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Page 2018 Choosing a medication brand excipients, food intolerance and prescribing in older people.pdf

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  Contents lists available at ScienceDirect Maturitas  journal homepage: www.elsevier.com/locate/maturitas Review Article Choosing a medication brand: Excipients, food intolerance and prescribingin older people Amy Page ⁎ , Christopher Etherton-Beer Western Australian Centre for Health and Ageing, University of Western Australia A R T I C L E I N F O  Keywords: Generic medicationsBrandsExcipients A B S T R A C T Multiple brands of the same active ingredient may be available for the same strength, administration route anddose form. Generic brands needs to demonstrate bioequivalence to the srcinator brand, but the appearance of the generic and srcinator brands are not required to match. This variation is possible because di ff  erent brandsmay vary in the excipients used in the formulation. Excipients are inactive ingredients, and typically make upabout 90% of the formulation of an individual medication. Individual preferences or requirements may a ff  ecttolerance of particular excipients, such as the use of animal products. The di ff  erent appearance of brands cana ff  ect medication management for some people. This review discusses the potential for excipients to alter theindividual response to or tolerance of a medication brand. 1. Introduction Medications come in many di ff  erent formulations, and multiplebrands of the same active ingredient may be available in the samestrength, administration route and dose form. Generic brands are re-quired to demonstrate bioequivalence to the srcinal brand prior tomarketing authorisation [1]. Australian pharmacies, for example, areonly permitted to substitute brands if the two brands are bioequivalent.Bioequivalence does not mean that the brands are identical. Whilecomparable plasma concentrations of the active ingredient(s) areachieved after healthy people take both brands, and the same clinicalresponse can be expected, bioequivalent brands can di ff  er substantially.The appearance  –  shape, colour, size  –  of the generic and srcinatorbrands are not required to match [2]. For example, tablet forms of thecommon antihypertensive ramipril are available in white, yellow, redand pink [3].Such variation is possible because di ff  erent pharmaceutical pro-ducts vary in the excipients used in the formulation [1]. The inactiveingredients are excipients, which typically make up about 90% of theformulation of an individual medication [4]. The term encompasses allingredients  –  except the active ingredient  –  found in pharmaceuticalpreparations. They are used to colour and  󿬂 avour pharmaceuticalpreparations, and to enhance the product ’ s performance. Binders holdall the ingredients together to provide structure and strength, diluentsadd bulk to allow small quantities to be measured accurately and dis-integrants enhance dispersion of the dose-form in the gastro-intestinaltract (Table 1) [5,6]. Some common excipients and their function are listed in Table 2 [5,6]. The many di ff  erent excipients included in a brand are availablefrom the manufacturer [4]. Excipients generally are listed in the writteninformation generally available online, namely the Product Informationor Consumer Medicine Information lea 󿬂 ets [4]. In Australia, the man-ufacturer must declare the presence, but not the quantity, of speci 󿬁 cingredients including lactose, gluten and tartrazine [3,7]. This in-formation must be on the label, except for prescription-only medica-tions where it is an option to provide the information in the writteninformation [3,7].Excipients may a ff  ect individual responses to di ff  erent brands. Thisconcern can be linked to individual preference or requirements (such asfor vegetarians or individuals with religious dietary restrictions) orphysiological response (including adverse reactions and intolerances),as well as adherence which could be impacted by di ff  erences in thephysical appearance of brands of active medicines. This review dis-cusses the potential for excipients to alter the individual response ortolerance to a medication brand. 2. Methods This paper examines the e ff  ect that excipients have on the choice of brand without respect to whether the formulation is the srcinator orgeneric brand. The emphasis is on the acceptability, safety and toler-ability of the excipients themselves, and the e ff  ect that has on brandchoice. Given the frequency of polypharmacy among older people [8],we have focused on the e ff  ect that excipients have on brand choice in http://dx.doi.org/10.1016/j.maturitas.2017.11.001Received 23 October 2017; Accepted 1 November 2017 ⁎ Corresponding author.  E-mail address:  amy.page@uwa.edu.au (A. Page). Maturitas 107 (2018) 103–1090378-5122/ © 2017 Elsevier B.V. All rights reserved. M R  older people.Articles were included that discussed the e ff  ect of excipients onacceptability, tolerance, safety or adherence. We only included oralpreparations. For relevance to current practice, we excluded reportswhere concerns about an individual excipient has led to a re-formula-tion of the product. An example of this issue were compounding in-compatibilities between an excipient and an active ingredient causede ff  ected the performance or stability of the product, which led to a re-formulation so that the issue is not a current concern.We conducted a search in the Medline, Scopus, and Google Scholardatabases using a combination of search terms including  “ excipient ” , “ brand ”  and speci 󿬁 c excipient names. Articles were included if theywere in English. Reference lists of identi 󿬁 ed papers were scanned forrelevant studies. 3. Adverse reactions to excipients An allergen is a substance that is harmless for most people but canproduce an immune-mediated response which triggers symptoms thatcan range from mild to life-threatening [9] in allergic individuals.Theoretically, any dietary protein can be a potential allergen [10]. In-tolerances can mimic allergic symptoms but are not immune-mediatedand include responses to a broad range of triggers [11].Adverse reactions to excipients are thought to be uncommon [12],however numerous case reports that outline patient sensitivity to aspeci 󿬁 c excipient describe allergic reactions [13 – 19]. The nature of these papers suggests such responses are rare but serious, though didnot report fatalities. Authors generally report that their investigationsdetermined the adverse events were con 󿬁 rmed allergic reactionsmediated by an immune system response [18,20 – 26]. These reportedadverse events varied from skin reactions to severe allergic reactionswith documented anaphylaxis [18,20 – 26].Individual reactions to excipients may go unnoticed, and thus un-reported, if mild or not identi 󿬁 ed as being due to an excipient [21].Those referenced above were typically only identi 󿬁 ed after the personexperienced the same or a similar adverse e ff  ect to multiple medica-tions, or reacted to one brand but not another [21]. Suspected reactionswere generally con 󿬁 rmed by patch or intradermal testing [18,20 – 26]. 3.1. Speci  󿬁 c excipientsColouring agents  are added to medications for reasons that includeease of identi 󿬁 cation, improved acceptability and stabilising light-sen-sitive ingredients [4]. Many di ff  erent agents may be used to produce thesame or similar colours, and numerous case reports exist of allergies tocolouring agents such as the yellow dye tartrazine [19]. Little researchhas been done to con 󿬁 rm the potential for pharmacological activity of these excipients. Tartrazine allergy, was not found in 26 people withatopic allergies in a pilot double-blind randomised controlled trial [17].However, allergic responses to excipients that are intended to be inert,are likely to be rare, and thus di ffi cult to detect in clinical trials. Gluten  triggers an immune response that causes chronic in 󿬂 amma-tion in the small intestine of people with coeliac disease which can leadto malabsorption. The exact quantity of ingested gluten that triggers anadverse e ff  ect is uncertain and may vary between people, though it maybe as little as 10 mg in a day and  “ gluten-free ”  is de 󿬁 ned by theAmerican Food and Drug Administration (FDA) as 20 parts per million(ppm) of gluten or less [27].Starch is used in oral formulations as a binder and disintegrant [4].It is derived from plant sources such as wheat, corn and potato, soconcerns have been expressed about the possible gluten content inwheat-derived starch. However, wheat starch is so highly processedthat it is unlikely to have any remaining gluten content. In Australia andthe UK, manufacturers must declare if they have used wheat starch intheir printed materials [3,28,29].  Lactose  is a disaccharide sugar present in milk and used as a binderand a diluent in pharmaceutical products. The lactase enzyme in thesmall intestine metabolises lactose into two smaller sugars, glucose andgalactose, that are absorbed into the blood stream [30]. Some peoplehave reduced or absent lactase activity so cannot completely metaboliseall the lactose in the small intestine, which means some lactose reachesthe large intestine [30]. The presence of lactose in the large intestinecan trigger the symptoms of lactose intolerance [30] when bacteriametabolise lactose, producing gases that cause symptoms includingabdominal cramps, bloating and  󿬂 atulence. Lactose intolerance is dis-tinct from a milk allergy, which is an immune reaction to milk proteins[30].The lactose volume required to cause symptoms is variable, and canchange with age [31]. It is suggested that lactose intolerant people canconsume 12 g in a single dose with either no e ff  ect or only minorsymptoms [32]. Oral preparations that contain lactose may range from4 mg to 600 mg [31] so it is unlikely that a single tablet or capsulewould contain su ffi cient lactose to cause symptoms [32]. No signi 󿬁 cantdi ff  erence in symptoms after eight hours was found with 400 mg lactosecompared to placebo in a blinded crossover RCT with 77 lactose- Table 1 Common reasons excipients are used during manufacturing medications.Category Function Example excipientsBinders Achieve the desired strength for themedicationCelluloseglues the powder together to formgranules or tabletsCalcium carbonateCarbomersGelatinHydrogenatedvegetable oilLactoseCoatings and 󿬁 lmsProtect medication from moisture HypromelloseAssist to swallow medication Beeswax, whiteAllow for medication release at aspeci 󿬁 c location in thegastrointestinal systemCalcium carbonateCarnauba waxColourants Identify medication CalciumProtect light-sensitive ingredients CarmineDies (water-soluble) and pigments(water-insoluble)Iron oxideQuinoline yellowTartrazideTitanium dioxideDiluents Provide bulk for the activeingredient;Lactoseimprove properties such ascohesionSimeticoneTalcCellulose,microcrystallineCalcium carbonateDisintegrants Promote dissolution in thegastrointestinal tractCellulose,microcrystallineCroscarmellose sodiumCrospovidonePovidoneSodium starchglycolateGlidants Help powders to  󿬂 ow TalcStarchLubricants Prevents the product adhering toequipment during manufacturingor other surfacesCastor oil,hydrogenatedVegetable oil,hydrogenatedMacrogolMagnesium stearateSodium benzoateSodium lauryl sulfateTalc  A. Page, C. Etherton-Beer   Maturitas 107 (2018) 103–109 104  intolerant participants [32].Written material from the manufacturer declares only the presenceof lactose, but not the volume, which can change considerably betweenactive ingredients and between brands. American pharmaceuticals cancontain up to 1020 mg lactose as an inert ingredient [33]. When lactoseis present, an average 300 mg immediate release tablet was found tocontain 240 mg lactose (80% of its weight) [33]. The lactose content isvariable as laboratory testing showed that, for example, maximum dailydose of loperamide, codeine and omeprazole would result in consuming1000 mg, 368 mg and 8 mg lactose respectively [31]. People who takemany lactose-containing medications at the same time may risk a cu-mulative lactose content that could trigger symptoms. The quantity of lactose in medications may be inconsequential for people only taking afew medications. The risk may be greater in older people as medicationuse often increases with age with estimates that three-quarters of olderpeople take  󿬁 ve or more medications every day [34]. For people withsevere lactose intolerance and take many medications, medicationscould be considered as a source of hidden lactose if symptoms occur[31]. 4. Personal preferences and values The source of excipients can be a contentious issue for some con-sumers: excipients can be synthetic or sourced from animals or plants.The avoidance of animal-derived excipients often relates to a personalpreference rather than a safety concern. Safety concerns from animal-derived excipients have included prion-related diseases, so extractedexcipients are further re 󿬁 ned and tested to reduce the risk of con-taminated products [35]. The USA and Australia, for example, havelimited some animal-derived excipients to those sourced from speci 󿬁 edlisted countries to address infection concerns [36]. Some authors haveargued that all medications should be suitable for vegetarians or ve-gans, or at least adequately labelled as safe for vegans or vegetarians[37]. However, there are practical considerations for the source of ex-cipients. For example, phospholipids can be derived either natural orsynthetic sources, with natural phospholipids sourced from vegetables(e.g soybeans or  󿬂 ax seed) or animal materials (eg. egg yolk, milk orkrill) [35]. Preference is given to sourcing phospholipids from naturalsources as it is more sustainable and less expensive [35].  Religious beliefs  can include dietary restrictions on certain animalproducts. These dietary restrictions can extend to excipients. Hinduismrestricts bovine products, while Judaism and Islam restrict porcineproducts [38]. The extent to which an individual adheres to these re-ligious restrictions varies, and provisions within some religious groupsallow for therapeutic use depending on the therapeutic need. A state-ment arose from a World Health Organisation seminar which declaredthe gelatin in pharmaceutical products to be halal, and thus acceptablefor consumption by Muslims [39]. Most Muslims are able to use othermedications with porcine-derived excipients (e.g. some anticoagulantssuch as pancreatic enzymes) if no alternative therapy is available as thepreservation of human life is considered to take precedence over dietarylaws [40]. Several reports exist of religious believers choosing not touse medications based on a religious aversion to an excipient [41,42]. Gelatin  is usually derived from either bovine or porcine bones, andcan be problematic for vegetarians and observant members of somereligions [43]. Most capsules (50 – 80%) contain gelatine, which meansthat, for strict vegetarians, the brand of capsules need to be carefullyselected [40]. For example, there are 14 brands of omeprazole, a protonpump inhibitor to reduce gastric acid, available in Denmark; 10 out of 12 contain porcine-derived gelatin and the other two contain gelatinfrom an alternative source [40]. A similar report from the UK found that20 out of 100 common medications contained gelatin, of which eightstated it was animal-derived but did not identify the animal [37]. InAustralia, the origin of gelatin is not stated in the manufacturer ’ swritten information but may be available from the Medical Informationdepartment of the pharmaceutical company.       T     a       b       l     e      2     (     c    o    n     t      i    n    u    e      d     )    E   x   c    i   p    i   e   n    t    S   y   n   o   n   y   m   s    (   o   r         ‘     E   n   u   m     b   e   r         ’     i     f   a   p   p     l    i   c   a     b     l   e    )    F   u   n   c    t    i   o   n   s ,   e   x   a   m   p     l   e   s    N   o    t   e   s   o   r   r   e   a   c    t    i   o   n   s    (    t     h   e   o   r   e    t    i   c   a     l ,   a    t    t   r    i     b   u    t   e     d   o   r   c   o   n       󿬁    r   m   e     d   r   e   a   c    t    i   o   n   s    )    S   o   u   r   c   e ,    i     f   a   n    i   m   a     l    T   a   r    t   r   a   z    i   n   e    F   o   o     d   y   e     l     l   o   w    4 ,    C   o     l   o   u   r   a   n    t .    S   e   n   s    i    t    i   v    i    t    i   e   s   r   e   p   o   r    t   e     d   o     f     b   o    t     h   s    i     d   e   e       ff    e   c    t   s   a   n     d   a     l     l   e   r   g    i   c   r   e   a   c    t    i   o   n   s    T    i    t   a   n    i   u   m     d    i   o   x    i     d   e    (    E    1    7    1    )    C   o     l   o   u   r   a   n    t .    C   o   n   s    i     d   e   r   e     d   n   o   n    t   o   x    i   c   a   n     d   n   o   n    i   r   r    i    t   a   n    t .    O   p   a   q   u   e .    T   r    i     b   u    t   y     l   c    i    t   r   a    t   e    C    i    t   r    i   c   a   c    i     d    P     l   a   s    t    i   c    i   z   e   r .    C   o   n   s    i     d   e   r   e     d   n   o   n    t   o   x    i   c   a   n     d   n   o   n    i   r   r    i    t   a   n    t .    L   a   r   g   e   q   u   a   n    t    i    t    i   e   s   m   a   y     b   e     h   a   r   m     f   u     l    T   r    i   e    t     h   y     l   c    i    t   r   a    t   e    C    i    t   r    i   c   a   c    i     d   e    t     h   y     l   e   s    t   e   r    P     l   a   s    t    i   c    i   z   e   r   ;    C   o   n   s    i     d   e   r   e     d   n   o   n    t   o   x    i   c   a   n     d   n   o   n    i   r   r    i    t   a   n    t .    S   o     l   v   e   n    t .    L   a   r   g   e   q   u   a   n    t    i    t    i   e   s   m   a   y     b   e     h   a   r   m     f   u     l          *     T   o     l   e   r   a     b    i     l    i    t    i   e   s   v   a   r   y     f   o   r   s   o   m   e   e   x   c    i   p    i   e   n    t   s    i     f   p   r   e   p   a   r   e     d     f   o   r   o    t     h   e   r   r   o   u    t   e   s   o     f   a     d   m    i   n    i   s    t   r   a    t    i   o   n ,    t     h   e   r   e     f   o   r   e ,   c   o   m   m   e   n    t   s     h   e   r   e   a   p   p     l   y   o   n     l   y    t   o    t     h   e   o   r   a     l   r   o   u    t   e   o     f   a     d   m    i   n    i   s    t   r   a    t    i   o   n .    R   e     f   e   r   e   n   c   e   s   c   o   m   p    i     l   e     d     f   r   o   m   m   u     l    t    i   p     l   e   s   o   u   r   c   e ,   p   r    i   m   a   r    i     l   y   :      •     (    2    0    1    4    ) .    M   a   r    t    i   n     d   a     l   e    [    6    ]   :    T     h   e   c   o   m   p     l   e    t   e     d   r   u   g   r   e     f   e   r   e   n   c   e    –     3    8    t     h   e     d    i    t    i   o   n .    L   o   n     d   o   n ,    B    M    J    P   u     b     l    i   s     h    i   n   g    G   r   o   u   p    L    T    D .      •     R   o   w   e ,    R .    C . ,   e    t   a     l .    [    5    ] .    H   a   n     d     b   o   o     k   o     f    P     h   a   r   m   a   c   e   u    t    i   c   a     l    E   x   c    i   p    i   e   n    t   s .    L   o   n     d   o   n    U    K   a   n     d    W   a   s     h    i   n   g    t   o   n    D    C ,    P     h   a   r   m   a   c   e   u    t    i   c   a     l    P   r   e   s   s   a   n     d    A   m   e   r    i   c   a   n    P     h   a   r   m   a   c    i   s    t   s    A   s   s   o   c    i   a    t    i   o   n .  A. Page, C. Etherton-Beer   Maturitas 107 (2018) 103–109 107

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