Suffolk PCT Drug & Therapeutics Committee New Medicine Report

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1 Suffolk PCT Drug & Therapeutics Committee New Medicine Report This drug has been reviewed because it is a product that may be prescribed in primary care. Medicine Nalmefene (Selincro, Lundbeck) Document status For consideration January 2012 Date of last revision Reviewed on 22 nd January 2013 Traffic light decision Double Red no prescribing pending discussions with Public Health and Specialist Alcohol Services Prescribers rating Possibly helpful Mechanism of action Nalmefene is an opioid receptor modulator, exhibiting antagonist activity at μ- and δ-opioid receptors (MOR and DOR respectively) and partial agonist activity at κ-opioid receptors (KOR) in in vitro studies. The opioidergic system plays a crucial role in mediating the rewarding effects of alcohol, in part by modulating dopaminergic neurotransmission in mesolimbic brain areas. Acute ethanol intake stimulates the release of the endogenous opioid peptides β-endorphin (the ligand for MOR), enkephalin (the ligand for DOR), and dynorphin (DYN, the ligand for KOR). Subtype-selective antagonists of MOR and DOR have been shown to reduce ethanol self-administration. In addition, the dysregulation of DYN/KOR systems contributes directly to the excessive self-administration of alcohol, and selective KOR agonists may also reduce ethanol intake. (1,2) Medicine class Drugs used in substance dependence BNF Indication Nalmefene is intended for the reduction of alcohol consumption in those aged 18 years with alcohol dependence that have a high drinking risk level, without physical withdrawal symptoms and who do not require immediate detoxification. (1) Dosage Nalmefene is administered orally at 18mg as needed. Maximum one tablet once daily. (1) Treatment alternatives There is no anticipated requirement for liver monitoring or detoxification/physical withdrawal before use. Nalmefene is for patients who do not have physical withdrawal symptoms and who do not require immediate detoxification. (1) Treatments for alcohol dependence include pharmacological and/or psychological/psychosocial therapy for the management of withdrawal symptoms and the prevention of relapse. People with mild

2 dependence usually do not require assisted alcohol withdrawal. People with moderate to severe alcohol dependence will usually need assisted alcohol withdrawal, with treatment options including psychological as well as pharmacological interventions. People with moderate to severe dependence can typically be managed in the community, however those with previous complications e.g. delirium tremens (DTs) or seizures may require management in a residential setting. (1,2) Current treatment options include: Mild alcohol dependence Psychological intervention (such as cognitive behavioural therapies, behavioural therapies or social network and environment-based therapies) focused specifically on alcohol-related cognitions, behaviour, problems and social networks. Moderate to severe alcohol dependence Psychological intervention. Assisted withdrawal -Benzodiazepines (chlordiazepoxide, diazepam or oxazepam gammaaminobutyric acid (GABA) agonist first line. -Clomethiazole GABA agonist second line. Relapse prevention (in combination with an individual psychological intervention) -Acamprosate GABA agonist. -Disulfiram aldehyde dehydrogenase inhibitor. -Oral naltrexone opioid receptor antagonist. Place in therapy Other treatments for assisted withdrawal also include high potency vitamin supplementation (e.g. Pabrinex), and the use of medications for symptomatic relief e.g. loperamide and analgesics. There is commonly also a need for the concurrent treatment of psychiatric complications. (1,2) Alcohol dependence: patients aged 18 years who are unable to achieve abstinence, or for whom reduction is a more appropriate goal. Nalmefene would be for people with less severe dependence who do not have physical withdrawal symptoms and who do not require immediate detoxification or for people who have failed to achieve abstinence. Nalmefene would provide a treatment which specifically targets the opioidergic system. However, unlike naltrexone, another opioid receptor antagonist currently recommended by NICE, nalmefene has a

3 greater affinity for KOR which may increase its effectiveness. Nalmefene will also be dosed as-needed, with no anticipated requirement for liver monitoring or detoxification/physical withdrawal before us. It is for patients who do not have physical withdrawal symtoms and who do not require immediate detoxification. It may be suitable for initiation in community settings, potentially by non-specialists. Alcohol dependence is categorised clinically as mild, moderate or severe according to the SADQ instrument*. Future alternatives Evidence for use * Severity of Alcohol Dependence Questionnaire (SADQ), a short, self-administered, 20-item questionnaire quantifying the severity of dependence on alcohol. None known Nalmefene has completed clinical trials in three multicountry European phase 3 studies, enrolling approximately 2,000 patients in total. These studies compared its effect on alcohol consumption by the monthly number of heavy drinking days (HDDs) and monthly total alcohol consumption (TAC) against treatment with placebo. Three phase 3 clinical studies were submitted to the EMA for the marketing authorisation; ESENSE 1, ESENSE 2 and SENSE. Only SENSE 1 is fully published. The other two trials are currently only available in abstract/poster form only. Please see also appendix 1. ESENSE 1 was a 6 month study N=604 (placebo 298, nalmefene 306), mean age 51.6 years, (67% men). At the co-primary outcome, nalmefene was significantly superior to placebo in reducing the number of Heavy Drinking Days (HDDs) and Total Alcohol Consumption (TAC) at month 6 when compared to placebo. However withdrawal rates were high and only 142 of the 302 nalmefene patients completed the study compared with 205 of the 296 taking placebo. Nalmefene was statistically superior to placebo at a variety of secondary outcomes. Adverse events were more common in the nalmefene group and were generally transient and mild or

4 moderate. Withdrawals were more common in the nalmefene group. ESENSE 2 was a 6 month study. N=718 (placebo 360, nalmefene 358), mean age 44.8 years, (73% men). With regard to the 2 primary end points, at month 6 nalmefene was statistically superior to placebo in reducing HDDs but did not achieve a statistically significant reduction in TAC. Nalmefene was statistically superior to placebo at a variety of secondary outcomes. Adverse events were more common in the nalmefene group however the incidence of adverse events leading to withdrawal was at the placebo level. SENSE was a 12 month study. N=675 (placebo 166, nalmefene (509), mean age 44.3 years, (77% men). 422 of 665 treated patients (63%) completed the study. Nalmefene did reduce the number of HDDs and the TAC, over the study period and at most time points this favoured nalmefene. However, it did not achieve a statistically significantly effect when compared to placebo at the primary endpoint of reduction in HDDs and TAC at 6 months. NNT Cautions / side effects At month 13 the mean number of TDDs with nalmefene had decreased from 15 to 3 days per month (75 to 16 in the placebo group) and the TAC had decreased from 75 to 16g per day (75 to 27 in the placebo group). Not possible to calculate for the primary outcome. The most frequent adverse events (nausea, insomnia, dizziness, headache and vomiting) occurred within hours to days of the first dose and, while leading to withdrawal in some cases were generally transient and mild or moderate. Nalmefene should not be prescribed to patients in the acute phase of opiod withdrawal syndrome, or those with a current opioid dependence or opioid abuse due to the risk of precipitating an acute opioid withdrawal syndrome. (1) Cost within PbR tariff? Cost (prices from Lundbeck) Mental health services are being brought into PbR during 2012/13. Approx 2 per tablet.

5 Comparative costs of other medicines (BNF 64) Potential number of patients & usage in Suffolk PCT Drug (dose) Cost per 28 days Acamprosate Calcium 666mg 24 orally three times daily Disulfiram 200mg orally daily 14 Naltrexone 50mg orally daily 47 The price of nalmefene is not yet confirmed, a provisional cost is around 2 per tablet and annual prescribing costs are estimated to be 364. According to an example projection provided by the manufacturer, the anticipated incremental prescribing cost of nalmefene to the NHS per 100,000 population is estimated to be approximately 13,000 in year 1. (1) Points for consideration In England, alcohol dependence affects around 4% of people aged years: around 1.1 million people (6% of men and 2% of women), of which around 6% per year receive treatment. It is estimated that around 85,083 people with moderate or severe dependence receive specialist treatment each year. Alcohol dependence is associated with an increased rate of significant mental and physical disorders including seizures, delirium tremens, liver disease, acute and/or chronic pancreatitis, depression, anxiety disorders, drug misuse and Wernicke s encephalopathy. (2) In 2010, there were 8,095 (16.1 males and 7.5 females per 100,000) and 494 (18.9 males and 10.2 females per 100,000) alcohol-related deaths in England and Wales, respectively. (2) In , there were an estimated 1,168,300 admissions related to alcohol consumption in England. Of these 75% (880,200) were due to conditions which were categorised as chronic. In 2008, it was estimated that the cost of alcohol related harm to the NHS in England was 2.7 billion (in prices). (2) In 2011, there were 167,764 prescription items for drugs for the treatment of alcohol dependence prescribed in primary care settings (94%) or NHS hospitals (6%), which equates to 302 prescription items per 100,000 population and a net ingredient cost of 2.49 million. The two main drugs prescribed were acamprosate (64% of the prescription items prescribed in primary care for alcohol dependence) and disulfiram (52% of the items prescribed in hospitals for alcohol dependence). (2) If licensed, nalmefene would be the first pharmacological option for the reduction of alcohol consumption in adult patients with alcohol dependence.

6 Current treatments for alcohol dependence are aimed at a goal of abstinence and generally delivered by specialist alcohol services. The manufacturers anticipate that nalmefene will be initiated in primary care. Relevant related guidance The Government s Alcohol Strategy (2012). NICE clinical guideline. Psychosis with coexisting substance misuse. Assessment and management in adults and young people (CG120). March NICE clinical guideline. Alcohol use disorders: diagnosis, assessment and management of harmful drinking and alcohol dependence (CG115). February NICE clinical guideline. Alcohol-use disorders: physical complications (CG100). June NICE quality standard. Alcohol dependence and harmful alcohol use. May NICE public health guidance. Alcohol use disorders - preventing harmful drinking (PH24). May NICE public health guidance. Interventions to reduce substance misuse among vulnerable young people (PH4). March Scottish Intercollegiate Guidelines Network. The management of harmful drinking and alcohol dependence in primary care (SIGN 74) (updated 2004). Is the drug on the WSH or IHT formularies? Decisions from other bodies Decision review date West Suffolk Hospital - TBC Ipswich Hospital - TBC NICE - see above Cambridgeshire JPG not considered Norfolk TAG- not considered SMC not considered TBC References 1. Nalmefene for managing alcohol dependence in primary and secondary care. Advanced planning information for the NHS. Lundbeck. Date of preparation 31 st May 2012 and personal communication -Jan Nalmefene (Selincro) for the reduction of alcohol consumption first line pharmacological therapy for alcohol dependence. Horizon Scanning Centre September NIHR HSC ID:3557. Available via 3. BNF 64 Clinical Trials 4. ESENSE1 Mann K et al. Extending the treatment Options in alcohol dependence: A randomised Controlled Study of As-Needed Nalmefene. Biol Pychiatry ESENSE 2

7 Gual A et al. A randomised, double blind, placebo-controlled study of nalmefene, asneeded use in alcohol dependent patients Presented at the 35 1 " Annual RSA Scientific Meeting, San Francisco, California, USA, June 23-27, SENSE Van den Brink W. et al. Long-term efficacy, tolerability and safety of nalmefene asneeded in alcohol dependence: a randomised, double-blind, placebo controlled study. Presented at the 35 1 " Annual RSA Scientific Meeting, San Francisco, California, USA, June 23-27, 2012.

8 Appendix 1. Table 1: Trial design and outcomes Trial Design Treatment Primary outcome Secondary outcomes ESENSE 1 Double blind, placebo controlled 24 week studies (plus a 4 week run out). N=604 Included adults 18 years old with a primary diagnosis of DSM-IV alcohol dependence, 6 HDDs and a drinking risk level of medium or above (WHO classification) in the 4 weeks preceding screening. A HDD is defined as a day with a consumption of alcohol 60g alcohol for men or 40g alcohol for women. ESENSE 2 Excluded: participants with a DSM- N=718 IV Axis 1 disorder other than alcohol or nicotine dependence, antisocial nalmefene personality disorder, risk of suicide, N=358 history of DTs or alcohol withdrawal seizures, or recent treatment with placebo antipsychotics or antidepressants. N=360 Participants received motivational and adherence-enhancing intervention (BRENDA) to support behavioural change and enhance nalmefene N=306 placebo N=298 There were 2 primary outcomes; Change in monthly number of HDDs at 24 weeks and Change in TAC at 24 weeks. The difference in change from baseline to week 24 for nalmefene vs. placebo was -2.3 HDD (-3.8, - 0.8) 95% CI p=0.002 and -11.0g/day TAC (-16.8, -5.1) 95%CI p< i.e. statistical significance at both these primary outcomes was demonstrated. There were 2 primary outcomes; Change in monthly number of HDDs at week 24 and Change in TAC at week 24. The difference in change from baseline to week 24 for nalmefene vs. placebo was -1.7 HDDs (-3.1; - 0.4) 95% CI p=0.012 and -5.0g TAC (-10.6; -0.7) 95%CI p< i.e. statistical significance was demonstrated with respect to the Proportion of responders based on drinking measures; alcohol dependence symptoms and clinical status; liver function and other biological tests; pharmacoeconomic outcomes; treatment discontinuation effects; safety and tolerability. Improvements in CGI-I and CGI- S greater in the nalmefene group (p<0.05); reductions in GGT and AT greater in the nalmefene group (p<0.05). Proportion of responders based on drinking measures; alcohol dependence symptoms and clinical status; liver function and other biological tests; pharmacoeconomic outcomes; treatment discontinuation effects; safety and tolerability. Improvements in CGI-S (but not CGI-I) significantly greater in the nalmefene group (p<0.05).

9 adherence to treatment. SENSE Randomised placebo controlled 52 week trial (plus 4 week run out) conducted in the EU including the UK, the Russian Federation and Ukraine. Included: adults 18 years old with a primary diagnosis of DSM-IV alcohol dependence, 6 HDDs and a drinking risk level of medium or above (WHO classification) in the 4 weeks preceding screening. Excluded were participants with a DSM-IV Axis 1 disorder other than alcohol or nicotine dependence, antisocial personality disorder, risk of suicide, history of DTs or alcohol withdrawal seizures, or recent treatment with antipsychotics or antidepressants. Participants received motivational and adherence-enhancing intervention (BRENDA) to support behavioural change and enhance adherence to treatment. N=675 nalmefene N=509 placebo N=166 HDDs but not the TAC primary outcome. Long term safety and tolerability at 52 weeks. Change in monthly number of HDDs at 24 weeks and Change in TAC at 24 weeks. At week 24 the mean change in HDDs difference between the groups, and the mean change in TAC, difference between the groups were not significantly different for nalmefene compared with placebo. HDDs 24 weeks -0.9 days/month (95% CI:-9.2; 2.2; p=0.232). Reductions in AT (but not GGT) significantly greater in the nalmefene group (p<0.05). At both 24 weeks and 52 weeks: proportion of responders based on drinking measures; alcohol dependence symptoms and clinical status; liver function and other biological laboratory tests and pharmacoeconomic outcomes. At week 52: mean change in HDDs difference between groups, was -1.6 days (p=0.017); mean change in TAC difference between groups was 6.5g/day (p=<0.036). Improvements in Clinical Global Impression, CGI-I was significant (but not for CGI-S). Reductions in ALT and GGT seen in the nalmefene group were significant compared with placebo.

10 Grids used to assist the NHS Suffolk PCT Drug & Therapeutics Committee in reaching a decision about new medications For many years scientists have recognised two types of research: Primary: original studies, based on observation or experimentation on subjects. Secondary: reviews of published research, drawing together the findings of two or more primary studies. In biomedical science there is general agreement over a hierarchy: the higher up a methodology is ranked, the more robust and closer to objective truth it is assumed to be. The orthodox hierarchy looks something like this- Rank: Methodology Description 1 Systematic reviews and meta-analyses Systematic review: review of a body of data that uses explicit methods to locate primary studies, and explicit criteria to assess their quality. Meta-analysis: A statistical analysis that combines or integrates the results of several independent clinical trials considered by the analyst to be "combinable" usually to the level of re-analysing the original data, also sometimes called: pooling, quantitative synthesis. Both are sometimes called "overviews." 2 Randomised controlled trials (finer distinctions may be drawn within this group based on statistical parameters like the confidence intervals) Individuals are randomly allocated to a control group and a group who receive a specific intervention. Otherwise the two groups are identical for any significant variables. They are followed up for specific end points. 3 Cohort studies Groups of people are selected on the basis of their exposure to a particular agent and followed up for specific outcomes. 4 Case-control studies "Cases" with the condition are matched with "controls" without, and a retrospective analysis used to look for differences between the two groups. 5 Cross sectional surveys Survey or interview of a sample of the population of interest at one point in time 6 Case reports. A report based on a single patient or subject; sometimes collected together into a short series 7 Expert opinion A consensus of experience from the good and the great. 8 Anecdotal Something a bloke told you after a meeting or in the bar. Adapted from Systematic reviews, What are they and why are they useful? ScHARR 2008

11 To Decide if a Medication Is To Be Used In Suffolk Criterion to be measured Poor -5 4 Medium-3 2 Tends to good- 1 Quality of evidence in the papers reviewed Cross sectional surveys or Case controlled studies Cohort studies RCTs Systematic reviews and meta- analyses lower Magnitude of effect inferred from trials reviewed Low Medium High Are trial end-points surrogate markers or clinical outcomes? Surrogate markers Clinical usefulness of trial end-points Medium Known Side Effect Profile High 4 Medium Low Known Interactions High Medium Low Concern re Possible Side Effects Not Yet Uncovered High 4 Medium Low Balance of Benefit To Harm (side effects toxicity interactions etc) Poor 4 Medium Good NNT High Medium Low Comparison Of Effectiveness With Other Medicines In Use For The Same Condition Poor Medium Good Severity of Condition to be Treated Trivial Medium 2 Severe Novel drug or member of existing class Novel drug Uptake (estimated proportion of people with this condition likely to be prescribed the medication under consideration maximum and minimum uptake) Is the drug to be used in Suffolk? Yes Prescriber s Rating Definitions Bravo! -The drug is a major therapeutic advance in an area where previously no treatment was available. A real advance - The product is an important therapeutic innovation but has certain limitations. Offers an advantage - The product has some value but does not fundamentally change present therapeutic practice. Possibly Helpful - The product has minimal additional value, and should not change prescribing habits except in rare circumstances. Judgement reserved - The Committee postpones its judgement until better data and a more thorough evaluation of the drug are available. Nothing New - The product may be a new substance but is superfluous because it does not add to the clinical possibilities offered by previous products available. In most cases these are me-too products. Not acceptable - Product without evident benefit over others but with potential or real disadvantages. (With acknowledgement to Prescrire)

12 Skills of the prescriber Criterion Red Amber Green Blue Experience Of The Condition Specific Specific Specific General Diagnosis Specific Specific Specific General Monitoring Progress Of Treatment Difficult Specific General General Therapy Patient Selection Difficult Specific Specific Easy Initiation Of Treatment Difficult Difficult Easy Easy Dose Titration Difficult Specific Easy Easy Monitoring Of Side Effects Complex Easy Easy Easy Method Of Administration Complex Normal Normal Normal Discontinuation Of Treatment Complex Complex Easy Easy References Jonsen A. Bentham in a box: Technology assessment and health care allocation. Law Med. Health Care. 1986;14: Suffolk Drug & Therapeutics Committee Responsibility for prescribing, Hospital Trust or GP Attached as Appendix 1 & Appendix 2 Traffic Light: Green but initiated by specialist alcohol service QIPP Rating:- Nalmefene is currently lacking long term evidence and there is a risk of it being misused. It needs to be tightly controlled and a treatment pathway may need to be developed..