Source: European Medicines Agency (EU) Revision Year: 2019 Publisher: H. Lundbeck A/S, Ottiliavej 9, DK-2500, Valby, Denmark
Pharmacotherapeutic group: Other nervous system drugs, drugs used in alcohol dependence
ATC code: N07BB05
Nalmefene is an opioid system modulator with a distinct μ, δ, and κ receptor profile.
In vitro studies have demonstrated that nalmefene is a selective opioid receptor ligand with antagonist activity at the μ and δ receptors and partial agonist activity at the κ receptor.
In vivo studies have demonstrated that nalmefene reduces alcohol consumption, possibly by modulating cortico-mesolimbic functions.
Data from the nonclinical studies, the clinical studies, and the literature do not suggest any form of dependence or abuse potential with Selincro.
The efficacy of Selincro in reducing alcohol consumption in patients with alcohol dependence (DSMIV) was evaluated in two efficacy studies. Patients with a history of delirium tremens, hallucinations, seizures, significant psychiatric comorbidity, or significant abnormalities of liver function as well as those with significant physical withdrawal symptoms at screening or randomisation were excluded. The majority (80%) of the patients included had a high or very high DRL (alcohol consumption >60 g/day for men and >40 g/day for women according to the WHO DRLs of alcohol consumption) at screening, of these 65% maintained a high or very high DRL between screening and randomisation.
Both studies were randomised, double-blind, parallel-group and placebo-controlled, and after 6 months of treatment, patients who received Selincro were re-randomised to receive either placebo or Selincro in a 1-month run-out period. The efficacy of Selincro was also evaluated in a randomised, double-blind, parallel-group, placebo-controlled 1-year study. Overall, the studies included 1,941 patients, 1,144 of whom were treated with Selincro 18 mg as-needed.
At the initial visit, the patients' clinical status, social situation, and alcohol consumption pattern were evaluated (based on patient reporting). At the randomisation visit, which occurred 1 to 2 weeks later, the DRL was re-assessed and treatment with Selincro was initiated together with a psychosocial intervention (BRENDA) focused on treatment adherence and reduction of alcohol consumption. Selincro was prescribed as-needed, which resulted in patients taking Selincro, on average, approximately half of the days.
The efficacy of Selincro was measured using two co-primary endpoints: the change from baseline to Month 6 in the monthly number of heavy drinking days (HDDs) and the change from baseline to Month 6 in the daily total alcohol consumption (TAC). An HDD was defined as a day with a consumption ≥60 g of pure alcohol for men and ≥40 g for women.
A significant reduction in the number of HDDs and TAC occurred in some patients in the period between the initial visit (screening) and randomisation due to non-pharmacological effects.
In Studies 1 (n=579), and 2 (n=655), 18%, and 33%, of the total population, respectively, considerably reduced their alcohol consumption in the period between screening and randomisation. As concerns the patients with high or very high DRL at baseline, 35% of patients experienced improvement due to non-pharmacological effects in the period between the initial visit (screening) and randomisation. At randomisation, these patients consumed such a small amount of alcohol that there was little room for further improvement (floor effect). Therefore, the patients who maintained a high or very high DRL at randomisation were defined post hoc as the target population. In this post hoc population, the treatment effect was larger than that in the total population.
The clinical efficacy and the clinical relevance of Selincro were analysed in patients with a high or very high DRL at screening and randomisation. At baseline, the patients had, on average, 23 HDDs per month (11% of patients had fewer than 14 HDDs per month) and consumed 106 g/day. The majority of the patients had low (55% had a score of 0-13) or intermediate (36% had a score of 14-21) alcohol dependence according to the Alcohol Dependence Scale.
In Study 1, the proportion of patients who withdrew was higher in the Selincro group than in the placebo group (50% versus 32%, respectively). For HDDs there were 23 days/month at baseline in the Selincro group (n=171) and 23 days/month at baseline in the placebo group (n=167). For the patients who continued in the study and provided efficacy data at Month 6, the number of HDDs was 9 days/month in the Selincro group (n=85) and 14 days/month in the placebo group (n=114). The TAC was 102 g/day at baseline in the Selincro group (n=171) and 99 g/day at baseline in the placebo group (n=167). For the patients who continued in the study and provided efficacy data at Month 6, the TAC was 40 g/day in the Selincro-group (n=85) and 57 g/day in the placebo group (n=114). In Study 2, the proportion of patients who withdrew was higher in the Selincro group than in the placebo group (30% versus 28%, respectively). For HDDs there were 23 days/month at baseline in the Selincro group (n=148) and 22 days/month at baseline in the placebo group (n=155). For the patients who continued in the study and provided efficacy data at Month 6, the number of HDDs was 10 days/month in the Selincro group (n=103) and 12 days/month in the placebo group (n=111). The TAC was 113 g/day at baseline in the Selincro group (n=148) and 108 g/day at baseline in the placebo group (n=155). For the patients who continued in the study and provided efficacy data at Month 6, the TAC was 44 g/day in the Selincro group (n=103) and 52 g/day in the placebo group (n=111).
Responder analyses of the pooled data from the two studies are provided in Table 2.
Table 2. Pooled Responder Analysis Results in Patients with a High or Very High DRL at screening and Randomisation:
| Responsea | Placebo | Nalmefene | Odds Ratio (95% CI) | p-value |
|---|---|---|---|---|
| TAC R70b | 19.9% | 25.4% | 1.44 (0.97, 2.13) | 0.067 |
| 0-4 HDDc | 16.8% | 22.3% | 1.54 (1.02, 2.35) | 0.040 |
a Analysis treats patients who withdrew as non-responder
b ≥70% reduction from baseline in TAC at Month 6 (28-day period)
c 0 to 4 HDDs/month at Month 6 (28-day period)
Limited data are available for Selincro in the 1-month run-out period.
This study comprised a total of 665 patients. 52% of these patients had a high or very high DRL at baseline; of these, 52% (representing 27% of the total population) continued to have a high or very high DRL at randomisation. In this post-hoc target population, more patients receiving nalmefene discontinued (45%) as compared to those receiving placebo (31%). For HDDs there were 19 days/month at baseline in the Selincro-group (n=141) and19 days/month at baseline in the placebo group (n=42). For the patients who continued in the study and provided efficacy data at 1 year, the number of HDDs was 5 days/month in the Selincro group (n=78) and 10 days/month in the placebo group (n=29). The TAC was 100 g/day at baseline in the Selincro group (n=141) and 101 g/day at baseline in the placebo group (n=42). For the patients who continued in the study and provided efficacy data at 1 year, the TAC was 24 g/day in the Selincro group (n=78) and 47 g/day in the placebo group (n=29).
The European Medicines Agency has waived the obligation to submit the results of studies with Selincro in all subsets of the paediatric population for the treatment of alcohol dependence (see section 4.2 for information on paediatric use).
Nalmefene is rapidly absorbed after a single oral administration of 18.06 mg, with a peak concentration (Cmax) of 16.5 ng/ml after approximately 1.5 hours and an exposure (AUC) of 131 ng*h/ml.
The absolute oral bioavailability of nalmefene is 41%. Administration of high-fat food increases the total exposure (AUC) by 30% and the peak concentration (Cmax) by 50%; the time to peak concentration (tmax) is delayed by 30 min (tmax is 1.5 hours). This change is considered unlikely to be of clinical relevance.
The average protein-bound fraction of nalmefene in plasma is approximately 30%. The estimated volume of distribution (Vd/F) is approximately 3200 l.
Occupancy data obtained in a PET study after single and repeated daily dosing with 18.06 mg nalmefene show 94% to 100% receptor occupancy within 3 hours after dosing, which suggests that nalmefene readily crosses the blood-brain barrier.
Following oral administration, nalmefene undergoes extensive, rapid metabolism to the major metabolite nalmefene 3-O-glucuronide, with the UGT2B7 enzyme being primarily responsible for the conversion, and with the UGT1A3 and UGT1A8 enzymes as minor contributors. A small proportion of nalmefene is converted to nalmefene 3-O-sulphate by sulphation and to nornalmefene by CYP3A4/5. Nornalmefene is further converted to nornalmefene 3-O-glucuronide and nornalmefene 3-O-sulphate. The metabolites are not considered to contribute with significant pharmacological effect on the opioid receptors in humans, except for nalmefene 3-O-sulphate, which has a potency comparable to that of nalmefene. However, nalmefene 3-O-sulphate is present in concentrations less than 10% of that of nalmefene and thus considered highly unlikely to be a major contributor to the pharmacological effect of nalmefene.
Metabolism by glucuronide conjugation is the primary mechanism of clearance for nalmefene, with renal excretion being the main route of elimination of nalmefene and its metabolites. 54% of the total dose is excreted in the urine as nalmefene 3-O-glucuronide, while nalmefene and its other metabolites are present in the urine in amounts of less than 3% each.
The oral clearance of nalmefene (CL/F) was estimated as 169 l/h and the terminal half-life was estimated as 12.5 hours.
From distribution, metabolism, and excretion data, it appears that nalmefene has a high hepatic extraction ratio.
Nalmefene exhibits a dose-independent linear pharmacokinetic profile in the dose interval of 18.06 mg to 72.24 mg, with a 4.4 times increase in Cmax and a 4.3 times increase in AUC0-tau (at or near steady state).
Nalmefene does not exhibit any substantial pharmacokinetic differences between sexes, between young and elderly, or between ethnic groups.
However, body size seems to affect the clearance of nalmefene to a minor degree (clearance increases with increasing body size), but this is considered unlikely to be of clinical relevance.
Administration of a single oral dose of nalmefene 18.06 mg to patients with mild, moderate or severe renal impairment, classified using the estimated glomerular filtration rate, resulted in an increased exposure to nalmefene relative to that in healthy subjects. For patients with mild, moderate or severe renal impairment the AUC for nalmefene was 1.1 times, 1.4 times and 2.4 times higher, respectively. Further, the Cmax and elimination half-life for nalmefene was up to 1.6 times higher in patients with severe renal impairment. No clinically relevant changes were seen in tmax for any of the groups. For the inactive major metabolite nalmefene 3-O-glucuronide, the AUC and Cmax were up to 5.1 times and 1.8 times higher in patients with severe renal impairment, respectively (see sections 4.3 and 4.4).
Administration of a single dose of nalmefene 18.06 mg to patients with mild or moderate hepatic impairment increased exposure relative to that in healthy subjects. In patients with mild hepatic impairment, exposure increased 1.5 times and oral clearance decreased by approximately 35%. In patients with moderate hepatic impairment, exposure increased 2.9 times for AUC and 1.7 times for Cmax, while oral clearance decreased by approximately 60%. No clinically relevant changes were seen in tmax or elimination half-life for any of the groups.
Pharmacokinetic data after oral administration of nalmefene to patients with severe hepatic impairment are not available (see sections 4.3 and 4.4).
No specific study with oral dosing has been conducted in patients ≥65 years of age. A study with IV administration suggested that there were no relevant changes in the pharmacokinetics in the elderly as compared to non-elderly adults (see sections 4.2 and 4.4).
Nalmefene was shown to have skin sensitisation potential in the Local Lymph Node Assay in mice after topical application.
Studies in animals do not indicate direct harmful effects with respect to fertility, pregnancy, embryonic/foetal development, parturition, or postnatal development.
In a rabbit embryo-foetal developmental toxicity study, effects on foetuses in terms of reduced foetal weight and delayed ossification, but no major abnormalities were seen. The AUC at the no observed adverse effect level (NOAEL) for these effects was below the human exposure at the recommended clinical dose.
An increase in still-born pups and decrease in post-natal viability of pups was observed in prepostnatal toxicity studies in rats. This effect was considered to be an indirect effect related to toxicity to the dams.
Studies in rats have shown excretion of nalmefene or its metabolites in milk.
The nonclinical data reveal no special hazard for humans based on conventional studies of safety pharmacology, repeated-dose toxicity, genotoxicity, or carcinogenic potential.
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