Selinkro

General characteristics. Structure:

Active ingredient: 21,917 mg of a nalmefen of a hydrochloride of a dihydrate in terms of a nalmefen a hydrochloride of 20,0 mg, in terms of налмефен 18,06 mg.

Excipients: cellulose of microcrystallic 61,4 mg, lactose of anhydrous 60,683 mg, кросповидон (type A) of 4,5 mg, magnesium stearate of 1,5 mg.

Film cover: опадрай OY-S-28849 of white 4,5 mg (gipromelloz (5mpa.s), macrogoal 400, titanium dioxide (E171)).

Pharmacological properties:

Pharmacodynamics. Action mechanism. Nalmefen is the modulator of opioid system with the expressed affinity µ-, δ-and to k-receptors.

- The researches in vitro showed what налмефен is the selection ligand of opioid receptors, showing properties of the antagonist in the relation µ-and δ-receptors and a partial agonist concerning k-of receptors.
- The researches in vivo showed what налмефен reduces alcohol consumption, most likely, modulating kortiko-mesolimbic functions.

The data obtained from preclinical trials, clinical trials and literature do not assume existence at a nalmefen of ability to cause dependence or abuse.

Clinical performance and safety. Efficiency of a nalmefen in decrease in consumption of alcohol at patients with alcohol addiction was estimated in two researches. Patients with a tremens in the anamnesis, hallucinations, convulsive attacks, serious mental disorders, patients with considerable disturbance of functions of a liver were excluded from researches. Also patients at whom at the time of screening or randomization the expressed physical symptoms of cancellation of alcohol were revealed were excluded. A big part of the patients (80%) included in researches at the time of screening had high or very high risk level of development of harmful effects of alcohol intake (DRL) (according to definition of WHO reception> 60 g of pure alcohol a day for men and> 40 g of pure alcohol a day for women), from them 65% kept high or very much a high risk until randomization.

Both researches were randomized, double blind people, placebo - controlled researches in parallel groups, and in 6 months of treatment the patients receiving налмефен were repeatedly randomizirovana to receive or налмефен, or placebo within 1 month of so-called run-out of the period. Efficiency of a nalmefen was also studied in the 1-year randomized, double blind person, placebo - a controlled research in parallel groups. In total in these researches 1941 patients from which 1144 patients received налмефен in a dose 18 mg as necessary were treated.

During the first visit the clinical status of the patient, a social situation and the nature of consumption of alcohol was estimated (according to the patient). At randomization which was carried out 1-2 weeks later risk level of development of harmful effects of alcohol intake was repeatedly estimated and therapy nalmefeny in a complex with psychosocial intervention (BRENDA) directed to maintenance of commitment to treatment and decrease in consumption of alcohol was appointed. Nalmefen was accepted as necessary that averaged a half of days of stay in a research.

Efficiency of a nalmefen was estimated by two main criteria: change of number of the days of heavy alcoholism (DHA) in a month for the period between initial inspection and 6th month and change of the daily dose of alcohol (DDA) for the period between initial inspection and 6th month. Was defined by road accident as day in which it was consumed> 60 g of pure alcohol men and> 40 g women.

During the period between an initial visit (screening) and randomization at some patients the significant reduction of road accident and SDA caused by not pharmacological effects was noted. In Researches 1 (n=579) and 2 (n = 655) 18% and 33% of total number of the patients participating in a research, respectively, considerably reduced consumption of alcohol during the period between screening and randomization. As for patients with initially high and very high risk of development of harmful effects of alcohol intake, from them at 35% indicators improved in connection with not pharmacological reasons during the period between screening and randomization. These patients by the time of randomization had so small amount of the consumed alcohol that possibilities of further improvement were very limited (initial level almost corresponded to minimum). The patients who kept high and very high risk levels of development of harmful effects of alcohol intake between screening and randomization retrospectively made target population. In this group the effect of treatment was more significant, than in population in general.

Clinical performance of a nalmefen and reliability of data were analyzed at patients with high and very high risk of development of harmful effects of alcohol intake during the screening and randomization. Initially at such patients 23 road accidents a month were observed on average (at 11% of patients - less than 14 road accidents a month) at daily consumption of 106 g of pure alcohol. Most of patients had a low the level of alcohol addiction measured on the Scale of alcohol addiction (0-13 points at 55% of patients) or intermediate (14-21 points at 36% of patients).

The retrospective analysis of efficiency at patients with high and very high risk level of development of harmful effects of alcohol intake at the time of randomization.

In the Research 1 share of the patients who left a research was higher in group of a nalmefen, than in group of placebo (50% and 32% respectively). The number of road accident at initial inspection made 23 days a month both in group of a nalmefen (n=171), and in group of placebo (n=167). Among the patients who continued participation in a research and at which data on efficiency in 6 months were obtained the number of road accident made 9 days a month in group of a nalmefen (n=85) and 14 days a month in group of placebo (n=114). At initial inspection of SDA made 102 g in group of a nalmefen and 99 g in group of placebo. Among the patients who continued participation in a research and at which data on efficiency in 6 months were obtained SDA made 40 g in group of a nalmefen and 57 g in group of placebo.

In the Research 2 the share of the patients who left a research was higher in group of a nalmefen, than in group of placebo (30% and 28% respectively). At initial inspection the number of road accident made 23 days a month in group of a nalmefen (n=148) and 22 days a month in group of placebo (n=155). Among the patients who continued participation in a research and at which data on efficiency in 6 months were obtained the number of road accident made 10 days a month in group of a nalmefen (n=103) and 12 days a month in group of placebo (n=111). At initial inspection of SDA made 113 g in group of a nalmefen and 108 g in group of placebo. Among the patients who continued participation in a research and at which data on efficiency in 6 months were obtained SDA made 44 g in group of a nalmefen and 52 g in group of placebo.

The analysis of the generalized data on the patients who were participating in two researches, answered therapy is given in the table below.

The generalized results of the analysis of patients with high and very high risk of development of harmful effects of alcohol intake at the time of the screening and randomization which answered therapy:

Answer	Placebo	Nalmefen	Inequality coefficient (95% of CI)	p-size
SDA R70b	19,9%	25,4%	1,44 (0,97; 2,13)	0,067
0-4 DTPS	16,8%	22,3%	1,54 (1,02; 2,35)	0,040

When carrying out the analysis of the patients who left a research classified as not answered therapy.
B-reduction on> 70% of the SDA initial level by 6th month (the 28-day period) from from 0 to 4 road accidents a month by 6th month (the 28-day period).

For group of a nalmefen there are only limited data on efficiency received during 1-month run-out of the period.

Year research. The research included 665 patients. 52% from them had high or very high risk of development of harmful effects of alcohol intake at the time of screening, in turn, 52% of these patients (27% of the general population) kept high or very much a high risk by the time of randomization. In this target population among more patients who ahead of schedule stopped treatment of patients was in group of a nalmefen (45%) in comparison with the patients who stopped treatment in group of placebo (31%). At initial inspection the number of road accident made 19 days a month both in group of a nalmefen (n=141), and in group of placebo (n=42). Among the patients who continued participation in a research and at which data on efficiency in 1 year were obtained the number of road accident made 5 days a month in group of a nalmefen (n=78) and 10 days a month in group of placebo (n=29). At initial inspection of SDA made 100 g in group of a nalmefen and 101 g in group of placebo. Among the patients who continued participation in a research and at which data on efficiency in 1 year were obtained SDA made 24 g in group of a nalmefen and 47 g in group of placebo.

Pharmacokinetics. Absorption. After introduction of a single peroral dose of 18,06 mg налмефен it is quickly soaked up. The maximum concentration in a blood plasma (Cmax) - 16,5 ng/ml – is reached approximately in 1,5 h. Exposure (AUC) makes 131 ¡ú*þ/ml.

Absolute bioavailability of a nalmefen after intake makes 41%. The concomitant use with food with the high content of fats increases the general exposure (AUC) by 30% and Cmax for 50%, at the same time time of achievement of the maximum concentration in a blood plasma (Tmax) increases for 30 min. that is not considered clinically significant.

Distribution. Linkng with proteins of plasma makes about 30%. The seeming volume of distribution (Vd/F) about 3200 l.

According to the data obtained during the research by the positron emission tomography (PET) after single and repeated dose of a nalmefen in a daily dose of 18,06 mg binding of 94-100% of receptors is reached already in 3 h that assumes what налмефен easily gets through a blood-brain barrier.

Biotransformation. At intake налмефен is exposed to extensive metabolism to the main metabolite налмефен - 3 mainly mainly under the influence of an isoenzyme of UGT2B7 and, to a lesser extent, at the expense of isoenzymes of UGT1A3 and UGT1A8. Rather small amount of a nalmefen is metabolized to a nornalmefen under the influence of an isoenzyme of CYP3A4/5 and налмефен - the 3rd sulphonation by sulphonation. Nornalmefen in turn turns in норналмефен - 3 and and норналмефен - 3........... Metabolites do not make a significant contribution to the pharmakodinamichesky effects connected with impact on opioid receptors at people behind an exception налмефен - 3, which has comparable with nalmefeny activity. However concentration налмефен - 3 makes makes less than 10% of concentration of a nalmefen. For this reason it is improbable that this metabolite makes a significant contribution to development of pharmacological effects of a nalmefen.

Removal. Linkng with glucuronides is the main mechanism defining clearance of a nalmefen. Renal excretion is the main way of removal of a nalmefen and its metabolites. 54% are removed with urine in a look налмефен - 3, itself налмефен and other its metabolites are defined in urine in the quantity which is not exceeding 3% everyone. The clearance of a nalmefen at intake (CL/F) makes 169 l/h. The final elimination half-life (T½) is equal to 12,5 h. The provided data on distribution, metabolism and removal of a nalmefen confirm its high hepatic clearance.

Linearity/nonlinearity. The pharmacokinetics of a nalmefen has dozonezavisimy linear character in the range of doses from 18,06 mg to 72,24 mg. In an equilibrium state in comparison with a single dose of a nalmefen increase in Cmax by 4,4 times and the general exposure of drug (AUC0 tau) by 4,3 times is observed. Significant distinctions in pharmacokinetics of a nalmefen depending on a sex, age or an ethnic origin are not revealed. It is revealed that the body size in the minimum degree influences pharmacokinetic parameters of a nalmefen (with increase in the size of a body the clearance increases), but probably this distinction is not clinically significant.

Renal failure. Now patients have no data on pharmacokinetics of a nalmefen at oral administration with a renal failure. Introduction of 1 mg of a nalmefen intravenously to patients with a heavy renal failure led to increase in exposure of a nalmefen (AUCinf corrected taking into account a dose) by 1,6 times in comparison with healthy subjects. The elimination half-life increased to 26 h in comparison with healthy subjects.

Abnormal liver function. At reception of a single dose of a nalmefen of 18,06 mg at patients with a slight and moderate liver failure increase in exposure of a nalmefen in comparison with healthy subjects was observed. At patients with a slight liver failure increase in exposure of drug by 1,5 times and decrease in clearance approximately by 35% was observed.

At patients with a moderate liver failure exposure increased by 2,9 times, Cmax by 1,7 times, and the clearance decreased approximately by 60%. Changes of Tmax and T½ had no clinical value in one group of patients. Now patients have no data on pharmacokinetics of a nalmefen after oral administration with a heavy liver failure.

Elderly patients. Also is more senior than special researches of pharmacokinetics of a nalmefen after oral administration at patients at the age of 65 years it was not carried out. In a research with intravenous administration of a nalmefen significant distinctions of pharmacokinetics between age groups are not revealed.

Indications to use:

Decrease in consumption of alcohol at the adult patients with alcohol addiction having high risk of an alcohol abuse (see the section "Pharmacodynamics"), in the absence of physical manifestations of a withdrawal or need of carrying out an immediate detoxication.

It is recommended to Selinkro to apply in combination with the long psychosocial support directed to preservation of commitment to treatment and decrease in consumption of alcohol.

Selinkro is appointed after two weeks of observation of the patient with the remaining high risk of an alcohol abuse.

Route of administration and doses:

During primary visit, before Selinkro's appointment, the doctor needs to estimate a clinical condition of the patient and level of consumption of alcohol (from his words). In cases where additional information is required, the patient is offered to register level of consumption of alcohol approximately within the next two weeks. To those patients at whom for these two weeks level of consumption of alcohol remained comparable with initial Selinkro can be appointed at a repeated visit.

It is recommended to Selinkro to apply in combination with the psychosocial support directed to preservation of commitment to treatment and decrease in level of consumption of alcohol.

Selinkro is not intended for achievement of immediate abstention from alcohol. Decrease in consumption of alcohol is the intermediate purpose on the way to full abstention.

Selinkro is applied as necessary. The decision on administration of drug is made by the patient: those days when, in his opinion, the probability of alcohol intake is high, in 1-2 hours prior to the estimated moment of reception 1 pill of Selinkro in a dose of 18 mg is taken. If the patient began to accept alcohol, without having taken previously Selinkro's pill, he needs to make it as soon as possible.

The maximum daily dose of Selinkro makes 1 tablet. Selinkro can be accepted regardless of meal.

During clinical trials the maximum improvement was observed within the first 4 weeks of therapy. The response of the patient to treatment and expediency of continuation of pharmacotherapy needs to be estimated regularly (for example, monthly). The doctor has to define constantly progress of the patient in decrease in consumption of alcohol, its general condition, commitment of therapy and emergence of side effects. Duration of clinical trials of Selinkro did not exceed 12 months therefore its appointment to term more than one year has to be carried out with care.

Tablets, film coated, it is necessary to accept entirely. Tablets should not be divided or to otherwise break their integrity as налмефен can cause irritation in case of direct contact with skin.

Special groups of patients. Elderly (> 65 years). It is not required from this group of patients of dose adjustment.

Renal failures. With a slight and moderate renal failure of dose adjustment it is not required from patients.

Abnormal liver functions. With a slight and moderate liver failure of dose adjustment it is not required from patients.

Children and teenagers (up to 18 years). Safety and Selinkro's efficiency at patients are younger than 18 years is not established. Data on this age group are absent.

Features of use:

Selinkro is not intended for achievement of immediate abstention from alcohol. Decrease in consumption of alcohol is the intermediate purpose on the way to full abstention.

Use of opioids. In emergency situation when the patient accepting Selinkro needs administration of opioids, the doses of the last which are required for achievement of desirable effect can exceed standard. At the same time it is necessary to trace attentively symptoms of the respiratory depression which is result of administration of opioids and other undesirable reactions.

If assistance to the patient in emergency situation requires administration of opioids, their doses have to be selected individually. In case use of too high doses of opioids is required, it is necessary to watch a condition of the patient carefully.

Selinkro needs to cancel temporarily in 1 week prior to intended application of opioids, for example, during planned surgical intervention.
The doctor appointing Selinkro has to recommend to the patient to report to health workers about time of the last administration of drug in cases when there is necessary a use of opioids.

It is necessary to be careful in case the medicines containing opioids (for example, antibechic drugs and opioid analgetics), are applied at the patients who are already receiving Selinkro's therapy. Nalmefen is contraindicated at the patients accepting now opioid analgetics.

Associated diseases. Mental disorders. During conduct of clinical trials it was reported about side reactions from mentality (see the section "Side effect"). If the patient has frustration from mentality which are not connected with the beginning of use of Selinkro and/or they are not temporary, the doctor has to consider alternative origins of these symptoms and estimate need of continuation of therapy by Selinkro's drug.

Selinkro was not investigated at patients with the unstable course of mental diseases. It is necessary to appoint Selinkro with care to patients with the accompanying mental diseases in a decompensation phase, including to patients with the diagnosis "big depressive frustration".

Convulsive frustration. Experience of use of drug for patients with convulsive frustration in the anamnesis, including the spasms developing at alcohol cancellation is limited. It is recommended to be careful if Selinkro is applied for the purpose of reduction of consumption of alcohol in this group of patients.

Renal failure or liver. Selinkro is actively metabolized in a liver and brought preferential with urine. For this reason patients should be careful at Selinkro's appointment with a slight or moderate renal or liver failure. It is necessary to be careful at Selinkro's appointment to patients with the increased ALT and nuclear Heating Plant level (more, than by 3 times exceeding upper limits of norm) as this category of patients was excluded during clinical trials.

Elderly patients (> 65 years). Clinical data on Selinkro's use for patients with alcohol addiction at the age of 65 years are also more senior are limited. It is necessary to be careful at Selinkro's appointment to patients at the age of 65 years and is more senior.

Others. It is necessary to be careful at simultaneous use of Selinkro with powerful inhibitors of an isoenzyme UGT2B7.

Lactose. Patients with such rare hereditary problems as intolerance of a galactose, deficit of lactase or glyukozo-galaktozny malabsorption should not use this drug.

Use at pregnancy and during breastfeeding. Data on use of a nalmefen for pregnant women are limited (less than 300 cases of result of pregnancy). Researches at animals revealed reproductive toxicity of a nalmefen.

Researches at animals did not reveal direct harmful effects of a nalmefen concerning fertility, pregnancy, embrio-fetalis development, childbirth and post-natal development. In a research of embrio-fetalis toxicity at rabbits decrease in mass of a fruit and a delay of ossification (process of formation of a bone tissue) was observed, any other serious violations it was not revealed. Exposure (AUC) at reception of the highest nontoxic dose (NOAEL/VNTD) at these undesirable effects was below exposure at reception of the therapeutic dose recommended for the person. Increase in frequency of appearance of mortinatus cubs and reduction of their post-natal survival was observed in researches pre-and post-natal toxicity at rats. This effect was considered indirect and connected with toxicity at females. Preclinical data did not reveal special danger of a nalmefen to the person on the basis of standard researches of pharmacological safety, toxicity at repeated use, genotoxicity and cancerogenic potential.

It is not recommended to Selinkro to apply during pregnancy. Available pharmakodinamichesky and toxicological data at animals showed ability of a nalmefen and metabolites to get into breast milk. It is unknown whether gets налмефен into breast milk of the person.

Now it is impossible to exclude potential risk for newborns/babies therefore it is not recommended to Selinkro to apply during breastfeeding.

Fertility. Researches on rats did not reveal influence of a nalmefen on fertility, pairing process, pregnancy, or process of a spermatogenesis.

Influence on driving of the car and work with mechanisms. Influence of a nalmefen on ability to manage vehicles and to work with mechanisms it was not studied.

Selinkro can cause undesirable reactions, such as nausea, dizziness, sleeplessness and a headache. The most part of these reactions had easy and moderate severity and was noted only in an initiation of treatment.

The patients accepting Selinkro are not recommended to manage vehicles and to work with mechanisms until individual reaction to drug is found out.

Side effects:

In clinical trials more than 3000 patients received treatment nalmefeny. In general, the profile of safety looked in a similar way in all the conducted researches.

Nausea, dizziness, sleeplessness and headache were the most widespread undesirable reactions. The most part of these reactions had easy and moderate severity and was noted only in an initiation of treatment.

Confusion of consciousness and, more rare, hallucinations and dissociative frustration were also observed during clinical trials. The most part of these reactions had easy and moderate severity and was noted only in an initiation of treatment (the first hours or days). The majority of similar undesirable reactions was allowed at continuation of therapy and was not resumed at repeated use of drug. These frustration in general having short-term character can be symptoms of alcoholic psychoses, an alcoholic hungover syndrome or komorbidny mental disorders.

Calculation of frequency of undesirable side reactions was carried out on the basis of results of three randomized, double blind people, placebo of controlled researches at patients with alcohol addiction (1144 patients received Selinkro in the mode "as necessary" and 797 received placebo in the mode "as necessary").

Frequency is defined as follows: very often (> 1/10), it is frequent (from> 1/100 to <1/10), infrequently (from> 1/1000 to <1/100), is rare (from> 1/10000 to <1/1000), is very rare (<1/10000), it is unknown (not possibly to estimate on the basis of the available data).

Bodies and systems of bodies	Frequency	Undesirable reaction
Disturbances from a metabolism and food	Often	Loss of appetite
Disturbances of mentality	Very often	Sleeplessness
	Often	Frustration of a dream
		Confusion of consciousness
		Concern
		Decrease in a libido (including absence)
	It is unknown	Hallucinations (including acoustical, tactile, visual and somatic)
		Dissociative frustration
Disturbances from a nervous system	Very often	Dizziness
		Headache
	Often	Drowsiness
		Tremor
		Disorders of attention
		Paresthesia
		Hypesthesia
Disturbances from heart	Often	Tachycardia
		Heart consciousness
Disturbances from digestive tract	Very often	Nausea
	Often	Vomiting
		Dryness in a mouth
Disturbances from skin and hypodermic fabrics	Often	The increased sweating
Disturbances from skeletal and muscular and connecting fabric	Often	Muscular spasms
The general frustration and disturbances in an injection site	Often	Fatigue
		Adynamy
		Indisposition
		Feeling of an izmenennost of a state (including feeling of fog in the head, catalepsy)
Laboratory and tool data	Often	Decrease in body weight

Interaction with other medicines:

Interaction researches with other in vivo medicines were not conducted.

According to data of the researches in vitro there are no bases to assume existence of clinically significant interaction between nalmefeny or its metabolites and medicines which are exposed to metabolism with participation of the majority of isoenzymes of CYP450 and UGT or membrane carriers.

Simultaneous use with the drugs which are powerful inhibitors of an isoenzyme UGT2B7 (for example, diclofenac, флуконазол, a medroksiprogesterona acetate, meklofenamovy acid), can increase exposure of a nalmefen considerably.

Rare use of these medicines along with nalmefeny can hardly lead to clinically significant effects.

In too time, in case of prolonged simultaneous use of powerful inhibitors of an isoenzyme of UGT2B7, it is impossible to exclude potentially possible increase in exposure of a nalmefen (see the section "Special Instructions and Precautionary Measures"). Respectively simultaneous use with the inductors UGT (for example, dexamethasone, phenobarbital, rifampicin, омепразол) can potentially lead to decrease in concentration of a nalmefen in plasma below therapeutic level.

In case of use of a nalmefen along with opioid agonists (for example, some antibechic, cold, antidiarrheal remedies and opioid analgetics) decrease in their therapeutic effect can be observed (see the section "Special Instructions and Precautionary Measures").

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

After use of a nalmefen insignificant deterioration in cognitive and psychomotor functions can be noted. However the result of a concomitant use of a nalmefen and alcohol did not surpass the sum of effects of each substance applied separately.

Simultaneous use of alcohol and Selinkro does not prevent development of a drunkenness.

Contraindications:

• Hypersensitivity to a nalmefen or any of drug components; hereditary intolerance of a galactose, deficit of lactase or glyukozo-galaktozny malabsorption.
• Use for the patients accepting now opioid analgetics.
• Current or recent opioid dependence.
• Acute symptoms of cancellation of opioids.
• Suspicion on recent reception of opioids.
• Heavy liver failure (classification by Chayld-Pyyu).
• Heavy renal failure (the calculated glomerular filtration rate (RSKF) <30 ml/min. on 1,73 sq.m).
• Condition of cancellation of alcohol (including hallucinations, spasms and a tremens) in the recent past.
• Children's and teenage age (up to 18 years) (efficiency and safety of use are not confirmed).
• Pregnancy, breastfeeding period.

With care: the accompanying mental disorders in a decompensation phase (due to the lack of clinical data); convulsive frustration in the anamnesis, including the spasms developing at alcohol cancellation; a slight or moderate renal or liver failure, the increased ALT and nuclear Heating Plant level (more, than by 3 times exceeding the upper bound of norm); simultaneous use of powerful inhibitors of an isoenzyme of UGT2B7 for a long time; elderly patients (> 65 years).

Overdose:

In a research at patients with the diagnosis of pathological addiction to gamblings налмефен it was applied in doses to 90 mg/days for 16 weeks. In a research at patients with intersticial cystitis of 20 patients accepted налмефен in a dose 108 mg/days for more than 2 years. It was reported about a case of a single dose of a nalmefen in a dose of 450 mg which was not followed by change of arterial pressure, heart rate, frequency of respiratory movements or body temperatures. In these cases the profile of safety of a nalmefen corresponded described above in the section "Side effect", however experience of observation is limited.

Treatment. At overdose symptomatic therapy and observation of a condition of the patient is recommended.

Storage conditions:

Period of validity - 3 years. Not to use on expiry date, specified on packaging. To store at a temperature not above 30 °C. To store in places, unavailable to children.

Issue conditions:

According to the recipe

Packaging:

Tablets, film coated, 18 mg. Packagings: 7 pieces, 14 pieces and 28 pieces. On 7 or 14 tablets in a blister strip packaging (blister) from PVC / PVDH and aluminum foil. 1 blister on 7 tablets or 1 or 2 blisters on 14 tablets with the application instruction in a cardboard pack.