VELTASSA 16.8g 16.8g / sachet powder for oral suspension medication leaflet

Veltassa 8.4 g powder for oral suspension

Veltassa 16.8 g powder for oral suspension

Veltassa 25.2 g powder for oral suspension

Veltassa 8.4 g powder for oral suspension

Each sachet contains 8.4 g patiromer (as patiromer sorbitex calcium).

Veltassa 16.8 g powder for oral suspension

Each sachet contains 16.8 g patiromer (as patiromer sorbitex calcium).

Veltassa 25.2 g powder for oral suspension

Each sachet contains 25.2 g patiromer (as patiromer sorbitex calcium).

For the full list of excipients, see section 6.1.

Powder for oral suspension.

Off white to light brown powder, with occasional white particles.

Veltassa is indicated for the treatment of hyperkalaemia in adults.

The recommended starting dose is 8.4 g patiromer once daily.

The daily dose may be adjusted in intervals of one week or longer, based on the serum potassium leveland the desired target range. The daily dose may be increased or decreased by 8.4 g as necessary toreach the desired target range, up to a maximum dose of 25.2 g daily. If serum potassium falls belowthe desired range, the dose should be reduced or discontinued.

If a dose is missed, the missed dose should be taken as soon as possible on the same day. The misseddose should not be taken with the next dose.

Administration of Veltassa should be separated by 3 hours from other oral medicinal products (seesection 4.5).

The onset of action of Veltassa occurs 4 - 7 hours after administration. It should not replaceemergency treatment for life threatening hyperkalaemia.

Elderly population (≥65 years of age)

No special dose and administration guidelines are recommended for this population.

Patients on dialysis

There is limited data on the use of Veltassa in patients on dialysis. No special dose and administrationguidelines were applied to these patients in clinical studies.

The safety and efficacy of Veltassa in children aged under 18 years have not yet been established. Nodata are available.

Oral use.

Veltassa should be mixed with water and stirred to a suspension of uniform consistency, according tothe following steps:

The complete dose should be poured into a glass containing approximately 40 mL of water, thenstirred. Another approximately 40 mL of water should be added, and the suspension stirred againthoroughly. The powder will not dissolve. More water may be added to the mixture as needed fordesired consistency.

The mixture should be taken within 1 hour of initial suspension. If powder remains in the glass afterdrinking, more water should be added and the suspension stirred and taken immediately. This may berepeated as needed to ensure the entire dose is administered.

The following liquids or soft foods can be used instead of water to prepare the mixture by followingthe same steps as described above: apple juice, cranberry juice, pineapple juice, orange juice, grapejuice, pear juice, apricot nectar, peach nectar, yoghurt, milk, thickener (for example: cornstarch), applesauce, vanilla and chocolate pudding.

The potassium content of liquids or soft foods used to prepare the mixture should be considered as partof the dietary recommendations on potassium intake for each individual patient.

In general, cranberry juice intake should be limited to moderate amounts (for example less than400 mL per day) due to its potential interaction with other medicinal products.

Veltassa can be taken with or without food. It should not be heated (e.g. microwaved) or added toheated foods or liquids. It should not be taken in its dry form.

Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.

Low Magnesium

In clinical studies, serum magnesium values <1.4 mg/dL (0.58 mmol/L) occurred in 9% of patientstreated with patiromer. Mean decreases in serum magnesium were 0.17 mg/dL (0.070 mmol/L) or less.

Serum magnesium should be monitored for at least 1 month after initiating treatment, and magnesiumsupplementation considered in patients who develop low serum magnesium levels.

Gastrointestinal Disorders

Patients with a history of bowel obstruction or major gastrointestinal surgery, severe gastrointestinaldisorders, or swallowing disorders were not included in the clinical studies. Gastrointestinal ischaemia,necrosis and/or intestinal perforation have been reported with other potassium binders. The benefitsand risks of administering patiromer should be carefully evaluated in patients with current or history ofsevere gastrointestinal disorders, before and during treatment.

Discontinuing patiromer

When discontinuing patiromer, serum potassium levels may rise, especially ifrenin-angiotensin-aldosterone system (RAAS) inhibitor treatment is continued. Patients should beinstructed not to discontinue therapy without consulting their physicians. Increases in serum potassiummay occur as early as 2 days after the last patiromer dose.

Serum potassium levels

Serum potassium should be monitored when clinically indicated, including after changes are made tomedicinal products that affect the serum potassium concentration (e.g. RAAS inhibitors or diuretics)and after the patiromer dose is titrated.

Limitations of the clinical data

Patients with end-stage renal disease (ESRD)

Patiromer has been studied only in a limited number of patients with estimated glomerular filtrationrate (eGFR) <15 mL/min/1.73 m² and patients receiving dialysis treatment.

Severe hyperkalaemia

There is limited experience in patients with serum potassium concentrations greater than 6.5 mmol/L.

Long term exposure

Clinical trials with patiromer have not included exposure longer than one year.

Information about sorbitol

Veltassa contains sorbitol as part of the counterion complex. The sorbitol content is approximately 4 g(10.4 kcal) per 8.4 g of patiromer. Patients with hereditary fructose intolerance (HFI) should not takethis medicinal product.

Information about calcium

Veltassa contains calcium as part of the counterion complex. Calcium is partially released some ofwhich may be absorbed (see section 5.1). The benefits and risks of administering this medicinalproduct should be carefully evaluated in patients at risk of hypercalcaemia.

Effect of patiromer on other medicinal products

Patiromer has the potential to bind some oral co administered medicinal products, which coulddecrease their gastrointestinal absorption. As patiromer is not absorbed or metabolised by the body,there are limited effects on the function of other medicinal products.

As precautionary measure, and based on the data summarised below, administration of patiromershould therefore be separated by at least 3 hours from other oral medicinal products.

Concomitant administration of patiromer showed reduced bioavailability of ciprofloxacin,levothyroxine and metformin. However, there was no interaction when patiromer and these medicinalproducts were taken 3 hours apart.

In vitro studies have shown potential interaction of patiromer with quinidine.

Concomitant administration of patiromer did however not affect the bioavailability as measured by thearea under the curve (AUC) of amlodipine, cinacalcet, clopidogrel, furosemide, lithium, metoprolol,trimethoprim, verapamil and warfarin.

In vitro studies have shown no potential interaction of patiromer with the following active substances:allopurinol, amoxicillin, apixaban, acetylsalicylic acid, atorvastatin, cephalexin, digoxin, glipizide,lisinopril, phenytoin, riboflavin, rivaroxaban, spironolactone and valsartan.

There are no data from the use of patiromer in pregnant women.

Animal studies do not indicate direct or indirect harmful effects with respect to reproductive toxicity(see section 5.3).

As a precautionary measure, it is preferable to avoid the use of patiromer during pregnancy.

Breast feeding

No effects on the breast fed newborn/infant are anticipated since the systemic exposure of thebreast-feeding woman to patiromer is negligible. A decision must be made whether to discontinuebreast feeding or to discontinue/abstain from patiromer therapy taking into account the benefit ofbreast feeding for the child and the benefit of therapy for the woman.

There are no data on the effect of patiromer on fertility in humans. Animal studies showed no effectson reproductive function or fertility (see section 5.3).

Patiromer has no or negligible influence on the ability to drive and use machines.

The majority of the adverse reactions (ARs) reported from trials were gastrointestinal disorders, withthe most frequently reported ARs being constipation (6.2%), diarrhoea (3%), abdominal pain (2.9%),flatulence (1.8%) and hypomagnesaemia (5.3%). Gastrointestinal disorder reactions were generallymild to moderate in nature, did not appear to be dose related, generally resolved spontaneously or withtreatment, and none were reported as serious. Hypomagnesaemia was mild to moderate, with nopatient developing a serum magnesium level <1 mg/dL (0.4 mmol/L).

Adverse reactions are listed below by system organ class and by frequency. Frequencies are definedas: very common (≥1/10), common (≥1/100 to <1/10) and uncommon (≥1/1,000 to <1/100), rare(≥1/10,000 to <1/1,000), very rare (<1/10,000), not known (cannot be estimated from the availabledata). Within each frequency grouping, undesirable effects are presented in order of decreasingseriousness.

MedDRA system organ class Common Uncommon

Metabolism and nutrition Hypomagnesaemiadisorders

Gastrointestinal disorders Constipation Nausea

Diarrhoea Vomiting

Abdominal pain

Flatulence

Reporting suspected adverse reactions after authorisation of the medicinal product is important. Itallows continued monitoring of the benefit/risk balance of the medicinal product. Healthcareprofessionals are asked to report any suspected adverse reactions via the national reporting systemlisted in Appendix V.

Since excessive doses of Veltassa may result in hypokalaemia, serum potassium levels should bemonitored. Patiromer is excreted after approximately 24 to 48 hours, based on average gastrointestinaltransit time. If it is determined that medical intervention is required, appropriate measures to restoreserum potassium may be considered.

Pharmacotherapeutic group: Drugs for treatment of hyperkalaemia and hyperphosphataemia. ATCcode: V03AE09

Patiromer is a non-absorbed, cation exchange polymer that contains a calcium-sorbitol complex as acounterion.

Patiromer increases faecal potassium excretion through binding of potassium in the lumen of thegastrointestinal tract. Binding of potassium reduces the concentration of free potassium in thegastrointestinal lumen, resulting in a reduction of serum potassium levels.

In healthy adult subjects, patiromer caused a dose dependent increase in faecal potassium excretion,and a corresponding decrease in urinary potassium excretion with no change in serum potassium.25.2 g of patiromer, administered once daily for 6 days, resulted in a mean increase in faecalpotassium excretion of 1,283 mg/day, and a mean decrease in urinary potassium excretion of1,438 mg/day. Daily urinary calcium excretion increased from baseline by 53 mg/day.

In an open label study to assess the time to onset of action, a statistically significant reduction in serumpotassium in hyperkalaemic patients was observed at 7 hours after the first dose. Followingdiscontinuation of patiromer, potassium levels remained stable for 24 hours after the last dose, thenrose again during a 4-day observation period.

The safety and efficacy of patiromer were demonstrated in a two-part, single blind randomisedwithdrawal study that evaluated this treatment in hyperkalaemic patients with chronic kidney disease(CKD) on stable doses of at least one RAAS inhibitor (i.e. angiotensin converting enzyme inhibitor[ACEI], angiotensin II receptor blocker [ARB] or aldosterone antagonist [AA]).

In Part A, 243 patients were treated with patiromer for 4 weeks. Patients with a baseline serumpotassium of 5.1 mEq/L to <5.5 mEq/L (mmol/L) received a starting dose of 8.4 g patiromer per day(as a divided dose) and patients with a baseline serum potassium of 5.5 mEq/L to <6.5 mEq/L receiveda starting dose of 16.8 g patiromer per day (as a divided dose). The dose was titrated, as needed, basedon the serum potassium level, assessed starting on Day 3 and then at weekly visits to the end of the4 week treatment period, with the aim of maintaining serum potassium in the target range (3.8 mEq/Lto <5.1 mEq/L). The mean daily doses of patiromer were 13 g and 21 g in patients with serumpotassium of 5.1 to <5.5 mEq/L and 5.5 to <6.5 mEq/L, respectively.

The mean age of patients was 64 years (54% aged 65 and over, 17% aged 75 and over), 58% ofpatients were men, and 98% were Caucasian. Approximately 97% of patients had hypertension, 57%had type 2 diabetes, and 42% had heart failure.

Mean serum potassium levels and change in serum potassium from Part A Baseline to Part A Week 4is shown in Table 1. For the Part A secondary outcome, 76% (95% CI: 70%, 81%) of patients had aserum potassium in the target range of 3.8 mEq/L to <5.1 mEq/L at Part A Week 4.

Table 1: Patiromer treatment phase (Part A): primary endpoint

Baseline potassium Overall population5.1 to <5.5 mEq/L 5.5 to <6.5 mEq/L (n=237)(n=90) (n=147)

Serum potassium (mEq/L)

Baseline, mean (SD) 5.31 (0.57) 5.74 (0.40) 5.58 (0.51)

Week 4 change from −0.65 ± 0.05 −1.23 ± 0.04 −1.01 ± 0.03baseline, mean ± SE(95% CI) (−0.74, −0.55) (−1.31, −1.16) (−1.07, −0.95)p value <0.001

In Part B, 107 patients with a Part A baseline serum potassium of 5.5 mEq/L to <6.5 mEq/L and whoseserum potassium was in the target range (3.8 mEq/L to <5.1 mEq/L) at Part A Week 4 and stillreceiving RAAS inhibitor treatment were randomised to continue patiromer or to receive placebo for8 weeks to evaluate the effect of withdrawing patiromer on serum potassium. In patients randomised topatiromer, the mean daily dose was 21 g at the start of Part B and during Part B.

The Part B primary endpoint was the change in serum potassium from Part B baseline to the earliestvisit at which the patient’s serum potassium was first outside of the range of 3.8 to <5.5 mEq/L or to

Part B Week 4 if the patient’s serum potassium remained in the range. In Part B, serum potassium inpatients on placebo increased significantly relative to patients who remained on patiromer (p<0.001).

More placebo patients (91% [95% CI: 83%, 99%]) developed a serum potassium ≥5.1 mEq/L at anytime during Part B than patiromer patients (43% [95% CI: 30%, 56%]), p<0.001. More placebopatients (60% [95% CI: 47%, 74%]) developed a serum potassium ≥5.5 mEq/L at any time during

Part B than patiromer patients (15% [95% CI: 6%, 24%]), p<0.001.

The potential of patiromer to enable concomitant RAAS inhibitor treatment was also assessed inpart B. Fifty two percent (52%) of subjects receiving placebo discontinued RAAS inhibitor treatmentbecause of recurrent hyperkalaemia compared with 5% of subjects treated with patiromer.

The effect of treatment with patiromer for up to 52 weeks was evaluated in an open label study of304 hyperkalaemic patients with CKD and type 2 diabetes mellitus on stable doses of a RAASinhibitor. The mean age of patients was 66 years (59.9% aged 65 and over, 19.7% aged 75 and over),63% of patients were men, and all were Caucasian. Decreases in serum potassium with patiromertreatment were maintained over 1 year of chronic treatment as shown in Figure 1, with a low incidenceof hypokalaemia (2.3%) and the majority of subjects reaching (97.7%) and maintaining target serumpotassium levels (overall during maintenance period, serum potassium was within the target range forapproximately 80% of the time). In patients with a baseline serum potassium of >5.0 to 5.5 mEq/Lwho received an initial dose of 8.4 g patiromer per day, the mean daily dose was 14 g; in those with abaseline serum potassium of >5.5 to <6.0 mEq/L who received an initial dose of 16.8 g patiromer perday, the mean daily dose was 20 g during the entire study.

Figure 1: Mean (95% CI) serum potassium over time

Baseline Serum K+ > 5.0 to 5.5 mEq/L

Baseline Serum K+ > 5.5 to < 6.0 mEq/L

Study Visit (week) Follow-Up(day)

Number of Subjects:

Lower K+ Stratum: 218 199 192 175 168 161 161 163 158 156 151 148 149 145 131 126

Higher K+ Stratum: 83 73 70 65 62 62 62 61 53 53 53 52 49 49 48 47

The ability of patiromer to enable concomitant spironolactone treatment was investigated in arandomised, double-blind, placebo-controlled study in heart failure patients who were clinicallyindicated to receive AA. Patients initiated spironolactone at 25 mg/day at the same time as theirrandomised treatment (patiromer 12.6 g BID or placebo), and were up-titrated to 50 mg/day after

Day 14 if serum potassium was >3.5 and ≤5.1 mEq/L. Of the 105 patients who were randomised andreceived study treatment (patiromer 56; placebo 49), mean age was 68.3 years, 60.6% were men,97.1% were Caucasian, and mean eGFR was 81.3 mL/min. Mean baseline serum potassium valueswere 4.71 mEq/L for patiromer and 4.68 mEq/L for placebo.

The primary efficacy endpoint, change from baseline in serum potassium to the end of the 28-daytreatment period, was significantly lower (p<0.001) in the patiromer group (LS mean [SEM]:

Mean (95% Cl) Serum Potassium (mEq/L)−0.21 [0.07] mEq/L) as compared to the placebo group (LS mean [SEM]: +0.23 [0.07] mEq/L). Therewere also fewer patients in the patiromer group with serum potassium values >5.5 mEq/L (7.3% vs.24.5%; p=0.027) and more patients on spironolactone 50 mg/day (90.9% versus 73.5%, p=0.022).

The ability of patiromer to enable concomitant spironolactone treatment in patients with resistanthypertension and CKD was further investigated in a randomised, double-blind, placebo-controlledstudy over 12 weeks. Normokalaemic patients initiated spironolactone at 25 mg QD together with theirrandomised treatment (patiromer 8.4 g QD or placebo). Patiromer/placebo was titrated weekly (up to25.2 g QD) to maintain serum potassium ≥4.0 mEq/L and ≤5.1 mEq/L. At week 3 or after,spironolactone dose was increased to 50 mg QD for subjects with systolic blood pressure ≥120 mmHgand serum potassium ≤5.1 mEq/L.

Of the 295 randomized patients receiving study treatment (patiromer 147; placebo 148), mean age was68.1 years, 51.9% were men, 98.3% were Caucasian, and mean eGFR was 35.73 mL/min/1.73 m2. Atrandomization, mean baseline serum potassium values were 4.74 mEq/L for patiromer and 4.69 mEq/Lfor placebo. The primary efficacy endpoint, the proportion of subjects remaining on spironolactone at

Week 12, was significantly higher (p<0.0001) in the patiromer group (85.7%) compared to the placebogroup (66.2%). Significantly more patients received spironolactone 50 mg/day (69.4% versus 51.4%).

Overall, patients in the patiromer group remained on spironolactone 7.1 days longer (95% CI 2.212.0;p=0.0045) compared to the placebo group and received significantly higher cumulative doses ofspironolactone (2942.3 (SE 80.1) mg vs 2580.7 (SE 95.8) mg, p=0.0021).

There were also significantly fewer patients in the patiromer group with serum potassium values≥5.5 mEq/L (35.4% vs. 64.2%, p<0.001).

At Week 12, the mean systolic blood pressure had decreased by 11.0 mmHg (SD 15.34) in thespironolactone + placebo group and by 11.3 mmHg (SD 14.11) in the spironolactone + patiromergroup. These decreases from baseline were statistically significant within each treatment group(p<0.0001), but not statistically significant between the groups.

Overall, in the phase 2 and 3 clinical studies, 99.5% of patients were receiving RAAS inhibitor therapyat baseline, 87.0% had CKD with eGFR <60 mL/min/1.73 m2, 65.6% had diabetes mellitus and47.5% had heart failure.

In an open-label study, 114 patients with hyperkalaemia were randomized to patiromer once daily withfood or without food. Serum potassium at the end of treatment, the change from baseline in serumpotassium, and the mean dose of patiromer were similar between groups.

The European Medicines Agency has deferred the obligation to submit the results of studies withpatiromer in one or more subsets of the paediatric population in the treatment of hyperkalaemia (seesection 4.2 for information on paediatric use).

Patiromer works by binding potassium in the gastrointestinal tract and thus the serum concentration isnot relevant for its efficacy. Due to the insolubility and nonabsorptive characteristics of this medicinalproduct, many classical pharmacokinetic studies cannot be carried out.

Patiromer is excreted approximately 24 to 48 hours after intake, based on average gastrointestinaltransit time.

In radiolabeled studies in rats and dogs, patiromer was not systemically absorbed and was excreted inthe faeces. Quantitative whole-body autoradiography analysis in rats demonstrated that radioactivitywas limited to the gastrointestinal tract, with no detectable level of radioactivity in any other tissues ororgans.

Non-clinical data reveal no special hazard for humans based on conventional studies of safetypharmacology, repeated dose toxicity, genotoxicity, toxicity to reproduction and development.

Patiromer was not genotoxic in the reverse mutation test (Ames assay), chromosome aberration or ratmicronucleus assays.

Carcinogenicity studies have not been performed.

Xanthan gum

Not applicable.

3 years

Store and transport refrigerated (2°C - 8°C).

If stored at room temperature (below 25°C), Veltassa should be used within 6 months of being takenout of the refrigerator.

For either storage condition, Veltassa should not be used after the expiry date printed on the sachet.

The mixture should be taken within 1 hour of initial suspension.

8.4 g, 16.8 g or 25.2 g of patiromer, as powder in sachets made of five layers: polyethylene,aluminium, polyethylene, polyester and paper.

Pack sizes: boxes of 30, 60 or 90 sachets.

Not all pack sizes may be marketed.

Any unused medicinal product or waste material should be disposed of in accordance with localrequirements.

Vifor Fresenius Medical Care Renal Pharma France100-101 Terrasse Boieldieu

Tour Franklin La Défense 892042 Paris La Défense Cedex

France

EU/1/17/1179/001

EU/1/17/1179/002

EU/1/17/1179/003

EU/1/17/1179/004

EU/1/17/1179/005

EU/1/17/1179/006

EU/1/17/1179/007

EU/1/17/1179/008

EU/1/17/1179/009

Date of first authorisation: 19 July 2017

Date of latest renewal:

Detailed information on this medicinal product is available on the website of the European Medicines

Agency http://www.ema.europa.eu.