Sorbifer Durules

Iron (Ferrous Sulfate):

• 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
• Sorbifer Durules (Iron (Ferrous Sulfate)) reviews

1 INDICATIONS AND USAGE

Sorbifer Durules (Iron (Ferrous Sulfate)) is indicated for the treatment of Sorbifer Durules (Iron (Ferrous Sulfate)) deficiency anemia in patients with chronic kidney disease (CKD).

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

2 DOSAGE AND ADMINISTRATION

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

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

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

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

Administer Sorbifer Durules (Iron (Ferrous Sulfate)) 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 Sorbifer Durules (Iron (Ferrous Sulfate)), 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. Sorbifer Durules (Iron (Ferrous Sulfate)) treatment may be repeated if Sorbifer Durules (Iron (Ferrous Sulfate)) deficiency reoccurs.

2.3 Adult Patients with Peritoneal Dialysis Dependent-Chronic Kidney Disease

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

2.4 Pediatric Patients with HDD-CKD for Sorbifer Durules (Iron (Ferrous Sulfate)) maintenance treatment

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

For Sorbifer Durules (Iron (Ferrous Sulfate)) maintenance treatment: Administer Sorbifer Durules (Iron (Ferrous Sulfate)) 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. Sorbifer Durules (Iron (Ferrous Sulfate)) treatment may be repeated if necessary.

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

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

For Sorbifer Durules (Iron (Ferrous Sulfate)) maintenance treatment: Administer Sorbifer Durules (Iron (Ferrous Sulfate)) 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. Sorbifer Durules (Iron (Ferrous Sulfate)) treatment may be repeated if necessary.

3 DOSAGE FORMS AND STRENGTHS

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

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

4 CONTRAINDICATIONS

• Known hypersensitivity to Sorbifer Durules (Iron (Ferrous Sulfate))

• Known hypersensitivity to Sorbifer Durules (Iron (Ferrous Sulfate)) (4)

5 WARNINGS AND PRECAUTIONS

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

5.2 Hypotension

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

5.3 Sorbifer Durules (Iron (Ferrous Sulfate)) Overload

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

6 ADVERSE REACTIONS

The following serious adverse reactions associated with Sorbifer Durules ) are described in other sections .

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

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

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

8.3 Nursing Mothers

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

8.4 Pediatric Use

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

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

Sorbifer Durules (Iron (Ferrous Sulfate)) has not been studied in patients younger than 2 years of age.

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

8.5 Geriatric Use

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

Toxicities in single-dose studies in mice and rats, at intravenous Sorbifer Durules (Iron (Ferrous Sulfate)) 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

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

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

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

12.2 Pharmacodynamics

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

12.3 Pharmacokinetics

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

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

Pharmacokinetics in Pediatric Patients

Pharmacokinetics in Pediatric Patients

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

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

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

Sorbifer Durules (Iron (Ferrous Sulfate)) sucrose at intravenous doses up to 15 mg/kg/day of elemental Sorbifer Durules (Iron (Ferrous Sulfate)) (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 Sorbifer Durules ).

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 Sorbifer Durules (Iron (Ferrous Sulfate)) treatment and 24 in the historical control group) with Sorbifer Durules (Iron (Ferrous Sulfate)) deficiency anemia. Eligibility criteria for Sorbifer Durules (Iron (Ferrous Sulfate)) 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.

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

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

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

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

AMERICAN

REGENT, INC.

SHIRLEY, NY 11967

Sorbifer Durules (Iron (Ferrous Sulfate)) is manufactured under license from Vifor (International) Inc., Switzerland.

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

PREMIERProRx^®

IN2340

MG #15727

Vitamin C (Ascorbic Acid):

• Pharmacological action
• Pharmacokinetics
• Why is Sorbifer Durules ) prescribed?
• Dosage and administration
• Sorbifer Durules (Vitamin C (Ascorbic Acid)) side effects, adverse reactions
• Sorbifer Durules ) contraindications
• Using during pregnancy and breastfeeding
• Special instructions
• Sorbifer Durules ) drug interactions
• Sorbifer Durules ) in case of emergency / overdose
• Sorbifer Durules (Vitamin C (Ascorbic Acid)) reviews

Pharmacological action

Sorbifer Durules ) (vitamin c) is essential for the formation of intracellular collagen, is required to strengthen the structure of teeth, bones, and the capillary walls. Sorbifer Durules (Vitamin C (Ascorbic Acid)) participates in redox reactions, the metabolism of tyrosine, converting folic acid into folinic acid, metabolism of carbohydrates, the synthesis of lipids and proteins, iron metabolism, processes of cellular respiration. Reduces the need for vitamins B1, B2, A, E, folic acid, pantothenic acid, enhances the body's resistance to infections; enhances iron absorption, contributing to its sequestration in reduced form. Sorbifer Durules (Vitamin C (Ascorbic Acid)) has antioxidant properties.

With intravaginal application of Sorbifer Durules (Vitamin C (Ascorbic Acid)) lowers the vaginal pH, inhibiting the growth of bacteria and helps to restore and maintain normal pH and vaginal flora (Lactobacillus acidophilus, Lactobacillus gasseri).

Pharmacokinetics

After oral administration Sorbifer Durules (Vitamin C (Ascorbic Acid)) is completely absorbed from the gastrointestinal tract. Widely distributed in body tissues.

The concentration of Sorbifer Durules (Vitamin C (Ascorbic Acid)) in blood plasma in normal amounts to approximately 10-20 mg / ml.

The concentration of Sorbifer Durules (Vitamin C (Ascorbic Acid)) in white blood cells and platelets is higher than in erythrocytes and plasma. When deficient state of concentration in leucocytes is reduced later and more slowly and is regarded as the best criterion for evaluating the deficit than the concentration in plasma.

Plasma protein binding is about 25%.

Sorbifer Durules (Vitamin C (Ascorbic Acid)) is reversibly oxidized to form dehydroascorbic acid, is metabolized with the formation of ascorbate-2-sulphate which is inactive and oxalic acid which is excreted in the urine.

Sorbifer Durules (Vitamin C (Ascorbic Acid)) taken in excessive quantities is rapidly excreted unchanged in urine, it usually happens when exceeding a daily dose is 200 mg.

Why is Sorbifer Durules ) prescribed?

For systemic use of Sorbifer Durules (Vitamin C (Ascorbic Acid)) RiteMED Phils: prevention and treatment of hypo- and avitaminosis of vitamin C; providing increased need for vitamin C during growth, pregnancy, lactation, with heavy loads, fatigue and during recovery after prolonged severe illness; in winter with an increased risk of infectious diseases.

For intravaginal use: chronic or recurrent vaginitis (bacterial vaginosis, nonspecific vaginitis) caused by the anaerobic flora (due to changes in pH of the vagina) in order to normalize disturbed vaginal microflora.

Dosage and administration

This medication administered orally, IM, IV, intravaginally.

For the prevention of deficiency conditions Sorbifer Durules ) dose is 25-75 mg / day, for the treatment - 250 mg / day or more in divided doses.

For intravaginal used Sorbifer Durules (Vitamin C (Ascorbic Acid)) drugs in appropriate dosage forms.

Sorbifer Durules (Vitamin C (Ascorbic Acid)) side effects, adverse reactions

CNS: headache, fatigue, insomnia.

Digestive system: stomach cramps, nausea and vomiting.

Allergic reaction: describes a few cases of skin reactions and manifestations of the respiratory system.

Urinary system: when used in high doses - hyperoxaluria and the formation of kidney stones of calcium oxalate.

Local reactions: with intravaginal application - a burning or itching in the vagina, increased mucous discharge, redness, swelling of the vulva. Other: sensation of heat.

Sorbifer Durules ) contraindications

Increased sensitivity to Sorbifer Durules (Vitamin C (Ascorbic Acid)).

Using during pregnancy and breastfeeding

The minimum daily requirement of Sorbifer Durules ) in the II and III trimester of pregnancy is about 60 mg.

Sorbifer Durules (Vitamin C (Ascorbic Acid)) crosses the placental barrier. It should be borne in mind that the fetus can adapt to high doses of Sorbifer Durules (Vitamin C (Ascorbic Acid)), which takes a pregnant woman, and then a newborn baby may develop the ascorbic disease as the reaction of cancel. Therefore, during pregnancy should not to take Sorbifer Durules (Vitamin C (Ascorbic Acid)) in high doses, except in cases where the expected benefit outweighs the potential risk.

The minimum daily requirement during lactation (breastfeeding) is 80 mg. Sorbifer Durules (Vitamin C (Ascorbic Acid)) is excreted in breast milk. A mother's diet that contains adequate amounts of Sorbifer Durules (Vitamin C (Ascorbic Acid)), is sufficient to prevent deficiency in an infant. It is unknown whether dangerous to the child's mother use of Sorbifer Durules (Vitamin C (Ascorbic Acid)) in high doses. Theoretically it is possible. Therefore, it is recommended not to exceed the maximum daily nursing mother needs to Sorbifer Durules (Vitamin C (Ascorbic Acid)), except when the expected benefit outweighs the potential risk.

Special instructions

Sorbifer Durules (Vitamin C (Ascorbic Acid)) is used with caution in patients with hyperoxaluria, renal impairment, a history of instructions on urolithiasis. Because Sorbifer Durules (Vitamin C (Ascorbic Acid)) increases iron absorption, its use in high doses can be dangerous in patients with hemochromatosis, thalassemia, polycythemia, leukemia, and sideroblastic anemia.

Patients with high content body iron should apply Sorbifer Durules (Vitamin C (Ascorbic Acid)) in minimal doses.

Sorbifer Durules (Vitamin C (Ascorbic Acid)) is used with caution in patients with deficiency of glucose-6-phosphate dehydrogenase.

The use of Sorbifer Durules (Vitamin C (Ascorbic Acid)) in high doses can cause exacerbation of sickle cell anemia.

Data on the diabetogenic action of Sorbifer Durules (Vitamin C (Ascorbic Acid)) are contradictory. However, prolonged use of Sorbifer Durules (Vitamin C (Ascorbic Acid)) should periodically monitor your blood glucose levels.

It is believed that the use of Sorbifer Durules (Vitamin C (Ascorbic Acid)) in patients with rapidly proliferating and widely disseminated tumors may worsen during the process. It should therefore be used with caution in Sorbifer Durules (Vitamin C (Ascorbic Acid)) in patients with advanced cancer.

Absorption of Sorbifer Durules (Vitamin C (Ascorbic Acid)) decreased while use of fresh fruit or vegetable juices, alkaline drinking.

Sorbifer Durules ) drug interactions

In an application with barbiturates, primidone increases the excretion of Sorbifer Durules (Vitamin C (Ascorbic Acid)) in the urine.

With the simultaneous use of oral contraceptives reduces the concentration of Sorbifer Durules (Vitamin C (Ascorbic Acid)) in blood plasma.

In an application of Sorbifer Durules (Vitamin C (Ascorbic Acid)) with iron preparations Sorbifer Durules (Vitamin C (Ascorbic Acid)), due to its regenerative properties, transforms ferric iron in the bivalent, which improves its absorption.

Sorbifer Durules (Vitamin C (Ascorbic Acid)) in high doses can decrease urine pH that while the application reduces the tubular reabsorption of amphetamine and tricyclic antidepressants.

With the simultaneous use of aspirin reduces the absorption of Sorbifer Durules (Vitamin C (Ascorbic Acid)) by about a third.

Sorbifer Durules (Vitamin C (Ascorbic Acid)) in an application with warfarin may decrease effects of warfarin.

With the simultaneous application of Sorbifer Durules (Vitamin C (Ascorbic Acid)) increases the excretion of iron in patients receiving deferoxamine. In the application of Sorbifer Durules (Vitamin C (Ascorbic Acid)) at a dose of 500 mg / day possibly left ventricular dysfunction.

In an application with tetracycline is increased excretion of Sorbifer Durules (Vitamin C (Ascorbic Acid)) in the urine.

There is a described case of reducing the concentration of fluphenazine in plasma in patients treated with Sorbifer Durules (Vitamin C (Ascorbic Acid)) 500 mg 2 times / day.

May increase the concentration of ethinyl estradiol in the blood plasma in its simultaneous application in the oral contraceptives.

Sorbifer Durules ) in case of emergency / overdose

Symptoms: long-term use of large doses (more than 1 g) - headache, increased CNS excitability, insomnia, nausea, vomiting, diarrhea, gastritis giperatsidnyh, ultseratsiya gastrointestinal mucosa, inhibition of the function insular apparatus of the pancreas (hyperglycemia, glycosuria), hyperoxaluria, nephrolithiasis (calcium oxalate), damage to the glomerular apparatus of the kidneys, moderate thamuria (when receiving a dose of 600 mg / day).

Decrease capillary permeability (possibly deteriorating trophic tissues, increased blood pressure, hypercoagulability, the development of microangiopathy).

When IV administration in high doses - the threat of termination of pregnancy (due to estrogenemia), hemolysis of red blood cells.