Editorial
Pharmacological interactions of phosphate binders
Interacciones farmacológicas de los captores del fósforo
Jordi Bover Sanjuána,
, Juan Francisco Navarro-Gonzálezb, M. Dolores Arenasc, José-Vicente Torregrosad, Juan Tamargo Menéndeze, Angel Luis Martín de Franciscof, Emilio González-Parrag, M. Jesús Lloret Coraa, J. Emilio Sánchez Álvarezh, Alejandro Martín-Maloi, Pablo Molina Vilaj, M. Auxiliadora Bajok, Iara DaSilva Santosa
Corresponding author
a Servicio de Nefrología, Fundació Puigvert, IIB Sant Pau, RedinRen, Barcelona, Spain
b Servicio de Nefrología y Unidad de Investigación, Hospital Universitario Nuestra Señora de la Candelaria, RedinRen, Santa Cruz de Tenerife, Spain
c Servicio de Nefrología, Hospital Vithas Perpetuo Internacional, Alicante, Spain
d Servicio de Nefrología, Hospital Clínico, RedinRen, Barcelona, Spain
e Departamento de Farmacología, Facultad de Medicina, Universidad Complutense, Madrid, Spain
f Servicio de Nefrología, HU Valdecilla, Santander, Spain
g Servicio de Nefrología, Fundación Jiménez Díaz, Madrid, Spain
h AGC Nefrología, Hospital Universitario Central de Asturias, Oviedo, Spain
i Servicio de Nefrología, Hospital Reina Sofía, RedinRen, Instituto Maimónides de Investigación Biomédica de Córdoba (IMIBIC), Universidad de Córdoba, Córdoba, Spain
j Servicio de Nefrología, FISABIO, Hospital Universitari Dr. Peset, Departament de Medicina, Universitat de València, Valencia, Spain
k Servicio de Nefrología, Hospital Universitario La Paz, RedinRen, Madrid, Spain
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El hidróxido de aluminio puede <span class="elsevierStyleItalic">aumentar</span> la concentración de ácido valproico (aunque su significado clínico no está establecido) y se han descrito intoxicaciones por quinidina y digoxina. Además de los mostrados, <span class="elsevierStyleItalic">reduce</span> la absorción o disminuye niveles de alopurinol y sucralfato, AINE, carbenoxolona, clorpromazina, epoetina, ketoconazol, etambutol, gabapentina, isoniazida, metronidazol, penicilamina, ranitidina, cloroquina, ciclinas, diflunisal, fluoruro de sodio, glucocorticoides, kayexalato, lincosamidas, fenotiazinas y neurolépticos, cefpodoxima, isoniacida y nitrofurantoína. A destacar también la disminución de la absorción de corticoides, aunque con repercusión clínica dudosa si se vigila la respuesta al fármaco. Es conocido el aumento de su toxicidad por citrato sódico y vitamina C. Aumenta la excreción de ácido acetil salicílico y puede alterar la distribución del pertecnetato de sodio en pruebas de radioimagen.</p> <p id="spar0040" class="elsevierStyleSimplePara elsevierViewall"><span class="elsevierStyleSup">b</span><elsevierMultimedia ident="201812130606084551"></elsevierMultimedia>Demostrada ausencia de interacción también con furosemida y losartán.</p> <p id="spar0045" class="elsevierStyleSimplePara elsevierViewall"><span class="elsevierStyleSup">c</span><elsevierMultimedia ident="201812130606084552"></elsevierMultimedia>No descrita pero con potencial efecto de clase.</p> <p id="spar0010" class="elsevierStyleSimplePara elsevierViewall"><elsevierMultimedia ident="201812130606084553"></elsevierMultimedia>Interacción no especificada.</p> <p id="spar0015" class="elsevierStyleSimplePara elsevierViewall"><elsevierMultimedia ident="201812130606084554"></elsevierMultimedia>No interacción (demostrada en estudios <span class="elsevierStyleItalic">in vitro</span> o <span class="elsevierStyleItalic">in vivo</span>)</p> <p id="spar0020" class="elsevierStyleSimplePara elsevierViewall"><elsevierMultimedia ident="201812130606084555"></elsevierMultimedia>Disminuye la absorción/eficacia reducida</p> <p id="spar0025" class="elsevierStyleSimplePara elsevierViewall"><elsevierMultimedia ident="201812130606084556"></elsevierMultimedia>Aumenta el riesgo de hipercalcemia y toxicidad farmacológica secundaria (i.e. digitálicos).</p> <p id="spar0030" class="elsevierStyleSimplePara elsevierViewall">En las celdas en las que no se indica nada, ni sevelámero ni lantano han sido estudiados con diuréticos, pero la hipercalcemia no es un efecto secundario.</p>" ] ] ] "autores" => array:1 [ 0 => array:2 [ "autoresLista" => "Jordi Bover Sanjuán, Juan Francisco Navarro-González, M. 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Auxiliadora" "apellidos" => "Bajo" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">k</span>" "identificador" => "aff0055" ] ] ] 12 => array:3 [ "nombre" => "Iara" "apellidos" => "DaSilva Santos" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">a</span>" "identificador" => "aff0005" ] ] ] ] "afiliaciones" => array:11 [ 0 => array:3 [ "entidad" => "Servicio de Nefrología, Fundació Puigvert, IIB Sant Pau, RedinRen, Barcelona, Spain" "etiqueta" => "a" "identificador" => "aff0005" ] 1 => array:3 [ "entidad" => "Servicio de Nefrología y Unidad de Investigación, Hospital Universitario Nuestra Señora de la Candelaria, RedinRen, Santa Cruz de Tenerife, Spain" "etiqueta" => "b" "identificador" => "aff0010" ] 2 => array:3 [ "entidad" => "Servicio de Nefrología, Hospital Vithas Perpetuo Internacional, Alicante, Spain" "etiqueta" => "c" "identificador" => "aff0015" ] 3 => array:3 [ "entidad" => "Servicio de Nefrología, Hospital Clínico, RedinRen, Barcelona, Spain" "etiqueta" => "d" "identificador" => "aff0020" ] 4 => array:3 [ "entidad" => "Departamento de Farmacología, Facultad de Medicina, Universidad Complutense, Madrid, Spain" "etiqueta" => "e" "identificador" => "aff0025" ] 5 => array:3 [ "entidad" => "Servicio de Nefrología, HU Valdecilla, Santander, Spain" "etiqueta" => "f" "identificador" => "aff0030" ] 6 => array:3 [ "entidad" => "Servicio de Nefrología, Fundación Jiménez Díaz, Madrid, Spain" "etiqueta" => "g" "identificador" => "aff0035" ] 7 => array:3 [ "entidad" => "AGC Nefrología, Hospital Universitario Central de Asturias, Oviedo, Spain" "etiqueta" => "h" "identificador" => "aff0040" ] 8 => array:3 [ "entidad" => "Servicio de Nefrología, Hospital Reina Sofía, RedinRen, Instituto Maimónides de Investigación Biomédica de Córdoba (IMIBIC), Universidad de Córdoba, Córdoba, Spain" "etiqueta" => "i" "identificador" => "aff0045" ] 9 => array:3 [ "entidad" => "Servicio de Nefrología, FISABIO, Hospital Universitari Dr. Peset, Departament de Medicina, Universitat de València, Valencia, Spain" "etiqueta" => "j" "identificador" => "aff0050" ] 10 => array:3 [ "entidad" => "Servicio de Nefrología, Hospital Universitario La Paz, RedinRen, Madrid, Spain" "etiqueta" => "k" "identificador" => "aff0055" ] ] "correspondencia" => array:1 [ 0 => array:3 [ "identificador" => "cor0005" "etiqueta" => "⁎" "correspondencia" => "<span class="elsevierStyleItalic">Corresponding author</span>." ] ] ] ] "titulosAlternativos" => array:1 [ "es" => array:1 [ "titulo" => "Interacciones farmacológicas de los captores del fósforo" ] ] "resumenGrafico" => array:2 [ "original" => 0 "multimedia" => array:7 [ "identificador" => "fig0005" "etiqueta" => "Figure 1" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr1.jpeg" "Alto" => 4350 "Ancho" => 3359 "Tamanyo" => 1280228 ] ] "descripcion" => array:1 [ "en" => "<p id="spar0005" class="elsevierStyleSimplePara elsevierViewall">Pharmacological interactions of major nephrological significance of the different phosphate binders available in Spain.</p> <p id="spar0010" class="elsevierStyleSimplePara elsevierViewall"># See text. Aluminum hydroxide may <span class="elsevierStyleItalic">increase</span> the concentration of valproic acid (although its clinical significance is not established) and intoxications have been described for quinidine and digoxin. In addition to those shown, it <span class="elsevierStyleItalic">reduces</span> absorption or decreases levels of allopurinol and sucralfate, NSAIDs, carbenoxolone, chlorpromazine, epoetin, ketoconazole, ethambutol, gabapentin, isoniazid, metronidazole, penicillamine, ranitidine, chloroquine, cyclins, diflunisal, sodium fluoride, glucocorticoids, kayexalate, lincosamides, phenothiazines and neuroleptics, cefpodoxime, isoniazid and nitrofurantoin. It should be mentioned the decrease in corticosteroid absorption, although with doubtful clinical repercussions if the response to the drug is monitored. It is known that toxicity is increased by sodium citrate and vitamin C. It increases the excretion of acetylsalicylic acid and may alter the distribution of sodium pertechnetate in radioimaging tests.</p> <p id="spar0015" class="elsevierStyleSimplePara elsevierViewall"><elsevierMultimedia ident="201812140610078301"></elsevierMultimedia>Reduced absorption/reduced efficiency</p> <p id="spar0020" class="elsevierStyleSimplePara elsevierViewall"><elsevierMultimedia ident="201812140610078302"></elsevierMultimedia>Increases the risk of hypercalcemia and secondary pharmacological toxicity (i.e. digitalis). In white, neither Sevelamer nor lanthanum have been studied with diuretics, but hypercalcemia is not a secondary effect.</p> <p id="spar0025" class="elsevierStyleSimplePara elsevierViewall"><elsevierMultimedia ident="201812140610078303"></elsevierMultimedia>No interaction (demonstrated in <span class="elsevierStyleItalic">in vitro</span> or <span class="elsevierStyleItalic">in vivo</span> studies).</p> <p id="spar0030" class="elsevierStyleSimplePara elsevierViewall"><elsevierMultimedia ident="201812140610078304"></elsevierMultimedia>Unspecified interaction.</p> <p id="spar0035" class="elsevierStyleSimplePara elsevierViewall"><elsevierMultimedia ident="201812140610078305"></elsevierMultimedia>Not described but with a potential class effect.</p> <p id="spar0040" class="elsevierStyleSimplePara elsevierViewall"><elsevierMultimedia ident="201812140610078306"></elsevierMultimedia>Demonstrated the absence of interaction also with furosemide and losartan.</p>" ] ] ] "textoCompleto" => "<span class="elsevierStyleSections"><span id="sec0005" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0005">Phosphate binders</span><p id="par0005" class="elsevierStylePara elsevierViewall">The use of phosphate binders is one of basic elements in the treatment of CKD-MBD (“Chronic Kidney Disease-Mineral and Bone Disorder”).<a class="elsevierStyleCrossRef" href="#bib0155"><span class="elsevierStyleSup">1</span></a></p><p id="par0010" class="elsevierStylePara elsevierViewall">It has been well known for decades that phosphate retention through direct and indirect mechanisms, contributes to the generation and progression of secondary hyperparathyroidism (SHP) and renal osteodystrophy in chronic kidney disease (CKD).<a class="elsevierStyleCrossRefs" href="#bib0155"><span class="elsevierStyleSup">1,2</span></a> In fact, phosphate retention blocks all hormonal counter-regulatory mechanisms, increases skeletal resistance to PTH and is considered a central factor in the physiopathology of other endocrine and systemic alterations such as the decrease in calcitriol, increase in fibroblast growth factor-23 (FGF-23), cardiovascular calcifications, premature aging and the high morbi-mortality of these patients.<a class="elsevierStyleCrossRefs" href="#bib0160"><span class="elsevierStyleSup">2,3</span></a> For all this, phosphate has been considered as “the silent killer” of patients with CKD.<a class="elsevierStyleCrossRef" href="#bib0170"><span class="elsevierStyleSup">4</span></a></p><p id="par0015" class="elsevierStylePara elsevierViewall">As a consequence, especially in dialysis patients, the recent KDIGO guidelines underline the importance of dietary phosphate restriction, an adequate dose of dialysis and the use of phosphate binders.<a class="elsevierStyleCrossRef" href="#bib0160"><span class="elsevierStyleSup">2</span></a> The evidence about the positive effect of the diet is limited and of low quality<a class="elsevierStyleCrossRef" href="#bib0175"><span class="elsevierStyleSup">5</span></a> and an aggressive phosphate restriction is not only difficult but could also compromise the patient's nutritional status, counterbalancing the benefit of controlling phosphorus.<a class="elsevierStyleCrossRef" href="#bib0180"><span class="elsevierStyleSup">6</span></a> In fact, the use of phosphate binders would allow a more liberal diet and a decreased risk of malnutrition.<a class="elsevierStyleCrossRef" href="#bib0180"><span class="elsevierStyleSup">6</span></a></p><p id="par0020" class="elsevierStylePara elsevierViewall">Although, by definition, all phosphate binders decrease the serum levels of phosphate, the characteristics of phosphate binders (with calcium, without calcium, with metals such as magnesium, iron or aluminum; polymers), in monotherapy or combination, seem to condition differential effects on a variety of aspects of the CKD-MBD complex (i.e. arterial calcification, FGF-23 levels) or on the survival of dialysis patients.<a class="elsevierStyleCrossRefs" href="#bib0185"><span class="elsevierStyleSup">7,8</span></a> The new KDIGO 2017 guidelines have increased the degree of evidence about the need to restrict the use of calcium containing phosphate binders in all CKD patients (evidence 2B)<a class="elsevierStyleCrossRef" href="#bib0160"><span class="elsevierStyleSup">2</span></a> and this restriction does not only apply to those patients with hypercalcemia, arterial calcification, adynamic bone disease or patients with parathormone (PTH) persistently reduced, as suggested in previous guidelines. Likewise, it is still considered reasonable to assess the presence of vascular/valvular calcifications in patients with CKD to guide pharmacological management.<a class="elsevierStyleCrossRefs" href="#bib0160"><span class="elsevierStyleSup">2,9</span></a></p></span><span id="sec0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0010">Binders: adherence and pharmacological interactions</span><p id="par0025" class="elsevierStylePara elsevierViewall">Nephrologists are generally aware that patients with CKD, especially on renal replacement therapy, have to take a large number of drugs and a lot of them are phosphate binders in form of tablets/capsules/daily sachets.<a class="elsevierStyleCrossRef" href="#bib0200"><span class="elsevierStyleSup">10</span></a> Simultaneous administration of several medications to the same patient is very frequent. Although this situation may be beneficial to improve therapeutic adherence, there are some drawbacks, as the possibility of pharmacological interactions, especially in patients of advanced age or with chronic pathologies.</p><p id="par0030" class="elsevierStylePara elsevierViewall">An aspect often forgotten by nephrologists is that phosphate binders, due to its different biochemical properties, may have a marked differential influence on the absorption and effectiveness of many drugs. In fact, its simultaneous administration with other drugs is frequent and its possible clinical implications may be frequently unnoticed. Therefore, we believe it is important to improve this practice and review the pharmacological interactions described on the different phosphorus binders.</p></span><span id="sec0015" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0015">Pharmacological interactions</span><p id="par0035" class="elsevierStylePara elsevierViewall">The different effect of phosphate binders on the absorption of other drugs implies a pharmacokinetic interaction (generally affecting the absorption) which is different from pharmacodynamic interactions (affecting the binding to receptors or changing mechanisms of signal transduction). There are many reviews and tables that summarize the different effects of phosphate binders (dose, number of tablets, side effects, levels of calcium, phosphate, PTH, FGF-23 and even on the progression of vascular calcification and/or survival/mortality)<a class="elsevierStyleCrossRef" href="#bib0195"><span class="elsevierStyleSup">9</span></a>; however, there are not publications that analyzed and compared possible drug interactions such as the ones summarized in <a class="elsevierStyleCrossRef" href="#fig0005">figure 1</a>. It can be seen that most drug interactions are observed with calcium and aluminum containing phosphate binders.</p><elsevierMultimedia ident="fig0005"></elsevierMultimedia><span id="sec0020" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0020">Calcium-based phosphate binders</span><span id="sec0025" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0025">Calcium carbonate (Mastical<span class="elsevierStyleSup">®</span>, Caosina<span class="elsevierStyleSup">®</span>)</span><p id="par0040" class="elsevierStylePara elsevierViewall">Calcium carbonate can modify the absorption of various drugs, so these should be administered at least 2<span class="elsevierStyleHsp" style=""></span>h before or 4–6<span class="elsevierStyleHsp" style=""></span>h after the binder. In addition to those shown, it should be highlighted other antibiotics such as neomycin, chloramphenicol and fosfomycin, systemic corticosteroids, phenytoin, barbiturates, antacids containing aluminum salts, cholestyramine, zinc, fluorides and iron salts.<a class="elsevierStyleCrossRefs" href="#bib0205"><span class="elsevierStyleSup">11,12</span></a> This last interaction is important to avoid combinations of the commonly used calcium-based phosphate binders<a class="elsevierStyleCrossRef" href="#bib0190"><span class="elsevierStyleSup">8</span></a> with binders containing iron. As observed with the other binders it is important to remember that the effectiveness of levothyroxine can be reduced by the concurrent use of calcium binders. This means that the administration of calcium carbonate and levothyroxine should be separated by at least 4<span class="elsevierStyleHsp" style=""></span>h.<a class="elsevierStyleCrossRef" href="#bib0215"><span class="elsevierStyleSup">13</span></a></p><p id="par0045" class="elsevierStylePara elsevierViewall">Another interaction to take into account, this one of a pharmacodynamic nature, is that hypercalcemia can increase the toxicity of digitalis (digoxin) and that thiazide diuretics reduce urinary calcium excretion, so there is an increased risk of hypercalcemia when coadministered with calcium-containing phosphate binders. Similarly, the concomitant treatment with vitamin D derivatives and/or medications or nutrients that contain calcium (milk) may favor hypercalcemia and the milk-alkaline syndrome. Besides, the intake of high amounts of calcium may cause a precipitation of bile and fatty acids in the form of soaps that could alter the absorption of ursodesoxycholic and chenodesoxycholic acid, as well as fats and fat-soluble vitamins.<a class="elsevierStyleCrossRefs" href="#bib0210"><span class="elsevierStyleSup">12,13</span></a></p></span><span id="sec0030" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0030">Calcium acetate (Royen<span class="elsevierStyleSup">®</span>, RenaCare<span class="elsevierStyleSup">®</span> calcium acetate)</span><p id="par0050" class="elsevierStylePara elsevierViewall">As mentioned for calcium carbonate, the administration of calcium acetate with some medications can alter its absorption or favor their toxicity through hypercalcemia. In addition to the information shown in the table, it should be highlighted the scarcely known effect on the impairment of calcium antagonists effectiveness.<a class="elsevierStyleCrossRef" href="#bib0220"><span class="elsevierStyleSup">14</span></a> Despite the fact that a retrospective pharmacoepidemiological study had referred to the little or no interference of calcium acetate with the absorption of levothyroxine,<a class="elsevierStyleCrossRef" href="#bib0225"><span class="elsevierStyleSup">15</span></a> recent data suggest that hypothyroid patients should be warned of taking the dose of levothyroxine clearly separated from <span class="elsevierStyleItalic">any</span> formulation with calcium.<a class="elsevierStyleCrossRef" href="#bib0230"><span class="elsevierStyleSup">16</span></a></p></span><span id="sec0035" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0035">Calcium acetate/magnesium carbonate (Osvaren<span class="elsevierStyleSup">®</span>)</span><p id="par0055" class="elsevierStylePara elsevierViewall">The combination calcium acetate/magnesium carbonate may alter the absorption of some medications included in the table, so they should not be taken within 2<span class="elsevierStyleHsp" style=""></span>h before or 3<span class="elsevierStyleHsp" style=""></span>h after the administration of the phosphate binder.<a class="elsevierStyleCrossRef" href="#bib0235"><span class="elsevierStyleSup">17</span></a> In addition to the decrease in the absorption of cefuroxime, cefpodoxime or nitrofurantoin, it is also described the interaction with the absorption of zinc, fluorides and the antimalarial halofantrine.<a class="elsevierStyleCrossRef" href="#bib0235"><span class="elsevierStyleSup">17</span></a> Likewise, the ingestion of magnesium can influence the absorption of iron, a common supplement included in the polymedication of the patient with CKD. Calcium acetate/magnesium carbonate may also produce hypermagnesemia, so antacids that contain not only calcium but also magnesium salts should be avoided. Magnesium salts may favor the absorption of digoxin in the gastrointestinal tract, decreasing its bioavailability, in addition to the possibility of increasing its potential toxicity due to hypercalcemia. The summary of product characteristics of this combination describes the possibility that concomitant use with estrogens may produce an increase sin serum calcium levels.<a class="elsevierStyleCrossRef" href="#bib0235"><span class="elsevierStyleSup">17</span></a> Interestingly, unlike the other binders, it is mentioned that an <span class="elsevierStyleItalic">increase</span> in the absorption of levothyroxine may occur if given in combination with aluminum hydroxide<a class="elsevierStyleCrossRefs" href="#bib0235"><span class="elsevierStyleSup">17,18</span></a>; however, as mentioned, recent data suggests that the administration of levothyroxine should be clearly separated from any formulation with calcium<a class="elsevierStyleCrossRef" href="#bib0230"><span class="elsevierStyleSup">16</span></a> and other binders.</p></span></span><span id="sec0040" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0040">Binders without calcium: polymers and metals</span><p id="par0060" class="elsevierStylePara elsevierViewall">As shown in <a class="elsevierStyleCrossRef" href="#fig0005">figure 1</a>, the number of pharmacological interactions described with binders of a polymer structure (sevelamer) or metals (lanthanum, iron) is lower than that of calcium-based phosphate binders. However, there is abundant information regarding drug interactions of these binders as they were incorporated more recently to the therapeutic arsenal and these drugs had to address more queries to the official agencies in their clinical trials. We emphasize that in these studies, patients on antiarrhythmic or anticonvulsant medications were specifically excluded. In general, it would also be advisable to avoid co-administration of these drugs with any type of phosphate binders.</p><span id="sec0045" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0045">Sevelamer (Renagel<span class="elsevierStyleSup">®</span>, Renvela<span class="elsevierStyleSup">®</span>, generic Sevelámero)</span><p id="par0065" class="elsevierStylePara elsevierViewall">Sevelamer is a nonabsorbable cross-linked polymer. Medications that show a reduction of their bioavailability by sevelamer should be given at least one hour before or three hours after the administration of sevelamer.<a class="elsevierStyleCrossRef" href="#bib0245"><span class="elsevierStyleSup">19</span></a> Studies on drug interactions in healthy volunteers revealed that sevelamer hydrochloride reduced the bioavailability of ciprofloxacin by approximately 50%.<a class="elsevierStyleCrossRef" href="#bib0250"><span class="elsevierStyleSup">20</span></a> It is very important to know that sevelamer can reduce plasma levels of cyclosporine, tacrolimus and mycophenolate mofetil in transplant patients although without apparent clinical consequences (for example, graft rejection). Still, monitoring of their plasma levels is advisable during the use of this combination and after its withdrawal. TSH levels should be monitored in patients receiving levothyroxine (as with any binder). Sevelamer can decrease the absorption of fat-soluble vitamins D, E, K and folic acid, with debatable clinical repercussion.<a class="elsevierStyleCrossRef" href="#bib0245"><span class="elsevierStyleSup">19</span></a> On the contrary, in healthy volunteers, sevelamer had no effect on the bioavailability of drugs as important as digoxin, warfarin, enalapril or metoprolol.<a class="elsevierStyleCrossRef" href="#bib0255"><span class="elsevierStyleSup">21</span></a> However, coadministration of proton pump inhibitors with sevelamer can increase, rarely, serum phosphate levels.<a class="elsevierStyleCrossRef" href="#bib0255"><span class="elsevierStyleSup">21</span></a></p></span><span id="sec0050" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0050">Lanthanum carbonate (Fosrenol<span class="elsevierStyleSup">®</span>)</span><p id="par0070" class="elsevierStylePara elsevierViewall">Lanthanum may increase gastric pH (a similar effect is seen with calcium-based phosphate binders which are often used in combinations of antacids) and decrease the oral absorption of weak alkaline drugs. It is recommended not to take these compounds two hours before or after the administration of lanthanum carbonate (i.e. antimalarials such as chloroquine and hydroxychloroquine, the antifungal agent ketoconazole or bisphosphonates).<a class="elsevierStyleCrossRef" href="#bib0260"><span class="elsevierStyleSup">22</span></a> The bioavailability of oral ciprofloxacin decreased by approximately 50% when administered together with lanthanum carbonate in a study on healthy volunteers.<a class="elsevierStyleCrossRef" href="#bib0265"><span class="elsevierStyleSup">23</span></a> In contrast, lanthanum carbonate did not affect the serum concentrations of the liposoluble vitamins A, D, E and K,<a class="elsevierStyleCrossRef" href="#bib0270"><span class="elsevierStyleSup">24</span></a> although recently <span class="elsevierStyleItalic">in vitro</span> interactions have been described with vitamin K<span class="elsevierStyleInf">2</span>.<a class="elsevierStyleCrossRef" href="#bib0275"><span class="elsevierStyleSup">25</span></a> It is also important to emphasize that, in healthy volunteers, the administration of lanthanum carbonate did not modify the pharmacokinetic profile of digoxin, warfarin, metoprolol, phenytoin or enalapril.<a class="elsevierStyleCrossRef" href="#bib0260"><span class="elsevierStyleSup">22</span></a></p></span><span id="sec0055" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0055">Sucroferric oxyhydroxide [(OHS), Velphoro<span class="elsevierStyleSup">®</span>]</span><p id="par0075" class="elsevierStylePara elsevierViewall">Unlike other phosphate binders, there is considerable information about the absence of OHS interactions with other drugs (see <a class="elsevierStyleCrossRef" href="#fig0005">figure 1</a>). Moreover, it has been described that there is no relevant interaction <span class="elsevierStyleItalic">in vitro</span> of OHS with cephalexin, nifedipine and quinidine, amongst others (<a class="elsevierStyleCrossRef" href="#fig0005">figure 1</a>).<a class="elsevierStyleCrossRef" href="#bib0280"><span class="elsevierStyleSup">26</span></a> In healthy volunteers there are no relevant interactions either with losartan, furosemide, omeprazole, digoxin or warfarin.<a class="elsevierStyleCrossRef" href="#bib0285"><span class="elsevierStyleSup">27</span></a> OHS does not interact with statins (atorvastatin and simvastatin) in dialysis patients, despite preliminary data <span class="elsevierStyleItalic">in vitro</span> suggested the possibility of such interaction. Unlike sevelamer, OHS does not affect the inhibitory activity of oral vitamin D upon PTH<a class="elsevierStyleCrossRef" href="#bib0290"><span class="elsevierStyleSup">28</span></a> and, unlike lanthanum, does not seem to interact with Vitamin K<span class="elsevierStyleInf">2</span>.<a class="elsevierStyleCrossRef" href="#bib0275"><span class="elsevierStyleSup">25</span></a> It may be possible to see a lower oral absorption of drugs that interact with iron (such as alendronate and doxycycline) or, like the other binders, with levothyroxine.<a class="elsevierStyleCrossRef" href="#bib0295"><span class="elsevierStyleSup">29</span></a></p></span><span id="sec0060" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0060">Aluminum-based binders</span><p id="par0080" class="elsevierStylePara elsevierViewall">Although KDIGO guidelines recommend (evidence 1C) to avoid the prolonged use of aluminum-based phosphate binders,<a class="elsevierStyleCrossRef" href="#bib0160"><span class="elsevierStyleSup">2</span></a><a class="elsevierStyleCrossRef" href="#fig0005">figure 1</a> presents the multiple possibilities of interactions either by its potential prescription outside our scope or as a master formula.<a class="elsevierStyleCrossRef" href="#bib0300"><span class="elsevierStyleSup">30</span></a> We must also highlight the possibility of unknown interactions with immunosuppressants or recently developed drugs.</p></span></span></span><span id="sec0065" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0065">Conclusion</span><p id="par0085" class="elsevierStylePara elsevierViewall">Apart from the described potential negative effects of calcium-containing phosphate binders, we should also be taking into account the greater frequency of possible drug interactions with many drugs routinely used in our polymedicated patients. In general, other binders such as sevelamer, lanthanum and OHS have proven the <span class="elsevierStyleItalic">absence</span> of significant interactions with drugs for which there is no information available with the older binders. Likewise, it should be kept in mind that those binders who need a smaller number pills in monotherapy, will not only improve adherence to treatment but will also decrease the risk of possible undesirable interactions. In any case, although the potential for interactions seems low for some binders, especially OHS, its use with drugs with a narrow therapeutic range would advise to separate the doses to achieve the clinical effect and reduce adverse reactions, both at the beginning of treatment and after subsequent dose adjustments.</p></span><span id="sec0070" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0070">Declaration of the authors</span><p id="par0090" class="elsevierStylePara elsevierViewall">The authors approve the submission of the article for publication in the Nefrologia journal and declare that it has not been sent simultaneously to any other journal for publication. The authors also declare that it is an idea not originated in the pharmaceutical industry and that its intellectual property is transferred to Nefrologia. The authors approve the final form and are responsible for its content.</p></span><span id="sec0075" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0075">Conflicts of interest</span><p id="par0095" class="elsevierStylePara elsevierViewall">J.B. has received lecture fees from Abbvie, Amgen, Genzyme and Shire, and as consultant from Abbvie, Amgen, Vifor/Fresenius-Renal Pharma, Chugai, Medice and Genzyme/Sanofi. J.F.N.G. has received lectures and/or consultancies fees from Abbvie, Amgen, Astra-Zeneca, Boehringer-Ingelheim, Esteve, Genzyme, Sanofi, Servier, Shire and Vifor/Fresenius-Renal Pharma. M.D.A. has received lectures or consultant fees from Shire, Fresenius, Abbvie and Amgen. E.G.P. has received consultant fees from Sanofi, Vifor/Fresenius-Renal Pharma, Amgen, Abbvie and Shire. A.L.M.F. has received lectures fees from General Electric and Astra Zeneca and consultant fees from Vifor/Fresenius-Renal Pharma. E.S. has received lectures fees from Abbvie, Sanofi, Shire, Vifor/Fresenius-Renal Pharma. A.M.M. has received lecture fees from Abbvie, Amgen, Shire, Bellco, Fresenius-Medical Care. M.J.Ll. has received lecture fees from Sanofi and Abbvie, and consultant fees from Vifor/Fresenius-Renal Pharma. P.M.V. has received lecture fees from Amgen, Sanofi and Vifor/Fresenius-Renal Pharma and consultant fees from Vifor/Fresenius-Renal Pharma. M.A.B. has received lecture fees from Vifor/Fresenius-Renal Pharma. I.D. has received fees for scientific collaboration with Vifor/Fresenius-Renal Pharma.</p></span></span>" "textoCompletoSecciones" => array:1 [ "secciones" => array:7 [ 0 => array:2 [ "identificador" => "sec0005" "titulo" => "Phosphate binders" ] 1 => array:2 [ "identificador" => "sec0010" "titulo" => "Binders: adherence and pharmacological interactions" ] 2 => array:3 [ "identificador" => "sec0015" "titulo" => "Pharmacological interactions" "secciones" => array:2 [ 0 => array:3 [ "identificador" => "sec0020" "titulo" => "Calcium-based phosphate binders" "secciones" => array:3 [ 0 => array:2 [ "identificador" => "sec0025" "titulo" => "Calcium carbonate (Mastical, Caosina)" ] 1 => array:2 [ "identificador" => "sec0030" "titulo" => "Calcium acetate (Royen, RenaCare calcium acetate)" ] 2 => array:2 [ "identificador" => "sec0035" "titulo" => "Calcium acetate/magnesium carbonate (Osvaren)" ] ] ] 1 => array:3 [ "identificador" => "sec0040" "titulo" => "Binders without calcium: polymers and metals" "secciones" => array:4 [ 0 => array:2 [ "identificador" => "sec0045" "titulo" => "Sevelamer (Renagel, Renvela, generic Sevelámero)" ] 1 => array:2 [ "identificador" => "sec0050" "titulo" => "Lanthanum carbonate (Fosrenol)" ] 2 => array:2 [ "identificador" => "sec0055" "titulo" => "Sucroferric oxyhydroxide [(OHS), Velphoro]" ] 3 => array:2 [ "identificador" => "sec0060" "titulo" => "Aluminum-based binders" ] ] ] ] ] 3 => array:2 [ "identificador" => "sec0065" "titulo" => "Conclusion" ] 4 => array:2 [ "identificador" => "sec0070" "titulo" => "Declaration of the authors" ] 5 => array:2 [ "identificador" => "sec0075" "titulo" => "Conflicts of interest" ] 6 => array:1 [ "titulo" => "Références" ] ] ] "pdfFichero" => "main.pdf" "tienePdf" => true "multimedia" => array:7 [ 0 => array:7 [ "identificador" => "fig0005" "etiqueta" => "Figure 1" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr1.jpeg" "Alto" => 4350 "Ancho" => 3359 "Tamanyo" => 1280228 ] ] "descripcion" => array:1 [ "en" => "<p id="spar0005" class="elsevierStyleSimplePara elsevierViewall">Pharmacological interactions of major nephrological significance of the different phosphate binders available in Spain.</p> <p id="spar0010" class="elsevierStyleSimplePara elsevierViewall"># See text. Aluminum hydroxide may <span class="elsevierStyleItalic">increase</span> the concentration of valproic acid (although its clinical significance is not established) and intoxications have been described for quinidine and digoxin. In addition to those shown, it <span class="elsevierStyleItalic">reduces</span> absorption or decreases levels of allopurinol and sucralfate, NSAIDs, carbenoxolone, chlorpromazine, epoetin, ketoconazole, ethambutol, gabapentin, isoniazid, metronidazole, penicillamine, ranitidine, chloroquine, cyclins, diflunisal, sodium fluoride, glucocorticoids, kayexalate, lincosamides, phenothiazines and neuroleptics, cefpodoxime, isoniazid and nitrofurantoin. It should be mentioned the decrease in corticosteroid absorption, although with doubtful clinical repercussions if the response to the drug is monitored. It is known that toxicity is increased by sodium citrate and vitamin C. It increases the excretion of acetylsalicylic acid and may alter the distribution of sodium pertechnetate in radioimaging tests.</p> <p id="spar0015" class="elsevierStyleSimplePara elsevierViewall"><elsevierMultimedia ident="201812140610078301"></elsevierMultimedia>Reduced absorption/reduced efficiency</p> <p id="spar0020" class="elsevierStyleSimplePara elsevierViewall"><elsevierMultimedia ident="201812140610078302"></elsevierMultimedia>Increases the risk of hypercalcemia and secondary pharmacological toxicity (i.e. digitalis). In white, neither Sevelamer nor lanthanum have been studied with diuretics, but hypercalcemia is not a secondary effect.</p> <p id="spar0025" class="elsevierStyleSimplePara elsevierViewall"><elsevierMultimedia ident="201812140610078303"></elsevierMultimedia>No interaction (demonstrated in <span class="elsevierStyleItalic">in vitro</span> or <span class="elsevierStyleItalic">in vivo</span> studies).</p> <p id="spar0030" class="elsevierStyleSimplePara elsevierViewall"><elsevierMultimedia ident="201812140610078304"></elsevierMultimedia>Unspecified interaction.</p> <p id="spar0035" class="elsevierStyleSimplePara elsevierViewall"><elsevierMultimedia ident="201812140610078305"></elsevierMultimedia>Not described but with a potential class effect.</p> <p id="spar0040" class="elsevierStyleSimplePara elsevierViewall"><elsevierMultimedia ident="201812140610078306"></elsevierMultimedia>Demonstrated the absence of interaction also with furosemide and losartan.</p>" ] ] 1 => array:5 [ "identificador" => "201812140610078301" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => false "mostrarDisplay" => true "figura" => array:1 [ 0 => array:4 [ "imagen" => "fx1.jpeg" "Alto" => 109 "Ancho" => 109 "Tamanyo" => 792 ] ] ] 2 => array:5 [ "identificador" => "201812140610078302" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => false "mostrarDisplay" => true "figura" => array:1 [ 0 => array:4 [ "imagen" => "fx2.jpeg" "Alto" => 109 "Ancho" => 109 "Tamanyo" => 1306 ] ] ] 3 => array:5 [ "identificador" => "201812140610078303" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => false "mostrarDisplay" => true "figura" => array:1 [ 0 => array:4 [ "imagen" => "fx3.jpeg" "Alto" => 108 "Ancho" => 109 "Tamanyo" => 498 ] ] ] 4 => array:5 [ "identificador" => "201812140610078304" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => false "mostrarDisplay" => true "figura" => array:1 [ 0 => array:4 [ "imagen" => "fx4.jpeg" "Alto" => 104 "Ancho" => 109 "Tamanyo" => 827 ] ] ] 5 => array:5 [ "identificador" => "201812140610078305" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => false "mostrarDisplay" => true "figura" => array:1 [ 0 => array:4 [ "imagen" => "fx5.jpeg" "Alto" => 108 "Ancho" => 109 "Tamanyo" => 1432 ] ] ] 6 => array:5 [ "identificador" => "201812140610078306" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => false "mostrarDisplay" => true "figura" => array:1 [ 0 => array:4 [ "imagen" => "fx6.jpeg" "Alto" => 108 "Ancho" => 109 "Tamanyo" => 2197 ] ] ] ] "bibliografia" => array:2 [ "titulo" => "Références" "seccion" => array:1 [ 0 => array:2 [ "identificador" => "bibs0015" "bibliografiaReferencia" => array:30 [ 0 => array:3 [ "identificador" => "bib0155" "etiqueta" => "1" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Spanish Society of Nephrology recommendations for controlling mineral and bone disorder in chronic kidney disease patients (SEN-MBD)" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ 0 => "J.-V. 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| Year/Month | Html | Total | |
|---|---|---|---|
| 2024 November | 38 | 10 | 48 |
| 2024 October | 304 | 105 | 409 |
| 2024 September | 310 | 79 | 389 |
| 2024 August | 319 | 141 | 460 |
| 2024 July | 371 | 57 | 428 |
| 2024 June | 316 | 87 | 403 |
| 2024 May | 275 | 78 | 353 |
| 2024 April | 245 | 102 | 347 |
| 2024 March | 281 | 86 | 367 |
| 2024 February | 220 | 76 | 296 |
| 2024 January | 241 | 63 | 304 |
| 2023 December | 184 | 75 | 259 |
| 2023 November | 183 | 78 | 261 |
| 2023 October | 289 | 107 | 396 |
| 2023 September | 243 | 61 | 304 |
| 2023 August | 224 | 56 | 280 |
| 2023 July | 223 | 114 | 337 |
| 2023 June | 259 | 53 | 312 |
| 2023 May | 203 | 83 | 286 |
| 2023 April | 216 | 55 | 271 |
| 2023 March | 356 | 112 | 468 |
| 2023 February | 207 | 40 | 247 |
| 2023 January | 222 | 67 | 289 |
| 2022 December | 196 | 72 | 268 |
| 2022 November | 229 | 76 | 305 |
| 2022 October | 209 | 85 | 294 |
| 2022 September | 253 | 146 | 399 |
| 2022 August | 280 | 161 | 441 |
| 2022 July | 245 | 141 | 386 |
| 2022 June | 236 | 155 | 391 |
| 2022 May | 327 | 63 | 390 |
| 2022 April | 360 | 111 | 471 |
| 2022 March | 406 | 95 | 501 |
| 2022 February | 359 | 85 | 444 |
| 2022 January | 364 | 91 | 455 |
| 2021 December | 236 | 74 | 310 |
| 2021 November | 261 | 68 | 329 |
| 2021 October | 657 | 121 | 778 |
| 2021 September | 292 | 99 | 391 |
| 2021 August | 242 | 110 | 352 |
| 2021 July | 279 | 88 | 367 |
| 2021 June | 303 | 85 | 388 |
| 2021 May | 234 | 161 | 395 |
| 2021 April | 466 | 191 | 657 |
| 2021 March | 281 | 136 | 417 |
| 2021 February | 345 | 87 | 432 |
| 2021 January | 220 | 73 | 293 |
| 2020 December | 198 | 77 | 275 |
| 2020 November | 156 | 46 | 202 |
| 2020 October | 132 | 48 | 180 |
| 2020 September | 170 | 42 | 212 |
| 2020 August | 163 | 48 | 211 |
| 2020 July | 187 | 47 | 234 |
| 2020 June | 198 | 56 | 254 |
| 2020 May | 172 | 45 | 217 |
| 2020 April | 303 | 51 | 354 |
| 2020 March | 287 | 36 | 323 |
| 2020 February | 246 | 56 | 302 |
| 2020 January | 209 | 67 | 276 |
| 2019 December | 188 | 36 | 224 |
| 2019 November | 156 | 47 | 203 |
| 2019 October | 199 | 50 | 249 |
| 2019 September | 217 | 51 | 268 |
| 2019 August | 389 | 55 | 444 |
| 2019 July | 172 | 46 | 218 |
| 2019 June | 147 | 48 | 195 |
| 2019 May | 228 | 56 | 284 |
| 2019 April | 260 | 65 | 325 |
| 2019 March | 146 | 61 | 207 |
| 2019 February | 105 | 53 | 158 |
| 2019 January | 95 | 57 | 152 |
| 2018 December | 236 | 77 | 313 |
| 2018 November | 368 | 26 | 394 |
| 2018 October | 151 | 15 | 166 |
| 2018 September | 27 | 3 | 30 |
Show all
