New agent to treat elevated phosphate levels: magnesium carbonate/calcium carbonate tablets.
Hyperphosphatemia is a persistent issue in patients with chronic kidney disease (CKD) due to decreased renal elimination of phosphate. Hyperphosphatemia is accompanied by hypocalcemia and low levels of vitamin D, and often leads to secondary hyperparathyroidism. Mainstay treatment involves strict dietary restriction of phosphorus. However, this is usually not sufficient and pharmacological intervention with phosphate binders is required (Tonelli, Pannu, & Manns, 2010).
In individuals without CKD, serum phosphate levels are maintained through dietary absorption, bone formation and resorption and renal excretion (Tonelli, Pannu, & Manns, 2010). Parathyroid hormone (PTH) decreases the reabsorption of phosphorus in the proximal tubule, allowing for increased excretion in the distal tubule in healthy individuals (Tomasello, 2007). However, once the glomerular filtration rate drops below 30 ml/min per 1.73 m2 of body-surface area, the body's natural compensatory mechanisms are impaired and phosphate levels rise considerably (Tonelli, Pannu, & Manns, 2010). In individuals with stage 4 or 5 kidney disease, dietary intake of phosphorus outweighs renal excretion and hyperphosphatemia inevitably occurs (Tomasello, 2007).
The activation of vitamin D is inhibited, as the activity of 1 [alpha]-hydroxylase in the kidney is diminished by inctcascs in phosphotous levels. The deficiency in vitamin D also impacts the intestinal absorption of calcium, resulting in lower scrum concentrations of calcium. Ultimately, the production and secretion of parathyroid hormone is increased, resulting in bone breakdown and calcium release (Tomascllo, 2007).
Phosphate control has become an emerging concern due to large observational studies that have demonstrated the link between elevated phosphate levels and all-cause mortality in patients requiring dialysis (Block, Hulbcn-Shearon, levin. & Port, 1998). Although there arc several plausible mechanisms that link elevated serum phosphate levels to increased cardiovascular events and mortality, the most likely explanation is due to vascular calcification (Giachclli, 2009).
In an effort to lower phosphate levels, phosphate binders arc utilized. They bind to phosphate, creatinga precipitant that cannot be absorbed into the bloodstream and is readily eliminated in the feces (Noris, 2001). The ideal phosphate binder would bind to dietary phosphate, have minimal side effiects, be inexpensive, and have a low pill burden and minimal systemic absorption (Tonclli, Pannu, & Manns, 2010). Unfortunately, the ideal phosphate binder does not currently exist.
There arc multiple pharmacological options available for use as phosphate binders. Many studies assessing the efficacy and safety of these agents arc available (Suki ct al., 2007; Tonclli ct al,, 2007; St. Peter, Liu, Wcinhandlc, & Fan, 2008; Chertow, Burke, & Raggi, 2002; Almirall ct al., 2004; Hutchinson ct al., 2005; Shigcmatsu, 2008; Pflanz, Henderson, McElduff, & Jones, 1994.). Originally, aluminum-containing agents were used, but due to the potential of systemic aluminum toxicity these agents were largely abandoned. Historically, magnesium-containing phosphate binders have not been used due to concerns over hypermagnesemia. Calcium-containing binders arc effective and inexpensive, but result in high pill burden and gastrointestinal side effiects. Newer agents, such as lanthanum and scvclamcr do not contain calcium, but arc expensive and also cause gastrointestinal side effects (Tonclli, Pannu, & Manns, 2010). A new magnesium-containing phosphate binder is currently being marketed--Binaphos CM[R].
Binaphos CM[R] contains two phosphate binding elements--magnesium carbonate 291 mg (80 mg elemental magnesium) and calcium carbonate 340 mg (120mg elemental calcium). (Searbrd Pharmaceutical Inc.).
Comparative studies on Binaphos CM" in the literature are lacking, however, three relevant studies are reviewed and summarized below.
The efficacy of a magnesium carbonate/calcium carbonate combination tablet, as a phosphate binder, was studied in a prospective, randomized, open-label trial in 30 hemodialysis patients over a three-month period. Inclusion criteria included: age greater than 18 years, on chronic hemodialysis for at least three months, use of a phosphate binder before entry into the study with an average serum calcium between 2.0mmol/L and 2.54mmol/L, and an average serum phosphate between O.97mmol/L and 2.23iTimol/L (Spiegel, Farmer, Smits, & Chonchol, 2007).
Patients were randomized in a 2:1 fashion to receive either a magnesium carbonate/calcium carbonate combination or calcium acetate after a one- to two-week washout phase. The 20 patients in the combination arm received lOOmg of elemental calcium and 86 mg of elemental magnesium, whereas the ten patients in the calcium acetate arm received their calcium dose pre-washout phase or an equivalent dose (depending on their previous phosphate binder: 1:1 sevelamer or 2:3 calcium carbonate). The dose of each agent was maintained to achieve a KDOQI phosphate target of < 1.78 mmol/L. Both treatment options provided equivalent control of serum phosphorus within the KDOQI guidelines (70.6% combination vs. 62.5% calcium acetate; p value = ns). As expected, serum magnesium levels were significantly higher in the combination arm with a mean serum level of 1.2 mmol/L (standard error mean, 1.1--l-3nimol/L) compared to the calcium acetate arm with a mean serum level of 0.93 mmol/L (standard error mean, 0.90--0.98 mmol/L). Three patients withdrew in the combination arm and one patient in the calcium acetate arm due to gastrointestinal side effects. One patient in the calcium acetate group was hospitalized and later returned to a rehabilitation facility. Therefore, the results are based on 25 patients (Spiegel ctal., 2007).
The efficacy and safety of magnesium carbonate alone, as a phosphate binder, was examined in a randomized controlled trial in 46 hemodialysis patients. Secondaty outcomes included changes in scrum calcium, scrum magnesium, bowel movements, calcium > phosphate product (Ca x P) and PTH levels. Exclusion criteria included patients under the age of IS, hemodialysis for lea than six months, psychiatric or odicr disorders leading to compliance issues, unlikely to continue dialysis lor mote than six months in thesame facility, critical illness or parathyroidectomy, severe hyperpararhyrodism(iPTH>50pmol/L), normal serum phosphate (<1.78mmol/L) without phosphate binders, disease resulting in diarrhea and lack of consent (Tzanakis et aL, 2008).
Patients were randomized to receive cither calcium carbonatc (n=2I) or magnesium carbonate (n=25) for a total of she months. Both phosphate binders were initiated at three tablevels (< 1.78mmol/L). Magnesium carbonate tablets contained 71 nig of elemental magnesium and calcium carbonate tablets contained 168 mg of elemental calcium. Magnesium concentration in the dialysate was adjusted appropriately for those in the magnesium carbonate arm. Results from the study showed non-significant differences in the levels of phosphate, Ca x P, magnesium and PTH at six months. Both groups had serum phosphate and PTH levels that fell within the accepted KDOQI guidelines. There was a significant difference between calcium levels, with those individuals in the calcium carbonate arm falling within the KDOQI guidelines less often due to hypercalcemia ([MgCO.sub.3] 73-9% versus [CaC0.sub.3] 25%, p<0.01). Two patients in the magnesium carbonate arm dropped out of the study due to adverse side effects (diarrhea and hypermagnesemia.) ( I/anakis et al., 2008).
Parsons et al. (1993) examined the use of a combination of calcium and magnesium carbonate as a phosphate binder in patients on continuous ambulatory peritoneal dialysis (CAPD) for a one-year period. Thirty-two patients were given the magnesium carbonate (2.2g)/calcium carbonate (2.2 g) combination, 10 patients received calcium carbonate alone due to a negative history with magnesium phosphate binders and eight patients used aluminum hydroxide as their phosphate binder. Patients were initiated on phosphate binders if they had three occasions where phosphorous levels exceeded 2.0 mmol/L, were outpatients and had no complications that would likely lead to a change in therapy. The doses were adjusted to maintain a phosphate concentration below 2.0 mmol/L (Parsons et al., 1993).
When comparing the magnesium carbonate/calcium carbonate combination against calcium carbonate alone after one year, changes in serum calcium (2.41 [+ or -]0.15 vs 2.43[+ or -]0.19 mmol/L), phosphate (1.36[+ or -]0.4l vs 1.38[+ or -]0.27 mmol/L), magnesium (0.97[+ or -]0.21 vs 0.96[+ or -]0.26 mmol/L) and PTH (121[+ or -]146 vs 141[+ or -]188 pmol/L) were non significant. One patient required a parathyroidectomy secondary to elevated PTH, persistent hypocalcaemia, elevated alkaline phosphatase and bone changes. It is unclear why adequate control of hyperparathyroidism is mentioned, as phosphate binders manage hyperphosphatemia.
Limitations in the literature
All three studies had significant limitations. They consisted of non-blinded, single-centre studies, small sample sizes and were short in duration. Due to the lack of follow-up there is insufficient long-term data on safety and efficacy with this phosphate binder.
In the study performed by Spiegel et al. (2007), patients were eliminated if they had a history of diarrhea and, so, in this patient population, it is uncertain if this medication would worsen diarrhea, thus impacting medication compliance. In the study by Tzanakis et al. (2008), the patients enrolled had low phosphate levels and the majority of patients did not use vitamin D supplementation. This is not consistent with the general hemodialysis population and, therefore, affects the external validity of the study.
Although not a prevalent adverse effect reported, hypermagnesemia is a serious concern and one of the main reasons magnesium-containing phosphate binders are not currently used in practice. It is unclear how magnesium levels were monitored in all three studies. Hypermagnesemia at levels > 1.5 mmol/L presents as nausea, vomiting, skin flushing, weakness and lightheadedness. At higher levels, it is associated with loss of consciousness, respiratory depression and cardiac arrest. Magnesium levels should be monitored and, if elevated, the magnesium-containing phosphate binder should be stopped (Smilkstein, Smolinske, Kulig, & Rumack, 1988).
Dosing and administration
Binaphos CM[R] is taken with meals and snacks. The dose can range from one to multiple tablets at each meal or snack depending on the phosphorus content. Additional phosphate binders are discontinued upon starting Binaphos CM[R]. Binaphos CM[R] is sold for roughly 12 cents per tablet or $12/bottle. It is sold in bottles of 100 tablets (Seaford Pharmaceuticals Inc.).
The side effects of Binaphos CM [R] are similar to calcium-containing phosphate binders and include constipation, diarrhea, upset stomach and, in rare instances, hypermagnesemia (Lexicomp, 2012). Hypermagnesemia, although uncommon, must be monitored due to the potential for severity. Iron supplements need to be taken one to two hours before or after taking Binaphos CM[R] to improve iron absorption (Lexicomp, 2012).
In summary, Binaphos CM[R], a magnesium carbonate/calcium carbonate combination phosphate binder, is marketed for treating elevated phosphate levels in dialysis patients. Although studies using magnesium/calcium carbonate as a phosphate binder are short term with small numbers of patients, this phosphate binder has shown some promising results and may provide clinicians with an alternative for phosphate binding. Using a combination phosphate binder may reduce pill burden and encourage patient compliance. In addition to calcium and phosphate, it is imperative to diligently monitor magnesium levels in patients started on this medication, as magnesium levels may increase with longer duration of use. Additional randomized controlled trials are necessary to evaluate long-term efficacy and safety of this combination phosphate binder.
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By Caitlin Meyer, Karen Cameron, BScPhm, ACPR, CGP, and Marisa Battistella, BScPhm, PharmD, ACPR
Caitlin Meyer, 4th Year Pharmacy Student, University of Waterloo, Waterloo, ON
Karen Cameron, BScPhm, AC PR, CGP, Education Coordinator, University Health Network, Toronto, ON
Marisa Battistella, BScPhm, PharmD, ACPR, Clinician Scientist, Assistant Professor, Leslie Dan Faculty of Pharmacy, University of Toronto, Clinical Pharmacist--Nephrology, University Health Network
Address correspondence to: Marisa Battistella, BSc Phm, PharmD, ACPR, Clinical Pharmacist--Nephrology, University Health Network, 200 Elizabeth Street, EB 214, Toronto, ON, M5G 2C4
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|Title Annotation:||CONTINUING EDUCATION SERIES|
|Author:||Meyer, Caitlin; Cameron, Karen; Battistella, Marisa|
|Date:||Oct 1, 2012|
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