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GREATER MANCHESTER INTERFACE PRESCRIBING GROUP On behalf of the GREATER MANCHESTER MEDICINES MANAGEMENT GROUP SHARED CARE GUIDELINE FOR ACAMPROSATE (CAMPRAL EC) Scope: As above Reference Number ACAM 06 fnl Classification SHARED CARE GUIDELINE Issue date: December 2006 Author(s)/Originator(s) Pennine Care NHS Trust To be read in conjunction with the following documents British National Formulary (BNF) and BNF for Children Summary of Product Characteristics (SPC) Pharmaceutical company’s Patient Information Leaflet (PIL) Drugs & Therapeutics Date: Oct 20 Committee 2006 20 October 2008 Authorised by Review Date: to be confirmed 1. Introduction Acamprosate (calcium acetylhomotaurinate) is marketed in the U.K. by Merck Pharmaceuticals under the brand name campral EC®. Acamprosate has a chemical structure similar to that of amino acid neuromediators, such as taurine or gamma-amino-butyric acid (GABA), Acamprosate is indicated for the maintenance of abstinence in alcohol dependent patients. Acamprosate has been shown to increase abstinence rates in people receiving treatment for alcohol dependence (i.e. from 10% to 20% or at best up to 40%). (Slattery J. et al, 2003). Although its mechanism of action is not clearly defined, acamprosate appears to block excitatory activity in the brain (NMDA Glutamate) – which is thought to underlie some aspects of CNS vulnerability to relapse. It also enhances the inhibitory system (GABA) by stimulating GABAergic inhibitory neurotransmission. Whilst it has been known as an “anti-craving” drug, the evidence from trials is less conclusive about this as a major effect. Acamprosate has also been shown to reduce the number of drinks and number of days drinking in somebody who lapses into heavy drinking. Patients have reported that they do not feel the need to drink as much alcohol as they would normally (Chick J. et al, 2003). ACAM 06 fnl In addition, Acamprosate use in animal models appears to have a neuroprotective effect in that the number of brain cells that die during alcohol detoxification can be reduced with Acamprosate. (Koob et al, 2002). Acamprosate does not constitute treatment for the symptoms of alcohol withdrawal. Acamprosate does not prevent the harmful effects of continuous alcohol abuse. Acamprosate should not impair the patient's ability to drive or operate machinery. There are no NICE recommendations available for the prescribing of acamprosate. The British Association for Psychopharmacology recommends the use of acamprosate in the treatment of alcohol dependency (Lingford-Hughes, A.R., et al 2004). The Scottish Intercollegiate Guidelines Network has also advised on the use of acamprosate – though has emphasized the need for the medication to be prescribed alongside psycho-social interventions such as counselling. (The Scottish Intercollegiate Guidelines Network, 2003). 2. Scope This protocol covers prescribing by Pennine Care NHS Trust; Pennine Acute Hospitals NHS Trust and General Practitioners working both within and outside of the National Enhanced Services for alcohol and drugs. 3. Clinical condition being treated Acamprosate is licensed for the treatment of the alcohol dependency syndrome (Edwards and Gross, 1976). This syndrome consists of the following seven features: physiological withdrawal symptoms, such as tremor, sweating and hallucinations; relief-drinking – i.e. the use of alcohol to attenuate the above withdrawal symptoms (often in the morning when blood alcohol levels have fallen during the night); raised tolerance to alcohol – i.e. an ability to consume greater amounts of alcohol without developing the usual effects of intoxication (such as slurred speech and impaired balance); salience of drinking behaviour – i.e. neglect of other areas of life (such as marital relationships and employment) as drinking assumes a primary aspect of the individual’s life; ACAM 06 fnl 2 rapid reinstatement of syndrome – this refers to the recurrence of withdrawal symptoms when drinking is resumed following a period of abstinence; loss of control over alcohol use (i.e. an inability to drink in social or moderate manner); subjective awareness of a compulsion to use alcohol (i.e. identified craving for alcohol). Acamprosate is principally used to reduce the risk of relapse into heavy drinking (for example, following detoxification) – though it may also attenuate the level of alcohol use if a relapse occurs. Acamprosate appears to be particularly effective in the following situations (Lesch, O.M. and Walter, H. 1996): moderate or severe dependence; recent physiological withdrawal symptoms; current abstinence; recent withdrawal (i.e. within the past 2 weeks); patient aiming for complete abstinence; concurrent involvement in psychosocial therapy; craving for alcohol. Other indications (though with lesser evidence) include the following: tendency to mild anxiety or tension in the post-withdrawal phase (not marked anxiety disorder or panic disorder) reported craving. Acamprosate appears to be less effective in the following situations: those with repeated self-harm; antisocial personality disorder; evidence of childhood conduct disorder; minimal brain damage; marked social problems (and lack of support); those with primary psychiatric disorders (NB. acamprosate has been successfully used with antidepressants and drugs for anxiety disorders). Prescribing should be reviewed on a periodic basis e.g. at 6 weeks; 12 weeks; 6 months; 9 months and 12 months. Reviews should determine whether or not the patient is continuing to take the medication as prescribed; their level of ACAM 06 fnl 3 alcohol consumption (if any); any relevant health problems (such as liver disease); their continuing use of support services; and the patient’s views on the effectiveness of the medication. The medication will usually be discontinued if contra-indications develop (such as renal insufficiency) and / or the medication appears to be ineffective (e.g. if the patient continues to drink heavily). Prescribing is normally discontinued after a maximum of one year. 4. Product information and treatment regimen to be used Acamprosate calcium is prepared in 333mg enteric-coated tablets (campral EC®). The tablets are packaged in aluminium / PVC sheets of blisters presented in cartons of 168 tablets. The following doses are recommended: Adults > 60kg: 2 tablets three times a day with meals. Adults < 60kg: 2 tablets in the morning, 1 tablet at noon and 1 tablet at night with meals. The maximum daily dose that can be prescribed is 1998 mg. Acamprosate taken with food has lower bioavailability than in the fasting state. Some patients, however, are more comfortable taking the tablets with food. Steady state levels of acamprosate are achieved by the seventh day of dosing. It is recommended that acamprosate is commenced as soon as possible after detoxification is completed – especially if the patient reports intense/pervasive craving for alcohol. In some cases, however, it may be beneficial to commence prescribing during detoxification (e.g. if the patient has previously experienced severe craving for alcohol). Acamprosate may also be useful in the absence of a formal detoxification programme – e.g. when the patient has significantly reduced his/her level of alcohol consumption. If a relapse occurs acamprosate does not interact with alcohol and so treatment should be continued. Acamprosate does not interact with benzodiazepines, so assisted withdrawal can be instigated if needed. Acamprosate should be discontinued after 6 weeks, or earlier, if more than one relapse has occurred which is not significantly attenuated by comparison to the patient’s previous history of relapse. Acamprosate is classified as an “Amber” drug under the Greater Manchester Red/Amber/ Green model. This means that when it is prescribed by nonspecialist GPs it should be in accordance with an approved shared care protocol and in the context of an ongoing package of support and assessment. ACAM 06 fnl 4 Acamprosate will usually be initiated by a GPWSI; an accredited General Practitioner working within the National Enhanced Service (NES) for alcohol; or a Consultant Psychiatrist working within a either a Specialist Alcohol Treatment Service or in General Psychiatry. It can also, however, be prescribed by a GP operating outside of the NES framework. In addition, it is also possible that acamprosate may be prescribed by a nurse prescriber within a supplementary prescribing / clinical management prescribing framework (providing that this is within their scope of competence). In addition, acamprosate may be prescribed by Hospital Physicians who are providing treatment for alcohol-dependant patients (providing that they can offer or arrange for the ongoing package of care that its use demands). Continued heavy alcohol use negates the therapeutic benefits of acamprosate and therefore it is usually only initiated following detoxification (i.e. once the patient is abstinent from alcohol). Acamprosate should be combined with counselling or other forms of therapeutic intervention (Soyka M, 1994). The recommended treatment period is a maximum of one year. Acamprosate has a shelf-life of three years. Acamprosate currently costs £28.92 for a 168-tablet pack (- which provides 28 days treatment at a dose of 2 tablets three times a day, or 42 days treatment at a dose of 2 tablets twice a day). The cost per patient year based on this dose is therefore approximately £251 for patients weighing less than 60 kg and £377 for patients over 60 kg. 5. Regimen Management The Substance Misuse Service (SMS) can provide advice and guidance on the use of acamprosate. This may be offered on an on-going basis for patients who remain under the care of the SMS – or on an ad hoc basis for other patients. The National Enhanced Service (alcohol) clinics can also be used to provide assessment and guidance regarding clinical management. The prescribing clinician, however, will hold continuing responsibility for the overall regimen management. If the medication is being prescribed by a doctor within the National Enhanced Service and the patient is registered with a different practice it is essential that there is effective communication between the two services. Prior to commencing prescribing relevant health information should be obtained – especially regarding the presence of any possible contra-indications. The patient’s GP should be informed (in writing) when prescribing is initiated. The GP should also be advised of any relevant clinical issues – such as the presence of troublesome side-effects. In addition, the patient’s GP should be requested to provide information regarding all relevant clinical developments – such as a deterioration in the patient’s health, prescribing of additional ACAM 06 fnl 5 medication, etc. Finally, the patient’s GP should be advised when prescribing is discontinued. Acamprosate is seen as being most effective when used in conjunction with other forms of therapeutic intervention, such as counselling and AA attendance (Soyka M, 1994). It is important, therefore that agreement is reached with the patient regarding continued use of therapeutic resources whilst acamprosate is being prescribed. 6. Summary of cautions, contra indications, side-effects Adverse events associated with acamprosate tend to be mild and transient in nature. The following have been reported: diarrhoea; nausea; vomiting; abdominal pain; pruritus; maculopapular rash; bullous skin reactions (rarely); fluctuation in libido; psychiatric disorders (mainly depression). Contra-indications include the following: hypersensitivity to the drug; renal insufficiency (serum creatinine >120 micromol/l); severe hepatic failure (Childs-Pugh classification C); pregnancy; lactation. No interactions have been shown between acamprosate and diazepam, disulfiram or imipramine. There is no information available on the concomitant administration of acamprosate with diuretics. ACAM 06 fnl 6 There are no specific monitoring requirements for patients on acamprosate. Five cases of overdose associated with acamprosate therapy have been reported, including one patient who ingested 43g of acamprosate. After gastric lavage all patients had an uneventful recovery. Diarrhoea was observed in two cases. No case of hypercalcaemia was reported in the course of these overdoses. However, should this occur, the patients should be treated for acute hypercalcaemia. Acamprosate should not be administered to children and the elderly (i.e. over 65 years). Patients should be advised to report the development of side-effects to the prescribing doctor (or other clinician). In most cases these will be mild and transient. If troublesome side-effects persist, however, consideration should be given to discontinuation of the medication. The responsibility for adjusting or discontinuing treatment will rest with the prescribing clinician (see above). In addition, patients should also be encouraged to advise their prescriber if they become pregnant (or plan to become pregnant) during treatment and / or if they commence breast-feeding. 7. Special considerations There are no known reported sensitivity reactions regarding the handling or preparation of acamprosate. 8. Back-up care available to GP from Hospital, including emergency contact procedures and help line numbers Information on acamprosate can be provided by the Substance Misuse Service (available 9.00 a.m. – 4.45 p.m., Monday to Friday). Further information can be obtained from the manufacturer as follows: Merck Pharmaceuticals, Harrier House, High St., West Drayton, Middx. UB7 7QG Tel: (01895) 452 307 Fax: (01895) 452 296 Email: [email protected] 9. Statement of agreement It is anticipated that the most acamprosate prescribing will be initiated in primary care by either the patient’s own GP or a GP working within the NES framework. If prescribing is initiated by a consultant psychiatrist, however, a request may be made to the relevant GP to continue prescribing in accordance with the suggested care pathway. If agreement cannot be obtained the GP should advise the consultant within 14 days of the request and should state any relevant concerns. 10. Written information provided to the patient ACAM 06 fnl 7 Patients will be provided with the manufacturer’s product information sheet. Addition information is available as follows: What is Acamprosate ? Acamprosate is a drug used in the treatment of people who have been dependant on alcohol and who are aiming to abstain. It is often known by the trade name “campral”. It appears to reduce the urge or “craving” for alcohol. It is believed that this craving may be caused by a change in the chemicals in the brain - and that acamprosate works by helping to reverse these changes. Acamprosate appears to be particularly helpful for those who have recently stopped drinking - such as those undergoing detoxification programmes. Acamprosate should always be used alongside other types of help, such as counselling. The medication is provided in 330 mg. tablets and up to 6 are taken daily. The medication should then be taken on a regular basis for up to one year. The Benefits / Advantages of Acamprosate Prescribing Acamprosate can be very effective in reducing craving for alcohol. This will often greatly help reduce the risk of a relapse into heavy drinking. Acamprosate is not a sedating drug and therefore should not cause drowsiness or tiredness. Acamprosate appears to compatible with most other drugs, including anti-depressants and tranquillisers. Acamprosate is not an addictive drug and can be stopped without the risk of withdrawal symptoms. Whilst side effects can occur (see below) these are relatively rare and are usually short - lived. Problems do not occur if an occasional dose is accidentally missed. Possible Disadvantages / Risks of Acamprosate Prescribing Acamprosate does not usually provide many benefits during the first few days it is taken - and it may take a week or two to produce it’s full effect. Possible side effects associated with acamprosate include skin reactions and gastrointestinal disturbances such as diarrhoea, nausea, vomiting and abdominal discomfort. Some people also experience a loss of their sex drive. Acamprosate does not seem to work well for people who start to take it when they are drinking heavily. Some people mistakenly believe that acamprosate is a “miracle cure” for all their problems - and they then fail to use other types of help such as attending A.A. Fellowship meetings. Acamprosate is not recommended for people with very severe liver or kidney problems. It is also not usually used during pregnancy or breast - feeding. 11. Supporting References ACAM 06 fnl 8 Chick J, Lehert P, Landron F (2003) Does acamprosate improve reduction of drinking as well as aiding abstinence? J Psychopharmacol 17: 397–402. Koob G, Mason B, De Witte P, Littlejohn J, Siggins G (2002) Potential neuroprotective effects of acamprosate. Alcohol Clin Exp Res 26: 586–592. Lesch O M, Walter H (1996) Subtypes of alcoholism and their role in therapy. Alcohol 31 (Suppl 1): 63–67. Lingford-Hughes, A.R., et al (2004) Journal of Psychopharmacology 18(3) (2004) 293–335. Evidence-based guidelines for the pharmacological management of substance misuse, addiction and comorbidity: recommendations from the British Association for Psychopharmacology. Scottish Intercollegiate Guidelines Network (2003) The management of harmful drinking and alcohol dependence in primary care. Slattery J, Chick J, Cochrane M, Godfrey C, Kohli H, Macpherson K, Parott S, Quinn S, Single A, Tochel C, Watson H (2003) Prevention of relapse in alcohol dependence. Health Technology Assessment Report 3. Health Technology Board for Scotland, Glasgow. Soyka M, Sass H (1994) Acamprosate: a new pharmacotherapeutic approach to relapse prevention in alcoholism – preliminary data. Alcohol Alcohol 2: 531–536. The Child’s Pugh Classification 12. Score 1 2 3 bilirubin (micromol/l) <34 34-50 >50 albumin (g/l) >35 28-35 <28 PT (s prolonged) <4 4-6 >6 encephalopathy none mild marked ascites none mild marked If there is primary biliary cirrhosis or sclerosing cholangitis then bilirubin is classified as <68=1; 68-170=2; >170=3. The individual scores are summed and then grouped as: <7 = A 7-9 = B >9 = C ACAM 06 fnl 9