StressForm 605 with Iron

Iron:

• 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
• StressForm 605 with Iron (Iron) reviews

1 INDICATIONS AND USAGE

StressForm 605 with Iron (Iron) is indicated for the treatment of StressForm 605 with Iron (Iron) deficiency anemia in patients with chronic kidney disease (CKD).

StressForm 605 with Iron (Iron) is an StressForm 605 with Iron (Iron) replacement product indicated for the treatment of StressForm 605 with Iron (Iron) deficiency anemia in patients with chronic kidney disease (CKD). (1)

2 DOSAGE AND ADMINISTRATION

StressForm 605 with Iron must only be administered intravenously either by slow injection or by infusion. The dosage of StressForm 605 with Iron (Iron) is expressed in mg of elemental StressForm 605 with Iron (Iron). Each mL contains 20 mg of elemental StressForm 605 with Iron (Iron).

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

Administer StressForm 605 with Iron (Iron) 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. StressForm 605 with Iron (Iron) should be administered early during the dialysis session. The usual total treatment course of StressForm 605 with Iron (Iron) is 1000 mg. StressForm 605 with Iron (Iron) treatment may be repeated if StressForm 605 with Iron (Iron) deficiency reoccurs.

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

Administer StressForm 605 with Iron (Iron) 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 StressForm 605 with Iron (Iron), 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. StressForm 605 with Iron (Iron) treatment may be repeated if StressForm 605 with Iron (Iron) deficiency reoccurs.

2.3 Adult Patients with Peritoneal Dialysis Dependent-Chronic Kidney Disease

Administer StressForm 605 with Iron (Iron) 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 StressForm 605 with Iron (Iron) in a maximum of 250 mL of 0.9% NaCl. StressForm 605 with Iron (Iron) treatment may be repeated if StressForm 605 with Iron (Iron) deficiency reoccurs.

2.4 Pediatric Patients with HDD-CKD for StressForm 605 with Iron (Iron) maintenance treatment

The dosing for StressForm 605 with Iron (Iron) replacement treatment in pediatric patients with HDD-CKD has not been established.

For StressForm 605 with Iron (Iron) maintenance treatment: Administer StressForm 605 with Iron (Iron) 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. StressForm 605 with Iron (Iron) treatment may be repeated if necessary.

2.5 Pediatric Patients with NDD-CKD or PDD-CKD who are on erythropoietin therapy for StressForm 605 with Iron (Iron) maintenance treatment

The dosing for StressForm 605 with Iron (Iron) replacement treatment in pediatric patients with NDD-CKD or PDD-CKD has not been established.

For StressForm 605 with Iron (Iron) maintenance treatment: Administer StressForm 605 with Iron (Iron) 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. StressForm 605 with Iron (Iron) treatment may be repeated if necessary.

3 DOSAGE FORMS AND STRENGTHS

• 10 mL single-use vial / 200 mg elemental StressForm 605 with Iron (Iron) (20 mg/mL)
• 5 mL single-use vial / 100 mg elemental StressForm 605 with Iron (Iron) (20 mg/mL)
• 2.5 mL single-use vial / 50 mg elemental StressForm 605 with Iron (Iron) (20 mg/mL)

• 10 mL single-use vial / 200 mg elemental StressForm 605 with Iron (Iron) (20 mg/mL) (3)
• 5 mL single-use vial / 100 mg elemental StressForm 605 with Iron (Iron) (20 mg/mL) (3)
• 2.5 mL single-use vial / 50 mg elemental StressForm 605 with Iron (Iron) (20 mg/mL) (3)

4 CONTRAINDICATIONS

• Known hypersensitivity to StressForm 605 with Iron (Iron)

• Known hypersensitivity to StressForm 605 with Iron (Iron) (4)

5 WARNINGS AND PRECAUTIONS

• Hypersensitivity Reactions: Observe for signs and symptoms of hypersensitivity during and after StressForm 605 with Iron administration for at least 30 minutes and until clinically stable following completion of each administration. Only administer StressForm 605 with Iron (Iron) when personnel and therapies are immediately available for the treatment of serious hypersensitivity reactions. (5.1)
• Hypotension: StressForm 605 with Iron (Iron) may cause hypotension. Monitor for signs and symptoms of hypotension during and following each administration of StressForm 605 with Iron (Iron). (5.2)
• StressForm 605 with Iron (Iron) Overload: Regularly monitor hematologic responses during StressForm 605 with Iron (Iron) therapy. Do not administer StressForm 605 with Iron (Iron) to patients with StressForm 605 with Iron (Iron) 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 StressForm 605 with Iron (Iron). 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 StressForm 605 with Iron (Iron) immediately. Monitor patients for signs and symptoms of hypersensitivity during and after StressForm 605 with Iron (Iron) administration for at least 30 minutes and until clinically stable following completion of the infusion. Only administer StressForm 605 with Iron (Iron) when personnel and therapies are immediately available for the treatment of serious hypersensitivity reactions. Most reactions associated with intravenous StressForm 605 with Iron (Iron) preparations occur within 30 minutes of the completion of the infusion .

5.2 Hypotension

StressForm 605 with Iron may cause clinically significant hypotension. Monitor for signs and symptoms of hypotension following each administration of StressForm 605 with Iron (Iron). Hypotension following administration of StressForm 605 with Iron (Iron) may be related to the rate of administration and/or total dose administered .

5.3 StressForm 605 with Iron (Iron) Overload

Excessive therapy with parenteral StressForm 605 with Iron (Iron) can lead to excess storage of StressForm 605 with Iron (Iron) with the possibility of iatrogenic hemosiderosis. All adult and pediatric patients receiving StressForm 605 with Iron (Iron) require periodic monitoring of hematologic and StressForm 605 with Iron (Iron) parameters (hemoglobin, hematocrit, serum ferritin and transferrin saturation). Do not administer StressForm 605 with Iron (Iron) to patients with evidence of StressForm 605 with Iron (Iron) overload. Transferrin saturation (TSAT) values increase rapidly after intravenous administration of StressForm 605 with Iron (Iron) sucrose; do not perform serum StressForm 605 with Iron (Iron) measurements for at least 48 hours after intravenous dosing .

6 ADVERSE REACTIONS

The following serious adverse reactions associated with StressForm 605 with Iron are described in other sections .

• The most common adverse reactions (≥2%) following the administration of StressForm 605 with Iron (Iron) 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 StressForm 605 with Iron 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 StressForm 605 with Iron (Iron) 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 StressForm 605 with Iron (Iron) therapy and were reported to be intolerant (defined as precluding further use of that StressForm 605 with Iron (Iron) product). When these patients were treated with StressForm 605 with Iron (Iron) there were no occurrences of adverse reactions that precluded further use of StressForm 605 with Iron (Iron) .

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 StressForm 605 with Iron (Iron) maintenance treatment with StressForm 605 with Iron (Iron) 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 StressForm 605 with Iron (Iron) 0.5 mg/kg, 53% (25/47) of the patients receiving StressForm 605 with Iron (Iron) 1.0 mg/kg, and 55% (26/47) of the patients receiving StressForm 605 with Iron (Iron) 2.0 mg/kg.

A total of 5 (11%) subjects in the StressForm 605 with Iron (Iron) 0.5 mg/kg group, 10 (21%) patients in the StressForm 605 with Iron (Iron) 1.0 mg/kg group, and 10 (21%) patients in the StressForm 605 with Iron (Iron) 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 StressForm 605 with Iron (Iron). 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 StressForm 605 with Iron (Iron) 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 StressForm 605 with Iron (Iron) injection. Reactions have occurred following the first dose or subsequent doses of StressForm 605 with Iron (Iron). 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 StressForm 605 with Iron (Iron) have not been studied. However, StressForm 605 with Iron (Iron) may reduce the absorption of concomitantly administered oral StressForm 605 with Iron (Iron) 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, StressForm 605 with Iron sucrose was administered intravenously to rats and rabbits during the period of organogenesis at doses up to 13 mg/kg/day of elemental StressForm 605 with Iron (Iron) (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 StressForm 605 with Iron (Iron) sucrose. Because animal reproductive studies are not always predictive of human response, StressForm 605 with Iron (Iron) should be used during pregnancy only if clearly needed.

8.3 Nursing Mothers

It is not known whether StressForm 605 with Iron (Iron) sucrose is excreted in human milk. StressForm 605 with Iron (Iron) sucrose is secreted into the milk of lactating rats. Because many drugs are excreted in human milk, caution should be exercised when StressForm 605 with Iron (Iron) is administered to a nursing woman.

8.4 Pediatric Use

Safety and effectiveness of StressForm 605 with Iron for StressForm 605 with Iron (Iron) replacement treatment in pediatric patients with dialysis-dependent or non-dialysis-dependent CKD have not been established.

Safety and effectiveness of StressForm 605 with Iron (Iron) for StressForm 605 with Iron (Iron) maintenance treatment in pediatric patients 2 years of age and older with dialysis-dependent or non-dialysis-dependent CKD receiving erythropoietin therapy were studied. StressForm 605 with Iron (Iron) 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)]

StressForm 605 with Iron (Iron) has not been studied in patients younger than 2 years of age.

In a country where StressForm 605 with Iron (Iron) 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 StressForm 605 with Iron (Iron), several other medications and erythropoietin. Necrotizing enterocolitis may be a complication of prematurity in very low birth weight infants. No causal relationship to StressForm 605 with Iron (Iron) or any other drugs could be established.

8.5 Geriatric Use

Clinical studies of StressForm 605 with Iron (Iron) 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 StressForm 605 with Iron (Iron), 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 StressForm 605 with Iron (Iron) in humans. Excessive dosages of StressForm 605 with Iron (Iron) may lead to accumulation of StressForm 605 with Iron (Iron) in storage sites potentially leading to hemosiderosis. Do not administer StressForm 605 with Iron (Iron) to patients with StressForm 605 with Iron (Iron) overload.

Toxicities in single-dose studies in mice and rats, at intravenous StressForm 605 with Iron (Iron) 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

StressForm 605 with Iron (Iron) (iron sucrose injection, USP), an StressForm 605 with Iron (Iron) replacement product, is a brown, sterile, aqueous, complex of polynuclear StressForm 605 with Iron (Iron) (III)-hydroxide in sucrose for intravenous use. StressForm 605 with Iron (Iron) 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 StressForm 605 with Iron (Iron) polymerization and m is the number of sucrose molecules associated with the StressForm 605 with Iron (Iron) (III)-hydroxide.

Each mL contains 20 mg elemental StressForm 605 with Iron (Iron) as StressForm 605 with Iron (Iron) sucrose in water for injection. StressForm 605 with Iron (Iron) is available in 10 mL single-use vials (200 mg elemental StressForm 605 with Iron (Iron) per 10 mL), 5 mL single-use vials (100 mg elemental StressForm 605 with Iron (Iron) per 5 mL), and 2.5 mL single-use vials (50 mg elemental StressForm 605 with Iron (Iron) 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

StressForm 605 with Iron is an aqueous complex of poly-nuclear StressForm 605 with Iron (Iron) (III)-hydroxide in sucrose. Following intravenous administration, StressForm 605 with Iron (Iron) is dissociated into StressForm 605 with Iron (Iron) and sucrose and the StressForm 605 with Iron (Iron) is transported as a complex with transferrin to target cells including erythroid precursor cells. The StressForm 605 with Iron (Iron) in the precursor cells is incorporated into hemoglobin as the cells mature into red blood cells.

12.2 Pharmacodynamics

Following intravenous administration, StressForm 605 with Iron (Iron) is dissociated into StressForm 605 with Iron (Iron) and sucrose. In 22 patients undergoing hemodialysis and receiving erythropoietin (recombinant human erythropoietin) therapy treated with StressForm 605 with Iron (Iron) sucrose containing 100 mg of StressForm 605 with Iron (Iron), three times weekly for three weeks, significant increases in serum StressForm 605 with Iron (Iron) and serum ferritin and significant decreases in total StressForm 605 with Iron (Iron) binding capacity occurred four weeks from the initiation of StressForm 605 with Iron (Iron) sucrose treatment.

12.3 Pharmacokinetics

In healthy adults administered intravenous doses of StressForm 605 with Iron, its StressForm 605 with Iron (Iron) 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 StressForm 605 with Iron (Iron) component appeared to distribute mainly in blood and to some extent in extravascular fluid. A study evaluating StressForm 605 with Iron (Iron) containing 100 mg of StressForm 605 with Iron (Iron) labeled with ⁵²Fe/⁵⁹Fe in patients with StressForm 605 with Iron (Iron) deficiency showed that a significant amount of the administered StressForm 605 with Iron (Iron) is distributed to the liver, spleen and bone marrow and that the bone marrow is an irreversible StressForm 605 with Iron (Iron) trapping compartment.

Following intravenous administration of StressForm 605 with Iron (Iron), StressForm 605 with Iron (Iron) sucrose is dissociated into StressForm 605 with Iron (Iron) and sucrose. The sucrose component is eliminated mainly by urinary excretion. In a study evaluating a single intravenous dose of StressForm 605 with Iron (Iron) containing 1,510 mg of sucrose and 100 mg of StressForm 605 with Iron (Iron) 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 StressForm 605 with Iron (Iron) 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 StressForm 605 with Iron (Iron) sucrose containing 500 to 700 mg of StressForm 605 with Iron (Iron) in 26 patients with anemia on erythropoietin therapy (23 female, 3 male; age range 16 to 60), approximately 5% of the StressForm 605 with Iron (Iron) was eliminated in urine in 24 h at each dose level. The effects of age and gender on the pharmacokinetics of StressForm 605 with Iron (Iron) have not been studied.

Pharmacokinetics in Pediatric Patients

Pharmacokinetics in Pediatric Patients

In a single-dose PK study of StressForm 605 with Iron (Iron), patients with NDD-CDK ages 12 to 16 (N=11) received intravenous bolus doses of StressForm 605 with Iron (Iron) at 7 mg/kg (maximum 200 mg) administered over 5 minutes. Following single dose StressForm 605 with Iron (Iron), the half-life of total serum StressForm 605 with Iron (Iron) 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.

StressForm 605 with Iron (Iron) is not dialyzable through CA210 (Baxter) High Efficiency or Fresenius F80A High Flux dialysis membranes. In in vitro studies, the amount of StressForm 605 with Iron (Iron) 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 StressForm 605 with Iron (Iron) sucrose.

StressForm 605 with Iron (Iron) sucrose was not mutagenic in vitro in the bacterial reverse mutation assay (Ames test) or the mouse lymphoma assay. StressForm 605 with Iron (Iron) sucrose was not clastogenic in the in vitro chromosome aberration assay using human lymphocytes or in the in vivo mouse micronucleus assay.

StressForm 605 with Iron (Iron) sucrose at intravenous doses up to 15 mg/kg/day of elemental StressForm 605 with Iron (Iron) (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 StressForm 605 with Iron.

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 StressForm 605 with Iron (Iron) treatment and 24 in the historical control group) with StressForm 605 with Iron (Iron) deficiency anemia. Eligibility criteria for StressForm 605 with Iron (Iron) 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.

StressForm 605 with Iron (Iron) 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 StressForm 605 with Iron (Iron), who were off intravenous StressForm 605 with Iron (Iron) 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 StressForm 605 with Iron (Iron) 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 StressForm 605 with Iron (Iron) in 23 patients with StressForm 605 with Iron (Iron) deficiency and HDD-CKD who had been discontinued from StressForm 605 with Iron (Iron) 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 StressForm 605 with Iron (Iron). Exclusion criteria were similar to those in studies A and B. StressForm 605 with Iron (Iron) was administered in doses of 100 mg during sequential dialysis sessions until a pre-determined (calculated) total dose of StressForm 605 with Iron (Iron) 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 StressForm 605 with Iron (Iron) versus StressForm 605 with Iron (Iron) 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 StressForm 605 with Iron (Iron) (325 mg ferrous sulfate three times daily for 56 days); or StressForm 605 with Iron (Iron) (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 StressForm 605 with Iron (Iron) 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 StressForm 605 with Iron (Iron) group.

A statistically significantly greater proportion of StressForm 605 with Iron (Iron) subjects (35/79; 44.3%) compared to oral StressForm 605 with Iron (Iron) 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 StressForm 605 with Iron (Iron) to patients with PDD-CKD receiving an erythropoietin alone without StressForm 605 with Iron (Iron) 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 StressForm 605 with Iron (Iron) or StressForm 605 with Iron (Iron) (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 StressForm 605 with Iron (Iron) / 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 StressForm 605 with Iron (Iron) / 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 StressForm 605 with Iron (Iron) / 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: StressForm 605 with Iron 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 StressForm 605 with Iron (Iron) 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 StressForm 605 with Iron (Iron) (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 StressForm 605 with Iron (Iron) once every other week for 6 doses. Patients with PDD-CKD or NDD-CKD received StressForm 605 with Iron (Iron) 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 StressForm 605 with Iron (Iron) 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

StressForm 605 with Iron is supplied sterile in 10 mL, 5 mL, and 2.5 mL single-use vials. Each 10 mL vial contains 200 mg elemental StressForm 605 with Iron (Iron), each 5 mL vial contains 100 mg elemental StressForm 605 with Iron (Iron), and each 2.5 mL vial contains 50 mg elemental StressForm 605 with Iron (Iron) (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: StressForm 605 with Iron (Iron), when diluted with 0.9% NaCl at concentrations ranging from 2 mg to 10 mg of elemental StressForm 605 with Iron (Iron) per mL, or undiluted (20 mg elemental StressForm 605 with Iron (Iron) 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: StressForm 605 with Iron (Iron), 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 StressForm 605 with Iron (Iron) 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 StressForm 605 with Iron (Iron) 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 StressForm 605 with Iron (Iron) administration:

• Question patients regarding any prior history of reactions to parenteral StressForm 605 with Iron (Iron) products
• Advise patients of the risks associated with StressForm 605 with Iron (Iron)
• Advise patients to report any symptoms of hypersensitivity that may develop during and following StressForm 605 with Iron (Iron) administration, such as rash, itching, dizziness, light-headedness, swelling, and breathing problems [see Warnings and Precautions (5)]

AMERICAN

REGENT, INC.

SHIRLEY, NY 11967

StressForm 605 with Iron (Iron) is manufactured under license from Vifor (International) Inc., Switzerland.

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

PREMIERProRx^®

IN2340

MG #15727