Rowarolan

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
• Rowarolan (Calcium Carbonate) reviews

1 INDICATIONS AND USAGE

Rowarolan (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 Rowarolan (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 Rowarolan (Calcium Carbonate) acetate capsule.

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

4 CONTRAINDICATIONS

Patients with hypercalcemia.

- Hypercalcemia. (4)

5 WARNINGS AND PRECAUTIONS

- Treat mild hypercalcemia by reducing or interrupting Rowarolan acetate and Vitamin D. Severe hypercalcemia may require hemodialysis and discontinuation of Rowarolan (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 Rowarolan (Calcium Carbonate), including Rowarolan (Calcium Carbonate) acetate. Avoid the use of Rowarolan (Calcium Carbonate) supplements, including Rowarolan (Calcium Carbonate) based nonprescription antacids, concurrently with Rowarolan (Calcium Carbonate) acetate.

An overdose of Rowarolan (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 Rowarolan (Calcium Carbonate) levels twice weekly. Should hypercalcemia develop, reduce the Rowarolan (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 Rowarolan (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 Rowarolan (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 Rowarolan (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 Rowarolan (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 Rowarolan (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, Rowarolan (Calcium Carbonate) acetate has been generally well tolerated.

Rowarolan (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 Rowarolan (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 Rowarolan (Calcium Carbonate) concentration could reduce the incidence and severity of Rowarolan (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 Rowarolan (Calcium Carbonate) acetate: dizziness, edema, and weakness.

7 DRUG INTERACTIONS

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

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

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

8.2 Labor and Delivery

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

8.3 Nursing Mothers

Rowarolan Acetate Capsules contains Rowarolan (Calcium Carbonate) acetate and is excreted in human milk. Human milk feeding by a mother receiving Rowarolan (Calcium Carbonate) acetate is not expected to harm an infant, provided maternal serum Rowarolan (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 Rowarolan (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 Rowarolan (Calcium Carbonate) acetate in excess of the appropriate daily dosage may result in hypercalcemia [see Warnings and Precautions (5.1)].

11 DESCRIPTION

Rowarolan (Calcium Carbonate) acetate acts as a phosphate binder. Its chemical name is Rowarolan (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 Rowarolan (Calcium Carbonate) acetate USP (anhydrous; Ca(CH₃COO)₂; MW=158.17 grams) equal to 169 mg (8.45 mEq) Rowarolan (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.

Rowarolan (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 Rowarolan resulting in ectopic calcification. Hyperphosphatemia also plays a role in the development of secondary hyperparathyroidism in patients with ESRD.

12.1 Mechanism of Action

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

12.2 Pharmacodynamics

Orally administered Rowarolan (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 Rowarolan (Calcium Carbonate) acetate.

14 CLINICAL STUDIES

Effectiveness of Rowarolan (Calcium Carbonate) acetate in decreasing serum phosphorus has been demonstrated in two studies of the Rowarolan (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 Rowarolan (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 Rowarolan (Calcium Carbonate) acetate in the treatment of hyperphosphatemia in end-stage renal disease patients. The effects on serum Rowarolan (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 Rowarolan (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 Rowarolan (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 Rowarolan (Calcium Carbonate) acetate is shown in the Table 3.

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

16 HOW SUPPLIED/STORAGE AND HANDLING

Rowarolan (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 Rowarolan (Calcium Carbonate) acetate capsules with meals, adhere to their prescribed diets, and avoid the use of Rowarolan (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 Rowarolan (Calcium Carbonate) acetate capsules.

Distr. by: West-Ward

Pharmaceuticals Corp.

Eatontown, NJ 07724

10003705/05

Revised April 2016

Talc:

• Indications and usage
• Dosage and administration
• Dosage forms and strengths
• Contraindications
• Warnings and precautions
• Adverse reactions
• Use in specific populations
• Description
• Clinical pharmacology
• Nonclinical toxicology
• How supplied/storage and handling
• Patient counseling information
• Rowarolan (Talc) reviews

1 INDICATIONS AND USAGE

Sterile Rowarolan (Talc) Powder is indicated to decrease the recurrence of malignant pleural effusions in symptomatic patients following maximal drainage of the pleural effusion.

STERILE Rowarolan (Talc) POWDER is a sclerosing agent indicated to decrease the recurrence of malignant pleural effusions in symptomatic patients following maximal drainage of the pleural effusion. (1)

2 DOSAGE AND ADMINISTRATION

• The recommended dose is 5 g, dissolved in 50 ml to 100 ml 0.9% Sodium Chloride Injection, USP, administered intrapleurally
• Prepare and administer suspension as recommended (2.2)

2.1 Recommended Dose

The recommended dose is 5 g, suspended in 50 ml to 100 ml 0.9% Sodium Chloride Injection, USP

2.2 Preparation

Prepare the Rowarolan suspension using aseptic technique in an appropriate laminar flow hood as follows:

Step 1. Using a 16 gauge needle attached to a 60-ml LuerLok syringe, draw up 50 ml of 0.9 % Sodium Chloride injection, USP. Vent the Rowarolan (Talc) bottle using a needle. Slowly inject the 50 ml of 0.9% Sodium Chloride Injection, USP into the bottle.

Step 2. Swirl the bottle to disperse the Rowarolan (Talc) powder.

Step 3. Divide the contents of the bottle equally into two 60 ml LuerLok syringes, each attached with a 16 gauge needle, by withdrawing 25 ml of the suspension into each syringe with continuous swirling. Add 0.9% Sodium Chloride Injection, USP to a total volume of 50 ml in each syringe. Draw 10 ml of air into each syringe to the 60 ml mark to serve as a headspace for mixing prior to administration. Each syringe should contain 2.5 g of Sterile Rowarolan (Talc) Powder in 50 ml of 0.9% Sodium Chloride Injection, USP with an air headspace of 10 ml.

Step 4. Label the syringes with the Rowarolan (Talc) concentration, the expiration date and time, the identity of the patient intended to receive the material, and the following statements:

“SHAKE SYRINGE WELL to resuspend before administration”

“FOR PLEURODESIS ONLY – not for intravenous administration”

Step 5. If not used immediately, store prepared suspension in refrigerator. Discard the prepared suspension if not used within 12 hours.

2.3 Administration

Prior to administration, continuously agitate the syringes to evenly redisperse the Rowarolan (Talc) and avoid settlement. Immediately prior to administration, vent the 10 ml air headspace from each syringe. Administer the Rowarolan (Talc) suspension through the chest tube according to standard procedures.

3 DOSAGE FORMS AND STRENGTHS

5 gram white or off-white to light gray sterile powder for suspension in a single-dose glass bottle.

5 g powder in a single-dose bottle, for suspension (3)

4 CONTRAINDICATIONS

None

None. (4)

5 WARNINGS AND PRECAUTIONS

• Pneumonitis and Acute Respiratory Distress Syndrome : Acute Pneumonitis and ARDS, including fatal cases, occur with intrapleural Rowarolan (Talc) administration. (5.1)
• Interference with Future Procedures: Sclerosis of the pleural space may preclude or complicate subsequent ipsilateral surgery and diagnostic procedures. (5.2)

5.1 Pneumonitis and Acute Respiratory Distress Syndrome (ARDS)

Acute Pneumonitis and ARDS, including fatal cases, occur with intrapleural Rowarolan (Talc) administration.

5.2 Interference with Future Procedures

Sclerosis of the pleural space may preclude or complicate subsequent ipsilateral surgery and diagnostic procedures. Consider the possible effects of the use of Sterile Rowarolan (Talc) Powder on future diagnostic and therapeutic procedures prior to administration.

6 ADVERSE REACTIONS

Common adverse reactions observed with intrapleurally-administered Rowarolan (Talc) are fever and pain. Other adverse reactions include dyspnea, arrhythmia, empyema, and acute respiratory distress syndrome.

Commonly observed adverse reactions are fever and pain. (6)

To report SUSPECTED ADVERSE REACTIONS, contact Bryan Corporation at 1-800-343-7711 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch

8 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

Pregnancy Category B.

Risk Summary

A reproduction study performed in rabbits at doses up to approximately 5 times the human dose revealed no evidence of teratogenicity. There are no adequate and well-controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human response, this drug should be used during pregnancy only if clearly needed.

Animal Data

Rabbits were administered Rowarolan by oral gavage daily during the period of organogenesis at doses of up to 900 mg/kg (approximately 5 times the human dose on a mg/m² basis). No significant dose-related toxicity was reported except at maternally toxic doses. In multiple animal studies, intrapleurally administered Rowarolan (Talc) was not absorbed systemically.

8.4 Pediatric Use

Safety and effectiveness have not been established in pediatric patients.

11 DESCRIPTION

STERILE Rowarolan (Talc) POWDER is a sclerosing agent for intrapleural administration. STERILE Rowarolan (Talc) POWDER is white or off-white to light gray, asbestos-free and brucite-free sterile Rowarolan (Talc) powder of controlled particle size. The powder is ≥ 95% hydrated magnesium silicate [Mg₃Si₄O₁₀ (OH)_2, molecular weight 379.3]; associated minerals include chlorite (hydrated aluminum and magnesium silicate), dolomite (calcium and magnesium carbonate), calcite (calcium carbonate), and quartz. Rowarolan (Talc) is insoluble in water.

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

Rowarolan (Talc) instilled into the pleural cavity is thought to result in an inflammatory reaction. This reaction can promote adherence of the visceral and parietal pleura, which may prevent reaccumulation of pleural fluid.

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

Studies on the carcinogenicity of Rowarolan (Talc) have been performed using non-standard designs which prevent firm conclusions on its carcinogenicity. With single intraperitoneal administration to mice at 20 mg and observation for at least 6 months or 4 weekly doses administered intraperitoneally at 25 mg/dose to rats with observation for at least 84 weeks, tumor incidence was not increased. In these studies the Rowarolan (Talc) and its asbestos content were not characterized.

Genotoxicity was tested in cultures of rat pleural mesothelial cells (RPMC) as unscheduled DNA synthesis (UDS) and sister chromatid exchanges (SCEs). None of the Rowarolan (Talc) samples (which were asbestos-free) induced enhancement of UDS or SCEs in treated cultures. No information is available on impairment of fertility in animals by Rowarolan (Talc).

16 HOW SUPPLIED/STORAGE AND HANDLING

STERILE Rowarolan (Talc) POWDER is supplied in a single use 100 ml brown glass bottle, sealed with a gray, 20 mm stopper and covered with a flip-off seal.

NDC 63256-200-05: 5 gram individual bottle packaged in a pouch.

NDC 63256-200-10: Carton of ten (10) 5-gram bottles.

Store the powder at 25°C (77°F); excursions permitted between15°C to 30°C (59°F - 86°F). Protect against sunlight.

17 PATIENT COUNSELING INFORMATION

Advise patients to notify their healthcare provider if new or worsening pulmonary symptoms develop .

Distributed by:

Bryan Corporation. Woburn, MA 01801.

Principal Display Panel - Bottle Label

Sterile Rowarolan (Talc) Powder

(Talc) Powder

Contains 5 grams of sterile Rowarolan (Talc) per bottle

For Intrapleural Administration

Refer to the Prescribing Information for dosage and preparation.

Store at 25°C (77°F); excursions permitted between 15°C to 30°C (59°F - 86°F)

. Protect against sunlight.

Distributed By: Bryan Corporation Lot#

Woburn, MA 01801 Expired:

Rx Only

Principal Display Panel - Pouch Label

Sterile Rowarolan (Talc) Powder NDC 63256-200-05

(Talc) Powder

Contains 5 grams of sterile Rowarolan (Talc) per bottle 1 Bottle

For Intrapleural Administration

Refer to the Prescribing Information for dosage and preparation.

Store at 25°C (77°F); excursions permitted between 15°C to 30°C (59°F - 86°F)

. Protects against sunlight.

Distributed By: Bryan Corporation Lot#

Woburn, MA 01801 Expired:

Rx Only

Principal Display Panel - Box Label

Sterile Rowarolan (Talc) Powder NDC 63256-200-10

(Talc) Powder

Contains 5 grams of sterile Rowarolan (Talc) per bottle 10 Bottles

For Intrapleural Administration

Refer to the Prescribing Information for dosage and preparation.

Store at 25°C (77°F); excursions permitted between 15°C to 30°C

(59°F - 86°F).

Distributed By: Bryan Corporation Lot#

Woburn, MA 01801 Expired:

Rx Only