VeltassaTM; Worth the 50-Year Wait?
Tenielle Watkins, PharmD Candidate 2017
Oxana Placinta, PharmD Candidate 2018
Jennifer Andres, PharmD, BCPS
Temple University School of Pharmacy
On October 21st, 2015, Relypsa, Inc. announced that the U.S. Food and Drug Administration
(FDA) approved its very first medication, VeltassaTM (patiromer) for oral suspension. Patiromer is a
polymer medicine indicated for the treatment of hyperkalemia. Patiromer binds potassium primarily
in the distal colon where the concentration of free potassium tends to be highest, increasing fecal
potassium excretion and subsequently lowering serum potassium levels.1The most common
treatment for chronic hyperkalemia, KayexalateTM (sodium polystyrene sulfonate), was initially
approved by the FDA in 1958,2 over 50 years ago, making patiromer a very innovative and exciting
new option. Several clinical trials have documented the safety and efficacy of patiromer in at-risk
patient populations.
Hyperkalemia is defined as potassium levels above 5.5 mEq/L, and can occur as a result
of increased potassium intake, decreased renal excretion, or imbalanced distribution of
potassium between the intracellular and extracellular space.3 The prevalence of hyperkalemia in
the general population is approximately 2-3%, but can be as high as 50% in patients with
chronic kidney disease (CKD).4 Other risk factors associated with hyperkalemia include diabetes
mellitus, decompensated congestive heart failure, and the administration of agents such as
renin-angiotensin-aldosterone system inhibitors (RAASIs), beta blockers, calcineurin inhibitors,
potassium sparing diuretics, and potassium supplements.
Maintaining potassium levels within the normal range is extremely important. The
likelihood of mortality within 1 day of moderate (K ≥ 5.5 and < 6.0 mEq/L) and severe (≥ 6.0
mEq/L) hyperkalemic events is significant, with odds ratios of 10.3 and 31.6 (p < .001),
respectively, in patients with normal kidney function.5 Considering the potential for negative
outcomes, outpatient treatment of hyperkalemia (both acute and chronic) is essential, but is
limited by the lack of safe and efficacious agents. Most currently available treatments for
hyperkalemia are indicated for acute treatment, and either shift potassium into the intracellular
space (beta receptor agonists, insulin/glucagon, and sodium bicarbonate), or remove potassium
from the body (loop diuretics and dialysis). Sodium polystyrene is an agent commonly
considered for the treatment of hyperkalemia, however, long-term use of this agent has been
associated with rare but potentially severe side effects such as colonic (intestinal) necrosis,
bleeding, and bowel perforation.6 These side effects are more commonly seen in patients with
abnormal bowel function, or those at risk for constipation or impaction. Additionally, the
concomitant use of sodium polystyrene with sorbitol (a combination that was previously used to
treat hyperkalemia in patients with renal insufficiency) has been implicated as a cause of
intestinal necrosis and is not recommended.7
OPAL-HK, a multi-national, single-blind, two-phase study, demonstrated the effectiveness of
patiromer in CKD patients who were receiving RAASIs. In Phase I, all study participants received
patiromer at a starting dose of either 8.4g or 16.8g daily, in two divided doses, for 4 weeks.8 Results
registered a mean decrease in serum potassium concentration of 1.01 mEq/L, and 76% of patients
had serum potassium levels within the target range (3.8-5.1 mEq/L) at the end of 4 weeks. Phase II
of the OPAL-HK study was an 8-week, randomized withdrawal phase, aimed at examining the
effects of continuation of patiromer versus administration of placebo. Phase II registered no change
in potassium levels in participants that continued patiromer, and a mean increase of 0.72 mEq/L in
serum potassium levels over the first 4 weeks for patients who received placebo. These results
indicate the need for continuous treatment in this population, and support the long-term use of
patiromer to successfully maintain proper potassium levels.
AMETHYST-DN, a 4-week, Phase II, multi-center, open-label, randomized clinical trial
evaluated the efficacy and safety of patiromer in the treatment of patients with diabetes and CKD,
+/- hypertension. Patients were stratified by baseline serum potassium level, and received 1 of 3
randomized starting doses ranging from 4.2g twice daily to 16.8g twice daily. Doses were titrated
throughout the study to achieve and maintain serum potassium levels of ≤ 5.0 mEq/L. Decreases in
serum potassium of between 0.35 mEq/L (for the lowest dose) and 0.92 mEq/L (for the highest
dose) were registered.9
The PEARL-HF clinical trial was a double-blind, randomized, placebo-controlled, parallelgroup trial evaluating the efficacy and safety of patiromer over 4 weeks in chronic heart failure
patients with an indication to initiate spironolactone and serum potassium concentration of between
4.3 and 5.1 mEq/L. Patients had CKD or were receiving one or more heart failure therapies
(ACEI/ARB/Beta Blocker). The study found a decreased serum potassium of 0.22 mEq/L versus an
increase of 0.23 mEq/L with placebo.10 While the patients in this study all had baseline serum
potassium concentrations less than 5.1 mEq/L, patiromer was able to prevent increases in
potassium levels with concurrent use of spironolactone, a potassium sparing diuretic commonly
used in heart failure regimens.
The main advantage of patiromer over sodium polystyrene is the reported reduced side
effect profile. Patiromer is flavorless11, which may help avoid lack of adherence due to unfavorable
flavors. Patiromer is recommended to be dissolved in 90ml (3oz) of water in preparation for
administration12, which limits the amount of fluid required to take this drug. The most common
adverse effects reported by patients taking patiromer were constipation (7.2%), hypomagnesaemia
(5.3%) and diarrhea (4.8%). Most adverse reactions were mild to moderate. There is currently only
one contraindication to patiromer; sensitivity to patiromer or any component of the drug formulation.
A Black Box Warning instructs users to separate patiromer administration from other orally
administered medications by at least 6 hours (before and after) due to the possibility for patiromer
to bind to other medications, leading to potentially reduced absorption of either drug, and therefore
reduced efficacy. Due to the incidence of constipation as a side effect, patiromer should be avoided
in patients that have severe constipation, history of obstructed or impacted bowels, and bowel
motility disorders. It should be noted that patiromer also binds magnesium. Patients should be
periodically monitored for hypomagnesemia.12
Drug
Cost Analysis*
30-day cost for minimum recommended
30-day cost for maximum recommended
daily dose (8.4g/day patiromer;
daily dose (25.2g/day patiromer;
15g/60ml/day sodium polystyrene)
60g/240ml/day sodium polystyrene)
VeltassaTM
$595.0013 ($19.83/day)
$1,785.00 ($59.50/day)
KayexalateTM
$337.50 ($11.2514/day)
$1,350.00 (45.00/day)
*Analysis does not take into account the costs to treat adverse effects or costs for return visits to the doctor/changes in
treatment due to adverse effects
Based on trial evidence to date, patiromer appears to be a viable option for the
management of hyperkalemia, especially in patients with CKD, diabetes, and heart failure who
may experience hyperkalemia chronically. It is important to bear in mind that completed trials
have not evaluated the use of patiromer beyond 12 weeks. Although most of the trials
conducted thus far reviewed the use of patiromer chronically over 4 weeks, the drug was noted
to begin reducing potassium levels as early as day 1 of treatment initiation8, and significant
reductions were seen on day 2.9 The clinical impact of this new medication may be quite
considerable. Based upon the 2-3% incidence of hyperkalemia in the general population4, 6.49.6 million people in the United States alone may qualify for treatment with patiromer. As with all
new drugs, acceptance by the medical community remains to be seen. The improved side effect
profile over current therapy and the potentially manageable price difference make patiromer an
exciting avenue to be further explored.
References:
1. Weir MR, Bakris GL, Bushinsky DA, et al. Patiromer in patients with kidney disease and
hyperkalemia receiving RAAS inhibitors. N Engl J Med. 2015;372(3):211-21.
2. Hagan AE, Farrington CA, Wall GC, Belz MM. Sodium polystyrene sulfonate for the
treatment of acute hyperkalemia: a retrospective study. Clin Nephrol. 2016;85(1):38-43.
3. Tamargo J, Caballero R, Delpón E. New drugs for the treatment of hyperkalemia in
patients treated with renin-angiotensin-aldosterone system inhibitors -- hype or hope?.
Discov Med. 2014; 18(100):249-54.
4. Palmer B, Clegg D. Hyperkalemia. JAMA. 2015; 314(22); 2405.
5. Einhorn LM, Zhan M, Hsu VD, et al. The frequency of hyperkalemia and its significance
in chronic kidney disease. Arch Intern Med. 2009;169(12):1156-62.
6. Winkelmayer WC. Treatment of hyperkalemia: From "Hyper K+" strikeout to home run?.
JAMA. 2015;314(2):129-30.
7. U.S. Food and Drug Administration; Safety; Kayexalate (sodium polystyrene sulfonate)
powder. http://www.fda.gov/Safety/MedWatch/SafetyInformation/ucm186845.htm.
Updated February 17, 2011. Accessed January 7, 2015.
8. Weir MR, Bakris GL, Bushinsky DA, et al. Patiromer in patients with kidney disease and
hyperkalemia receiving RAAS inhibitors. N Engl J Med. 2015;372(3):211-21.
9. Bakris GL, Pitt B, Weir MR, et al. Effect of Patiromer on Serum Potassium Level in
Patients With Hyperkalemia and Diabetic Kidney Disease: The AMETHYST-DN
Randomized Clinical Trial. JAMA. 2015;314(2):151-61.
10. Pitt B, Anker SD, Bushinsky DA, et al. Evaluation of the efficacy and safety of RLY5016,
a polymeric potassium binder, in a double-blind, placebo-controlled study in patients with
chronic heart failure (the PEARL-HF) trial. Eur Heart J. 2011;32(7):820-8.
11. Center for Drug Evaluation and Research; Application Number 205739Orig1s000. Office
Director Memo.
http://www.accessdata.fda.gov/drugsatfda_docs/nda/2015/205739Orig1s000ODMemo.p
df . Published October 21, 2015. Accessed January 7, 2016.
12. VeltassaTM [package insert]. Redwood,CA. Relypsa, Inc.; 2016.
13. United States Securities and Exchange Comission; Form 8-K, Relypsa, Inc.
http://investor.relypsa.com/secfiling.cfm?filingid=1193125-15-350034&cik=1416792 .
Published October 21, 2015. Accessed December 21, 2015.
14. KayexalateTM [package insert]. Bridgewater, NJ. Sanofi-Aventis U.S. LLC; 2009.