Dosage Forms
Excipient information presented when available (limited, particularly for generics); consult specific product labeling.
Tablet, Oral:
Lucemyra: 0.18 mg [contains fd&c blue #2 (indigotine), fd&c yellow #6 (sunset yellow)]
Pharmacology
Mechanism of Action
Lofexidine is a central alpha-2 adrenergic agonist that reduces the release of norepinephrine and decreases sympathetic tone. It binds to alpha-2A (ki=7.2 nM) and alpha-2C (ki=12 nM) adrenoreceptors. Due to its high selectivity for the alpha-2A receptor, lofexidine is thought to be associated with less anti-hypertensive activity than clonidine (Gish 2010).
Pharmacokinetics/Pharmacodynamics
Absorption
Well-absorbed
Distribution
Oral: Vdapparent = 480 L; IV: Vd = 297.9 L
Metabolism
First pass effect associated with gut absorption (~30% of the dose is converted to inactive metabolites); hepatic via CYP2D6 (primary), CYP1A2 and CYP2C19
Excretion
Urine (93.5%; 15% to 20% unchanged); feces (0.92%)
Time to Peak
3 to 5 hours
Half-Life Elimination
11 to 13 hours (first dose); 17 to 22 hours (steady state)
Protein Binding
~55%
Use in Specific Populations
Special Populations: Renal Function Impairment
Cmax, AUC and half-life increased slightly with the severity of renal impairment.
Special Populations: Hepatic Function Impairment
Half-life was prolonged in patients with hepatic impairment.
Use: Labeled Indications
Opioid withdrawal: Mitigation of opioid withdrawal symptoms to facilitate abrupt opioid discontinuation in adults.
Contraindications
There are no contraindications listed in the manufacturer's labeling.
Dosage and Administration
Dosing: Adult
Opioid withdrawal: Oral: Initial: 0.54 mg 4 times daily (every 5 to 6 hours) during peak withdrawal symptoms (generally the first 5 to 7 days after last opioid use); adjust dosing based on tolerability and withdrawal symptoms and may continue for up to 14 days if needed; maximum dose: 0.72 mg/dose or 2.88 mg/day. Note: Lower doses may be appropriate as opioid withdrawal symptoms wane.
Discontinuation of therapy: Decrease dose gradually over 2 to 4 days (eg, reduce by 0.18 mg per dose every 1 to 2 days).
Dosing: Geriatric
Refer to adult dosing; use with caution; consider lower doses
Administration
Oral: Administer with or without food.
Storage
Store at 25°C (77°F); excursions permitted between 15°C to 30°C (59°F to 86°F). Protect from excess heat and moisture.
Drug Interactions
Ajmaline: Lofexidine may enhance the QTc-prolonging effect of Ajmaline. Management: Consider alternatives to this combination. Patients with other risk factors (eg, older age, female sex, bradycardia, hypokalemia, hypomagnesemia, heart disease, and higher drug concentrations) are likely at greater risk for these toxicities. Consider therapy modification
Alfuzosin: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Monitor therapy
Amifostine: Blood Pressure Lowering Agents may enhance the hypotensive effect of Amifostine. Management: When amifostine is used at chemotherapy doses, blood pressure lowering medications should be withheld for 24 hours prior to amifostine administration. If blood pressure lowering therapy cannot be withheld, amifostine should not be administered. Consider therapy modification
Amiodarone: Lofexidine may enhance the QTc-prolonging effect of Amiodarone. Management: Consider alternatives to this combination. Patients with other risk factors (eg, older age, female sex, bradycardia, hypokalemia, hypomagnesemia, heart disease, and higher drug concentrations) are likely at greater risk for these toxicities. Consider therapy modification
Antipsychotic Agents (Second Generation [Atypical]): Blood Pressure Lowering Agents may enhance the hypotensive effect of Antipsychotic Agents (Second Generation [Atypical]). Monitor therapy
Benperidol: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Monitor therapy
Beta-Blockers: Alpha2-Agonists may enhance the AV-blocking effect of Beta-Blockers. Sinus node dysfunction may also be enhanced. Beta-Blockers may enhance the rebound hypertensive effect of Alpha2-Agonists. This effect can occur when the Alpha2-Agonist is abruptly withdrawn. Management: Closely monitor heart rate during treatment with a beta blocker and clonidine. Withdraw beta blockers several days before clonidine withdrawal when possible, and monitor blood pressure closely. Recommendations for other alpha2-agonists are unavailable. Exceptions: Levobunolol; Metipranolol. Consider therapy modification
Blood Pressure Lowering Agents: May enhance the hypotensive effect of Hypotension-Associated Agents. Monitor therapy
Bradycardia-Causing Agents: May enhance the bradycardic effect of other Bradycardia-Causing Agents. Monitor therapy
Brimonidine (Topical): May enhance the hypotensive effect of Blood Pressure Lowering Agents. Monitor therapy
Bromperidol: Blood Pressure Lowering Agents may enhance the hypotensive effect of Bromperidol. Bromperidol may diminish the hypotensive effect of Blood Pressure Lowering Agents. Avoid combination
Chloroquine: QT-prolonging Miscellaneous Agents (Moderate Risk) may enhance the QTc-prolonging effect of Chloroquine. Management: Monitor for QTc interval prolongation and ventricular arrhythmias when these agents are combined. Patients with additional risk factors for QTc prolongation may be at even higher risk. Monitor therapy
Clofazimine: QT-prolonging Miscellaneous Agents (Moderate Risk) may enhance the QTc-prolonging effect of Clofazimine. Management: Monitor for QTc interval prolongation and ventricular arrhythmias when these agents are combined. Patients with additional risk factors for QTc prolongation may be at even higher risk. Monitor therapy
CNS Depressants: Lofexidine may enhance the CNS depressant effect of CNS Depressants. Management: Drugs listed as exceptions to this monograph are discussed in further detail in separate drug interaction monographs. Exceptions: Amisulpride; CloZAPine; Droperidol; Flupentixol; OLANZapine; QUEtiapine; RisperiDONE; Thioridazine. Monitor therapy
CYP2D6 Inhibitors (Strong): May increase the serum concentration of Lofexidine. Monitor therapy
Diazoxide: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Monitor therapy
Domperidone: QT-prolonging Agents (Moderate Risk) may enhance the QTc-prolonging effect of Domperidone. Management: Consider alternatives to this drug combination. If combined, monitor for QTc interval prolongation and ventricular arrhythmias. Patients with additional risk factors for QTc prolongation may be at even higher risk. Consider therapy modification
Doxepin-Containing Products: May enhance the QTc-prolonging effect of Lofexidine. Lofexidine may enhance the QTc-prolonging effect of Doxepin-Containing Products. Doxepin-Containing Products may diminish the therapeutic effect of Lofexidine. Management: Consider avoiding this combination when possiblke. Monitor for QTc interval prolongation and ventricular arrhythmias when these agents are combined. Patients with additional risk factors for QTc prolongation may be at even higher risk. Consider therapy modification
Dronedarone: Lofexidine may enhance the QTc-prolonging effect of Dronedarone. Management: Consider alternatives to this combination. Patients with other risk factors (eg, older age, female sex, bradycardia, hypokalemia, hypomagnesemia, heart disease, and higher drug concentrations) are likely at greater risk for these toxicities. Consider therapy modification
DULoxetine: Blood Pressure Lowering Agents may enhance the hypotensive effect of DULoxetine. Monitor therapy
Fexinidazole [INT]: May enhance the QTc-prolonging effect of QT-prolonging Agents (Moderate Risk). Avoid combination
Fexinidazole [INT]: Bradycardia-Causing Agents may enhance the arrhythmogenic effect of Fexinidazole [INT]. Avoid combination
Gadobenate Dimeglumine: QT-prolonging Miscellaneous Agents (Moderate Risk) may enhance the QTc-prolonging effect of Gadobenate Dimeglumine. Management: Monitor for QTc interval prolongation and ventricular arrhythmias when these agents are combined. Patients with additional risk factors for QTc prolongation may be at even higher risk. Monitor therapy
Halofantrine: QT-prolonging Miscellaneous Agents (Moderate Risk) may enhance the QTc-prolonging effect of Halofantrine. Management: Monitor for QTc interval prolongation and ventricular arrhythmias when these agents are combined. Patients with additional risk factors for QTc prolongation may be at even higher risk. Monitor therapy
Haloperidol: QT-prolonging Miscellaneous Agents (Moderate Risk) may enhance the QTc-prolonging effect of Haloperidol. Management: Monitor for QTc interval prolongation and ventricular arrhythmias when these agents are combined. Patients with additional risk factors for QTc prolongation may be at even higher risk. Monitor therapy
Herbs (Hypotensive Properties): May enhance the hypotensive effect of Blood Pressure Lowering Agents. Monitor therapy
Hypotension-Associated Agents: Blood Pressure Lowering Agents may enhance the hypotensive effect of Hypotension-Associated Agents. Monitor therapy
Ivabradine: Bradycardia-Causing Agents may enhance the bradycardic effect of Ivabradine. Monitor therapy
Lacosamide: Bradycardia-Causing Agents may enhance the AV-blocking effect of Lacosamide. Monitor therapy
Levodopa-Containing Products: Blood Pressure Lowering Agents may enhance the hypotensive effect of Levodopa-Containing Products. Monitor therapy
Lormetazepam: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Monitor therapy
Methadone: Lofexidine may enhance the QTc-prolonging effect of Methadone. Management: Consider alternatives to this drug combination. If combined, monitor for QTc interval prolongation and ventricular arrhythmias. Patients with additional risk factors for QTc prolongation may be at even higher risk. Consider therapy modification
Midodrine: May enhance the bradycardic effect of Bradycardia-Causing Agents. Monitor therapy
Mirtazapine: May diminish the antihypertensive effect of Alpha2-Agonists. Management: Consider avoiding concurrent use. If the combination cannot be avoided, monitor for decreased effects of alpha2-agonists if mirtazapine is initiated/dose increased, or increased effects if mirtazapine is discontinued/dose decreased. Consider therapy modification
Molsidomine: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Monitor therapy
Naftopidil: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Monitor therapy
Naltrexone: Lofexidine may decrease the serum concentration of Naltrexone. Monitor therapy
Nicergoline: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Monitor therapy
Nicorandil: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Monitor therapy
Nitroprusside: Blood Pressure Lowering Agents may enhance the hypotensive effect of Nitroprusside. Monitor therapy
Obinutuzumab: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Management: Consider temporarily withholding blood pressure lowering medications beginning 12 hours prior to obinutuzumab infusion and continuing until 1 hour after the end of the infusion. Consider therapy modification
Ondansetron: QT-prolonging Miscellaneous Agents (Moderate Risk) may enhance the QTc-prolonging effect of Ondansetron. Management: Monitor for QTc interval prolongation and ventricular arrhythmias when these agents are combined. Patients with additional risk factors for QTc prolongation may be at even higher risk. Monitor therapy
Pentamidine (Systemic): QT-prolonging Miscellaneous Agents (Moderate Risk) may enhance the QTc-prolonging effect of Pentamidine (Systemic). Management: Monitor for QTc interval prolongation and ventricular arrhythmias when these agents are combined. Patients with additional risk factors for QTc prolongation may be at even higher risk. Monitor therapy
Pentoxifylline: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Monitor therapy
Pholcodine: Blood Pressure Lowering Agents may enhance the hypotensive effect of Pholcodine. Monitor therapy
Phosphodiesterase 5 Inhibitors: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Monitor therapy
Pimozide: May enhance the QTc-prolonging effect of QT-prolonging Agents (Moderate Risk). Avoid combination
Prostacyclin Analogues: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Monitor therapy
QT-prolonging Agents (Highest Risk): May enhance the QTc-prolonging effect of Lofexidine. Management: Consider alternatives to this combination. If combined, monitor for QTc interval prolongation and ventricular arrhythmias. Patients with additional risk factors for QTc prolongation may be at even higher risk. Exceptions: Ajmaline; Amiodarone; Dronedarone; Methadone; Sotalol. Consider therapy modification
QT-prolonging Antidepressants (Moderate Risk): May enhance the QTc-prolonging effect of Lofexidine. Lofexidine may enhance the QTc-prolonging effect of QT-prolonging Antidepressants (Moderate Risk). Management: Monitor for QTc interval prolongation and ventricular arrhythmias when these agents are combined. Patients with additional risk factors for QTc prolongation may be at even higher risk. Exceptions: Doxepin (Systemic); Doxepin (Topical). Monitor therapy
QT-prolonging Antipsychotics (Moderate Risk): QT-prolonging Miscellaneous Agents (Moderate Risk) may enhance the QTc-prolonging effect of QT-prolonging Antipsychotics (Moderate Risk). Management: Monitor for QTc interval prolongation and ventricular arrhythmias when these agents are combined. Patients with additional risk factors for QTc prolongation may be at even higher risk. Exceptions: Pimozide. Monitor therapy
QT-prolonging Class IC Antiarrhythmics (Moderate Risk): QT-prolonging Miscellaneous Agents (Moderate Risk) may enhance the QTc-prolonging effect of QT-prolonging Class IC Antiarrhythmics (Moderate Risk). Management: Monitor for QTc interval prolongation and ventricular arrhythmias when these agents are combined. Patients with additional risk factors for QTc prolongation may be at even higher risk. Monitor therapy
QT-prolonging Kinase Inhibitors (Moderate Risk): May enhance the QTc-prolonging effect of QT-prolonging Miscellaneous Agents (Moderate Risk). Management: Monitor for QTc interval prolongation and ventricular arrhythmias when these agents are combined. Patients with additional risk factors for QTc prolongation may be at even higher risk. Monitor therapy
QT-prolonging Miscellaneous Agents (Moderate Risk): May enhance the QTc-prolonging effect of Lofexidine. Management: Monitor for QTc interval prolongation and ventricular arrhythmias when these agents are combined. Patients with additional risk factors for QTc prolongation may be at even higher risk. Exceptions: Chloroquine; Clofazimine; Domperidone; Gadobenate Dimeglumine; Halofantrine. Monitor therapy
QT-prolonging Moderate CYP3A4 Inhibitors (Moderate Risk): May enhance the QTc-prolonging effect of QT-prolonging Miscellaneous Agents (Moderate Risk). QT-prolonging Moderate CYP3A4 Inhibitors (Moderate Risk) may increase the serum concentration of QT-prolonging Miscellaneous Agents (Moderate Risk). Management: Monitor for QTc interval prolongation and ventricular arrhythmias when these agents are combined. Patients with additional risk factors for QTc prolongation may be at even higher risk. Monitor therapy
QT-prolonging Quinolone Antibiotics (Moderate Risk): QT-prolonging Miscellaneous Agents (Moderate Risk) may enhance the QTc-prolonging effect of QT-prolonging Quinolone Antibiotics (Moderate Risk). Management: Monitor for QTc interval prolongation and ventricular arrhythmias when these agents are combined. Patients with additional risk factors for QTc prolongation may be at even higher risk. Monitor therapy
QT-prolonging Strong CYP3A4 Inhibitors (Moderate Risk): May enhance the QTc-prolonging effect of QT-prolonging Miscellaneous Agents (Moderate Risk). QT-prolonging Strong CYP3A4 Inhibitors (Moderate Risk) may increase the serum concentration of QT-prolonging Miscellaneous Agents (Moderate Risk). Avoid combination
Quinagolide: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Monitor therapy
Ruxolitinib: May enhance the bradycardic effect of Bradycardia-Causing Agents. Management: Ruxolitinib Canadian product labeling recommends avoiding use with bradycardia-causing agents to the extent possible. Monitor therapy
Serotonin/Norepinephrine Reuptake Inhibitors: May diminish the antihypertensive effect of Alpha2-Agonists. Monitor therapy
Siponimod: Bradycardia-Causing Agents may enhance the bradycardic effect of Siponimod. Management: Avoid coadministration of siponimod with drugs that may cause bradycardia. Consider therapy modification
Sotalol: Lofexidine may enhance the QTc-prolonging effect of Sotalol. Management: Consider alternatives to this combination. Patients with other risk factors (eg, older age, female sex, bradycardia, hypokalemia, hypomagnesemia, heart disease, and higher drug concentrations) are likely at greater risk for these toxicities. Consider therapy modification
Terlipressin: May enhance the bradycardic effect of Bradycardia-Causing Agents. Monitor therapy
Tofacitinib: May enhance the bradycardic effect of Bradycardia-Causing Agents. Monitor therapy
Tricyclic Antidepressants: May diminish the therapeutic effect of Lofexidine. Management: Consider avoiding this drug combination when possible. If concurrent administration is required, monitor blood pressure carefully at the beginning of the combined therapy and when either drug is stopped. Adjust the dosage accordingly. Exceptions: Doxepin (Systemic); Doxepin (Topical). Consider therapy modification
Adverse Reactions
>10%:
Cardiovascular: Orthostatic hypotension (29% to 42%), bradycardia (24% to 32%), hypotension (30%)
Central nervous system: Insomnia (51% to 55%), dizziness (19% to 23%), sedation (12% to 13%), drowsiness (11% to 13%)
Gastrointestinal: Xerostomia (10% to 11%)
1% to 10%
Cardiovascular: Syncope (≤1%)
Otic: Tinnitus (≤3%)
<1%, postmarketing, and/or case reports: Prolonged QT interval on ECG, torsades de pointes
Warnings/Precautions
Concerns related to adverse effects:
- Accidental opioid overdose: Lofexidine is not a treatment for opioid use disorder, and it should be used only in conjunction with a comprehensive management program for the treatment of opioid use disorder. Patients who had been treated with lofexidine may respond to lower opioid doses than previously used. This could result in potentially life-threatening opioid overdose. Patients should be aware that they may be more sensitive to lower doses of opioids after lofexidine treatment is discontinued, after a missed dose, or near the end of the dosing interval.
- Cardiovascular effects: May cause syncope or a decrease in blood pressure or heart rate; monitor vital signs before dosing and observe for symptoms of bradycardia and syncope. Reduce dose or interrupt therapy if clinically significant bradycardia and/or hypotension occur. Avoid use in patients with severe coronary insufficiency, recent myocardial infarction, significant bradycardia, cerebrovascular disease, and chronic renal failure.
- CNS depression: May cause CNS depression, which may impair physical or mental abilities; patients must be cautioned about performing tasks that require mental alertness (eg, operating machinery or driving).
- QT prolongation: May cause QT prolongation; avoid use in patients with congenital long QT syndrome. Monitor ECG in at-risk patients (heart failure, bradyarrhythmias, hepatic impairment, renal impairment, concomitant QT-prolonging medications). In patients with electrolyte abnormalities, correct abnormality first, then monitor ECG before initiating lofexidine.
Disease-related concerns:
- Hepatic impairment: Prolongation of the QTc interval is more pronounced in patients with severe hepatic impairment. Use caution in patients with hepatic impairment.
- Renal impairment: Prolongation of the QTc interval is more pronounced in patients with severe renal impairment. Use caution in patients with renal impairment; avoid use in patients with chronic renal failure.
Concurrent drug therapy issues:
- Drug-drug interactions: Potentially significant interactions may exist, requiring dose or frequency adjustment, additional monitoring, and/or selection of alternative therapy. Consult drug interactions database for more detailed information.
Special populations:
- CYP2D6 poor metabolizers: Exposure to lofexidine may be increased; monitor for orthostasis and bradycardia.
Other warnings/precautions:
- Discontinuation of therapy: Discontinuing lofexidine abruptly may result in a marked rise in blood pressure, anxiety, chills, diarrhea, extremity pain, hyperhidrosis and insomnia. When discontinuing therapy, treatment should be gradually reduced to avoid these symptoms. Do not abruptly discontinue.
Monitoring Parameters
Blood pressure; heart rate; electrolytes and ECG at baseline in at-risk populations; opioid withdrawal symptoms
Pregnancy
Pregnancy Considerations
Information related to the use of lofexidine in pregnancy is limited (Akhurst 2000). Abrupt discontinuation of opioid therapy in dependent females is generally not recommended during pregnancy (Kampman 2015).
Patient Education
- Discuss specific use of drug and side effects with patient as it relates to treatment. (HCAHPS: During this hospital stay, were you given any medicine that you had not taken before? Before giving you any new medicine, how often did hospital staff tell you what the medicine was for? How often did hospital staff describe possible side effects in a way you could understand?)
- Patient may experience trouble sleeping, fatigue, or dry mouth. Have patient report immediately to prescriber dizziness, passing out, slow heartbeat, abnormal heartbeat, or fast heartbeat (HCAHPS).
- Educate patient about signs of a significant reaction (eg, wheezing; chest tightness; fever; itching; bad cough; blue skin color; seizures; or swelling of face, lips, tongue, or throat). Note: This is not a comprehensive list of all side effects. Patient should consult prescriber for additional questions.
Intended Use and Disclaimer: Should not be printed and given to patients. This information is intended to serve as a concise initial reference for health care professionals to use when discussing medications with a patient. You must ultimately rely on your own discretion, experience, and judgment in diagnosing, treating, and advising patients.
