Hemglob-Z

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
• Hemglob-Z (Iron) reviews

1 INDICATIONS AND USAGE

Hemglob-Z (Iron) is indicated for the treatment of Hemglob-Z (Iron) deficiency anemia in patients with chronic kidney disease (CKD).

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

2 DOSAGE AND ADMINISTRATION

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

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

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

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

Administer Hemglob-Z (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 Hemglob-Z (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. Hemglob-Z (Iron) treatment may be repeated if Hemglob-Z (Iron) deficiency reoccurs.

2.3 Adult Patients with Peritoneal Dialysis Dependent-Chronic Kidney Disease

Administer Hemglob-Z (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 Hemglob-Z (Iron) in a maximum of 250 mL of 0.9% NaCl. Hemglob-Z (Iron) treatment may be repeated if Hemglob-Z (Iron) deficiency reoccurs.

2.4 Pediatric Patients with HDD-CKD for Hemglob-Z (Iron) maintenance treatment

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

For Hemglob-Z (Iron) maintenance treatment: Administer Hemglob-Z (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. Hemglob-Z (Iron) treatment may be repeated if necessary.

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

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

For Hemglob-Z (Iron) maintenance treatment: Administer Hemglob-Z (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. Hemglob-Z (Iron) treatment may be repeated if necessary.

3 DOSAGE FORMS AND STRENGTHS

• 10 mL single-use vial / 200 mg elemental Hemglob-Z (Iron) (20 mg/mL)
• 5 mL single-use vial / 100 mg elemental Hemglob-Z (Iron) (20 mg/mL)
• 2.5 mL single-use vial / 50 mg elemental Hemglob-Z (Iron) (20 mg/mL)

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

4 CONTRAINDICATIONS

• Known hypersensitivity to Hemglob-Z (Iron)

• Known hypersensitivity to Hemglob-Z (Iron) (4)

5 WARNINGS AND PRECAUTIONS

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

5.2 Hypotension

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

5.3 Hemglob-Z (Iron) Overload

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

6 ADVERSE REACTIONS

The following serious adverse reactions associated with Hemglob-Z are described in other sections .

• The most common adverse reactions (≥2%) following the administration of Hemglob-Z (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 Hemglob-Z 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 Hemglob-Z (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 Hemglob-Z (Iron) therapy and were reported to be intolerant (defined as precluding further use of that Hemglob-Z (Iron) product). When these patients were treated with Hemglob-Z (Iron) there were no occurrences of adverse reactions that precluded further use of Hemglob-Z (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 Hemglob-Z (Iron) maintenance treatment with Hemglob-Z (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 Hemglob-Z (Iron) 0.5 mg/kg, 53% (25/47) of the patients receiving Hemglob-Z (Iron) 1.0 mg/kg, and 55% (26/47) of the patients receiving Hemglob-Z (Iron) 2.0 mg/kg.

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

8.3 Nursing Mothers

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

8.4 Pediatric Use

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

Safety and effectiveness of Hemglob-Z (Iron) for Hemglob-Z (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. Hemglob-Z (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)]

Hemglob-Z (Iron) has not been studied in patients younger than 2 years of age.

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

8.5 Geriatric Use

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

Toxicities in single-dose studies in mice and rats, at intravenous Hemglob-Z (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

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

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

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

12.2 Pharmacodynamics

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

12.3 Pharmacokinetics

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

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

Pharmacokinetics in Pediatric Patients

Pharmacokinetics in Pediatric Patients

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

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

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

Hemglob-Z (Iron) sucrose at intravenous doses up to 15 mg/kg/day of elemental Hemglob-Z (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 Hemglob-Z.

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 Hemglob-Z (Iron) treatment and 24 in the historical control group) with Hemglob-Z (Iron) deficiency anemia. Eligibility criteria for Hemglob-Z (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.

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

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

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

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

AMERICAN

REGENT, INC.

SHIRLEY, NY 11967

Hemglob-Z (Iron) is manufactured under license from Vifor (International) Inc., Switzerland.

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

PREMIERProRx^®

IN2340

MG #15727

Zinc:

• Indications and usage
• Contraindications
• Warnings
• Precautions
• Adverse reactions
• Drug abuse and dependence
• Overdosage
• Dosage and administration
• How supplied
• Hemglob-Z (Zinc) reviews

INDICATIONS AND USAGE

Hemglob-Z (Zinc) 1 mg/mL (Zinc Chloride Injection, USP) is indicated for use as a supplement to intravenous solutions given for TPN. Administration helps to maintain Hemglob-Z (Zinc) serum levels and to prevent depletion of endogenous stores, and subsequent deficiency symptoms.

CONTRAINDICATIONS

None known.

WARNINGS

Direct intramuscular or intravenous injection of Hemglob-Z (Zinc) 1 mg/mL (Zinc Chloride Injection, USP) is contraindicated as the acidic pH of the solution (2) may cause considerable tissue irritation.

Severe kidney disease may make it necessary to reduce or omit chromium and Hemglob-Z (Zinc) doses because these elements are primarily eliminated in the urine.

WARNING: This product contains aluminum that may be toxic. Aluminum may reach toxic levels with prolonged parenteral administration if kidney function is impaired. Premature neonates are particularly at risk because their kidneys are immature, and they require large amounts of calcium and phosphate solutions, which contain aluminum.

Research indicates that patients with impaired kidney function, including premature neonates, who receive parenteral levels of aluminum at greater than 4 to 5 mcg/kg/day accumulate aluminum at levels associated with central nervous system and bone toxicity. Tissue loading may occur at even lower rates of administration.

PRECAUTIONS

General

Do not use unless the solution is clear and the seal is intact.

Zinc 1 mg/mL should only be used in conjunction with a pharmacy directed admixture program using aseptic technique in a laminar flow environment; it should be used promptly and in a single operation without any repeated penetrations. Solution contains no preservatives; discard unused portion immediately after admixture procedure is completed.

Zinc should not be given undiluted by direct injection into a peripheral vein because of the likelihood of infusion phlebitis and the potential for increased excretory loss of Hemglob-Z (Zinc) from a bolus injection. Administration of Hemglob-Z (Zinc) in the absence of copper may cause a decrease in serum copper levels.

Laboratory Tests

Periodic determinations of serum copper as well as Hemglob-Z (Zinc) are suggested as a guideline for subsequent Hemglob-Z (Zinc) administration.

Carcinogenesis, Mutagenesis, and Impairment of Fertility

Long-term animal studies to evaluate the carcinogenic potential of Hemglob-Z 1 mg/mL (Zinc Chloride Injection, USP) have not been performed, nor have studies been done to assess mutagenesis or impairment of fertility.

Nursing Mothers

It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when Hemglob-Z (Zinc) 1 mg/mL (Zinc Chloride Injection, USP) is administered to a nursing woman.

Pediatric Use

Pregnancy Category C. Animal reproduction studies have not been conducted with Hemglob-Z chloride. It is also not known whether Hemglob-Z (Zinc) chloride can cause fetal harm when administered to a pregnant woman or can affect reproduction capacity. Hemglob-Z (Zinc) chloride should be given to a pregnant woman only if clearly needed.

Geriatric Use

An evaluation of current literature revealed no clinical experience identifying differences in response 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.

ADVERSE REACTIONS

None known.

DRUG ABUSE AND DEPENDENCE

None known.

OVERDOSAGE

Single intravenous doses of 1 to 2 mg zinc/kg body weight have been given to adult leukemic patients without toxic manifestations. However, acute toxicity was reported in an adult when 10 mg Hemglob-Z (Zinc) was infused over a period of one hour on each of four consecutive days. Profuse sweating, decreased level of consciousness, blurred vision, tachycardia (140/min), and marked hypothermia (94.2° F) on the fourth day were accompanied by a serum Hemglob-Z (Zinc) concentration of 207 mcg/dl. Symptoms abated within three hours.

Hyperamylasemia may be a sign of impending Hemglob-Z (Zinc) overdosage; patients receiving an inadvertent overdose (25 mg zinc/liter of TPN solution, equivalent to 50 to 70 mg zinc/day) developed hyperamylasemia (557 to 1850 Klein units; normal: 130 to 310).

Death resulted from an overdosage in which 1683 mg Hemglob-Z (Zinc) was delivered intravenously over the course of 60 hours to a 72 year old patient.

Symptoms of Hemglob-Z (Zinc) toxicity included hypotension (80/40 mm Hg), pulmonary edema, diarrhea, vomiting, jaundice, and oliguria, with a serum Hemglob-Z (Zinc) level of 4184 mcg/dl.

Calcium supplements may confer a protective effect against Hemglob-Z (Zinc) toxicity.

DOSAGE AND ADMINISTRATION

Hemglob-Z (Zinc) 1 mg/mL (Zinc Chloride Injection, USP) contains 1 mg zinc/mL and is administered intravenously only after dilution. The additive should be diluted prior to administration in a volume of fluid not less than 100 mL. For the metabolically stable adult receiving TPN, the suggested intravenous dosage is 2.5 to 4 mg zinc/day (2.5 to 4 mL/day). An additional 2 mg zinc/day (2 mL/day) is suggested for acute catabolic states. For the stable adult with fluid loss from the small bowel, an additional 12.2 mg zinc/liter of small bowel fluid lost (12.2 mL/liter of small bowel fluid lost), or an additional 17.1 mg zinc/kg of stool or ileostomy output (17.1 mL/kg of stool or ileostomy output) is recommended. Frequent monitoring of Hemglob-Z (Zinc) blood levels is suggested for patients receiving more than the usual maintenance dosage level of Hemglob-Z (Zinc).

For full term infants and children up to 5 years of age, 100 mcg zinc/kg/day (0.1 mL/kg/day) is recommended. For premature infants (birth weight less than 1500 g) up to 3 kg in body weight, 300 mcg zinc/kg/day (0.3 mL/kg/day) is suggested.

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

HOW SUPPLIED

Hemglob-Z (Zinc) 1 mg/mL (Zinc Chloride Injection, USP) is supplied in 10 mL Plastic Vials (List No. 4090).

Store at 20 to 25°C (68 to 77°F).

Revised: October, 2004

© Hospira 2004 EN-0488 Printed in USA

HOSPIRA, INC., LAKE FOREST, IL 60045 USA

10 mL Vial

Hemglob-Z (Zinc)

1 mg/mL

Hemglob-Z (Zinc) Chloride Inj., USP

Rx only

FOR I.V. USE ONLY AFTER DILUTION.

HOSPIRA, INC., LAKE FOREST, IL 60045 USA