Lofexidine
Lofexidine Uses, Dosage, Side Effects, Food Interaction and all others data.
Lofexidine is a non-opioid centrally acting alpha2-adrenergic receptor agonist that was first approved for the treatment of opioid withdrawal in the United Kingdom in 1992. It was first studied for use as an antihypertensive in 1980, but its researched was stopped as it was found less effective for the treatment of hypertension than clonidine. Lofexidine was then repurposed for the treatment of opioid withdrawal, as it was seen to be more economical and have fewer side effects than clonidine. Lofexidine was developed by US Woldmeds LLC and it was approved by the FDA on May 16, 2018.
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.
| Trade Name | Lofexidine |
| Availability | Prescription only |
| Generic | Lofexidine |
| Lofexidine Other Names | Lofexidina, Lofexidine, Lofexidinum |
| Related Drugs | Subutex, Sublocade, Zubsolv, Probuphine, Buprenex, Bunavail, methadone, chlorpromazine, Thorazine, Dolophine |
| Type | |
| Formula | C11H12Cl2N2O |
| Weight | Average: 259.132 Monoisotopic: 258.03266843 |
| Protein binding | The protein binding of lofexidine is determined to be moderate and it represents about 55% of the administered dose. |
| Groups | Approved, Investigational |
| Therapeutic Class | |
| Manufacturer | |
| Available Country | United States |
| Last Updated: | September 19, 2023 at 7:00 am |
Uses
Lofexidine is a centrally acting alpha2-adrenergic agonist used for the symptomatic treatment of acute opioid withdrawal syndrome to facilitate abrupt opioid discontinuation in adults.
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.
Lofexidine is also used to associated treatment for these conditions: Abrupt opioid withdrawal
How Lofexidine works
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.
Toxicity
Lofexidine did not exhibit genotoxic, mutagenic nor mutagenic potential. Administration at gestational period showed a reduction in the neonatal weight, survival, and increased abortion.
Food Interaction
- Avoid excessive or chronic alcohol consumption. Lofexidine may potentiate the CNS depressant effects of alcohol.
- Take with or without food.
[Moderate] GENERALLY AVOID: Alcohol may potentiate some of the pharmacologic effects of CNS-active agents.
Use in combination may result in additive central nervous system depression and
MANAGEMENT: Patients receiving CNS-active agents should be warned of this interaction and advised to avoid or limit consumption of alcohol.
Ambulatory patients should be counseled to avoid hazardous activities requiring complete mental alertness and motor coordination until they know how these agents affect them, and to notify their physician if they experience excessive or prolonged CNS effects that interfere with their normal activities.
Lofexidine Drug Interaction
Major: citalopram, escitalopramModerate: aripiprazole, loxapine, lorazepam, buprenorphine, nebivolol, acetaminophen / butalbital / caffeine, benazepril, prazosin, quetiapine, carisoprodolUnknown: amphotericin b lipid complex, isotretinoin, tocilizumab, corticotropin, alteplase, amphetamine / dextroamphetamine, lacosamide, cholecalciferol
Lofexidine Disease Interaction
Major: hypotensionModerate: alcoholism, hepatic impairment, QT prolongation, renal impairment
Volume of Distribution
Lofexidine has a volume of distribution of 300 L, indicating that it distributes readily into the tissues.
Elimination Route
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.
Half Life
The reported elimination half-life of lofexidine is 11 hours.
Clearance
The total elimination clearance following intravenous administration is 17.6 L/h.
Elimination Route
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.
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