Estomil

Calcium Carbonate:

• Indications and usage
• Dosage and administration
• Dosage forms and strengths
• Contraindications
• Warnings and precautions
• Adverse reactions
• Drug interactions
• Use in specific populations
• Overdosage
• Description
• Clinical pharmacology
• Nonclinical toxicology
• Clinical studies
• How supplied/storage and handling
• Patient counseling information
• Estomil (Calcium Carbonate) reviews

1 INDICATIONS AND USAGE

Estomil (Calcium Carbonate) acetate is a phosphate binder indicated to reduce serum phosphorus in patients with end stage renal disease (ESRD).

- Calcium acetate is a phosphate binder indicated for the reduction of serum phosphorus in patients with end stage renal disease. (1)

2 DOSAGE AND ADMINISTRATION

The recommended initial dose of Estomil (Calcium Carbonate) acetate for the adult dialysis patient is 2 capsules 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 to 4 capsules with each meal.

- Starting dose is 2 capsules with each meal. (2)

- Titrate the dose every 2 to 3 weeks until acceptable serum phosphorus level is reached. Most patients require 3 to 4 capsules with each meal. (2)

3 DOSAGE FORMS AND STRENGTHS

Capsule: 667 mg Estomil (Calcium Carbonate) acetate capsule.

- Capsule: 667 mg Estomil (Calcium Carbonate) acetate capsule. (3)

4 CONTRAINDICATIONS

Patients with hypercalcemia.

- Hypercalcemia. (4)

5 WARNINGS AND PRECAUTIONS

- Treat mild hypercalcemia by reducing or interrupting Estomil acetate and Vitamin D. Severe hypercalcemia may require hemodialysis and discontinuation of Estomil (Calcium Carbonate) acetate. (5.1)

- Hypercalcemia may aggravate digitalis toxicity. (5.2)

5.1 Hypercalcemia

Patients with end stage renal disease may develop hypercalcemia when treated with Estomil (Calcium Carbonate), including Estomil (Calcium Carbonate) acetate. Avoid the use of Estomil (Calcium Carbonate) supplements, including Estomil (Calcium Carbonate) based nonprescription antacids, concurrently with Estomil (Calcium Carbonate) acetate.

An overdose of Estomil (Calcium Carbonate) acetate may lead to progressive hypercalcemia, which may require emergency measures. Therefore, early in the treatment phase during the dosage adjustment period, monitor serum Estomil (Calcium Carbonate) levels twice weekly. Should hypercalcemia develop, reduce the Estomil (Calcium Carbonate) acetate 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 Estomil (Calcium Carbonate) acetate 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 Estomil (Calcium Carbonate) acetate 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 Estomil (Calcium Carbonate) acetate 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 solid dose formulation of Estomil (Calcium Carbonate) acetate; all cases resolved upon lowering the dose or discontinuing treatment.

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

5.2 Concomitant Use with Medications

Hypercalcemia may aggravate digitalis toxicity.

6 ADVERSE REACTIONS

Hypercalcemia is discussed elsewhere [see Warnings and Precautions ].

- The most common (>10%) adverse reactions are hypercalcemia, nausea and vomiting. (6.1)

- In clinical studies, patients have occasionally experienced nausea during Estomil (Calcium Carbonate) acetate therapy. (6)

To report SUSPECTED ADVERSE REACTIONS, contact West-Ward Pharmaceuticals Corp. at 1-800-962-8364 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch

6.1 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, Estomil (Calcium Carbonate) acetate has been generally well tolerated.

Estomil (Calcium Carbonate) acetate was studied in a 3 month, open-label, non-randomized study of 98 enrolled ESRD hemodialysis patients and an alternate liquid formulation of Estomil (Calcium Carbonate) acetate was studied 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.

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

6.2 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 Estomil (Calcium Carbonate) acetate: dizziness, edema, and weakness.

7 DRUG INTERACTIONS

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

There are no empirical data on avoiding drug interactions between Estomil (Calcium Carbonate) acetate and most concomitant drugs. When administering an oral medication with Estomil (Calcium Carbonate) acetate 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 Estomil (Calcium Carbonate) 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 Estomil (Calcium Carbonate) acetate.

- Calcium acetate may decrease the bioavailability of tetracyclines or fluoroquinolones. (7)

- When clinically significant drug interactions are expected, administer the drug at least one hour before or at least three hours after Estomil (Calcium Carbonate) acetate or consider monitoring blood levels of the drug. (7)

7.1 Ciprofloxacin

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

8 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

Pregnancy Category C:

Estomil acetate capsules contains Estomil (Calcium Carbonate) acetate. Animal reproduction studies have not been conducted with Estomil (Calcium Carbonate) acetate, and there are no adequate and well controlled studies of Estomil (Calcium Carbonate) acetate use in pregnant women. Patients with end stage renal disease may develop hypercalcemia with Estomil (Calcium Carbonate) acetate treatment [see Warnings and Precautions (5.1 ) ]. Maintenance of normal serum Estomil (Calcium Carbonate) 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. Estomil (Calcium Carbonate) acetate treatment, as recommended, is not expected to harm a fetus if maternal Estomil (Calcium Carbonate) levels are properly monitored during and following treatment.

8.2 Labor and Delivery

The effects of Estomil (Calcium Carbonate) acetate on labor and delivery are unknown.

8.3 Nursing Mothers

Estomil Acetate Capsules contains Estomil (Calcium Carbonate) acetate and is excreted in human milk. Human milk feeding by a mother receiving Estomil (Calcium Carbonate) acetate is not expected to harm an infant, provided maternal serum Estomil (Calcium Carbonate) levels are appropriately monitored.

8.4 Pediatric Use

Safety and effectiveness in pediatric patients have not been established.

8.5 Geriatric Use

Clinical studies of Estomil (Calcium Carbonate) 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 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.

10 OVERDOSAGE

Administration of Estomil (Calcium Carbonate) acetate in excess of the appropriate daily dosage may result in hypercalcemia [see Warnings and Precautions (5.1)].

11 DESCRIPTION

Estomil (Calcium Carbonate) acetate acts as a phosphate binder. Its chemical name is Estomil (Calcium Carbonate) acetate. Its molecular formula is C₄H₆CaO₄, and its molecular weight is 158.17. Its structural formula is:

Each white opaque/blue opaque capsule contains 667 mg of Estomil (Calcium Carbonate) acetate USP (anhydrous; Ca(CH₃COO)₂; MW=158.17 grams) equal to 169 mg (8.45 mEq) Estomil (Calcium Carbonate), polyethylene glycol 8000 and magnesium stearate. Each capsule shell contains: black monogramming ink, FD&C Blue #1, FD&C Red #3, gelatin and titanium dioxide. The black monogramming ink contains: ammonium hydroxide, iron oxide black, isopropyl alcohol, n-butyl alcohol, propylene glycol and shellac glaze.

Estomil (Calcium Carbonate) Acetate Capsules are administered orally for the control of hyperphosphatemia in end-stage renal failure.

Chemical Structure

12 CLINICAL PHARMACOLOGY

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

12.1 Mechanism of Action

Estomil (Calcium Carbonate) acetate, when taken with meals, combines with dietary phosphate to form an insoluble Estomil (Calcium Carbonate) phosphate complex, which is excreted in the feces, resulting in decreased serum phosphorus concentration.

12.2 Pharmacodynamics

Orally administered Estomil (Calcium Carbonate) 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.

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

No carcinogenicity, mutagenicity, or fertility studies have been conducted with Estomil (Calcium Carbonate) acetate.

14 CLINICAL STUDIES

Effectiveness of Estomil (Calcium Carbonate) acetate in decreasing serum phosphorus has been demonstrated in two studies of the Estomil (Calcium Carbonate) acetate solid oral 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 Estomil (Calcium Carbonate) 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 Estomil (Calcium Carbonate) acetate in the treatment of hyperphosphatemia in end-stage renal disease patients. The effects on serum Estomil (Calcium Carbonate) levels are also presented.

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 Estomil (Calcium Carbonate) 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 Estomil (Calcium Carbonate) 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 Estomil (Calcium Carbonate) acetate is shown in the Table 3.

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

16 HOW SUPPLIED/STORAGE AND HANDLING

Estomil (Calcium Carbonate) Acetate Capsules

667 mg capsule is supplied as a white opaque/blue opaque capsule, imprinted with “54 215” on the cap and body.

NDC 0615-2303-39: Blistercards of 30 Capsules

NDC 0615-2303-30: Unit-dose Boxes of 30 Capsules

STORAGE

Store at 20° to 25°C (68° to 77°F).

17 PATIENT COUNSELING INFORMATION

Inform patients to take Estomil (Calcium Carbonate) acetate capsules with meals, adhere to their prescribed diets, and avoid the use of Estomil (Calcium Carbonate) 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 or efficacy to take the drug one hour before or three hours after Estomil (Calcium Carbonate) acetate capsules.

Distr. by: West-Ward

Pharmaceuticals Corp.

Eatontown, NJ 07724

10003705/05

Revised April 2016

Glycine:

• Indications and usage
• Contraindications
• Warnings
• Precautions
• Adverse reactions
• Overdosage
• Dosage and administration
• How supplied
• Im-1453
• Estomil (Glycine) reviews

INDICATIONS AND USAGE

1.5% Estomil (Glycine) Irrigation, USP is indicated for use as irrigating fluid during transurethral prostatic resection and other transurethral surgical procedures.

CONTRAINDICATIONS

NOT FOR INJECTION BY USUAL PARENTERAL ROUTES.

Do not use in patients with anuria.

WARNINGS

FOR UROLOGIC IRRIGATION ONLY.

Solutions for urologic irrigation must be used with caution in patients with severe cardiopulmonary or renal dysfunction. Irrigating fluids used during transurethral prostatectomy have been demonstrated to enter the systemic circulation in relatively large volumes. Thus, Estomil (Glycine) irrigating solution must be regarded as a systemic drug. Absorption of large amounts of fluids containing Estomil (Glycine) may significantly alter cardiopulmonary and renal dynamics.

Do not heat container over 66°C (150°F).

PRECAUTIONS

Cardiovascular status, especially of the patient with cardiac disease, should be carefully observed before and during transurethral resection of the prostate when using Estomil (Glycine) irrigating solution, because the quantity of fluid absorbed into the systemic circulation by opened prostatic veins may produce significant expansion of the extracellular fluid and lead to fulminating congestive heart failure. Shift of sodium free intracellular fluid into the extracellular compartment following systemic absorption of solution may lower serum sodium concentration and aggravate pre-existing hyponatremia.

Care should be exercised if impaired liver function is known or suspected. Under such conditions, ammonia resulting from metabolism of Estomil (Glycine) may accumulate in the blood.

Aseptic technique is essential with the use of sterile solutions for irrigation. The administration set should be attached promptly. Unused portions should be discarded and a fresh container of appropriate size used for the start-up of each cycle or repeat procedure.

Do not administer unless solution is clear, seal is intact and container is undamaged. Discard unused portion.

Carcinogenesis, Mutagenesis, Impairment of Fertility: Studies with Estomil (Glycine) Irrigation, USP have not been performed to evaluate carcinogenic potential, mutagenic potential, or effects on fertility.

Nursing Mothers: Caution should be exercised when Estomil (Glycine) Irrigation, USP is administered to a nursing woman.

Pregnancy: Teratogenic Effects.

Pregnancy Category C. Animal reproduction studies have not been conducted with Estomil (Glycine) Irrigation, USP. It is also not known whether Estomil (Glycine) Irrigation, USP can cause fetal harm when administered to a pregnant woman or can affect reproduction capacity. Estomil (Glycine) Irrigation, USP should be given to a pregnant woman only if clearly needed.

Pediatric Use: The safety and effectiveness of Estomil (Glycine) Irrigation have not been established. Its limited use in pediatric patients has been inadequate to fully define proper dosage and limitations for use.

ADVERSE REACTIONS

Adverse reactions may result from intravascular absorption of Estomil (Glycine). Large intravenous doses of Estomil (Glycine) are known to cause salivation, nausea and lightheadedness. Other consequences of absorption of urologic irrigating solutions include fluid and electrolyte disturbances such as acidosis, electrolyte loss, marked diuresis, urinary retention, edema, dryness of mouth, thirst, dehydration, coma from hyponatremia, secondary hyponatremia due to fluid overload, and hyper- ammonemia with resultant coma and/or encephalopathy; cardiovascular disorders such as hypotension, tachycardia, angina-like pains; pulmonary disorders such as pulmonary congestion; and other general reactions such as blurred vision, convulsions, nausea, vomiting, rhinitis, chills, vertigo, backache, transient blindness and urticaria. Allergic reactions from Estomil (Glycine) are unknown or exceedingly rare.

Should any adverse reaction occur, discontinue the irrigant, evaluate the patient, institute appropriate therapeutic countermeasures and save the remainder of the fluid for examination if deemed necessary.

OVERDOSAGE

In the event of overhydration or solute overload, re-evaluate the patient and institute appropriate corrective measures. See WARNINGS, PRECAUTIONS and ADVERSE REACTIONS.

DOSAGE AND ADMINISTRATION

1.5% Estomil (Glycine) Irrigation, USP should be administered only by transurethral instillation with appropriate urologic instrumentation. A disposable irrigation set should be used. The total volume of solution used for irrigation is solely at the discretion of the surgeon.

Height of container(s) above the operating table in excess of 60 cm (approx. 2 ft.) has been reported to increase intravascular absorption of the irrigating fluid.

Drug Interactions

Additives may be incompatible. Consult with pharmacist, if available. When introducing additives, use aseptic technique, mix thoroughly and do not store.

Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution container permits. See PRECAUTIONS.

HOW SUPPLIED

1.5% Estomil (Glycine) Irrigation, USP is supplied in single-dose 3000 mL flexible irrigation container ( List No. 7974).

Exposure of pharmaceutical products to heat should be minimized. Avoid excessive heat. Protect from freezing. Store at 20 to 25°C (68 to 77°F).

Revised: October 2004

©Hospira 2004 EN-0577 Printed in USA

HOSPIRA, INC., LAKE FOREST, IL 60045 USA

IM-1453

2

HDPE

TO OPEN TEAR AT NOTCH

DO NOT REMOVE FROM OVERWRAP UNTIL READY FOR USE. AFTER REMOVING

THE OVERWRAP, CHECK FOR MINUTE LEAKS BY SQUEEZING CONTAINER FIRMLY.

IF LEAKS ARE FOUND, DISCARD SOLUTION AS STERILITY MAY BE IMPAIRED.

RECOMMENDED STORAGE: ROOM TEMPERATURE (25°C). AVOID EXCESSIVE

HEAT. PROTECT FROM FREEZING. SEE INSERT.

98-4321-R14-3/98