Patiromer

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# Overview
Patiromer is a potassium binder that is FDA approved for the treatment of patients with hyperkalemia.   Common adverse reactions include constipation, hypomagnesemia, diarrhea, nausea, abdominal discomfort and flatulence (2%).

# Adult Indications and Dosage

## FDA-Labeled Indications and Dosage (Adult)
Patiromer is indicated for the treatment of hyperkalemia.
Limitation of Use: Patiromer should not be used as an emergency treatment for life-threatening hyperkalemia because of its delayed onset of action.
Administer Patiromer at least 3 hours before or 3 hours after other oral medications.
Administer Patiromer with food. Do not heat Patiromer (e.g., microwave) or add to heated foods or liquids. Do not take Patiromer in its dry form.
- Recommended Dosing and Titration
The recommended starting dose of Patiromer is 8.4 grams once daily. Monitor serum potassium and adjust the dose of Patiromer based on the serum potassium level and the desired target range. The dose may be increased or decreased, as necessary, to reach the desired serum potassium concentration, up to a maximum dose of 25.2 grams once daily. The dose can be up-titrated based on serum potassium level at 1-week or longer intervals, in increments of 8.4 grams.

## Off-Label Use and Dosage (Adult)

### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Patiromer in adult patients.

### NonGuideline-Supported Use
There is limited information regarding Off-Label NonGuideline-Supported Use of Patiromer in adult patients.

# Pediatric Indications and Dosage

## FDA-Labeled Indications and Dosage (Pediatric)
Safety and efficacy in pediatric patients have not been established.

## Off-Label Use and Dosage (Pediatric)

### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Patiromer in pediatric patients.

### NonGuideline-Supported Use
There is limited information regarding Off-Label NonGuideline-Supported Use of Patiromer in pediatric patients.

# Contraindications
Patiromer is contraindicated in patients with a history of a hypersensitivity reaction to Patiromer or any of its components

# Warnings
- Worsening of Gastrointestinal Motility
Avoid use of Patiromer in patients with severe constipation, bowel obstruction or impaction, including abnormal post-operative bowel motility disorders, because Patiromer may be ineffective and may worsen gastrointestinal conditions.
Patients with a history of bowel obstruction or major gastrointestinal surgery, severe gastrointestinal disorders, or swallowing disorders were not included in the clinical studies.
- Hypomagnesemia
Patiromer binds to magnesium in the colon, which can lead to hypomagnesemia. In clinical studies, hypomagnesemia was reported as an adverse reaction in 5.3% of patients treated with Patiromer. Monitor serum magnesium. Consider magnesium supplementation in patients who develop low serum magnesium levels on Patiromer.

# Adverse Reactions

## Clinical Trials Experience
The following adverse reaction is discussed in greater detail elsewhere in the label:
- Hypomagnesemia
Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of Patiromer cannot be directly compared to rates in the clinical trials of other drugs and may not reflect the rates observed in practice.
In the safety and efficacy clinical trials, 666 adult patients received at least one dose of Patiromer, including 219 exposed for at least 6 months and 149 exposed for at least one year.
Table 1 provides a summary of the most common adverse reactions (occurring in  2% of patients) in patients treated with Patiromer in these clinical trials. Most adverse reactions were mild to moderate. Constipation generally resolved during the course of treatment.
- Table 1: Adverse Reactions Reported in  2% of Patients
Veltassa: Patiromer's Brand name
During the clinical studies, the most commonly reported adverse reactions leading to discontinuation of Patiromer were gastrointestinal adverse reactions (2.7%), including vomiting (0.8%), diarrhea (0.6%), constipation (0.5%) and flatulence (0.5%).
Mild to moderate hypersensitivity reactions were reported in 0.3% of patients treated with Patiromer in clinical trials. Reactions have included edema of the lips.
- Laboratory Abnormalities
- Approximately 4.7% of patients in clinical trials developed hypokalemia with a serum potassium value < 3.5 mEq/L.
- Approximately 9% of patients in clinical trials developed hypomagnesemia with a serum magnesium value < 1.4 mg/dL.

## Postmarketing Experience
There is limited information regarding Patiromer Postmarketing Experience in the drug label.

# Drug Interactions
In clinical studies, Patiromer decreased systemic exposure of some coadministered oral medications. Binding of Patiromer to other oral medications could cause decreased gastrointestinal absorption and loss of efficacy when taken close to the time Patiromer is administered. Administer other oral medications at least 3 hours before or 3 hours after Patiromer.

# Use in Specific Populations

### Pregnancy
Pregnancy Category (FDA): 
Patiromer is not absorbed systemically following oral administration and maternal use is not expected to result in fetal risk.
Pregnancy Category (AUS): 
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Patiromer in women who are pregnant.

### Labor and Delivery
There is no FDA guidance on use of Patiromer during labor and delivery.

### Nursing Mothers
Patiromer is not absorbed systemically by the mother, so breastfeeding is not expected to result in risk to the infant.

### Pediatric Use
Safety and efficacy in pediatric patients have not been established.

### Geriatic Use
Of the 666 patients treated with Patiromer in clinical studies, 59.8% were age 65 and over, and 19.8% were age 75 and over. No overall differences in effectiveness were observed between these patients and younger patients. Patients age 65 and older reported more gastrointestinal adverse reactions than younger patients.

### Gender
There is no FDA guidance on the use of Patiromer with respect to specific gender populations.

### Race
There is no FDA guidance on the use of Patiromer with respect to specific racial populations.

### Renal Impairment
Of the 666 patients treated with Patiromer in clinical studies, 93% had chronic kidney disease (CKD). No special dosing adjustments are needed for patients with renal impairment.

### Hepatic Impairment
There is no FDA guidance on the use of Patiromer in patients with hepatic impairment.

### Females of Reproductive Potential and Males
There is no FDA guidance on the use of Patiromer in women of reproductive potentials and males.

### Immunocompromised Patients
There is no FDA guidance one the use of Patiromer in patients who are immunocompromised.

# Administration and Monitoring

### Administration
- Preparation of Patiromer
Prepare each dose immediately prior to administration.
Measure 1/3 cup of water. Pour half of the water into a glass, then add Patiromer and stir. Add the remaining half of the water and stir thoroughly. The powder will not dissolve and the mixture will look cloudy. Add more water to the mixture as needed for desired consistency.
Drink the mixture immediately. If powder remains in the glass after drinking, add more water, stir and drink immediately. Repeat as needed to ensure the entire dose is administered.

### Monitoring
There is limited information regarding Patiromer Monitoring in the drug label.

# IV Compatibility
There is limited information regarding the compatibility of Patiromer and IV administrations.

# Overdosage
Doses of Patiromer in excess of 50.4 grams per day have not been tested. Excessive doses of Patiromer may result in hypokalemia. Restore serum potassium if hypokalemia occurs.

# Pharmacology

## Mechanism of Action
Patiromer is a non-absorbed, cation exchange polymer that contains a calcium-sorbitol counterion.
Patiromer 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.

## Structure
Patiromer is a powder for suspension in water for oral administration. The active ingredient is patiromer sorbitex calcium which consists of the active moiety, patiromer, a non-absorbed potassium-binding polymer, and a calcium-sorbitol counterion. Each gram of patiromer is equivalent to a nominal amount of 2 grams of patiromer sorbitex calcium.
The chemical name for patiromer sorbitex calcium is cross-linked polymer of calcium 2-fluoroprop-2-enoate with diethenylbenzene and octa-1,7-diene, combination with D-glucitol.
Patiromer sorbitex calcium is an amorphous, free-flowing powder that is composed of individual spherical beads. Patiromer sorbitex calcium is insoluble in solvents such as water, 0.1 M HCl, n-heptane and methanol. The chemical structure of patiromer sorbitex calcium is presented in Figure 1.
- Figure 1: Chemical Structure of Patiromer Sorbitex Calcium
Each packet of this drug contains 8.4 grams, 16.8 grams or 25.2 grams of patiromer, the active moiety. The inactive ingredient is xanthan gum.

## Pharmacodynamics
In a Phase 1 study in healthy adult subjects (6 to 8 subjects per group), Patiromer (0 grams to 50.4 grams per day) administered three times a day for 8 days caused a dose-dependent increase in fecal potassium excretion. A corresponding dose-dependent decrease in urinary potassium excretion with no change in serum potassium were also observed. Compared to placebo, Patiromer doses of 25.2 and 50.4 grams per day significantly decreased mean daily urinary potassium excretion.
In a Phase 1, open-label, multiple-dose crossover study in 12 healthy subjects, 25.2 grams of patiromer per day was administered orally as a once daily, twice daily or thrice daily regimen for 6 days in a randomly assigned order. A significant increase in mean daily fecal potassium excretion and concomitant decrease in mean daily urinary potassium excretion were observed during the treatment periods for all three dosing regimens. The mean increase in fecal potassium excretion ranged from 1283 to 1550 mg/day, and the mean decrease in urinary potassium excretion ranged from 1438 to 1534 mg/day across the three dosing regimens. No significant differences were observed among the dosing regimens with respect to mean daily fecal potassium and urinary potassium excretion. This was true for the overall comparison among the three dosing regimens, as well as for the pairwise comparisons.
In an open-label, uncontrolled study, 25 patients with hyperkalemia (mean baseline serum potassium of 5.9 mEq/L) and chronic kidney disease were given a controlled potassium diet for 3 days, followed by 16.8 grams patiromer daily (as divided doses) for 2 days while the controlled diet was continued. A statistically significant reduction in serum potassium (-0.2 mEq/L) was observed at 7 hours after the first dose. Serum potassium levels continued to decline during the 48-hour treatment period (-0.8 mEq/L at 48 hours after the first dose). Potassium levels remained stable for 24 hours after the last dose, then rose during the 4-day observation period following discontinuation of Patiromer.

## Pharmacokinetics
In radiolabeled ADME studies in rats and dogs, patiromer was not systemically absorbed and was excreted in the feces. Quantitative whole-body autoradiography analysis in rats demonstrated that radioactivity was limited to the gastrointestinal tract, with no detectable level of radioactivity in any other tissues or organs.
- Drug Interactions
Twenty-eight (28) drugs were tested to determine the potential for interaction with Patiromer.
Fourteen (14) drugs tested did not show an in vitro interaction with Patiromer (acetylsalicylic acid, allopurinol, amoxicillin, apixaban, atorvastatin, cephalexin, digoxin, glipizide, lisinopril, phenytoin, riboflavin, rivaroxaban, spironolactone and valsartan).
Twelve (12) of the 14 drugs that showed an in vitro interaction were subsequently tested in vivo. These studies in healthy volunteers showed that Patiromer did not alter the systemic exposure of amlodipine, cinacalcet, clopidogrel, furosemide, lithium, metoprolol, trimethoprim, verapamil or warfarin when coadministered with Patiromer. Patiromer decreased the systemic exposure of coadministered ciprofloxacin, levothyroxine and metformin. However, there was no interaction when Patiromer and these drugs were taken 3 hours apart (Figure 2).
- Figure 2: Effects of Patiromer on the Pharmacokinetic Exposures of Other Orally Administered Medications with No Dosing Separation and with a 3-Hour Separation

## Nonclinical Toxicology
Patiromer was not genotoxic in the reverse mutation test (Ames assay), chromosome aberration or rat micronucleus assays.
Carcinogenicity studies have not been performed.
Patiromer did not impair the fertility in male or female rats at doses up to 10-fold the maximum recommended human dose (MRHD).

# Clinical Studies
- Two-Part, Randomized Withdrawal Study
The efficacy of Patiromer was demonstrated in a two-part, single-blind randomized withdrawal study that evaluated Patiromer in hyperkalemic patients with CKD on stable doses of at least one renin-angiotensin-aldosterone system inhibitor (i.e., angiotensin-converting enzyme inhibitor, angiotensin II receptor blocker, or aldosterone antagonist).
In Part A, 243 patients were treated with Patiromer for 4 weeks. Patients with a baseline serum potassium of 5.1 mEq/L to < 5.5 mEq/L received a starting Patiromer dose of 8.4 grams patiromer per day (as a divided dose) and patients with a baseline serum potassium of 5.5 mEq/L to < 6.5 mEq/L received a starting Patiromer dose of 16.8 grams patiromer per day (as a divided dose). The dose of Patiromer was titrated, as needed, based on the serum potassium level, assessed starting on Day 3 and then at weekly visits (Weeks 1, 2 and 3) to the end of the 4-week treatment period, with the aim of maintaining serum potassium in the target range (3.8 mEq/L to < 5.1 mEq/L).
The mean age of patients was 64 years, 58% of patients were men, and 98% were Caucasian. Approximately 97% of patients had hypertension, 57% had type 2 diabetes, and 42% had heart failure.
Results for the Part A primary endpoint, the change in serum potassium from Baseline to Week 4, are summarized in Table 2. Mean serum potassium over time for the intent-to-treat population is displayed in Figure 3. For the Part A secondary endpoint, 76% (95% confidence interval : 70%, 81%) of patients had a serum potassium in the target range of 3.8 mEq/L to < 5.1 mEq/L at Week 4. The mean daily doses of Patiromer were 13 grams and 21 grams in patients with serum potassium of 5.1 to < 5.5 mEq/L and 5.5 to < 6.5 mEq/L, respectively.
- Table 2: Patiromer Treatment Phase (Part A): Primary Endpoint
- Figure 3: Estimated Mean (95% CI) of Central Serum Potassium (mEq/L) Over Time
In Part B, 107 patients with a Part A baseline serum potassium of 5.5 mEq/L to < 6.5 mEq/L and whose serum potassium was in the target range (3.8 mEq/L to < 5.1 mEq/L) at Part A Week 4 and still receiving RAAS inhibitor medication were randomized to continue Patiromer or to receive placebo to evaluate the effect of withdrawing Patiromer on serum potassium. In patients randomized to Patiromer, the mean daily dose was 21 grams 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 earliest visit 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 rose by 0.72 mEq/L in patients who were switched to placebo, versus no change in patients who remained on Patiromer. Results are summarized in Table 3.
- Table 3: Randomized, Placebo-Controlled Withdrawal Phase (Part B): Primary Endpoint
Veltassa: Patiromer's Brand name
More placebo patients (91%; 95% CI: 83%, 99%) developed a serum potassium  5.1 mEq/L at any time during Part B than Patiromer patients (43%; 95% CI: 30%, 56%), p < 0.001. More placebo patients (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.
- One-Year Study
The effect of treatment with Patiromer for up to 52 weeks was evaluated in an open-label study of 304 hyperkalemic patients with CKD and type 2 diabetes mellitus on RAAS inhibitor therapy. Figure 4 shows that the treatment effect on serum potassium was maintained during continued therapy. In patients with a baseline serum potassium of > 5.0 to 5.5 mEq/L who received an initial dose of 8.4 grams patiromer per day (as a divided dose), the mean daily dose was 14 grams; in those with a baseline serum potassium of > 5.5 to < 6.0 mEq/L who received an initial dose of 16.8 grams patiromer per day (as a divided dose), the mean daily dose was 20 grams during the entire study.
- Figure 4: Mean (95% CI) Serum Potassium over Time

# How Supplied
Patiromer is supplied as an off-white to light-brown powder for oral suspension formulated with xanthan gum. Patiromer is packaged in single-use packets containing 8.4 grams, 16.8 grams or 25.2 grams patiromer as follows:
Veltassa: Patiromer's Brand name

## Storage
Patiromer should be stored in the refrigerator at 2C to 8C (36F to 46F).
If stored at room temperature (25C  2C ), Patiromer must be used within 3 months of being taken out of the refrigerator. For either storage condition, do not use Patiromer after the expiration date printed on the packet.
Avoid exposure to excessive heat above 40C (104F).

# Images

## Drug Images

## Package and Label Display Panel

# Patient Counseling Information
- Drug Interactions
Advise patients who are taking other oral medication to separate the dosing of Patiromer by at least 3 hours (before or after).
- Dosing Recommendations
Inform patients to take Patiromer as directed with food and adhere to their prescribed diets.
Inform patients that Patiromer should not be heated (e.g., microwaved) or added to heated foods or liquids and should not be taken in its dry form.

# Precautions with Alcohol
Alcohol-Patiromer interaction has not been established. Talk to your doctor regarding the effects of taking alcohol with this medication.

# Brand Names
Veltassa

# Look-Alike Drug Names
There is limited information regarding Patiromer Look-Alike Drug Names in the drug label.

# Drug Shortage Status

# Price