Lofexidine

259.13

259.13

DTXSID7023221

N - Nervous system

33.6

5.37

Solid

1.4±0.1 g/cm3

127 °C

421.5

208.7±25.9 °C

1.611

H2O: soluble

Store in original container in a cool dark place.

9.43None

9.43

3

S24/25

Lofexidine did not exhibit genotoxic, mutagenic nor mutagenic potential. Administration at gestational period showed a reduction in the neonatal weight, survival, and increased abortion.

The protein binding of lofexidine is determined to be moderate and it represents about 55% of the administered dose.

Lofexidine is indicated for mitigation of symptoms associated with acute withdrawal from opioids and for facilitation of the completion of opioid discontinuation treatment. It is the first non-opioid medication for the symptomatic management of opioid discontinuation. Opioid withdrawal syndrome is a debilitating manifestation of opioid dependence. This condition is extremely unpleasant lasting several days with some of the main features being abdominal pain, nausea, diarrhea, mydriasis, lacrimation, and piloerection. These symptoms are often observed after abrupt reductions in the opioid dose and can be resolved by re-administration of the opioid.|FDA Label

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.

Drugs used in the treatment of acute or chronic vascular HYPERTENSION regardless of pharmacological mechanism. Among the antihypertensive agents are DIURETICS; (especially DIURETICS, THIAZIDE); ADRENERGIC BETA-ANTAGONISTS; ADRENERGIC ALPHA-ANTAGONISTS; ANGIOTENSIN-CONVERTING ENZYME INHIBITORS; CALCIUM CHANNEL BLOCKERS; GANGLIONIC BLOCKERS; and VASODILATOR AGENTS. (See all compounds classified as Antihypertensive Agents.)|Agents inhibiting the effect of narcotics on the central nervous system. (See all compounds classified as Narcotic Antagonists.)|Compounds that bind to and activate ADRENERGIC ALPHA-2 RECEPTORS. (See all compounds classified as Adrenergic alpha-2 Receptor Agonists.)

Lofexidine has a good oral bioavailability and the peak plasma concentration occurs after 2-5 hours of oral administration. The bioavailability is registered to be even higher than 72%. About 30% of the administered dose of lofexidine is lost during first-pass metabolism. The absorption is registered to be very rapidly recirculated in the gut. After oral administration of 0.8 mg of lofexidine, a maximal dose of 1.26 ng/ml is achieved after 3 hours.|The elimination of lofexidine is primarily through the renal system and it represents 94% of the administered dose while elimination in feces corresponds to only 0.93%. From the eliminated dose in urine, about 10% is formed by unchanged drug and 5% is constituted by the first hydrolysis product N-(2-aminoethyl)-2-(2,6-dichlorophenoxy)propanamide. 2,6-dichlorophenol represents the majority of the administered dose by occupying about 80% of the administered dose.|Lofexidine has a volume of distribution of 300 L, indicating that it distributes readily into the tissues.|The total elimination clearance following intravenous administration is 17.6 L/h.

Lofexidine metabolic ratio is highly variable among people. It is metabolized mainly by the activity of CYP2D6 and in a minor degree by CYP1A2 and CYP2C19. These enzymes catalyze the hydroxylation of lofexidine and the opening of imidazoline ring to form N-(2-aminoethyl)-2-(2,6-dichlorophenoxy)propanamide. This metabolite is deamidated and forms 2-(2,6-dichlorophenoxy) propionic acid and 2,6-dichlorophenol. These three main metabolites are inactive.

The reported elimination half-life of lofexidine is 11 hours.

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.

2-(alpha-(2,6-dichlorophenoxy)ethyl) delta-2-imidazoline

Human Drugs -> FDA Approved Drug Products with Therapeutic Equivalence Evaluations (Orange Book) -> Active Ingredients