Ameferex

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
• Ameferex (Iron) reviews

1 INDICATIONS AND USAGE

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

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

2 DOSAGE AND ADMINISTRATION

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

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

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

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

Administer Ameferex (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 Ameferex (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. Ameferex (Iron) treatment may be repeated if Ameferex (Iron) deficiency reoccurs.

2.3 Adult Patients with Peritoneal Dialysis Dependent-Chronic Kidney Disease

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

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

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

For Ameferex (Iron) maintenance treatment: Administer Ameferex (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. Ameferex (Iron) treatment may be repeated if necessary.

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

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

For Ameferex (Iron) maintenance treatment: Administer Ameferex (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. Ameferex (Iron) treatment may be repeated if necessary.

3 DOSAGE FORMS AND STRENGTHS

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

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

4 CONTRAINDICATIONS

• Known hypersensitivity to Ameferex (Iron)

• Known hypersensitivity to Ameferex (Iron) (4)

5 WARNINGS AND PRECAUTIONS

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

5.2 Hypotension

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

5.3 Ameferex (Iron) Overload

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

6 ADVERSE REACTIONS

The following serious adverse reactions associated with Ameferex are described in other sections .

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

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

8.3 Nursing Mothers

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

8.4 Pediatric Use

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

Safety and effectiveness of Ameferex (Iron) for Ameferex (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. Ameferex (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)]

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

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

8.5 Geriatric Use

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

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

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

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

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

12.2 Pharmacodynamics

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

12.3 Pharmacokinetics

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

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

Pharmacokinetics in Pediatric Patients

Pharmacokinetics in Pediatric Patients

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

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

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

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

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

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

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

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

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

AMERICAN

REGENT, INC.

SHIRLEY, NY 11967

Ameferex (Iron) is manufactured under license from Vifor (International) Inc., Switzerland.

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

PREMIERProRx^®

IN2340

MG #15727

Vitamin B12 (Cyanocobalamin):

• Pharmacological action
• Pharmacokinetics
• Why is Ameferex ) prescribed?
• Dosage and administration
• Ameferex (Vitamin B12 (Cyanocobalamin)) side effects, adverse reactions
• Ameferex ) contraindications
• Ameferex ) using during pregnancy and breastfeeding
• Special instructions
• Ameferex (Vitamin B12 (Cyanocobalamin)) drug interactions
• Ameferex (Vitamin B12 (Cyanocobalamin)) reviews

Pharmacological action

Ameferex ) refers to a group of water-soluble vitamins. It has high biological activity. Ameferex (Vitamin B12 (Cyanocobalamin)) is necessary for normal hematopoiesis (promotes maturation of erythrocytes). Involved in the processes of transmethylation, hydrogen transport, synthesis of methionine, nucleic acids, choline, creatine. Contributes to the accumulation in erythrocytes of compounds containing sulfhydryl groups. Has a beneficial effect on liver function and the nervous system. Activates the coagulation of blood in high doses causes an increase in the activity of thromboplastin and prothrombin.

Pharmacokinetics

After oral administration Ameferex (Vitamin B12 (Cyanocobalamin)) absorbed from the gastrointestinal tract. Metabolized in the tissues, becoming a co-enzyme form - adenosylcobalamin which is the active form of cyanocobalamin. Excreted in bile and urine.

Why is Ameferex ) prescribed?

Anemia due to B12-deficiency conditions; in the complex therapy for iron and posthemorrhagic anemia; aplastic anemia caused by toxic substances and drugs; liver disease (hepatitis, cirrhosis); funicular myelosis; polyneuritis, radiculitis, neuralgia, amyotrophic lateral sclerosis; children cerebral palsy, Down syndrome, peripheral nerve injury; skin diseases (psoriasis, photodermatosis, herpetiformis dermatitis, neurodermatitis); to prevent and treat symptoms of deficiency of Ameferex (Vitamin B12 (Cyanocobalamin)) (including the application of biguanide, PASA, vitamin C in high doses); radiation sickness.

Dosage and administration

Ameferex ) is used as injections SC, IV, IM, intralumbar, and also oral. With anemia associated with Ameferex (Vitamin B12 (Cyanocobalamin)) deficiency is introduced on 100-200 mcg in 2 days. In anemia with symptoms of funicular myelosis and megalocytic anemia with diseases of the nervous system - 400-500 micrograms in the first 7 days daily, then 1 time every 5-7 days. In the period of remission in the absence of events funicular myelosis maintenance dose - 100 mcg 2 times a month, in the presence of neurological symptoms - at 200-400 mcg 2-4 times a month. In acute post-hemorrhagic anemia and iron anemia by 30-100 mcg 2-3 times a week. When aplastic anemia (especially in children) - 100 micrograms before clinical improvement. When nutritional anemia in infants and preterm - 30 mcg / day during 15 days.

In diseases of the central and peripheral nervous system and neurological diseases with a pain syndrome is administered in increasing doses - 200-500 mcg, with the improvement in the state - 100 mcg / day. The course of treatment with Ameferex (Vitamin B12 (Cyanocobalamin)) is 2 weeks. In traumatic lesions of peripheral nervous system - at 200-400 mcg every other day for 40-45 days.

When hepatitis and cirrhosis - 30-60 mcg / day or 100 mg every other day for 25-40 days.

Dystrophy in young children, Down syndrome and cerebral palsy - by 15-30 mcg every other day.

When funicular myelosis, amyotrophic lateral sclerosis can be introduced into the spinal canal at 15-30 mcg, gradually increasing the dose of 200-250 micrograms.

In radiation sickness, diabetic neuropathy, sprue - by 60-100 mcg daily for 20-30 days.

When deficiency of Ameferex (Vitamin B12 (Cyanocobalamin)) to prevent - IV or IM for 1 mg 1 time a month; for treatment - IV or IM for 1 mg daily for 1-2 weeks, the maintenance dose is 1-2 mg IV or IM from 1 per week, up to 1 per month. Duration of treatment is determined individually.

Ameferex (Vitamin B12 (Cyanocobalamin)) side effects, adverse reactions

CNS: rarely - a state of arousal.

Cardiovascular system: rarely - pain in the heart, tachycardia.

Allergic reactions: rarely - urticaria.

Ameferex ) contraindications

Thromboembolism, erythremia, erythrocytosis, increased sensitivity to cyanocobalamin.

Ameferex ) using during pregnancy and breastfeeding

Cyanocobalamin can be used in pregnancy according to prescriptions.

Special instructions

When stenocardia should be used with caution in a single dose of Ameferex ) 100 mcg. During treatment should regularly monitor the blood picture and coagulation. It is unacceptable to enter in the same syringe with cyanocobalamin solutions of thiamine and pyridoxine.

Ameferex (Vitamin B12 (Cyanocobalamin)) drug interactions

In an application of Ameferex (Vitamin B12 (Cyanocobalamin)) with hormonal contraceptives for oral administration may decrease the concentration of cyanocobalamin in plasma.

In an application with anticonvulsant drugs decreased cyanocobalamin absorption from the gut.

In an Ameferex (Vitamin B12 (Cyanocobalamin)) application with neomycin, aminosalicylic acid, colchicine, cimetidine, ranitidine, drugs potassium decreased cyanocobalamin absorption from the gut.

Cyanocobalamin may exacerbate allergic reactions caused by thiamine.

When parenteral application of chloramphenicol may decrease the hematopoietic effects of cyanocobalamin with anemia.

Pharmaceutical incompatibility

Contained in the molecule of cyanocobalamin cobalt ion contributes to the destruction of ascorbic acid, thiamine bromide, riboflavin in one solution.