Summary Basis of Decision for Veltassa

Review decision

The Summary Basis of Decision explains why the product was approved for sale in Canada. The document includes regulatory, safety, effectiveness and quality (in terms of chemistry and manufacturing) considerations.


Product type:

Drug

Summary Basis of Decision (SBD) documents provide information related to the original authorization of a product. The SBD for Veltassa is located below.

Recent Activity for Veltassa

The SBDs written for eligible drugs (as outlined in Frequently Asked Questions: Summary Basis of Decision [SBD] Project: Phase II) approved after September 1, 2012 will be updated to include post-authorization information. This information will be compiled in a Post-Authorization Activity Table (PAAT). The PAAT will include brief summaries of activities such as submissions for new uses of the product, and whether Health Canada's decisions were negative or positive. The PAATs will be updated regularly with post-authorization activity throughout the product life cycle.

 

The following table describes post-authorization activity for Veltassa, a product which contains the medicinal ingredient patiromer (supplied as patiromer sorbitex calcium). For more information on the type of information found in PAATs, please refer to the Frequently Asked Questions: Summary Basis of Decision (SBD) Project: Phase II and to the List of abbreviations found in Post-Authorization Activity Tables (PAATs).

 

For additional information about the drug submission process, refer to the Guidance Document: The Management of Drug Submissions and Applications.

 

Updated: 2024-08-16

 

Drug Identification Number (DIN):

  • DIN 02481359 - 8.4 g/sachet, patiromer, powder for suspension, oral administration
  • DIN 02481367 - 16.8 g/sachet, patiromer, powder for suspension, oral administration
  • DIN 02481375 - 25.2 g/sachet, patiromer, powder for suspension, oral administration

 

Post-Authorization Activity Table (PAAT)

 

Activity/Submission Type, Control Number

Date Submitted

Decision and Date

Summary of Activities

SNDS # 280775

2023-11-07

Issued NOC 2024-04-05

Submission filed as a Level II – Supplement (Safety) to update the PM with new safety information. The submission was reviewed and considered acceptable. As a result of the SNDS, modifications were made to the Warnings and Precautions; Dosage and Administration; and Clinical Trials sections of the PM, and corresponding changes were made to Part III: Patient Medication Information and to the package insert. An NOC was issued.

SNDS # 266183

2022-07-18

Issued NOC 2023-09-06

Submission filed as a Level I – Supplement to update the PM, and migrate it to the 2020 format. The submission was reviewed and considered acceptable. As a result of the SNDS, modifications were made to the Drug Interactions and Dosage and Administration sections of the PM, and corresponding changes were made to Part III: Patient Medication Information and to the package insert. An NOC was issued.

SNDS # 246108

2020-11-06

Issued NOC 2022-05-31

Submission filed as a Level I – Supplement for a change in the manufacturing process. The submission was reviewed and considered acceptable, and an NOC was issued.

SNDS # 234330

2019-12-11

Issued NOC 2020-07-17

Submission filed as a Level I – Supplement for the addition of a manufacturer involving the production of the starting material. The submission was reviewed and considered acceptable, and an NOC was issued.

Drug product (DIN 02481359) market notification

Not applicable

Date of first sale: 2020-03-09

The manufacturer notified Health Canada of the date of first sale pursuant to C.01.014.3 of the Food and Drug Regulations.

Drug product (DIN 02481367) market notification

Not applicable

Date of first sale: 2019-11-27

The manufacturer notified Health Canada of the date of first sale pursuant to C.01.014.3 of the Food and Drug Regulations.

SNDS # 229946

2019-07-29

Issued NOC 2019-10-07

Submission filed as a Level I – Supplement to revise the labels to reflect a change in importer. The submission was reviewed and considered acceptable. As a result of the SNDS, modifications were made to the PM, the package insert, and the inner and outer labels. An NOC was issued.

NDS # 210368

2017-10-20

Issued NOC 2018-10-03

NOC issued for New Drug Submission.
Summary Basis of Decision (SBD) for Veltassa

Date SBD issued: 2019-02-11

The following information relates to the New Drug Submission for Veltassa.

Patiromer (supplied as patiromer sorbitex calcium)
8.4 g, 16.8 g, 25.2 g, powder for suspension, oral

Drug Identification Number (DIN):

  • 02481359 - 8.4 g/sachet, powder for suspension
  • 02481367 - 16.8 g/sachet, powder for suspension
  • 02481375 - 25.2 g/sachet, powder for suspension

Vifor Fresenius Medical Care Renal Pharma Ltd.

New Drug Submission Control Number: 210368

 

On October 3, 2018, Health Canada issued a Notice of Compliance to Vifor Fresenius Medical Care Renal Pharma Ltd. for the drug product Veltassa.

The market authorization was based on quality (chemistry and manufacturing), non-clinical (pharmacology and toxicology), and clinical (pharmacology, safety, and efficacy) information submitted. Based on Health Canada's review, the benefit-risk profile of Veltassa is considered favourable for the treatment of hyperkalemia in adults with chronic kidney disease (estimated glomerular filtration rate ≥15 mL/min/1.73 m2).

 

1 What was approved?

 

Veltassa, a potassium binder, was authorized for the treatment of hyperkalemia in adults with chronic kidney disease (estimated glomerular filtration rate ≥15 mL/min/1.73 m2).

No data are available to Health Canada regarding the use of Veltassa in patients younger than 18 years of age. Consequently, an indication for pediatric use has not been authorized.

Evidence from clinical studies and experience suggests that the use of Veltassa in the geriatric population (patients aged 65 years and over) is not associated with significant differences in safety or efficacy when compared to younger patients.

Veltassa is contraindicated in:

  • patients who are hypersensitive to this drug or to any ingredient in the formulation, including any non-medicinal ingredient, or component of the container; and
  • patients with the rare hereditary condition of fructose intolerance (as Veltassa contains approximately 11 g of sorbitol per its maximum recommended daily dose).

Veltassa was approved for use under the conditions stated in its Product Monograph taking into consideration the potential risks associated with the administration of this drug product.

Veltassa (8.4 g, 16.8 g, 25.2 g patiromer, supplied as patiromer sorbitex calcium) is presented as powder for oral suspension. Veltassa contains sorbitol and calcium as part of the drug substance. The sorbitol content is about 4 g (10.4 kcal) per 8.4 g of patiromer. In addition, the powder contains xanthan gum.

For more information, refer to the Clinical, Non-clinical, and Quality (Chemistry and Manufacturing) Basis for Decision sections.

Additional information may be found in the Veltassa Product Monograph, approved by Health Canada and available through the Drug Product Database.

 

2 Why was Veltassa approved?

 

Health Canada considers that the benefit-risk profile of Veltassa is favourable for the treatment of hyperkalemia in adults with chronic kidney disease (who have estimated glomerular filtration rate [eGFR] ≥15 mL/min/1.73 m2).

Hyperkalemia refers to an elevated concentration of potassium (K+) in the plasma, typically defined as serum K+ levels >5.0 mmol/L. It represents a serious condition that can result in muscle weakness, paralysis, life-threatening arrhythmias and sudden death.

Chronic kidney disease is the most common risk factor for hyperkalemia. It is estimated that between 1.3 million and 2.6 million Canadians have chronic kidney disease. The prevalence of hyperkalemia in patients with renal insufficiency or chronic kidney disease ranges from 5% to 50% and increases as renal function declines. Other risk factors for hyperkalemia include heart failure, diabetes mellitus, older age, and the use of renin-angiotensin-aldosterone system inhibitors.

The objective of potassium binder therapy in hyperkalemic patients is to lower serum potassium levels to achieve and maintain a healthy range (3.5-5.0 mmol/L). Existing approaches for the management of chronic hyperkalemia have relied on dietary potassium restriction, dose reduction or discontinuation of renin-angiotensin-aldosterone system inhibitors, use of potassium wasting diuretics, oral sodium bicarbonate, and cation-exchange resins (sodium polystyrene sulfonate or calcium polystyrene sulfonate). However, these approaches have limitations. Adherence to low-potassium diets can be challenging for patients; the effectiveness of diuretics is greatly diminished in patients with chronic kidney disease; oral sodium bicarbonate is not highly effective in reducing serum potassium levels; and discontinuing or lowering the dose of renin-angiotensin-aldosterone system inhibitors can lead to increased cardio-renal events and mortality in patients with chronic kidney disease and heart failure. The potassium binders, sodium polystyrene sulfonate and calcium polystyrene sulfonate, are not well tolerated and often increase serum levels of sodium or calcium in patients who cannot tolerate excessive loading.

Veltassa is an orally administered, non-absorbed, high capacity potassium binder. The drug substance consists of the polymer anion (patiromer) and a calcium-sorbitol counterion complex. Doses stated in the approved Veltassa Product Monograph are based on the quantity of patiromer. Veltassa increases fecal potassium excretion through binding of potassium in the lumen of the gastrointestinal tract. This reduces the concentration of free potassium in the gastrointestinal lumen, leading to a reduction of serum potassium levels.

Veltassa has been shown to be efficacious in treatment of hyperkalemia in adults with chronic kidney disease. The market authorization was primarily based on data derived from a Phase III pivotal study, which included 243 patients and a Phase II long-term (52 weeks) dose-ranging supporting study conducted in 304 patients. Patients enrolled in both studies were adults with chronic kidney disease (eGFR ≥15 and <60 mL/min/1.73 m2) who had chronic hyperkalemia (serum potassium of 5.1 to <6.5 mmol/L). These patients were receiving a stable dose of at least one renin-angiotensin-aldosterone system inhibitor, and may have had heart failure, type 2 diabetes mellitus, and hypertension. A majority of patients were elderly and of Caucasian descent. The pivotal trial was conducted in two sequential parts. Part A consisted of a four-week period that assessed the extent to which Veltassa reduced serum potassium levels. The responders were then randomized in Part B to either continue Veltassa treatment or receive placebo. The primary endpoints were mainly the serum potassium changes from baseline to Week 4.

In the pivotal trial, Veltassa at a titrated dose of 8-37 g/day patiromer caused a clinically relevant mean reduction in serum potassium from baseline at Week 4 of -1.01 mmol/L (95% confidence interval [CI]: -1.07, -0.95; p<0.001) in the overall study population. Furthermore, 76% (95% CI: 70%, 81%) of patients were within the serum potassium target range (3.8 to <5.1 mmol/L) at Week 4. In patients that progressed into Part B of the study, the continued treatment with Veltassa caused no change in serum potassium (0 mmol/L [95% CI: -0.3, 0.3]) in the active treatment group, whereas an increase of 0.72 mmol/L (95 CI: 0.46, 0.99) was observed in the group switched to placebo (p<0.001). Fewer patients discontinued or reduced the dose of their renin-angiotensin-aldosterone system inhibitor in the Veltassa group (16%) compared to the placebo group (62%) throughout part B (p<0.001). The results of the Phase II dose-ranging study showed that Veltassa caused a mean change from baseline in serum potassium at Week 4 of -0.47 mmol/L and -0.92 mmol/L in patients with a baseline serum potassium of 5.0 to 5.5 mmol/L and >5.5 to 6.0 mmol/L, respectively. Serum potassium was within the target range for approximately 80% of the long-term maintenance period (up to 44 weeks). Efficacy was consistent across age, gender, region, assessed chronic kidney disease stages, and patients with and without diabetes mellitus.

Throughout all the studies in the clinical development program, Veltassa was well tolerated at the proposed doses. The safety profile of Veltassa was primarily defined by gastrointestinal adverse events. In the overall safety pooled population consisting of 666 patients in all clinical trials, the most common drug-related adverse events were constipation (6.2%), hypomagnesemia (5.3%), diarrhea (3.0%), abdominal pain (2.9%), flatulence (1.8%), and hypokalemia (1.5%). Gastrointestinal events tended to occur within the first 30 to 60 days of Veltassa treatment, were typically mild and moderate in nature, and could be managed effectively. Hypokalemia was also mild to moderate in nature (<3.0 to 3.5 mmol/L), and its frequency reported in the overall safety pooled population (4.7%) was based on clinical trials that used fixed-dose regimens (hypokalemia frequency of approximately 7%) as well as individualized dose titrations (hypokalemia frequency of approximately 1.5-2.5%). In order to mitigate the potential risk of developing hypokalemia, serum potassium monitoring is recommended in the Dosing Considerations and Warnings and Precautions sections of the Veltassa Product Monograph. In addition, the dose of Veltassa should be down-titrated if serum potassium levels decrease below 3.5 mmol/L or the desired target range.

Based on the mechanism of action, there is a concern with respect to the potential of Veltassa to interact with other medications taken orally. Drug-drug interaction studies, conducted with 12 medications commonly used by hyperkalemic patients, have demonstrated that Veltassa had clinically meaningful interactions with ciprofloxacin, levothyroxine and metformin. However, there were no interactions observed when these medications were taken three hours apart from Veltassa. Therefore, as a precaution, the Dosing Considerations section of the Veltassa Product Monograph specifies that the administration of Veltassa should be separated by three hours from other orally administered drugs. All pertinent in vitro and clinical drug interaction studies are outlined in the Drug-Drug Interactions section of the Veltassa Product Monograph.

A Risk Management Plan (RMP) for Veltassa was submitted by Vifor Fresenius Medical Care Renal Pharma Ltd. to Health Canada. Upon review, the RMP was considered to be acceptable. The RMP is designed to describe known and potential safety issues, to present the monitoring scheme and when needed, to describe measures that will be put in place to minimize risks associated with the product.

The submitted inner and outer labels, package insert and Patient Medication Information section of the Veltassa Product Monograph meet the necessary regulatory labelling, plain language and design element requirements.

A Look-alike Sound-alike brand name assessment was performed and the proposed name Veltassa was accepted.

Overall, Veltassa has shown clinically meaningful reductions of serum potassium in hyperkalemic patients with chronic kidney disease, with a majority of patients achieving normal serum potassium levels within four weeks of commencing treatment. As an additional benefit, Veltassa treatment allowed fewer hyperkalemic patients to discontinue or reduce the dose of their renin-angiotensin-aldosterone system inhibitor, thereby promoting the therapeutic benefits of renin-angiotensin-aldosterone system inhibition in the target population. The safety profile of Veltassa was primarily defined by gastrointestinal adverse events, hypomagnesemia, and hypokalemia. The identified safety issues can be managed through labelling and adequate monitoring. Appropriate warnings and precautions are in place in the Veltassa Product Monograph to address the identified safety concerns.

This New Drug Submission complies with the requirements of sections C.08.002 and C.08.005.1 and therefore Health Canada has granted the Notice of Compliance pursuant to section C.08.004 of the Food and Drug Regulations. For more information, refer to the Clinical, Non-clinical, and Quality (Chemistry and Manufacturing) Basis for Decision sections.

 

3 What steps led to the approval of Veltassa?

 

Submission Milestones: Veltassa

Submission Milestone Date
Pre-submission meeting: 2017-08-22
Submission filed: 2017-10-20
Screening  
Screening Acceptance Letter issued: 2017-12-07
Review  
Review of Risk Management Plan complete: 2018-09-27
Quality Evaluation complete: 2018-10-01
Labelling Review complete, including Look-alike Sound-alike brand name assessment: 2018-10-01
Clinical Evaluation complete: 2018-10-02
Notice of Compliance issued by Director General, Therapeutic Products Directorate: 2018-10-03

 

The Canadian regulatory decision on the quality, non-clinical and clinical review of Veltassa was based on a critical assessment of the data package submitted to Health Canada. The foreign reviews completed by the European Medicines Agency (EMA) and the United States Food and Drug Administration (FDA) were used as added references.

For additional information about the drug submission process, refer to the Management of Drug Submissions Guidance.

 

4 What follow-up measures will the company take?

 

Requirements for post-market commitments are outlined in the Food and Drugs Act and Regulations.

 

5 What post-authorization activity has taken place for Veltassa?

 

Summary Basis of Decision documents (SBDs) for eligible drugs authorized after September 1, 2012 will include post-authorization information in a table format. The Post-Authorization Activity Table (PAAT) will include brief summaries of activities such as submissions for new uses of the product, and whether Health Canada's decisions were negative or positive. The PAAT will continue to be updated during the product's life cycle.

The PAAT for Veltassa is found above.

For the latest advisories, warnings and recalls for marketed products, see MedEffect Canada.

 

6 What other information is available about drugs?

 

Up to date information on drug products can be found at the following links:

 

7 What was the scientific rationale for Health Canada's decision?
7.1 Clinical Basis for Decision

 

Clinical Pharmacology

Veltassa is a non-absorbed, cation-exchange polymer that contains a calcium-sorbitol complex as a counterion. Veltassa increases fecal potassium excretion through binding of potassium in the lumen of the gastrointestinal tract. Binding of potassium reduces the concentration of free potassium in the gastrointestinal lumen, resulting in a reduction of serum potassium levels.

Given that Veltassa is not absorbed systemically following oral administration, traditional clinical pharmacokinetic studies were not conducted by the sponsor (e.g., determination of the distribution volume, or bioavailability). Overall, the sponsor conducted five pharmacodynamic clinical studies evaluating Veltassa at doses of up to 50.4 g/day patiromer via single or repeated daily administration.

In two Phase I studies in healthy adults, Veltassa caused a dose-dependent increase in fecal potassium excretion and a corresponding decrease in urinary potassium excretion, with no change in serum potassium. No trends were observed in serum, fecal, or urinary levels of other cations (e.g., sodium, magnesium and phosphate). There were no differences in fecal or urinary potassium excretion when Veltassa was administered three times daily (TID), twice daily (BID), or once daily (QD), thereby providing support for the QD dosage regimen recommended in the Veltassa Product Monograph.

In a proof-of-concept, Phase II clinical trial conducted in hemodialysis patients with hyperkalemia (>5.5 mmol/L), Veltassa decreased serum potassium and increased fecal potassium levels, thereby providing first support for its mechanism of action in hyperkalemic patients. In a Phase I open-label study to assess the time to onset of action, Veltassa (8.4 g patiromer BID) caused a statistically significant reduction in serum potassium (-0.2 mmol/L) at 7 hours after the first dose in hyperkalemic (study entry criteria: 5.5 to 6.2 mmol/L) patients with chronic kidney disease. Serum potassium levels continued to decline during the 48-hour treatment period (-0.8 mmol/L at 48 hours after the first dose). Following discontinuation of Veltassa, potassium levels remained stable for 24 hours after the last dose, and then rose again during a four-day observation period. In an open-label, Phase IV food-effect study, patients with hyperkalemia were randomized to Veltassa (8.4 g/day patiromer initiation dose) once daily with food or without food for 4 weeks. The mean daily titrated dose of Veltassa, its safety profile, and the mean reduction from baseline in serum potassium were similar when Veltassa was taken with or without food.

In vitro drug-binding studies performed in biologically relevant matrices assessed whether there were interactions between Veltassa and 28 common orally administered drugs. Fourteen of these drugs demonstrated in vitro binding with Veltassa in at least one test matrix, and 12 of these were selected for testing in human drug-drug interaction studies. Of these 12 drugs, Veltassa decreased the systemic exposure of ciprofloxacin, levothyroxine, and metformin based on the area under the concentration-time curve (AUC) and the maximum serum concentration (Cmax) standard criteria. However, there was no interaction observed when these drugs were taken three hours apart from Veltassa, suggesting that Veltassa should be separated by at least three hours from these medications. In addition, in vitro studies showed potential interaction of Veltassa with quinidine and thiamine, but these drugs were not evaluated in vivo. A list of established or potential drug-drug interactions, along with appropriate precautionary measures, has been included in the approved Veltassa Product Monograph.

Veltassa was well tolerated in all the clinical pharmacology studies, with mainly gastrointestinal adverse events reported (e.g., constipation, flatulence, nausea).

The clinical pharmacological data support the use of Veltassa for the specified indication.

For further details, please refer to the Veltassa Product Monograph, approved by Health Canada and available through the Drug Product Database.

Clinical Efficacy

The efficacy of Veltassa was primarily demonstrated in one randomized, single-blind, Phase III pivotal study (RLY5016-301) including 243 patients, and one randomized, Phase II long-term dose-ranging supporting study (RLY5016-205) conducted in 304 patients. The patients enrolled in both studies were adults with chronic kidney disease (estimated glomerular filtration rate [eGFR] ≥15 and <60 mL/min/1.73 m2) and hyperkalemia (serum potassium of 5.1 to <6.5 mmol/L). They were receiving a stable dose of at least one renin-angiotensin-aldosterone system inhibitor, and may have had chronic heart failure, type 2 diabetes mellitus, and hypertension. The patients were primarily of Caucasian descent. There was a higher proportion of male (61%) compared to female patients (39%). A majority of patients were elderly (65 years of age or older), as would be expected for the target population.

Study RLY5016-301 was conducted in two sequential parts. Part A consisted of a four-week period that assessed the extent to which Veltassa reduced serum potassium levels in patients with hyperkalemia. Part B assessed whether chronic (eight-week) administration of Veltassa maintained control of serum potassium and prevented the recurrence of hyperkalemia. Given that all patients entering Part A of the study were hyperkalemic, a placebo control arm was considered unethical. Patients whose serum potassium was controlled at the end of Part A were eligible for randomization into Part B for either continued treatment or placebo.

In both studies, patients were given starting doses of 8.4 and 16.8 g/day patiromer according to their baseline serum potassium level. Study RLY5016-205 also evaluated starting doses of 25.2 and 33.6 g/day patiromer. After three days of treatment, doses could be down-titrated to 0 g/day or up-titrated to 50.4 g/day to maintain serum potassium within the target range of 3.8 to <5.1 mmol/L. In Part A of study RLY5016-301, the mean change from baseline in serum potassium at Week 4 was -0.65 mmol/L (95% confidence interval [CI]: -0.74, -0.55) and -1.23 mmol/L (95% CI: -1.31, -1.16) for patients with a baseline serum potassium of 5.1 to 5.5 mmol/L and >5.5 to <6.5 mmol/L, respectively. In the overall study population (baseline serum potassium of 5.1 to <6.5 mmol/L), there was a clinically relevant mean reduction in serum potassium from baseline at Week 4 of -1.01 mmol/L (95% CI: -1.07, -0.95; p<0.001). Overall, 76% (95% CI: 70%, 81%) of patients were within the serum potassium target range (3.8 to <5.1 mmol/L) at Week 4. In patients that progressed into Part B of the study, continued treatment with Veltassa from Part B baseline up to Week 4 caused no change in serum potassium (0 mmol/L; 95% CI: -0.3, 0.3) in the active treatment group. However, there was an increase of 0.72 mmol/L (95 CI: 0.46; 0.99) at Week 4 in the group switched to placebo at the beginning of Part B (p<0.001). The proportion of patients with a serum potassium ≥5.1 mmol/L at any time during Part B was significantly (p<0.001) lower in the Veltassa group (43%) compared to the placebo group (91%).

Study RLY5016-205 adequately supported the long-term efficacy of Veltassa (52-week study period). Similar to RLY5016-301, Veltassa caused a mean change from baseline in serum potassium at Week 4 of -0.47 mmol/L and -0.92 mmol/L for patients with a baseline serum potassium of 5.0 to 5.5 mmol/L and >5.5 to 6.0 mmol/L, respectively. A larger reduction in serum potassium was observed in patients that had higher baseline potassium levels. In both baseline serum potassium stratums, mean serum potassium was maintained between approximately 4.4 and 4.8 mmol/L during the long-term maintenance period (up to 44 weeks). Serum potassium was within the target range (3.8-5.0 mmol/L) for approximately 80% of the maintenance period. Efficacy was consistent across age, gender, region, assessed chronic kidney disease stages, and patients with and without diabetes mellitus.

The dosage range, dosage regimen, and titration intervals utilized in the studies RLY5016-301 and RLY5016-205 were not consistent with those indicated in the sponsor's proposed Product Monograph for Veltassa. However, based on supportive data from the clinical pharmacological studies, and the in-depth pivotal efficacy data analyses conducted by the sponsor and the United States Food and Drug Administration, the efficacy of a starting dose of 8.4 g/day Veltassa is supported, irrespective of the patient's baseline serum potassium level. The cumulative data also demonstrate that the daily dose can be titrated by 8.4 g in one- to two-week intervals in order to achieve and maintain serum potassium levels within the normal range. In addition, a maximum titrated daily dose of 25.2 g/day achieves normal serum potassium levels in a majority of patients, and avoids possible adverse effects associated with higher doses.

Overall, Veltassa has shown clinically meaningful reductions of serum potassium in hyperkalemic patients with chronic kidney disease, with a majority of patients achieving normal serum potassium levels within four weeks of commencing treatment.

Indication

The New Drug Submission for Veltassa was filed by the sponsor with the following indication:

  • Veltassa (patiromer as patiromer sorbitex calcium) is indicated for the treatment of hyperkalemia in adults.

Health Canada revised the proposed indication to reflect the population included in the sponsor's main efficacy studies, i.e., adults with chronic kidney disease who had estimated glomerular filtration rate (eGFR) ≥15 mL/min/1.73 m2. Accordingly, Health Canada approved the following indication:

  • Veltassa (patiromer as patiromer sorbitex calcium) is indicated for the treatment of hyperkalemia in adults with chronic kidney disease (eGFR ≥15 mL/min/1.73 m2.

For more information, refer to the Veltassa Product Monograph, approved by Health Canada and available through the Drug Product Database.

Clinical Safety

In the clinical development program, 791 subjects were exposed to at least one dose of Veltassa. Of these, the safety population (number of subjects [n] = 734) included patients with moderate to severe chronic kidney disease with or without heart failure and a significant burden of chronic comorbidities and cardiovascular risk factors, including hypertension, diabetes mellitus, cardiac arrhythmias and hyperlipidemia. The overall safety pooled data population consisted of 666 patients from four studies (RLY5016-205, -301, -202 and -204). The sponsor did not report any exposure in pregnant or breastfeeding women. In addition, the clinical studies did not include a pediatric population.

In the pooled safety population, the most commonly (≥5%) reported treatment emergent adverse events were constipation (7.2%), chronic renal failure (5.4%) and hypomagnesemia (5.3%). Additional common treatment emergent adverse events (≥2%) were diarrhea, hypertension, hypokalemia, anemia, headache, nausea, hyperglycemia, abdominal discomfort, flatulence, hypoglycemia, peripheral edema and ventricular/supraventricular extrasystoles. These adverse events were mild to moderate in nature. Gastrointestinal events were also the most frequently occurring treatment emergent adverse events of interest, occurring in approximately 19% of patients treated with Veltassa in the pooled safety population. Gastrointestinal events tended to occur within the first 30 to 60 days of Veltassa treatment, were typically mild and moderate in nature, and could be managed effectively. Considering the number of confounding factors such as comorbidities, dose titrations, or variations in treatment duration, no conclusions can be drawn whether there is a dose-response relationship between dosage and the frequency of adverse events in the pooled safety data.

Similar to the most common adverse events, the most common drug-related adverse events (≥1%) were constipation (6.2%), hypomagnesemia (5.3%), diarrhea (3.0%), abdominal pain (2.9%), flatulence (1.8%), and hypokalemia (1.5%). Allergic reactions associated with study drug administration occurred in two patients. These allergic reactions were not serious in nature, and resolved with cessation of treatment.

In the pooled safety population, 8.3% of patients reported at least one serious adverse event. Cardiovascular events, renal events, and infection were the most common types of serious adverse events. However, they appear to be related to the subject's underlying diseases. Overall, 21 deaths were reported in the drug development program. Nineteen of these deaths were in patients receiving Veltassa. An independent Safety Review Board adjudicated all deaths that occurred in the studies, and the deaths were assessed as unlikely to be related to hypokalemia or hyperkalemia. Given the comorbidities of the patient population, this number of deaths is not unexpected.

No safety signals were detected with respect to hematological parameters (e.g, hemoglobin, hematocrit, erythrocytes, platelets or leukocytes), vital signs, electrocardiogram values and corrected QT interval (QTc). There were 4.7% of patients in the overall pooled safety population who experienced serum potassium values <3.5 mmol/L, while no patients had a serum potassium value <3.0 mmol/L. Studies that utilized individualized dose titrations had lower adverse events rates of hypokalemia (approximately 1.5-2.5%) compared to those that used fixed-dose regimen (approximately 7%). These findings support the inclusion of recommendations for dose titrations in the Dosage and Administration section of the Veltassa Product Monograph.

In pooled safety data, 44.2% of patients experienced a decrease from baseline in serum magnesium of ≥0.4 mg/dL, with approximately 9.3% and 2.0% of patients experiencing a serum magnesium value of <1.4 mg/dL and <1.2 mg/dL, respectively. No patients experienced a serum magnesium level <1.0 mg/dL and no serious adverse events of hypomagnesemia were reported. The Warnings and Precautions section of the Veltassa Product Monograph includes hypomagnesemia and recommends serum magnesium monitoring during treatment with Veltassa, as well as magnesium supplementation in patients who develop low serum magnesium levels.

Mean calcium and phosphate serum levels in the safety pooled population fluctuated around their baseline mean values, without any trends observed. Considering that the maximum recommended daily dose of Veltassa (25.2 g/day) could provide up to 4.75 g of calcium for absorption, there is a safety concern for hypercalcemia. However, none of the patients in the pooled safety population experienced a serious adverse event of hypercalcemia or hypocalcemia. There were no patients who discontinued treatment because of a calcium- or phosphate-related adverse event. In addition, the absorption efficiency of calcium is only 15-20% in adulthood, and urinary calcium excretion data from studies RLY5016-101 and RLY5016-102, conducted in healthy subjects, suggest that only modest amounts of calcium were absorbed. Accordingly, there does not appear to be a risk associated with Veltassa and excess calcium absorption. However, the benefits and risks of administering Veltassa should be carefully evaluated in patients at risk of hypercalcemia. Furthermore, calcium supplementation is not recommended in patients taking Veltassa.

Overall, Veltassa was well tolerated in the pooled safety population, with mainly hypomagnesemia, hypokalemia, and gastrointestinal drug-related adverse events reported.

The available international post-marketing safety data for Veltassa (for the period between October, 2015 and October, 2017) is consistent with the known safety profile seen in clinical trials.

Appropriate warnings and precautions are in place in the approved Veltassa Product Monograph to address the identified safety concerns.

For more information, refer to the Veltassa Product Monograph, approved by Health Canada and available through the Drug Product Database.

 

 

 

7.2 Non-Clinical Basis for Decision

 

Patiromer sorbitex calcium, the medicinal ingredient in Veltassa, is a non-absorbed, crosslinked polymer anion of patiromer with calcium-sorbitol counterion. Calcium and sorbitol are released in aqueous milieux, making space for the crosslinked polymer anion to bind cations such as potassium.

Under physiological conditions (pH 6.5) in in vitro experiments, between 8.4 and 9.1 milliequivalent (mEq) of potassium were bound to the polymer, which is in line with its theoretical binding capacities (8.4-10 mEq). In vivo studies in healthy and diseased animals confirmed the potency of the polymer anion to bind potassium and increase potassium fecal excretion. The decreased gastrointestinal motility and stomach emptying observed are of uncertain clinical relevance, but these events are expected side effects of this non-absorbed polymer.

Absorption and distribution studies using radioactive tracers in rats and dogs found only traces of radioactivity in blood and urine while most of the drug product was confined to the gastrointestinal tract. Veltassa is not metabolized, but it releases calcium, sorbitol and fluoride in vivo as confirmed in rats and dogs. The calcium released from Veltassa is expected to be partly absorbed and partly excreted after binding with fluoride present in the drug substance. The maximum total calcium that could be released or absorbed from Veltassa is 4.75 g at the maximum approved dose of 25.2 g/day. Hence, calcium monitoring is recommended in patients taking Veltassa, and concomitant calcium supplementation should be avoided. Veltassa is mostly excreted (>99%) in the feces and its use is associated with higher fecal excretion of calcium and potassium, as expected. An unintended effect is higher fecal excretion of magnesium, which can lead to hypomagnesemia. Accordingly, serum magnesium monitoring is recommended for at least one month after initiating treatment with Veltassa, and magnesium supplementation should be considered in patients who develop low serum magnesium levels.

The polymer anion capacity to bind positively charged drugs and vitamins was tested and confirmed in vitro and in vivo (in rats and humans).

Use of Veltassa was not found to lead to acute toxicity, and long term repeat-dose toxicity studies (26 weeks in rats, 39 weeks in dogs) did not show specific toxicity associated with chronic use. No carcinogenicity study was conducted, as accepted by Health Canada at the pre-submission meeting. Veltassa was not genotoxic in the reverse mutation test (Ames assay), chromosome aberration or rat micronucleus assays.

Fertility, reproductive and developmental studies in rats and rabbits were inconclusive due to important methodological variations (e.g., consistent underdosing of male rats in the fertility study). Nonetheless, there were signals of reduced male fertility (decreased sperm motility and velocity at a high dose of the drug) and potentially altered fetal growth (e.g., variations in fetal ossification, which could be related to the effect of Veltassa on circulating levels of ions as well as vitamins important in fetal development). Statistical significance was not reached for many of these signals, probably due to the many subgroups evaluated, category breakdowns (e.g., many different ossification variations divided in subgroups) and the small sample size for the number of safety outcomes assessed. However, as no postnatal assessment was conducted to confirm that none of these effects were associated with long-term negative outcomes in offspring, use of Veltassa during pregnancy is not recommended. Additionally, although Veltassa is not absorbed systemically, its established effects on the levels of circulating ions and vitamins could potentially adversely affect the composition of breast milk. Therefore, caution should be exercised if Veltassa is to be used in nursing women.

The results of the non-clinical studies as well as the potential risks to humans have been included in the Veltassa Product Monograph. In view of the intended use of Veltassa, there are no pharmacological or toxicological issues within this submission which preclude authorization of the product.

For more information, refer to the Veltassa Product Monograph, approved by Health Canada and available through the Drug Product Database.

 

 

7.3 Quality Basis for Decision

 

The Chemistry and Manufacturing information submitted for Veltassa has demonstrated that the drug substance and drug product can be consistently manufactured to meet the approved specifications. Proper development and validation studies were conducted, and adequate controls are in place for the commercial processes. Changes to the manufacturing process and formulation made throughout the pharmaceutical development are considered acceptable upon review. Stability data support the storage recommendations included in the approved Veltassa Product Monograph.

Proposed limits of drug-related impurities are considered adequately qualified, i.e., within the International Council for Harmonisation limits and/or qualified from toxicological studies.

All sites involved in production are compliant with Good Manufacturing Practices.

The only excipient (xanthan gum) found in the drug product is acceptable for use in drugs according to the Food and Drug Regulations. This excipient is not of human or animal origin.

 

Report a problem or mistake on this page
Please select all that apply:
Date modified: