Selincro 18 mg 14 pcs. film-coated tablets

Description of the drug SELINKRO

After administration of a single oral dose of 18.06 mg, nalmefene is rapidly absorbed. Cmax in blood plasma - 16.5 ng/ml - is achieved after approximately 1.5 hours. Exposure (AUC) is 131 ng×h/ml. The absolute bioavailability of nalmefene after oral administration is 41%. Concomitant administration with a high-fat meal increases total exposure (AUC) by 30% and Cmax by 50%, while plasma Tmax increases by 30 minutes, which is not considered clinically significant. Plasma protein binding is about 30%. Apparent volume of distribution (Vd/F) approx. 3200 l. According to data obtained in a positron emission tomography (PET) study, after a single and repeated dose of nalmefene at a daily dose of 18.06 mg, binding of 94-100% of receptors is achieved after 3 hours, which suggests that nalmefene easily penetrates the BBB. When taken orally, nalmefene is extensively metabolized to the major metabolite nalmethea-3-O-glucuronide, primarily by the UGT2B7 isoenzyme and, to a lesser extent, by the UGT1A3 and UGT1A8 isoenzymes. A relatively small amount of nalmefene is metabolized to nornalmefene by the isoenzyme CYP3A4/5 and nalmefene-3-O-sulfate by sulfonation. Nornalmefene in turn is converted to nornalmefene-3-O-glucuronide and nornalmefene-3-O-sulfate. The metabolites do not significantly contribute to the pharmacodynamic effects associated with opioid receptors in humans, with the exception of nalmefene-3-O-sulfate, which has comparable activity to nalmefene. However, the concentration of nalmefene-3-O-sulfate is less than 10% of the concentration of nalmefene. For this reason, it is unlikely that this metabolite makes a significant contribution to the pharmacological effects of nalmefene.

Binding to glucuronides is the main mechanism determining the clearance of nalmefene. Renal excretion is the main route of elimination of nalmefene and its metabolites. 54% is excreted in the urine in the form of nalmefene-3-O-glucuronide, nalmefene itself and its other metabolites are determined in the urine in an amount not exceeding 3% each.

The oral clearance of nalmefene (CL/F) is 169 L/h. The final T1/2 is 12.5 hours. The given data on the distribution, metabolism and excretion of nalmefene indicate its high hepatic clearance.

The pharmacokinetics of nalmefene is dose-independent and linear in the dose range from 18.06 mg to 72.24 mg. At steady state, compared with a single dose of nalmefene, there is an increase in Cmax by 4.4 times and total drug exposure (AUCinf) by 4.3 times.

When a single dose of nalmefene 18.06 mg was administered to patients with mild to moderate hepatic impairment, increased exposure to nalmefene was observed compared to healthy subjects. In patients with mild hepatic impairment, there was an increase in drug exposure by 1.5 times and a decrease in clearance by approximately 35%. In patients with moderate hepatic impairment, exposure increased by 2.9 times, Cmax by 1.7 times, and clearance decreased by approximately 60%. Changes in Tmax and T1/2 had no clinical significance in any group of patients. There are currently no data on the pharmacokinetics of nalmefene following oral administration in patients with severe hepatic impairment.

Selincro 18 mg 14 pcs. film-coated tablets

pharmachologic effect

Anti-alcohol.

Composition and release form Selincro 18 mg 14 pcs. film-coated tablets

Film-coated tablets - 1 tablet:

• active substance: nalmefene hydrochloride dihydrate - 21.917 mg. (in terms of nalmefene hydrochloride - 20 mg; in terms of nalmefene - 18.06 mg);
• excipients: MCC - 61.4 mg; lactose anhydrous - 60.683 mg; crospovidone (type A) - 4.5 mg; magnesium stearate - 1.5 mg;
• film shell: Opadry OY-S-28849 white (hypromellose (5 mPa s), macrogol 400, titanium dioxide (E171)) - 4.5 mg.

Film-coated tablets, 18 mg. 7 or 14 tablets each. in a blister pack (blister) made of PVC/PVDC and aluminum foil. 1 bl. 7 tables each; 1 or 2 bl. 14 tables each placed in a cardboard box.

Description of the dosage form

Oval, biconvex, white, film-coated tablets with an "S" embossed on one side.

Directions for use and doses

During the initial visit, before prescribing Selincro, the doctor needs to assess the patient’s clinical condition and level of alcohol consumption (in his words). In cases where additional information is required, the patient is asked to record the level of alcohol consumption for approximately the next 2 weeks. For those patients who during these 2 weeks have maintained a level of alcohol consumption comparable to the initial level, Selincro can be prescribed at a follow-up visit.

Selincro is recommended to be used in combination with psychosocial support aimed at maintaining treatment adherence and reducing alcohol consumption.

Selincro is not intended to achieve immediate abstinence from alcohol. Reducing alcohol consumption is an intermediate goal on the path to complete abstinence.

Selincro is used as needed. The decision to take the drug is made by the patient himself: on those days when, in his opinion, there is a high probability of drinking alcohol, 1-2 hours before the expected moment, 1 tablet is taken. Selincro at a dose of 18 mg. If a patient starts drinking alcohol without first taking a Selincro tablet, he needs to do this as quickly as possible.

The maximum daily dose of Selincro is 1 tablet.

In clinical studies, maximum improvement was observed during the first 4 weeks of therapy. The patient's response to treatment and the advisability of continuing pharmacotherapy should be assessed regularly (eg monthly). The physician should continually assess the patient's progress in reducing alcohol consumption, his general condition, adherence to therapy, and the occurrence of side effects. The duration of clinical studies of Selincro did not exceed 12 months, so its prescribing for more than one year should be done with caution.

Mode of application

Inside, regardless of food intake. Film-coated tablets should be taken whole. The tablets should not be divided or otherwise disrupted, as Nalmefene may cause irritation if in direct contact with skin.

Special patient groups

Elderly patients (≥65 years). In this group of patients, no dose adjustment is required.

Renal dysfunction. In patients with mild to moderate renal impairment, no dose adjustment is required.

Liver dysfunction. In patients with mild to moderate hepatic impairment, no dose adjustment is required.

Children and teenagers (up to 18 years old). The safety and effectiveness of Selincro in patients under 18 years of age have not been established. There are no data available for this age group.

Pharmacodynamics

Mechanism of action

Nalmefene is a modulator of the opioid system with pronounced affinity for μ-, δ- and κ-receptors.

In vitro studies have shown that nalmefene is a selective ligand of opioid receptors, exhibiting antagonistic properties for the μ- and δ-receptors and a partial agonist for the κ-receptors.

In vivo studies have shown that nalmefene reduces alcohol consumption, apparently by modulating corticomesolimbic functions.

Data obtained from preclinical studies, clinical studies and the literature do not suggest that nalmefene has any potential for dependence or abuse.

Clinical efficacy and safety

The effectiveness of nalmefene in reducing alcohol consumption in patients with alcohol dependence was assessed in two studies. Patients with a history of delirium tremens, hallucinations, seizures, serious mental disorders, and patients with significant impairment of liver function were excluded from the studies. Patients who had significant physical symptoms of alcohol withdrawal at the time of screening or randomization were also excluded. The majority of patients (80%) included in the studies were at high or very high risk of developing harmful consequences of alcohol use at the time of screening (according to the WHO definition of intake of >60 g/day pure alcohol for men and >40 g/day pure alcohol for women), of whom 65% remained at high or very high risk until randomization.

Both studies were randomized, double-blind, placebo-controlled, parallel group studies, and after 6 months of treatment, patients receiving nalmefene were re-randomized to receive either nalmefene or placebo for 1 month. run-out period. The effectiveness of nalmefene was also studied in a 1-year, randomized, double-blind, placebo-controlled, parallel group study. A total of 1941 patients were treated in these studies, of whom 1144 patients received nalmefene 18 mg (as needed).

During the first visit, the patient's clinical status, social situation and alcohol consumption patterns (according to the patient) were assessed. At randomization, which was carried out 1–2 weeks later, the level of risk of developing the harmful consequences of alcohol consumption was re-assessed and nalmefene therapy was prescribed in combination with a psychosocial intervention (BRENDA), aimed at maintaining treatment adherence and reducing alcohol consumption. Nalmefene was taken as needed, which accounted for an average of half the study days.

The effectiveness of nalmefene was assessed according to two main criteria: the change in the number of days of heavy drinking (HDD) per month between the baseline examination and the 6th month and the change in the daily alcohol intake (DDA) between the baseline examination and the 6th month. A traffic accident was defined as a day on which ≥60 g of pure alcohol was consumed by men and ≥40 g by women.

During the period between the baseline visit (screening) and randomization, some patients showed a significant reduction in RTA and SDA due to non-pharmacological effects. In Studies 1 (n=579) and 2 (n=655), 18 and 33% of the total study population, respectively, significantly reduced their alcohol consumption between screening and randomization. For patients at initially high and very high risk of developing harmful consequences of alcohol use, 35% of them improved due to non-pharmacological reasons between screening and randomization. In these patients, at the time of randomization, the amount of alcohol consumed was so low that the scope for further improvement was very limited (the baseline level was almost the minimum level).

Patients who remained at high and very high risk of developing harmful consequences of alcohol use between screening and randomization retrospectively constituted the target population. In this group, the treatment effect was greater than in the general population.

The clinical efficacy of nalmefene and the validity of the data were analyzed in patients at high and very high risk of developing harmful consequences of alcohol use at screening and randomization. Initially, such patients had an average of 23 accidents/month (11% of patients had less than 14 accidents/month) with a daily consumption of 106 g of pure alcohol. In most patients, the level of alcohol dependence, as measured by the Alcohol Dependence Scale, was low (0–13 points in 55% of patients) or intermediate (14–21 points in 36% of patients).

Retrospective analysis of effectiveness in patients at high and very high risk of developing harmful consequences of alcohol use at the time of randomization

In Study 1, the proportion of patients who dropped out of the study was higher in the nalmefene group than in the placebo group (50% and 32%, respectively). The number of motor vehicle crashes at baseline was 23 days per month in both the nalmefene group (n=171) and placebo group (n=167). Among patients who remained in the study and had efficacy data available at 6 months, the number of accidents was 9 days per month in the nalmefene group (n=85) and 14 days per month in the placebo group (n=114). At baseline, SDA was 102 g in the nalmefene group and 99 g in the placebo group. Among patients who remained in the study and had efficacy data available at 6 months, the MDA was 40 g in the nalmefene group and 57 g in the placebo group.

In Study 2, the proportion of patients who dropped out of the study was higher in the nalmefene group than in the placebo group (30% and 28%, respectively). At baseline, the number of traffic accidents was 23 days per month in the nalmefene group (n=148) and 22 days per month in the placebo group (n=155). Among patients who remained in the study and had efficacy data available at 6 months, the number of accidents was 10 days per month in the nalmefene group (n=103) and 12 days per month in the placebo group (n=111). At baseline, MDA was 113 g in the nalmefene group and 108 g in the placebo group. Among patients who remained in the study and had efficacy data available at 6 months, the MDA was 44 g in the nalmefene group and 52 g in the placebo group.

One-year study

The study included 665 patients, 52% of whom were at high or very high risk of developing harmful consequences of alcohol use at the time of screening, in turn, 52% of these patients (27% of the total population) remained at high or very high risk at the time of screening. randomization. In this target population, more early discontinuers were in the nalmefene group (45%) compared with discontinuations in the placebo group (31%). At baseline, the number of motor vehicle crashes was 19 days per month in both the nalmefene group (n = 141) and placebo group (n = 42). Among patients who remained in the study and had efficacy data available at 1 year, the number of motor vehicle accidents was 5 days per month in the nalmefene group (n=78) and 10 days per month in the placebo group (n=29). At baseline, SDA was 100 g in the nalmefene group and 101 g in the placebo group. Among patients who remained in the study and had efficacy data available at 1 year, the MDA was 24 g in the nalmefene group and 47 g in the placebo group.

Pharmacokinetics

Suction. After administration of a single oral dose of 18.06 mg, nalmefene is rapidly absorbed. Cmax in blood plasma - 16.5 ng/ml - is achieved after approximately 1.5 hours. Exposure (AUC) is 131 ng h/ml.

The absolute bioavailability of nalmefene after oral administration is 41%. Coadministration with a high-fat meal increases total exposure (AUC) by 30% and Cmax by 50%, with an increase in plasma Tmax by 30 minutes, which is not considered clinically significant.

Distribution. Plasma protein binding is about 30%. Apparent Vd - about 3200 l.

According to data obtained in a positron emission tomography (PET) study, after a single and repeated dose of nalmefene at a daily dose of 18.06 mg, binding of 94-100% of receptors was achieved after 3 hours, which suggests that nalmefene easily penetrates the BBB.

Biotransformation. When taken orally, nalmefene is extensively metabolized to the main metabolite nalmefene-3-O-glucuronide, mainly by the UGT2B7 isoenzyme and to a lesser extent by the UGT1A3 and UGT1A8 isoenzymes. A relatively small amount of nalmefene is metabolized to nornalmefene by the isoenzyme CYP3A4/5 and nalmefene-3-O-sulfate by sulfonation. Nornalmefene in turn is converted to nornalmefene-3-O-glucuronide and nornalmefene-3-O-sulfate. The metabolites do not significantly contribute to the pharmacodynamic effects associated with opioid receptors in humans, with the exception of nalmefene-3-O-sulfate, which has comparable activity to nalmefene. However, the concentration of nalmefene-3-O-sulfate is less than 10% of the concentration of nalmefene. For this reason, it is unlikely that this metabolite makes a significant contribution to the pharmacological effects of nalmefene.

Excretion. Binding to glucuronides is the main mechanism determining the clearance of nalmefene. Renal excretion is the main route of elimination of nalmefene and its metabolites. 54% is excreted in the urine in the form of nalmefene-3-O-glucuronide, nalmefene itself and its other metabolites are determined in the urine in an amount not exceeding 3% each.

The clearance of nalmefene when taken orally is 169 l/h. The final T1/2 is 12.5 hours. The given data on the distribution, metabolism and excretion of nalmefene indicate its high hepatic clearance.

Linearity/nonlinearity. The pharmacokinetics of nalmefene is dose-independent and linear in the dose range from 18.06 to 72.24 mg. At steady state, compared with a single dose of nalmefene, there is an increase in Cmax by 4.4 times and total drug exposure (AUC0–τ) by 4.3 times. There were no significant differences in the pharmacokinetics of nalmefene depending on gender, age or ethnicity. Body size was found to have a minimal effect on the pharmacokinetic parameters of nalmefene (clearance increases with increasing body size), but this difference is likely not clinically significant.

Renal dysfunction. There are currently no data on the pharmacokinetics of nalmefene when administered orally in patients with renal impairment. Administration of nalmefene 1 mg IV to patients with severe renal impairment resulted in a 1.6-fold increase in nalmefene exposure (dose-adjusted AUCinf) compared to healthy subjects. T1/2 increased to 26 hours compared to healthy subjects.

Liver dysfunction. When a single dose of nalmefene 18.06 mg was administered to patients with mild to moderate hepatic impairment, increased exposure to nalmefene was observed compared to healthy subjects. In patients with mild hepatic impairment, a 1.5-fold increase in drug exposure and a decrease in clearance of approximately 35% were observed. In patients with moderate hepatic impairment, exposure increased by 2.9 times, Cmax by 1.7 times, and clearance decreased by approximately 60%. Changes in Tmax and T1/2 were not clinically significant in any group of patients. There are currently no data on the pharmacokinetics of nalmefene following oral administration in patients with severe hepatic impairment.

Elderly patients. Specific studies of the pharmacokinetics of nalmefene after oral administration have not been conducted in patients aged 65 years and older. In a study with intravenous administration of nalmefene, no significant differences in pharmacokinetics were detected between age groups.

Indications for use Selincro 18 mg 14 pcs. film-coated tablets

Reducing alcohol consumption in adult patients with alcohol dependence who are at high risk of alcohol abuse, in the absence of physical manifestations of withdrawal syndrome or the need for immediate detoxification.

Selincro is recommended to be used in combination with long-term psychosocial support aimed at maintaining treatment adherence and reducing alcohol consumption.

Selincro is prescribed after 2 weeks of observation of a patient with a continuing high risk of alcohol abuse.

Contraindications

• hypersensitivity to nalmefene or any of the components of the drug;
• hereditary galactose intolerance, lactase deficiency or glucose-galactose malabsorption;
• use in patients currently taking opioid analgesics;
• current or recent opioid dependence;
• acute opioid withdrawal symptoms;
• suspected recent use of opioids;
• severe liver failure (Child-Pugh classification);
• severe renal failure (estimated glomerular filtration rate (eGFR)
• recent history of alcohol withdrawal (including hallucinations, seizures, and delirium tremens);
• pregnancy;
• breastfeeding period;
• children and adolescents (up to 18 years) (efficacy and safety of use have not been confirmed).

With caution: concomitant mental disorders in the decompensation phase (due to the lack of clinical data); history of seizure disorders, including seizures that develop during alcohol withdrawal; mild or moderate renal or liver failure, elevated levels of ALT and AST (more than 3 times the ULN); simultaneous use of powerful inhibitors of the UGT2B7 isoenzyme for a long time; elderly patients (≥65 years).

Application of Selincro 18 mg 14 pcs. film-coated tablets during pregnancy and breastfeeding

Data on the use of nalmefene in pregnant women are limited (less than 300 cases of pregnancy outcomes). Animal studies have demonstrated reproductive toxicity of nalmefene.

Animal studies have not demonstrated any direct harmful effects of nalmefene on fertility, pregnancy, embryo-fetal development, parturition or postnatal development. In an embryo-fetal toxicity study in rabbits, decreased fetal weight and delayed ossification (the process of bone formation) were observed, but no other serious abnormalities were identified.

The exposure (AUC) at the highest nontoxic dose (NOAEL) for these adverse effects was lower than the exposure at the therapeutic dose recommended for humans. An increase in the incidence of stillborn pups and a decrease in their postnatal survival have been observed in pre- and postnatal toxicity studies in rats. This effect was thought to be indirect and related to toxicity in females. Preclinical data have not identified nalmefene as being particularly hazardous to humans based on standard studies of pharmacological safety, repeated dose toxicity, genotoxicity and carcinogenic potential.

Selincro is not recommended for use during pregnancy.

Available pharmacodynamic and toxicological data in animals have shown the ability of nalmefene and metabolites to pass into breast milk. It is not known whether nalmefene passes into human breast milk.

A potential risk to newborns/infants cannot be ruled out at this time and Selincro is not recommended for use during breastfeeding.

Fertility. Studies in rats have not shown an effect of nalmefene on fertility, mating, pregnancy, or spermatogenesis.

special instructions

Selincro is not intended to achieve immediate abstinence from alcohol. Reducing alcohol consumption is an intermediate goal on the path to complete abstinence.

Opioid use. In an emergency situation when a patient taking Selincro requires the administration of opioids, the doses of the latter required to achieve the desired effect may exceed the standard ones. Patients should be closely monitored for symptoms of opioid-induced respiratory depression and other adverse reactions.

If opioid administration is necessary to provide care to a patient in an emergency, dosages must be individualized. If excessively high doses of opioids are required, the patient should be carefully monitored.

Selincro should be temporarily discontinued 1 week before the intended use of opioids, for example during elective surgery.

A physician prescribing Selincro should advise the patient to inform health care providers of the time of last use of the drug in cases where the use of opioids becomes necessary.

Caution should be exercised when medications containing opioids (such as antitussives and opioid analgesics) are used in patients already receiving Selincro therapy. Nalmefene is contraindicated in patients currently taking opioid analgesics.

Accompanying illnesses

Mental disorders. Psychiatric adverse reactions were reported during clinical trials. If the patient experiences mental disorders that are not associated with the initiation of Selincro and/or they are not temporary, the physician should consider alternative causes of these symptoms and assess the need to continue therapy with Selincro.

Selincro has not been studied in patients with unstable mental illness. Selincro should be prescribed with caution to patients with concomitant mental illnesses in the decompensation phase, incl. patients diagnosed with major depressive disorder.

Convulsive disorders. Experience with the drug in patients with a history of seizure disorders, including seizures that develop during alcohol withdrawal, is limited. Caution is recommended if Selincro is used to reduce alcohol consumption in this patient population.

Impaired kidney or liver function. Selincro is actively metabolized in the liver and is excreted primarily in the urine. For this reason, caution should be exercised when prescribing Selincro to patients with mild or moderate renal or hepatic impairment. Caution should be exercised when prescribing Selincro to patients with elevated levels of ALT and AST (more than 3 times the ULN), because this category of patients was excluded during clinical studies.

Elderly patients (≥65 years). Clinical data on the use of Selincro in alcohol-dependent patients aged 65 years and older are limited. Caution should be exercised when prescribing Selincro to patients aged 65 years and older.

Other. Caution should be exercised when using Selincro simultaneously with potent inhibitors of the UGT2B7 isoenzyme.

Lactose. Patients with rare hereditary problems such as galactose intolerance, lactase deficiency or glucose-galactose malabsorption should not use this drug.

Impact on the ability to drive vehicles and operate machinery. The effect of nalmefene on the ability to drive vehicles and operate machines has not been studied. Selincro may cause unwanted reactions such as nausea, dizziness, insomnia and headache. Most of these reactions were mild to moderate in severity and were observed only at the beginning of treatment. Patients taking Selincro are not recommended to drive vehicles or operate machinery until their individual response to the drug is determined.

Overdose

In a study of patients diagnosed with pathological gambling, nalmefene was used in doses of up to 90 mg/day for 16 weeks. In a study of patients with interstitial cystitis, 20 patients took nalmefene 108 mg/day for more than 2 years. A case of a single dose of nalmefene 450 mg has been reported, which was not accompanied by changes in blood pressure, heart rate, respiratory rate or body temperature.

In these cases, the safety profile of nalmefene was consistent with that described above in the “Side Effects” section, but observational experience is limited.

Treatment: in case of overdose, symptomatic therapy and monitoring of the patient's condition are recommended.

Side effects Selincro 18 mg 14 pcs. film-coated tablets

In clinical studies, more than 3,000 patients were treated with nalmefene. Overall, the safety profile appeared similar in all studies performed.

The most common adverse reactions were nausea, dizziness, insomnia and headache. Most of these reactions were mild to moderate in severity and were observed only at the beginning of treatment.

Confusion and, less commonly, hallucinations and dissociative disorders have also been observed in clinical studies. Most of these reactions were mild to moderate in severity and were observed only at the beginning of treatment (the first hours or days). Most of these adverse reactions resolved with continued therapy and did not recur with repeated use of the drug. These disorders, generally of a short-term nature, may be symptoms of alcoholic psychosis, alcoholic hangover syndrome or comorbid mental disorders.

The incidence of adverse reactions was calculated based on the results of three randomized, double-blind, placebo-controlled studies in patients with alcohol dependence (1144 patients received Selincro as needed and 797 received placebo as needed).

Frequency is defined as follows: very often (≥1/10), often (≥1/100 to

Drug interactions

In vivo interaction studies with other drugs have not been conducted.

Based on in vitro data, there is no evidence to suggest a clinically significant interaction between nalmefene or its metabolites and drugs metabolized by most CYP450 and UGT isoenzymes or membrane transporters. Concomitant use with drugs that are potent inhibitors of the UGT2B7 isoenzyme (for example, diclofenac, fluconazole, medroxyprogesterone acetate, meclofenamic acid) can significantly increase the exposure of nalmefene. Rare use of these drugs simultaneously with nalmefene is unlikely to lead to clinically significant consequences. At the same time, in case of long-term simultaneous use of potent inhibitors of the UGT2B7 isoenzyme, a potential increase in nalmefene exposure cannot be ruled out. Accordingly, concomitant use with UGT inducers (eg, dexamethasone, phenobarbital, rifampicin, omeprazole) may potentially result in a decrease in plasma concentrations of nalmefene below therapeutic levels.

When nalmefene is used concomitantly with opioid agonists (for example, some antitussives, colds, antidiarrheals and opioid analgesics), a decrease in their therapeutic effect may be observed.

There is no clinically significant pharmacokinetic interaction between nalmefene and alcohol.

After using nalmefene, there may be a slight deterioration in cognitive and psychomotor functions. However, the result of simultaneous administration of nalmefene and alcohol did not exceed the sum of the effects of each substance used separately.

The simultaneous use of alcohol and Selincro does not prevent the development of alcohol intoxication.

Nalmefene

Pharmacokinetics

After administration of a single oral dose of 18.06 mg, nalmefene is rapidly absorbed. Cmax in blood plasma - 16.5 ng/ml - is achieved after approximately 1.5 hours. Exposure (AUC) is 131 ng×h/ml. The absolute bioavailability of nalmefene after oral administration is 41%. Concomitant administration with a high-fat meal increases total exposure (AUC) by 30% and Cmax by 50%, while plasma Tmax increases by 30 minutes, which is not considered clinically significant. Plasma protein binding is about 30%. Apparent volume of distribution (Vd/F) approx. 3200 l. According to data obtained in a positron emission tomography (PET) study, after a single and repeated dose of nalmefene at a daily dose of 18.06 mg, binding of 94-100% of receptors is achieved after 3 hours, which suggests that nalmefene easily penetrates the BBB. When taken orally, nalmefene is extensively metabolized to the major metabolite nalmethea-3-O-glucuronide, primarily by the UGT2B7 isoenzyme and, to a lesser extent, by the UGT1A3 and UGT1A8 isoenzymes. A relatively small amount of nalmefene is metabolized to nornalmefene by the isoenzyme CYP3A4/5 and nalmefene-3-O-sulfate by sulfonation. Nornalmefene in turn is converted to nornalmefene-3-O-glucuronide and nornalmefene-3-O-sulfate. The metabolites do not significantly contribute to the pharmacodynamic effects associated with opioid receptors in humans, with the exception of nalmefene-3-O-sulfate, which has comparable activity to nalmefene. However, the concentration of nalmefene-3-O-sulfate is less than 10% of the concentration of nalmefene. For this reason, it is unlikely that this metabolite makes a significant contribution to the pharmacological effects of nalmefene.

Binding to glucuronides is the main mechanism determining the clearance of nalmefene. Renal excretion is the main route of elimination of nalmefene and its metabolites. 54% is excreted in the urine in the form of nalmefene-3-O-glucuronide, nalmefene itself and its other metabolites are determined in the urine in an amount not exceeding 3% each.

The oral clearance of nalmefene (CL/F) is 169 L/h. The final T1/2 is 12.5 hours. The given data on the distribution, metabolism and excretion of nalmefene indicate its high hepatic clearance.

The pharmacokinetics of nalmefene is dose-independent and linear in the dose range from 18.06 mg to 72.24 mg. At steady state, compared with a single dose of nalmefene, there is an increase in Cmax by 4.4 times and total drug exposure (AUCinf) by 4.3 times.

When a single dose of nalmefene 18.06 mg was administered to patients with mild to moderate hepatic impairment, increased exposure to nalmefene was observed compared to healthy subjects. In patients with mild hepatic impairment, there was an increase in drug exposure by 1.5 times and a decrease in clearance by approximately 35%. In patients with moderate hepatic impairment, exposure increased by 2.9 times, Cmax by 1.7 times, and clearance decreased by approximately 60%. Changes in Tmax and T1/2 had no clinical significance in any group of patients. There are currently no data on the pharmacokinetics of nalmefene following oral administration in patients with severe hepatic impairment.