Veltassa(patiromer)口服混悬剂-被美国FDA批准用于治疗高钾血症
近日，美国FDA批准Veltassa（patiromer 口服混悬剂）用于治疗高血钾，高血钾是一种严重疾病，患有该病的患者其血液中钾的量过高。血液中有太多的钾可导致危险的、甚至致命的心脏节律变化，FDA药物评价与研究中心心血管及肾脏产品部门主任、医学博士、哲学博士Stockbridge称。有治疗选择可供用于高血钾患者是非常重要的。
钾是一种矿物质成分，其通过食物被输送到人体，它是细胞正常功能所必需的。肾脏将钾从血液中移除，以保持体内钾的正常平衡。但当肾脏不能从血液移除足够多的钾时，钾的水平可能会变得过高。
高血钾通常发生于有急性或慢性肾病或心力衰竭的患者中，尤其是那些服用能抑制肾素-血管紧张素-醛固酮系统药物的患者，肾素-血管紧张素-醛固酮系统负责调节体内的血压及液体平衡。
Veltassa是一种粉末状药物，患者可将其与水混合口服使用，该药物在胃肠道通过与钾结合、降低其吸收而发挥作用。在临床试验中，Veltassa在服用至少一种能抑制肾素-血管紧张素-醛固酮系统药物的慢性肾病高血钾受试者中有效地降低了钾水平。
临床试验中，服用Veltassa的受试者最常报告的不良反应是便秘、血液中镁水平降低（低镁症）、腹泻、恶心、腹部不适及肠胃气胀。Veltassa不适合用于严重高血钾的快速修正，因为降低血清钾水平可能要花费数小时到数天的时间。
Veltassa有一项黑框警告，因为它能与多种其它口服使用的药物结合，这可能降低它们的吸收并降低它们的效果。这项警告建议服用这款药物时至少隔6个小时再服用其它药物。这款药物必须与患者用药指南一起分发，该用药指南描述了有关该药物应用与风险的重要信息。
批准日期：2015年10月21日；公司：Relypsa，Inc.
VELTASSA(patiromer)供口服悬液使用
美国初次批准：2015
适应证和用途
Veltassa是一种钾结合剂适用为高钾血症的治疗。
使用的限制
Veltassa不应被用作对危及生命高钾血症紧急治疗因为其作用的延迟开始。
剂量和给药方法
Veltassa的推荐起始剂量是8.4克口服给药与食物每天1次。
需要时每天调整剂量8.4克间隔一周以得到想要血清钾目标范围。
剂型和规格
粉：8.4，16.8和25.2克patiromer包装
包装规格
8.4克*1包 4包 30包
16.8克*1包      30包
25.2克*1包      30包
Veltassa, patiromer (RLY5016) (formerly Patiromer FOS)
HIGHLIGHTS OF PRESCRIBING INFORMATION
These highlights do not include all the information needed to use VELTASSA™ safely and effectively. See full prescribing information for VELTASSA.
VELTASSA (patiromer) for oral suspension
Initial U.S. Approval: 2015
WARNING: BINDING TO OTHER ORAL MEDICATIONS Veltassa binds to many orally administered medications, which could decrease their absorption and reduce their effectiveness. Administer other oral medications at least 6 hours before or 6 hours after Veltassa. Choose Veltassa or the other oral medication if adequate dosing separation is not possible. (2.1, 5.1, 7)
INDICATIONS AND USAGE
Veltassa is a potassium binder indicated for the treatment of hyperkalemia. (1)
Limitation of Use
Veltassa should not be used as an emergency treatment for life-threatening hyperkalemia because of its delayed onset of action. (1)
DOSAGE AND ADMINISTRATION
The recommended starting dose of Veltassa is 8.4 grams administered orally once daily with food. (2.2)
Adjust dose by 8.4 grams daily as needed at one week intervals to obtain desired serum potassium target range. (2.2)
DOSAGE FORMS AND STRENGTHS
Powder: 8.4, 16.8 and 25.2 grams patiromer packets. (3)
CONTRAINDICATIONS
Known hypersensitivity to Veltassa or any of its components. (4)
WARNINGS AND PRECAUTIONS
Worsening of Gastrointestinal Motility (5.2)
Hypomagnesemia (5.3)
ADVERSE REACTIONS
Most common adverse reactions (incidence ≥ 2%) are constipation, hypomagnesemia, diarrhea, nausea, abdominal discomfort and flatulence. (6.1)
To report SUSPECTED ADVERSE REACTIONS, contact Relypsa at 1-844-VELTASSA (1-844-835-8277) or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.
DRUG INTERACTIONS
Take other orally administered drugs at least 6 hours before or 6 hours after Veltassa. (2.1, 5.1, 7)
See 17 for PATIENT COUNSELING INFORMATION and Medication Guide.
Revised: 10/2015
FULL PRESCRIBING INFORMATION: CONTENTS*
1 INDICATIONS AND USAGE
Veltassa is indicated for the treatment of hyperkalemia.
Limitation of Use: Veltassa should not be used as an emergency treatment for life-threatening hyperkalemia because of its delayed onset of action [see Pharmacodynamics (12.2)].
2 DOSAGE AND ADMINISTRATION
2.1 General Information
Administer Veltassa at least 6 hours before or 6 hours after other oral medications [see Warnings and Precautions (5.1) and Drug Interactions (7)].
Administer Veltassa with food. Do not heat Veltassa (e.g., microwave) or add to heated foods or liquids. Do not take Veltassa in its dry form.
2.2 Recommended Dosing and Titration
The recommended starting dose of Veltassa is 8.4 grams patiromer once daily. Monitor serum potassium and adjust the dose of Veltassa 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.
2.3 Preparation of Veltassa
Prepare each dose immediately prior to administration following the steps below:

Step 1:	Add about 1 ounce (30 milliliters) of water to an empty glass or cup.
Step 2:	Empty the entire contents of the packet(s) into the glass or cup.
Step 3:	Stir the mixture thoroughly.
Step 4:	Add an additional 2 ounces (60 milliliters) of water to the glass or cup containing the mixture.
Step 5:	Stir the mixture thoroughly; the powder will not dissolve and the mixture will look cloudy.
Step 6:	Drink the mixture immediately. If some powder remains in the glass after drinking, add more water, stir and drink immediately. Repeat as needed to ensure the entire dose is administered.

3 DOSAGE FORMS AND STRENGTHS
Veltassa is an off-white to light-brown powder for oral suspension packaged in single-use packets containing 8.4 grams, 16.8 grams or 25.2 grams patiromer.
4 CONTRAINDICATIONS
Veltassa is contraindicated in patients with a history of a hypersensitivity reaction to Veltassa or any of its components [see Adverse Reactions (6.1)].
5 WARNINGS AND PRECAUTIONS
5.1 Binding to Other Orally Administered Medications
Veltassa binds many orally administered medications, which could decrease their gastrointestinal absorption and lead to reduced efficacy. Administer other oral medications at least 6 hours before or 6 hours after Veltassa. Choose Veltassa or the other oral medication if adequate dosing separation is not possible [see Dosage and Administration (2.1) and Drug Interactions (7)].
5.2 Worsening of Gastrointestinal Motility
Avoid use of Veltassa in patients with severe constipation, bowel obstruction or impaction, including abnormal post-operative bowel motility disorders, because Veltassa 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.
5.3 Hypomagnesemia
Veltassa 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 Veltassa [see Adverse Reactions (6.1)]. Monitor serum magnesium. Consider magnesium supplementation in patients who develop low serum magnesium levels on Veltassa.
6 ADVERSE REACTIONS
The following adverse reaction is discussed in greater detail elsewhere in the label:
Hypomagnesemia [see Warnings and Precautions (5.3)]
6.1 Clinical Trials Experience
Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of Veltassa 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 Veltassa, 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 Veltassa 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 

Adverse Reactions	Patients treated with Veltassa (N=666)
Constipation	7.2%
Hypomagnesemia	5.3%
Diarrhea	4.8%
Nausea	2.3%
Abdominal discomfort	2.0%
Flatulence	2.0%

During the clinical studies, the most commonly reported adverse reactions leading to discontinuation of Veltassa 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 Veltassa 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.
7 DRUG INTERACTIONS
No formal drug interaction studies have been conducted in humans.
In in vitro binding studies, Veltassa was shown to bind about half of the oral medications that were tested. Binding of Veltassa to other oral medications could cause decreased gastrointestinal absorption and loss of efficacy when taken close to the time Veltassa is administered. Administer other oral medications at least 6 hours before or 6 hours after Veltassa. Monitor for clinical response and/or blood levels where possible.
8 USE IN SPECIFIC POPULATIONS
8.1 Pregnancy
Risk Summary
Veltassa is not absorbed systemically following oral administration and maternal use is not expected to result in fetal risk.
8.2 Lactation
Risk Summary
Veltassa is not absorbed systemically by the mother, so breastfeeding is not expected to result in risk to the infant.
8.4 Pediatric Use
Safety and efficacy in pediatric patients have not been established.
8.5 Geriatric Use
Of the 666 patients treated with Veltassa 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.
8.6 Renal Impairment
Of the 666 patients treated with Veltassa in clinical studies, 93% had chronic kidney disease (CKD). No special dosing adjustments are needed for patients with renal impairment.
10 OVERDOSAGE
Doses of Veltassa in excess of 50.4 grams per day have not been tested. Excessive doses of Veltassa may result in hypokalemia. Restore serum potassium if hypokalemia occurs.
11 DESCRIPTION
Veltassa 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 Veltassa contains 8.4 grams, 16.8 grams or 25.2 grams of patiromer, the active moiety. The inactive ingredient is xanthan gum.
12 CLINICAL PHARMACOLOGY
12.1 Mechanism of Action
Veltassa is a non-absorbed, cation exchange polymer that contains a calcium-sorbitol 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.
12.2 Pharmacodynamics
In a Phase 1 study in healthy adult subjects (6 to 8 subjects per group), Veltassa (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, Veltassa 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 Veltassa.
12.3 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
Veltassa binds many other orally administered medications in the gastrointestinal tract, which could lead to a decrease in absorption of other medications.
13 NONCLINICAL TOXICOLOGY
13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
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).
14 CLINICAL STUDIES
14.1 Two-Part, Randomized Withdrawal Study
The efficacy of Veltassa was demonstrated in a two-part, single-blind randomized withdrawal study that evaluated Veltassa 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 Veltassa for 4 weeks. Patients with a baseline serum potassium of 5.1 mEq/L to < 5.5 mEq/L received a starting Veltassa 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 Veltassa dose of 16.8 grams patiromer per day (as a divided dose). The dose of Veltassa 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 2. For the Part A secondary endpoint, 76% (95% confidence interval [CI]: 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 Veltassa 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: Veltassa Treatment Phase (Part A): Primary Endpoint 

Baseline Potassium		Overall Population (n=237)
	5.1 to < 5.5 mEq/L (n=90)		5.5 to < 6.5 mEq/L (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 Baseline, Mean ± SE (95% CI)	-0.65 ± 0.05 (-0.74, -0.55)	-1.23 ± 0.04 (-1.31, -1.16)	-1.01 ± 0.03 (-1.07, -0.95)
p-value			< 0.001

Figure 2: 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 Veltassa or to receive placebo to evaluate the effect of withdrawing Veltassa on serum potassium. In patients randomized to Veltassa, 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 Veltassa. Results are summarized in Table 3.
Table 3: Randomized, Placebo-Controlled Withdrawal Phase (Part B): Primary Endpoint 

Placebo (n=52)	Veltassa (n=55)	Difference
		Estimate (95% CI)	p-value
Estimated Median Change in Serum Potassium from Baseline (mEq/L)	0.72	0.00	0.72 (0.46, 0.99)	< 0.001

More placebo patients (91%; 95% CI: 83%, 99%) developed a serum potassium ≥ 5.1 mEq/L at any time during Part B than Veltassa 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 Veltassa patients (15%; 95% CI: 6%, 24%), p < 0.001.
14.2 One-Year Study
The effect of treatment with Veltassa 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 3 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 17 grams patiromer per day (as a divided dose), the mean daily dose was 20 grams during the entire study.
Figure 3: Mean (95% CI) Serum Potassium over Time

16 HOW SUPPLIED/STORAGE AND HANDLING
16.1 How Supplied
Veltassa is supplied as a powder for oral suspension formulated with xanthan gum. Veltassa is packaged in single-use packets containing 8.4 grams, 16.8 grams or 25.2 grams patiromer as follows:

Veltassa (grams)	Single Use Packet	Carton of 4 Packets	Carton of 30 Packets
8.4	NDC 53436-084-01	NDC 53436-084-04	NDC 53436-084-30
16.8	NDC 53436-168-01	-	NDC 53436-168-30
25.2	NDC 53436-252-01	-	NDC 53436-252-30

16.2 Stability and Storage
Veltassa should be stored in the refrigerator at 2°C to 8°C (36°F to 46°F).
If stored at room temperature (25°C ± 2°C [77°F ± 4°F]), Veltassa must be used within 3 months of being taken out of the refrigerator. For either storage condition, do not use Veltassa after the expiration date printed on the packet.
Avoid exposure to excessive heat above 40°C (104°F).
17 PATIENT COUNSELING INFORMATION
Advise the patient to read the FDA-approved patient labeling (Medication Guide).
Drug Interactions
Advise patients who are taking other oral medication to separate the dosing of Veltassa by at least 6 hours (before or after) [see Drug Interactions (7)].
Dosing Recommendations
Inform patients to take Veltassa as directed with food and adhere to their prescribed diets. Instruct patients to prepare each dose separately using the preparation instructions provided in the FDA-approved patient labeling (Medication Guide).
Inform patients that Veltassa should not be heated (e.g., microwaved) or added to heated foods or liquids and should not be taken in its dry form.