اطلاعات دارویی لوفکسیدین

Lofexidine is a potent alpha2-adrenergic receptor agonist with some moderate agonistic affinity towards Alpha-1A adrenergic receptor and 5-HT1a, 5-HT7, 5HT2c and 5HT1d receptors

The alpha2-adrenergic receptor is normally targeted by norepinephrine and its activation inhibits the synthesis of cAMP which in turn leads to potassium efflux and suppression of neural firing and inhibition of norepinephrine release. All of this activity can reduce the heart rate, blood pressure, and attenuate sympathetic stress response

Opioids inhibit cAMP in the noradrenergic neurons and their discontinuation produces a rise in the level of cAMP. This will generate an increase in norepinephrine which is associated with the symptoms of withdrawal. The magnitude of the effect is augmented by chronic opioid use due to the compensatory mechanisms of continuous negative feedback. Therefore, chronic opioid use translates into an exacerbated production of cAMP and norepinephrine release

Lofexidine replaces the opioid-driven inhibition of cAMP production by activating the alpha2-adrenergic receptor and moderating the symptoms of opioid withdrawal. This effect is performed without interacting with opioid receptors which mediate other activities of opioid dependence or addiction

In clinical trials, lofexidine presented more severe opioid withdrawal effects than observed with methadone. On the other hand, in clinical trials of methadone withdrawal, lofexidine effectively reduced withdrawal symptoms, especially hypotension. The clinical reports have also indicated that lofexidine presents a better outcome when used briefly. In phase 3 clinical trials, lofexidine was shown to generate a significantly higher completion rate of opioid discontinuation. Some pharmacological studies were performed and there were no off-target effects reported

Starting dose: Three 0.18-mg tablets (0.54 mg) PO QID (5-6 hr between doses) during the period of peak withdrawal symptoms (generally the first 5-7 days after last opioid use)

Not to exceed a total daily dose of 2.88 mg (16 tablets)

No single dose should exceed 0.72 mg (4 tablets)

Treatment may be continued for up to 14 days with dosing guided by symptoms

Dose should be reduced, held, or discontinued for individuals who demonstrate a greater sensitivity

Lower doses may be appropriate as opioid withdrawal symptoms wane

Discontinue by gradually reducing dose over a 2- to 4-day period to mitigate lofexidine withdrawal symptoms (eg, reducing by 1 tablet per dose every 1-2 days)

:Hepatic Impairment
Mild (Child-Pugh score 5-6): 3 tablets QID (2.16 mg/day)
Moderate (Child-Pugh score 7-9): 2 tablets QID (1.44 mg/day)
Severe (Child-Pugh score >9): 1 tablet QID (0.72 mg/day)

:Renal Impairment
Mild or moderate (eGFR 30-89.9 mL/min/1.73 m²): 2 tablets QID (1.44 mg/day)
Severe (eGFR <30 mL/min/1.73 m²), ESRD, or dialysis: 1 tablet QID (0.72 mg/day)
May be administered without regard to timing of dialysis

May cause hypotension, bradycardia, and syncope; monitor vital signs before dosing and symptoms related to bradycardia and orthostasis; avoid use in patients with severe coronary insufficiency, recent myocardial infarction, cerebrovascular disease, chronic renal failure, and in patients with marked bradycardia

Increased risk of QT prolongation; monitor ECG in congestive heart failure, bradyarrhythmias, hepatic impairment, renal impairment, or patients taking medications that lead to QT prolongation (eg, methadone); correct any electrolyte abnormalities (eg, hypokalemia, hypomagnesemia) prior to initiating treatment

Patients administering therapy in outpatient setting should be capable of and instructed on self-monitoring for hypotension, orthostasis, bradycardia, and associated symptoms; instruct outpatients to withhold doses when experiencing symptoms of hypotension or bradycardia and to contact health care provider for guidance on how to adjust dosing; if clinically significant or symptomatic hypotension and/or bradycardia occur, next dose should be reduced in amount, delayed, or skipped

:Increased risk of opioid overdose after opioid discontinuation
Not a treatment for opioid use disorder
Patients who complete opioid discontinuation are likely to have a reduced tolerance to opioids and are at increased risk of fatal overdose should they resume opioid use
Use lofexidine in patients with opioid use disorder only in conjunction with a comprehensive management program for the treatment of opioid use disorder and inform patients and caregivers of this increased risk of overdose

:Sudden discontinuation of treatment
Stopping abruptly can cause a marked rise in blood pressure; symptoms including diarrhea, insomnia, anxiety, chills, hyperhidrosis, and extremity pain have been observed with discontinuation
Instruct patients not to discontinue therapy without consulting their healthcare provider
When discontinuing therapy with tablets, gradually reduce the dose
Manage symptoms related to discontinuation by administering the previous dose and subsequent taper

:Drug-Interaction Overview
Avoid use in combination with medications that decrease pulse or blood pressure to avoid the risk of excessive bradycardia and hypotension
Methadone and lofexidine both prolong the QT interval; monitor ECG when used concomitantly
Coadministration with naltrexone may reduce efficacy of oral naltrexone
Coadministration with CYP2D6 inhibitors: Concomitant use of paroxetine resulted in increased plasma levels of lofexidine; monitor for symptoms of orthostasis and bradycardia with concomitant use of a CYP2D6 inhibitor