DESCRIPTION
Feraheme, an iron replacement product, is a non-stoichiometric magnetite (superparamagnetic iron oxide) coated with polyglucose sorbitol carboxymethylether. The overall colloidal particle size is 17-31 nm in diameter. The chemical formula of Feraheme is Fe5874O8752-C11719H18682O9933Na414 with an apparent molecular weight of 750 kDa.

Feraheme injection is an aqueous colloidal product that is formulated with mannitol. It is a black to reddish brown liquid, and is provided in single use vials containing 510 mg of elemental iron. Each mL of the sterile colloidal solution of Feraheme injection contains 30 mg of elemental iron and 44 mg of mannitol, and has low bleomycin-detectable iron. The formulation is isotonic with an osmolality of 270-330 mOsm/kg. The product contains no preservatives, and has a pH of 6 to 8.

CLINICAL PHARMACOLOGY
Mechanism of Action
Feraheme consists of a superparamagnetic iron oxide that is coated with a carbohydrate shell, which helps to isolate the bioactive iron from plasma components until the iron-carbohydrate complex enters the reticuloendothelial system macrophages of the liver, spleen and bone marrow. The iron is released from the iron-carbohydrate complex within vesicles in the macrophages. Iron then either enters the intracellular storage iron pool (e.g., ferritin) or is transferred to plasma transferrin for transport to erythroid precursor cells for incorporation into hemoglobin.

INDICATIONS AND USAGE:
Feraheme is an iron replacement product indicated for the treatment of iron deficiency anemia in adult patients with chronic kidney disease (CKD).

DOSAGE AND ADMINISTRATION:
The recommended dose of Feraheme is an initial 510 mg dose followed by a second 510 mg dose 3 to 8 days later. Administer Feraheme as an intravenous infusion in 50-200 mL 0.9% Sodium Chloride Injection, USP or 5% Dextrose Injection, USP over at least 15 minutes. Administer while the patient is in a reclined or semi-reclined position.

Feraheme, when added to intravenous infusion bags containing either 0.9% Sodium Chloride Injection, USP (normal saline), or 5% Dextrose Injection, USP, at concentrations of 2-8 mg elemental iron per mL, should be used immediately but may be stored at controlled room temperature (25°C +/- 2°C) for up to 4 hours.

The dosage is expressed in terms of mg of elemental iron, with each mL of Feraheme containing 30 mg of elemental iron. Evaluate the hematologic response (hemoglobin, ferritin, iron and transferrin saturation) at least one month following the second Feraheme infusion. The recommended Feraheme dose may be readministered to patients with persistent or recurrent iron deficiency anemia.

For patients receiving hemodialysis, administer Feraheme once the blood pressure is stable and the patient has completed at least one hour of hemodialysis. Monitor for signs and symptoms of hypotension following each Feraheme infusion.

Allow at least 30 minutes between administration of Feraheme and administration of other medications that could potentially cause serious hypersensitivity reactions and/or hypotension, such as chemotherapeutic agents or monoclonal antibodies.

Inspect parenteral drug products visually for the absence of particulate matter and discoloration prior to administration.

CONTRAINDICATIONS:
Known hypersensitivity to Feraheme or any of its components.

History of allergic reaction to any intravenous iron product.

WARNINGS AND PRECAUTIONS
--Hypersensitivity Reactions: Observe for signs and symptoms of hypersensitivity during and after Feraheme administration for at least 30 minutes and until clinically stable following completion of each administration.
--Hypotension: Feraheme may cause hypotension. Monitor for signs and symptoms of hypotension following each administration of Feraheme.
--Iron Overload: Regularly monitor hematologic responses during Feraheme therapy. Do not administer Feraheme to patients with iron overload.
-- Magnetic Resonance Imaging: Feraheme can alter magnetic resonance imaging (MRI) studies.

ADVERSE REACTIONS
The most common adverse reactions (≥ 2%) following the administration of Feraheme are diarrhea, nausea, dizziness, hypotension, constipation, and peripheral edema.

DOSAGE FORMS AND STRENGTHS:
Feraheme (30 mg/mL) is available for intravenous injection in single use vials. Each vial contains 510 mg of elemental iron in 17 mL.

Source:
Package Insert data: 
FERAHEME
ferumoxytol injection
Manufactured and Distributed by:

AMAG Pharmaceuticals Inc.
Lexington, MA 02421
Revised: 03/2015

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

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

INDICATIONS AND USAGE:
Venofer is an iron replacement product indicated for the treatment of iron deficiency anemia in patients with chronic kidney disease (CKD).

DOSAGE AND ADMINISTRATION:

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

Adult Patients with Hemodialysis Dependent-Chronic Kidney Disease (HDD-CKD)
Administer Venofer 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. Venofer should be administered early during the dialysis session. The usual total treatment course of Venofer is 1000 mg. Venofer treatment may be repeated if iron deficiency reoccurs.

Adult Patients with Non-Dialysis Dependent-Chronic Kidney Disease (NDD-CKD)
Administer Venofer 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 Venofer, 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. Venofer treatment may be repeated if iron deficiency reoccurs.

Adult Patients with Peritoneal Dialysis Dependent-Chronic Kidney Disease (PDD-CKD)
Administer Venofer 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 Venofer in a maximum of 250 mL of 0.9% NaCl. Venofer treatment may be repeated if iron deficiency reoccurs.

Pediatric Patients (2 years of age and older) with HDD-CKD for iron maintenance treatment
The dosing for iron replacement treatment in pediatric patients with HDD-CKD has not been established.

For iron maintenance treatment: Administer Venofer 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. Venofer treatment may be repeated if necessary.

Pediatric Patients (2 years of age and older) with NDD-CKD or PDD-CKD who are on erythropoietin therapy for iron maintenance treatment

The dosing for iron replacement treatment in pediatric patients with NDD-CKD or PDD-CKD has not been established.

For iron maintenance treatment: Administer Venofer 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. Venofer treatment may be repeated if necessary.

CONTRAINDICATIONS:
Known hypersensitivity to Venofer

WARNINGS AND PRECAUTIONS
--Hypersensitivity Reactions: Observe for signs and symptoms of hypersensitivity during and after Venofer administration for at least 30 minutes and until clinically stable following completion of each administration. Only administer Venofer when personnel and therapies are immediately available for the treatment of serious hypersensitivity reactions.

---Hypotension: Venofer may cause hypotension. Monitor for signs and symptoms of hypotension during and following each administration of Venofer.

--Iron Overload: Regularly monitor hematologic responses during Venofer therapy. Do not administer Venofer to patients with iron overload.

ADVERSE REACTIONS
The most common adverse reactions (≥2%) following the administration of Venofer are diarrhea, nausea, vomiting, headache, dizziness, hypotension, pruritus, pain in extremity, arthralgia, back pain, muscle cramp, injection site reactions, chest pain, and peripheral edema.

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.

DOSAGE FORMS AND STRENGTHS:
Venofer is supplied sterile in 10 mL, 5 mL, and 2.5 mL single-use vials. Each 10 mL vial contains 200 mg elemental iron, each 5 mL vial contains 100 mg elemental iron, and each 2.5 mL vial contains 50 mg elemental iron (20 mg/mL).

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

Monitoring Parameters:
Patients receiving regular parenteral iron therapy require monitoring of hematologic parameters and iron indices (Hb, Hct, TSAT, and ferritin)
Sufficient IV iron should be administered to maintain TSAT between 20% and 50%. Iron therapy should be withheld in patients with TSAT ≥50%
Iron therapy should be withheld in patients with ferritin values ≥800 ng/mL. Since transferrin saturation values increase rapidly after IV administration of iron sucrose, serum iron values may be reliably obtained 48 hours after IV iron sucrose dosing .

Pharmacy Specifications:
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). [See USP Controlled Room Temperature]. Do not freeze.

Syringe Stability: Venofer, when diluted with 0.9% NaCl at concentrations ranging from 2 mg to 10 mg of elemental iron per mL, or undiluted (20 mg elemental 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).

IV Admixture Stability: Venofer, when added to IV infusion bags (PVC or non-PVC) containing 0.9% NaCl at concentrations ranging from 1 mg to 2 mg of elemental 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 Venofer 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.

Source:
Package Insert data: 

AMERICAN REGENT, INC.
SHIRLEY, NY 11967

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

Revised: 9/2012

INDICATIONS AND USAGE:
Injectafer is indicated for the treatment of iron deficiency anemia in adult patients:
    >who have intolerance to oral iron or have had unsatisfactory response to oral iron;
    >who have non-dialysis dependent chronic kidney disease.

USE IN SPECIFIC POPULATIONS --------------
Pregnancy
Pregnancy Category C
Risk Summary
Adequate and well controlled studies in pregnant women have not been conducted. However, animal reproduction studies have been conducted with ferric carboxymaltose. In these studies, administration of ferric carboxymaltose to rabbits during the period of organogenesis caused fetal malformations and increased implantation loss at maternally toxic doses of approximately 12% to 23% of the human weekly dose of 750 mg (based on body surface area). The incidence of major malformations in human pregnancies has not been established for Injectafer. However, all pregnancies, regardless of exposure to any drug, has a background rate of 2 to 4% for major malformations, and 15 to 20% for pregnancy loss. Injectafer should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.
Animal Data
Administration of ferric carboxymaltose to rats as a one-hour intravenous infusion up to 30 mg/kg/day iron on gestation days 6 to 17 did not result in adverse embryofetal findings. This daily dose in rats is approximately 40% of the human weekly dose of 750 mg based on body surface area. In rabbits, ferric carboxymaltose was administered as a one-hour infusion on gestation days 6 to 19 at iron doses of 4.5, 9, 13.5, and 18 mg/kg/day. Malformations were seen starting at the daily dose of 9 mg/kg (23% of the human weekly dose of 750 mg). Spontaneous abortions occurred starting at the daily iron dose of 4.5 mg/kg (12% of the human weekly dose based on body surface area). Pre-implantation loss was at the highest dose. Adverse embryofetal effects were observed in the presence of maternal toxicity.

A pre- and post-natal development study was conducted in rats at intravenous doses up to 18 mg/kg/day of iron (approximately 23% of the weekly human dose of 750 mg on a body surface area basis). There were no adverse effects on survival of offspring, their behavior, sexual maturation or reproductive parameters.

Nursing Mothers
A study to determine iron concentrations in breast milk after administration of Injectafer (n=11) or oral ferrous sulfate (n=14) was conducted in 25 lactating women with postpartum iron deficiency anemia. Mean breast milk iron levels were higher in lactating women receiving Injectafer than in lactating women receiving oral ferrous sulfate.

Pediatric Use
Safety and effectiveness have not been established in pediatric patients.

Geriatric Use
Of the 1775 subjects in clinical studies of Injectafer, 50% were 65 years and over, while 25% were 75 years and over. No overall differences in safety or effectiveness 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.

WARNINGS AND PRECAUTIONS:

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 Injectafer. Patients may present with shock, clinically significant hypotension, loss of consciousness, and/or collapse. Monitor patients for signs and symptoms of hypersensitivity during and after Injectafer administration for at least 30 minutes and until clinically stable following completion of the infusion. Only administer Injectafer when personnel and therapies are immediately available for the treatment of serious hypersensitivity reactions. [see Adverse Reactions ]. In clinical trials, serious anaphylactic/anaphylactoid reactions were reported in 0.1% (2/1775) of subjects receiving Injectafer. Other serious or severe adverse reactions potentially associated with hypersensitivity which included, but not limited to, pruritus, rash, urticaria, wheezing, or hypotension were reported in 1.5% (26/1775) of these subjects.
2. Hypertension
   In clinical studies, hypertension was reported in 3.8% (67/1,775) of subjects in clinical trials 1 and 2. Transient elevations in systolic blood pressure, sometimes occurring with facial flushing, dizziness, or nausea were observed in 6% (106/1,775) of subjects in these two clinical trials. These elevations generally occurred immediately after dosing and resolved within 30 minutes. Monitor patients for signs and symptoms of hypertension following each Injectafer administration [see Dosage and Administration].
3. Laboratory Test Alterations
   In the 24 hours following administration of Injectafer, laboratory assays may overestimate serum iron and transferrin bound iron by also measuring the iron in Injectafer.

DOSAGE AND ADMINISTRATION
For patients weighing 50 kg (110 lb) or more:  Give Injectafer in two doses separated by at least 7 days.  Give each dose as 750 mg for a total cumulative dose not to exceed 1500 mg of iron per course.

For patients weighing less than 50 kg (110 lb):  Give Injectafer in two doses separated by at least 7 days. Give each dose as 15 mg/kg body weight for a total cumulative dose not to exceed 1500 mg of iron per course. 

The dosage of Injectafer is expressed in mg of elemental iron. Each mL of Injectafer contains 50 mg of elemental iron.  Injectafer treatment may be repeated if iron deficiency anemia reoccurs.  

Administer Injectafer intravenously, either as an undiluted slow intravenous push or by infusion.  When administering as a slow intravenous push, give at the rate of approximately 100 mg (2 mL) per minute.  When administered via infusion, dilute up to 750 mg of iron in no more than 250 mL of sterile 0.9% sodium chloride injection, USP, such that the concentration of the infusion is not less than 2 mg of iron per mL and administer over at least 15 minutes.

When added to an infusion bag containing 0.9% sodium chloride injection, USP, at concentrations ranging from 2 mg to 4 mg of iron per mL, Injectafer solution is physically and chemically stable for 72 hours when stored at room temperature.  To maintain stability, do not dilute to concentrations less than 2 mg iron/mL.

Inspect parenteral drug products visually for the absence of particulate matter and discoloration prior to administration.  The product contains no preservatives. Each vial of Injectafer is intended for single-use only. Any unused drug remaining after injection must be discarded.

Avoid extravasation of Injectafer since brown discoloration of the extravasation site may be long lasting.  Monitor for extravasation.  If extravasation occurs, discontinue the Injectafer administration at that site.

SUMMARY

[Patients weighing 50 kg (110 lb) or more ]
May administer undiluted slow  intravenous push at ~ 100mg/min.
[750mg]  [15 ml]  [~7.5 minutes]

 -OR-
Administer via infusion, dilute up to 750 mg of iron in no more than 250 mL of sterile 0.9% sodium chloride injection, USP, such that the concentration of the infusion is in the range of 2 mg to 4 mg of iron per mL.
[750mg]  [250 ml]  [15-20 minutes]

Each mL of Injectafer contains 50 mg of elemental iron.

[Patients weighing LESS than 50 kg (110 lb) ]
May administer undiluted slow  intravenous push at ~ 100mg/min.
[15mg/kg ]  [dose (ml)=  (15mg/kg) / 50  ]  [~7.5 minutes]

 -OR-
Administer via infusion, dilute up to 750 mg of iron in no more than 250 mL of sterile 0.9% sodium chloride injection, USP, such that the concentration of the infusion is in the range of 2 mg to 4 mg of iron per mL.
[15 mg/kg]  [250 ml]  [15-20 minutes]

DOSAGE FORMS AND STRENGTHS:

750 mg iron/15 mL single-use vial.

NDC 0517-0650-01 750 mg iron/15 mL Single-Use Vial Individually boxed
NDC 0517-0650-02 750 mg iron/15 mL Single-Use Vial Packages of 2

DOSAGE AND ADMINISTRATION:
Summary:

• Adult Patients - The recommended adult dosage is 10mL (125 mg of elemental iron) diluted in 100 mL of 0.9% sodium chloride administered by intravenous infusion over 1 hour per dialysis session or undiluted as a slow intravenous injection (at a rate of up to 12.5 mg/min) per dialysis session.
• Pediatric Patients - The recommended pediatric dosage is 0.12 mL/kg (1.5 mg/kg of elemental iron) diluted in 25 mL 0.9% sodium chloride and administered by intravenous infusion over 1 hour per dialysis session.
• Do not mix Ferrlecit with other medications or add to parenteral nutrition solutions for intravenous infusion.
• Administer in 0.9% saline

Detailed info: 
The dosage of Ferrlecit is expressed in terms of mg of elemental iron. Each 5 mL sterile, single-use ampule or vial contains 62.5 mg of elemental iron (12.5 mg/mL).

Do not mix Ferrlecit with other medications, or add to parenteral nutrition solutions for intravenous infusion. The compatibility of Ferrlecit with intravenous infusion vehicles other than 0.9% sodium chloride has not been evaluated. Parenteral drug products should be inspected visually for particulate matter and discoloration before administration, whenever the solution and container permit. If diluted, use immediately.

Ferrlecit treatment may be repeated if iron deficiency reoccurs.

Adult Dosage and Administration
The recommended dosage of Ferrlecit for the repletion treatment of iron deficiency in hemodialysis patients is 10 mL of Ferrlecit (125 mg of elemental iron). Ferrlecit may be diluted in 100 mL of 0.9% sodium chloride administered by intravenous infusion over 1 hour per dialysis session. Ferrlecit may also be administered undiluted as a slow intravenous injection (at a rate of up to 12.5 mg/min) per dialysis session. For repletion treatment most patients may require a cumulative dose of 1000 mg of elemental iron administered over 8 dialysis sessions. Ferrlecit has been administered at sequential dialysis sessions by infusion or by slow intravenous injection during the dialysis session itself.

Data from Ferrlecit postmarketing spontaneous reports indicate that individual doses exceeding 125 mg may be associated with a higher incidence and/or severity of adverse events.

Pediatric Dosage and Administration
The recommended pediatric dosage of Ferrlecit for the repletion treatment of iron deficiency in hemodialysis patients is 0.12 mL/kg Ferrlecit (1.5 mg/kg of elemental iron) diluted in 25 mL 0.9% sodium chloride and administered by intravenous infusion over 1 hour per dialysis session. The maximum dosage should not exceed 125 mg per dose.

CONTRAINDICATIONS:
Known hypersensitivity to sodium ferric gluconate or any of its inactive components.

WARNINGS AND PRECAUTIONS

ADVERSE REACTIONS
The most commonly reported adverse reactions (≥10%) in adult patients were nausea, vomiting and/or diarrhea, injection site reaction, hypotension, cramps, hypertension, dizziness, dyspnea, chest pain, leg cramps and pain. In patients 6 to 15 years of age the most common adverse reactions (≥10%) were hypotension, headache, hypertension, tachycardia and vomiting.

DOSAGE FORMS AND STRENGTHS::
Ferrlecit is supplied in a single use ampule or vial containing 62.5 mg of elemental iron in 5 mL.

Source:
Package Insert data: 
sanofi-aventis U.S. LLC
Bridgewater, NJ 08807
©2011 sanofi-aventis U.S. LLC
Revised: 8/2011

Initial U.S. Approval:  2015

Mechanism of Action: Triferic contains iron in the form of ferric pyrophosphate citrate and is added to hemodialysate solution to be administered to patients by transfer across the dialyzer membrane. Iron delivered into the circulation binds to transferrin for transport to erythroid precursor cells to be incorporated into hemoglobin.

INDICATIONS AND USAGE:
TRIFERIC is indicated for the replacement of iron to maintain hemoglobin in adult patients with hemodialysis-dependent chronic kidney disease (HDD- CKD).

Limitation of Use
Triferic is not intended for use in patients receiving peritoneal dialysis. ( 1.1)
Triferic has not been studied in patients receiving home hemodialysis ( 1.1)

HOW SUPPLIED:
Ampule: 27.2 mg of iron (III) per 5 mL (5.44 mg of iron (III) per mL).
Multiple dose ampule 272 mg iron (III) per 50 mL .(5.44 mg Fe (III)/mL)

Normal Serum Iron Levels

See IV dilution section. Also see iron dextran calculator.

Alternatively: 
(a) 500mg slow IV infusion on day 1 and day 14.

OR

(b) 300 mg, 300 mg, then 400mg - each dose 14 days apart,

b. Jain AK, Bastani B. Safety profile of a high dose ferric gluconate in patients with severe chronic renal insufficiency. J Nephrol 2002;15:681-3.

c.Javier AM. Weekly administration of high-dose sodium ferric gluconate is safe and effective in peritoneal dialysis patients. Nephrol Nurs J 2002;29:183-6.

d. Seligman PA, Dahl NV, Strobos J, Kimko HC, Schleicher RB, Jones M, Ducharme MP. Single-dose pharmacokinetics of sodium ferric gluconate complex in iron-deficient subjects.Pharmacotherapy. 2004 May;24(5):574-83.