Tardyferon-Fol

Folic Acid Anhydrous:

• Indications and usage
• Contraindications
• Precautions
• Adverse reactions
• Dosage and administration
• How supplied
• Storage
• Tardyferon-Fol (Folic Acid Anhydrous) reviews

INDICATIONS AND USAGE

Tardyferon-Fol (Folic Acid Anhydrous)^® 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

Tardyferon-Fol (Folic Acid Anhydrous) 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 Tardyferon-Fol (Folic Acid Anhydrous) acid.

DOSAGE AND ADMINISTRATION

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

HOW SUPPLIED

Tardyferon-Fol (Folic Acid Anhydrous)^® 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.

Tardyferon-Fol (Folic Acid Anhydrous) and the BIFERA logo are registered trademarks and the Tardyferon-Fol (Folic Acid Anhydrous) 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 (Ferrous Sulfate Sesquihydrate):

• 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
• Tardyferon-Fol (Iron (Ferrous Sulfate Sesquihydrate)) reviews

1 INDICATIONS AND USAGE

Tardyferon-Fol (Iron (Ferrous Sulfate Sesquihydrate)) is indicated for the treatment of Tardyferon-Fol (Iron (Ferrous Sulfate Sesquihydrate)) deficiency anemia in patients with chronic kidney disease (CKD).

Tardyferon-Fol (Iron (Ferrous Sulfate Sesquihydrate)) is an Tardyferon-Fol (Iron (Ferrous Sulfate Sesquihydrate)) replacement product indicated for the treatment of Tardyferon-Fol (Iron (Ferrous Sulfate Sesquihydrate)) deficiency anemia in patients with chronic kidney disease (CKD). (1)

2 DOSAGE AND ADMINISTRATION

Tardyferon-Fol ) must only be administered intravenously either by slow injection or by infusion. The dosage of Tardyferon-Fol (Iron (Ferrous Sulfate Sesquihydrate)) is expressed in mg of elemental Tardyferon-Fol (Iron (Ferrous Sulfate Sesquihydrate)). Each mL contains 20 mg of elemental Tardyferon-Fol (Iron (Ferrous Sulfate Sesquihydrate)).

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

Administer Tardyferon-Fol (Iron (Ferrous Sulfate Sesquihydrate)) 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. Tardyferon-Fol (Iron (Ferrous Sulfate Sesquihydrate)) should be administered early during the dialysis session. The usual total treatment course of Tardyferon-Fol (Iron (Ferrous Sulfate Sesquihydrate)) is 1000 mg. Tardyferon-Fol (Iron (Ferrous Sulfate Sesquihydrate)) treatment may be repeated if Tardyferon-Fol (Iron (Ferrous Sulfate Sesquihydrate)) deficiency reoccurs.

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

Administer Tardyferon-Fol (Iron (Ferrous Sulfate Sesquihydrate)) 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 Tardyferon-Fol (Iron (Ferrous Sulfate Sesquihydrate)), 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. Tardyferon-Fol (Iron (Ferrous Sulfate Sesquihydrate)) treatment may be repeated if Tardyferon-Fol (Iron (Ferrous Sulfate Sesquihydrate)) deficiency reoccurs.

2.3 Adult Patients with Peritoneal Dialysis Dependent-Chronic Kidney Disease

Administer Tardyferon-Fol (Iron (Ferrous Sulfate Sesquihydrate)) 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 Tardyferon-Fol (Iron (Ferrous Sulfate Sesquihydrate)) in a maximum of 250 mL of 0.9% NaCl. Tardyferon-Fol (Iron (Ferrous Sulfate Sesquihydrate)) treatment may be repeated if Tardyferon-Fol (Iron (Ferrous Sulfate Sesquihydrate)) deficiency reoccurs.

2.4 Pediatric Patients with HDD-CKD for Tardyferon-Fol (Iron (Ferrous Sulfate Sesquihydrate)) maintenance treatment

The dosing for Tardyferon-Fol (Iron (Ferrous Sulfate Sesquihydrate)) replacement treatment in pediatric patients with HDD-CKD has not been established.

For Tardyferon-Fol (Iron (Ferrous Sulfate Sesquihydrate)) maintenance treatment: Administer Tardyferon-Fol (Iron (Ferrous Sulfate Sesquihydrate)) 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. Tardyferon-Fol (Iron (Ferrous Sulfate Sesquihydrate)) treatment may be repeated if necessary.

2.5 Pediatric Patients with NDD-CKD or PDD-CKD who are on erythropoietin therapy for Tardyferon-Fol (Iron (Ferrous Sulfate Sesquihydrate)) maintenance treatment

The dosing for Tardyferon-Fol (Iron (Ferrous Sulfate Sesquihydrate)) replacement treatment in pediatric patients with NDD-CKD or PDD-CKD has not been established.

For Tardyferon-Fol (Iron (Ferrous Sulfate Sesquihydrate)) maintenance treatment: Administer Tardyferon-Fol (Iron (Ferrous Sulfate Sesquihydrate)) 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. Tardyferon-Fol (Iron (Ferrous Sulfate Sesquihydrate)) treatment may be repeated if necessary.

3 DOSAGE FORMS AND STRENGTHS

• 10 mL single-use vial / 200 mg elemental Tardyferon-Fol (Iron (Ferrous Sulfate Sesquihydrate)) (20 mg/mL)
• 5 mL single-use vial / 100 mg elemental Tardyferon-Fol (Iron (Ferrous Sulfate Sesquihydrate)) (20 mg/mL)
• 2.5 mL single-use vial / 50 mg elemental Tardyferon-Fol (Iron (Ferrous Sulfate Sesquihydrate)) (20 mg/mL)

• 10 mL single-use vial / 200 mg elemental Tardyferon-Fol (Iron (Ferrous Sulfate Sesquihydrate)) (20 mg/mL) (3)
• 5 mL single-use vial / 100 mg elemental Tardyferon-Fol (Iron (Ferrous Sulfate Sesquihydrate)) (20 mg/mL) (3)
• 2.5 mL single-use vial / 50 mg elemental Tardyferon-Fol (Iron (Ferrous Sulfate Sesquihydrate)) (20 mg/mL) (3)

4 CONTRAINDICATIONS

• Known hypersensitivity to Tardyferon-Fol (Iron (Ferrous Sulfate Sesquihydrate))

• Known hypersensitivity to Tardyferon-Fol (Iron (Ferrous Sulfate Sesquihydrate)) (4)

5 WARNINGS AND PRECAUTIONS

• Hypersensitivity Reactions: Observe for signs and symptoms of hypersensitivity during and after Tardyferon-Fol ) administration for at least 30 minutes and until clinically stable following completion of each administration. Only administer Tardyferon-Fol (Iron (Ferrous Sulfate Sesquihydrate)) when personnel and therapies are immediately available for the treatment of serious hypersensitivity reactions. (5.1)
• Hypotension: Tardyferon-Fol (Iron (Ferrous Sulfate Sesquihydrate)) may cause hypotension. Monitor for signs and symptoms of hypotension during and following each administration of Tardyferon-Fol (Iron (Ferrous Sulfate Sesquihydrate)). (5.2)
• Tardyferon-Fol (Iron (Ferrous Sulfate Sesquihydrate)) Overload: Regularly monitor hematologic responses during Tardyferon-Fol (Iron (Ferrous Sulfate Sesquihydrate)) therapy. Do not administer Tardyferon-Fol (Iron (Ferrous Sulfate Sesquihydrate)) to patients with Tardyferon-Fol (Iron (Ferrous Sulfate Sesquihydrate)) 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 Tardyferon-Fol (Iron (Ferrous Sulfate Sesquihydrate)). 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 Tardyferon-Fol (Iron (Ferrous Sulfate Sesquihydrate)) immediately. Monitor patients for signs and symptoms of hypersensitivity during and after Tardyferon-Fol (Iron (Ferrous Sulfate Sesquihydrate)) administration for at least 30 minutes and until clinically stable following completion of the infusion. Only administer Tardyferon-Fol (Iron (Ferrous Sulfate Sesquihydrate)) when personnel and therapies are immediately available for the treatment of serious hypersensitivity reactions. Most reactions associated with intravenous Tardyferon-Fol (Iron (Ferrous Sulfate Sesquihydrate)) preparations occur within 30 minutes of the completion of the infusion .

5.2 Hypotension

Tardyferon-Fol ) may cause clinically significant hypotension. Monitor for signs and symptoms of hypotension following each administration of Tardyferon-Fol (Iron (Ferrous Sulfate Sesquihydrate)). Hypotension following administration of Tardyferon-Fol (Iron (Ferrous Sulfate Sesquihydrate)) may be related to the rate of administration and/or total dose administered .

5.3 Tardyferon-Fol (Iron (Ferrous Sulfate Sesquihydrate)) Overload

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

6 ADVERSE REACTIONS

The following serious adverse reactions associated with Tardyferon-Fol ) are described in other sections .

• The most common adverse reactions (≥2%) following the administration of Tardyferon-Fol (Iron (Ferrous Sulfate Sesquihydrate)) 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 Tardyferon-Fol ) 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 Tardyferon-Fol (Iron (Ferrous Sulfate Sesquihydrate)) 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 Tardyferon-Fol (Iron (Ferrous Sulfate Sesquihydrate)) therapy and were reported to be intolerant (defined as precluding further use of that Tardyferon-Fol (Iron (Ferrous Sulfate Sesquihydrate)) product). When these patients were treated with Tardyferon-Fol (Iron (Ferrous Sulfate Sesquihydrate)) there were no occurrences of adverse reactions that precluded further use of Tardyferon-Fol (Iron (Ferrous Sulfate Sesquihydrate)) .

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 Tardyferon-Fol (Iron (Ferrous Sulfate Sesquihydrate)) maintenance treatment with Tardyferon-Fol (Iron (Ferrous Sulfate Sesquihydrate)) 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 Tardyferon-Fol (Iron (Ferrous Sulfate Sesquihydrate)) 0.5 mg/kg, 53% (25/47) of the patients receiving Tardyferon-Fol (Iron (Ferrous Sulfate Sesquihydrate)) 1.0 mg/kg, and 55% (26/47) of the patients receiving Tardyferon-Fol (Iron (Ferrous Sulfate Sesquihydrate)) 2.0 mg/kg.

A total of 5 (11%) subjects in the Tardyferon-Fol (Iron (Ferrous Sulfate Sesquihydrate)) 0.5 mg/kg group, 10 (21%) patients in the Tardyferon-Fol (Iron (Ferrous Sulfate Sesquihydrate)) 1.0 mg/kg group, and 10 (21%) patients in the Tardyferon-Fol (Iron (Ferrous Sulfate Sesquihydrate)) 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 Tardyferon-Fol (Iron (Ferrous Sulfate Sesquihydrate)). 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 Tardyferon-Fol (Iron (Ferrous Sulfate Sesquihydrate)) 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 Tardyferon-Fol (Iron (Ferrous Sulfate Sesquihydrate)) injection. Reactions have occurred following the first dose or subsequent doses of Tardyferon-Fol (Iron (Ferrous Sulfate Sesquihydrate)). 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 Tardyferon-Fol (Iron (Ferrous Sulfate Sesquihydrate)) have not been studied. However, Tardyferon-Fol (Iron (Ferrous Sulfate Sesquihydrate)) may reduce the absorption of concomitantly administered oral Tardyferon-Fol (Iron (Ferrous Sulfate Sesquihydrate)) 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, Tardyferon-Fol ) sucrose was administered intravenously to rats and rabbits during the period of organogenesis at doses up to 13 mg/kg/day of elemental Tardyferon-Fol (Iron (Ferrous Sulfate Sesquihydrate)) (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 Tardyferon-Fol (Iron (Ferrous Sulfate Sesquihydrate)) sucrose. Because animal reproductive studies are not always predictive of human response, Tardyferon-Fol (Iron (Ferrous Sulfate Sesquihydrate)) should be used during pregnancy only if clearly needed.

8.3 Nursing Mothers

It is not known whether Tardyferon-Fol (Iron (Ferrous Sulfate Sesquihydrate)) sucrose is excreted in human milk. Tardyferon-Fol (Iron (Ferrous Sulfate Sesquihydrate)) sucrose is secreted into the milk of lactating rats. Because many drugs are excreted in human milk, caution should be exercised when Tardyferon-Fol (Iron (Ferrous Sulfate Sesquihydrate)) is administered to a nursing woman.

8.4 Pediatric Use

Safety and effectiveness of Tardyferon-Fol ) for Tardyferon-Fol (Iron (Ferrous Sulfate Sesquihydrate)) replacement treatment in pediatric patients with dialysis-dependent or non-dialysis-dependent CKD have not been established.

Safety and effectiveness of Tardyferon-Fol (Iron (Ferrous Sulfate Sesquihydrate)) for Tardyferon-Fol (Iron (Ferrous Sulfate Sesquihydrate)) maintenance treatment in pediatric patients 2 years of age and older with dialysis-dependent or non-dialysis-dependent CKD receiving erythropoietin therapy were studied. Tardyferon-Fol (Iron (Ferrous Sulfate Sesquihydrate)) 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)]

Tardyferon-Fol (Iron (Ferrous Sulfate Sesquihydrate)) has not been studied in patients younger than 2 years of age.

In a country where Tardyferon-Fol (Iron (Ferrous Sulfate Sesquihydrate)) 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 Tardyferon-Fol (Iron (Ferrous Sulfate Sesquihydrate)), several other medications and erythropoietin. Necrotizing enterocolitis may be a complication of prematurity in very low birth weight infants. No causal relationship to Tardyferon-Fol (Iron (Ferrous Sulfate Sesquihydrate)) or any other drugs could be established.

8.5 Geriatric Use

Clinical studies of Tardyferon-Fol (Iron (Ferrous Sulfate Sesquihydrate)) 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 Tardyferon-Fol (Iron (Ferrous Sulfate Sesquihydrate)), 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 Tardyferon-Fol (Iron (Ferrous Sulfate Sesquihydrate)) in humans. Excessive dosages of Tardyferon-Fol (Iron (Ferrous Sulfate Sesquihydrate)) may lead to accumulation of Tardyferon-Fol (Iron (Ferrous Sulfate Sesquihydrate)) in storage sites potentially leading to hemosiderosis. Do not administer Tardyferon-Fol (Iron (Ferrous Sulfate Sesquihydrate)) to patients with Tardyferon-Fol (Iron (Ferrous Sulfate Sesquihydrate)) overload.

Toxicities in single-dose studies in mice and rats, at intravenous Tardyferon-Fol (Iron (Ferrous Sulfate Sesquihydrate)) 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

Tardyferon-Fol (Iron (Ferrous Sulfate Sesquihydrate)) (iron sucrose injection, USP), an Tardyferon-Fol (Iron (Ferrous Sulfate Sesquihydrate)) replacement product, is a brown, sterile, aqueous, complex of polynuclear Tardyferon-Fol (Iron (Ferrous Sulfate Sesquihydrate)) (III)-hydroxide in sucrose for intravenous use. Tardyferon-Fol (Iron (Ferrous Sulfate Sesquihydrate)) 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 Tardyferon-Fol (Iron (Ferrous Sulfate Sesquihydrate)) polymerization and m is the number of sucrose molecules associated with the Tardyferon-Fol (Iron (Ferrous Sulfate Sesquihydrate)) (III)-hydroxide.

Each mL contains 20 mg elemental Tardyferon-Fol (Iron (Ferrous Sulfate Sesquihydrate)) as Tardyferon-Fol (Iron (Ferrous Sulfate Sesquihydrate)) sucrose in water for injection. Tardyferon-Fol (Iron (Ferrous Sulfate Sesquihydrate)) is available in 10 mL single-use vials (200 mg elemental Tardyferon-Fol (Iron (Ferrous Sulfate Sesquihydrate)) per 10 mL), 5 mL single-use vials (100 mg elemental Tardyferon-Fol (Iron (Ferrous Sulfate Sesquihydrate)) per 5 mL), and 2.5 mL single-use vials (50 mg elemental Tardyferon-Fol (Iron (Ferrous Sulfate Sesquihydrate)) 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

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

12.2 Pharmacodynamics

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

12.3 Pharmacokinetics

In healthy adults administered intravenous doses of Tardyferon-Fol ), its Tardyferon-Fol (Iron (Ferrous Sulfate Sesquihydrate)) 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 Tardyferon-Fol (Iron (Ferrous Sulfate Sesquihydrate)) component appeared to distribute mainly in blood and to some extent in extravascular fluid. A study evaluating Tardyferon-Fol (Iron (Ferrous Sulfate Sesquihydrate)) containing 100 mg of Tardyferon-Fol (Iron (Ferrous Sulfate Sesquihydrate)) labeled with ⁵²Fe/⁵⁹Fe in patients with Tardyferon-Fol (Iron (Ferrous Sulfate Sesquihydrate)) deficiency showed that a significant amount of the administered Tardyferon-Fol (Iron (Ferrous Sulfate Sesquihydrate)) is distributed to the liver, spleen and bone marrow and that the bone marrow is an irreversible Tardyferon-Fol (Iron (Ferrous Sulfate Sesquihydrate)) trapping compartment.

Following intravenous administration of Tardyferon-Fol (Iron (Ferrous Sulfate Sesquihydrate)), Tardyferon-Fol (Iron (Ferrous Sulfate Sesquihydrate)) sucrose is dissociated into Tardyferon-Fol (Iron (Ferrous Sulfate Sesquihydrate)) and sucrose. The sucrose component is eliminated mainly by urinary excretion. In a study evaluating a single intravenous dose of Tardyferon-Fol (Iron (Ferrous Sulfate Sesquihydrate)) containing 1,510 mg of sucrose and 100 mg of Tardyferon-Fol (Iron (Ferrous Sulfate Sesquihydrate)) 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 Tardyferon-Fol (Iron (Ferrous Sulfate Sesquihydrate)) 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 Tardyferon-Fol (Iron (Ferrous Sulfate Sesquihydrate)) sucrose containing 500 to 700 mg of Tardyferon-Fol (Iron (Ferrous Sulfate Sesquihydrate)) in 26 patients with anemia on erythropoietin therapy (23 female, 3 male; age range 16 to 60), approximately 5% of the Tardyferon-Fol (Iron (Ferrous Sulfate Sesquihydrate)) was eliminated in urine in 24 h at each dose level. The effects of age and gender on the pharmacokinetics of Tardyferon-Fol (Iron (Ferrous Sulfate Sesquihydrate)) have not been studied.

Pharmacokinetics in Pediatric Patients

Pharmacokinetics in Pediatric Patients

In a single-dose PK study of Tardyferon-Fol (Iron (Ferrous Sulfate Sesquihydrate)), patients with NDD-CDK ages 12 to 16 (N=11) received intravenous bolus doses of Tardyferon-Fol (Iron (Ferrous Sulfate Sesquihydrate)) at 7 mg/kg (maximum 200 mg) administered over 5 minutes. Following single dose Tardyferon-Fol (Iron (Ferrous Sulfate Sesquihydrate)), the half-life of total serum Tardyferon-Fol (Iron (Ferrous Sulfate Sesquihydrate)) 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.

Tardyferon-Fol (Iron (Ferrous Sulfate Sesquihydrate)) is not dialyzable through CA210 (Baxter) High Efficiency or Fresenius F80A High Flux dialysis membranes. In in vitro studies, the amount of Tardyferon-Fol (Iron (Ferrous Sulfate Sesquihydrate)) 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 Tardyferon-Fol (Iron (Ferrous Sulfate Sesquihydrate)) sucrose.

Tardyferon-Fol (Iron (Ferrous Sulfate Sesquihydrate)) sucrose was not mutagenic in vitro in the bacterial reverse mutation assay (Ames test) or the mouse lymphoma assay. Tardyferon-Fol (Iron (Ferrous Sulfate Sesquihydrate)) sucrose was not clastogenic in the in vitro chromosome aberration assay using human lymphocytes or in the in vivo mouse micronucleus assay.

Tardyferon-Fol (Iron (Ferrous Sulfate Sesquihydrate)) sucrose at intravenous doses up to 15 mg/kg/day of elemental Tardyferon-Fol (Iron (Ferrous Sulfate Sesquihydrate)) (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 Tardyferon-Fol ).

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 Tardyferon-Fol (Iron (Ferrous Sulfate Sesquihydrate)) treatment and 24 in the historical control group) with Tardyferon-Fol (Iron (Ferrous Sulfate Sesquihydrate)) deficiency anemia. Eligibility criteria for Tardyferon-Fol (Iron (Ferrous Sulfate Sesquihydrate)) 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.

Tardyferon-Fol (Iron (Ferrous Sulfate Sesquihydrate)) 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 Tardyferon-Fol (Iron (Ferrous Sulfate Sesquihydrate)), who were off intravenous Tardyferon-Fol (Iron (Ferrous Sulfate Sesquihydrate)) 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 Tardyferon-Fol (Iron (Ferrous Sulfate Sesquihydrate)) 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 Tardyferon-Fol (Iron (Ferrous Sulfate Sesquihydrate)) in 23 patients with Tardyferon-Fol (Iron (Ferrous Sulfate Sesquihydrate)) deficiency and HDD-CKD who had been discontinued from Tardyferon-Fol (Iron (Ferrous Sulfate Sesquihydrate)) 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 Tardyferon-Fol (Iron (Ferrous Sulfate Sesquihydrate)). Exclusion criteria were similar to those in studies A and B. Tardyferon-Fol (Iron (Ferrous Sulfate Sesquihydrate)) was administered in doses of 100 mg during sequential dialysis sessions until a pre-determined (calculated) total dose of Tardyferon-Fol (Iron (Ferrous Sulfate Sesquihydrate)) 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 Tardyferon-Fol (Iron (Ferrous Sulfate Sesquihydrate)) versus Tardyferon-Fol (Iron (Ferrous Sulfate Sesquihydrate)) 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 Tardyferon-Fol (Iron (Ferrous Sulfate Sesquihydrate)) (325 mg ferrous sulfate three times daily for 56 days); or Tardyferon-Fol (Iron (Ferrous Sulfate Sesquihydrate)) (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 Tardyferon-Fol (Iron (Ferrous Sulfate Sesquihydrate)) 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 Tardyferon-Fol (Iron (Ferrous Sulfate Sesquihydrate)) group.

A statistically significantly greater proportion of Tardyferon-Fol (Iron (Ferrous Sulfate Sesquihydrate)) subjects (35/79; 44.3%) compared to oral Tardyferon-Fol (Iron (Ferrous Sulfate Sesquihydrate)) 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 Tardyferon-Fol (Iron (Ferrous Sulfate Sesquihydrate)) to patients with PDD-CKD receiving an erythropoietin alone without Tardyferon-Fol (Iron (Ferrous Sulfate Sesquihydrate)) 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 Tardyferon-Fol (Iron (Ferrous Sulfate Sesquihydrate)) or Tardyferon-Fol (Iron (Ferrous Sulfate Sesquihydrate)) (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 Tardyferon-Fol (Iron (Ferrous Sulfate Sesquihydrate)) / 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 Tardyferon-Fol (Iron (Ferrous Sulfate Sesquihydrate)) / 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 Tardyferon-Fol (Iron (Ferrous Sulfate Sesquihydrate)) / 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: Tardyferon-Fol ) 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 Tardyferon-Fol (Iron (Ferrous Sulfate Sesquihydrate)) 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 Tardyferon-Fol (Iron (Ferrous Sulfate Sesquihydrate)) (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 Tardyferon-Fol (Iron (Ferrous Sulfate Sesquihydrate)) once every other week for 6 doses. Patients with PDD-CKD or NDD-CKD received Tardyferon-Fol (Iron (Ferrous Sulfate Sesquihydrate)) 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 Tardyferon-Fol (Iron (Ferrous Sulfate Sesquihydrate)) 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

Tardyferon-Fol ) is supplied sterile in 10 mL, 5 mL, and 2.5 mL single-use vials. Each 10 mL vial contains 200 mg elemental Tardyferon-Fol (Iron (Ferrous Sulfate Sesquihydrate)), each 5 mL vial contains 100 mg elemental Tardyferon-Fol (Iron (Ferrous Sulfate Sesquihydrate)), and each 2.5 mL vial contains 50 mg elemental Tardyferon-Fol (Iron (Ferrous Sulfate Sesquihydrate)) (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: Tardyferon-Fol (Iron (Ferrous Sulfate Sesquihydrate)), when diluted with 0.9% NaCl at concentrations ranging from 2 mg to 10 mg of elemental Tardyferon-Fol (Iron (Ferrous Sulfate Sesquihydrate)) per mL, or undiluted (20 mg elemental Tardyferon-Fol (Iron (Ferrous Sulfate Sesquihydrate)) 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: Tardyferon-Fol (Iron (Ferrous Sulfate Sesquihydrate)), 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 Tardyferon-Fol (Iron (Ferrous Sulfate Sesquihydrate)) 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 Tardyferon-Fol (Iron (Ferrous Sulfate Sesquihydrate)) 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 Tardyferon-Fol (Iron (Ferrous Sulfate Sesquihydrate)) administration:

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

AMERICAN

REGENT, INC.

SHIRLEY, NY 11967

Tardyferon-Fol (Iron (Ferrous Sulfate Sesquihydrate)) is manufactured under license from Vifor (International) Inc., Switzerland.

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

PREMIERProRx^®

IN2340

MG #15727