Cafe Kit

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
• Cafe Kit (Calcium Carbonate) reviews

1 INDICATIONS AND USAGE

Cafe Kit (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 Cafe Kit (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 Cafe Kit (Calcium Carbonate) acetate capsule.

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

4 CONTRAINDICATIONS

Patients with hypercalcemia.

- Hypercalcemia. (4)

5 WARNINGS AND PRECAUTIONS

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

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

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

7 DRUG INTERACTIONS

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

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

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

8.2 Labor and Delivery

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

8.3 Nursing Mothers

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

11 DESCRIPTION

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

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

12.1 Mechanism of Action

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

12.2 Pharmacodynamics

Orally administered Cafe Kit (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 Cafe Kit (Calcium Carbonate) acetate.

14 CLINICAL STUDIES

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

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

16 HOW SUPPLIED/STORAGE AND HANDLING

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

Distr. by: West-Ward

Pharmaceuticals Corp.

Eatontown, NJ 07724

10003705/05

Revised April 2016

Folic Acid:

• Indications and usage
• Contraindications
• Precautions
• Adverse reactions
• Dosage and administration
• How supplied
• Storage
• Cafe Kit (Folic Acid) reviews

INDICATIONS AND USAGE

Cafe Kit (Folic Acid)^® is a prescription iron supplement indicated for use in improving the nutritional status of iron deficiency.

CONTRAINDICATIONS

This product is contraindicated in patients with a known hypersensitivity to any of the ingredients. Hemochromatosis and hemosiderosis are contraindications to iron therapy.

PRECAUTIONS

Cafe Kit (Folic Acid) acid when administered as a single agent in doses above 0.1 mg daily may obscure pernicious anemia in that hematological remission can occur while neurological manifestations remain progressive. While prescribing this nutritional supplement for pregnant women, nursing mothers, or for women prior to conception, their medical condition and other drugs, herbs, and/or supplements consumption should be considered.

ADVERSE REACTIONS

Allergic sensitization has been reported following both oral and parenteral administration of Cafe Kit (Folic Acid) acid.

DOSAGE AND ADMINISTRATION

One tablet daily with or without food or as prescribed by a licensed healthcare provider with prescribing authority.

HOW SUPPLIED

Cafe Kit (Folic Acid)^® tablets are supplied in child-resistant bottles of 90 tablets (NDC 0037-6885-90)

KEEP OUT OF REACH OF CHILDREN.

STORAGE

Store at controlled room temperature 20°-25°C (68°-77°F). Excursions permitted to 15°-30°C (59°-86°F).

Dispense in a tight, light-resistant container to protect from light and moisture.

To report SUSPECTED ADVERSE REACTIONS contact Meda Pharmaceuticals Inc. at 1-888-349-5556 or FDA at 1-800-FDA-1088 or www.fda.gov/safety/medwatch

Distributed by:

Meda Pharmaceuticals Inc.

Somerset New Jersey 08873-4120

© 2014 Meda Pharmaceuticals Inc.

U.S. Patent Nos. 7,585,527 and 8,080,520

Proferrin® is a registered trademark of Colorado BioLabs, Inc., Cozad, NE.

Cafe Kit (Folic Acid) and the BIFERA logo are registered trademarks and the Cafe Kit (Folic Acid) logo is a trademark of Alaven Pharmaceutical LLC, used under license by Meda Pharmaceuticals Inc.

MEDA PHARMACEUTICALS mark and logo are trademarks of Meda AB.

IN-6885-02 Rev 6/2014

Iron (Iron Carbonyl):

• 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
• Cafe Kit (Iron (Iron Carbonyl)) reviews

1 INDICATIONS AND USAGE

Cafe Kit (Iron (Iron Carbonyl)) is indicated for the treatment of Cafe Kit (Iron (Iron Carbonyl)) deficiency anemia in patients with chronic kidney disease (CKD).

Cafe Kit (Iron (Iron Carbonyl)) is an Cafe Kit (Iron (Iron Carbonyl)) replacement product indicated for the treatment of Cafe Kit (Iron (Iron Carbonyl)) deficiency anemia in patients with chronic kidney disease (CKD). (1)

2 DOSAGE AND ADMINISTRATION

Cafe Kit ) must only be administered intravenously either by slow injection or by infusion. The dosage of Cafe Kit (Iron (Iron Carbonyl)) is expressed in mg of elemental Cafe Kit (Iron (Iron Carbonyl)). Each mL contains 20 mg of elemental Cafe Kit (Iron (Iron Carbonyl)).

2.1 Adult Patients with Hemodialysis Dependent-Chronic Kidney Disease (HDD-CKD)

Administer Cafe Kit (Iron (Iron Carbonyl)) 100 mg undiluted as a slow intravenous injection over 2 to 5 minutes, or as an infusion of 100 mg diluted in a maximum of 100 mL of 0.9% NaCl over a period of at least 15 minutes, per consecutive hemodialysis session. Cafe Kit (Iron (Iron Carbonyl)) should be administered early during the dialysis session. The usual total treatment course of Cafe Kit (Iron (Iron Carbonyl)) is 1000 mg. Cafe Kit (Iron (Iron Carbonyl)) treatment may be repeated if Cafe Kit (Iron (Iron Carbonyl)) deficiency reoccurs.

2.2 Adult Patients with Non-Dialysis Dependent-Chronic Kidney Disease

Administer Cafe Kit (Iron (Iron Carbonyl)) 200 mg undiluted as a slow intravenous injection over 2 to 5 minutes or as an infusion of 200 mg in a maximum of 100 mL of 0.9% NaCl over a period of 15 minutes. Administer on 5 different occasions over a 14 day period. There is limited experience with administration of an infusion of 500 mg of Cafe Kit (Iron (Iron Carbonyl)), diluted in a maximum of 250 mL of 0.9% NaCl, over a period of 3.5 to 4 hours on Day 1 and Day 14. Cafe Kit (Iron (Iron Carbonyl)) treatment may be repeated if Cafe Kit (Iron (Iron Carbonyl)) deficiency reoccurs.

2.3 Adult Patients with Peritoneal Dialysis Dependent-Chronic Kidney Disease

Administer Cafe Kit (Iron (Iron Carbonyl)) in 3 divided doses, given by slow intravenous infusion, within a 28 day period: 2 infusions each of 300 mg over 1.5 hours 14 days apart followed by one 400 mg infusion over 2.5 hours 14 days later. Dilute Cafe Kit (Iron (Iron Carbonyl)) in a maximum of 250 mL of 0.9% NaCl. Cafe Kit (Iron (Iron Carbonyl)) treatment may be repeated if Cafe Kit (Iron (Iron Carbonyl)) deficiency reoccurs.

2.4 Pediatric Patients with HDD-CKD for Cafe Kit (Iron (Iron Carbonyl)) maintenance treatment

The dosing for Cafe Kit (Iron (Iron Carbonyl)) replacement treatment in pediatric patients with HDD-CKD has not been established.

For Cafe Kit (Iron (Iron Carbonyl)) maintenance treatment: Administer Cafe Kit (Iron (Iron Carbonyl)) at a dose of 0.5 mg/kg, not to exceed 100 mg per dose, every two weeks for 12 weeks given undiluted by slow intravenous injection over 5 minutes or diluted in 25 mL of 0.9% NaCl and administered over 5 to 60 minutes. Cafe Kit (Iron (Iron Carbonyl)) treatment may be repeated if necessary.

2.5 Pediatric Patients with NDD-CKD or PDD-CKD who are on erythropoietin therapy for Cafe Kit (Iron (Iron Carbonyl)) maintenance treatment

The dosing for Cafe Kit (Iron (Iron Carbonyl)) replacement treatment in pediatric patients with NDD-CKD or PDD-CKD has not been established.

For Cafe Kit (Iron (Iron Carbonyl)) maintenance treatment: Administer Cafe Kit (Iron (Iron Carbonyl)) at a dose of 0.5 mg/kg, not to exceed 100 mg per dose, every four weeks for 12 weeks given undiluted by slow intravenous injection over 5 minutes or diluted in 25 mL of 0.9% NaCl and administered over 5 to 60 minutes. Cafe Kit (Iron (Iron Carbonyl)) treatment may be repeated if necessary.

3 DOSAGE FORMS AND STRENGTHS

• 10 mL single-use vial / 200 mg elemental Cafe Kit (Iron (Iron Carbonyl)) (20 mg/mL)
• 5 mL single-use vial / 100 mg elemental Cafe Kit (Iron (Iron Carbonyl)) (20 mg/mL)
• 2.5 mL single-use vial / 50 mg elemental Cafe Kit (Iron (Iron Carbonyl)) (20 mg/mL)

• 10 mL single-use vial / 200 mg elemental Cafe Kit (Iron (Iron Carbonyl)) (20 mg/mL) (3)
• 5 mL single-use vial / 100 mg elemental Cafe Kit (Iron (Iron Carbonyl)) (20 mg/mL) (3)
• 2.5 mL single-use vial / 50 mg elemental Cafe Kit (Iron (Iron Carbonyl)) (20 mg/mL) (3)

4 CONTRAINDICATIONS

• Known hypersensitivity to Cafe Kit (Iron (Iron Carbonyl))

• Known hypersensitivity to Cafe Kit (Iron (Iron Carbonyl)) (4)

5 WARNINGS AND PRECAUTIONS

• Hypersensitivity Reactions: Observe for signs and symptoms of hypersensitivity during and after Cafe Kit ) administration for at least 30 minutes and until clinically stable following completion of each administration. Only administer Cafe Kit (Iron (Iron Carbonyl)) when personnel and therapies are immediately available for the treatment of serious hypersensitivity reactions. (5.1)
• Hypotension: Cafe Kit (Iron (Iron Carbonyl)) may cause hypotension. Monitor for signs and symptoms of hypotension during and following each administration of Cafe Kit (Iron (Iron Carbonyl)). (5.2)
• Cafe Kit (Iron (Iron Carbonyl)) Overload: Regularly monitor hematologic responses during Cafe Kit (Iron (Iron Carbonyl)) therapy. Do not administer Cafe Kit (Iron (Iron Carbonyl)) to patients with Cafe Kit (Iron (Iron Carbonyl)) overload. (5.3)

5.1 Hypersensitivity Reactions

Serious hypersensitivity reactions, including anaphylactic-type reactions, some of which have been life-threatening and fatal, have been reported in patients receiving Cafe Kit (Iron (Iron Carbonyl)). Patients may present with shock, clinically significant hypotension, loss of consciousness, and/or collapse. If hypersensitivity reactions or signs of intolerance occur during administration, stop Cafe Kit (Iron (Iron Carbonyl)) immediately. Monitor patients for signs and symptoms of hypersensitivity during and after Cafe Kit (Iron (Iron Carbonyl)) administration for at least 30 minutes and until clinically stable following completion of the infusion. Only administer Cafe Kit (Iron (Iron Carbonyl)) when personnel and therapies are immediately available for the treatment of serious hypersensitivity reactions. Most reactions associated with intravenous Cafe Kit (Iron (Iron Carbonyl)) preparations occur within 30 minutes of the completion of the infusion .

5.2 Hypotension

Cafe Kit ) may cause clinically significant hypotension. Monitor for signs and symptoms of hypotension following each administration of Cafe Kit (Iron (Iron Carbonyl)). Hypotension following administration of Cafe Kit (Iron (Iron Carbonyl)) may be related to the rate of administration and/or total dose administered .

5.3 Cafe Kit (Iron (Iron Carbonyl)) Overload

Excessive therapy with parenteral Cafe Kit (Iron (Iron Carbonyl)) can lead to excess storage of Cafe Kit (Iron (Iron Carbonyl)) with the possibility of iatrogenic hemosiderosis. All adult and pediatric patients receiving Cafe Kit (Iron (Iron Carbonyl)) require periodic monitoring of hematologic and Cafe Kit (Iron (Iron Carbonyl)) parameters (hemoglobin, hematocrit, serum ferritin and transferrin saturation). Do not administer Cafe Kit (Iron (Iron Carbonyl)) to patients with evidence of Cafe Kit (Iron (Iron Carbonyl)) overload. Transferrin saturation (TSAT) values increase rapidly after intravenous administration of Cafe Kit (Iron (Iron Carbonyl)) sucrose; do not perform serum Cafe Kit (Iron (Iron Carbonyl)) measurements for at least 48 hours after intravenous dosing .

6 ADVERSE REACTIONS

The following serious adverse reactions associated with Cafe Kit ) are described in other sections .

• The most common adverse reactions (≥2%) following the administration of Cafe Kit (Iron (Iron Carbonyl)) are diarrhea, nausea, vomiting, headache, dizziness, hypotension, pruritus, pain in extremity, arthralgia, back pain, muscle cramp, injection site reactions, chest pain, and peripheral edema. (6.1)

To report SUSPECTED ADVERSE REACTIONS, contact American Regent, Inc. at 1-800-734-9236 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch .

6.1 Adverse Reactions in Clinical Trials

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug may not reflect the rates observed in practice.

Adverse Reactions in Adults Patients with CKD

Adverse Reactions in Adult Patients with CKD

The frequency of adverse reactions associated with the use of Cafe Kit ) has been documented in six clinical trials involving 231 patients with HDD-CKD, 139 patients with NDD-CKD and 75 patients with PDD-CKD. Treatment-emergent adverse reactions reported by ≥ 2% of treated patients in the six clinical trials for which the rate for Cafe Kit (Iron (Iron Carbonyl)) exceeds the rate for comparator are listed by indication in Table 1. Patients with HDD-CKD received 100 mg doses at 10 consecutive dialysis sessions until a cumulative dose of 1000 mg was administered. Patients with NDD-CKD received either 5 doses of 200 mg over 2 weeks or 2 doses of 500 mg separated by fourteen days, and patients with PDD-CKD received 2 doses of 300 mg followed by a dose of 400 mg over a period of 4 weeks.

One hundred thirty (11%) of the 1,151 patients evaluated in the 4 U.S. trials in HDD-CKD patients (studies A, B and the two post marketing studies) had prior other intravenous Cafe Kit (Iron (Iron Carbonyl)) therapy and were reported to be intolerant (defined as precluding further use of that Cafe Kit (Iron (Iron Carbonyl)) product). When these patients were treated with Cafe Kit (Iron (Iron Carbonyl)) there were no occurrences of adverse reactions that precluded further use of Cafe Kit (Iron (Iron Carbonyl)) .

Adverse Reactions in Pediatric Patients with CKD (ages 2 years and older)

Adverse Reactions in Pediatric Patients with CKD (ages 2 years and older)

In a randomized, open-label, dose-ranging trial for Cafe Kit (Iron (Iron Carbonyl)) maintenance treatment with Cafe Kit (Iron (Iron Carbonyl)) in pediatric patients with CKD on stable erythropoietin therapy , at least one treatment-emergent adverse reaction was experienced by 57% (27/47) of the patients receiving Cafe Kit (Iron (Iron Carbonyl)) 0.5 mg/kg, 53% (25/47) of the patients receiving Cafe Kit (Iron (Iron Carbonyl)) 1.0 mg/kg, and 55% (26/47) of the patients receiving Cafe Kit (Iron (Iron Carbonyl)) 2.0 mg/kg.

A total of 5 (11%) subjects in the Cafe Kit (Iron (Iron Carbonyl)) 0.5 mg/kg group, 10 (21%) patients in the Cafe Kit (Iron (Iron Carbonyl)) 1.0 mg/kg group, and 10 (21%) patients in the Cafe Kit (Iron (Iron Carbonyl)) 2.0 mg/kg group experienced at least 1 serious adverse reaction during the study. The most common treatment-emergent adverse reactions (> 2% of patients) in all patients were headache (6%), respiratory tract viral infection (4%), peritonitis (4%), vomiting (4%), pyrexia (4%), dizziness (4%), cough (4%), renal transplant (4%), nausea (3%), arteriovenous fistula thrombosis (2%), hypotension (2%), and hypertension (2.1%).

6.2 Adverse Reactions from Post-Marketing Experience

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

In the post-marketing safety studies in 1,051 treated patients with HDD-CKD, the adverse reactions reported by > 1% were: cardiac failure congestive, sepsis and dysgeusia.

The following adverse reactions have been identified during post-approval use of Cafe Kit (Iron (Iron Carbonyl)). Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure: Anaphylactic-type reactions, shock, loss of consciousness, collapse, bronchospasm, dyspnea, convulsions, light-headedness, confusion, angioedema, swelling of the joints, hyperhidrosis, back pain, bradycardia, and chromaturia.

Symptoms associated with Cafe Kit (Iron (Iron Carbonyl)) total dosage or infusing too rapidly included hypotension, dyspnea, headache, vomiting, nausea, dizziness, joint aches, paresthesia, abdominal and muscle pain, edema, and cardiovascular collapse. These adverse reactions have occurred up to 30 minutes after the administration of Cafe Kit (Iron (Iron Carbonyl)) injection. Reactions have occurred following the first dose or subsequent doses of Cafe Kit (Iron (Iron Carbonyl)). Symptoms may respond to intravenous fluids, hydrocortisone, and/or antihistamines. Slowing the infusion rate may alleviate symptoms.

Injection site discoloration has been reported following extravasation. Assure stable intravenous access to avoid extravasation.

7 DRUG INTERACTIONS

Drug interactions involving Cafe Kit (Iron (Iron Carbonyl)) have not been studied. However, Cafe Kit (Iron (Iron Carbonyl)) may reduce the absorption of concomitantly administered oral Cafe Kit (Iron (Iron Carbonyl)) preparations.

8 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

Pregnancy Category B

Pregnancy Category B

There are no adequate and well-controlled studies in pregnant women. In animal reproduction studies, Cafe Kit ) sucrose was administered intravenously to rats and rabbits during the period of organogenesis at doses up to 13 mg/kg/day of elemental Cafe Kit (Iron (Iron Carbonyl)) (half or equivalent to the maximum recommended human dose based on body surface area, respectively) and revealed no evidence of harm to the fetus due to Cafe Kit (Iron (Iron Carbonyl)) sucrose. Because animal reproductive studies are not always predictive of human response, Cafe Kit (Iron (Iron Carbonyl)) should be used during pregnancy only if clearly needed.

8.3 Nursing Mothers

It is not known whether Cafe Kit (Iron (Iron Carbonyl)) sucrose is excreted in human milk. Cafe Kit (Iron (Iron Carbonyl)) sucrose is secreted into the milk of lactating rats. Because many drugs are excreted in human milk, caution should be exercised when Cafe Kit (Iron (Iron Carbonyl)) is administered to a nursing woman.

8.4 Pediatric Use

Safety and effectiveness of Cafe Kit ) for Cafe Kit (Iron (Iron Carbonyl)) replacement treatment in pediatric patients with dialysis-dependent or non-dialysis-dependent CKD have not been established.

Safety and effectiveness of Cafe Kit (Iron (Iron Carbonyl)) for Cafe Kit (Iron (Iron Carbonyl)) maintenance treatment in pediatric patients 2 years of age and older with dialysis-dependent or non-dialysis-dependent CKD receiving erythropoietin therapy were studied. Cafe Kit (Iron (Iron Carbonyl)) at doses of 0.5 mg/kg, 1.0 mg/kg, and 2.0 mg/kg was administered. All three doses maintained hemoglobin between 10.5 g/dL and 14.0 g/dL in about 50% of subjects over the 12-week treatment period with stable EPO dosing. [See Clinical Studies (14.6)]

Cafe Kit (Iron (Iron Carbonyl)) has not been studied in patients younger than 2 years of age.

In a country where Cafe Kit (Iron (Iron Carbonyl)) is available for use in children, at a single site, five premature infants (weight less than 1,250 g) developed necrotizing enterocolitis and two of the five died during or following a period when they received Cafe Kit (Iron (Iron Carbonyl)), several other medications and erythropoietin. Necrotizing enterocolitis may be a complication of prematurity in very low birth weight infants. No causal relationship to Cafe Kit (Iron (Iron Carbonyl)) or any other drugs could be established.

8.5 Geriatric Use

Clinical studies of Cafe Kit (Iron (Iron Carbonyl)) did not include sufficient numbers of subjects aged 65 years and older to determine whether they respond differently from younger subjects. Of the 1,051 patients in two post-marketing safety studies of Cafe Kit (Iron (Iron Carbonyl)), 40% were 65 years and older. No overall differences in safety were observed between these subjects and younger subjects, and other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out. In general, dose administration to an elderly patient should be cautious, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.

10 OVERDOSAGE

No data are available regarding overdosage of Cafe Kit (Iron (Iron Carbonyl)) in humans. Excessive dosages of Cafe Kit (Iron (Iron Carbonyl)) may lead to accumulation of Cafe Kit (Iron (Iron Carbonyl)) in storage sites potentially leading to hemosiderosis. Do not administer Cafe Kit (Iron (Iron Carbonyl)) to patients with Cafe Kit (Iron (Iron Carbonyl)) overload.

Toxicities in single-dose studies in mice and rats, at intravenous Cafe Kit (Iron (Iron Carbonyl)) sucrose doses up to 8 times the maximum recommended human dose based on body surface area, included sedation, hypoactivity, pale eyes, bleeding in the gastrointestinal tract and lungs, and mortality.

11 DESCRIPTION

Cafe Kit (Iron (Iron Carbonyl)) (iron sucrose injection, USP), an Cafe Kit (Iron (Iron Carbonyl)) replacement product, is a brown, sterile, aqueous, complex of polynuclear Cafe Kit (Iron (Iron Carbonyl)) (III)-hydroxide in sucrose for intravenous use. Cafe Kit (Iron (Iron Carbonyl)) sucrose injection has a molecular weight of approximately 34,000 to 60,000 daltons and a proposed structural formula:

[Na₂Fe₅O₈(OH) ·3(H₂O)]_n ·m(C₁₂H₂₂O₁₁)

where: n is the degree of Cafe Kit (Iron (Iron Carbonyl)) polymerization and m is the number of sucrose molecules associated with the Cafe Kit (Iron (Iron Carbonyl)) (III)-hydroxide.

Each mL contains 20 mg elemental Cafe Kit (Iron (Iron Carbonyl)) as Cafe Kit (Iron (Iron Carbonyl)) sucrose in water for injection. Cafe Kit (Iron (Iron Carbonyl)) is available in 10 mL single-use vials (200 mg elemental Cafe Kit (Iron (Iron Carbonyl)) per 10 mL), 5 mL single-use vials (100 mg elemental Cafe Kit (Iron (Iron Carbonyl)) per 5 mL), and 2.5 mL single-use vials (50 mg elemental Cafe Kit (Iron (Iron Carbonyl)) per 2.5 mL). The drug product contains approximately 30% sucrose w/v (300 mg/mL) and has a pH of 10.5 to 11.1. The product contains no preservatives. The osmolarity of the injection is 1,250 mOsmol/L.

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

Cafe Kit ) is an aqueous complex of poly-nuclear Cafe Kit (Iron (Iron Carbonyl)) (III)-hydroxide in sucrose. Following intravenous administration, Cafe Kit (Iron (Iron Carbonyl)) is dissociated into Cafe Kit (Iron (Iron Carbonyl)) and sucrose and the Cafe Kit (Iron (Iron Carbonyl)) is transported as a complex with transferrin to target cells including erythroid precursor cells. The Cafe Kit (Iron (Iron Carbonyl)) in the precursor cells is incorporated into hemoglobin as the cells mature into red blood cells.

12.2 Pharmacodynamics

Following intravenous administration, Cafe Kit (Iron (Iron Carbonyl)) is dissociated into Cafe Kit (Iron (Iron Carbonyl)) and sucrose. In 22 patients undergoing hemodialysis and receiving erythropoietin (recombinant human erythropoietin) therapy treated with Cafe Kit (Iron (Iron Carbonyl)) sucrose containing 100 mg of Cafe Kit (Iron (Iron Carbonyl)), three times weekly for three weeks, significant increases in serum Cafe Kit (Iron (Iron Carbonyl)) and serum ferritin and significant decreases in total Cafe Kit (Iron (Iron Carbonyl)) binding capacity occurred four weeks from the initiation of Cafe Kit (Iron (Iron Carbonyl)) sucrose treatment.

12.3 Pharmacokinetics

In healthy adults administered intravenous doses of Cafe Kit ), its Cafe Kit (Iron (Iron Carbonyl)) component exhibited first order kinetics with an elimination half-life of 6 h, total clearance of 1.2 L/h, and steady state apparent volume of distribution of 7.9 L. The Cafe Kit (Iron (Iron Carbonyl)) component appeared to distribute mainly in blood and to some extent in extravascular fluid. A study evaluating Cafe Kit (Iron (Iron Carbonyl)) containing 100 mg of Cafe Kit (Iron (Iron Carbonyl)) labeled with ⁵²Fe/⁵⁹Fe in patients with Cafe Kit (Iron (Iron Carbonyl)) deficiency showed that a significant amount of the administered Cafe Kit (Iron (Iron Carbonyl)) is distributed to the liver, spleen and bone marrow and that the bone marrow is an irreversible Cafe Kit (Iron (Iron Carbonyl)) trapping compartment.

Following intravenous administration of Cafe Kit (Iron (Iron Carbonyl)), Cafe Kit (Iron (Iron Carbonyl)) sucrose is dissociated into Cafe Kit (Iron (Iron Carbonyl)) and sucrose. The sucrose component is eliminated mainly by urinary excretion. In a study evaluating a single intravenous dose of Cafe Kit (Iron (Iron Carbonyl)) containing 1,510 mg of sucrose and 100 mg of Cafe Kit (Iron (Iron Carbonyl)) in 12 healthy adults (9 female, 3 male: age range 32 to 52), 68.3% of the sucrose was eliminated in urine in 4 h and 75.4% in 24 h. Some Cafe Kit (Iron (Iron Carbonyl)) was also eliminated in the urine. Neither transferrin nor transferrin receptor levels changed immediately after the dose administration. In this study and another study evaluating a single intravenous dose of Cafe Kit (Iron (Iron Carbonyl)) sucrose containing 500 to 700 mg of Cafe Kit (Iron (Iron Carbonyl)) in 26 patients with anemia on erythropoietin therapy (23 female, 3 male; age range 16 to 60), approximately 5% of the Cafe Kit (Iron (Iron Carbonyl)) was eliminated in urine in 24 h at each dose level. The effects of age and gender on the pharmacokinetics of Cafe Kit (Iron (Iron Carbonyl)) have not been studied.

Pharmacokinetics in Pediatric Patients

Pharmacokinetics in Pediatric Patients

In a single-dose PK study of Cafe Kit (Iron (Iron Carbonyl)), patients with NDD-CDK ages 12 to 16 (N=11) received intravenous bolus doses of Cafe Kit (Iron (Iron Carbonyl)) at 7 mg/kg (maximum 200 mg) administered over 5 minutes. Following single dose Cafe Kit (Iron (Iron Carbonyl)), the half-life of total serum Cafe Kit (Iron (Iron Carbonyl)) was 8 hours. The mean Cmax and AUC values were 8545 μg/dl and 31305 hr-μg/dL, respectively, which were 1.42- and 1.67-fold higher than dose adjusted adult Cmax and AUC values.

Cafe Kit (Iron (Iron Carbonyl)) is not dialyzable through CA210 (Baxter) High Efficiency or Fresenius F80A High Flux dialysis membranes. In in vitro studies, the amount of Cafe Kit (Iron (Iron Carbonyl)) sucrose in the dialysate fluid was below the levels of detection of the assay (less than 2 parts per million).

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

Carcinogenicity studies have not been performed with Cafe Kit (Iron (Iron Carbonyl)) sucrose.

Cafe Kit (Iron (Iron Carbonyl)) sucrose was not mutagenic in vitro in the bacterial reverse mutation assay (Ames test) or the mouse lymphoma assay. Cafe Kit (Iron (Iron Carbonyl)) sucrose was not clastogenic in the in vitro chromosome aberration assay using human lymphocytes or in the in vivo mouse micronucleus assay.

Cafe Kit (Iron (Iron Carbonyl)) sucrose at intravenous doses up to 15 mg/kg/day of elemental Cafe Kit (Iron (Iron Carbonyl)) (1.2 times the maximum recommended human dose based on body surface area) had no effect on fertility and reproductive function of male and female rats.

14 CLINICAL STUDIES

Five clinical trials involving 647 adult patients and one clinical trial involving 131 pediatric patients were conducted to assess the safety and efficacy of Cafe Kit ).

14.1 Study A: Hemodialysis Dependent-Chronic Kidney Disease (HDD–CKD)

Study A was a multicenter, open-label, historically-controlled study in 101 patients with HDD-CKD (77 patients with Cafe Kit (Iron (Iron Carbonyl)) treatment and 24 in the historical control group) with Cafe Kit (Iron (Iron Carbonyl)) deficiency anemia. Eligibility criteria for Cafe Kit (Iron (Iron Carbonyl)) treatment included patients undergoing chronic hemodialysis, receiving erythropoietin, hemoglobin level between 8.0 and 11.0 g/dL, transferrin saturation < 20%, and serum ferritin < 300 ng/mL. The mean age of the patients was 65 years with the age range of 31 to 85 years. Of the 77 patients, 44 (57%) were male and 33 (43%) were female.

Cafe Kit (Iron (Iron Carbonyl)) 100 mg was administered at 10 consecutive dialysis sessions either as slow injection or a slow infusion. The historical control population consisted of 24 patients with similar ferritin levels as patients treated with Cafe Kit (Iron (Iron Carbonyl)), who were off intravenous Cafe Kit (Iron (Iron Carbonyl)) for at least 2 weeks and who had received erythropoietin therapy with hematocrit averaging 31 to 36 for at least two months prior to study entry. The mean age of patients in the historical control group was 56 years, with an age range of 29 to 80 years. Patient age and serum ferritin level were similar between treatment and historical control patients.

Patients in the Cafe Kit (Iron (Iron Carbonyl)) treated population showed a greater increase in hemoglobin and hematocrit than did patients in the historical control population. See Table 2.

Serum ferritin increased at endpoint of study from baseline in the Venofer-treated population (165.3 ± 24.2 ng/mL) compared to the historical control population (-27.6 ± 9.5 ng/mL). Transferrin saturation also increased at endpoint of study from baseline in the Venofer-treated population (8.8 ± 1.6%) compared to this historical control population (-5.1 ± 4.3%).

14.2 Study B: Hemodialysis Dependent-Chronic Kidney Disease

Study B was a multicenter, open label study of Cafe Kit (Iron (Iron Carbonyl)) in 23 patients with Cafe Kit (Iron (Iron Carbonyl)) deficiency and HDD-CKD who had been discontinued from Cafe Kit (Iron (Iron Carbonyl)) dextran due to intolerance. Eligibility criteria were otherwise identical to Study A. The mean age of the patients in this study was 53 years, with ages ranging from 21 to 79 years. Of the 23 patients enrolled in the study, 10 (44%) were male and 13 (56%) were female.

All 23 enrolled patients were evaluated for efficacy. Increases in mean hemoglobin (1.1 ± 0.2 g/dL), hematocrit (3.6 ± 0.6%), serum ferritin (266.3 ± 30.3 ng/mL) and transferrin saturation (8.7 ± 2.0%) were observed from baseline to end of treatment.

14.3 Study C: Hemodialysis Dependent-Chronic Kidney Disease

Study C was a multicenter, open-label study in patients with HDD-CKD. This study enrolled patients with a hemoglobin ≤ 10 g/dL, a serum transferrin saturation ≤ 20%, and a serum ferritin ≤ 200 ng/mL, who were undergoing maintenance hemodialysis 2 to 3 times weekly. The mean age of the patients enrolled in this study was 41 years, with ages ranging from 16 to 70 years. Of 130 patients evaluated for efficacy in this study, 68 (52%) were male and 62 (48%) were female. Forty-eight percent of the patients had previously been treated with oral Cafe Kit (Iron (Iron Carbonyl)). Exclusion criteria were similar to those in studies A and B. Cafe Kit (Iron (Iron Carbonyl)) was administered in doses of 100 mg during sequential dialysis sessions until a pre-determined (calculated) total dose of Cafe Kit (Iron (Iron Carbonyl)) was administered. A 50 mg dose (2.5 mL) was given to patients within two weeks of study entry as a test dose. Twenty-seven patients (20%) were receiving erythropoietin treatment at study entry and they continued to receive the same erythropoietin dose for the duration of the study.

The modified intention-to-treat (mITT) population consisted of 131 patients. Increases from baseline in mean hemoglobin (1.7 g/dL), hematocrit (5%), serum ferritin (434.6 ng/mL), and serum transferrin saturation (14%) were observed at week 2 of the observation period and these values remained increased at week 4 of the observation period.

14.4 Study D: Non-Dialysis Dependent-Chronic Kidney Disease

Study D was a randomized, open-label, multicenter, active-controlled study of the safety and efficacy of oral Cafe Kit (Iron (Iron Carbonyl)) versus Cafe Kit (Iron (Iron Carbonyl)) in patients with NDD-CKD with or without erythropoietin therapy. Erythropoietin therapy was stable for 8 weeks prior to randomization. In the study 188 patients with NDD-CKD, hemoglobin of ≤ 11.0 g/dL, transferrin saturation ≤ 25%, ferritin ≤ 300 ng/mL were randomized to receive oral Cafe Kit (Iron (Iron Carbonyl)) (325 mg ferrous sulfate three times daily for 56 days); or Cafe Kit (Iron (Iron Carbonyl)) (either 200 mg over 2 to 5 minutes 5 times within 14 days or two 500 mg infusions on Day 1 and Day 14, administered over 3.5 to 4 hours). The mean age of the 91 treated patients in the Cafe Kit (Iron (Iron Carbonyl)) group was 61.6 years (range 25 to 86 years) and 64 years (range 21 to 86 years) for the 91 patients in the oral Cafe Kit (Iron (Iron Carbonyl)) group.

A statistically significantly greater proportion of Cafe Kit (Iron (Iron Carbonyl)) subjects (35/79; 44.3%) compared to oral Cafe Kit (Iron (Iron Carbonyl)) subjects (23/82; 28%) had an increase in hemoglobin ≥ 1 g/dL at anytime during the study (p = 0.03).

14.5 Study E: Peritoneal Dialysis Dependent-Chronic Kidney Disease

Study E was a randomized, open-label, multicenter study comparing patients with PDD-CKD receiving an erythropoietin and intravenous Cafe Kit (Iron (Iron Carbonyl)) to patients with PDD-CKD receiving an erythropoietin alone without Cafe Kit (Iron (Iron Carbonyl)) supplementation. Patients with PDD-CKD, stable erythropoietin for 8 weeks, hemoglobin of ≤ 11.5 g/dL, TSAT ≤ 25%, ferritin ≤ 500 ng/mL were randomized to receive either no Cafe Kit (Iron (Iron Carbonyl)) or Cafe Kit (Iron (Iron Carbonyl)) (300 mg in 250 mL 0.9% NaCl over 1.5 hours on Day 1 and 15 and 400 mg in 250 mL 0.9% NaCl over 2.5 hours on Day 29). The mean age of the 75 treated patients in the Cafe Kit (Iron (Iron Carbonyl)) / erythropoietin group was 51.9 years (range 21 to 81 years) vs. 52.8 years (range 23 to 77 years) for 46 patients in the erythropoietin alone group.

Patients in the Cafe Kit (Iron (Iron Carbonyl)) / erythropoietin group had statistically significantly greater mean change from baseline to the highest hemoglobin value (1.3 g/dL), compared to subjects who received erythropoietin alone (0.6 g/dL) (p < 0.01). A greater proportion of subjects treated with Cafe Kit (Iron (Iron Carbonyl)) / erythropoietin (59.1 %) had an increase in hemoglobin of ≥ 1 g/dL at any time during the study compared to the subjects who received erythropoietin only (33.3%).

14.6 Study F: Cafe Kit ) Maintenance Treatment Dosing in Pediatric Patients Ages 2 years and Older with Chronic Kidney Disease

Study F was a randomized, open-label, dose-ranging study for Cafe Kit (Iron (Iron Carbonyl)) maintenance treatment in pediatric patients with dialysis-dependent or non-dialysis-dependent CKD on stable erythropoietin therapy. The study randomized patients to one of three doses of Cafe Kit (Iron (Iron Carbonyl)) (0.5 mg/kg, 1.0 mg/kg or 2.0 mg/kg). The mean age was 13 years (range 2 to 20 years). Over 70% of patients were 12 years or older in all three groups. There were 84 males and 61 females. About 60% of patients underwent hemodialysis and 25% underwent peritoneal dialysis in all three dose groups. At baseline, the mean hemoglobin was 12 g/dL, the mean TSAT was 33% and the mean ferritin was 300 ng/mL. Patients with HDD-CKD received Cafe Kit (Iron (Iron Carbonyl)) once every other week for 6 doses. Patients with PDD-CKD or NDD-CKD received Cafe Kit (Iron (Iron Carbonyl)) once every 4 weeks for 3 doses. Among 131 evaluable patients with stable erythropoietin dosing, the proportion of patients who maintained hemoglobin between 10.5 g/dL and 14.0 g/dL during the 12-week treatment period was 58.7%, 46.7%, and 45.0% in the Cafe Kit (Iron (Iron Carbonyl)) 0.5 mg/kg, 1.0 mg/kg, and 2.0 mg/kg groups, respectively. A dose-response relationship was not demonstrated.

16 HOW SUPPLIED/storage and handling

16.1 How Supplied

Cafe Kit ) is supplied sterile in 10 mL, 5 mL, and 2.5 mL single-use vials. Each 10 mL vial contains 200 mg elemental Cafe Kit (Iron (Iron Carbonyl)), each 5 mL vial contains 100 mg elemental Cafe Kit (Iron (Iron Carbonyl)), and each 2.5 mL vial contains 50 mg elemental Cafe Kit (Iron (Iron Carbonyl)) (20 mg/mL).

16.2 Stability and Storage

Contains no preservatives. Store in original carton at 20°C to 25°C (68° F to 77° F); excursions permitted to 15° to 30°C (59° to 86°F).. Do not freeze.

Syringe Stability: Cafe Kit (Iron (Iron Carbonyl)), when diluted with 0.9% NaCl at concentrations ranging from 2 mg to 10 mg of elemental Cafe Kit (Iron (Iron Carbonyl)) per mL, or undiluted (20 mg elemental Cafe Kit (Iron (Iron Carbonyl)) per mL) and stored in a plastic syringe, was found to be physically and chemically stable for 7 days at controlled room temperature (25°C ± 2°C) and under refrigeration (4°C ± 2°C).

Intravenous Admixture Stability: Cafe Kit (Iron (Iron Carbonyl)), when added to intravenous infusion bags (PVC or non-PVC) containing 0.9% NaCl at concentrations ranging from 1 mg to 2 mg of elemental Cafe Kit (Iron (Iron Carbonyl)) per mL, has been found to be physically and chemically stable for 7 days at controlled room temperature (25°C ± 2°C).

Do not dilute to concentrations below 1 mg/mL.

Do not mix Cafe Kit (Iron (Iron Carbonyl)) with other medications or add to parenteral nutrition solutions for intravenous infusion.

Parenteral drug products should be inspected visually for particulate matter and discoloration prior to infusion.

17 PATIENT COUNSELING INFORMATION

Prior to Cafe Kit (Iron (Iron Carbonyl)) administration:

• Question patients regarding any prior history of reactions to parenteral Cafe Kit (Iron (Iron Carbonyl)) products
• Advise patients of the risks associated with Cafe Kit (Iron (Iron Carbonyl))
• Advise patients to report any symptoms of hypersensitivity that may develop during and following Cafe Kit (Iron (Iron Carbonyl)) administration, such as rash, itching, dizziness, light-headedness, swelling, and breathing problems [see Warnings and Precautions (5)]

AMERICAN

REGENT, INC.

SHIRLEY, NY 11967

Cafe Kit (Iron (Iron Carbonyl)) is manufactured under license from Vifor (International) Inc., Switzerland.

PremierProRx^® is a trademark of Premier, Inc., used under license.

PREMIERProRx^®

IN2340

MG #15727