lofexidine prolongs the QT interval.
Amitriptyline: (Moderate) Monitor for excessive hypotension and sedation during coadministration of lofexidine and tricyclic antidepressants. Lofexidine can potentiate the effects of CNS depressants. Additionally, monitor ECG during coadministration due to the potential risk for additive QT prolongation. Lofexidine prolongs the QT interval. In addition, there are postmarketing reports of torsade de pointes. Tricyclic antidepressants (TCAs) share pharmacologic properties similar to the Class IA antiarrhythmic agents and may prolong the QT interval, particularly in overdose or with higher-dose prescription therapy (elevated serum concentrations).
Amlodipine; Celecoxib: (Moderate) A dosage adjustment may be warranted for lofexidine if coadministered with celecoxib due to the potential for celecoxib to enhance the exposure and toxicity of lofexidine. Celecoxib is a CYP2D6 inhibitor, and lofexidine is a CYP2D6 substrate.
Amobarbital: (Moderate) Monitor for additive sedation during coadministration of lofexidine and barbiturates. Lofexidine can potentiate the effects of CNS depressants such as barbiturates. Patients should be advised to avoid driving or performing any other tasks requiring mental alertness until the effects of the combination are known. The use of barbiturates parenterally may cause vasodilation and an additive risk for hypotension and may lead to bradycardia and syncope; in these patients, careful monitoring of blood pressure should occur.
Amoxapine: (Moderate) Monitor for excessive hypotension and sedation during coadministration of lofexidine and amoxapine. Lofexidine can potentiate the effects of CNS depressants.
Amoxicillin; Clarithromycin; Omeprazole: (Major) Monitor ECG if lofexidine is coadministered with clarithromycin due to the potential for additive QT prolongation and torsade de pointes (TdP). Lofexidine prolongs the QT interval. In addition, there are postmarketing reports of TdP. Clarithromycin is associated with an established risk for QT prolongation and TdP.
Anagrelide: (Major) Avoid coadministration of lofexidine and anagrelide due to the potential for additive QT prolongation and torsade de pointes (TdP). Monitor ECG for QT prolongation if coadministration is required. Lofexidine prolongs the QT interval. In addition, there are postmarketing reports of TdP. TdP and ventricular tachycardia have been reported with anagrelide. In addition, dose-related increases in mean QTc and heart rate were observed in healthy subjects. A cardiovascular examination, including an ECG, should be obtained in all patients prior to initiating anagrelide therapy.
Anxiolytics; Sedatives; and Hypnotics: (Moderate) Monitor for additive sedation during coadministration of lofexidine and anxiolytics, sedatives, and hypnotics. Lofexidine can potentiate the effects of CNS depressants. Patients should be advised to avoid driving or performing any other tasks requiring mental alertness until the effects of the combination are known.
Apomorphine: (Major) Monitor the ECG if lofexidine is coadministered with apomorphine due to the potential for additive QT prolongation. Additionally, both drugs are associated with orthostatic hypotension and sedation and careful monitoring for these adverse effects is recommended. Lofexidine prolongs the QT interval, and torsade de pointes (TdP) has been reported during postmarketing use. Dose-related QTc prolongation is associated with therapeutic apomorphine exposure.
Aripiprazole: (Moderate) Monitor ECG and for hypotension if lofexidine is coadministered with aripiprazole due to the potential for additive QT prolongation and effects on blood pressure. Due to its alpha adrenergic antagonism, aripiprazole has the potential to enhance the effect of lofexidine on blood pressure. Lofexidine may also cause additive sedation with CNS depressants, such as the atypical antipsychotics. Lofexidine prolongs the QT interval, and torsade de pointes (TdP) has been reported during postmarketing use. QT prolongation has occurred during therapeutic use of aripiprazole and following overdose. 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.
Arsenic Trioxide: (Major) Avoid coadministration of lofexidine and arsenic trioxide due to the potential for additive QT prolongation and torsade de pointes (TdP). Monitor ECG frequently if coadministration is required. Lofexidine prolongs the QT interval. In addition, there are postmarketing reports of TdP. QT interval prolongation, TdP, and complete atrioventricular block have been reported with arsenic trioxide use.
Artemether; Lumefantrine: (Major) Avoid coadministration of lofexidine and artemether; lumefantrine due to the potential for additive QT prolongation and other serious adverse effects. Monitor ECG for QT prolongation and monitor for orthostatic hypotension and bradycardia if coadministration is required. Coadministration may increase lofexidine exposure. Lofexidine is a CYP2D6 substrate that prolongs the QT interval. In addition, there are postmarketing reports of torsade de pointes (TdP). Artemether; lumefantrine is a CYP2D6 inhibitor associated with QT interval prolongation. Coadministration with a strong CYP2D6 inhibitor increased the lofexidine AUC by 28%.
Asenapine: (Major) Monitoring the ECG is recommended if lofexidine and asenapine are used together due to the potential for additive QT prolongation. In addition, torsade de pointes (TdP) has occurred during postmarketing use of lofexidine. Also monitor for additive orthostatic hypotension and sedation if coadministration is required.
Aspirin, ASA; Butalbital; Caffeine: (Moderate) Monitor for additive sedation during coadministration of lofexidine and barbiturates. Lofexidine can potentiate the effects of CNS depressants such as barbiturates. Patients should be advised to avoid driving or performing any other tasks requiring mental alertness until the effects of the combination are known. The use of barbiturates parenterally may cause vasodilation and an additive risk for hypotension and may lead to bradycardia and syncope; in these patients, careful monitoring of blood pressure should occur.
Aspirin, ASA; Caffeine; Orphenadrine: (Major) Monitor for excessive hypotension and sedation during coadministration of lofexidine and orphenadrine. Lofexidine can potentiate the effects of CNS depressants.
Aspirin, ASA; Carisoprodol; Codeine: (Moderate) Monitor for excessive hypotension and sedation during coadministration of lofexidine and carisoprodol. Lofexidine can potentiate the effects of CNS depressants. (Moderate) Monitor for excessive hypotension and sedation during coadministration of lofexidine and codeine. Lofexidine can potentiate the effects of CNS depressants.
Aspirin, ASA; Oxycodone: (Moderate) Monitor for excessive hypotension and sedation during coadministration of lofexidine and oxycodone. Lofexidine can potentiate the effects of CNS depressants.
Atenolol: (Major) Because both lofexidine and atenolol can cause hypotension and bradycardia, concurrent use should be avoided if possible. 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.
Atenolol; Chlorthalidone: (Major) Because both lofexidine and atenolol can cause hypotension and bradycardia, concurrent use should be avoided if possible. 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.
Atomoxetine: (Moderate) Concomitant use of atomoxetine and lofexidine may increase the risk of QT/QTc prolongation and torsade de pointes (TdP) in some patients. Consider taking steps to minimize the risk of QT/QTc interval prolongation and TdP, such as avoidance, electrolyte monitoring and repletion, and ECG monitoring, especially in patients with additional risk factors for TdP.
Atropine: (Moderate) Monitor for excessive hypotension and sedation during coadministration of lofexidine and atropine. Lofexidine can potentiate the effects of CNS depressants.
Atropine; Difenoxin: (Moderate) Monitor for excessive hypotension and sedation during coadministration of lofexidine and atropine. Lofexidine can potentiate the effects of CNS depressants.
Azelastine: (Moderate) Monitor for additive sedation during coadministration of lofexidine and azelastine. Lofexidine can potentiate the effects of CNS depressants. Patients should be advised to avoid driving or performing any other tasks requiring mental alertness until the effects of the combination are known.
Azelastine; Fluticasone: (Moderate) Monitor for additive sedation during coadministration of lofexidine and azelastine. Lofexidine can potentiate the effects of CNS depressants. Patients should be advised to avoid driving or performing any other tasks requiring mental alertness until the effects of the combination are known.
Azithromycin: (Major) Concomitant use of lofexidine and azithromycin increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary.
Baclofen: (Moderate) Monitor for additive sedation during coadministration of lofexidine and baclofen. Lofexidine can potentiate the effects of CNS depressants. Patients should be advised to avoid driving or performing any other tasks requiring mental alertness until the effects of the combination are known. In the use of intrathecal baclofen, hypotension is possible, so the additive effects of lofexidine on blood pressure should be considered. Carefully monitor blood pressure and heart rate in such patients.
Barbiturates: (Moderate) Monitor for additive sedation during coadministration of lofexidine and barbiturates. Lofexidine can potentiate the effects of CNS depressants such as barbiturates. Patients should be advised to avoid driving or performing any other tasks requiring mental alertness until the effects of the combination are known. The use of barbiturates parenterally may cause vasodilation and an additive risk for hypotension and may lead to bradycardia and syncope; in these patients, careful monitoring of blood pressure should occur.
Bedaquiline: (Major) Monitor ECG if lofexidine is coadministered with bedaquiline due to the potential for additive QT prolongation. Lofexidine prolongs the QT interval. In addition, there are postmarketing reports of torsade de pointes (TdP). Bedaquiline has been reported to prolong the QT interval.
Belladonna; Opium: (Moderate) Monitor for excessive hypotension and sedation during coadministration of lofexidine and belladonna. Lofexidine can potentiate the effects of CNS depressants. (Moderate) Monitor for excessive hypotension and sedation during coadministration of lofexidine and opium. Lofexidine can potentiate the effects of CNS depressants.
Benzodiazepines: (Moderate) Monitor for excessive hypotension and sedation during coadministration of lofexidine and benzodiazepines. Lofexidine can potentiate the effects of CNS depressants such as benzodiazepines.
Berotralstat: (Moderate) Monitor for orthostatic hypotension and bradycardia during concurrent use of lofexidine and berotralstat. Coadministration may increase lofexidine exposure. Lofexidine is a CYP2D6 substrate; berotralstat is a CYP2D6 inhibitor.
Betaxolol: (Major) Because both lofexidine and betaxolol can cause hypotension and bradycardia, concurrent use should be avoided if possible. 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.
Bismuth Subcitrate Potassium; Metronidazole; Tetracycline: (Major) Concomitant use of metronidazole and lofexidine increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary.
Bismuth Subsalicylate; Metronidazole; Tetracycline: (Major) Concomitant use of metronidazole and lofexidine increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary.
Bisoprolol: (Major) Because both lofexidine and bisoprolol can cause hypotension and bradycardia, concurrent use should be avoided if possible. 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.
Bisoprolol; Hydrochlorothiazide, HCTZ: (Major) Because both lofexidine and bisoprolol can cause hypotension and bradycardia, concurrent use should be avoided if possible. 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.
Brexpiprazole: (Major) Monitor for excessive hypotension and sedation during coadministration of lofexidine and brexpiprazole. Lofexidine can potentiate the effects of CNS depressants.
Brimonidine; Timolol: (Major) Because both lofexidine and timolol can cause hypotension and bradycardia, concurrent use should be avoided if possible. 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.
Brompheniramine: (Moderate) Monitor for excessive hypotension and sedation during coadministration of lofexidine and brompheniramine. Lofexidine can potentiate the effects of CNS depressants.
Brompheniramine; Dextromethorphan; Phenylephrine: (Moderate) Monitor for excessive hypotension and sedation during coadministration of lofexidine and brompheniramine. Lofexidine can potentiate the effects of CNS depressants.
Brompheniramine; Phenylephrine: (Moderate) Monitor for excessive hypotension and sedation during coadministration of lofexidine and brompheniramine. Lofexidine can potentiate the effects of CNS depressants.
Brompheniramine; Pseudoephedrine: (Moderate) Monitor for excessive hypotension and sedation during coadministration of lofexidine and brompheniramine. Lofexidine can potentiate the effects of CNS depressants.
Brompheniramine; Pseudoephedrine; Dextromethorphan: (Moderate) Monitor for excessive hypotension and sedation during coadministration of lofexidine and brompheniramine. Lofexidine can potentiate the effects of CNS depressants.
Buprenorphine: (Major) Monitor ECG if lofexidine is coadministered with buprenorphine due to the potential for additive QT prolongation and torsade de pointes (TdP). Additionally, monitor for excessive hypotension and sedation during coadministration. Lofexidine can potentiate the effects of CNS depressants. Lofexidine prolongs the QT interval and there are postmarketing reports of TdP. Buprenorphine has been associated with QT prolongation and has a possible risk of TdP. FDA-approved labeling for some buprenorphine products recommends avoiding use with Class 1A and Class III antiarrhythmic medications while other labels recommend avoiding use with any drug that has the potential to prolong the QT interval. In electrophysiology studies, lofexidine (2.88 mg/day) coadministered with buprenorphine (16 to 24 mg/day) resulted in a maximum mean QTcF increase of 15 (5.6) msec from buprenorphine-alone baseline.
Buprenorphine; Naloxone: (Major) Monitor ECG if lofexidine is coadministered with buprenorphine due to the potential for additive QT prolongation and torsade de pointes (TdP). Additionally, monitor for excessive hypotension and sedation during coadministration. Lofexidine can potentiate the effects of CNS depressants. Lofexidine prolongs the QT interval and there are postmarketing reports of TdP. Buprenorphine has been associated with QT prolongation and has a possible risk of TdP. FDA-approved labeling for some buprenorphine products recommends avoiding use with Class 1A and Class III antiarrhythmic medications while other labels recommend avoiding use with any drug that has the potential to prolong the QT interval. In electrophysiology studies, lofexidine (2.88 mg/day) coadministered with buprenorphine (16 to 24 mg/day) resulted in a maximum mean QTcF increase of 15 (5.6) msec from buprenorphine-alone baseline.
Bupropion: (Moderate) Monitor for orthostatic hypotension and bradycardia during concurrent use of lofexidine and bupropion. Coadministration may increase lofexidine exposure. Lofexidine is a CYP2D6 substrate; bupropion is a strong CYP2D6 inhibitor. Coadministration with a strong CYP2D6 inhibitor increased the lofexidine AUC by 28%.
Bupropion; Naltrexone: (Major) Separate administration of lofexidine and oral naltrexone by 2 hours as simultaneous administration may reduce the efficacy of naltrexone. Coadministration of lofexidine and oral naltrexone resulted in statistically significant differences in the steady state pharmacokinetics of naltrexone. This interaction is not expected if naltrexone is administered by non-oral routes. (Moderate) Monitor for orthostatic hypotension and bradycardia during concurrent use of lofexidine and bupropion. Coadministration may increase lofexidine exposure. Lofexidine is a CYP2D6 substrate; bupropion is a strong CYP2D6 inhibitor. Coadministration with a strong CYP2D6 inhibitor increased the lofexidine AUC by 28%.
Butalbital; Acetaminophen: (Moderate) Monitor for additive sedation during coadministration of lofexidine and barbiturates. Lofexidine can potentiate the effects of CNS depressants such as barbiturates. Patients should be advised to avoid driving or performing any other tasks requiring mental alertness until the effects of the combination are known. The use of barbiturates parenterally may cause vasodilation and an additive risk for hypotension and may lead to bradycardia and syncope; in these patients, careful monitoring of blood pressure should occur.
Butalbital; Acetaminophen; Caffeine: (Moderate) Monitor for additive sedation during coadministration of lofexidine and barbiturates. Lofexidine can potentiate the effects of CNS depressants such as barbiturates. Patients should be advised to avoid driving or performing any other tasks requiring mental alertness until the effects of the combination are known. The use of barbiturates parenterally may cause vasodilation and an additive risk for hypotension and may lead to bradycardia and syncope; in these patients, careful monitoring of blood pressure should occur.
Butalbital; Acetaminophen; Caffeine; Codeine: (Moderate) Monitor for additive sedation during coadministration of lofexidine and barbiturates. Lofexidine can potentiate the effects of CNS depressants such as barbiturates. Patients should be advised to avoid driving or performing any other tasks requiring mental alertness until the effects of the combination are known. The use of barbiturates parenterally may cause vasodilation and an additive risk for hypotension and may lead to bradycardia and syncope; in these patients, careful monitoring of blood pressure should occur. (Moderate) Monitor for excessive hypotension and sedation during coadministration of lofexidine and codeine. Lofexidine can potentiate the effects of CNS depressants.
Butalbital; Aspirin; Caffeine; Codeine: (Moderate) Monitor for additive sedation during coadministration of lofexidine and barbiturates. Lofexidine can potentiate the effects of CNS depressants such as barbiturates. Patients should be advised to avoid driving or performing any other tasks requiring mental alertness until the effects of the combination are known. The use of barbiturates parenterally may cause vasodilation and an additive risk for hypotension and may lead to bradycardia and syncope; in these patients, careful monitoring of blood pressure should occur. (Moderate) Monitor for excessive hypotension and sedation during coadministration of lofexidine and codeine. Lofexidine can potentiate the effects of CNS depressants.
Butorphanol: (Moderate) Monitor for excessive hypotension and sedation during coadministration of lofexidine and butorphanol. Lofexidine can potentiate the effects of CNS depressants.
Cabotegravir; Rilpivirine: (Major) Monitor ECG if lofexidine is coadministered with rilpivirine due to the potential for additive QT prolongation. Lofexidine prolongs the QT interval. In addition, there are postmarketing reports of torsade de pointes. Supratherapeutic doses of rilpivirine (75 to 300 mg/day) have caused QT prolongation; caution is advised when administering rilpivirine with other drugs that may prolong the QT or PR interval.
Calcium, Magnesium, Potassium, Sodium Oxybates: (Moderate) Monitor for additive sedation during coadministration of lofexidine and sodium oxybate. Lofexidine can potentiate the effects of CNS depressants. Patients should be advised to avoid driving or performing any other tasks requiring mental alertness until the effects of the combination are known.
Cannabidiol: (Moderate) Monitor for excessive sedation and somnolence during coadministration. Cannabidiol may potentiate the sedative effects of lofexidine.
Capivasertib: (Moderate) Monitor for orthostatic hypotension and bradycardia during concurrent use of lofexidine and capivasertib. Coadministration may increase lofexidine exposure. Lofexidine is a CYP2D6 substrate; capivasertib is a CYP2D6 inhibitor. Coadministration with a strong CYP2D6 inhibitor increased the lofexidine AUC by 28%.
Capsaicin; Metaxalone: (Moderate) Monitor for additive sedation during coadministration of lofexidine and metaxalone. Lofexidine can potentiate the effects of CNS depressants. Patients should be advised to avoid driving or performing any other tasks requiring mental alertness until the effects of the combination are known.
Carbidopa; Levodopa; Entacapone: (Major) Monitor for excessive hypotension and sedation during coadministration of lofexidine and entacapone. Lofexidine can potentiate the effects of CNS depressants.
Cariprazine: (Moderate) Monitor for excessive hypotension and sedation during coadministration of lofexidine and cariprazine. Lofexidine can potentiate the effects of CNS depressants.
Carisoprodol: (Moderate) Monitor for excessive hypotension and sedation during coadministration of lofexidine and carisoprodol. Lofexidine can potentiate the effects of CNS depressants.
Carteolol: (Major) Because both lofexidine and carteolol can cause hypotension and bradycardia, concurrent use should be avoided if possible. 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.
Carvedilol: (Major) Because both lofexidine and carvedilol can cause hypotension and bradycardia, concurrent use should be avoided if possible. 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.
Celecoxib: (Moderate) A dosage adjustment may be warranted for lofexidine if coadministered with celecoxib due to the potential for celecoxib to enhance the exposure and toxicity of lofexidine. Celecoxib is a CYP2D6 inhibitor, and lofexidine is a CYP2D6 substrate.
Celecoxib; Tramadol: (Moderate) A dosage adjustment may be warranted for lofexidine if coadministered with celecoxib due to the potential for celecoxib to enhance the exposure and toxicity of lofexidine. Celecoxib is a CYP2D6 inhibitor, and lofexidine is a CYP2D6 substrate. (Moderate) Monitor for excessive hypotension and sedation during coadministration of lofexidine and tramadol. Lofexidine can potentiate the effects of CNS depressants.
Cenobamate: (Moderate) Monitor for excessive sedation and somnolence during coadministration of cenobamate and lofexidine. Concurrent use may result in additive CNS depression.
Central-acting adrenergic agents: (Major) Lofexidine is a central alpha-2 adrenergic agonist, and its effects can be additive to other medications in the same class. Monitor for excessive hypotension, bradycardia, and sedation during coadministration. 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.
Ceritinib: (Major) Avoid coadministration of ceritinib with lofexidine if possible due to the risk of QT prolongation. If concomitant use is unavoidable, periodically monitor ECGs and electrolytes; an interruption of ceritinib therapy, dose reduction, or discontinuation of therapy may be necessary if QT prolongation occurs. Lofexidine prolongs the QT interval. Ceritinib also causes concentration-dependent prolongation of the QT interval.
Cetirizine: (Moderate) Concurrent use of cetirizine/levocetirizine with lofexidine should generally be avoided. Coadministration may increase the risk of CNS depressant-related side effects. If concurrent use is necessary, monitor for excessive sedation and somnolence.
Cetirizine; Pseudoephedrine: (Moderate) Concurrent use of cetirizine/levocetirizine with lofexidine should generally be avoided. Coadministration may increase the risk of CNS depressant-related side effects. If concurrent use is necessary, monitor for excessive sedation and somnolence.
Chlordiazepoxide: (Moderate) Monitor for excessive hypotension and sedation during coadministration of lofexidine and benzodiazepines. Lofexidine can potentiate the effects of CNS depressants such as benzodiazepines.
Chlordiazepoxide; Amitriptyline: (Moderate) Monitor for excessive hypotension and sedation during coadministration of lofexidine and benzodiazepines. Lofexidine can potentiate the effects of CNS depressants such as benzodiazepines. (Moderate) Monitor for excessive hypotension and sedation during coadministration of lofexidine and tricyclic antidepressants. Lofexidine can potentiate the effects of CNS depressants. Additionally, monitor ECG during coadministration due to the potential risk for additive QT prolongation. Lofexidine prolongs the QT interval. In addition, there are postmarketing reports of torsade de pointes. Tricyclic antidepressants (TCAs) share pharmacologic properties similar to the Class IA antiarrhythmic agents and may prolong the QT interval, particularly in overdose or with higher-dose prescription therapy (elevated serum concentrations).
Chlordiazepoxide; Clidinium: (Moderate) Monitor for excessive hypotension and sedation during coadministration of lofexidine and benzodiazepines. Lofexidine can potentiate the effects of CNS depressants such as benzodiazepines.
Chloroquine: (Major) Avoid coadministration of chloroquine with lofexidine due to the increased risk of QT prolongation. If use together is necessary, obtain an ECG at baseline to assess initial QT interval and determine frequency of subsequent ECG monitoring, avoid any non-essential QT prolonging drugs, and correct electrolyte imbalances. Chloroquine is associated with an increased risk of QT prolongation and torsade de pointes (TdP); the risk of QT prolongation is increased with higher chloroquine doses. Lofexidine also prolongs the QT interval.
Chlorpheniramine: (Moderate) Monitor for additive sedation during coadministration of lofexidine and chlorpheniramine. Lofexidine can potentiate the effects of CNS depressants. Patients should be advised to avoid driving or performing any other tasks requiring mental alertness until the effects of the combination are known.
Chlorpheniramine; Codeine: (Moderate) Monitor for additive sedation during coadministration of lofexidine and chlorpheniramine. Lofexidine can potentiate the effects of CNS depressants. Patients should be advised to avoid driving or performing any other tasks requiring mental alertness until the effects of the combination are known. (Moderate) Monitor for excessive hypotension and sedation during coadministration of lofexidine and codeine. Lofexidine can potentiate the effects of CNS depressants.
Chlorpheniramine; Dextromethorphan: (Moderate) Monitor for additive sedation during coadministration of lofexidine and chlorpheniramine. Lofexidine can potentiate the effects of CNS depressants. Patients should be advised to avoid driving or performing any other tasks requiring mental alertness until the effects of the combination are known.
Chlorpheniramine; Dextromethorphan; Phenylephrine: (Moderate) Monitor for additive sedation during coadministration of lofexidine and chlorpheniramine. Lofexidine can potentiate the effects of CNS depressants. Patients should be advised to avoid driving or performing any other tasks requiring mental alertness until the effects of the combination are known.
Chlorpheniramine; Dextromethorphan; Pseudoephedrine: (Moderate) Monitor for additive sedation during coadministration of lofexidine and chlorpheniramine. Lofexidine can potentiate the effects of CNS depressants. Patients should be advised to avoid driving or performing any other tasks requiring mental alertness until the effects of the combination are known.
Chlorpheniramine; Hydrocodone: (Moderate) Monitor for additive sedation during coadministration of lofexidine and chlorpheniramine. Lofexidine can potentiate the effects of CNS depressants. Patients should be advised to avoid driving or performing any other tasks requiring mental alertness until the effects of the combination are known. (Moderate) Monitor for excessive hypotension and sedation during coadministration of lofexidine and hydrocodone. Lofexidine can potentiate the effects of CNS depressants.
Chlorpheniramine; Ibuprofen; Pseudoephedrine: (Moderate) Monitor for additive sedation during coadministration of lofexidine and chlorpheniramine. Lofexidine can potentiate the effects of CNS depressants. Patients should be advised to avoid driving or performing any other tasks requiring mental alertness until the effects of the combination are known.
Chlorpheniramine; Phenylephrine: (Moderate) Monitor for additive sedation during coadministration of lofexidine and chlorpheniramine. Lofexidine can potentiate the effects of CNS depressants. Patients should be advised to avoid driving or performing any other tasks requiring mental alertness until the effects of the combination are known.
Chlorpheniramine; Pseudoephedrine: (Moderate) Monitor for additive sedation during coadministration of lofexidine and chlorpheniramine. Lofexidine can potentiate the effects of CNS depressants. Patients should be advised to avoid driving or performing any other tasks requiring mental alertness until the effects of the combination are known.
Chlorpromazine: (Major) Monitor the ECG for QT prolongation and monitor for additive orthostatic hypotension and sedation during concurrent use of lofexidine and chlorpromazine. Lofexidine prolongs the QT interval and torsade de pointes (TdP) has been reported during postmarketing use. Chlorpromazine is associated with an established risk of QT prolongation and TdP. Both agents can cause orthostasis and sedation, which may be additive during coadministration.
Chlorzoxazone: (Moderate) Monitor for additive sedation during coadministration of lofexidine and chlorzoxazone. Lofexidine can potentiate the effects of CNS depressants. Patients should be advised to avoid driving or performing any other tasks requiring mental alertness until the effects of the combination are known.
Cinacalcet: (Moderate) Monitor for orthostatic hypotension and bradycardia during concurrent use of lofexidine and cinacalcet. Coadministration may increase lofexidine exposure. Lofexidine is a CYP2D6 substrate; cinacalcet is a CYP2D6 inhibitor. Coadministration with a strong CYP2D6 inhibitor increased the lofexidine AUC by 28%.
Ciprofloxacin: (Moderate) Concomitant use of ciprofloxacin and lofexidine may increase the risk of QT/QTc prolongation and torsade de pointes (TdP) in some patients. Consider taking steps to minimize the risk of QT/QTc interval prolongation and TdP, such as avoidance, electrolyte monitoring and repletion, and ECG monitoring, especially in patients with additional risk factors for TdP.
Cisapride: (Contraindicated) Concomitant use of lofexidine and cisapride is contraindicated due to the potential for additive QT prolongation and torsade de pointes (TdP). Lofexidine prolongs the QT interval. In addition, there are postmarketing reports of TdP. QT prolongation and ventricular arrhythmias, including TdP and death, have been reported with cisapride.
Citalopram: (Major) Concomitant use of lofexidine and citalopram increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary.
Clarithromycin: (Major) Monitor ECG if lofexidine is coadministered with clarithromycin due to the potential for additive QT prolongation and torsade de pointes (TdP). Lofexidine prolongs the QT interval. In addition, there are postmarketing reports of TdP. Clarithromycin is associated with an established risk for QT prolongation and TdP.
Clemastine: (Moderate) Monitor for excessive hypotension and sedation during coadministration of lofexidine and clemastine. Lofexidine can potentiate the effects of CNS depressants.
Clobazam: (Moderate) Monitor for excessive sedation during coadministration of lofexidine and clobazam, a benzodiazepine. Lofexidine can potentiate the effects of CNS depressants.
Clofazimine: (Major) Concomitant use of clofazimine and lofexidine increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary.
Clomipramine: (Moderate) Monitor for excessive hypotension and sedation during coadministration of lofexidine and tricyclic antidepressants. Lofexidine can potentiate the effects of CNS depressants. Additionally, monitor ECG during coadministration due to the potential risk for additive QT prolongation. Lofexidine prolongs the QT interval. In addition, there are postmarketing reports of torsade de pointes. Tricyclic antidepressants (TCAs) share pharmacologic properties similar to the Class IA antiarrhythmic agents and may prolong the QT interval, particularly in overdose or with higher-dose prescription therapy (elevated serum concentrations).
Clonazepam: (Moderate) Monitor for excessive hypotension and sedation during coadministration of lofexidine and benzodiazepines. Lofexidine can potentiate the effects of CNS depressants such as benzodiazepines.
Clonidine: (Major) Lofexidine is a central alpha-2 adrenergic agonist, and its effects can be additive to other medications in the same class. Monitor for excessive hypotension, bradycardia, and sedation during coadministration. 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.
Clorazepate: (Moderate) Monitor for excessive hypotension and sedation during coadministration of lofexidine and benzodiazepines. Lofexidine can potentiate the effects of CNS depressants such as benzodiazepines.
Clozapine: (Major) Monitor ECG if lofexidine is coadministered with clozapine due to the potential for additive QT prolongation and torsade de pointes (TdP). Additionally, monitor for excessive hypotension and sedation during coadministration as lofexidine can potentiate the effects of CNS depressants. Lofexidine prolongs the QT interval. In addition, there are postmarketing reports of TdP. Treatment with clozapine has been associated with QT prolongation, TdP, cardiac arrest, and sudden death.
Codeine: (Moderate) Monitor for excessive hypotension and sedation during coadministration of lofexidine and codeine. Lofexidine can potentiate the effects of CNS depressants.
Codeine; Guaifenesin: (Moderate) Monitor for excessive hypotension and sedation during coadministration of lofexidine and codeine. Lofexidine can potentiate the effects of CNS depressants.
Codeine; Guaifenesin; Pseudoephedrine: (Moderate) Monitor for excessive hypotension and sedation during coadministration of lofexidine and codeine. Lofexidine can potentiate the effects of CNS depressants.
Codeine; Phenylephrine; Promethazine: (Moderate) Monitor ECG for QT prolongation and excessive sedation during concurrent use of lofexidine and promethazine. Lofexidine prolongs the QT interval and torsade de pointes (TdP) has been reported during postmarketing use. Promethazine is associated with a possible risk of QT prolongation and TdP. In addition, lofexidine can potentiate the effects of CNS depressants, including promethazine. (Moderate) Monitor for excessive hypotension and sedation during coadministration of lofexidine and codeine. Lofexidine can potentiate the effects of CNS depressants.
Codeine; Promethazine: (Moderate) Monitor ECG for QT prolongation and excessive sedation during concurrent use of lofexidine and promethazine. Lofexidine prolongs the QT interval and torsade de pointes (TdP) has been reported during postmarketing use. Promethazine is associated with a possible risk of QT prolongation and TdP. In addition, lofexidine can potentiate the effects of CNS depressants, including promethazine. (Moderate) Monitor for excessive hypotension and sedation during coadministration of lofexidine and codeine. Lofexidine can potentiate the effects of CNS depressants.
Crizotinib: (Major) Avoid coadministration of crizotinib with lofexidine due to the risk of QT prolongation. If concomitant use is unavoidable, monitor ECGs for QT prolongation and monitor electrolytes. An interruption of therapy, dose reduction, or discontinuation of therapy may be necessary for crizotinib if QT prolongation occurs. Crizotinib has been associated with concentration-dependent QT prolongation. Lofexidine also prolongs the QT interval.
Cyclobenzaprine: (Moderate) Monitor for excessive hypotension and sedation during coadministration of lofexidine and cyclobenzaprine. Lofexidine can potentiate the effects of CNS depressants.
Cyproheptadine: (Moderate) Monitor for excessive hypotension and sedation during coadministration of lofexidine and cyproheptadine. Lofexidine can potentiate the effects of CNS depressants.
Dacomitinib: (Moderate) Monitor for orthostatic hypotension and bradycardia during concurrent use of lofexidine and dacomitinib. Coadministration may increase lofexidine exposure. Lofexidine is a CYP2D6 substrate; dacomitinib is a strong CYP2D6 inhibitor. Coadministration with a strong CYP2D6 inhibitor increased the lofexidine AUC by 28%.
Dantrolene: (Moderate) Monitor for additive sedation during coadministration of lofexidine and dantrolene. Lofexidine can potentiate the effects of CNS depressants. Patients should be advised to avoid driving or performing any other tasks requiring mental alertness until the effects of the combination are known.
Dasatinib: (Major) Monitor ECG if lofexidine is coadministered with dasatinib due to the potential for additive QT prolongation. Lofexidine prolongs the QT interval. In addition, there are postmarketing reports of torsade de pointes. In vitro studies have shown that dasatinib has the potential to prolong the QT interval.
Degarelix: (Major) Monitor ECG if lofexidine is coadministered with degarelix due to the potential for additive QT prolongation. Lofexidine prolongs the QT interval. In addition, there are postmarketing reports of torsade de pointes. Androgen deprivation therapy (i.e., degarelix) may prolong the QT/QTc interval.
Desflurane: (Major) Monitor ECG if lofexidine is coadministered with halogenated anesthetics due to the potential for additive QT prolongation. Lofexidine prolongs the QT interval. In addition, there are postmarketing reports of torsade de pointes. Halogenated anesthetics can prolong the QT interval. Additionally, monitor for excessive hypotension and sedation during coadministration as lofexidine can potentiate the effects of CNS depressants.
Desipramine: (Moderate) Monitor for excessive hypotension and sedation during coadministration of lofexidine and tricyclic antidepressants. Lofexidine can potentiate the effects of CNS depressants. Additionally, monitor ECG during coadministration due to the potential risk for additive QT prolongation. Lofexidine prolongs the QT interval. In addition, there are postmarketing reports of torsade de pointes. Tricyclic antidepressants (TCAs) share pharmacologic properties similar to the Class IA antiarrhythmic agents and may prolong the QT interval, particularly in overdose or with higher-dose prescription therapy (elevated serum concentrations).
Deutetrabenazine: (Major) ECG monitoring is recommended if lofexidine is coadministered with deutetrabenazine due to the potential for additive QT prolongation. Lofexidine prolongs the QT interval. Deutetrabenazine may prolong the QT interval, but the degree of QT prolongation is not clinically significant when deutetrabenazine is administered within the recommended dosage range. Also, monitor for excessive sedation and somnolence during coadministration of lofexidine and deutetrabenazine. Concurrent use may result in additive CNS depression.
Dexmedetomidine: (Major) Concomitant use of dexmedetomidine and lofexidine increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary.
Dextromethorphan; Bupropion: (Moderate) Monitor for orthostatic hypotension and bradycardia during concurrent use of lofexidine and bupropion. Coadministration may increase lofexidine exposure. Lofexidine is a CYP2D6 substrate; bupropion is a strong CYP2D6 inhibitor. Coadministration with a strong CYP2D6 inhibitor increased the lofexidine AUC by 28%.
Dextromethorphan; Diphenhydramine; Phenylephrine: (Major) Monitor for excessive sedation during coadministration of diphenhydramine and lofexidine due to the potential for additive CNS depressant effects. Patients should be advised to avoid driving or performing any other tasks requiring mental alertness until the effects of the combination are known.
Dextromethorphan; Quinidine: (Contraindicated) Concomitant use of lofexidine and quinidine is contraindicated due to the potential for additive QT prolongation and torsade de pointes (TdP). Lofexidine is a CYP2D6 substrate that prolongs the QT interval. In addition, there are postmarketing reports of TdP. Quinidine is a CYP2D6 inhibitor and is associated with QT prolongation and TdP.
Diazepam: (Moderate) Monitor for excessive hypotension and sedation during coadministration of lofexidine and benzodiazepines. Lofexidine can potentiate the effects of CNS depressants such as benzodiazepines.
Diazoxide: (Major) Because the central alpha-2 agonist effects of lofexidine can cause hypotension and orthostasis, the drug should be avoided, if possible, in combination with other medications that can decrease blood pressure such as systemic vasodilators. If coadministration is required, blood pressure should be monitored, particularly after dose changes of either agent. Adjustments should be made as clinically indicated.
Difelikefalin: (Moderate) Monitor for dizziness, somnolence, mental status changes, and gait disturbances if concomitant use of difelikefalin with CNS depressants is necessary. Concomitant use may increase the risk for these adverse reactions.
Diltiazem: (Moderate) Because both lofexidine and diltiazem can cause hypotension and bradycardia, concurrent use should be avoided if possible. 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.
Dimenhydrinate: (Moderate) Monitor for excessive hypotension and sedation during coadministration of lofexidine and dimenhydrinate. Lofexidine can potentiate the effects of CNS depressants.
Diphenhydramine: (Major) Monitor for excessive sedation during coadministration of diphenhydramine and lofexidine due to the potential for additive CNS depressant effects. Patients should be advised to avoid driving or performing any other tasks requiring mental alertness until the effects of the combination are known.
Diphenhydramine; Ibuprofen: (Major) Monitor for excessive sedation during coadministration of diphenhydramine and lofexidine due to the potential for additive CNS depressant effects. Patients should be advised to avoid driving or performing any other tasks requiring mental alertness until the effects of the combination are known.
Diphenhydramine; Naproxen: (Major) Monitor for excessive sedation during coadministration of diphenhydramine and lofexidine due to the potential for additive CNS depressant effects. Patients should be advised to avoid driving or performing any other tasks requiring mental alertness until the effects of the combination are known.
Diphenhydramine; Phenylephrine: (Major) Monitor for excessive sedation during coadministration of diphenhydramine and lofexidine due to the potential for additive CNS depressant effects. Patients should be advised to avoid driving or performing any other tasks requiring mental alertness until the effects of the combination are known.
Diphenoxylate; Atropine: (Moderate) Monitor for excessive hypotension and sedation during coadministration of lofexidine and atropine. Lofexidine can potentiate the effects of CNS depressants.
Disopyramide: (Major) Monitor ECG if lofexidine is coadministered with disopyramide due to the potential for additive QT prolongation and torsade de pointes (TdP). Lofexidine prolongs the QT interval. In addition, there are postmarketing reports of TdP. Disopyramide administration is associated with QT prolongation and TdP.
Dofetilide: (Major) Coadministration of dofetilide and lofexidine is not recommended as concurrent use may increase the risk of QT prolongation. If coadministration cannot be avoided, monitor ECG. Dofetilide, a Class III antiarrhythmic agent, is associated with a well-established risk of QT prolongation and torsade de pointes (TdP). Lofexidine prolongs the QT interval.
Dolasetron: (Major) Monitor ECG if lofexidine is coadministered with dolasetron due to the potential for additive QT prolongation. Lofexidine prolongs the QT interval. In addition, there are postmarketing reports of torsade de pointes. Dolasetron has been associated with a dose-dependent prolongation in the QT, PR, and QRS intervals.
Dolutegravir; Rilpivirine: (Major) Monitor ECG if lofexidine is coadministered with rilpivirine due to the potential for additive QT prolongation. Lofexidine prolongs the QT interval. In addition, there are postmarketing reports of torsade de pointes. Supratherapeutic doses of rilpivirine (75 to 300 mg/day) have caused QT prolongation; caution is advised when administering rilpivirine with other drugs that may prolong the QT or PR interval.
Donepezil: (Major) Monitor ECG if lofexidine is coadministered with donepezil due to the potential for additive QT prolongation and torsade de pointes (TdP). Lofexidine prolongs the QT interval. In addition, there are postmarketing reports of TdP. Case reports indicate that QT prolongation and TdP can occur during donepezil therapy. Donepezil is considered a drug with a known risk of TdP.
Donepezil; Memantine: (Major) Monitor ECG if lofexidine is coadministered with donepezil due to the potential for additive QT prolongation and torsade de pointes (TdP). Lofexidine prolongs the QT interval. In addition, there are postmarketing reports of TdP. Case reports indicate that QT prolongation and TdP can occur during donepezil therapy. Donepezil is considered a drug with a known risk of TdP.
Dorzolamide; Timolol: (Major) Because both lofexidine and timolol can cause hypotension and bradycardia, concurrent use should be avoided if possible. 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.
Doxazosin: (Major) Because the central alpha-2 agonist effects of lofexidine can cause hypotension and orthostasis, the drug should be avoided, if possible, in combination with other medications that can significantly decrease blood pressure such as the antihypertensive alpha-blockers. If coadministration is required, blood pressure should be monitored, particularly after dose changes of either agent. Adjustments should be made as clinically indicated. 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.
Doxepin: (Moderate) Monitor for excessive hypotension and sedation during coadministration of lofexidine and tricyclic antidepressants. Lofexidine can potentiate the effects of CNS depressants. Additionally, monitor ECG during coadministration due to the potential risk for additive QT prolongation. Lofexidine prolongs the QT interval. In addition, there are postmarketing reports of torsade de pointes. Tricyclic antidepressants (TCAs) share pharmacologic properties similar to the Class IA antiarrhythmic agents and may prolong the QT interval, particularly in overdose or with higher-dose prescription therapy (elevated serum concentrations).
Doxylamine: (Moderate) Monitor for additive sedation during coadministration of lofexidine and doxylamine. Lofexidine can potentiate the effects of CNS depressants. Patients should be advised to avoid driving or performing any other tasks requiring mental alertness until the effects of the combination are known.
Doxylamine; Pyridoxine: (Moderate) Monitor for additive sedation during coadministration of lofexidine and doxylamine. Lofexidine can potentiate the effects of CNS depressants. Patients should be advised to avoid driving or performing any other tasks requiring mental alertness until the effects of the combination are known.
Dronedarone: (Contraindicated) Concomitant use of lofexidine and dronedarone is contraindicated due to the potential for additive QT prolongation. Lofexidine is a CYP2D6 substrate that prolongs the QT interval. In addition, there are postmarketing reports of torsade de pointes (TdP). Dronedarone is a CYP2D6 inhibitor and is associated with a dose-related increase in the QTc interval. The increase in QTc is approximately 10 milliseconds at doses of 400 mg twice daily (the FDA-approved dose) and up to 25 milliseconds at doses of 1600 mg twice daily.
Droperidol: (Major) Avoid coadministration of lofexidine and droperidol due to the potential for additive QT prolongation and torsade de pointes (TdP). If coadministration cannot be avoided, use extreme caution and monitor ECG; initiate droperidol at a low dose and increase the dose as needed to achieve the desired effect. Additionally, monitor for excessive hypotension and sedation during coadministration as lofexidine can potentiate the effects of CNS depressants. Lofexidine prolongs the QT interval. In addition, there are postmarketing reports of TdP. Droperidol administration is associated with an established risk for QT prolongation and TdP. Some cases have occurred in patients with no known risk factors for QT prolongation and some cases have been fatal.
Efavirenz: (Major) Monitor ECG if lofexidine is coadministered with efavirenz due to the potential for additive QT prolongation. Lofexidine prolongs the QT interval. In addition, there are postmarketing reports of torsade de pointes. QTc prolongation has been observed with the use of efavirenz.
Efavirenz; Emtricitabine; Tenofovir Disoproxil Fumarate: (Major) Monitor ECG if lofexidine is coadministered with efavirenz due to the potential for additive QT prolongation. Lofexidine prolongs the QT interval. In addition, there are postmarketing reports of torsade de pointes. QTc prolongation has been observed with the use of efavirenz.
Efavirenz; Lamivudine; Tenofovir Disoproxil Fumarate: (Major) Monitor ECG if lofexidine is coadministered with efavirenz due to the potential for additive QT prolongation. Lofexidine prolongs the QT interval. In addition, there are postmarketing reports of torsade de pointes. QTc prolongation has been observed with the use of efavirenz.
Eliglustat: (Major) Monitor the ECG for QT prolongation during concurrent use of lofexidine and eliglustat. Lofexidine may prolong the QT interval, and torsade de pointes (TdP) has been reported during postmarketing use. Eliglustat is predicted to cause PR, QRS, and/or QT prolongation at significantly elevated plasma concentrations.
Emtricitabine; Rilpivirine; Tenofovir alafenamide: (Major) Monitor ECG if lofexidine is coadministered with rilpivirine due to the potential for additive QT prolongation. Lofexidine prolongs the QT interval. In addition, there are postmarketing reports of torsade de pointes. Supratherapeutic doses of rilpivirine (75 to 300 mg/day) have caused QT prolongation; caution is advised when administering rilpivirine with other drugs that may prolong the QT or PR interval.
Emtricitabine; Rilpivirine; Tenofovir Disoproxil Fumarate: (Major) Monitor ECG if lofexidine is coadministered with rilpivirine due to the potential for additive QT prolongation. Lofexidine prolongs the QT interval. In addition, there are postmarketing reports of torsade de pointes. Supratherapeutic doses of rilpivirine (75 to 300 mg/day) have caused QT prolongation; caution is advised when administering rilpivirine with other drugs that may prolong the QT or PR interval.
Enasidenib: (Moderate) Monitor for orthostatic hypotension and bradycardia during concurrent use of lofexidine and enasidenib. Coadministration may increase lofexidine exposure. Lofexidine is a CYP2D6 substrate; enasidenib is a CYP2D6 inhibitor. Coadministration with a strong CYP2D6 inhibitor increased the lofexidine AUC by 28%.
Encorafenib: (Major) Avoid coadministration of encorafenib and lofexidine due to QT prolongation. If concurrent use cannot be avoided, monitor ECGs for QT prolongation and monitor electrolytes; correct hypokalemia and hypomagnesemia prior to treatment. Encorafenib is associated with dose-dependent prolongation of the QT interval. Lofexidine has also been associated with QT prolongation.
Entacapone: (Major) Monitor for excessive hypotension and sedation during coadministration of lofexidine and entacapone. Lofexidine can potentiate the effects of CNS depressants.
Entrectinib: (Major) Avoid coadministration of entrectinib with lofexidine due to the risk of QT prolongation. If coadministration cannot be avoided, ECG monitoring is recommended. Entrectinib has been associated with QT prolongation. Lofexidine also prolongs the QT interval.
Eribulin: (Major) Monitor ECG if lofexidine is coadministered with eribulin due to the potential for additive QT prolongation. Lofexidine prolongs the QT interval. In addition, there are postmarketing reports of torsade de pointes. Eribulin has been associated with QT prolongation.
Erythromycin: (Major) Concomitant use of lofexidine and erythromycin increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary.
Escitalopram: (Moderate) Concomitant use of escitalopram and lofexidine may increase the risk of QT/QTc prolongation and torsade de pointes (TdP) in some patients. Consider taking steps to minimize the risk of QT/QTc interval prolongation and TdP, such as avoidance, electrolyte monitoring and repletion, and ECG monitoring, especially in patients with additional risk factors for TdP.
Esketamine: (Moderate) Closely monitor patients receiving esketamine and lofexidine for sedation and other CNS depressant effects. Instruct patients who receive a dose of esketamine not to drive or engage in other activities requiring alertness until the next day after a restful sleep.
Estazolam: (Moderate) Monitor for excessive hypotension and sedation during coadministration of lofexidine and benzodiazepines. Lofexidine can potentiate the effects of CNS depressants such as benzodiazepines.
Eszopiclone: (Moderate) Monitor for additive sedation during coadministration of lofexidine and anxiolytics, sedatives, and hypnotics. Lofexidine can potentiate the effects of CNS depressants. Patients should be advised to avoid driving or performing any other tasks requiring mental alertness until the effects of the combination are known.
Ethanol: (Major) Advise patients to avoid alcohol consumption while taking CNS depressants. Alcohol consumption may result in additive CNS depression. (Moderate) Monitor for excessive hypotension and sedation if lofexidine and alcohol are use concomitantly. Lofexidine can potentiate the effects of CNS depressants such as alcohol.
Etomidate: (Moderate) Monitor for additive hypotension, bradycardia, and sedation during coadministration of lofexidine and etomidate. Patients should be advised to avoid driving or performing any other tasks requiring mental alertness until the effects of the combination are known.
Etrasimod: (Major) Concomitant use of etrasimod and lofexidine increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary. Etrasimod has a limited effect on the QT/QTc interval at therapeutic doses but may cause bradycardia and atrioventricular conduction delays which may increase the risk for TdP in patients with a prolonged QT/QTc interval.
Everolimus: (Moderate) Monitor for orthostatic hypotension and bradycardia during concurrent use of lofexidine and everolimus. Coadministration may increase lofexidine exposure. Lofexidine is a CYP2D6 substrate; everolimus is a CYP2D6 inhibitor. Coadministration with a strong CYP2D6 inhibitor increased the lofexidine AUC by 28%.
Fedratinib: (Moderate) Monitor for orthostatic hypotension and bradycardia during concurrent use of lofexidine and fedratinib. Coadministration may increase lofexidine exposure. Lofexidine is a CYP2D6 substrate; fedratinib is a CYP2D6 inhibitor. Coadministration with a strong CYP2D6 inhibitor increased the lofexidine AUC by 28%.
Fenfluramine: (Moderate) Monitor for excessive sedation and somnolence during coadministration of fenfluramine and lofexidine. Concurrent use may result in additive CNS depression.
Fenoldopam: (Major) Because the central alpha-2 agonist effects of lofexidine can cause hypotension and orthostasis, the drug should be avoided, if possible, in combination with other medications that can decrease blood pressure such as systemic vasodilators. If coadministration is required, blood pressure should be monitored, particularly after dose changes of either agent. Adjustments should be made as clinically indicated.
Fentanyl: (Moderate) Monitor for excessive hypotension and sedation during coadministration of lofexidine and fentanyl. Lofexidine can potentiate the effects of CNS depressants.
Fexinidazole: (Major) Concomitant use of fexinidazole and lofexidine increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary.
Fingolimod: (Major) Monitor ECG continuously overnight in a medical facility after the first fingolimod dose if lofexidine is coadministered due to the potential for additive QT prolongation. Lofexidine prolongs the QT interval. In addition, there are postmarketing reports of torsade de pointes. Fingolimod initiation results in decreased heart rate and may prolong the QT interval. Fingolimod has not been studied in patients treated with drugs that prolong the QT interval, but drugs that prolong the QT interval have been associated with cases of TdP in patients with bradycardia.
Flecainide: (Major) Monitor ECG if lofexidine is coadministered with flecainide due to the potential for additive QT prolongation and torsade de pointes (TdP). Lofexidine prolongs the QT interval. In addition, there are postmarketing reports of TdP. Flecainide is a Class IC antiarrhythmic associated with a possible risk for QT prolongation and/or TdP; flecainide increases the QT interval, but largely due to prolongation of the QRS interval. Although causality for TdP has not been established for flecainide, patients receiving concurrent drugs that have the potential for QT prolongation may have an increased risk of developing proarrhythmias.
Flibanserin: (Major) Monitor for excessive hypotension and sedation during coadministration of lofexidine and flibanserin. Lofexidine can potentiate the effects of CNS depressants.
Fluconazole: (Major) Concomitant use of lofexidine and fluconazole increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary.
Fluoxetine: (Major) Monitor ECG for QT prolongation and monitor for orthostatic hypotension and bradycardia during concurrent use of lofexidine and fluoxetine. Coadministration may increase lofexidine exposure. Lofexidine is a CYP2D6 substrate that prolongs the QT interval. In addition, there are postmarketing reports of TdP. Fluoxetine is a CYP2D6 inhibitor associated with an established risk of QT prolongation and TdP. Coadministration with a strong CYP2D6 inhibitor increased the lofexidine AUC by 28%.
Fluphenazine: (Moderate) Monitor ECG for QT prolongation and monitor for additive sedation during concurrent use of lofexidine and fluphenazine. Lofexidine may prolong the QT interval, and torsade de pointes (TdP) has been reported during postmarketing use. Fluphenazine is associated with a possible risk for QT prolongation. Lofexidine may potentiate the effects of CNS depressants, including fluphenazine.
Flurazepam: (Moderate) Monitor for excessive hypotension and sedation during coadministration of lofexidine and benzodiazepines. Lofexidine can potentiate the effects of CNS depressants such as benzodiazepines.
Fluvoxamine: (Moderate) Monitor ECG if lofexidine is coadministered with fluvoxamine due to the potential for additive QT prolongation and torsade de pointes (TdP). Lofexidine prolongs the QT interval. In addition, there are postmarketing reports of TdP. QT prolongation and TdP have been reported during fluvoxamine postmarketing use.
Food: (Major) Advise patients to avoid cannabis use while taking CNS depressants due to the risk for additive CNS depression and potential for other cognitive adverse reactions.
Foscarnet: (Major) Avoid coadministration of lofexidine and foscarnet due to the potential for additive QT prolongation and torsade de pointes (TdP). Monitor ECG if coadministration unavoidable. Lofexidine prolongs the QT interval. In addition, there are postmarketing reports of TdP. Both QT prolongation and TdP have been reported during postmarketing use of foscarnet.
Fostemsavir: (Major) ECG monitoring is recommended if lofexidine is coadministered with fostemsavir due to the potential for additive QT prolongation. Lofexidine prolongs the QT interval. Supratherapeutic doses of fostemsavir (2,400 mg twice daily, four times the recommended daily dose) have been shown to cause QT prolongation. Fostemsavir causes dose-dependent QT prolongation.
Gabapentin: (Moderate) Monitor for excessive sedation and somnolence during coadministration of lofexidine and gabapentin. Concurrent use may result in additive CNS depression.
Gemifloxacin: (Major) Monitor ECG if lofexidine is coadministered with gemifloxacin due to the potential for additive QT prolongation. Lofexidine prolongs the QT interval. In addition, there are postmarketing reports of torsade de pointes. Gemifloxacin may prolong the QT interval in some patients. The maximal change in the QTc interval occurs approximately 5 to 10 hours following oral administration of gemifloxacin. The likelihood of QTc prolongation may increase with increasing dose of the drug; therefore, the recommended dose should not be exceeded especially in patients with renal or hepatic impairment where the Cmax and AUC are slightly higher.
Gemtuzumab Ozogamicin: (Moderate) Monitor ECG and electrolytes if lofexidine is coadministered with gemtuzumab due to the potential for additive QT prolongation. Lofexidine prolongs the QT interval. In addition, there are postmarketing reports of torsade de pointes. Although QT interval prolongation has not been reported with gemtuzumab, it has been reported with other drugs that contain calicheamicin.
Gilteritinib: (Major) Use caution and monitor for additive QT prolongation if concurrent use of gilteritinib and lofexidine is necessary. Monitor ECG. Both drugs have been associated with QT prolongation.
Glasdegib: (Major) Avoid coadministration of glasdegib with lofexidine due to the potential for additive QT prolongation. If coadministration cannot be avoided, monitor patients for increased risk of QT prolongation with increased frequency of ECG monitoring. Glasdegib therapy may result in QT prolongation and ventricular arrhythmias including ventricular fibrillation and ventricular tachycardia. Lofexidine also prolongs the QT interval.
Goserelin: (Moderate) Monitor ECGs for QT prolongation if coadministration of lofexidine with goserelin is necessary. Lofexidine prolongs the QT interval. Androgen deprivation therapy (i.e., goserelin) may also prolong the QT/QTc interval.
Granisetron: (Major) Monitor ECG if lofexidine is coadministered with granisetron due to the potential for additive QT prolongation. Lofexidine prolongs the QT interval. In addition, there are postmarketing reports of torsade de pointes. Granisetron has been associated with QT prolongation.
Guanfacine: (Major) Lofexidine is a central alpha-2 adrenergic agonist, and its effects can be additive to other medications in the same class. Monitor for excessive hypotension, bradycardia, and sedation during coadministration. 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.
Halogenated Anesthetics: (Major) Monitor ECG if lofexidine is coadministered with halogenated anesthetics due to the potential for additive QT prolongation. Lofexidine prolongs the QT interval. In addition, there are postmarketing reports of torsade de pointes. Halogenated anesthetics can prolong the QT interval. Additionally, monitor for excessive hypotension and sedation during coadministration as lofexidine can potentiate the effects of CNS depressants.
Haloperidol: (Major) Monitor ECG for QT prolongation during concurrent use of lofexidine and haloperidol. Lofexidine may prolong the QT interval, torsade de pointes (TdP) has been reported during postmarketing use. Haloperidol is associated with an established risk of QT prolongation and TdP. Excessive doses (particularly in the overdose setting) or IV administration of haloperidol may be associated with a higher risk of QT prolongation.
Histrelin: (Moderate) Monitor ECGs for QT prolongation if coadministration of lofexidine with histrelin is necessary. Lofexidine prolongs the QT interval. Androgen deprivation therapy (i.e., histrelin) may also prolong the QT/QTc interval.
Homatropine; Hydrocodone: (Moderate) Monitor for excessive hypotension and sedation during coadministration of lofexidine and hydrocodone. Lofexidine can potentiate the effects of CNS depressants.
Hydralazine: (Major) Because the central alpha-2 agonist effects of lofexidine can cause hypotension and orthostasis, the drug should be avoided, if possible, in combination with other medications that can decrease blood pressure such as systemic vasodilators. If coadministration is required, blood pressure should be monitored, particularly after dose changes of either agent. Adjustments should be made as clinically indicated.
Hydralazine; Isosorbide Dinitrate, ISDN: (Major) Because the central alpha-2 agonist effects of lofexidine can cause hypotension and orthostasis, the drug should be avoided, if possible, in combination with other medications that can decrease blood pressure such as systemic vasodilators. If coadministration is required, blood pressure should be monitored, particularly after dose changes of either agent. Adjustments should be made as clinically indicated.
Hydrocodone: (Moderate) Monitor for excessive hypotension and sedation during coadministration of lofexidine and hydrocodone. Lofexidine can potentiate the effects of CNS depressants.
Hydrocodone; Ibuprofen: (Moderate) Monitor for excessive hypotension and sedation during coadministration of lofexidine and hydrocodone. Lofexidine can potentiate the effects of CNS depressants.
Hydromorphone: (Moderate) Monitor for excessive hypotension and sedation during coadministration of lofexidine and hydromorphone. Lofexidine can potentiate the effects of CNS depressants.
Hydroxychloroquine: (Major) Concomitant use of lofexidine and hydroxychloroquine increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary.
Hydroxyzine: (Major) Monitor ECG if lofexidine is coadministered with hydroxyzine due to the potential for additive QT prolongation and torsade de pointes (TdP). Additionally, monitor for excessive hypotension and sedation during coadministration as lofexidine can potentiate the effects of CNS depressants. Lofexidine prolongs the QT interval. In addition, there are postmarketing reports of TdP. Postmarketing data indicate that hydroxyzine causes QT prolongation and TdP.
Ibuprofen; Oxycodone: (Moderate) Monitor for excessive hypotension and sedation during coadministration of lofexidine and oxycodone. Lofexidine can potentiate the effects of CNS depressants.
Ibutilide: (Major) Monitor ECG if lofexidine is coadministered with ibutilide due to the potential for additive QT prolongation and torsade de pointes (TdP). Lofexidine prolongs the QT interval. In addition, there are postmarketing reports of TdP. Ibutilide administration can cause QT prolongation and TdP; proarrhythmic events should be anticipated. The potential for proarrhythmic events with ibutilide increases with the coadministration of other drugs that prolong the QT interval.
Iloperidone: (Major) Avoid coadministration of lofexidine and iloperidone due to the potential for additive QT prolongation. Monitor ECG if coadministration cannot be avoided. Additionally, monitor for excessive hypotension and sedation during coadministration as lofexidine can potentiate the effects of CNS depressants. Lofexidine prolongs the QT interval. In addition, there are postmarketing reports of torsade de pointes. Iloperidone has been associated with QT prolongation.
Imipramine: (Moderate) Monitor for excessive hypotension and sedation during coadministration of lofexidine and tricyclic antidepressants. Lofexidine can potentiate the effects of CNS depressants. Additionally, monitor ECG during coadministration due to the potential risk for additive QT prolongation. Lofexidine prolongs the QT interval. In addition, there are postmarketing reports of torsade de pointes. Tricyclic antidepressants (TCAs) share pharmacologic properties similar to the Class IA antiarrhythmic agents and may prolong the QT interval, particularly in overdose or with higher-dose prescription therapy (elevated serum concentrations).
Indinavir: (Moderate) Monitor for orthostatic hypotension and bradycardia during concurrent use of lofexidine and indinavir. Coadministration may increase lofexidine exposure. Lofexidine is a CYP2D6 substrate; indinavir is a CYP2D6 inhibitor. Coadministration with a strong CYP2D6 inhibitor increased the lofexidine AUC by 28%.
Inotuzumab Ozogamicin: (Major) Avoid coadministration of lofexidine and inotuzumab due to the potential for additive QT prolongation. If coadministration is unavoidable, obtain ECGs prior to the start of treatment and periodically during treatment. Lofexidine prolongs the QT interval. In addition, there are postmarketing reports of torsade de pointes. Inotuzumab has been associated with QT interval prolongation.
Isoflurane: (Major) Monitor ECG if lofexidine is coadministered with halogenated anesthetics due to the potential for additive QT prolongation. Lofexidine prolongs the QT interval. In addition, there are postmarketing reports of torsade de pointes. Halogenated anesthetics can prolong the QT interval. Additionally, monitor for excessive hypotension and sedation during coadministration as lofexidine can potentiate the effects of CNS depressants.
Itraconazole: (Major) Monitor ECG if lofexidine is coadministered with itraconazole due to the potential for additive QT prolongation. Lofexidine prolongs the QT interval. In addition, there are postmarketing reports of torsade de pointes. Itraconazole has been associated with prolongation of the QT interval.
Ivosidenib: (Major) Avoid coadministration of ivosidenib with lofexidine due to an increased risk of QT prolongation. If concomitant use is unavoidable, monitor ECGs for QTc prolongation and monitor electrolytes; correct any electrolyte abnormalities as clinically appropriate. An interruption of therapy and dose reduction of ivosidenib may be necessary if QT prolongation occurs. Prolongation of the QTc interval and ventricular arrhythmias have been reported in patients treated with ivosidenib. Lofexidine prolongs the QT interval.
Ketamine: (Moderate) Monitor for excessive hypotension and sedation during coadministration of lofexidine and ketamine. Lofexidine can potentiate the effects of CNS depressants.
Ketoconazole: (Contraindicated) Avoid concomitant use of ketoconazole and lofexidine due to an increased risk for torsade de pointes (TdP) and QT/QTc prolongation.
Labetalol: (Major) Because both lofexidine and labetalol can cause hypotension and bradycardia, concurrent use should be avoided if possible. 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.
Lansoprazole; Amoxicillin; Clarithromycin: (Major) Monitor ECG if lofexidine is coadministered with clarithromycin due to the potential for additive QT prolongation and torsade de pointes (TdP). Lofexidine prolongs the QT interval. In addition, there are postmarketing reports of TdP. Clarithromycin is associated with an established risk for QT prolongation and TdP.
Lapatinib: (Major) Monitor ECGs for QT prolongation and monitor electrolytes if coadministration of lapatinib with lofexidine is necessary; correct electrolyte abnormalities prior to treatment. Lofexidine prolongs the QT interval. Lapatinib has also been associated with concentration-dependent QT prolongation; ventricular arrhythmias and torsade de pointes (TdP) have been reported in postmarketing experience with lapatinib.
Lasmiditan: (Moderate) Monitor for excessive sedation and somnolence during coadministration of lasmiditan and lofexidine. Concurrent use may result in additive CNS depression.
Lefamulin: (Major) Avoid coadministration of lefamulin with lofexidine as concurrent use may increase the risk of QT prolongation. If coadministration cannot be avoided, monitor ECG during treatment. Lefamulin has a concentration dependent QTc prolongation effect. The pharmacodynamic interaction potential to prolong the QT interval of the electrocardiogram between lefamulin and other drugs that effect cardiac conduction is unknown. Lofexidine also prolongs the QT interval.
Lemborexant: (Moderate) Monitor for excessive sedation and somnolence during coadministration of lemborexant and lofexidine. Dosage adjustments of lemborexant and lofexidine may be necessary when administered together because of potentially additive CNS effects. The risk of next-day impairment, including impaired driving, is increased if lemborexant is taken with other CNS depressants.
Lenvatinib: (Major) Concomitant use of lofexidine and lenvatinib increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary.
Leuprolide: (Moderate) Monitor ECGs for QT prolongation if coadministration of lofexidine with leuprolide is necessary. Lofexidine prolongs the QT interval. Androgen deprivation therapy (i.e., leuprolide) may also prolong the QT/QTc interval.
Leuprolide; Norethindrone: (Moderate) Monitor ECGs for QT prolongation if coadministration of lofexidine with leuprolide is necessary. Lofexidine prolongs the QT interval. Androgen deprivation therapy (i.e., leuprolide) may also prolong the QT/QTc interval.
Levocetirizine: (Moderate) Concurrent use of cetirizine/levocetirizine with lofexidine should generally be avoided. Coadministration may increase the risk of CNS depressant-related side effects. If concurrent use is necessary, monitor for excessive sedation and somnolence.
Levofloxacin: (Major) Concomitant use of levofloxacin and lofexidine increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary.
Levoketoconazole: (Contraindicated) Avoid concomitant use of ketoconazole and lofexidine due to an increased risk for torsade de pointes (TdP) and QT/QTc prolongation.
Levorphanol: (Moderate) Monitor for excessive hypotension and sedation during coadministration of lofexidine and levorphanol. Lofexidine can potentiate the effects of CNS depressants.
Lithium: (Moderate) Monitor ECG if lofexidine is coadministered with lithium due to the potential for additive QT prolongation. Lofexidine prolongs the QT interval. In addition, there are postmarketing reports of torsade de pointes. Lithium has been associated with QT prolongation.
Loperamide: (Moderate) Monitor ECG if lofexidine is coadministered with loperamide due to the potential for additive QT prolongation and torsade de pointes (TdP). Lofexidine prolongs the QT interval. In addition, there are postmarketing reports of TdP. At high doses, loperamide has been associated with serious cardiac toxicities, including syncope, ventricular tachycardia, QT prolongation, TdP, and cardiac arrest.
Loperamide; Simethicone: (Moderate) Monitor ECG if lofexidine is coadministered with loperamide due to the potential for additive QT prolongation and torsade de pointes (TdP). Lofexidine prolongs the QT interval. In addition, there are postmarketing reports of TdP. At high doses, loperamide has been associated with serious cardiac toxicities, including syncope, ventricular tachycardia, QT prolongation, TdP, and cardiac arrest.
Lopinavir; Ritonavir: (Major) Avoid coadministration of lopinavir with lofexidine due to the potential for additive QT prolongation. If use together is necessary, obtain a baseline ECG to assess initial QT interval and determine frequency of subsequent ECG monitoring, avoid any non-essential QT prolonging drugs, and correct electrolyte imbalances. Both drugs have been associated with QT prolongation.
Lorazepam: (Moderate) Monitor for excessive hypotension and sedation during coadministration of lofexidine and benzodiazepines. Lofexidine can potentiate the effects of CNS depressants such as benzodiazepines.
Loxapine: (Major) Monitor for excessive hypotension and sedation during coadministration of lofexidine and loxapine. Lofexidine can potentiate the effects of CNS depressants.
Lumateperone: (Moderate) Monitor for excessive sedation and somnolence during coadministration of lumateperone and lofexidine. Concurrent use may result in additive CNS depression.
Lurasidone: (Major) Monitor for excessive hypotension and sedation during coadministration of lofexidine and lurasidone. Lofexidine can potentiate the effects of CNS depressants.
Macimorelin: (Major) Avoid concurrent administration of macimorelin with drugs that prolong the QT interval, such as lofexidine. Use of these drugs together may increase the risk of developing torsade de pointes-type ventricular tachycardia. Sufficient washout time of drugs that are known to prolong the QT interval prior to administration of macimorelin is recommended. Treatment with macimorelin has been associated with an increase in the corrected QT (QTc) interval. Lofexidine prolongs the QT interval.
Maprotiline: (Major) Monitor the ECG if lofexidine is coadministered with maprotiline due to the potential for additive QT prolongation and torsade de pointes (TdP). Lofexidine may prolong the QT interval, and TdP has been reported during postmarketing use. Maprotiline has been reported to prolong the QT interval, particularly in overdose or with higher-dose prescription therapy (elevated serum concentrations). Cases of long QT syndrome and TdP tachycardia have been described with maprotiline use, but rarely occur when the drug is used alone in normal prescribed doses and in the absence of other known risk factors for QT prolongation. Limited data are available regarding the safety of maprotiline in combination with other QT-prolonging drugs.
Meclizine: (Moderate) Monitor for excessive hypotension and sedation during coadministration of lofexidine and meclizine. Lofexidine can potentiate the effects of CNS depressants.
Mefloquine: (Major) Monitor ECG if lofexidine is coadministered with mefloquine due to the potential for additive QT prolongation. Lofexidine prolongs the QT interval. In addition, there are postmarketing reports of torsade de pointes. There is evidence that the use of halofantrine after mefloquine causes a significant lengthening of the QTc interval. Mefloquine alone has not been reported to cause QT prolongation. However, due to the lack of clinical data, mefloquine should be used with caution in patients receiving drugs that prolong the QT interval.
Melatonin: (Moderate) Monitor for additive sedation during coadministration of lofexidine and melatonin. Lofexidine can potentiate the effects of CNS depressants. Patients should be advised to avoid driving or performing any other tasks requiring mental alertness until the effects of the combination are known.
Meperidine: (Moderate) Monitor for excessive hypotension and sedation during coadministration of lofexidine and meperidine. Lofexidine can potentiate the effects of CNS depressants.
Meprobamate: (Moderate) Monitor for additive sedation during coadministration of lofexidine and anxiolytics, sedatives, and hypnotics. Lofexidine can potentiate the effects of CNS depressants. Patients should be advised to avoid driving or performing any other tasks requiring mental alertness until the effects of the combination are known.
Metaxalone: (Moderate) Monitor for additive sedation during coadministration of lofexidine and metaxalone. Lofexidine can potentiate the effects of CNS depressants. Patients should be advised to avoid driving or performing any other tasks requiring mental alertness until the effects of the combination are known.
Methadone: (Major) Monitor ECG if lofexidine is coadministered with methadone due to the potential for additive QT prolongation and torsade de pointes (TdP). Additionally, monitor for excessive hypotension and sedation during coadministration as lofexidine can potentiate the effects of CNS depressants. Lofexidine prolongs the QT interval. In addition, there are postmarketing reports of TdP. Methadone is considered to be associated with an increased risk for QT prolongation and TdP, especially at higher doses (more than 200 mg/day but averaging approximately 400 mg/day in adult patients). Most cases involve patients being treated for pain with large, multiple daily doses of methadone, although cases have been reported in patients receiving doses commonly used for maintenance treatment of opioid addiction. In electrophysiology studies, lofexidine (2.88 mg/day) coadministered with methadone (80 to 120 mg/day) resulted in a maximum mean QTcF increase of 9.1 (14.2) msec from methadone-alone baseline.
Methocarbamol: (Moderate) Monitor for additive hypotension, bradycardia, and sedation during coadministration of lofexidine and methocarbamol. Lofexidine can potentiate the effects of CNS depressants. Patients should be advised to avoid driving or performing any other tasks requiring mental alertness until the effects of the combination are known.
Methohexital: (Moderate) Monitor for additive sedation during coadministration of lofexidine and barbiturates. Lofexidine can potentiate the effects of CNS depressants such as barbiturates. Patients should be advised to avoid driving or performing any other tasks requiring mental alertness until the effects of the combination are known. The use of barbiturates parenterally may cause vasodilation and an additive risk for hypotension and may lead to bradycardia and syncope; in these patients, careful monitoring of blood pressure should occur.
Methyldopa: (Major) Lofexidine is a central alpha-2 adrenergic agonist, and its effects can be additive to other medications in the same class. Monitor for excessive hypotension, bradycardia, and sedation during coadministration. 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.
Metoprolol: (Major) Because both lofexidine and metoprolol can cause hypotension and bradycardia, concurrent use should be avoided if possible. 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.
Metoprolol; Hydrochlorothiazide, HCTZ: (Major) Because both lofexidine and metoprolol can cause hypotension and bradycardia, concurrent use should be avoided if possible. 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.
Metronidazole: (Major) Concomitant use of metronidazole and lofexidine increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary.
Midazolam: (Moderate) Monitor for excessive hypotension and sedation during coadministration of lofexidine and benzodiazepines. Lofexidine can potentiate the effects of CNS depressants such as benzodiazepines.
Midostaurin: (Major) Monitor ECG if lofexidine is coadministered with midostaurin due to the potential for additive QT prolongation. Lofexidine prolongs the QT interval. In addition, there are postmarketing reports of torsade de pointes. QT prolongation was reported in patients who received midostaurin in clinical trials.
Mifepristone: (Moderate) Concomitant use of mifepristone and lofexidine may increase the risk of QT/QTc prolongation and torsade de pointes (TdP) in some patients. Consider taking steps to minimize the risk of QT/QTc interval prolongation and TdP, such as avoidance, electrolyte monitoring and repletion, and ECG monitoring, especially in patients with additional risk factors for TdP.
Minoxidil: (Major) Because the central alpha-2 agonist effects of lofexidine can cause hypotension and orthostasis, the drug should be avoided, if possible, in combination with other medications that can decrease blood pressure such as systemic vasodilators. If coadministration is required, blood pressure should be monitored, particularly after dose changes of either agent. Adjustments should be made as clinically indicated.
Mirtazapine: (Moderate) Monitor ECG if lofexidine is coadministered with mirtazapine due to the potential for additive QT prolongation and torsade de pointes (TdP). Additionally, monitor for excessive hypotension and sedation during coadministration as lofexidine can potentiate the effects of CNS depressants. Lofexidine prolongs the QT interval. In addition, there are postmarketing reports of TdP. Mirtazapine has been associated with dose-dependent prolongation of the QT interval. TdP has been reported postmarketing, primarily in overdose or in patients with other risk factors for QT prolongation.
Mobocertinib: (Major) Concomitant use of mobocertinib and lofexidine increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary.
Molindone: (Major) Monitor for excessive hypotension and sedation during coadministration of lofexidine and molindone. Lofexidine can potentiate the effects of CNS depressants.
Morphine: (Moderate) Monitor for excessive hypotension and sedation during coadministration of lofexidine and morphine. Lofexidine can potentiate the effects of CNS depressants.
Morphine; Naltrexone: (Moderate) Monitor for excessive hypotension and sedation during coadministration of lofexidine and morphine. Lofexidine can potentiate the effects of CNS depressants.
Moxifloxacin: (Major) Monitor ECG if lofexidine is coadministered with moxifloxacin due to the potential for additive QT prolongation and torsade de pointes (TdP). Lofexidine prolongs the QT interval. In addition, there are postmarketing reports of TdP. Moxifloxacin has been associated with prolongation of the QT interval. Additionally, rare cases of TdP have been spontaneously reported with moxifloxacin during postmarketing surveillance. These reports generally involved patients with concurrent medical conditions or concomitant medications that may have been contributory.
Nabilone: (Moderate) Monitor for excessive sedation and somnolence during coadministration of nabilone and lofexidine. Concurrent use may result in additive CNS depression.
Nadolol: (Major) Because both lofexidine and nadolol can cause hypotension and bradycardia, concurrent use should be avoided if possible. 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.
Nalbuphine: (Moderate) Monitor for excessive hypotension and sedation during coadministration of lofexidine and nalbuphine. Lofexidine can potentiate the effects of CNS depressants.
Naltrexone: (Major) Separate administration of lofexidine and oral naltrexone by 2 hours as simultaneous administration may reduce the efficacy of naltrexone. Coadministration of lofexidine and oral naltrexone resulted in statistically significant differences in the steady state pharmacokinetics of naltrexone. This interaction is not expected if naltrexone is administered by non-oral routes.
Nebivolol: (Major) Because both lofexidine and nebivolol can cause hypotension and bradycardia, concurrent use should be avoided if possible. 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.
Nebivolol; Valsartan: (Major) Because both lofexidine and nebivolol can cause hypotension and bradycardia, concurrent use should be avoided if possible. 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.
Nefazodone: (Major) Monitor for excessive hypotension and sedation during coadministration of lofexidine and nefazodone. Lofexidine can potentiate the effects of CNS depressants.
Nilotinib: (Major) Avoid the concomitant use of nilotinib and lofexidine; significant prolongation of the QT interval may occur. Sudden death and QT prolongation have been reported in patients who received nilotinib therapy. Lofexidine prolongs the QT interval. In addition, there are postmarketing reports of torsade de pointes.
Nitroprusside: (Major) Because the central alpha-2 agonist effects of lofexidine can cause hypotension and orthostasis, the drug should be avoided, if possible, in combination with other medications that can decrease blood pressure such as systemic vasodilators. If coadministration is required, blood pressure should be monitored, particularly after dose changes of either agent. Adjustments should be made as clinically indicated.
Nortriptyline: (Moderate) Monitor for excessive hypotension and sedation during coadministration of lofexidine and tricyclic antidepressants. Lofexidine can potentiate the effects of CNS depressants. Additionally, monitor ECG during coadministration due to the potential risk for additive QT prolongation. Lofexidine prolongs the QT interval. In addition, there are postmarketing reports of torsade de pointes. Tricyclic antidepressants (TCAs) share pharmacologic properties similar to the Class IA antiarrhythmic agents and may prolong the QT interval, particularly in overdose or with higher-dose prescription therapy (elevated serum concentrations).
Ofloxacin: (Major) Concomitant use of ofloxacin and lofexidine increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary.
Olanzapine: (Moderate) Monitor ECG if lofexidine is coadministered with olanzapine due to the potential for additive QT prolongation. Additionally, monitor for excessive hypotension and sedation during coadministration as lofexidine can potentiate the effects of CNS depressants. Lofexidine prolongs the QT interval. In addition, there are postmarketing reports of torsade de pointes. Limited data, including some case reports, suggest that olanzapine may be associated with a significant prolongation of the QTc interval.
Olanzapine; Fluoxetine: (Major) Monitor ECG for QT prolongation and monitor for orthostatic hypotension and bradycardia during concurrent use of lofexidine and fluoxetine. Coadministration may increase lofexidine exposure. Lofexidine is a CYP2D6 substrate that prolongs the QT interval. In addition, there are postmarketing reports of TdP. Fluoxetine is a CYP2D6 inhibitor associated with an established risk of QT prolongation and TdP. Coadministration with a strong CYP2D6 inhibitor increased the lofexidine AUC by 28%. (Moderate) Monitor ECG if lofexidine is coadministered with olanzapine due to the potential for additive QT prolongation. Additionally, monitor for excessive hypotension and sedation during coadministration as lofexidine can potentiate the effects of CNS depressants. Lofexidine prolongs the QT interval. In addition, there are postmarketing reports of torsade de pointes. Limited data, including some case reports, suggest that olanzapine may be associated with a significant prolongation of the QTc interval.
Olanzapine; Samidorphan: (Moderate) Monitor ECG if lofexidine is coadministered with olanzapine due to the potential for additive QT prolongation. Additionally, monitor for excessive hypotension and sedation during coadministration as lofexidine can potentiate the effects of CNS depressants. Lofexidine prolongs the QT interval. In addition, there are postmarketing reports of torsade de pointes. Limited data, including some case reports, suggest that olanzapine may be associated with a significant prolongation of the QTc interval.
Oliceridine: (Moderate) Concomitant use of oliceridine with lofexidine may cause excessive sedation and somnolence. Limit the use of oliceridine with lofexidine to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect.
Ondansetron: (Major) Concomitant use of ondansetron and lofexidine increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary. Do not exceed 16 mg of IV ondansetron in a single dose; the degree of QT prolongation associated with ondansetron significantly increases above this dose.
Opicapone: (Moderate) Opicapone should be given cautiously with other agents that cause CNS depression, including lofexidine, due to the possibility of additive sedation. COMT inhibitors, such as opicapone, have also been associated with sudden sleep onset during activities of daily living such as driving, which has resulted in accidents in some cases. Prescribers should re-assess patients for drowsiness or sleepiness regularly throughout treatment, especially since events may occur well after the start of treatment. Patients should be advised to avoid driving or other tasks requiring mental alertness until they know how the combination affects them.
Orphenadrine: (Major) Monitor for excessive hypotension and sedation during coadministration of lofexidine and orphenadrine. Lofexidine can potentiate the effects of CNS depressants.
Osilodrostat: (Moderate) Monitor ECG for QT prolongation and monitor for orthostatic hypotension and bradycardia during concurrent use of lofexidine and osilodrostat. Coadministration may increase lofexidine exposure. Lofexidine is a CYP2D6 substrate that prolongs the QT interval; there are also postmarketing reports of torsade de pointes. Osilodrostat is a CYP2D6 inhibitor that is associated with dose-dependent QT prolongation. Coadministration with a strong CYP2D6 inhibitor increased the lofexidine AUC by 28%.
Osimertinib: (Major) Avoid coadministration of lofexidine with osimertinib if possible due to the risk of QT prolongation and torsade de pointes (TdP). If concomitant use is unavoidable, periodically monitor ECGs for QT prolongation and monitor electrolytes; an interruption of osimertinib therapy with dose reduction or discontinuation may be necessary if QT prolongation occurs. Lofexidine prolongs the QT interval. In addition, there are postmarketing reports of torsade de pointes. Concentration-dependent QTc prolongation occurred during clinical trials of osimertinib.
Oxaliplatin: (Major) Monitor ECG and electrolytes if lofexidine is coadministered with oxaliplatin due to the potential for additive QT prolongation and torsade de pointes (TdP). Correct electrolyte abnormalities prior to administration of oxaliplatin. Lofexidine prolongs the QT interval. In addition, there are postmarketing reports of TdP. QT prolongation and ventricular arrhythmias including fatal TdP have been reported with oxaliplatin use in postmarketing experience.
Oxazepam: (Moderate) Monitor for excessive hypotension and sedation during coadministration of lofexidine and benzodiazepines. Lofexidine can potentiate the effects of CNS depressants such as benzodiazepines.
Oxycodone: (Moderate) Monitor for excessive hypotension and sedation during coadministration of lofexidine and oxycodone. Lofexidine can potentiate the effects of CNS depressants.
Oxymorphone: (Moderate) Monitor for excessive hypotension and sedation during coadministration of lofexidine and oxymorphone. Lofexidine can potentiate the effects of CNS depressants.
Ozanimod: (Major) In general, do not initiate ozanimod in patients taking lofexidine due to the risk of additive bradycardia, QT prolongation, and torsade de pointes (TdP). If concomitant use is necessary, monitor ECGs. Ozanimod initiation may result in a transient decrease in heart rate and atrioventricular conduction delays. Ozanimod has not been studied in patients taking concurrent QT prolonging drugs; however, QT prolonging drugs have been associated with TdP in patients with bradycardia. Lofexidine has been associated with QT prolongation.
Pacritinib: (Major) Concomitant use of pacritinib and lofexidine increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary.
Paliperidone: (Major) Avoid coadministration of lofexidine and paliperidone due to the potential for additive QT prolongation. Monitor ECG if coadministration is necessary. Additionally, monitor for excessive hypotension and sedation during coadministration since lofexidine can potentiate the effects of CNS depressants. Lofexidine prolongs the QT interval; there are postmarketing reports of torsade de pointes (TdP). Paliperidone has been associated with QT prolongation; TdP and ventricular fibrillation have been reported in the setting of overdose.
Panobinostat: (Major) Coadministration of lofexidine and panobinostat is not recommended due to the potential for additive QT prolongation. Monitor the ECG for QT prolongation if coadministration is required. Lofexidine may prolong the QT interval, and torsade de pointes (TdP) has been reported during postmarketing use. Panobinostat can cause QT prolongation.
Paroxetine: (Moderate) Monitor for orthostatic hypotension and bradycardia during concurrent use of lofexidine and paroxetine. Coadministration may increase lofexidine exposure. Lofexidine is a CYP2D6 substrate; paroxetine is a strong CYP2D6 inhibitor. Coadministration with paroxetine increased the lofexidine AUC by 28%.
Pasireotide: (Major) Monitor ECG if lofexidine is coadministered with pasireotide due to the potential for additive QT prolongation. Lofexidine prolongs the QT interval. In addition, there are postmarketing reports of torsade de pointes. QT prolongation has occurred with pasireotide at therapeutic and supra-therapeutic doses.
Pazopanib: (Major) Coadministration of lofexidine and pazopanib is not recommended due to the risk of additive QT prolongation and torsade de pointes (TdP). Monitor the ECG for QT prolongation if coadministration is required. Lofexidine may prolong the QT interval, and TdP has been reported during postmarketing use. Pazopanib is associated with QT interval prolongation.
Pentamidine: (Major) Monitor ECG if lofexidine is coadministered with pentamidine due to the potential for additive QT prolongation. Lofexidine prolongs the QT interval. In addition, there are postmarketing reports of torsade de pointes. Systemic pentamidine has been associated with QT prolongation.
Pentazocine; Naloxone: (Moderate) Monitor for excessive hypotension and sedation during coadministration of lofexidine and pentazocine. Lofexidine can potentiate the effects of CNS depressants.
Pentobarbital: (Moderate) Monitor for additive sedation during coadministration of lofexidine and barbiturates. Lofexidine can potentiate the effects of CNS depressants such as barbiturates. Patients should be advised to avoid driving or performing any other tasks requiring mental alertness until the effects of the combination are known. The use of barbiturates parenterally may cause vasodilation and an additive risk for hypotension and may lead to bradycardia and syncope; in these patients, careful monitoring of blood pressure should occur.
Perampanel: (Moderate) Monitor for excessive sedation and somnolence during coadministration. Perampanel may potentiate the sedative effects of lofexidine.
Perphenazine: (Moderate) Monitor the ECG for QT prolongation and monitor for excessive sedation during concurrent use of lofexidine and perphenazine. Lofexidine may prolong the QT interval, and torsade de pointes (TdP) has been reported during postmarketing use. Perphenazine is associated with a possible risk for QT prolongation. In addition, lofexidine can potentiate the effects of CNS depressants, including perphenazine.
Perphenazine; Amitriptyline: (Moderate) Monitor for excessive hypotension and sedation during coadministration of lofexidine and tricyclic antidepressants. Lofexidine can potentiate the effects of CNS depressants. Additionally, monitor ECG during coadministration due to the potential risk for additive QT prolongation. Lofexidine prolongs the QT interval. In addition, there are postmarketing reports of torsade de pointes. Tricyclic antidepressants (TCAs) share pharmacologic properties similar to the Class IA antiarrhythmic agents and may prolong the QT interval, particularly in overdose or with higher-dose prescription therapy (elevated serum concentrations). (Moderate) Monitor the ECG for QT prolongation and monitor for excessive sedation during concurrent use of lofexidine and perphenazine. Lofexidine may prolong the QT interval, and torsade de pointes (TdP) has been reported during postmarketing use. Perphenazine is associated with a possible risk for QT prolongation. In addition, lofexidine can potentiate the effects of CNS depressants, including perphenazine.
Phenobarbital: (Moderate) Monitor for additive sedation during coadministration of lofexidine and barbiturates. Lofexidine can potentiate the effects of CNS depressants such as barbiturates. Patients should be advised to avoid driving or performing any other tasks requiring mental alertness until the effects of the combination are known. The use of barbiturates parenterally may cause vasodilation and an additive risk for hypotension and may lead to bradycardia and syncope; in these patients, careful monitoring of blood pressure should occur.
Phenobarbital; Hyoscyamine; Atropine; Scopolamine: (Moderate) Monitor for additive sedation during coadministration of lofexidine and barbiturates. Lofexidine can potentiate the effects of CNS depressants such as barbiturates. Patients should be advised to avoid driving or performing any other tasks requiring mental alertness until the effects of the combination are known. The use of barbiturates parenterally may cause vasodilation and an additive risk for hypotension and may lead to bradycardia and syncope; in these patients, careful monitoring of blood pressure should occur. (Moderate) Monitor for excessive hypotension and sedation during coadministration of lofexidine and atropine. Lofexidine can potentiate the effects of CNS depressants. (Moderate) Monitor for excessive hypotension and sedation during coadministration of lofexidine and scopolamine. Lofexidine can potentiate the effects of CNS depressants.
Phenoxybenzamine: (Major) Because the central alpha-2 agonist effects of lofexidine can cause hypotension and orthostasis, the drug should be avoided, if possible, in combination with other medications that can significantly decrease blood pressure such as the antihypertensive alpha-blockers. If coadministration is required, blood pressure should be monitored, particularly after dose changes of either agent. Adjustments should be made as clinically indicated. 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.
Phentolamine: (Major) Because the central alpha-2 agonist effects of lofexidine can cause hypotension and orthostasis, the drug should be avoided, if possible, in combination with other medications that can significantly decrease blood pressure such as the antihypertensive alpha-blockers. If coadministration is required, blood pressure should be monitored, particularly after dose changes of either agent. Adjustments should be made as clinically indicated. 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.
Pimavanserin: (Major) Avoid coadministration of lofexidine and pimavanserin due to the potential for additive QT prolongation. Monitor ECG if coadministration cannot be avoided. Additionally, monitor for excessive hypotension and sedation during coadministration as lofexidine can potentiate the effects of CNS depressants. Lofexidine prolongs the QT interval. In addition, there are postmarketing reports of torsade de pointes. Pimavanserin may cause QT prolongation.
Pimozide: (Contraindicated) Concomitant use of lofexidine and pimozide is contraindicated due to the potential for additive QT prolongation and torsade de pointes (TdP). Lofexidine may prolong the QT interval, and TdP has been reported during postmarketing use. Pimozide is associated with a well-established risk of QT prolongation and TdP.
Pindolol: (Major) Because both lofexidine and pindolol can cause hypotension and bradycardia, concurrent use should be avoided if possible. 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.
Pitolisant: (Major) Avoid coadministration of pitolisant with lofexidine as concurrent use may increase the risk of QT prolongation. If coadministration cannot be avoided, ECG monitoring is recommended during treatment. Both pitolisant and lofexidine prolong the QT interval.
Ponesimod: (Major) In general, do not initiate ponesimod in patients taking lofexidine due to the risk of additive bradycardia, QT prolongation, and torsade de pointes (TdP). If treatment initiation is considered, seek advice from a cardiologist. Ponesimod initiation may result in a transient decrease in heart rate and atrioventricular conduction delays. Ponesimod has not been studied in patients taking concurrent QT prolonging drugs; however, QT prolonging drugs have been associated with TdP in patients with bradycardia. Lofexidine has been associated with QT prolongation.
Posaconazole: (Major) Monitor ECG if lofexidine is coadministered with posaconazole due to the potential for additive QT prolongation and torsade de pointes (TdP). Lofexidine prolongs the QT interval. In addition, there are postmarketing reports of TdP. Posaconazole has been associated with prolongation of the QT interval as well as rare cases of TdP.
Pramipexole: (Major) Monitor for excessive hypotension and sedation during coadministration of lofexidine and pramipexole. Lofexidine can potentiate the effects of CNS depressants.
Prazosin: (Major) Because the central alpha-2 agonist effects of lofexidine can cause hypotension and orthostasis, the drug should be avoided, if possible, in combination with other medications that can significantly decrease blood pressure such as the antihypertensive alpha-blockers. If coadministration is required, blood pressure should be monitored, particularly after dose changes of either agent. Adjustments should be made as clinically indicated. 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.
Pregabalin: (Moderate) Monitor for excessive sedation and somnolence during coadministration of lofexidine and pregabalin. Concurrent use may result in additive CNS depression.
Primaquine: (Major) Monitor ECG if lofexidine is coadministered with primaquine due to the potential for additive QT prolongation. Lofexidine prolongs the QT interval. In addition, there are postmarketing reports of torsade de pointes. Primaquine has the potential to prolong the QT interval.
Primidone: (Moderate) Monitor for additive sedation during coadministration of lofexidine and barbiturates. Lofexidine can potentiate the effects of CNS depressants such as barbiturates. Patients should be advised to avoid driving or performing any other tasks requiring mental alertness until the effects of the combination are known. The use of barbiturates parenterally may cause vasodilation and an additive risk for hypotension and may lead to bradycardia and syncope; in these patients, careful monitoring of blood pressure should occur.
Procainamide: (Major) Monitor ECG if lofexidine is coadministered with procainamide due to the potential for additive QT prolongation and torsade de pointes (TdP). Lofexidine prolongs the QT interval. In addition, there are postmarketing reports of TdP. Procainamide is associated with a well-established risk of QT prolongation and TdP.
Prochlorperazine: (Moderate) Monitor for excessive hypotension and sedation during coadministration of lofexidine and prochlorperazine. Lofexidine can potentiate the effects of CNS depressants. Additionally, monitor ECG during coadministration due to the potential for additive QT prolongation. Lofexidine prolongs the QT interval. In addition, there are postmarketing reports of torsade de pointes. Prochlorperazine is associated with a possible risk for QT prolongation.
Promethazine: (Moderate) Monitor ECG for QT prolongation and excessive sedation during concurrent use of lofexidine and promethazine. Lofexidine prolongs the QT interval and torsade de pointes (TdP) has been reported during postmarketing use. Promethazine is associated with a possible risk of QT prolongation and TdP. In addition, lofexidine can potentiate the effects of CNS depressants, including promethazine.
Promethazine; Dextromethorphan: (Moderate) Monitor ECG for QT prolongation and excessive sedation during concurrent use of lofexidine and promethazine. Lofexidine prolongs the QT interval and torsade de pointes (TdP) has been reported during postmarketing use. Promethazine is associated with a possible risk of QT prolongation and TdP. In addition, lofexidine can potentiate the effects of CNS depressants, including promethazine.
Promethazine; Phenylephrine: (Moderate) Monitor ECG for QT prolongation and excessive sedation during concurrent use of lofexidine and promethazine. Lofexidine prolongs the QT interval and torsade de pointes (TdP) has been reported during postmarketing use. Promethazine is associated with a possible risk of QT prolongation and TdP. In addition, lofexidine can potentiate the effects of CNS depressants, including promethazine.
Propafenone: (Major) Monitor ECG for QT prolongation and monitor for bradycardia during concurrent use of lofexidine and propafenone. Lofexidine may prolong the QT interval, and torsade de pointes (TdP) has been reported during postmarketing use. Propafenone is a Class IC antiarrhythmic which increases the QT interval, but largely due to prolongation of the QRS interval.
Propantheline: (Moderate) Monitor for excessive hypotension and sedation during coadministration of lofexidine and propantheline. Lofexidine can potentiate the effects of CNS depressants.
Propofol: (Moderate) Monitor for excessive hypotension and sedation during coadministration of lofexidine and propofol. Lofexidine can potentiate the effects of CNS depressants.
Propranolol: (Major) Because both lofexidine and propranolol can cause hypotension and bradycardia, concurrent use should be avoided if possible. 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.
Protriptyline: (Moderate) Monitor for excessive hypotension and sedation during coadministration of lofexidine and tricyclic antidepressants. Lofexidine can potentiate the effects of CNS depressants. Additionally, monitor ECG during coadministration due to the potential risk for additive QT prolongation. Lofexidine prolongs the QT interval. In addition, there are postmarketing reports of torsade de pointes. Tricyclic antidepressants (TCAs) share pharmacologic properties similar to the Class IA antiarrhythmic agents and may prolong the QT interval, particularly in overdose or with higher-dose prescription therapy (elevated serum concentrations).
Quazepam: (Moderate) Monitor for excessive hypotension and sedation during coadministration of lofexidine and benzodiazepines. Lofexidine can potentiate the effects of CNS depressants such as benzodiazepines.
Quetiapine: (Major) Avoid coadministration of lofexidine and quetiapine due to the potential for additive QT prolongation. Monitor ECG if coadministration cannot be avoided. Additionally, monitor for excessive hypotension and sedation during coadministration as lofexidine can potentiate the effects of CNS depressants. Lofexidine prolongs the QT interval. In addition, there are postmarketing reports of torsade de pointes. Limited data, including some case reports, suggest that quetiapine may be associated with a significant prolongation of the QTc interval in rare instances.
Quinidine: (Contraindicated) Concomitant use of lofexidine and quinidine is contraindicated due to the potential for additive QT prolongation and torsade de pointes (TdP). Lofexidine is a CYP2D6 substrate that prolongs the QT interval. In addition, there are postmarketing reports of TdP. Quinidine is a CYP2D6 inhibitor and is associated with QT prolongation and TdP.
Quinine: (Major) Avoid coadministration of lofexidine and quinine due to the potential for additive QT prolongation and torsade de pointes (TdP). Monitor the ECG for QT prolongation if coadministration is required. Lofexidine may prolong the QT interval, and TdP has been reported during postmarketing use. Quinine has been associated with QT prolongation and rare cases of TdP.
Quizartinib: (Major) Concomitant use of quizartinib and lofexidine increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary.
Ramelteon: (Moderate) Monitor for excessive sedation during coadministration of lofexidine and ramelteon. Lofexidine can potentiate the effects of CNS depressants.
Ranolazine: (Moderate) Monitor the ECG for QT prolongation during concurrent use of lofexidine and ranolazine. Lofexidine may prolong the QT interval, and torsade de pointes (TdP) has been reported during postmarketing use. Ranolazine is associated with dose- and plasma concentration-related increases in the QTc interval.
Relugolix: (Major) ECG monitoring is recommended if lofexidine is coadministered with relugolix due to the potential for additive QT prolongation. Lofexidine prolongs the QT interval. Androgen deprivation therapy (i.e., relugolix) may also prolong the QT/QTc interval.
Relugolix; Estradiol; Norethindrone acetate: (Major) ECG monitoring is recommended if lofexidine is coadministered with relugolix due to the potential for additive QT prolongation. Lofexidine prolongs the QT interval. Androgen deprivation therapy (i.e., relugolix) may also prolong the QT/QTc interval.
Remifentanil: (Moderate) Monitor for excessive hypotension and sedation during coadministration of lofexidine and remifentanil. Lofexidine can potentiate the effects of CNS depressants.
Remimazolam: (Moderate) Monitor for excessive hypotension and sedation during coadministration of lofexidine and benzodiazepines. Lofexidine can potentiate the effects of CNS depressants such as benzodiazepines.
Ribociclib: (Major) Avoid coadministration of lofexidine and ribociclib due to the potential for additive QT prolongation. Lofexidine prolongs the QT interval; in addition, there are postmarketing reports of torsade de pointes. Ribociclib has also been shown to prolong the QT interval in a concentration-dependent manner.
Ribociclib; Letrozole: (Major) Avoid coadministration of lofexidine and ribociclib due to the potential for additive QT prolongation. Lofexidine prolongs the QT interval; in addition, there are postmarketing reports of torsade de pointes. Ribociclib has also been shown to prolong the QT interval in a concentration-dependent manner.
Rilpivirine: (Major) Monitor ECG if lofexidine is coadministered with rilpivirine due to the potential for additive QT prolongation. Lofexidine prolongs the QT interval. In addition, there are postmarketing reports of torsade de pointes. Supratherapeutic doses of rilpivirine (75 to 300 mg/day) have caused QT prolongation; caution is advised when administering rilpivirine with other drugs that may prolong the QT or PR interval.
Risperidone: (Major) Monitor ECG if lofexidine is coadministered with risperidone due to the potential for additive QT prolongation and torsade de pointes (TdP). Additionally, monitor for excessive hypotension and sedation during coadministration as lofexidine can potentiate the effects of CNS depressants. Lofexidine prolongs the QT interval. In addition, there are postmarketing reports of TdP. Risperidone has been associated with a possible risk for QT prolongation and/or TdP, primarily in the overdose setting.
Rolapitant: (Moderate) Monitor for orthostatic hypotension and bradycardia during concurrent use of lofexidine and rolapitant. Coadministration may increase lofexidine exposure. Lofexidine is a CYP2D6 substrate; rolapitant is a CYP2D6 inhibitor. Coadministration with a strong CYP2D6 inhibitor increased the lofexidine AUC by 28%.
Romidepsin: (Major) Monitor ECG and electrolytes if lofexidine is coadministered with romidepsin due to the potential for additive QT prolongation. Lofexidine prolongs the QT interval. In addition, there are postmarketing reports of torsade de pointes. Romidepsin has been reported to prolong the QT interval.
Ropinirole: (Major) Monitor for excessive hypotension and sedation during coadministration of lofexidine and ropinirole. Lofexidine can potentiate the effects of CNS depressants.
Rotigotine: (Major) Monitor for excessive hypotension and sedation during coadministration of lofexidine and rotigotine. Lofexidine can potentiate the effects of CNS depressants.
Saquinavir: (Major) Avoid coadministration of lofexidine and saquinavir boosted with ritonavir due to the potential for additive QT prolongation and torsade de pointes (TdP). Monitor ECG at baseline and during therapy if coadministration cannot be avoided. Lofexidine prolongs the QT interval. In addition, there are postmarketing reports of TdP. Saquinavir boosted with ritonavir increases the QT interval in a dose-dependent fashion, which may increase the risk for serious arrhythmias such as TdP.
Scopolamine: (Moderate) Monitor for excessive hypotension and sedation during coadministration of lofexidine and scopolamine. Lofexidine can potentiate the effects of CNS depressants.
Secobarbital: (Moderate) Monitor for additive sedation during coadministration of lofexidine and barbiturates. Lofexidine can potentiate the effects of CNS depressants such as barbiturates. Patients should be advised to avoid driving or performing any other tasks requiring mental alertness until the effects of the combination are known. The use of barbiturates parenterally may cause vasodilation and an additive risk for hypotension and may lead to bradycardia and syncope; in these patients, careful monitoring of blood pressure should occur.
Selpercatinib: (Major) Monitor ECGs more frequently for QT prolongation if coadministration of selpercatinib with lofexidine is necessary due to the risk of additive QT prolongation. Concentration-dependent QT prolongation has been observed with selpercatinib therapy. Lofexidine prolongs the QT interval.
Sertraline: (Major) Concomitant use of sertraline and lofexidine increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary. The degree of QT prolongation associated with sertraline is not clinically significant when administered within the recommended dosage range; QT prolongation has been described at 2 times the maximum recommended dose.
Sevoflurane: (Major) Monitor ECG if lofexidine is coadministered with halogenated anesthetics due to the potential for additive QT prolongation. Lofexidine prolongs the QT interval. In addition, there are postmarketing reports of torsade de pointes. Halogenated anesthetics can prolong the QT interval. Additionally, monitor for excessive hypotension and sedation during coadministration as lofexidine can potentiate the effects of CNS depressants.
Siponimod: (Major) In general, do not initiate treatment with siponimod in patients receiving lofexidine due to the potential for QT prolongation. Consult a cardiologist regarding appropriate monitoring if siponimod use is required. Siponimod therapy prolonged the QT interval at recommended doses in a clinical study. Lofexidine also prolongs the QT interval.
Sodium Oxybate: (Moderate) Monitor for additive sedation during coadministration of lofexidine and sodium oxybate. Lofexidine can potentiate the effects of CNS depressants. Patients should be advised to avoid driving or performing any other tasks requiring mental alertness until the effects of the combination are known.
Sodium Stibogluconate: (Major) Concomitant use of sodium stibogluconate and lofexidine increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary.
Solifenacin: (Moderate) Monitor ECG if lofexidine is coadministered with solifenacin due to the potential for additive QT prolongation and torsade de pointes (TdP). Lofexidine prolongs the QT interval. In addition, there are postmarketing reports of TdP. Solifenacin has been associated with dose-dependent prolongation of the QT interval. TdP has been reported with postmarketing use, although causality was not determined.
Sorafenib: (Major) Avoid coadministration of sorafenib with lofexidine due to the risk of additive QT prolongation. If concomitant use is unavoidable, monitor electrocardiograms and correct electrolyte abnormalities. An interruption or discontinuation of sorafenib therapy may be necessary if QT prolongation occurs. Lofexidine prolongs the QT interval. Sorafenib is also associated with QTc prolongation.
Sotalol: (Major) Because both lofexidine and sotalol can cause hypotension and bradycardia, concurrent use should be avoided if possible. In addition, both drugs have been associated with QT prolongation and torsade de pointes (TdP) and additive effects are possible. If coadministration is necessary, monitor the ECG during treatment. Proarrhythmic events should be anticipated after initiation of therapy and after each upward dosage adjustment. 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.
Stiripentol: (Moderate) Monitor for excessive sedation and somnolence during coadministration. Stiripentol may potentiate the sedative effects of lofexidine.
Sufentanil: (Moderate) Monitor for excessive hypotension and sedation during coadministration of lofexidine and sufentanil. Lofexidine can potentiate the effects of CNS depressants.
Sunitinib: (Major) Monitor ECG if lofexidine is coadministered with sunitinib due to the potential for additive QT prolongation. Lofexidine prolongs the QT interval. In addition, there are postmarketing reports of torsade de pointes. Sunitinib can prolong the QT interval.
Suvorexant: (Moderate) Monitor for additive sedation during coadministration of lofexidine and suvorexant. Lofexidine can potentiate the effects of CNS depressants. Patients should be advised to avoid driving or performing any other tasks requiring mental alertness until the effects of the combination are known.
Tacrolimus: (Major) Monitor ECG if lofexidine is coadministered with tacrolimus due to the potential for additive QT prolongation. Lofexidine prolongs the QT interval. In addition, there are postmarketing reports of torsade de pointes. Tacrolimus causes QT prolongation.
Tamoxifen: (Moderate) Concomitant use of tamoxifen and lofexidine may increase the risk of QT/QTc prolongation and torsade de pointes (TdP) in some patients. Consider taking steps to minimize the risk of QT/QTc interval prolongation and TdP, such as avoidance, electrolyte monitoring and repletion, and ECG monitoring, especially in patients with additional risk factors for TdP.
Tapentadol: (Moderate) Monitor for excessive hypotension and sedation during coadministration of lofexidine and tapentadol. Lofexidine can potentiate the effects of CNS depressants.
Tasimelteon: (Moderate) Monitor for excessive sedation during coadministration of lofexidine and tasimelteon. Lofexidine can potentiate the effects of CNS depressants.
Telavancin: (Major) Monitor ECG if lofexidine is coadministered with telavancin due to the potential for additive QT prolongation. Lofexidine prolongs the QT interval. In addition, there are postmarketing reports of torsade de pointes. Telavancin has been associated with QT prolongation.
Temazepam: (Moderate) Monitor for excessive hypotension and sedation during coadministration of lofexidine and benzodiazepines. Lofexidine can potentiate the effects of CNS depressants such as benzodiazepines.
Terazosin: (Major) Because the central alpha-2 agonist effects of lofexidine can cause hypotension and orthostasis, the drug should be avoided, if possible, in combination with other medications that can significantly decrease blood pressure such as the antihypertensive alpha-blockers. If coadministration is required, blood pressure should be monitored, particularly after dose changes of either agent. Adjustments should be made as clinically indicated. 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.
Terbinafine: (Moderate) Monitor for orthostatic hypotension and bradycardia during concurrent use of lofexidine and terbinafine. Coadministration may increase lofexidine exposure. Lofexidine is a CYP2D6 substrate; terbinafine is a strong CYP2D6 inhibitor. Coadministration with a strong CYP2D6 inhibitor increased the lofexidine AUC by 28%.
Tetrabenazine: (Major) Avoid coadministration of lofexidine with tetrabenazine due to the potential for additive QT prolongation. Monitor ECG if coadministration cannot be avoided. Additionally, monitor for excessive hypotension and sedation during coadministration as lofexidine can potentiate the effects of CNS depressants. Lofexidine prolongs the QT interval. In addition, there are postmarketing reports of torsade de pointes. Tetrabenazine causes a small increase in the corrected QT interval (QTc).
Thalidomide: (Moderate) Monitor for additive hypotension, bradycardia, and sedation during coadministration of lofexidine and thalidomide. Lofexidine can potentiate the effects of CNS depressants. Patients should be advised to avoid driving or performing any other tasks requiring mental alertness until the effects of the combination are known.
Thioridazine: (Contraindicated) Concomitant use of lofexidine and thioridazine is contraindicated due to the potential for additive QT prolongation and torsade de pointes (TdP). Lofexidine is a CYP2D6 substrate that prolongs the QT interval. In addition, there are postmarketing reports of TdP. Thioridazine is a CYP2D6 inhibitor and is associated with a well-established risk of QT prolongation and TdP.
Thiothixene: (Moderate) Monitor for excessive sedation during concurrent use of lofexidine and thiothixene. Lofexidine can potentiate the effects of CNS depressants, including thiothixene.
Timolol: (Major) Because both lofexidine and timolol can cause hypotension and bradycardia, concurrent use should be avoided if possible. 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.
Tipranavir: (Moderate) Monitor for orthostatic hypotension and bradycardia during concurrent use of lofexidine and tipranavir. Coadministration may increase lofexidine exposure. Lofexidine is a CYP2D6 substrate; tipranavir is a strong CYP2D6 inhibitor. Coadministration with a strong CYP2D6 inhibitor increased the lofexidine AUC by 28%.
Tizanidine: (Moderate) Use tizanidine and lofexidine together with caution due to additive CNS depression. Monitor patients for symptoms of excess sedation and hypotension.
Tolcapone: (Major) Monitor for excessive hypotension and sedation during coadministration of lofexidine and tolcapone. Lofexidine can potentiate the effects of CNS depressants.
Tolterodine: (Moderate) Monitor ECG if lofexidine is coadministered with tolterodine due to the potential for additive QT prolongation. Tolterodine has been associated with dose-dependent prolongation of the QT interval, especially in poor CYP2D6 metabolizers.
Toremifene: (Major) Avoid coadministration of lofexidine with toremifene due to the potential for additive QT prolongation. Monitor ECG and electrolytes if coadministration cannot be avoided. Lofexidine prolongs the QT interval. In addition, there are postmarketing reports of torsade de pointes. Toremifene has been shown to prolong the QTc interval in a dose- and concentration-related manner.
Tramadol: (Moderate) Monitor for excessive hypotension and sedation during coadministration of lofexidine and tramadol. Lofexidine can potentiate the effects of CNS depressants.
Tramadol; Acetaminophen: (Moderate) Monitor for excessive hypotension and sedation during coadministration of lofexidine and tramadol. Lofexidine can potentiate the effects of CNS depressants.
Trandolapril; Verapamil: (Moderate) Because both lofexidine and verapamil can cause hypotension and bradycardia, concurrent use should be avoided if possible. 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.
Trazodone: (Major) Avoid coadministration of lofexidine with trazodone due to the potential for additive QT prolongation and torsade de pointes (TdP). Monitor ECG if coadministration cannot be avoided. Additionally, monitor for excessive hypotension and sedation during coadministration as lofexidine can potentiate the effects of CNS depressants. Lofexidine prolongs the QT interval. In addition, there are postmarketing reports of TdP. Trazodone can prolong the QT/QTc interval at therapeutic doses. In addition, there are postmarketing reports of TdP.
Triazolam: (Moderate) Monitor for excessive hypotension and sedation during coadministration of lofexidine and benzodiazepines. Lofexidine can potentiate the effects of CNS depressants such as benzodiazepines.
Triclabendazole: (Major) Concomitant use of triclabendazole and lofexidine increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary.
Tricyclic antidepressants: (Moderate) Monitor for excessive hypotension and sedation during coadministration of lofexidine and tricyclic antidepressants. Lofexidine can potentiate the effects of CNS depressants. Additionally, monitor ECG during coadministration due to the potential risk for additive QT prolongation. Lofexidine prolongs the QT interval. In addition, there are postmarketing reports of torsade de pointes. Tricyclic antidepressants (TCAs) share pharmacologic properties similar to the Class IA antiarrhythmic agents and may prolong the QT interval, particularly in overdose or with higher-dose prescription therapy (elevated serum concentrations).
Trifluoperazine: (Moderate) Monitor for excessive hypotension and sedation during coadministration of lofexidine and trifluoperazine. Lofexidine can potentiate the effects of CNS depressants. Additionally, monitor ECG during coadministration due to the potential for additive QT prolongation. Lofexidine prolongs the QT interval. In addition, there are postmarketing reports of torsade de pointes. Trifluoperazine is associated with a possible risk for QT prolongation.
Trimipramine: (Moderate) Monitor for excessive hypotension and sedation during coadministration of lofexidine and tricyclic antidepressants. Lofexidine can potentiate the effects of CNS depressants. Additionally, monitor ECG during coadministration due to the potential risk for additive QT prolongation. Lofexidine prolongs the QT interval. In addition, there are postmarketing reports of torsade de pointes. Tricyclic antidepressants (TCAs) share pharmacologic properties similar to the Class IA antiarrhythmic agents and may prolong the QT interval, particularly in overdose or with higher-dose prescription therapy (elevated serum concentrations).
Triptorelin: (Major) ECG monitoring is recommended if lofexidine is coadministered with triptorelin due to the potential for additive QT prolongation. Consider whether the benefits of androgen deprivation therapy outweigh the potential risks in patients receiving other QT prolonging agents. Androgen deprivation therapy (i.e., triptorelin) may prolong the QT/QTc interval.
Valbenazine: (Moderate) Monitor for excessive hypotension and sedation during coadministration of lofexidine and valbenazine. Lofexidine can potentiate the effects of CNS depressants.
Valerian, Valeriana officinalis: (Moderate) Monitor for additive sedation during coadministration of lofexidine and valerian. Lofexidine can potentiate the effects of CNS depressants. Patients should be advised to avoid driving or performing any other tasks requiring mental alertness until the effects of the combination are known.
Valproic Acid, Divalproex Sodium: (Moderate) Monitor for additive sedation during coadministration of lofexidine and valproic acid or related agents (divalproex, valproate). Lofexidine can potentiate the effects of CNS depressants. Patients should be advised to avoid driving or performing any other tasks requiring mental alertness until the effects of the combination are known.
Vandetanib: (Major) Avoid coadministration of vandetanib with lofexidine due to an increased risk of QT prolongation and torsade de pointes (TdP). If concomitant use is unavoidable, monitor ECGs for QT prolongation and monitor electrolytes; correct hypocalcemia, hypomagnesemia, and/or hypomagnesemia prior to vandetanib administration. An interruption of vandetanib therapy or dose reduction may be necessary for QT prolongation. Vandetanib can prolong the QT interval in a concentration-dependent manner; TdP and sudden death have been reported in patients receiving vandetanib. Lofexidine also prolongs the QT interval.
Vardenafil: (Major) Concomitant use of vardenafil and lofexidine increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary.
Vasodilators: (Major) Because the central alpha-2 agonist effects of lofexidine can cause hypotension and orthostasis, the drug should be avoided, if possible, in combination with other medications that can decrease blood pressure such as systemic vasodilators. If coadministration is required, blood pressure should be monitored, particularly after dose changes of either agent. Adjustments should be made as clinically indicated.
Vemurafenib: (Major) Monitor ECG if lofexidine is coadministered with vemurafenib due to the potential for additive QT prolongation and torsade de pointes (TdP). Lofexidine prolongs the QT interval. In addition, there are postmarketing reports of TdP. Vemurafenib has been associated with QT prolongation and TdP.
Venlafaxine: (Major) Concomitant use of venlafaxine and lofexidine increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary.
Verapamil: (Moderate) Because both lofexidine and verapamil can cause hypotension and bradycardia, concurrent use should be avoided if possible. 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.
Viloxazine: (Moderate) Monitor for orthostatic hypotension and bradycardia during concurrent use of lofexidine and viloxazine. Coadministration may increase lofexidine exposure. Lofexidine is a CYP2D6 substrate; viloxazine is a CYP2D6 inhibitor. Coadministration with a strong CYP2D6 inhibitor increased the lofexidine AUC by 28%.
Voclosporin: (Major) Monitor ECG if lofexidine is coadministered with voclosporin due to the risk for additive QT prolongation. Lofexidine prolongs the QT interval. Voclosporin has been associated with QT prolongation at supratherapeutic doses.
Vonoprazan; Amoxicillin; Clarithromycin: (Major) Monitor ECG if lofexidine is coadministered with clarithromycin due to the potential for additive QT prolongation and torsade de pointes (TdP). Lofexidine prolongs the QT interval. In addition, there are postmarketing reports of TdP. Clarithromycin is associated with an established risk for QT prolongation and TdP.
Voriconazole: (Major) Monitor ECG if lofexidine is coadministered with voriconazole due to the potential for additive QT prolongation. Lofexidine prolongs the QT interval. Voriconazole has been associated with QT prolongation and rare cases of torsade de pointes (TdP).
Vorinostat: (Major) ECG monitoring is recommended if lofexidine is coadministered with vorinostat due to the potential for additive QT prolongation. Lofexidine prolongs the QT interval. Vorinostat therapy is associated with a risk of QT prolongation.
Zaleplon: (Moderate) Monitor for additive sedation during coadministration of lofexidine and anxiolytics, sedatives, and hypnotics. Lofexidine can potentiate the effects of CNS depressants. Patients should be advised to avoid driving or performing any other tasks requiring mental alertness until the effects of the combination are known.
Ziprasidone: (Major) Avoid coadministration of lofexidine with ziprasidone due to the potential for additive QT prolongation and torsade de pointes (TdP). Monitor ECG if coadministration cannot be avoided. Lofexidine prolongs the QT interval. In addition, there are postmarketing reports of TdP. Clinical trial data indicate that ziprasidone causes QT prolongation; there are postmarketing reports of TdP in patients with multiple confounding factors.
Zolpidem: (Moderate) Monitor for additive sedation during coadministration of lofexidine and anxiolytics, sedatives, and hypnotics. Lofexidine can potentiate the effects of CNS depressants. Patients should be advised to avoid driving or performing any other tasks requiring mental alertness until the effects of the combination are known.
Zuranolone: (Major) Avoid the use of multiple sedating agents due to the risk for additive CNS depression. If use is necessary, consider a downward dosage adjustment of either or both medications, especially in patients with additional risk factors for sedation-related harm.
Lofexidine is a central alpha-2 agonist that binds to adrenergic receptors, resulting in a reduction in the release of norepinephrine and a decrease in sympathetic tone. Central alpha-2 agonists are particularly beneficial for treating opiate withdrawal symptoms related to autonomic hyperactivity such as tachycardia, increased blood pressure, anxiety, nausea, vomiting, chills, and sweating. Due to the central alpha-2 agonist effects of lofexidine, hypotension, orthostasis, and syncope can occur. Available data indicate that the hypotensive effects of lofexidine are less significant than with clonidine, another central alpha-2 agonist used in the treatment of opiate agonist withdrawal. Lofexidine has been associated with QT prolongation. In a cardiac electrophysiology study, single doses of lofexidine of 1.44 mg to 1.8 mg resulted in maximum mean changes from baseline QTcF of 14.4 msec and 13.6 msec, respectively, in healthy normal volunteers. In a dose response study in opioid-dependent subjects, doses of lofexidine of 2.16 mg and 2.88 mg were associated with maximum mean prolongations of the QTcF interval of 7.3 msec and 9.3 msec, respectively.
Lofexidine is administered orally. The drug has an extensive volume of distribution. Protein binding is not significant (55%). About 30% of a dose is converted to inactive metabolites during first pass metabolism. The major isoenzyme involved in the metabolism of lofexidine is CYP2D6, with CYP1A2 and CYP2C19 also capable of metabolizing lofexidine. When following the recommended dosing regimen, accumulation occurs up to 4 days with repeat dosing. The primary route of elimination of the parent drug and its metabolites is via the kidney. Renal elimination of unchanged drug accounts for about 15% to 20% of the administered dose. The terminal elimination half-life following the first dose is 11 to 13 hours, and the steady-state terminal half-life is 17 to 22 hours.
Affected cytochrome P450 (CYP450) isoenzymes and drug transporters: CYP2D6, CYP1A2, CYP2C19
The major isoenzyme involved in the metabolism of lofexidine is CYP2D6, and drug interactions may occur with potent inhibitors of this enzyme. CYP1A2 and CYP2C19 are also capable of metabolizing lofexidine. In an open-label, single-sequence study of 24 healthy subjects, the concurrent use of a strong CYP2D6 inhibitor (paroxetine, 40 mg/day) increased lofexidine maximum concentration (Cmax) and exposure (AUC) by approximately 11% and 28%, respectively. Patients receiving potent CYP2D6 inhibitors may experience more lofexidine-related side effects, such as hypotension and bradycardia. Slight inhibition of CYP2D6 by lofexidine is not expected to be clinically significant.
-Route-Specific Pharmacokinetics
Oral Route
Lofexidine is well absorbed orally and achieves peak plasma concentrations 3 to 5 hours after administration of a single oral dose. Lofexidine may be taken with or without food. The absolute bioavailability of a single oral dose compared with intravenous infusion is 72%.
-Special Populations
Hepatic Impairment
Hepatic impairment decreases the elimination of lofexidine and dosage adjustments are recommended in patients with hepatic impairment. Mean peak plasma concentrations following a single dose were similar in subjects with normal hepatic function and those with mild to severe hepatic impairment whereas the relative AUC percentages for those with normal hepatic function versus mild, moderate, and severe hepatic impairment were increased from 100% to 117%, 185%, and 260%, respectively. The relative half-life percentages increased from 100% in those with normal hepatic function to 139%, 281%, and 401% in those with mild, moderate, and severe hepatic impairment, respectively. Lofexidine prolongs the QT interval. Administration of lofexidine to subjects with hepatic impairment was associated with QT prolongation, which was more pronounced in subjects with severe hepatic impairment.
Renal Impairment
Renal impairment decreases the elimination of lofexidine and dosage adjustments are recommended in patients with renal impairment. Mean peak plasma concentrations following a single dose were similar in subjects with normal renal function and those with end-stage renal disease (ESRD) on dialysis whereas the relative AUC percentages for those with normal renal function versus mild impairment, moderate impairment, severe impairment, and ESRD or dialysis were increased from 100% to 144%, 173%, 243%, and 171%, respectively. The relative half-life percentages increased from 100% in those with normal renal function to 111%, 145%, 157%, and 137% in those with mild impairment, moderate impairment, severe impairment, and ESRD or dialysis, respectively. Lofexidine prolongs the QT interval. Administration of lofexidine to subjects with renal impairment was associated with QT prolongation, which was more pronounced in subjects with severe renal impairment.
Pediatrics
Safety and effectiveness have not been established in pediatric patients.
Geriatric
No studies have been performed to determine the kinetics or the safety and effectiveness of lofexidine in geriatric adults. Dose adjustments similar to those recommended in patients with renal impairment should be considered.
Other
CYP2D6 Poor Metabolizers (PMs)
Although the kinetics of lofexidine have not been formally evaluated in patients who do not express CYP2D6, it is likely that exposure to the drug would be increased similarly to taking a strong CYP2D6 inhibitor (about 28%). Monitor for adverse effects such as orthostatic hypotension and bradycardia in known CYP2D6 poor metabolizers.