Phoslo

calcium acetate

Dosage Form: capsule
FULL PRESCRIBING INFORMATION

INDICATIONS & USAGE

Phoslo® is a phosphate binder indicated to reduce serum phosphorus in patients with end stage renal disease (ESRD).

DOSAGE & ADMINISTRATION

The recommended initial dose of Phoslo® for the adult dialysis patient is 2 gelcaps with each meal.  Increase the dose gradually to lower serum phosphorus levels to the target range, as long as hypercalcemia does not develop.  Most patients require 3-4 gelcaps with each meal.

DOSAGE FORMS & STRENGTHS

Capsule:  667 mg calcium acetate per gelcap.

CONTRAINDICATIONS

Patients with hypercalcemia.

WARNINGS AND PRECAUTIONS

Hypercalcemia

Patients with end stage renal disease may develop hypercalcemia when treated with calcium, including calcium acetate (Phoslo®).  Avoid the use of calcium supplements, including calcium-based nonprescription antacids, concurrently with Phoslo®.

An overdose of Phoslo 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 Phoslo® 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 Phoslo® 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 Phoslo® dose or temporarily discontinuing therapy.  Decreasing or discontinuing Vitamin D 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 Phoslo® on the progression of vascular or soft tissue calcification has not been determined.

Hypercalcemia (>11 mg/dL) was reported in 16% of patients in a 3-month study of a solid dose formulation of calcium acetate; all cases resolved upon lowering the dose or discontinuing treatment.

Maintain the serum calcium-phosphorus (Ca x P) product below 55 mg2/dL2.

Concomitant Use with Medications

Hypercalcemia may aggravate digitalis toxicity.

ADVERSE REACTIONS

Hypercalcemia is discussed elsewhere [see Warnings and Precautions (5.1)].

Clinical Trial Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

In clinical studies, calcium acetate has been generally well tolerated.

Phoslo® was studied in a 3-month, open-label, non-randomized study of 98 enrolled ESRD hemodialysis patients and in a two week double-blind, placebo-controlled, cross-over study with 69 enrolled ESRD hemodialysis patients.  Adverse reactions (>2% on treatment) from these trials are presented in Table 1.

Table 1: Adverse Reactions in Patients with End-Stage Renal Disease Undergoing Hemodialysis

Preferred Term	Total adverse reactions reported for calcium acetate n = 167 n (%)	3-mo, open-label study of calcium acetate n = 98 n (%)	Double-blind, placebo-controlled, cross-over study of calcium acetate n = 69
			Calcium acetate n (%)	Placebo n (%)
Nausea	6 (3.6)	6 (6.1)	0 (0.0)	0 (0.0)
Vomiting	4 (2.4)	4 (4.1)	0 (0.0)	0 (0.0)
Hypercalcemia	21 (12.6)	16 (16.3)	5 (7.2)	0 (0.0)

Mild hypercalcemia may be asymptomatic or manifest itself as constipation, anorexia, neusea, and vomiting.  More severe hypercalcemia is associated with confusion, delirium, stupor, and coma.  Decreasing dialysate calcium concentration could reduce the incidence and severity of Phoslo®-induced hypercalcemia.  Isolated cases of pruritus have been reported, which may represent allergic reactions.

Postmarketing Experience

Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to estimate their frequency or to establish a causal relationship to drug exposure.

The following additional adverse reactions have been identified during post-approval of calcium acetate:  dizziness, edema, and weakness.

DRUG INTERACTIONS

The drug interaction of Phoslo® is characterized by the potential of calcium to bind to drugs with anionic functions (e.g., carboxyl and hydroxyl groups).  Phoslo® may decrease the bioavailability of tetracyclines or fluoroquinolones via this mechanism.

There are no empirical data on avoiding drug interactions between calcium acetate or Phoslo® and most concomitant drugs.  When administering an oral medication with Phoslo® where a reduction in the bioavailability of that medication would have a clinically significant effect on its safety or efficacy, administer the drug one hour before or three hours after Phoslo® or calcium acetate.  Monitor blood levels of the concomitant drugs that have a narrow therapeutic range.  Patients taking anti-arrhythmic medications for the control of arrhythmias and anti-seizure medications for the control of seizure disorders were excluded from the clinical trials with all forms of calcium acetate.

Ciprofloxacin

In a study of 15 healthy subjects, a co-administered single dose of 4 calcium acetate tablets approximately 2.7 g, decreased the bioavailability of ciprofloxacin by approximately 50%.

USE IN SPECIFIC POPULATIONS

PREGNANCY

Pregnancy Category C

Phoslo® contains calcium acetate.  Animal reproduction studies have not been conducted with Phoslo®, and there are no adequate and well controlled studies of Phoslo® use in pregnant women.  Patients with end stage renal disease may develop hypercalcemia with calcium acetate treatment [see Warnings and Precautions (5.1)].  Maintenance of normal serum calcium levels is important for maternal and fetal well being.  Hypercalcemia during pregnancy may increase the risk for maternal and neonatal complications such as stillbirth, preterm delivery, and neonatal hypocalcemia and hypoparathyroidism.  Phoslo® treatment, as recommended, is not expected to harm a fetus if maternal calcium levels are properly monitored during and following treatment.

  LABOR & DELIVERY

The effects of Phoslo® on labor and delivery are unknown.

  NURSING MOTHERS

Phoslo® contains calcium acetate and is excreted in human milk.  Human milk feeding by a mother receiving Phoslo® is not expected to harm an infant, provided maternal serum calcium levels are appropriately monitored.

  PEDIATRIC USE

Safety and effectiveness in pediatric patients have not been established.

  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 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.

OVERDOSAGE

Administration of Phoslo® in excess of the appropriate daily dosage may result in hypercalcemia [see Warnings and Precautions (5.1)].

DESCRIPTION

Phoslo® acts as a phosphate binder.  Its chemical name is calcium acetate.  Its molecular formula is C4H6CaO4, and its molecular weight is 158.17.  Its structural formula is:

Each opaque gelcap with a blue cap and white body is spin printed in blue and white ink with “Phoslo®” printed on the cap and “667 mg” printed on the body.  Each gelcap contains 667 mg calcium acetate, USP (anhydrous; Ca(CH3COO)2; MW=158.17 grams) equal to 169 mg (8.45 mEq) calcium, and 10 mg of the inert binder, polyethylene glycol 8000 NF.  The gelatin cap and body have the following inactive ingredients: FD&C blue #1, D&C red #28, titanium dioxide, USP and gelatin, USP.

CLINICAL PHARMACOLOGY

Patients with ESRD retain phosphorus and can develop hyperphosphatemia.  High serum phosphorus can precipitate serum calcium resulting in ectopic calcification.  Hyperphosphatemia also plays a role in the development of secondary hyperparathyroidism in patients with ESRD.

  MECHANISM OF ACTION

Calcium acetate, (Phoslo®) 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 concentration.

  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 non-fasting conditions.  This range represents data from both healthy subjects and renal dialysis patients under various conditions.

NONCLINICAL TOXICOLOGY

  CARCINOGENESIS & MUTAGENESIS & IMPAIRMENT OF FERTILITY

No carcinogenicity, mutagenicity, or fertility studies have been conducted with calcium acetate.

CLINICAL STUDIES

Effectiveness of calcium acetate in decreasing serum phosphorus has been demonstrated in two studies of the calcium acetate solid dosage form.

Ninety-one patients with end-stage renal disease who were undergoing hemodialysis and were hyperphosphatemic (serum phosphorus >5.5 mg/dL) following a 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 a period of 12 weeks.  The initial starting dose was 2 tablets per meal for 3 meals a 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 a decrease in serum phosphorus, in the absence of a control group the true magnitude of effect is uncertain.

The data presented in Table 2 demonstrate the efficacy of calcium acetate in the treatment of hyperphosphatemia in end-stage renal disease patients.  The effects on serum calcium levels are also presented.

Table 2: Average Serum Phosphorous and Calcium Levels at Pre-Study, Interim, and Study Completion Time points

Parameter	Pre-Study	Week 4b	Week 8	Week 12	p-valuec
a Values expressed as mean ± SE.
b Ninety-one patients completed at least 6 weeks of the study.
c ANOVA of difference in values at pre-study and study completion.
Phosphorus (mg/dL)a	7.4 ± 0.17	5.9 ± 0.16	5.6 ± 0.17	5.2 ± 0.17	≤0.01
Calcium (mg/dL)a	8.9 ± 0.09	9.5 ± 0.10	9.7 ± 0.10	9.7 ± 0.10	≤0.01

There was a 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 a 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 2 weeks of treatment, patients switched to the alternative therapy for an additional 2 weeks.

The phosphate binding effect of calcium acetate is shown in the Table 3.

Table 3: Serum Phosphorus and Calcium Levels at Study Initiation and After Completion of Each Treatment Arm

Parameter	Pre-Study	Post-Treatment		p-valueb
		Calcium Acetate	Placebo
a Values expressed as mean ± SE.
b ANOVA of calcium acetate vs. placebo after 2 weeks of treatment.
Phosphorus (mg/dL)a	7.3 ± 0.18	5.9 ± 0.24	7.8 ± 0.22	<0.01
Calcium (mg/dL)a	8.9 ± 0.11	9.5 ± 0.13	8.8 ± 0.12	<0.01

Overall, 2 weeks of treatment with calcium acetate statistically significantally (p<0.01) decreased serum phosphorus by a mean of 19% and increased serum calcium by a statistically significant (p<0.01) but clinically unimportant mean of 7%.

HOW SUPPLIED/STORAGE AND HANDLING

Gelcap A white and blue gelcap for oral administration containing 667 mg calcium acetate (anhydrous Ca(CH3COO)2; MW=158.17 grams) equal to 169 mg (8.45 mEq) calcium.

Gelcap NDC 49230-640-21 Bottles of 200

STORAGE:  Store at 25°C (77°F); excursions permitted to 15-30°C (59-86°F) [See USP “Controlled Room Temperature”].

PATIENT COUNSELING INFORMATION

Inform patients to take Phoslo® with meals, adhere to their prescribed diets, and avoid the use of calcium supplements including nonprescription antacids.  Inform the 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 and efficacy to take the drug one hour before or three hours after Phoslo®.

Manufactured for

Fresenius Medical Care North America

Waltham, MA  02451

by

Pharmaceutics International, Inc.

10819 Gilroy Road

Hunt Valley, MD  21031

100623.02 04 / 2011                                                

PACKAGE LABEL.PRINCIPAL DISPLAY PANEL

Phoslo  calcium acetate  capsule

Product Information Product Type HUMAN PRESCRIPTION DRUG NDC Product Code (Source) 49230-640 Route of Administration ORAL DEA Schedule

Active Ingredient/Active Moiety Ingredient Name Basis of Strength Strength CALCIUM ACETATE (CALCIUM CATION) CALCIUM ACETATE 667 mg

Inactive Ingredients Ingredient Name Strength POLYETHYLENE GLYCOL 8000   FD&C BLUE NO. 1   D&C RED NO. 28   TITANIUM DIOXIDE   GELATIN

Product Characteristics Color WHITE, BLUE Score no score Shape CAPSULE Size 20mm Flavor Imprint Code Phoslo;667mg Contains

Packaging # NDC Package Description Multilevel Packaging 1 49230-640-21 1 BOTTLE In 1 CARTON contains a BOTTLE 1 200 CAPSULE In 1 BOTTLE This package is contained within the CARTON (49230-640-21)

Marketing Information
Marketing Category	Application Number or Monograph Citation	Marketing Start Date	Marketing End Date
NDA	NDA021160	04/02/2001

Labeler - Fresenius Medical Care North America (075684324)

Establishment
Name	Address	ID/FEI	Operations
Pharmaceutics International, Inc.		878265586	MANUFACTURE

Establishment
Name	Address	ID/FEI	Operations
Kemira Chemicals Inc		403364669	API MANUFACTURE

Revised: 04/2011Fresenius Medical Care North America

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