ADVERSE REACTIONS SECTION.

6 ADVERSE REACTIONS. No clinical trials have been performed with PHOSLYRA in the intended population. Because the dose and active ingredients of PHOSLYRA are equivalent to that of the calcium acetate gelcaps or tablets, the scope of the adverse reactions is anticipated to be similar.Hypercalcemia is discussed elsewhere [see Warnings and Precautions 5.1)] . The most common (>10%) adverse reactions are hypercalcemia, nausea, and diarrhea. 6.1) To report SUSPECTED ADVERSE REACTIONS, contact Fresenius Medical Care North America at 1-800-323-5188 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. The most common (>10%) adverse reactions are hypercalcemia, nausea, and diarrhea. 6.1) 6.1 Clinical Trial Experience. Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice.In clinical studies, calcium acetate has been generally well tolerated.The solid dose formulation of calcium acetate was studied in two clinical trials: 3-month, openlabel, non-randomized study with 98 kidney failure patients on hemodialysis (HD); and in 2week, double-blind, placebo-controlled, cross-over clinical trial with 69 kidney failure patients on HD.Table 1: Adverse Reactions in Kidney Failure Patients on HemodialysisPreferred TermTotal adverse reactionsreported forcalcium acetate n=167n (%) 3-mo, openlabel study ofcalcium acetate n=98n (%) Double-blind, placebo-controlled, cross-over study of calciumacetate n=69Calcium acetaten (%) Placebon (%) Nausea6 (3.6)6 (6.1)0 (0.0)0 (0.0)Vomiting4 (2.4)4 (4.1)0 (0.0)0 (0.0)Hypercalcemia21 (12.6)16 (16.3)5 (7.2)0 (0.0)Calcium acetate oral solution was studied in randomized, controlled, 3-arm, open label, crossover, single-dose study comparing calcium acetate oral solution to solid formulation in healthy volunteers on controlled diet. Of the observed drug-related adverse reactions, diarrhea (5/38, 13.2%) was more common with the oral solution.. 6.2 Postmarketing Experience. Because these reactions are reported voluntarily from population of uncertain size, it is not always possible to estimate their frequency or to establish causal relationship to drug exposure.The following additional adverse reactions have been identified during post-approval of calcium acetate: dizziness, edema, and weakness.

CLINICAL PHARMACOLOGY SECTION.

12 CLINICAL PHARMACOLOGY. 12.1 Mechanism of Action. Calcium acetate, when taken with meals, combines with dietary phosphate to form an insoluble calcium-phosphate complex, which is excreted in the feces, resulting in decreased serum phosphorus concentrations.. 12.2 Pharmacodynamics. Orally administered calcium acetate from pharmaceutical dosage forms is systemically absorbed up to approximately 40% under fasting conditions and up to approximately 30% under nonfasting conditions. This range represents data from both healthy subjects and renal dialysis patients under various conditions.A randomized, 3-arm, open-label, cross-over study in healthy volunteers evaluated the bioavailability of PHOSLYRA compared to calcium acetate gelcaps. Each subject received ~1000 mg elemental calcium from each dose of the following study medications: 30 mL PHOSLYRA (test), calcium acetate gelcaps (reference), or calcium citrate caplets (positive control) in three periods. The study medications were administered three times per day with meals from Day through Day and one morning dose on Day of each period.Treatment (baseline-subtracted) related changes (AUC and max) in serum calcium and phosphorus assessed over the hours following dosing were similar for PHOSLYRA and calcium acetate gelcaps. Urinary excretion of calcium and phosphorus were not significantly increased with PHOSLYRA compared to calcium acetate gelcaps. 12.3 Pharmcokinetics. Drug Interactions. In vivoIn study of 15 healthy subjects, co-administered single dose of calcium acetate tablets (approximately 2.7 g) decreased the bioavailability of ciprofloxacin by approximately 50%.

INFORMATION FOR PATIENTS SECTION.

17 PATIENT COUNSELING INFORMATION. Inform patients to take PHOSLYRA with meals, adhere to their prescribed diets, and avoid the use of calcium supplements including nonprescription antacids. Inform patients about the symptoms of hypercalcemia [see Warnings and Precautions 5.1) and Adverse Reactions 6.1)]. Advise patients who are taking an oral medication where reduction in the bioavailability of that medication would have clinically significant effect on its safety or efficacy to take the drug one hour before or three hours after PHOSLYRA.Manufactured for: Fresenius Medical Care North America Waltham, MA 02451 1-800-323-5188 Manufactured by: Lyne Laboratories Brockton, MA 02301 1-800-525-0450 (C) 2011-2020 Fresenius Medical Care North America. All Rights Reserved.101087.D Fresenius Medical Care Logo.

CLINICAL STUDIES SECTION.

14 CLINICAL STUDIES. Effectiveness of calcium acetate in decreasing serum phosphorus has been demonstrated in two studies of the solid dosage form.Ninety-one patients with kidney failure who were undergoing hemodialysis and were hyperphosphatemic (serum phosphorus >5.5 mg/dL) following 1-week phosphate binder washout period contributed efficacy data to an open-label, non-randomized study.The patients received calcium acetate 667 mg tablets at each meal for period of 12 weeks. The initial starting dose was tablets per meal for meals day, and the dose was adjusted as necessary to control serum phosphorus levels. The average final dose after 12 weeks of treatment was 3.4 tablets per meal. Although there was decrease in serum phosphorus, in the absence of control group the true magnitude of effect is uncertain.The data presented in Table demonstrate the efficacy of calcium acetate in the treatment of hyperphosphatemia in kidney failure on patients on Hemodialysis. The effects on serum calcium levels are also presented. Table 2: Average Serum Phosphorus and Calcium Levels at Pre-Study, Interim, and Study Completion Time pointsa Values expressed as mean +- SE. Ninety-one patients completed at least weeks of the study. ANOVA of difference in values at pre-study and study completion. ParameterPre-StudyWeek 4bWeek 8Week 12p-valuecPhosphorus (mg/dL) 7.4 +- 0.175.9 +- 0.165.6 +- 0.175.2 +- 0.17<=0.01Calcium (mg/dL) 8.9 +- 0.099.5 +- 0.109.7 +- 0.109.7 +- 0.10<=0.01There was 30% decrease in serum phosphorus levels during the 12 week study period (p <0.01). Two-thirds of the decline occurred in the first month of the study. Serum calcium increased 9% during the study mostly in the first month of the study.Treatment with the phosphate binder was discontinued for patients from the open-label study, and those patients whose serum phosphorus exceeded 5.5 mg/dL were eligible for entry into double-blind, placebo-controlled, cross-over study. Patients were randomized to receive calcium acetate or placebo, and each continued to receive the same number of tablets as had been individually established during the previous study. Following weeks of treatment, patients switched to the alternative therapy for an additional weeks.The phosphate binding effect of calcium acetate is shown in Table 3. Table 3: Serum Phosphorus and Calcium Levels at Study Initiation and After Completion of Each Treatment Arma Values expressed as mean +- SEM ANOVA of calcium acetate vs. placebo after weeks of treatment. ParameterPre-StudyPost-Treatmentp-valuebCalcium AcetatePlaceboPhosphorus (mg/dL) 7.3 +- 0.185.9 +- 0.247.8 +- 0.22<0.01Calcium (mg/dL) 8.9 +- 0.119.5 +- 0.138.8 +- 0.12<0.01Overall, weeks of treatment with calcium acetate statistically significantly (p <0.01) decreased serum phosphorus by mean of 19% and increased serum calcium by statistically significant (p <0.01) but clinically unimportant mean of 7%.

DESCRIPTION SECTION.

11 DESCRIPTION. PHOSLYRA acts as phosphate binder. Its chemical name is calcium acetate. Its molecular formula is 4H 6CaO 4, and its molecular weight is 158.17. Its structural formula is: PHOSLYRA for oral administration is provided as pale to light greenish-yellow clear liquid. Each mL of PHOSLYRA contains 667 mg calcium acetate, USP equal to 169 mg (8.45 mEq) calcium. PHOSLYRA also contains the following inactive ingredients: maltitol NF, glycerin USP, Magnasweet 110, propylene glycol USP, povidone K25 USP, sucralose NF, methylparaben NF, artificial black cherry flavor, menthol flavor, purified water USP.. Structural Formula.

DOSAGE & ADMINISTRATION SECTION.

2 DOSAGE AND ADMINISTRATION. The recommended initial dose of PHOSLYRA for the adult dialysis patient is 10 mL with each meal. Increase the dose gradually to lower serum phosphorus levels to the target range, as long as hypercalcemia does not develop. Titrate the dose every to weeks until an acceptable serum phosphorus level is reached. Most patients require 15-20 mL with each meal.. Starting dose is 10 mL with each meal. 2) Titrate the dose every to weeks until an acceptable serum phosphorus level is reached. Most patients require 15 to 20 mL with each meal. 2) Starting dose is 10 mL with each meal. 2) Titrate the dose every to weeks until an acceptable serum phosphorus level is reached. Most patients require 15 to 20 mL with each meal. 2).

DRUG INTERACTIONS SECTION.

7 DRUG INTERACTIONS. Oral drugs that have to be separated from PhoslyraDosing RecommendationsFlouroquinolonesTake at least hours before or hours after PhoslyraTetracyclinesTake at least hour before PhoslyraLevothyroxineTake at least hours before or hours after Phoslyra. PHOSLYRA may decrease the bioavailability of tetracyclines fluoroquinolones or levothyroxine. 7) When clinically significant drug interactions are expected, separate dosing from PHOSLYRA, or consider monitoring blood levels of the drug. 7) PHOSLYRA may decrease the bioavailability of tetracyclines fluoroquinolones or levothyroxine. 7) When clinically significant drug interactions are expected, separate dosing from PHOSLYRA, or consider monitoring blood levels of the drug. 7) Oral medications not listed in the TableThere are no empirical data on avoiding drug interactions between Phoslyra and most concomitant oral drugs. For oral medications where reduction in the bioavailability of that medication would have clinically significant effect on its safety or efficacy, consider separation of the timing of the administration of the two drugs. The duration of separation depends upon the absorption characteristics of the medication concomitantly administered, such as the time to reach peak systemic levels and whether the drug is an immediate release or an extended release product. Consider monitoring clinical responses or blood levels of concomitant medications that have narrow therapeutic range.

GERIATRIC USE SECTION.

8.5 Geriatric Use. Clinical studies of calcium acetate did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.

HOW SUPPLIED SECTION.

16 HOW SUPPLIED/STORAGE AND HANDLING. PHOSLYRA for oral administration is clear solution containing 667 mg calcium acetate per mL. PHOSLYRA is supplied in amber-colored, multiple-dose bottles, packaged with marked dosing cup in the following size:473 mL (16 fl. oz) bottle ................................................................................. (NDC 49230-643-31). Storage: Store at 25C (77F); excursions permitted to 15-30C (59-86F) [see USP Controlled Room Temperature]. The shelf life is 36 months.

INDICATIONS & USAGE SECTION.

1 INDICATIONS AND USAGE. PHOSLYRA (R) is indicated as an adjunct to reduction in dietary intake of phosphate and dialysis to reduce serum phosphorus in patients with kidney failure on dialysis. PHOSLYRA is phosphate binder indicated as an adjunct to reduction in dietary intake of phosphate and dialysis to reduce serum phosphorus in patients with kidney failure on dialysis. 1) PHOSLYRA is phosphate binder indicated as an adjunct to reduction in dietary intake of phosphate and dialysis to reduce serum phosphorus in patients with kidney failure on dialysis. 1).

PHARMACODYNAMICS SECTION.

12.2 Pharmacodynamics. Orally administered calcium acetate from pharmaceutical dosage forms is systemically absorbed up to approximately 40% under fasting conditions and up to approximately 30% under nonfasting conditions. This range represents data from both healthy subjects and renal dialysis patients under various conditions.A randomized, 3-arm, open-label, cross-over study in healthy volunteers evaluated the bioavailability of PHOSLYRA compared to calcium acetate gelcaps. Each subject received ~1000 mg elemental calcium from each dose of the following study medications: 30 mL PHOSLYRA (test), calcium acetate gelcaps (reference), or calcium citrate caplets (positive control) in three periods. The study medications were administered three times per day with meals from Day through Day and one morning dose on Day of each period.Treatment (baseline-subtracted) related changes (AUC and max) in serum calcium and phosphorus assessed over the hours following dosing were similar for PHOSLYRA and calcium acetate gelcaps. Urinary excretion of calcium and phosphorus were not significantly increased with PHOSLYRA compared to calcium acetate gelcaps.

PREGNANCY SECTION.

8.1 Pregnancy. Risk SummaryAdministration of the recommended dose of PHOSLYRA is not expected to cause major birth defects, miscarriage, or adverse maternal or fetal outcomes. Patients with kidney failure on dialysis may develop hypercalcemia with calcium acetate treatment [see Contraindications 4)] and [Warnings and Precautions 5.1)]. Maintenance of normal serum calcium levels is important for maternal and fetal wellbeing. There are adverse effects on maternal and fetal outcomes associated with kidney failure on dialysis in pregnancy (see Clinical Considerations). Animal reproduction studies have not been conducted with PHOSLYRA. Clinical Consideration. Disease-Associated Maternal and/or Embryo/Fetal RiskPregnancies that occur in women with kidney failure on dialysis are associated with high rate of complications, including increased maternal mortality, hypertension, preeclampsia, anemia, intrauterine growth restriction, preterm delivery, and still birth.. Maternal and Fetal/Neonatal Adverse ReactionsHypercalcemia during pregnancy may increase the risk for maternal and neonatal complications such as stillbirth, preterm delivery, and neonatal hypocalcemia and hypoparathyroidism. Monitor maternal serum calcium levels to maintain normal serum calcium.

SPL UNCLASSIFIED SECTION.

5.1 Hypercalcemia. Patients with kidney failure on dialysis may develop hypercalcemia when treated with calcium, including calcium acetate (PHOSLYRA). Avoid the concurrent use of calcium supplements, including calcium-based nonprescription antacids, with PHOSLYRA.An overdose of PHOSLYRA may lead to progressive hypercalcemia which may require emergency measures. Therefore, early in the treatment phase during the dosage adjustment period, monitor serum calcium levels twice weekly. Should hypercalcemia develop, reduce the PHOSLYRA dosage or discontinue the treatment, depending on the severity of hypercalcemia. More severe hypercalcemia (Ca >12 mg/dL) is associated with confusion, delirium, stupor and coma. Severe hypercalcemia can be treated by acute hemodialysis and discontinuing PHOSLYRA therapy.Mild hypercalcemia (10.5 to 11.9 mg/dL) may be asymptomatic or manifest as constipation, anorexia, nausea, and vomiting. Mild hypercalcemia is usually controlled by reducing the PHOSLYRA dose or temporarily discontinuing therapy. Decreasing or discontinuing Vitamin therapy is recommended as well.Chronic hypercalcemia may lead to vascular calcification and other soft-tissue calcification. Radiographic evaluation of suspected anatomical regions may be helpful in early detection of soft tissue calcification. The long-term effect of PHOSLYRA on the progression of vascular or soft tissue calcification has not been determined.Hypercalcemia (>11 mg/dL) was reported in 16% of patients in 3-month study of solid dose formulation of calcium acetate; all cases resolved upon lowering the dose or discontinuing treatment.

USE IN SPECIFIC POPULATIONS SECTION.

8 USE IN SPECIFIC POPULATIONS. 8.1 Pregnancy. Risk SummaryAdministration of the recommended dose of PHOSLYRA is not expected to cause major birth defects, miscarriage, or adverse maternal or fetal outcomes. Patients with kidney failure on dialysis may develop hypercalcemia with calcium acetate treatment [see Contraindications 4)] and [Warnings and Precautions 5.1)]. Maintenance of normal serum calcium levels is important for maternal and fetal wellbeing. There are adverse effects on maternal and fetal outcomes associated with kidney failure on dialysis in pregnancy (see Clinical Considerations). Animal reproduction studies have not been conducted with PHOSLYRA. Clinical Consideration. Disease-Associated Maternal and/or Embryo/Fetal RiskPregnancies that occur in women with kidney failure on dialysis are associated with high rate of complications, including increased maternal mortality, hypertension, preeclampsia, anemia, intrauterine growth restriction, preterm delivery, and still birth.. Maternal and Fetal/Neonatal Adverse ReactionsHypercalcemia during pregnancy may increase the risk for maternal and neonatal complications such as stillbirth, preterm delivery, and neonatal hypocalcemia and hypoparathyroidism. Monitor maternal serum calcium levels to maintain normal serum calcium.. 8.2 Lactation. Risk SummaryCalcium and acetate are excreted in human milk. There are no data on the effects of calcium acetate on the concentration of calcium or acetate in milk, the effect on the breastfed child, or the effects on milk production.. 8.4 Pediatric Use. Safety and effectiveness of PHOSLYRA in pediatric patients have not been established.. 8.5 Geriatric Use. Clinical studies of calcium acetate did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.

WARNINGS AND PRECAUTIONS SECTION.

5 WARNINGS AND PRECAUTIONS. Treat mild hypercalcemia by reducing or interrupting PHOSLYRA and Vitamin D. Severe hypercalcemia may require hemodialysis and discontinuation of PHOSLYRA. 5.1) May cause diarrhea with nutritional supplements that contain maltitol 5.2) Treat mild hypercalcemia by reducing or interrupting PHOSLYRA and Vitamin D. Severe hypercalcemia may require hemodialysis and discontinuation of PHOSLYRA. 5.1) May cause diarrhea with nutritional supplements that contain maltitol 5.2) 5.1 Hypercalcemia. Patients with kidney failure on dialysis may develop hypercalcemia when treated with calcium, including calcium acetate (PHOSLYRA). Avoid the concurrent use of calcium supplements, including calcium-based nonprescription antacids, with PHOSLYRA.An overdose of PHOSLYRA may lead to progressive hypercalcemia which may require emergency measures. Therefore, early in the treatment phase during the dosage adjustment period, monitor serum calcium levels twice weekly. Should hypercalcemia develop, reduce the PHOSLYRA dosage or discontinue the treatment, depending on the severity of hypercalcemia. More severe hypercalcemia (Ca >12 mg/dL) is associated with confusion, delirium, stupor and coma. Severe hypercalcemia can be treated by acute hemodialysis and discontinuing PHOSLYRA therapy.Mild hypercalcemia (10.5 to 11.9 mg/dL) may be asymptomatic or manifest as constipation, anorexia, nausea, and vomiting. Mild hypercalcemia is usually controlled by reducing the PHOSLYRA dose or temporarily discontinuing therapy. Decreasing or discontinuing Vitamin therapy is recommended as well.Chronic hypercalcemia may lead to vascular calcification and other soft-tissue calcification. Radiographic evaluation of suspected anatomical regions may be helpful in early detection of soft tissue calcification. The long-term effect of PHOSLYRA on the progression of vascular or soft tissue calcification has not been determined.Hypercalcemia (>11 mg/dL) was reported in 16% of patients in 3-month study of solid dose formulation of calcium acetate; all cases resolved upon lowering the dose or discontinuing treatment.. 5.2 Concomitant Use with Medications. Hypercalcemia may aggravate digitalis toxicity.PHOSLYRA contains maltitol (1 per mL) and may induce laxative effect, especially if taken with other products containing maltitol.