Universal reference book for medicines
Product name: SELINCRO

Active substance: nalmefene

Type: Drug for alcohol dependence treatment

Manufacturer: H.LUNDBECK (Denmark)
Composition, form of production and packaging
The tablets covered with a film shell of
white color, oval, biconcave, with an embossed "S" on one side.

1 tab.

nalmefene hydrochloride dihydrate 21.917 mg,

which corresponds to the content of nalmefene 18 mg

[PRING] microcrystalline cellulose - 61.4 mg, anhydrous lactose - 60.683 mg, type A crospovidone - 4.5 mg, magnesium stearate - 1.5 mg.

Sheath composition: opedrai OY-S-28849 white - 4.5 mg (hypromellose (5 mPa.s), macrogol 400, titanium dioxide (E171)).

7 pcs.
- Packings contour mesh (1) - packs cardboard.
14 pcs.
- Packings contour mesh (1) - packs cardboard.
14 pcs.
- packings contour mesh (2) - packs cardboard.
INSTRUCTION FOR THE SPECIALIST.

Description of the drug approved by the manufacturer for the printed edition of 2015.

PHARMACHOLOGIC EFFECT

Mechanism of action

Nalmefene is a modulator of the opioid system with pronounced affinity for the β, β, and β receptors.

In vitro studies have shown that nalmefene is a selective ligand of opioid receptors, exhibiting properties of an antagonist for β and β receptors and a partial agonist for α-receptors.

In vivo studies have shown that nalmefene reduces alcohol consumption, apparently modulating cortico-mesolimbic functions.
Data from preclinical studies, clinical studies and literature do not imply that nalmefene has the ability to cause addiction or abuse.
Clinical efficacy and safety

The effectiveness of nalmefene in reducing alcohol consumption in patients with alcohol dependence was evaluated in two studies.
From the study excluded patients with alcohol delirium in history, hallucinations, convulsive seizures, serious mental disorders, patients with significant impairment of liver function. Also excluded were patients who, at the time of screening or randomization, showed significant physical symptoms of alcohol withdrawal. Most of the patients (80%) included in the study had a high or very high risk of developing harmful effects of alcohol use (DRL) at the time of screening (according to WHO definition> 60 g pure alcohol per day for men and> 40 g pure alcohol per day for women), of whom 65% retained a high or very high risk before randomization.
Both studies were randomized, double-blind, placebo-controlled studies in parallel groups, and after 6 months of treatment patients who received nalmefene were re-randomized to receive either nalmefene or placebo for 1 month of the so-called run-out period.
The efficacy of ialmefen was also studied in a 1-year, randomized, double-blind, placebo-controlled study in parallel groups. In total, 1941 patients were treated in these studies, of which 1144 patients received nalmefene in a dose of 18 mg as needed.
During the first visit, the clinical status of the patient, the social situation and the nature of alcohol consumption were assessed (from the patient's words).
At randomization, which was carried out after 1-2 weeks, the level of risk of development of harmful consequences of alcohol consumption was reassessed and nalmefene therapy combined with psychosocial intervention (BRENDA) aimed at maintaining adherence to treatment and reducing alcohol consumption was prescribed. Nalmefene was taken as needed, which was an average of half the days of study.
The effectiveness of nalmefene was assessed by two main criteria: a change in the number of days of heavy drunkenness (RTA) per month for the period between the baseline survey and the 6th month and the change in the daily dose of alcohol (SDA) for the period between the baseline survey and the 6th month.
Accident was defined as the day in which it was consumed? 60 g of pure alcohol by men and? 40 g by women.
In the period between the initial visit (screening) and randomization, a significant reduction in the number of road accidents and SDA caused by non-pharmacological effects was noted in some patients.
In Studies 1 (n = 579) and 2 (n = 655), 18% and 33% of the total number of patients participating in the study, respectively, significantly reduced alcohol consumption between screening and randomization. As for patients with an initially high and very high risk of developing harmful effects of alcohol use, 35% of them improved because of non-pharmacological causes between screening and randomization. In these patients, by the time of randomization, the amount of alcohol consumed was so small that the possibilities for further improvement were very limited (the baseline was almost at a minimum level). Patients who maintained a high and very high risk of developing harmful effects of alcohol use between screening and randomization, retrospectively composed the target population. In this group, the effect of treatment was more significant than in the population as a whole.
The clinical efficacy of nalmefene and the reliability of the data were analyzed in patients with a high and very high risk of developing harmful effects of alcohol use in screening and randomisation.
Initially, these patients had an average of 23 accidents per month (11% of patients - less than 14 accidents per month) with a daily intake of 106 grams 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 efficacy in patients with a high and very high risk of developing harmful effects of alcohol use at the time of randomization

In Study 1, the proportion of patients dropping out of the study was higher in the nalmefene group than in the placebo group (50% and 32%, respectively).
The number of road accidents at the initial examination was 23 days per month in both the nalmefene group (n = 171) and the placebo group (n = 167). Among patients who continued to participate in the study and who received efficacy data at 6 months, the number of road accidents was 9 days per month in the nalmefene group (n = 85) and 14 days per month in the placebo group (n = 114). At the initial examination, SDA was 102 g in the nalmefene group and 99 g in the placebo group. Among patients who continued to participate in the study and who received efficacy data at 6 months, SDA was 40 g in the nalmefen group and 57 g in the placebo group.
In Study 2, the proportion of patients dropping out of the study was higher in the nalmefene group than in the placebo group (30% and 28%, respectively).
At the initial examination, the number of road 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 continued to participate in the study and who received efficacy data at 6 months, the number of road accidents was 10 days per month in the nalmefene group (n = 103) and 12 days per month in the placebo group (n = 111). At the initial examination, SDA was 113 g in the nalmefene group and 108 g in the placebo group. Among patients who continued to participate in the study and who received efficacy data at 6 months, SDA was 44 g in the nalmefene group and 52 g in the placebo group.
An analysis of the generalized data on patients who participated in two studies responding to therapy is given in the table below.

A summary of the analysis of patients with a high and very high risk of developing harmful effects of alcohol use at the time of screening and randomization responding to therapy

Answer a Placebo Nalmefen Inequality ratio (95% Cl) p-value

SDA R70 b 19.9% ​​25.4% 1.44 (0.97, 2.13) 0.067

0-4 Accident from 16.8% 22.3% 1.54 (1.02, 2.35) 0.040

a In the analysis, patients who left the study were classified as not responding to therapy.

b Decrease by? 70% of the initial level of SOM by 6 months (28-day period).

c from 0 to 4 accidents per month to 6 months (28-day period).

For the nalmefene group, only limited performance data are available for the 1-month run-out period.

Annual research

The study included 665 patients.
52% of them had a high or very high risk of developing harmful effects of alcohol use at the time of screening; in turn, 52% of these patients (27% of the total population) retained a high or very high risk by the time of randomization. In this target population, among patients who stopped treatment prematurely, more patients were in the nalmefene group (45%) compared with patients who discontinued treatment in the placebo group (31%). At the initial examination, the number of road accidents was 19 days per month, both in the nalmefene group (n = 141) and in the placebo group (n = 42). Among patients who continued to participate in the study and who received performance data at 1 year, the number of road accidents was 5 days per month in the nalmefene group (n = 78) and 10 days per month in the placebo group (n = 29). At the initial examination, SDA was 100 g in the nalmefen group and 101 g in the placebo group. Among patients who continued to participate in the study and who received efficacy data at 1 year, SDA was 24 g in the nalmefen group and 47 g in the placebo group.
PHARMACOKINETICS

Suction


After the administration of a single oral dose, 18.06 mg of nalmefene is rapidly absorbed.
With max in blood plasma - 16.5 ng / ml - achieved after approximately 1.5 hours. The exposure (AUC) is 131 ng * h / ml.
Absolute bioavailability of nalmefene after oral administration is 41%.
Simultaneous intake with high-fat foods increases the total exposure (AUC) by 30% and C maxby 50%, while T max in the blood plasma increases by 30 min, which is not considered clinically significant.
Distribution

Binding to plasma proteins is about 30%.
Apparent volume of distribution (V d / F) about 3200 liters.
According to the data obtained during the study by positron emission tomography (PET), after single and repeated administration of nalmefene in a daily dose of 18.06 mg, binding of 94-100% of the receptors is achieved already after 3 hours, which suggests that nalmefene easily penetrates the BBB.

Viotransformation

When ingested, nalmefene undergoes extensive metabolism to the main metabolite of nalmefei-3-O-glucuronide, mainly under the action of the isoenzyme UGT2B7 and, to a lesser extent, due to the isoenzymes UGT1A3 and UGT1A8.
A relatively small amount of nalmefene is metabolized to nornalmefene by the action of the CYP3A4 / 5 isoenzyme and nalmefene-3-O-sulfate by sulfonation. Nornalmefen in turn turns into nornalmefen-3-O-glucuronide and nornalmefen-3-O-sulfate.Metabolites do not make a significant contribution to the pharmacodynamic effects associated with exposure to opioid receptors in humans, except for nalmefene-3-O-sulfate, which has a 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 development of pharmacological effects of nalmefene.
Excretion

Binding to glucuronides is the main mechanism determining the clearance of nalmefene.
Renal excretion is the main way of removing nalmefene and its metabolites.54% is excreted in the urine in the form of nalmefene-3-O-glucuronide, while nalmefene and its other metabolites are determined in urine in an amount not exceeding 3% each.
The clearance of nalmefene when ingested (CL / F) is 169 l / h.
The final T 1/2 is 12.5 hours. The data given on the distribution, metabolism and excretion of nalmefene indicate its high hepatic clearance.
Linearity / nonlinearity

The pharmacokinetics of nalmefene is dose-independent linear in the dose range from 18.06 mg to 72.24 mg.
In the equilibrium state, in comparison with a single administration of nalmefene, an increase in C max was observed 4.4-fold and a total exposure of the drug (AUC inf ) 4.3-fold. There were no significant differences in the pharmacokinetics of nalmefene, depending on sex, age or ethnicity. It has been found that the body size has a minimal effect on the pharmacokinetic parameters of nalmefene (with increasing body size, the clearance increases), but probably this difference is not clinically significant.
Impaired renal function

At present, there is no data on the pharmacokinetics of nalmefene in oral administration in patients with renal insufficiency.
Administration of 1 mg of nalmefene to / in patients with severe renal insufficiency resulted in a 1.6-fold increase in nalmefene exposure (adjusted for AUC inf ), compared with healthy subjects. T 1/2increased to 26 hours compared with healthy subjects.
Impaired liver function

When taking a single dose of nalmefene 18.06 mg in patients with mild and moderate hepatic insufficiency, an increase in the exposure of nalmefene was observed in comparison with healthy subjects.
In patients with mild hepatic insufficiency, an increase in the exposure of the drug was observed 1.5 times and a decrease in clearance by approximately 35%. In patients with moderate hepatic insufficiency, the exposure increased by 2.9 times, C max in 1.7 times, and the clearance decreased by about 60%. Changes in T max and T 1/2 did not have clinical significance in any group of patients. At present, there is no data on the pharmacokinetics of nalmefene after oral administration in patients with severe hepatic insufficiency.
Elderly patients

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

- Decrease in alcohol consumption in adult patients with alcohol dependence who have a high risk of alcohol abuse (see section "Pharmacodynamics"), 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 adherence to treatment and reducing alcohol consumption.

Celinkro is administered after two weeks of monitoring a patient with a continuing high risk of alcohol abuse.

DOSING MODE

During the initial visit, before Selincro is appointed, the doctor needs to assess the patient's clinical condition and the level of alcohol consumption (with his words).
In cases where additional information is required, the patient is asked to register the level of alcohol consumption approximately for the next two weeks. For those patients who have remained comparable to the initial level of alcohol consumption during these two weeks, Selinkro can be appointed on a second visit.
Selincro is recommended to be used in conjunction with psychosocial support aimed at maintaining adherence to treatment and reducing alcohol consumption.

Celinkro is not intended to achieve immediate abstinence from alcohol.
Reducing alcohol consumption is an intermediate goal on the road to complete abstinence.
Selinkro is applied as needed.
The decision on taking the drug is taken by the patient himself: on those days when, in his opinion, the probability of drinking is high, 1 tablet is taken 1-2 hours before the expected moment of taking. Selinkro in a dose of 18 mg. If the patient began taking alcohol without taking Selincro's pill first, he needs to do it as quickly as possible.
The maximum daily dose of Selincro is 1 tab.
Selincro can be taken regardless of the meal.
In clinical trials, the maximum improvement was observed during the first 4 weeks of therapy.
The patient's response to treatment and the appropriateness of continuing pharmacotherapy should be assessed regularly (for example, monthly). The doctor must constantly determine the progress of the patient in reducing alcohol consumption, his general condition, adherence to therapy and the occurrence of side effects. The duration of clinical studies of Selinkro did not exceed 12 months, so its appointment for a period of more than one year should be carried out with caution.
Mode of application

Tablets, covered with a film shell, should be taken whole.
Tablets should not be divided or otherwise disrupted by their integrity, since nalmefene can cause irritation in case of direct contact with the skin.
Special patient groups

The elderly (? 65 years old)

This group of patients does not require dose adjustment.

Renal impairment

In patients with mild and moderate renal failure, dose adjustment is not required.

Dysfunction of the liver

In patients with mild and moderate hepatic insufficiency, dose adjustment is not required.

Children and adolescents (under 18 years of age)

Safety and efficacy of Selincro in patients younger than 18 years of age have not been established.
There is no data for this age group.
SIDE EFFECT

In clinical trials, more than 3,000 patients received nalmefene treatment.
Overall, the safety profile looked similar in all studies conducted.
The most common adverse reactions were nausea, dizziness, insomnia and headache.
Most of these reactions had mild and moderate severity and were noted only at the beginning of treatment.
Confusion and, less commonly, hallucinations and dissociative disorders have also been observed in clinical trials.
Most of these reactions had mild and moderate severity and were noted only at the beginning of treatment (the first hours or days). Most of these unwanted reactions were resolved with continued therapy and did not resume with repeated use of the drug. These disorders are generally wearing short duration, may be symptoms of alcoholic psychosis, alcohol withdrawal syndrome or comorbid psychiatric disorders.
Calculation of the incidence of adverse side effects was conducted on the basis of results of three randomized, double-blind, placebo-controlled studies in patients with alcohol dependence (1144 patients received Selinkro mode "as needed" and 797 received placebo "as needed" mode).
The frequency is defined as follows: very common (1/10?), Common (1/100 to <1 / U?), Rarely (from 1/1000 to <1/100?), Rarely (from 1/10000 up? <1/1000), very rare (<1/10000), not known (can not be estimated from the available data).
Organs and organ systems Frequency Adverse reaction
Violations of the metabolism and nutrition often Decreased appetite
Mental Disorders Very often Insomnia
Often Sleep disorders
Confusion
Anxiety

Decreased libido (including lack of it)
is not known Hallucinations (including auditory, tactile, visual, and somatic)
Dissociative Disorders
Disorders of the nervous system is often Dizziness
Headache
Often Drowsiness
Tremor
Disorders attention
Paresthesia
hypoesthesia
Violations of the heart often tachycardia,
palpitations
Disorders of the gastrointestinal tract is often Nausea
frequent vomiting
Dry mouth
Violations of the skin and subcutaneous tissue disorders sweating often
Violations of the skeletal we echnoy and connective tissue disorders Muscle spasms often
General disorders and injection site often Fatigue
Asthenia

Malaise
oschuschunie izmenennoosti states (including mist sensation in the head, numbness)
Laboratory and instrumental data of the decline in body weight
CONTRAINDICATIONS

- nalmefene or hypersensitivity to any component of the drug;
- hereditary galactose intolerance, lactase deficiency or glucose-galactose malabsorption;
- the application of patients currently taking opioid analgesics;
- current or recent opioid dependence;
- the acute symptoms of opioid withdrawal;
- suspected recent acquisition of opioids;
- severe liver failure (in Child-Pugh classification);
- severe renal failure (calculated glomerular filtration rate (eGFR) <30 ml / min per 1.73 m 2 );
- the state of alcohol withdrawal (including hallucinations, seizures and delirium tremens) in the recent past;
- childhood and adolescence (18 years) (efficacy and safety have not been confirmed);
- pregnancy, breast-feeding.
Carefully

Comorbid psychiatric disorder in decompensation phase (in the absence of clinical data); seizure disorders history, including seizures, developing cases of alcohol;mild or moderate renal or hepatic failure, elevated levels of ALT and ACT (more than 3 times the upper limit of normal); simultaneous application of potent inhibitors isoenzyme UGT2B7 for a long time; elderly patients (? 65 years).
PREGNANCY AND LACTATION

Data on the use of nalmefene in pregnant women is limited (less than 300 pregnancy outcomes). Studies in animals have revealed reproductive toxicity nalmefene.
Studies in animals did not reveal any direct harmful effects of nalmefene in relation to fertility, pregnancy, embryo-fetal development, childbirth and post-natal development. The study embryo-fetal toxicity was observed in the rabbits decreased fetal weight and delayed ossification (bone formation), any other serious disorders have been identified. Exposure (AUC) when receiving the highest nontoxic dose (NOAEL / VNTD) for these unwanted effects was lower exposure at the therapeutic dose recommended for humans. Increased frequency of stillborn pups and decrease their postnatal survival was observed in the pre- and postnatal toxicity studies in rats. This effect was considered as indirect and related to toxicity in females.Preclinical data revealed no special hazard nalmefene for the person on the basis of standard pharmacological safety studies, toxicity after repeated use, genotoxicity and carcinogenic potential.
Selinkro not recommended for use during pregnancy.
Available pharmacodynamic and toxicological data in animals have shown the ability to penetrate nalmefene and metabolites in breast milk. It is unknown whether nalmefene in human breast milk.
At the present time we can not exclude the potential risk to newborns / infants, so Selinkro not recommended for use during breastfeeding.
Fertility

Studies in rats showed no influence on the fertility of nalmefene, the pairing process, pregnancy, or the process of spermatogenesis.
APPLICATION FOR FUNCTIONS OF THE LIVER

Precautions apply to patients with mild or moderate renal insufficiency.
Use of the drug in patients with severe renal impairment is contraindicated.
APPLICATION FOR VIOLATIONS OF THE FUNCTION OF KIDNEYS

Precautions apply to patients with mild to moderate hepatic impairment.
Use of the drug in patients with severe liver failure (classification Child-Pugh) is contraindicated.
APPLICATION FOR CHILDREN

Use of the drug for children and adolescents (under 18 years) is contraindicated (efficacy and safety have not been confirmed).
APPLICATION IN ELDERLY PATIENTS

Be wary of the drug to elderly patients (? 65 years). In this group of patients dose adjustment is required.
SPECIAL INSTRUCTIONS

Selinkro is not intended to achieve immediate abstinence from alcohol. Reducing alcohol consumption is an interim target on the way to total abstinence.
The use of opioids
in the emergency situation where a patient receiving Selinkro necessary administration of opioids, the doses of the latter required to achieve the desired effect may exceed the standard. Thus it is necessary to closely monitor symptoms of respiratory depression resulting from opioid administration, and other adverse reactions.
If the patient care in an emergency situation requires the introduction of opioids and their dose should be selected individually. In the event that requires the use of very high doses of opioids, should be carefully monitored for the patient's condition.
Selinkro to temporarily cancel 1 week prior to the intended use of opioids, such as during routine surgery.
The doctor, appointing Selinkro, should advise the patient to inform health care providers about the last dose in time when it becomes necessary to use opioids.
Care must be taken when the medicinal preparations containing opioids (e.g., antitussive drugs and opioid analgesics) are used in patients already receiving therapy Selinkro.
Nalmefene is contraindicated in patients currently taking opioid analgesics.
Concomitant diseases
Mental disorders
During the clinical trials reported adverse reactions on the part of the psyche (see. Section "Side effects"). If the patient has disorders of the psyche that are not related to the beginning of the application Selinkro and / or they are not temporary, the physician should consider alternative causes of these symptoms and to assess the need for continued therapy with Selinkro.
Selinkro has not been studied in patients with unstable over mental illness. Selinkro be administered with caution to patients with concomitant mental illness in decompensation phase including patients diagnosed with "major depressive disorder".
convulsive disorders
The experience of the drug in patients with seizure disorders history, including seizures, developing cases of alcohol is limited. We recommend caution when Selinkro used to reduce alcohol consumption in this group of patients.
Impaired renal or hepatic function
Selinkro actively metabolized in the liver and excreted predominantly in the urine. For this reason, caution should be exercised when assigning Selinkro patients with mild or moderate renal or hepatic insufficiency. Care must be taken when assigning Selinkro patients with elevated ALT and ACT (more than 3 times the upper limit of normal), as This category of patients excluded in clinical trials.
Elderly patients (? 65 years)
Clinical data on the use Selinkro in alcohol-dependent patients aged 65 years and older is limited. Caution should be exercised in the appointment Selinkro patients aged 65 years and older.
Other
Caution must be exercised while the use Selinkro with potent inhibitors isoenzyme UGT2B7.
Lactose
Patients with rare hereditary problems such as galactose intolerance, lactase deficiency or glucose-galactose malabsorption should not use this drug.
Influence on ability to drive vehicles and work with mechanisms

Nalmefene influence on the ability to drive vehicles and operate machinery has not been studied.
Selinkro may cause undesirable reactions such as nausea, dizziness, insomnia and headache. Most of these reactions had mild to moderate severity and was observed only at the beginning of treatment.
Patients taking Selinkro, it is not recommended to drive and use machines as long as has been ascertained individual reaction to the drug.
OVERDOSE

In a study in patients diagnosed with pathological gambling nalmefene applied in doses up to 90 mg / day for 16 weeks. In a study in patients with interstitial cystitis 20 patients received nalmefene dose of 108 mg / day for more than 2 years. It reported on single dose ialmefena case 450 mg, which is not accompanied by changes in blood pressure, heart rate, respiration rate or body temperature.
In these cases, the safety profile of nalmefene was consistent with that described above in the section "Side effects", but the experience of seeing limited.
Treatment

In case of overdose symptomatic therapy is recommended, and monitoring of the patient.
DRUG INTERACTION

Studies of interaction with other drugs in vivo was conducted.
According to studies in vitro data no reason to assume the existence of clinically significant interaction between the nalmefene or its metabolites and drugs undergoing metabolism involving most CYP450 isozymes and UGT or membrane carriers. The simultaneous use of drugs, which are potent inhibitors izofermemta UGT2B7 (e.g., diclofenac, fluconazole, medroxyprogesterone acetate, meclofenamic acid), can significantly increase the exposure of nalmefene. Rare use of these drugs simultaneously with nalmefene can hardly lead to clinically significant consequences. At the same time, in the case of simultaneous use of long potent inhibitors isoenzyme UGT2B7, we can not exclude possible potentially increasing exposure nalmefene (see.section "Special instructions and precautions"). Accordingly, the simultaneous application of inductors UGT (e.g., dexamethasone, phenobarbital, rifampin, omeprazole) can potentially lead to a decrease in the plasma concentration of nalmefene below therapeutic level.
In the case of nalmefene simultaneously with opioid agonists (eg, certain antitussive, cough, lrotivodiareynye agents and opioid analgesics) may experience a decrease in their therapeutic effect (see. Section "Special instructions and precautions").
There are no clinically significant pharmacokinetic interaction between the nalmefene and alcohol.
After application of nalmefene may experience little deterioration in cognitive and psychomotor functions. However, the result of simultaneous reception and nalmefene alcohol does not exceed the sum of the effects of each agent used singly.
Concomitant use of alcohol and Selinkro does not prevent the development of alcohol intoxication.
TERMS OF RELEASE FROM PHARMACY

The drug is released by prescription.

TERMS AND CONDITIONS OF STORAGE

The drug should be stored out of reach of children at a temperature of no higher than 30 ° C.
Shelf life - 3 years.
Do not use after the expiration date printed on the package.

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