VOLUME 11 NUMBER 4, 2000

Contents: Modified-release preparations

Modified-release preparations

With the ever increasing number of modified-release SUMMARY preparations on the market, the debate continues as to * The use of a modified-release (m/r) preparation cannot whether these products actually fulfil a clinical need be justified unless it offers clear clinical advantages or are merely premium priced over, often less expensive, conventional-release line-extensions to encourage preparations. brand name prescribing. * M/R preparations may be prescribed to: The recent NHS performance • reduce the dosing frequency and improve patient 1 indicators document has once compliance; again highlighted modified- release (m/r) preparations as • reduce fluctuations (peaks and troughs) in drug an area where there is often plasma concentrations, in order to reduce unnecessary prescribing. concentration-related side-effects or improve M/R preparations tend to be effectiveness; relatively expensive and in • control the site of drug delivery in the many cases, the clinical need could be met by a cheaper gastrointestinal tract. alternative. This Bulletin * There is little good quality evidence to suggest that discusses the various factors that need to be taken into once daily dosing has a clear clinical advantage over account when deciding if an twice daily dosing. Missing a once daily dose can result m/r preparation is appropriate. in long periods of subtherapeutic plasma concentrations. Therefore, twice daily dosing may be What is modified-release? preferred in patients known to miss doses. * Prescribers should always consider whether an The term modified-release defines preparations that have been m/r preparation is clinically justified. For those designed in such a way that the limited situations where this is the case, prescribing by rate or place at which the brand ensures the correct preparation is dispensed. active ingredients are released Brand name prescribing is particularly important for 2 has been modified. This is an theophylline nifedipine all encompassing term that the m/r preparations of , and BNF now uses to cover prepara- diltiazem, as there is concern over the clinical tions such as sustained-release, implications of switching between inequivalent controlled-release and delayed- preparations. release. Although theoretically covered by m/r, the BNF has * In general, m/r preparations should be reserved for retained the separate term specific patients where there is a problem with enteric coated. compliance, effectiveness or side-effects which these The sole use of the term preparations could help overcome. modified-release is helpful to simplify the confusing terminol- ogy. However, its use conceals The MeReC Bulletin is produced the differences between the drug delivery systems, which by the NHS for the NHS may be defined as:

MeReC Bulletin Volume 11, Number 4, 2000 13 • Sustained-release - the drug is released slowly at a rate gov- Pharmaceutical modification The rate of drug release is reduced by increasing particle size or forming insoluble erned by the delivery system.3 crystals e.g. Tegretol Retard or Adalat Retard. • Controlled-release - the drug is released at a constant rate Coated pellets Drug pellets are coated with a slowly dissolving polymer of varying thickness for and plasma concentrations varied release. The pellets can either be compressed into a tablet or put in a gelatin after administration do not capsule e.g. Fenbid, Slo-Phyllin or Inderal-LA. vary with time.3 Insoluble matrix • Delayed-release - the drug The drug is dispersed within an insoluble porous matrix. As fluid enters the matrix, is released at a time other the drug is dissolved and diffuses out slowly e.g. Slow-K, Imdur or Betaloc-SA. than immediately after Eroding matrix 3 administration i.e. the site The drug is dispersed within a soluble matrix. As the matrix is eroded, the drug is of release is controlled. slowly released e.g. MST Continus or Phyllocontin Continus. Osmotic pump There are many mechanisms by The drug and an osmotic agent are enclosed by a semipermeable membrane. As which drug release from a prepar- water is drawn into the tablet, dissolved drug is released in a controlled way through ation can be modified (see table 1). a laser-drilled hole e.g. Volmax, Adalat LA. pH sensitive coating The formulation is coated with a polymer of pH dependent solubility for site specific Why prescribe a modified-release delivery. This can either avoid drug release in the stomach (enteric coating) e.g. preparation? Nu-Seals Aspirin, or specifically deliver drug to the colon e.g. Asacol. Table 1. Some mechanisms of modified drug release M/R preparations may be prescribed to: manufacturers. However, this concentration-related side-effects, • reduce the dosing frequency and can have drawbacks. Patients particularly for rapidly absorbed improve patient compliance; may forget that a dose has drugs such as nifedipine.14 • reduce fluctuations (peaks and already been taken and repeat it Minimising the trough may troughs) in drug plasma con- later in the day.11 They may also improve effectiveness, for example centrations, in order to reduce miss a dose completely. Missing in maintaining 24-hour blood concentration-related side- a dose is a particular problem pressure control with certain effects or improve effectiveness; with a once daily preparation antihypertensive agents.15 • control the site of drug delivery as it can result in long periods in the gastrointestinal (GI) tract. where drug plasma concentra- M/R preparations are often tions are subtherapeutic. Twice used for drugs with a narrow Generally, the use of an m/r daily dosing may, therefore, therapeutic index, such as preparation cannot be justified be preferred, especially if the theophylline and lithium. This unless it offers clear clinical patient is known to miss doses.12 may help to maintain the plasma advantages over, often less concentration within the limits of expensive, conventional-release There are many reasons for effectiveness and toxicity.13 preparations. noncompliance. Polypharmacy is often a factor11 and the number of drugs should be reviewed and Controlling the site of delivery Improving patient compliance reduced to a minimum before considering m/r preparations. M/R preparations can be By slowing the rate of drug Patients’ understanding of their developed to deliver a drug to a release, m/r preparations allow condition and treatment should specific site in the GI tract. For drugs with short half-lives to be also be addressed if compliance example, enteric coated prepara- administered less frequently. It is is a problem. tions direct delivery to the small generally well accepted that, for intestine, preventing drug release the majority of patients, reducing in the stomach. This aims to the dosing frequency to once or Reducing fluctuations in drug either protect the stomach from twice daily improves compliance.4 plasma concentrations the drug, or protect the drug from the degrading environment of the However, there is little good By slowing the rate of drug stomach. Other preparations, quality evidence to suggest that release, and hence absorption, such as those containing once daily dosing has a clear m/r preparations aim to provide aminosalicylates for inflammatory clinical advantage over twice close to constant plasma concen- bowel disease, are formulated daily dosing. Most studies have trations over a prolonged period to allow site specific delivery to shown that compliance is either of time.13 the colon or small intestine to the same, or slightly improved, exert local effects. with a once daily preparation.5-11 Levelling out the plasma profile Whilst this improvement has can be advantageous, but only reached statistical significance in for drugs where there is a close Which drugs are suitable as m/r some studies,10-11 its clinical correlation between plasma preparations? significance is less clear. concentration and either therapeutic effect or toxicity. Apart from formulations that The ‘once a day is best’ belief Reducing high peak plasma control the site of drug delivery, is heavily promoted by concentrations can reduce most m/r preparations slow the

14 MeReC Bulletin Volume 11, Number 4, 2000 rate of drug release. To ensure Conventional-release characteristics. Therefore, maximum absorption from these carbamazepine is often bioequivalence cannot be as- preparations, it is essential that prescribed three or four times a sumed and all m/r preparations the drug is well absorbed day for epilepsy. M/R prepara- are licensed by brand name. throughout the entire GI tract. tions allow twice daily dosing and Drugs which are absorbed only at may also reduce the incidence of Switching between m/r specific sites, such as iron16, folic dose-related side-effects.16,19 preparations of drugs with a acid and vitamin B12, are not narrow therapeutic index may suitable as m/r preparations.13 have serious clinical conse- What are the problems with m/r quences. Therefore, both the Drugs with a narrow therapeutic preparations? Royal Pharmaceutical Society and index, those which are rapidly the BNF recommend brand name absorbed, and those with a The release of a drug from an prescribing for m/r theophylline short duration of action are m/r preparation is dependent (or aminophylline) prepara- often formulated into m/r on changes in GI transit time. In tions.16,20 This is also advisable for preparations. Drugs with a patients with ‘GI hurry’ some of all formulations of lithium. long duration of action, such the dose may be lost if the prep- as amitriptyline, do not need to aration passes through the body Brand name prescribing is also be given frequently and an m/r before drug release is complete. recommended for m/r preparation is unnecessary. Conversely, if the transit time is preparations of nifedipine and delayed, excessive release of the longer-acting diltiazem16,20 It is also important to consider drug or ‘dose dumping’ can where numerous formulations whether the therapeutic area occur. This may cause local GI exist. These preparations are lends itself to the use of m/r damage (e.g. with NSAIDs), or available in different strengths preparations. For example, m/r acute systemic toxicity. and have different licensed analgesic preparations with a dosage regimens (see table 2). slow onset of action are of little Breaking, chewing or crushing an They are not interchangeable value when immediate pain m/r preparation can result in the and, due to different release relief is required. immediate release of possibly characteristics, even formulations toxic amounts of drug. Therefore, containing the same strength of For some drugs, an m/r patients should be told to swallow drug may not be bioequivalent. preparation can offer clinical most m/r preparations whole. To advantages. If theophylline is avoid undue concern, patients If a prescription for an m/r prescribed for nocturnal asthma should also be informed if there preparation of theophylline, and early morning wheezing, an is a possibility of the tablet shell nifedipine or diltiazem is written m/r preparation given as a single passing through the GI tract generically, the pharmacist should dose at night is advisable.16 The unchanged, as with Slow-K. contact the prescriber to agree slow release of theophylline the brand before dispensing.20 decreases side-effects seen with By slowing the rate of drug rapid absorption and ensures release and prolonging its action, When local formularies are put in therapeutic levels are maintained m/r preparations can cause place it would be useful, if an m/r throughout the night, provided a problems if taken in overdose or if preparation is considered appro- suitable dose is prescribed. a severe adverse reaction occurs. priate, to select just one or two brands for inclusion. This en- If nifedipine is prescribed for sures familiarity for prescribers angina or hypertension, an m/r Prescribing issues and pharmacists, while prevent- preparation is recommended. ing the need for pharmacies to Short-acting preparations have Prescribers should always stock many different brands of been associated with large consider whether an m/r prep- one drug. The decision to include variations in blood pressure and aration is clinically justified. a particular brand should be reflex tachycardia.16 They have This decision should be based on based on licensed indications, also been controversially linked to both good quality clinical evidence supporting clinical evidence, an increase in the risk of cardio- and the individual requirements cost and availability. Close vascular events (see MeReC of the patient. collaboration between primary Bulletin Vol. 9 No. 4). A recent, and secondary care is also randomised double-blind trial in For those limited situations where necessary to ensure treatment 6321 patients with hypertension an m/r preparation is appropri- continuity for patients. found Adalat LA (a once daily m/r ate, it is important that the correct nifedipine preparation) to be as preparation, i.e. that intended by effective as co-amilozide the prescriber, is dispensed. As Conclusion (amiloride/hydrochlorothiazide) in confusion can arise if such pres- preventing overall cardiovascular criptions are written generically, Many m/r preparations offer no or cerebrovascular complica- it seems sensible to recommend clinical advantage and their use tions.17 PRODIGY guidance for brand name prescribing for m/r cannot be justified over equally prescribing nifedipine in angina preparations. Of more importance effective, often less expensive, and hypertension only offers the is the problem that different conventional-release preparations drug as an m/r preparation m/r preparations of the same in the same class. For some prescribed by brand name.18 drug have different release drugs e.g. nifedipine, m/r

MeReC Bulletin Volume 11, Number 4, 2000 15 Brand name Available strengths Licensed dose range Cost of 28 days therapy

Diltiazem (longer-acting*) once daily m/r preparations Adizem XL capsules 120mg, 180mg, 240mg, 300mg 120-300mg once daily £10.24 - £12.90 Angitil XL capsules 240mg, 300mg 240-300mg once daily £9.22 - £10.15 Dilzem XL capsules 120mg, 180mg, 240mg 120-360mg once daily £8.32 - £20.02 Optil XL capsules 240mg, 300mg 240-300mg once daily £9.22 - £10.15 Slozem capsules 120mg, 180mg, 240mg 120-360mg once daily £7.00 - £15.20 Tildiem LA capsules 200mg, 300mg 200-500mg once daily £11.61 - £24.41 Viazem XL capsules 120mg, 180mg, 240mg, 300mg, 360mg 120-360mg once daily £8.82 - £17.65 Zemtard XL capsules 120mg, 180mg, 240mg, 300mg 120-480mg once daily £7.65 - £16.30

Diltiazem (longer-acting*) twice daily m/r preparations Adizem SR capsules† 90mg, 120mg, 180mg 90-180mg twice daily £10.56 - £17.60 Angiozem CR tablets 90mg, 120mg 120mg daily-480mg daily in divided doses £5.53 - £22.12 Angitil SR capsules 90mg, 120mg, 180mg 90-180mg twice daily £8.45 - £14.08 Bi-Carzem SR capsules 60mg, 90mg, 120mg 60-180mg twice daily £8.00 - £20.00 Calcicard CR tablets 90mg, 120mg 120mg daily-480mg daily in divided doses £6.15 - £24.58 Dilcardia SR capsules 60mg, 90mg, 120mg 60-180mg twice daily £8.30 - £19.79 Dilzem SR capsules 60mg, 90mg, 120mg 60-180mg twice daily £8.32 - £20.79 Optil SR capsules 90mg, 120mg, 180mg 90-180mg twice daily £8.45 - £14.08 Tildiem Retard tablets 90mg, 120mg 120mg daily-480mg daily in divided doses £5.53 - £22.12

Nifedipine once daily m/r preparations Adalat LA tablets 20mg, 30mg, 60mg 20-90mg once daily £8.15 - £25.29 Coracten XL capsules 30mg, 60mg 30-90mg once daily £6.73 - £16.74 Fortipine LA 40 tablets 40mg 40-80mg daily in one or two divided doses £7.47 - £14.93 Slofedipine XL tablets 30mg, 60mg 30-90mg once daily £9.89 - £24.60

Nifedipine twice daily m/r preparations Adalat Retard tablets 10mg, 20mg 10-40mg twice daily £8.50 - £20.40 Adipine MR tablets 10mg, 20mg 10-40mg twice daily £6.62 - £16.52 Angiopine MR tablets 10mg, 20mg 10-40mg twice daily £6.24 - £15.40 Cardilate MR tablets 10mg, 20mg 10-40mg twice daily £6.93 - £20.55 Coracten SR capsules 10mg, 20mg 10-40mg twice daily £5.83 - £16.18 Coroday MR tablets 20mg 20-40mg twice daily £9.94 - £19.88 Hypolar Retard 20 tablets 20mg 20-40mg twice daily £10.12 - £20.24 Nifedipress MR tablets 10mg, 20mg 10-40mg twice daily £6.62 - £16.52 Nifopress Retard tablets 20mg 20-40mg twice daily £4.50 - £9.00 Nimodrel MR tablets 10mg, 20mg 10-40mg twice daily £6.62 - £16.52 Slofedipine tablets 20mg 20-40mg twice daily £10.32 - £20.64 Tensipine MR tablets 10mg, 20mg 10-40mg twice daily £7.62 - £19.02

Cost based on 28 days therapy over licensed dose ranges for both hypertension and angina (Chemist and Druggist, August 2000). * Longer-acting formulations differ from the standard formulations of diltiazem 60mg, which are given three times a day. Although the standard formulations are strictly called ‘m/r’ due to their formulation, they are licensed as generics and there is no requirement for brand name prescribing. † 120mg also available as tablets.

Table 2. Available diltiazem and nifedipine modified-release preparations preparations have all but between compliance and dosage frequency in Clin Pharmacokinet 1995; 28: 1-6 older people. Drugs Aging 1998; 13: 223-227 13 Benson HAE, Prankerd RJ. Optimisation of replaced conventional-release 5 Taggart AJ, Johnston GD, et al. Does the drug delivery: 3. Sustained/Controlled-release preparations. However, the frequency of daily dosage influence compliance oral drug delivery. Aust J Hosp Pharm 1997; with digoxin therapy? Br J Clin Pharmacol 27: 381-389 relative merits of any m/r 1981; 1: 31-34 14 Waller D. Modified-release drugs for cardiovas- preparation must always be 6 Greenberg RN. Overview of patient compliance cular disorders. Prescriber 1997; 8 (7): 19-31 with medication dosing: a literature review. 15 Chaplin S. Modified-release drugs: why, when compared with those of other Clin ther 1984; 6: 592-599 and how? Prescriber 1996; 7 (22): 77-81 products in the same class. 7 Pullar T, Birtwell AJ, et al. Use of a pharma- 16 British National Formulary, London, March cologic indicator to compare compliance with 2000: 39 Generally, m/r preparations tablets prescribed to be taken once, twice, or 17 Brown MJ, Palmer CR, et al. Morbidity and should be reserved for specific three times daily. Clin Pharmacol ther 1988; mortality in patients randomised to double- 44: 540-545 blind treatment with a long-acting calcium- patients where their use would 8 Cramer JA, Mattson RH, et al. How often is channel blocker or diuretic in the International help overcome a particular medication taken as prescribed? A novel Nifedipine GITS study: Intervention as a Goal assessment technique. JAMA 1989; 261: in Hypertension Treatment (INSIGHT). Lancet problem with compliance, 3273-3277 2000; 356: 366-372 effectiveness, or side-effects. 9 Eisen SA, Miller DK, et al. The effect of 18 Sowerby Centre for Health Informatics at prescribed daily dose frequency on patient Newcastle. PRODIGY Hypertension Guidance medication compliance. Arch Intern Med 1990; Jan 2000 and PRODIGY Angina Guidance July References 150: 1881-1884 1999. Available at: www.prodigy.nhs.uk/ 1 Quality and performance in the NHS: NHS 10 Brun J. Patient compliance with once-daily and 19 Feely M. Drug treatment of epilepsy. BMJ performance indicators. NHS Executive July twice-daily oral formulations of 5-isosorbide 1999; 318: 106-109 2000 mononitrate: a comparative study. J Int Med 20 Royal Pharmaceutical Society Council Advice. 2 British Pharmacopoeia 1999. London: HMSO Res 1994; 22: 266-272 Solid oral modified-release preparations. 3 British Pharmaceutical Codex, Principles and 11 Paes AHP, Bakker A, et al. Impact of dosage Pharm J 1993: 251: 528 Practice of Pharmaceutics 1994, 12th Edition. frequency on patient compliance. Diabetes London: The Pharmaceutical Press Care 1997: 20: 1512-1517 4 Pushpangadan M, Feely M. Once a day is best: 12 Rudd P, Lenert L. Pharmacokinetics as an aid Date of preparation: August 2000 evidence or assumption? The relationship to optimising compliance with medications. © The National Prescribing Centre, The Infirmary, 70 Pembroke Place, Liverpool, L69 3GF. Telephone: 0151-794 8146/48 Fax: 0151-794-8139/44 16 MeReC Bulletin Volume 11, Number 4, 2000