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A S E R V I C E P R O V I D E D B Y
®
A guide to the Injectafer® (ferric carboxymaltose injection)
and Venofer® (iron sucrose injection, USP)
INDICATIONS FOR INJECTAFER®Injectafer® is an iron replacement product indicated for the treatment of iron deficiency anemia in adult patients: • who have intolerance to or have had
unsatisfactory response to oral iron or
• who have non-dialysis dependent chronic kidney disease
CONTRAINDICATIONS FOR INJECTAFER®Injectafer® is contraindicated in patients with hypersensitivity to Injectafer® or any of its inactive components.
INDICATION FOR VENOFER®Venofer® is indicated for the treatment of iron deficiency anemia in patients with chronic kidney disease.
CONTRAINDICATIONS FOR VENOFER®Venofer® is contraindicated in patients with known hypersensitivity to Venofer®.
IV Iron Hotline Reimbursement & Patient Assistance Program
Please see attached Full Prescribing Information for Injectafer® and Venofer® and Important Safety Information on Pages 6 and 7.
For more information, please visit Injectafer.com
F O R R E I M B U R S E M E N T A S S I S TA N C E , P L E A S E C O N TA C T :
IV Iron Reimbursement Hotline1-877-4-IV-IRON (1-877-448-4766)
Monday through Friday between 9:00 AM and 8:00 PM, ET
SELECTED SAFETY INFORMATION FOR INJECTAFER®
WARNINGS AND PRECAUTIONSSerious 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.
Please see attached Full Prescribing Information for Injectafer® and Venofer® and Important Safety Information on Pages 6 and 7.
Reimbursement and Patient SupportAmerican Regent, Inc. has created a toll-free hotline to help physicians and other providers understand payers’ coverage and reimbursement policies for Injectafer® (ferric carboxymaltose injection) and Venofer® (iron sucrose injection, USP). When necessary, additional assistance is available to address reimbursement questions and concerns.
SELECTED SAFETY INFORMATION FOR VENOFER®
WARNINGS AND PRECAUTIONSSerious hypersensitivity reactions, including anaphylactic-type reactions, some of which have been life-threatening and fatal, have been reported in patients receiving Venofer®. 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 Venofer® immediately. Monitor patients for signs and symptoms of hypersensitivity during and after Venofer® administration for at least 30 minutes and until clinically stable following completion of the infusion. Only administer Venofer® when personnel and therapies are immediately available for the treatment of serious hypersensitivity reactions. Most reactions associated with intravenous iron preparations occur within 30 minutes of the completion of the infusion.
Hotline Reimbursement Specialists Can Assist With the Following:IInsuuuraannce VVVVerififificaattion Reqqquuests
Help providers verify payer coverage and reimbursement policies for Injectafer® and Venofer®. Reimbursement Specialists will determine patients’ benefit levels and discuss potential billing options with patient consent. An Insurance Verification Request Form can be downloaded at www.injectafer.com
BBillinngg aaand Codddinnggg Asssistaanceee
Assist providers with the proper completion of claim forms to facilitate appropriate reimbursement.
CClaimms AApppppealss
Support providers in appealing denied claims or inadequate reimbursement for Injectafer® and Venofer®. The hotline helps track claims throughout the appeals process, which includes regular follow-up with payers to facilitate reimbursement. If a claim is denied, our program staff is available to coordinate the appeals process through the development of letters of medical necessity and coverage appeal request letters.
PPatiennt Assiistannccee
Screen individuals without health insurance who are ineligible for public assistance for enrollment in a product replacement program. Please visit www.injectafer.com to download a copy of this form.
Patient information will be kept strictly confidential at all times.Every attempt is made to provide accurate, up-to-date information. The IV Iron Reimbursement Hotline cannot guarantee successful reimbursement.For American Regent’s Customer Service or Medical Affairs departments or to report an adverse reaction, please call 1-800-645-1706.
Patient Assistance ProgramAA ppproogggrammmm ffoorr pppatienttss wwwhoooo lacckk iinsuurranceeee cooovverraggeeAmerican Regent, Inc. created the IV Iron Patient Assistance Program to improve access to Injectafer® (ferric carboxymaltose injection) and Venofer® (iron sucrose injection, USP) for patients who lack health insurance and cannot afford therapy. If a patient is eligible, American Regent, Inc. will replace the Injectafer® or Venofer® provided free of charge while the patient is enrolled in the program. American Regent, Inc. reserves the right to modify or cancel the program immediately with respect to any patient, or in its entirety, at any time.
Progggrammm Eliigibbilittyy
To be eligible for the program, patients must completely lack health insurance and be ineligible for public insurance or financing. The patient must also be a US citizen, legal entrant in the United States, or permanent resident. Proof of citizenship or legal residency may also be required. Patients must also meet income and other criteria as established by American Regent, Inc.
Howww ttoo Appply
Providers (hospitals, physicians, or infusion centers) may apply to the Program on behalf of their patients. Please visit www.injectafer.com to download an enrollment application.
SELECTED SAFETY INFORMATION FOR INJECTAFER®
WARNINGS AND PRECAUTIONSIn clinical studies, hypertension was reported in 3.8% (67/1775) of subjects. Transient elevations in systolic blood pressure, sometimes occurring with facial flushing, dizziness, or nausea were observed in 6% (106/1775) of subjects. These elevations generally occurred immediately after dosing and resolved within 30 minutes. Monitor patients for signs and symptoms of hypertension following each Injectafer® administration.
Please see attached Full Prescribing Information for Injectafer® and Venofer® and Important Safety Information on Pages 6 and 7.
F O R R E I M B U R S E M E N T A S S I S TA N C E , P L E A S E C O N TA C T :
IV Iron Reimbursement Hotline1-877-4-IV-IRON (1-877-448-4766)Monday through Friday between 9:00 AM and 8:00 PM, ET
SELECTED SAFETY INFORMATION FOR VENOFER®
WARNINGS AND PRECAUTIONSVenofer® may cause clinically significant hypotension. Monitor for signs and symptoms of hypotension following each administration of Venofer®. Hypotension following administration of Venofer® may be related to rate of administration and/or total dose delivered.
Getting Started With the IV Iron Reimbursement Hotline
Insurance Verification Request
Download an Insurance Verification Request Form at www.injectafer.com
Submit Insurance Verification Request Form
Complete all information on this form– Patient consent required– Fax to IV Iron Reimbursement Hotline at 1-240-632-3805
Insurance Verified by IV Iron Reimbursement Hotline
If the patient is insured, you will receive a detailed insurance coverage profile. If the patient is uninsured, your patient will be assessed for eligibility in the Patient Assistance Program.
Step 1
Step 2
Step 3
ALL PROGRAM FORMS SHOULD BE SENT TO:
Injectafer® and Venofer® Patient Assistance Program c/o InTeleCenter™P.O. Box 4280Gaithersburg, MD 20885-4133
Fax: 1-240-632-3805
INJECTAFER® (FERRIC CARBOXYMALTOSE INJECTION)
INDICATIONSInjectafer® (ferric carboxymaltose injection) is an iron replacement product 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, and in adult patients with non-dialysis dependent chronic kidney disease.
IMPORTANT SAFETY INFORMATION
CONTRAINDICATIONSInjectafer® is contraindicated in patients with hypersensitivity to Injectafer® or any of its inactive components.
WARNINGS AND PRECAUTIONSSerious 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. 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 were not limited to, pruritus, rash, urticaria, wheezing, or hypotension were reported in 1.5% (26/1775) of these subjects.
In clinical studies, hypertension was reported in 3.8% (67/1775) of subjects. Transient elevations in systolic blood pressure, sometimes occurring with facial flushing, dizziness, or nausea were observed in 6% (106/ 1775) of subjects. These elevations generally occurred immediately after dosing and resolved within 30 minutes. Monitor patients for signs and symptoms of hypertension following each Injectafer® administration.
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®.
ADVERSE REACTIONSIn two randomized clinical studies, a total of 1775 patients were exposed to Injectafer®, 15 mg/kg of body weight, up to a single maximum dose of 750 mg of iron on two occasions, separated by at least 7 days, up to a cumulative dose of 1500 mg of iron. Adverse reactions reported by ≥2% of Injectafer®-treated patients were nausea (7.2%); hypertension (3.8%); flushing/hot flush (3.6%); blood phosphorus decrease (2.1%); and dizziness (2.0%).
The following serious adverse reactions have been most commonly reported from the post-marketing spontaneous reports: urticaria, dyspnea, pruritus, tachycardia, erythema, pyrexia, chest discomfort, chills, angioedema, back pain, arthralgia, and syncope.
VENOFER® (IRON SUCROSE INJECTION, USP)
INDICATIONVenofer® is indicated for the treatment of iron deficiency anemia in patients with chronic kidney disease.
IMPORTANT SAFETY INFORMATION
CONTRAINDICATIONSVenofer® is contraindicated in patients with known hypersensitivity to Venofer®.
WARNINGS AND PRECAUTIONSSerious hypersensitivity reactions, including anaphylactic-type reactions, some of which have been life-threatening and fatal, have been reported in patients receiving Venofer® (iron sucrose injection, USP). 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 Venofer® immediately. Monitor patients for signs and symptoms of hypersensitivity during and after Venofer® administration for at least 30 minutes and until clinically stable following completion of the infusion. Only administer Venofer® when personnel and therapies are immediately available for the treatment of serious hypersensitivity reactions. Most reactions associated with intravenous iron preparations occur within 30 minutes of the completion of the infusion.
Venofer® may cause clinically significant hypotension. Monitor for signs and symptoms of hypotension following each administration of Venofer®. Hypotension following administration of Venofer® may be related to rate of administration and/or total dose delivered.
Excessive therapy with parenteral iron can lead to excess storage of iron with the possibility of iatrogenic hemosiderosis. All adult and pediatric patients receiving Venofer® require periodic monitoring of hematologic and iron parameters (hemoglobin, hematocrit, serum ferritin and transferrin saturation). Do not administer Venofer® to patients with evidence of iron overload. Transferrin saturation (TSAT) values increase rapidly after intravenous administration of iron sucrose; do not perform serum iron measurements for at least 48 hours after intravenous dosing.
ADVERSE REACTIONSThe 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. Additional adverse reactions include infusion site pain or burning, graft complications, and nasopharyngitis, sinusitis, upper respiratory tract infections and pharyngitis.
In pediatric patients, more than 50% of the patients experienced at least one treatment-emergent reaction. The most common adverse reactions (≥2%) were headache, respiratory tract viral infection, peritonitis, vomiting, pyrexia, dizziness, cough, renal transplant, nausea, arteriovenous fistula thrombosis, hypotension and hypertension.
In post-marketing safety studies of Venofer® in 1,051 patients with HDD-CKD, adverse reactions reported by >1% were cardiac failure congestive, sepsis and dysgeusia.
Because adverse reactions from post-marketing experience 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 addition to potential serious hypersensitivity reactions, the following adverse reactions have been identified during post-approval use of Venofer®: bronchospasm, dyspnea, convulsions, light-headedness, confusion, angioedema, swelling of the joints, hyperhidrosis, bradycardia and chromaturia.
Symptoms associated with Venofer® 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 Venofer® injections. Reactions have occurred following the first dose or subsequent doses of Venofer®. Slowing the infusion rate may alleviate symptoms.
Injection site discoloration has been reported following extravasation. Assure stable intravenous access to avoid extravasation.
Please see attached Full Prescribing Information for Injectafer® and Venofer®.
VENOFER® IMPORTANT SAFETY INFORMATION (CONTINUED)
WARNINGS AND PRECAUTIONS (CONTINUED)
American Regent® is a registered trademark of Luitpold Pharmaceuticals, Inc.
Venofer®, Injectafer® and the Injectafer® logo are trademarks of Vifor (International), Inc., Switzerland. Venofer® and Injectafer® are manufactured under license from Vifor (International), Inc., Switzerland.
©2015 American Regent, Inc. FCM197EM Iss. 07/2015
PLEASE NOTE:This guide is not intended to provide legal, medical, or other professional advice. This information is provided as reference only. American Regent, Inc. makes no representations or guarantees regarding the completeness or accuracy of the information in this guide and has no obligation to update this guide to reflect changes in laws that may affect reimbursement for Injectafer® (ferric carboxymaltose injection) or Venofer® (iron sucrose injection, USP). For assistance with legal or medical issues, you are urged to consult a qualified professional.
®
Please see attached Full Prescribing Information for Injectafer® and Venofer® andImportant Safety Information on pages 6 and 7.
FULL PRESCRIBING INFORMATION1 INDICATIONS AND USAGEVenofer is indicated for the treatment of iron deficiency anemia in patients with chronic kidney disease (CKD).2 DOSAGE AND ADMINISTRATIONVenofer must only be administered intravenously either by slow injection or by infusion. The dosage of Venofer is expressed in mg of elemental iron. EachmL contains 20 mg of elemental iron.2.1 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 of0.9% 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. 2.2 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 infusionof 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 repeatedif iron deficiency reoccurs. 2.3 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 apartfollowed 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 repeatedif iron deficiency reoccurs. 2.4 Pediatric Patients (2 years of age and older) with HDD-CKD for iron maintenance treatmentThe 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 undilutedby 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 repeatedif necessary.2.5 Pediatric Patients (2 years of age and older) with NDD-CKD or PDD-CKD who are on erythropoietin therapy for iron maintenance treatmentThe 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 undilutedby 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 repeatedif necessary.3 DOSAGE FORMS AND STRENGTHS
• 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)
4 CONTRAINDICATIONS• Known hypersensitivity to Venofer
5 WARNINGS AND PRECAUTIONS5.1 Hypersensitivity ReactionsSerious hypersensitivity reactions, including anaphylactic-type reactions, some of which have been life-threatening and fatal, have been reported inpatients receiving Venofer. Patients may present with shock, clinically significant hypotension, loss of consciousness, and/or collapse. Ifhypersensitivity reactions or signs of intolerance occur during administration, stop Venofer immediately. Monitor patients for signs and symptomsof hypersensitivity during and after Venofer administration for at least 30 minutes and until clinically stable following completion of the infusion. Onlyadminister Venofer when personnel and therapies are immediately available for the treatment of serious hypersensitivity reactions. Most reactionsassociated with intravenous iron preparations occur within 30 minutes of the completion of the infusion [see Adverse Reactions (6.1 and 6.2)]. 5.2 HypotensionVenofer may cause clinically significant hypotension. Monitor for signs and symptoms of hypotension following each administration of Venofer. Hypotensionfollowing administration of Venofer may be related to the rate of administration and/or total dose administered [See Dosage and Administration (2),Warnings and Precautions (5.1), and Adverse Reactions (6.2)].5.3 Iron OverloadExcessive therapy with parenteral iron can lead to excess storage of iron with the possibility of iatrogenic hemosiderosis. All adult and pediatric patientsreceiving Venofer require periodic monitoring of hematologic and iron parameters (hemoglobin, hematocrit, serum ferritin and transferrin saturation). Donot administer Venofer to patients with evidence of iron overload. Transferrin saturation (TSAT) values increase rapidly after intravenous administrationof iron sucrose; do not perform serum iron measurements for at least 48 hours after intravenous dosing [See Dosage and Administration (2) and Overdosage(10)].6 ADVERSE REACTIONSThe following serious adverse reactions associated with Venofer are described in other sections [See Warnings and Precautions (5.1, 5.2 and 5.3)].6.1 Adverse Reactions in Clinical TrialsBecause clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug may not reflect the ratesobserved in practice.Adverse Reactions in Adult Patients with CKDThe frequency of adverse reactions associated with the use of Venofer 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 ³ 2% of treated patients in the six clinicaltrials for which the rate for Venofer exceeds the rate for comparator are listed by indication in Table 1. Patients with HDD-CKD received 100 mg doses at10 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 aperiod of 4 weeks.
Table 1. Treatment-Emergent Adverse Reactions Reported in ³ 2% of Study Populations and for which the Rate for Venofer Exceeds the Rate forComparator
* EPO=ErythropoietinOne 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) hadprior other intravenous iron therapy and were reported to be intolerant (defined as precluding further use of that iron product). When these patients weretreated with Venofer there were no occurrences of adverse reactions that precluded further use of Venofer [See Warning and Precautions (5)].
Adverse Reactions(Preferred Term)
HDD-CKD NDD-CKD PDD-CKDVenofer Venofer Oral Iron Venofer EPO* Only(N=231) (N=139) (N=139) (N=75) (N=46)% % % % %
Subjects with any adverse reaction 78.8 76.3 73.4 72.0 65.2Ear and Labyrinth DisordersEar Pain 0 2.2 0.7 0 0
Eye DisordersConjunctivitis 0.4 0 0 2.7 0
Gastrointestinal DisordersAbdominal pain 3.5 1.4 2.9 4.0 6.5Diarrhea 5.2 7.2 10.1 8.0 4.3Dysgeusia 0.9 7.9 0 0 0Nausea 14.7 8.6 12.2 5.3 4.3Vomiting 9.1 5.0 8.6 8.0 2.2
General Disorders andAdministration Site ConditionsAsthenia 2.2 0.7 2.2 2.7 0Chest pain 6.1 1.4 0 2.7 0Feeling abnormal 3.0 0 0 0 0Infusion site pain or burning 0 5.8 0 0 0Injection site extravasation 0 2.2 0 0 0Peripheral edema 2.6 7.2 5.0 5.3 10.9Pyrexia 3.0 0.7 0.7 1.3 0
Infections and InfestationsNasopharyngitis, Sinusitis, Upper respiratory tract infections, Pharyngitis 2.6 2.2 4.3 16.0 4.3
Injury, Poisoning and ProceduralComplicationsGraft complication 9.5 1.4 0 0 0
Metabolism and Nutrition DisordersFluid overload 3.0 1.4 0.7 1.3 0Gout 0 2.9 1.4 0 0Hyperglycemia 0 2.9 0 0 2.2Hypoglycemia 0.4 0.7 0.7 4.0 0
Musculoskeletal and ConnectiveTissue DisordersArthralgia 3.5 1.4 2.2 4.0 4.3Back pain 2.2 2.2 3.6 1.3 4.3Muscle cramp 29.4 0.7 0.7 2.7 0Myalgia 0 3.6 0 1.3 0Pain in extremity 5.6 4.3 0 2.7 6.5
Nervous System DisordersDizziness 6.5 6.5 1.4 1.3 4.3Headache 12.6 2.9 0.7 4.0 0
Respiratory, Thoracic andMediastinal DisordersCough 3.0 2.2 0.7 1.3 0Dyspnea 3.5 5.8 1.4 1.3 2.2Nasal congestion 0 1.4 2.2 1.3 0
Skin and SubcutaneousTissue DisordersPruritus 3.9 2.2 4.3 2.7 0
Vascular DisordersHypertension 6.5 6.5 4.3 8.0 6.5Hypotension 39.4 2.2 0.7 2.7 2.2
HIGHLIGHTS OF PRESCRIBING INFORMATIONThese highlights do not include all the information needed to use VENOFER safely and effectively. See fullprescribing information for VENOFER.Venofer ® (iron sucrose injection, USP)Initial U.S. Approval: 2000----------------------------------------------------INDICATIONS AND USAGE ---------------------------------------------------Venofer is an iron replacement product indicated for the treatment of iron deficiency anemia in patients with chronickidney disease (CKD). (1)------------------------------------------------DOSAGE AND ADMINISTRATION------------------------------------------------
----------------------------------------------DOSAGE FORMS AND STRENGTHS ----------------------------------------------• 10 mL single-use vial / 200 mg elemental iron (20 mg/mL) (3)• 5 mL single-use vial / 100 mg elemental iron (20 mg/mL) (3)• 2.5 mL single-use vial / 50 mg elemental iron (20 mg/mL) (3)------------------------------------------------------CONTRAINDICATIONS ------------------------------------------------------• Known hypersensitivity to Venofer (4) ------------------------------------------------WARNINGS AND PRECAUTIONS ------------------------------------------------• Hypersensitivity Reactions: Observe for signs and symptoms of hypersensitivity during and after Venoferadministration for at least 30 minutes and until clinically stable following completion of each administration. Onlyadminister Venofer when personnel and therapies are immediately available for the treatment of serioushypersensitivity reactions. (5.1)
• Hypotension: Venofer may cause hypotension. Monitor for signs and symptoms of hypotension during andfollowing each administration of Venofer. (5.2)
• Iron Overload: Regularly monitor hematologic responses during Venofer therapy. Do not administer Venofer topatients with iron overload. (5.3)
------------------------------------------------------ADVERSE REACTIONS ------------------------------------------------------• The most common adverse reactions (³2%) following the administration of Venofer are diarrhea, nausea, vomiting,headache, dizziness, hypotension, pruritus, pain in extremity, arthralgia, back pain, muscle cramp, injection sitereactions, 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.
See 17 for PATIENT COUNSELING INFORMATION Revised: 1/2014
Population DoseAdult patients Hemodialysis Dependent-
Chronic Kidney Disease (HDD-CKD) (2.1)
100 mg slow intravenous injection or infusion
Non-Dialysis Dependent-Chronic Kidney Disease (NDD-CKD) (2.2)
200 mg slow intravenous injection or infusion
Peritoneal Dialysis Dependent-Chronic Kidney Disease (PDD-CKD) (2.3)
300 mg or 400 mg intravenous infusion
Pediatric patients HDD-CKD (2.4), PDD-CKD or NDD-CKD (2.5)
0.5 mg/kg slow intravenous injection or infusion
FULL PRESCRIBING INFORMATION: CONTENTS*1 INDICATIONS AND USAGE 2 DOSAGE AND ADMINISTRATION
2.1 Adult Patients with Hemodialysis Dependent-Chronic Kidney Disease (HDD-CKD)2.2 Adult Patients with Non-Dialysis Dependent-Chronic Kidney Disease (NDD-CKD)2.3 Adult Patients with Peritoneal Dialysis Dependent-Chronic Kidney Disease (PDD-CKD)2.4 Pediatric Patients (2 years of age and older) with HDD-CKD for iron maintenance treatment2.5 Pediatric Patients (2 years of age and older) with NDD-CKD or PDD-CKD who are on erythropoietin therapy for iron maintenance treatment
3 DOSAGE FORMS AND STRENGTHS4 CONTRAINDICATIONS5 WARNINGS AND PRECAUTIONS
5.1 Hypersensitivity Reactions5.2 Hypotension5.3 Iron Overload
6 ADVERSE REACTIONS6.1 Adverse Reactions in Clinical Trials6.2 Adverse Reactions from Post-Marketing Experience
7 DRUG INTERACTIONS8 USE IN SPECIFIC POPULATIONS
8.1 Pregnancy8.3 Nursing Mothers8.4 Pediatric Use8.5 Geriatric Use
10 OVERDOSAGE11 DESCRIPTION12 CLINICAL PHARMACOLOGY
12.1 Mechanism of Action12.2 Pharmacodynamics12.3 Pharmacokinetics
13 NONCLINICAL TOXICOLOGY13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
14 CLINICAL STUDIES14.1 Study A: Hemodialysis Dependent-Chronic Kidney Disease (HDD-CKD)14.2 Study B: Hemodialysis Dependent-Chronic Kidney Disease (HDD-CKD)14.3 Study C: Hemodialysis Dependent-Chronic Kidney Disease (HDD-CKD)14.4 Study D: Non-Dialysis Dependent-Chronic Kidney Disease (NDD-CKD)14.5 Study E: Peritoneal Dialysis Dependent-Chronic Kidney Disease (PDD-CKD)14.6 Study F: Iron Maintenance Treatment Dosing in Pediatric Patients Ages 2 years and Older with Chronic Kidney Disease
16 HOW SUPPLIED/STORAGE AND HANDLING16.1 How Supplied16.2 Stability and Storage
17 PATIENT COUNSELING INFORMATION* Sections or subsections omitted from the full prescribing information are not listed.
Rx Only
(iron sucrose injection, USP)
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Rx Only
(iron sucrose injection, USP)
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Rx Only
(iron sucrose injection, USP)
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Rx Only
(iron sucrose injection, USP)
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Adverse Reactions in Pediatric Patients with CKD (ages 2 years and older)In a randomized, open-label, dose-ranging trial for iron maintenance treatment with Venofer in pediatric patients with CKD on stable erythropoietin therapy[see Clinical Studies (14.6)], at least one treatment-emergent adverse reaction was experienced by 57% (27/47) of the patients receiving Venofer 0.5 mg/kg,53% (25/47) of the patients receiving Venofer 1.0 mg/kg, and 55% (26/47) of the patients receiving Venofer 2.0 mg/kg. A total of 5 (11%) subjects in the Venofer 0.5 mg/kg group, 10 (21%) patients in the Venofer 1.0 mg/kg group, and 10 (21%) patients in the Venofer 2.0 mg/kg group experienced at least 1 serious adverse reaction during the study. The most common treatment-emergent adverse reactions (> 2% ofpatients) 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 ExperienceBecause these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establisha 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, sepsisand dysgeusia.The following adverse reactions have been identified during post-approval use of Venofer. Because these reactions are reported voluntarily from a populationof 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 Venofer 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 theadministration of Venofer injection. Reactions have occurred following the first dose or subsequent doses of Venofer. Symptoms may respond to intravenousfluids, 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 INTERACTIONSDrug interactions involving Venofer have not been studied. However, Venofer may reduce the absorption of concomitantly administered oral iron preparations.8 USE IN SPECIFIC POPULATIONS8.1 PregnancyPregnancy Category BThere are no adequate and well-controlled studies in pregnant women. In animal reproduction studies, iron sucrose was administered intravenously to ratsand rabbits during the period of organogenesis at doses up to 13 mg/kg/day of elemental iron (half or equivalent to the maximum recommended humandose based on body surface area, respectively) and revealed no evidence of harm to the fetus due to iron sucrose. Because animal reproductive studiesare not always predictive of human response, Venofer should be used during pregnancy only if clearly needed.8.3 Nursing MothersIt is not known whether iron sucrose is excreted in human milk. Iron sucrose is secreted into the milk of lactating rats. Because many drugs are excretedin human milk, caution should be exercised when Venofer is administered to a nursing woman.8.4 Pediatric Use Safety and effectiveness of Venofer for iron replacement treatment in pediatric patients with dialysis-dependent or non-dialysis-dependent CKD have notbeen established.Safety and effectiveness of Venofer for 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. Venofer at doses of 0.5 mg/kg, 1.0 mg/kg, and 2.0 mg/kg was administered. All three dosesmaintained 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 ClinicalStudies (14.6)]Venofer has not been studied in patients younger than 2 years of age.In a country where Venofer is available for use in children, at a single site, five premature infants (weight less than 1,250 g) developed necrotizing enterocolitisand two of the five died during or following a period when they received Venofer, several other medications and erythropoietin. Necrotizing enterocolitismay be a complication of prematurity in very low birth weight infants. No causal relationship to Venofer or any other drugs could be established. 8.5 Geriatric Use Clinical studies of Venofer did not include sufficient numbers of subjects aged 65 years and older to determine whether they respond differently fromyounger subjects. Of the 1,051 patients in two post-marketing safety studies of Venofer, 40% were 65 years and older. No overall differences in safetywere observed between these subjects and younger subjects, and other reported clinical experience has not identified differences in responses betweenthe elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out. In general, dose administration to an elderly patientshould be cautious, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy. 10 OVERDOSAGENo data are available regarding overdosage of Venofer in humans. Excessive dosages of Venofer may lead to accumulation of iron in storage sites potentiallyleading to hemosiderosis. Do not administer Venofer to patients with iron overload. [See Contraindications (4)]Toxicities in single-dose studies in mice and rats, at intravenous iron sucrose doses up to 8 times the maximum recommended human dose based on bodysurface area, included sedation, hypoactivity, pale eyes, bleeding in the gastrointestinal tract and lungs, and mortality.11 DESCRIPTIONVenofer (iron sucrose injection, USP), an iron replacement product, is a brown, sterile, aqueous, complex of polynuclear iron (III)-hydroxide in sucrose forintravenous use. 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 iron polymerization and m is the number of sucrose molecules associated with the iron (III)-hydroxide.Each mL contains 20 mg elemental iron as iron sucrose in water for injection. Venofer is available in 10 mL single-use vials (200 mg elemental iron per 10 mL), 5 mL single-use vials (100 mg elemental iron per 5 mL), and 2.5 mL single-use vials (50 mg elemental iron per 2.5 mL). The drug product containsapproximately 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 PHARMACOLOGY12.1 Mechanism of ActionVenofer is an aqueous complex of poly-nuclear iron (III)-hydroxide in sucrose. Following intravenous administration, Venofer is dissociated into iron andsucrose and the iron is transported as a complex with transferrin to target cells including erythroid precursor cells. The iron in the precursor cells isincorporated into hemoglobin as the cells mature into red blood cells.12.2 PharmacodynamicsFollowing 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 increasesin serum iron and serum ferritin and significant decreases in total iron binding capacity occurred four weeks from the initiation of iron sucrose treatment. 12.3 PharmacokineticsIn healthy adults administered intravenous doses of Venofer, its iron component exhibited first order kinetics with an elimination half-life of 6 h, totalclearance of 1.2 L/h, and steady state apparent volume of distribution of 7.9 L. The iron component appeared to distribute mainly in blood and to someextent in extravascular fluid. A study evaluating Venofer containing 100 mg of iron labeled with 52Fe/59Fe in patients with iron deficiency showed that asignificant amount of the administered iron is distributed to the liver, spleen and bone marrow and that the bone marrow is an irreversible iron trappingcompartment.Following intravenous administration of Venofer, iron sucrose is dissociated into iron and sucrose. The sucrose component is eliminated mainly by urinaryexcretion. In a study evaluating a single intravenous dose of Venofer containing 1,510 mg of sucrose and 100 mg of 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 iron was also eliminated in the urine. Neithertransferrin nor transferrin receptor levels changed immediately after the dose administration. In this study and another study evaluating a single intravenousdose of iron sucrose containing 500 to 700 mg of iron in 26 patients with anemia on erythropoietin therapy (23 female, 3 male; age range 16 to 60),approximately 5% of the iron was eliminated in urine in 24 h at each dose level. The effects of age and gender on the pharmacokinetics of Venofer havenot been studied.Pharmacokinetics in Pediatric PatientsIn a single-dose PK study of Venofer, patients with NDD-CDK ages 12 to 16 (N=11) received intravenous bolus doses of Venofer at 7 mg/kg (maximum 200 mg) administered over 5 minutes. Following single dose Venofer, the half-life of total serum iron was 8 hours. The mean Cmax and AUC values were8545 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.Venofer is not dialyzable through CA210 (Baxter) High Efficiency or Fresenius F80A High Flux dialysis membranes. In in vitro studies, the amount of ironsucrose in the dialysate fluid was below the levels of detection of the assay (less than 2 parts per million).13 NONCLINICAL TOXICOLOGY13.1 Carcinogenesis, Mutagenesis, Impairment of FertilityCarcinogenicity studies have not been performed with iron sucrose. Iron sucrose was not mutagenic in vitro in the bacterial reverse mutation assay (Ames test) or the mouse lymphoma assay. Iron sucrose was not clastogenicin the in vitro chromosome aberration assay using human lymphocytes or in the in vivo mouse micronucleus assay.Iron sucrose at intravenous doses up to 15 mg/kg/day of elemental 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 STUDIESFive clinical trials involving 647 adult patients and one clinical trial involving 131 pediatric patients were conducted to assess the safety and efficacy of Venofer. 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 Venofer treatment and 24 in the historicalcontrol group) with iron deficiency anemia. Eligibility criteria for Venofer treatment included patients undergoing chronic hemodialysis, receivingerythropoietin, hemoglobin level between 8.0 and 11.0 g/dL, transferrin saturation < 20%, and serum ferritin < 300 ng/mL. The mean age of the patientswas 65 years with the age range of 31 to 85 years. Of the 77 patients, 44 (57%) were male and 33 (43%) were female.Venofer 100 mg was administered at 10 consecutive dialysis sessions either as slow injection or a slow infusion. The historical control population consistedof 24 patients with similar ferritin levels as patients treated with Venofer, who were off intravenous iron for at least 2 weeks and who had receivederythropoietin therapy with hematocrit averaging 31 to 36 for at least two months prior to study entry. The mean age of patients in the historical controlgroup 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 Venofer treated population showed a greater increase in hemoglobin and hematocrit than did patients in the historical control population.See Table 2.Table 2. Changes from Baseline in Hemoglobin and Hematocrit
Serum ferritin increased at endpoint of study from baseline in the Venofer-treated population (165.3 ± 24.2 ng/mL) compared to the historical controlpopulation (-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 (HDD-CKD) Study B was a multicenter, open label study of Venofer in 23 patients with iron deficiency and HDD-CKD who had been discontinued from iron dextran dueto 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 (HDD-CKD) 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 transferrinsaturation 20%, and a serum ferritin 200 ng/mL, who were undergoing maintenance hemodialysis 2 to 3 times weekly. The mean age of the patientsenrolled 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 and62 (48%) were female. Forty-eight percent of the patients had previously been treated with oral iron. Exclusion criteria were similar to those in studies Aand B. Venofer was administered in doses of 100 mg during sequential dialysis sessions until a pre-determined (calculated) total dose of iron wasadministered. 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 receivingerythropoietin 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%), serumferritin (434.6 ng/mL), and serum transferrin saturation (14%) were observed at week 2 of the observation period and these values remained increased atweek 4 of the observation period.14.4 Study D: Non-Dialysis Dependent-Chronic Kidney Disease (NDD-CKD)Study D was a randomized, open-label, multicenter, active-controlled study of the safety and efficacy of oral iron versus Venofer in patients with NDD-CKDwith 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 iron (325 mg ferrous sulfate three timesdaily for 56 days); or Venofer (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 over3.5 to 4 hours). The mean age of the 91 treated patients in the Venofer 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 iron group. A statistically significantly greater proportion of Venofer subjects (35/79; 44.3%) compared to oral iron subjects (23/82; 28%) had an increase in hemoglobin³ 1 g/dL at anytime during the study (p = 0.03).14.5 Study E: Peritoneal Dialysis Dependent-Chronic Kidney Disease (PDD-CKD)Study E was a randomized, open-label, multicenter study comparing patients with PDD-CKD receiving an erythropoietin and intravenous iron to patientswith PDD-CKD receiving an erythropoietin alone without 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 iron or Venofer (300 mg in 250 mL 0.9% NaCl over 1.5 hours onDay 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 Venofer / erythropoietin groupwas 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 Venofer / 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 Venofer / erythropoietin (59.1 %) had an increase in hemoglobin of ³ 1 g/dL at any time during the study compared to the subjects who received erythropoietin only (33.3%). 14.6 Study F: Iron Maintenance Treatment Dosing in Pediatric Patients Ages 2 years and Older with Chronic Kidney DiseaseStudy F was a randomized, open-label, dose-ranging study for 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 Venofer (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 Venofer once every other week for 6 doses.Patients with PDD-CKD or NDD-CKD received Venofer 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 Venofer 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 HANDLING16.1 How SuppliedVenofer 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 mgelemental iron, and each 2.5 mL vial contains 50 mg elemental iron (20 mg/mL). NDC-0517-2310-05 200 mg/10 mL Single-Use Vial Packages of 5NDC-0517-2310-10 200 mg/10 mL Single-Use Vial Packages of 10NDC-0517-2340-01 100 mg/5 mL Single-Use Vial Individually BoxedNDC-0517-2340-10 100 mg/5 mL Single-Use Vial Packages of 10NDC-0517-2340-25 100 mg/5 mL Single-Use Vial Packages of 25NDC-0517-2340-99 100 mg/5 mL Single-Use Vial Packages of 10NDC-0517-2325-10 50 mg/2.5 mL Single-Use Vial Packages of 10 NDC-0517-2325-25 50 mg/2.5 mL Single-Use Vial Packages of 2516.2 Stability and StorageContains no preservatives. Store in original carton at 20° to 25°C (68° to 77°F); excursions permitted to 15° to 30°C (59° to 86°F). [See USP ControlledRoom 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 mgelemental 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: Venofer, when added to intravenous infusion bags (PVC or non-PVC) containing 0.9% NaCl at concentrations rangingfrom 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.17 PATIENT COUNSELING INFORMATIONPrior to Venofer administration:
• Question patients regarding any prior history of reactions to parenteral iron products • Advise patients of the risks associated with Venofer• Advise patients to report any symptoms of hypersensitivity that may develop during and following Venofer administration, such as rash, itching,
dizziness, light-headedness, swelling, and breathing problems [see Warnings and Precautions (5)]
IN2340ADVMG #15727
Venofer is manufactured under license from Vifor (International) Inc., Switzerland.
PREMIERProTMRx is a trademark of Premier, Inc., used under license.
Efficacyparameters
End of treatment 2 week follow-up 5 week follow-up
Venofer(n=69)
Historical Control (n=18)
Venofer(n=73)
Historical Control(n=18)
Venofer(n=71)
HistoricalControl(n=15)
Hemoglobin (g/dL) 1.0 ± 0.12** 0.0 ± 0.21 1.3 ± 0.14** -0.6 ± 0.24 1.2 ± 0.17* -0.1 ± 0.23
Hematocrit (%) 3.1 ± 0.37** -0.3 ± 0.65 3.6 ± 0.44** -1.2 ± 0.76 3.3 ± 0.54 0.2 ± 0.86
**p < 0.01 and *p < 0.05 compared to historical control from ANCOVA analysis with baseline hemoglobin, serum ferritin and erythropoietin dose ascovariates.
AMERICAN REGENT, INC.SHIRLEY, NY 11967
Rx Only
(iron sucrose injection, USP)
®
Rx Only
(iron sucrose injection, USP)
®
Rx Only
(iron sucrose injection, USP)
®
Rx Only
(iron sucrose injection, USP)
®
651 S ML King Jr Ave • Waukegan, IL 60085 • Phone 847.336.4200 • Fax 847.360.4924complete packaging | individual solutionsSM
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FULL PRESCRIBING INFORMATION
1 INDICATIONS AND USAGE
Injectafer is indicated for the treatment of iron deficiency anemia in adultpatients:• who have intolerance to oral iron or have had unsatisfactory response to
oral iron;• who have non-dialysis dependent chronic kidney disease.2 DOSAGE AND ADMINISTRATIONFor patients weighing 50 kg (110lb) or more: Give Injectafer in two dosesseparated by at least 7 days. Give each dose as 750 mg for a total cumulativedose not to exceed 1500 mg of iron per course.For patients weighing less than 50 kg (110lb): Give Injectafer in two dosesseparated by at least 7 days. Give each dose as 15 mg/kg body weight for atotal cumulative dose not to exceed 1500 mg of iron per course.The dosage of Injectafer is expressed in mg of elemental iron. Each mL ofInjectafer contains 50 mg of elemental iron. Injectafer treatment may berepeated if iron deficiency anemia reoccurs.Administer Injectafer intravenously, either as an undiluted slow intravenouspush or by infusion. When administering as a slow intravenous push, give atthe rate of approximately 100 mg (2 mL) per minute. When administered viainfusion, 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 isnot 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, Injectafersolution is physically and chemically stable for 72 hours when stored at roomtemperature. To maintain stability, do not dilute to concentrations less than2 mg iron/mL.Inspect parenteral drug products visually for the absence of particulatematter and discoloration prior to administration. The product contains nopreservatives. Each vial of Injectafer is intended for single-use only. Anyunused drug remaining after injection must be discarded.Avoid extravasation of Injectafer since brown discoloration of the extravasationsite may be long lasting. Monitor for extravasation. If extravasation occurs,discontinue the Injectafer administration at that site.
3 DOSAGE FORMS AND STRENGTHS
750 mg iron / 15 mL single-use vial
4 CONTRAINDICATIONS
Hypersensitivity to Injectafer or any of its components [see Warnings andPrecautions (5.1)].
5 WARNINGS AND PRECAUTIONS
5.1 Hypersensitivity ReactionsSerious hypersensitivity reactions, including anaphylactic-type reactions,some of which have been life-threatening and fatal, have been reported inpatients receiving Injectafer. Patients may present with shock, clinicallysignificant hypotension, loss of consciousness, and/or collapse. Monitorpatients for signs and symptoms of hypersensitivity during and afterInjectafer administration for at least 30 minutes and until clinically stablefollowing completion of the infusion. Only administer Injectafer whenpersonnel and therapies are immediately available for the treatment ofserious hypersensitivity reactions. [see Adverse Reactions (6.1 and 6.2)].
HIGHLIGHTS OF PRESCRIBING INFORMATIONThese highlights do not include all the information needed to useInjectafer safely and effectively. See full prescribing information forInjectafer.INJECTAFER® (ferric carboxymaltose injection)For intravenous useInitial U.S. Approval: 2013------------------------------INDICATIONS AND USAGE------------------------------Injectafer is an iron replacement product indicated for the treatment of irondeficiency 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.-------------------------DOSAGE AND ADMINISTRATION---------------------------For patients weighing 50 kg (110lb) or more: Give Injectafer in twodoses separated by at least 7 days. Give each dose as 750 mg for a totalcumulative dose of 1500 mg of iron per course.For patients weighing less than 50 kg (110lb): Give Injectafer in two dosesseparated by at least 7 days and give each dose as 15 mg/kg body weight.Injectafer treatment may be repeated if iron deficiency anemia reoccurs. (2)
FULL PRESCRIBING INFORMATION: CONTENTS*
1 INDICATIONS AND USAGE2 DOSAGE AND ADMINISTRATION3 DOSAGE FORMS AND STRENGTHS4 CONTRAINDICATIONS5 WARNINGS AND PRECAUTIONS
5.1 Hypersensitivity Reactions5.2 Hypertension5.3 Laboratory Test Alterations
6 ADVERSE REACTIONS6.1 Adverse Reactions in Clinical Trials6.2 Post-marketing Experience
7 DRUG INTERACTIONS8 USE IN SPECIFIC POPULATIONS
8.1 Pregnancy8.3 Nursing Mothers8.4 Pediatric Use8.5 Geriatric Use
--------------------------DOSAGE FORMS AND STRENGTHS-----------------------750 mg iron / 15 mL single-use vial. (3)-------------------------------CONTRAINDICATIONS---------------------------------Hypersensitivity to Injectafer or any of its inactive components. (4)------------------------WARNINGS AND PRECAUTIONS----------------------------• Hypersensitivity reactions: Observe for signs and symptoms of
hypersensitivity during and after Injectafer administration for at least30 minutes and until clinically stable following completion of eachadministration. (5.1)
• Hypertension: Monitor patients closely for signs and symptoms ofhypertension following each Injectafer administration. (5.2)
------------------------------ADVERSE REACTIONS----------------------------------The most common adverse reactions (≥ 2%) are nausea, hypertension,flushing, hypophosphatemia, and dizziness (6.1)To report SUSPECTED ADVERSE REACTIONS, contact American Regent at1-800-734-9236 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.------------------------USE IN SPECIFIC POPULATIONS----------------------------• Nursing Mothers: Exercise caution when administered to a nursing
woman. (8.3)See 17 for PATIENT COUNSELING INFORMATION and FDA-approvedpatient labeling.
Revised: July 2013
10 OVERDOSAGE11 DESCRIPTION12 CLINICAL PHARMACOLOGY
12.1 Mechanism of Action12.2 Pharmacodynamics12.3 Pharmacokinetics
13 NONCLINICAL TOXICOLOGY13.1 Carcinogenesis, Mutagenesis, and Impairment of Fertility
14 CLINICAL STUDIES14.1 Trial 1: Iron Deficiency Anemia in Patients Who are Intolerant to
Oral Iron or Have Had Unsatisfactory Response to Oral Iron14.2 Trial 2: Iron Deficiency Anemia in Patients with Non-Dialysis
Dependent Chronic Kidney Disease16 HOW SUPPLIED/STORAGE AND HANDLING17 PATIENT COUNSELING INFORMATION
*Sections or subsections omitted from the full prescribing informationare not listed.
In clinical trials, serious anaphylactic/anaphylactoid reactions were reportedin 0.1% (2/1775) of subjects receiving Injectafer. Other serious or severeadverse reactions potentially associated with hypersensitivity which included,but not limited to, pruritus, rash, urticaria, wheezing, or hypotension werereported in 1.5% (26/1775) of these subjects.5.2 HypertensionIn clinical studies, hypertension was reported in 3.8% (67/1,775) of subjectsin clinical trials 1 and 2. Transient elevations in systolic blood pressure,sometimes occurring with facial flushing, dizziness, or nausea were observedin 6% (106/1,775) of subjects in these two clinical trials. These elevationsgenerally occurred immediately after dosing and resolved within 30 minutes.Monitor patients for signs and symptoms of hypertension following eachInjectafer administration [see Dosage and Administration (2)].5.3 Laboratory Test AlterationsIn the 24 hours following administration of Injectafer, laboratory assays mayoverestimate serum iron and transferrin bound iron by also measuring theiron in Injectafer.
6 ADVERSE REACTIONS
The following adverse reactions are discussed in greater detail in othersections of the labeling:• Hypersensitivity Reactions [see Warnings and Precautions (5.1)]• Hypertension [see Warnings and Precautions (5.2)]• Laboratory Test Alterations [see Warnings and Precautions (5.3)]6.1 Adverse Reactions in Clinical TrialsBecause clinical trials are conducted under widely varying conditions, theadverse reaction rates observed cannot be directly compared to rates in otherclinical trials and may not reflect the rates observed in clinical practice.In two randomized clinical studies [Studies 1 and 2, See Clinical Studies (14)],a total of 1,775 patients were exposed to Injectafer 15 mg/kg body weight upto a maximum single dose of 750 mg of iron on two occasions separated byat least 7 days up to a cumulative dose of 1500 mg of iron.Adverse reactions reported by ≥ 1% of treated patients are shown in thefollowing table.Table 1. Adverse reactions reported in ≥ 1% of Study Patients in Clinical Trials1 and 2
Term Injectafer
(N=1775)%
PooledComparatorsa
(N=1783)%
Oraliron
(N=253)%
Nausea 7.2 1.8 1.2Hypertension 3.8 1.9 0.4Flushing/Hot Flush 3.6 0.2 0.0Blood Phosphorus Decrease 2.1 0.1 0.0Dizziness 2.0 1.2 0.0Vomiting 1.7 0.5 0.4Injection Site Discoloration 1.4 0.3 0.0Headache 1.2 0.9 0.0Alanine AminotransferaseIncrease 1.1 0.2 0.0
Dysgeusia 1.1 2.1 0.0Hypotension 1.0 1.9 0.0Constipation 0.5 0.9 3.2
a Includes oral iron and all formulations of IV iron other than Injectafer
INJE
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RQ105200
Other adverse reactions reported by ≥ 0.5% of treated patients includeabdominal pain, diarrhea, gamma glutamyl transferase increased, injectionsite pain/irritation, rash, paraesthesia, sneezing. Transient decreases inlaboratory blood phosphorus levels (< 2 mg/dL) have been observed in 27%(440/1638) patients in clinical trials.6.2 Post-marketing ExperienceBecause these reactions are reported voluntarily from a population of uncertainsize, it is not always possible to reliably estimate their frequency or establish acausal relationship to drug exposure. The following serious adverse reactionshave been most commonly reported from the post-marketing spontaneousreports with Injectafer: urticaria, dyspnea, pruritis, tachycardia, erythema,pyrexia, chest discomfort, chills, angioedema, back pain, arthralgia, andsyncope. One case of hypophosphatemic osteomalacia was reported ina subject who received 500 mg of Injectafer every 2 weeks for a total of16 weeks. Partial recovery followed discontinuation of Injectafer.
7 DRUG INTERACTIONS
Formal drug interaction studies have not been performed with Injectafer.
8 USE IN SPECIFIC POPULATIONS
8.1 PregnancyPregnancy Category CRisk SummaryAdequate and well controlled studies in pregnant women have not beenconducted. However, animal reproduction studies have been conducted withferric carboxymaltose. In these studies, administration of ferric carboxymaltoseto rabbits during the period of organogenesis caused fetal malformations andincreased 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 beenestablished for Injectafer. However, all pregnancies, regardless of exposure toany drug, has a background rate of 2 to 4% for major malformations, and 15to 20% for pregnancy loss. Injectafer should be used during pregnancy only ifthe potential benefit justifies the potential risk to the fetus.Animal DataAdministration of ferric carboxymaltose to rats as a one-hour intravenousinfusion up to 30 mg/kg/day iron on gestation days 6 to 17 did not result inadverse 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 gestationdays 6 to 19 at iron doses of 4.5, 9, 13.5, and 18 mg/kg/day. Malformationswere seen starting at the daily dose of 9 mg/kg (23% of the human weeklydose of 750 mg). Spontaneous abortions occurred starting at the daily irondose of 4.5 mg/kg (12% of the human weekly dose based on body surfacearea). Pre-implantation loss was at the highest dose. Adverse embryofetaleffects were observed in the presence of maternal toxicity.A pre- and post-natal development study was conducted in rats at intravenousdoses up to 18 mg/kg/day of iron (approximately 23% of the weekly humandose of 750 mg on a body surface area basis). There were no adverse effectson survival of offspring, their behavior, sexual maturation or reproductiveparameters.8.3 Nursing MothersA study to determine iron concentrations in breast milk after administration ofInjectafer (n=11) or oral ferrous sulfate (n=14) was conducted in 25 lactatingwomen with postpartum iron deficiency anemia. Mean breast milk iron levelswere higher in lactating women receiving Injectafer than in lactating womenreceiving oral ferrous sulfate.8.4 Pediatric UseSafety and effectiveness have not been established in pediatric patients.8.5 Geriatric UseOf the 1775 subjects in clinical studies of Injectafer, 50% were 65 years andover, while 25% were 75 years and over. No overall differences in safety oreffectiveness were observed between these subjects and younger subjects,and other reported clinical experience has not identified differences inresponses between the elderly and younger patients, but greater sensitivity ofsome older individuals cannot be ruled out.
10 OVERDOSAGEExcessive dosages of Injectafer may lead to accumulation of iron in storagesites potentially leading to hemosiderosis. A patient who received Injectafer18,000 mg over 6 months developed hemosiderosis with multiple jointdisorder, walking disability and asthenia . Hypophosphatemic osteomalaciawas reported in a patient who received Injectafer 4000 mg over 4 months.Partial recovery followed discontinuation of Injectafer. [see Post-marketingExperience (6.2)].
11 DESCRIPTION
Ferric carboxymaltose, an iron replacement product, is an iron carbohydratecomplex with the chemical name of polynuclear iron (III) hydroxide4(R)-(poly-(1→4)-O-a-D-glucopyranosyl)-oxy-2(R),3(S),5(R),6-tetrahydroxy-hexanoate. It has a relative molecular weight of approximately150,000 Da corresponding to the following empirical formula:[FeOx(OH)y(H2O)z]n [{(C6H10O5)m (C6H12O7)}l]k,
where n ≈ 103, m ≈ 8, l≈ 11, and k ≈ 4(l represents the mean branching degree of the ligand).
The chemical structure is presented below:
651 S M
L King Jr A
ve • Waukegan, IL 60085 • P
hone 847.336.4200 • Fax 847.360.4924co
mp
lete packag
ing
| ind
ividu
al solu
tion
sS
M
Pro
du
ct Info
rmatio
nS
pecified
Co
lors
P/N: J/N:C
ust:Size:
Pro
of A
7/26/2013A
pp
roved
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Nam
e
DateO
K to PrintN
ew Proof R
equired
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ent andcolor break. Actual colors w
ill be matched on
press to: PMS Book, O
n_Dem
and Solutions FourC
olor Book, On _D
emand Solutions Indichrom
ePlus Book and/or approved C
olor Standards.
258024LU
ITPOLD
PHAR
MAC
EUTIC
ALS INC
Cyan
Magenta
Yellow
Black
FULL PRESCRIBING INFORMATION
1INDICATIONS AND USAGE
Injectaferis
indicatedfor
thetreatm
entof
irondeficiency
anemia
inadult
patients:•
who
haveintolerance
tooraliron
orhavehad
unsatisfactoryresponse
tooral iron;
•who
havenon-dialysis
dependentchronickidney
disease.2
DOSAGE AND ADMINISTRATION
Forpatients
weighing
50kg
(110lb)or
more:
GiveInjectafer
intwodoses
separatedby
atleast7days.
Giveeach
doseas
750mgfora
totalcumulative
dosenotto
exceed1500
mgofiron
percourse.For
patientsweighing
lessthan
50kg
(110lb):Give
Injectaferin
twodoses
separatedby
atleast7days.Give
eachdose
as15
mg/kg
bodyweightfor
atotalcum
ulativedose
nottoexceed
1500mgofiron
percourse.The
dosageof
Injectaferis
expressedin
mgof
elementaliron.Each
mLof
Injectafercontains
50mgof
elemental
iron.Injectafer
treatment
may
berepeated
ifirondeficiency
anemiareoccurs.
Administer
Injectaferintravenously,either
asan
undilutedslow
intravenouspush
orbyinfusion.W
henadm
inisteringas
aslow
intravenouspush,give
atthe
rateofapproxim
ately100
mg(2
mL)perm
inute.When
administered
viainfusion,dilute
upto
750mgofiron
inno
more
than250
mLofsterile
0.9%sodium
chlorideinjection,USP,such
thattheconcentration
oftheinfusion
isnotless
than2mgofiron
permLand
administeroveratleast15
minutes.
When
addedto
aninfusion
bagcontaining
0.9%sodium
chlorideinjection,
USP,atconcentrationsranging
from2mgto
4mgofiron
permL,Injectafer
solutionisphysically
andchem
icallystable
for72hours
when
storedatroom
temperature.To
maintain
stability,donot
diluteto
concentrationsless
than2mgiron/m
L.Inspect
parenteraldrug
productsvisually
forthe
absenceof
particulatematter
anddiscoloration
priorto
administration.
Theproduct
containsno
preservatives.Each
vialof
Injectaferis
intendedfor
single-useonly.
Anyunused
drugrem
ainingafterinjection
mustbe
discarded.Avoid
extravasationofInjectafersince
browndiscoloration
oftheextravasation
sitemay
belong
lasting.Monitor
forextravasation.Ifextravasation
occurs,discontinue
theInjectaferadm
inistrationatthatsite.
3DOSAGE FORM
S AND STRENGTHS
750mgiron
/15mLsingle-use
vial
4CONTRAINDICATIONS
Hypersensitivityto
Injectaferor
anyof
itscom
ponents[see
Warnings
andPrecautions (5.1)].
5W
ARNINGS AND PRECAUTIONS
5.1Hypersensitivity Reactions
Serioushypersensitivity
reactions,including
anaphylactic-typereactions,
some
ofwhich
havebeen
life-threateningand
fatal,havebeen
reportedin
patientsreceiving
Injectafer.Patients
may
presentw
ithshock,
clinicallysignificant
hypotension,loss
ofconsciousness,
and/orcollapse.
Monitor
patientsfor
signsand
symptom
sof
hypersensitivityduring
andafter
Injectaferadministration
foratleast30m
inutesand
untilclinicallystable
following
completion
ofthe
infusion.Only
administer
Injectaferw
henpersonnel
andtherapies
areim
mediately
availablefor
thetreatm
entof
serioushypersensitivity
reactions.[see
AdverseReactions
(6.1and
6.2)].
HIGHLIGHTS OF PRESCRIBING INFORMATION
These highlights do not include all the information needed to use
Injectafer safely and effectively. See full prescribing information for
Injectafer.INJECTAFER
® (ferric carboxymaltose injection)
For intravenous useInitial U.S. Approval: 2013------------------------------INDICATIONS
ANDUSAGE------------------------------
Injectafer is an iron replacement product indicated for the treatm
ent of irondeficiency anem
ia in adult patients:•
who
haveintolerance
tooraliron
orhavehad
unsatisfactoryresponse
tooral iron;
•who
havenon-dialysis
dependentchronickidney
disease.-------------------------DOSAGE AND ADM
INISTRATION---------------------------Forpatients
weighing
50kg
(110lb)ormore:
GiveInjectaferin
two
dosesseparated
byatleast7
days.Give
eachdose
as750
mgfora
totalcum
ulativedose
of1500mgofiron
percourse.Forpatients
weighing
lessthan
50kg
(110lb):Give
Injectaferintwodoses
separatedby
atleast7days
andgive
eachdose
as15
mg/kg
bodyweight.
Injectafertreatmentm
aybe
repeatedifiron
deficiencyanem
iareoccurs.(2)
FULL PRESCRIBING INFORMATION: CONTENTS*
1INDICATIONS AND USAGE
2DOSAGE AND ADM
INISTRATION3
DOSAGE FORMS AND STRENGTHS
4CONTRAINDICATIONS
5W
ARNINGS AND PRECAUTIONS5.1
HypersensitivityReactions
5.2Hypertension
5.3Laboratory
TestAlterations6
ADVERSE REACTIONS6.1
AdverseReactions
inClinicalTrials
6.2Post-m
arketingExperience
7DRUG INTERACTIONS
8USE IN SPECIFIC POPULATIONS8.1
Pregnancy8.3
NursingMothers
8.4Pediatric
Use8.5
GeriatricUse
--------------------------DOSAGEFORM
SAND
STRENGTHS-----------------------750
mgiron
/15mLsingle-use
vial.(3)-------------------------------CONTRAINDICATIONS---------------------------------Hypersensitivity
toInjectaferorany
ofitsinactive
components.(4)
------------------------WARNINGS AND PRECAUTIONS----------------------------
•Hypersensitivity reactions:Observe
forsignsand
symptom
sof
hypersensitivityduring
andafterInjectaferadm
inistrationforatleast
30minutes
anduntilclinically
stablefollow
ingcom
pletionofeach
administration.(5.1)
•Hypertension:M
onitorpatientsclosely
forsignsand
symptom
sof
hypertensionfollow
ingeach
Injectaferadministration.(5.2)
------------------------------ADVERSE REACTIONS----------------------------------The
mostcom
mon
adversereactions
(≥2%
)arenausea,hypertension,
flushing,hypophosphatemia,and
dizziness(6.1)
To report SUSPECTED ADVERSE REACTIONS, contact American Regent at
1-800-734-9236 or FDA at 1-800-FDA-1088 orwww.fda.gov/m
edwatch.
------------------------USE IN SPECIFIC POPULATIONS----------------------------•
NursingMothers:Exercise
cautionwhen
administered
toanursing
wom
an.(8.3)See 17 for PATIENT COUNSELING INFORM
ATION and FDA-approvedpatient labeling.
Revised: July 2013
10OVERDOSAGE
11DESCRIPTION
12CLINICAL PHARM
ACOLOGY12.1
Mechanism
ofAction12.2
Pharmacodynam
ics12.3
Pharmacokinetics
13NONCLINICAL TOXICOLOGY13.1
Carcinogenesis,Mutagenesis,and
Impairm
entofFertility14
CLINICAL STUDIES14.1
Trial1:IronDeficiency
AnemiainPatients
Who
areIntolerantto
OralIronorHave
HadUnsatisfactory
Responseto
OralIron14.2
Trial2:IronDeficiency
AnemiainPatients
with
Non-DialysisDependentChronic
KidneyDisease
16HOW
SUPPLIED/STORAGE AND HANDLING17
PATIENT COUNSELING INFORMATION
*Sectionsorsubsections
omitted
fromthe
fullprescribinginform
ationare
notlisted.
Inclinicaltrials,serious
anaphylactic/anaphylactoidreactions
were
reportedin
0.1%(2/1775)
ofsubjects
receivingInjectafer.
Otherserious
orsevere
adversereactions
potentiallyassociated
with
hypersensitivitywhich
included,but
notlim
itedto,
pruritus,rash,
urticaria,wheezing,
orhypotension
were
reportedin1.5%
(26/1775)ofthesesubjects.
5.2Hypertension
Inclinicalstudies,hypertension
was
reportedin3.8%
(67/1,775)ofsubjectsin
clinicaltrials
1and
2.Transient
elevationsin
systolicblood
pressure,som
etimes
occurringwith
facialflushing,dizziness,ornauseawere
observedin
6%(106/1,775)
ofsubjects
inthese
twoclinicaltrials.
Theseelevations
generallyoccurred
immediately
afterdosingand
resolvedwithin
30minutes.
Monitor
patientsfor
signsand
symptom
sof
hypertensionfollow
ingeach
Injectaferadministration
[seeDosage and Adm
inistration(2)].
5.3Laboratory Test Alterations
Inthe
24hours
following
administration
ofInjectafer,laboratoryassays
may
overestimate
serumiron
andtransferrin
boundiron
byalso
measuring
theiron
inInjectafer.
6ADVERSE REACTIONS
Thefollow
ingadverse
reactionsare
discussedin
greaterdetail
inother
sectionsofthe
labeling:•
HypersensitivityReactions
[seeW
arnings and Precautions(5.1)]
•Hypertension
[seeW
arnings and Precautions(5.2)]
•Laboratory
TestAlterations[see
Warnings and Precautions
(5.3)]6.1
Adverse Reactions in Clinical TrialsBecause
clinicaltrials
areconducted
underwidely
varyingconditions,
theadverse
reactionrates
observedcannotbe
directlycom
paredto
ratesinother
clinicaltrialsand
may
notreflecttherates
observedinclinicalpractice.
Intworandom
izedclinicalstudies
[Studies1and
2,SeeClinicalStudies
(14)],atotalof1,775
patientswere
exposedto
Injectafer15mg/kg
bodyweightup
toamaxim
umsingle
doseof750
mgofiron
ontwooccasions
separatedby
atleast7days
upto
acum
ulativedose
of1500mgofiron.
Adversereactions
reportedby
≥1%
oftreated
patientsare
shownin
thefollow
ingtable.
Table1.
Adversereactions
reportedin
≥1%
ofStudyPatients
inClinicalTrials
1 and 2
TermInjectafer
(N=1775)%
PooledCom
paratorsa
(N=1783)%
Oraliron
(N=253)%
Nausea7.2
1.81.2
Hypertension3.8
1.90.4
Flushing/HotFlush3.6
0.20.0
BloodPhosphorus
Decrease2.1
0.10.0
Dizziness2.0
1.20.0
Vomiting
1.70.5
0.4Injection
SiteDiscoloration
1.40.3
0.0Headache
1.20.9
0.0Alanine Am
inotransferaseIncrease
1.10.2
0.0
Dysgeusia1.1
2.10.0
Hypotension1.0
1.90.0
Constipation0.5
0.93.2
a Includes oral iron and all formulations of IV iron other than Injectafer
INJECTAFER®
(ferric carboxymaltose injection)
RQ105200
Otheradverse
reactionsreported
by≥
0.5%of
treatedpatients
includeabdom
inalpain,
diarrhea,gam
maglutam
yltransferase
increased,injection
sitepain/irritation,
rash,paraesthesia,
sneezing.Transient
decreasesin
laboratoryblood
phosphoruslevels
(<2mg/dL)have
beenobserved
in27%
(440/1638)patientsinclinicaltrials.
6.2Post-m
arketing ExperienceBecause
thesereactions
arereported
voluntarilyfrom
apopulation
ofuncertainsize,itis
notalways
possibletoreliably
estimate
theirfrequencyorestablish
acausalrelationship
todrug
exposure.Thefollow
ingserious
adversereactions
havebeen
most
commonly
reportedfrom
thepost-m
arketingspontaneous
reportswith
Injectafer:urticaria,
dyspnea,pruritis,
tachycardia,erythem
a,pyrexia,
chestdiscom
fort,chills,
angioedema,
backpain,
arthralgia,and
syncope.One
caseof
hypophosphatemic
osteomalacia
was
reportedin
asubject
who
received500
mgof
Injectaferevery
2weeks
foratotal
of16
weeks.Partialrecovery
followed
discontinuationofInjectafer.
7DRUG INTERACTIONS
Formaldrug
interactionstudies
havenotbeen
performed
with
Injectafer.
8USE IN SPECIFIC POPULATIONS
8.1Pregnancy
PregnancyCategory
CRisk
Summ
aryAdequate
andwell
controlledstudies
inpregnant
wom
enhave
notbeen
conducted.However,anim
alreproductionstudies
havebeen
conductedwith
ferriccarboxymaltose.In
thesestudies,administration
offerriccarboxymaltose
torabbits
duringthe
periodoforganogenesis
causedfetalm
alformations
andincreased
implantation
lossatm
aternallytoxic
dosesofapproxim
ately12%
to23%
ofthehum
anweekly
doseof750
mg(based
onbody
surfacearea).
Theincidence
ofmajor
malform
ationsin
human
pregnancieshas
notbeen
establishedforInjectafer.How
ever,allpregnancies,regardlessofexposure
toany
drug,hasabackground
rateof2
to4%
formajorm
alformations,and
15to
20%forpregnancy
loss.Injectafershouldbe
usedduring
pregnancyonly
ifthe
potentialbenefitjustifiesthe
potentialriskto
thefetus.
Animal Data
Administration
offerric
carboxymaltose
torats
asaone-hour
intravenousinfusion
upto
30mg/kg/day
ironon
gestationdays
6to
17did
notresultinadverse
embryofetalfindings.This
dailydose
inrats
isapproxim
ately40%
ofthehum
anweekly
doseof750
mgbased
onbody
surfacearea.In
rabbits,ferric
carboxymaltose
was
administered
asaone-hour
infusionon
gestationdays
6to
19atiron
dosesof4.5,9,13.5,and
18mg/kg/day.M
alformations
were
seenstarting
atthedaily
doseof9
mg/kg
(23%ofthe
human
weekly
doseof750
mg).Spontaneous
abortionsoccurred
startingatthe
dailyiron
doseof4.5
mg/kg
(12%ofthe
human
weekly
dosebased
onbody
surfacearea).
Pre-implantation
losswas
atthe
highestdose.
Adverseem
bryofetaleffects
were
observedinthe
presenceofm
aternaltoxicity.Apre-and
post-nataldevelopmentstudy
was
conductedinrats
atintravenousdoses
upto
18mg/kg/day
ofiron(approxim
ately23%
oftheweekly
human
doseof750
mgon
abody
surfacearea
basis).Therewere
noadverse
effectson
survivalof
offspring,their
behavior,sexual
maturation
orreproductive
parameters.
8.3Nursing M
othersAstudy
todeterm
ineiron
concentrationsinbreastm
ilkafteradm
inistrationof
Injectafer(n=11)ororalferroussulfate
(n=14)was
conductedin25
lactatingwom
enwith
postpartumiron
deficiencyanem
ia.Mean
breastmilk
ironlevels
were
higherin
lactatingwom
enreceiving
Injectaferthan
inlactating
wom
enreceiving
oralferroussulfate.
8.4Pediatric Use
Safetyand
effectivenesshave
notbeenestablished
inpediatric
patients.8.5
Geriatric UseOfthe
1775subjects
inclinicalstudies
ofInjectafer,50%were
65years
andover,w
hile25%
were
75years
andover.No
overalldifferencesin
safetyor
effectivenesswere
observedbetw
eenthese
subjectsand
youngersubjects,
andother
reportedclinical
experiencehas
notidentified
differencesin
responsesbetw
eenthe
elderlyand
youngerpatients,butgreatersensitivityof
someolderindividuals
cannotberuled
out.
10OVERDOSAGE
Excessivedosages
ofInjectafermay
leadto
accumulation
ofironin
storagesites
potentiallyleading
tohem
osiderosis.Apatientw
horeceived
Injectafer18,000
mg
over6
months
developedhem
osiderosiswith
multiple
jointdisorder,
walking
disabilityand
asthenia.Hypophosphatem
icosteom
alaciawas
reportedin
apatient
who
receivedInjectafer
4000mgover
4months.
Partialrecoveryfollow
eddiscontinuation
ofInjectafer.
[seePost-m
arketingExperience (6.2)].
11DESCRIPTION
Ferriccarboxym
altose,aniron
replacementproduct,is
aniron
carbohydratecom
plexwith
thechem
icalnam
eof
polynucleariron
(III)hydroxide
4(R)-(poly-(1→
4)-O-a
-D-glucopyranosyl)-oxy-2(R
),3(S),5(R
),6-tetrahydroxy-hexanoate.It
hasarelative
molecular
weight
ofapproxim
ately150,000
Dacorresponding
tothe
following
empiricalform
ula:[FeO
x (OH)y (H2 O)z ]n [{(C
6 H10 O
5 )m(C
6 H12 O
7 )}l ]k ,
where
n≈10
3,m≈8,l≈
11,andk≈4
(lrepresentsthe
mean
branchingdegree
oftheligand).
Thechem
icalstructureispresented
below:
651 S M
L King Jr A
ve • Waukegan, IL 60085 • P
hone 847.336.4200 • Fax 847.360.4924co
mp
lete packag
ing
| ind
ividu
al solu
tion
sS
M
Pro
du
ct Info
rmatio
nS
pecified
Co
lors
P/N: J/N:C
ust:Size:
Pro
of A
7/26/2013A
pp
roved
By
Nam
e
DateO
K to PrintN
ew Proof R
equired
This proof is to show size, copy placem
ent andcolor break. Actual colors w
ill be matched on
press to: PMS Book, O
n_Dem
and Solutions FourC
olor Book, On _D
emand Solutions Indichrom
ePlus Book and/or approved C
olor Standards.
258024LU
ITPOLD
PHAR
MAC
EUTIC
ALS INC
Cyan
Magenta
Yellow
Black
FULL PRESCRIBING INFORMATION
1INDICATIONS AND USAGE
Injectaferis
indicatedfor
thetreatm
entof
irondeficiency
anemia
inadult
patients:•
who
haveintolerance
tooraliron
orhavehad
unsatisfactoryresponse
tooral iron;
•who
havenon-dialysis
dependentchronickidney
disease.2
DOSAGE AND ADMINISTRATION
Forpatients
weighing
50kg
(110lb)or
more:
GiveInjectafer
intwodoses
separatedby
atleast7days.
Giveeach
doseas
750mgfora
totalcumulative
dosenotto
exceed1500
mgofiron
percourse.For
patientsweighing
lessthan
50kg
(110lb):Give
Injectaferin
twodoses
separatedby
atleast7days.Give
eachdose
as15
mg/kg
bodyweightfor
atotalcum
ulativedose
nottoexceed
1500mgofiron
percourse.The
dosageof
Injectaferis
expressedin
mgof
elementaliron.Each
mLof
Injectafercontains
50mgof
elemental
iron.Injectafer
treatment
may
berepeated
ifirondeficiency
anemiareoccurs.
Administer
Injectaferintravenously,either
asan
undilutedslow
intravenouspush
orbyinfusion.W
henadm
inisteringas
aslow
intravenouspush,give
atthe
rateofapproxim
ately100
mg(2
mL)perm
inute.When
administered
viainfusion,dilute
upto
750mgofiron
inno
more
than250
mLofsterile
0.9%sodium
chlorideinjection,USP,such
thattheconcentration
oftheinfusion
isnotless
than2mgofiron
permLand
administeroveratleast15
minutes.
When
addedto
aninfusion
bagcontaining
0.9%sodium
chlorideinjection,
USP,atconcentrationsranging
from2mgto
4mgofiron
permL,Injectafer
solutionisphysically
andchem
icallystable
for72hours
when
storedatroom
temperature.To
maintain
stability,donot
diluteto
concentrationsless
than2mgiron/m
L.Inspect
parenteraldrug
productsvisually
forthe
absenceof
particulatematter
anddiscoloration
priorto
administration.
Theproduct
containsno
preservatives.Each
vialof
Injectaferis
intendedfor
single-useonly.
Anyunused
drugrem
ainingafterinjection
mustbe
discarded.Avoid
extravasationofInjectafersince
browndiscoloration
oftheextravasation
sitemay
belong
lasting.Monitor
forextravasation.Ifextravasation
occurs,discontinue
theInjectaferadm
inistrationatthatsite.
3DOSAGE FORM
S AND STRENGTHS
750mgiron
/15mLsingle-use
vial
4CONTRAINDICATIONS
Hypersensitivityto
Injectaferor
anyof
itscom
ponents[see
Warnings
andPrecautions (5.1)].
5W
ARNINGS AND PRECAUTIONS
5.1Hypersensitivity Reactions
Serioushypersensitivity
reactions,including
anaphylactic-typereactions,
some
ofwhich
havebeen
life-threateningand
fatal,havebeen
reportedin
patientsreceiving
Injectafer.Patients
may
presentw
ithshock,
clinicallysignificant
hypotension,loss
ofconsciousness,
and/orcollapse.
Monitor
patientsfor
signsand
symptom
sof
hypersensitivityduring
andafter
Injectaferadministration
foratleast30m
inutesand
untilclinicallystable
following
completion
ofthe
infusion.Only
administer
Injectaferw
henpersonnel
andtherapies
areim
mediately
availablefor
thetreatm
entof
serioushypersensitivity
reactions.[see
AdverseReactions
(6.1and
6.2)].
HIGHLIGHTS OF PRESCRIBING INFORMATION
These highlights do not include all the information needed to use
Injectafer safely and effectively. See full prescribing information for
Injectafer.INJECTAFER
® (ferric carboxymaltose injection)
For intravenous useInitial U.S. Approval: 2013------------------------------INDICATIONS
ANDUSAGE------------------------------
Injectafer is an iron replacement product indicated for the treatm
ent of irondeficiency anem
ia in adult patients:•
who
haveintolerance
tooraliron
orhavehad
unsatisfactoryresponse
tooral iron;
•who
havenon-dialysis
dependentchronickidney
disease.-------------------------DOSAGE AND ADM
INISTRATION---------------------------Forpatients
weighing
50kg
(110lb)ormore:
GiveInjectaferin
two
dosesseparated
byatleast7
days.Give
eachdose
as750
mgfora
totalcum
ulativedose
of1500mgofiron
percourse.Forpatients
weighing
lessthan
50kg
(110lb):Give
Injectaferintwodoses
separatedby
atleast7days
andgive
eachdose
as15
mg/kg
bodyweight.
Injectafertreatmentm
aybe
repeatedifiron
deficiencyanem
iareoccurs.(2)
FULL PRESCRIBING INFORMATION: CONTENTS*
1INDICATIONS AND USAGE
2DOSAGE AND ADM
INISTRATION3
DOSAGE FORMS AND STRENGTHS
4CONTRAINDICATIONS
5W
ARNINGS AND PRECAUTIONS5.1
HypersensitivityReactions
5.2Hypertension
5.3Laboratory
TestAlterations6
ADVERSE REACTIONS6.1
AdverseReactions
inClinicalTrials
6.2Post-m
arketingExperience
7DRUG INTERACTIONS
8USE IN SPECIFIC POPULATIONS8.1
Pregnancy8.3
NursingMothers
8.4Pediatric
Use8.5
GeriatricUse
--------------------------DOSAGEFORM
SAND
STRENGTHS-----------------------750
mgiron
/15mLsingle-use
vial.(3)-------------------------------CONTRAINDICATIONS---------------------------------Hypersensitivity
toInjectaferorany
ofitsinactive
components.(4)
------------------------WARNINGS AND PRECAUTIONS----------------------------
•Hypersensitivity reactions:Observe
forsignsand
symptom
sof
hypersensitivityduring
andafterInjectaferadm
inistrationforatleast
30minutes
anduntilclinically
stablefollow
ingcom
pletionofeach
administration.(5.1)
•Hypertension:M
onitorpatientsclosely
forsignsand
symptom
sof
hypertensionfollow
ingeach
Injectaferadministration.(5.2)
------------------------------ADVERSE REACTIONS----------------------------------The
mostcom
mon
adversereactions
(≥2%
)arenausea,hypertension,
flushing,hypophosphatemia,and
dizziness(6.1)
To report SUSPECTED ADVERSE REACTIONS, contact American Regent at
1-800-734-9236 or FDA at 1-800-FDA-1088 orwww.fda.gov/m
edwatch.
------------------------USE IN SPECIFIC POPULATIONS----------------------------•
NursingMothers:Exercise
cautionwhen
administered
toanursing
wom
an.(8.3)See 17 for PATIENT COUNSELING INFORM
ATION and FDA-approvedpatient labeling.
Revised: July 2013
10OVERDOSAGE
11DESCRIPTION
12CLINICAL PHARM
ACOLOGY12.1
Mechanism
ofAction12.2
Pharmacodynam
ics12.3
Pharmacokinetics
13NONCLINICAL TOXICOLOGY13.1
Carcinogenesis,Mutagenesis,and
Impairm
entofFertility14
CLINICAL STUDIES14.1
Trial1:IronDeficiency
AnemiainPatients
Who
areIntolerantto
OralIronorHave
HadUnsatisfactory
Responseto
OralIron14.2
Trial2:IronDeficiency
AnemiainPatients
with
Non-DialysisDependentChronic
KidneyDisease
16HOW
SUPPLIED/STORAGE AND HANDLING17
PATIENT COUNSELING INFORMATION
*Sectionsorsubsections
omitted
fromthe
fullprescribinginform
ationare
notlisted.
Inclinicaltrials,serious
anaphylactic/anaphylactoidreactions
were
reportedin
0.1%(2/1775)
ofsubjects
receivingInjectafer.
Otherserious
orsevere
adversereactions
potentiallyassociated
with
hypersensitivitywhich
included,but
notlim
itedto,
pruritus,rash,
urticaria,wheezing,
orhypotension
were
reportedin1.5%
(26/1775)ofthesesubjects.
5.2Hypertension
Inclinicalstudies,hypertension
was
reportedin3.8%
(67/1,775)ofsubjectsin
clinicaltrials
1and
2.Transient
elevationsin
systolicblood
pressure,som
etimes
occurringwith
facialflushing,dizziness,ornauseawere
observedin
6%(106/1,775)
ofsubjects
inthese
twoclinicaltrials.
Theseelevations
generallyoccurred
immediately
afterdosingand
resolvedwithin
30minutes.
Monitor
patientsfor
signsand
symptom
sof
hypertensionfollow
ingeach
Injectaferadministration
[seeDosage and Adm
inistration(2)].
5.3Laboratory Test Alterations
Inthe
24hours
following
administration
ofInjectafer,laboratoryassays
may
overestimate
serumiron
andtransferrin
boundiron
byalso
measuring
theiron
inInjectafer.
6ADVERSE REACTIONS
Thefollow
ingadverse
reactionsare
discussedin
greaterdetail
inother
sectionsofthe
labeling:•
HypersensitivityReactions
[seeW
arnings and Precautions(5.1)]
•Hypertension
[seeW
arnings and Precautions(5.2)]
•Laboratory
TestAlterations[see
Warnings and Precautions
(5.3)]6.1
Adverse Reactions in Clinical TrialsBecause
clinicaltrials
areconducted
underwidely
varyingconditions,
theadverse
reactionrates
observedcannotbe
directlycom
paredto
ratesinother
clinicaltrialsand
may
notreflecttherates
observedinclinicalpractice.
Intworandom
izedclinicalstudies
[Studies1and
2,SeeClinicalStudies
(14)],atotalof1,775
patientswere
exposedto
Injectafer15mg/kg
bodyweightup
toamaxim
umsingle
doseof750
mgofiron
ontwooccasions
separatedby
atleast7days
upto
acum
ulativedose
of1500mgofiron.
Adversereactions
reportedby
≥1%
oftreated
patientsare
shownin
thefollow
ingtable.
Table1.
Adversereactions
reportedin
≥1%
ofStudyPatients
inClinicalTrials
1 and 2
TermInjectafer
(N=1775)%
PooledCom
paratorsa
(N=1783)%
Oraliron
(N=253)%
Nausea7.2
1.81.2
Hypertension3.8
1.90.4
Flushing/HotFlush3.6
0.20.0
BloodPhosphorus
Decrease2.1
0.10.0
Dizziness2.0
1.20.0
Vomiting
1.70.5
0.4Injection
SiteDiscoloration
1.40.3
0.0Headache
1.20.9
0.0Alanine Am
inotransferaseIncrease
1.10.2
0.0
Dysgeusia1.1
2.10.0
Hypotension1.0
1.90.0
Constipation0.5
0.93.2
a Includes oral iron and all formulations of IV iron other than Injectafer
INJECTAFER®
(ferric carboxymaltose injection)
RQ105200
Otheradverse
reactionsreported
by≥
0.5%of
treatedpatients
includeabdom
inalpain,
diarrhea,gam
maglutam
yltransferase
increased,injection
sitepain/irritation,
rash,paraesthesia,
sneezing.Transient
decreasesin
laboratoryblood
phosphoruslevels
(<2mg/dL)have
beenobserved
in27%
(440/1638)patientsinclinicaltrials.
6.2Post-m
arketing ExperienceBecause
thesereactions
arereported
voluntarilyfrom
apopulation
ofuncertainsize,itis
notalways
possibletoreliably
estimate
theirfrequencyorestablish
acausalrelationship
todrug
exposure.Thefollow
ingserious
adversereactions
havebeen
most
commonly
reportedfrom
thepost-m
arketingspontaneous
reportswith
Injectafer:urticaria,
dyspnea,pruritis,
tachycardia,erythem
a,pyrexia,
chestdiscom
fort,chills,
angioedema,
backpain,
arthralgia,and
syncope.One
caseof
hypophosphatemic
osteomalacia
was
reportedin
asubject
who
received500
mgof
Injectaferevery
2weeks
foratotal
of16
weeks.Partialrecovery
followed
discontinuationofInjectafer.
7DRUG INTERACTIONS
Formaldrug
interactionstudies
havenotbeen
performed
with
Injectafer.
8USE IN SPECIFIC POPULATIONS
8.1Pregnancy
PregnancyCategory
CRisk
Summ
aryAdequate
andwell
controlledstudies
inpregnant
wom
enhave
notbeen
conducted.However,anim
alreproductionstudies
havebeen
conductedwith
ferriccarboxymaltose.In
thesestudies,administration
offerriccarboxymaltose
torabbits
duringthe
periodoforganogenesis
causedfetalm
alformations
andincreased
implantation
lossatm
aternallytoxic
dosesofapproxim
ately12%
to23%
ofthehum
anweekly
doseof750
mg(based
onbody
surfacearea).
Theincidence
ofmajor
malform
ationsin
human
pregnancieshas
notbeen
establishedforInjectafer.How
ever,allpregnancies,regardlessofexposure
toany
drug,hasabackground
rateof2
to4%
formajorm
alformations,and
15to
20%forpregnancy
loss.Injectafershouldbe
usedduring
pregnancyonly
ifthe
potentialbenefitjustifiesthe
potentialriskto
thefetus.
Animal Data
Administration
offerric
carboxymaltose
torats
asaone-hour
intravenousinfusion
upto
30mg/kg/day
ironon
gestationdays
6to
17did
notresultinadverse
embryofetalfindings.This
dailydose
inrats
isapproxim
ately40%
ofthehum
anweekly
doseof750
mgbased
onbody
surfacearea.In
rabbits,ferric
carboxymaltose
was
administered
asaone-hour
infusionon
gestationdays
6to
19atiron
dosesof4.5,9,13.5,and
18mg/kg/day.M
alformations
were
seenstarting
atthedaily
doseof9
mg/kg
(23%ofthe
human
weekly
doseof750
mg).Spontaneous
abortionsoccurred
startingatthe
dailyiron
doseof4.5
mg/kg
(12%ofthe
human
weekly
dosebased
onbody
surfacearea).
Pre-implantation
losswas
atthe
highestdose.
Adverseem
bryofetaleffects
were
observedinthe
presenceofm
aternaltoxicity.Apre-and
post-nataldevelopmentstudy
was
conductedinrats
atintravenousdoses
upto
18mg/kg/day
ofiron(approxim
ately23%
oftheweekly
human
doseof750
mgon
abody
surfacearea
basis).Therewere
noadverse
effectson
survivalof
offspring,their
behavior,sexual
maturation
orreproductive
parameters.
8.3Nursing M
othersAstudy
todeterm
ineiron
concentrationsinbreastm
ilkafteradm
inistrationof
Injectafer(n=11)ororalferroussulfate
(n=14)was
conductedin25
lactatingwom
enwith
postpartumiron
deficiencyanem
ia.Mean
breastmilk
ironlevels
were
higherin
lactatingwom
enreceiving
Injectaferthan
inlactating
wom
enreceiving
oralferroussulfate.
8.4Pediatric Use
Safetyand
effectivenesshave
notbeenestablished
inpediatric
patients.8.5
Geriatric UseOfthe
1775subjects
inclinicalstudies
ofInjectafer,50%were
65years
andover,w
hile25%
were
75years
andover.No
overalldifferencesin
safetyor
effectivenesswere
observedbetw
eenthese
subjectsand
youngersubjects,
andother
reportedclinical
experiencehas
notidentified
differencesin
responsesbetw
eenthe
elderlyand
youngerpatients,butgreatersensitivityof
someolderindividuals
cannotberuled
out.
10OVERDOSAGE
Excessivedosages
ofInjectafermay
leadto
accumulation
ofironin
storagesites
potentiallyleading
tohem
osiderosis.Apatientw
horeceived
Injectafer18,000
mg
over6
months
developedhem
osiderosiswith
multiple
jointdisorder,
walking
disabilityand
asthenia.Hypophosphatem
icosteom
alaciawas
reportedin
apatient
who
receivedInjectafer
4000mgover
4months.
Partialrecoveryfollow
eddiscontinuation
ofInjectafer.
[seePost-m
arketingExperience (6.2)].
11DESCRIPTION
Ferriccarboxym
altose,aniron
replacementproduct,is
aniron
carbohydratecom
plexwith
thechem
icalnam
eof
polynucleariron
(III)hydroxide
4(R)-(poly-(1→
4)-O-a
-D-glucopyranosyl)-oxy-2(R
),3(S),5(R
),6-tetrahydroxy-hexanoate.It
hasarelative
molecular
weight
ofapproxim
ately150,000
Dacorresponding
tothe
following
empiricalform
ula:[FeO
x (OH)y (H2 O)z ]n [{(C
6 H10 O
5 )m(C
6 H12 O
7 )}l ]k ,
where
n≈10
3,m≈8,l≈
11,andk≈4
(lrepresentsthe
mean
branchingdegree
oftheligand).
Thechem
icalstructureispresented
below:
1100 Venture Court • Suite 100 • Carrollton, Texas 75006 • Phone 972.478.6400 • Fax 972.478.6401651 S ML King Jr Ave • Waukegan, IL 60085 • Phone 847.336.4200 • Fax 847.360.4924
complete packaging | individual solutionsSM
Product Information Specified Colors
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258024LUITPOLD PHARMACEUTICALS INC
Black
Injectafer (ferric carboxymaltose injection) is a dark brown, sterile, aqueous,isotonic colloidal solution for intravenous injection. Each mL contains 50 mgiron as ferric carboxymaltose in water for injection. Injectafer is available in15 mL single-use vials. Sodium hydroxide and/or hydrochloric acid may havebeen added to adjust the pH to 5.0-7.0.Vial closure is not made with natural rubber latex.
12 CLINICAL PHARMACOLOGY
12.1 Mechanism of ActionFerric carboxymaltose is a colloidal iron (III) hydroxide in complex withcarboxymaltose, a carbohydrate polymer that releases iron.
12.2 PharmacodynamicsUsing positron emission tomography (PET) it was demonstrated that red celluptake of 59Fe and 52Fe from Injectafer ranged from 61% to 99%. In patientswith iron deficiency, red cell uptake of radio-labeled iron ranged from 91% to99% at 24 days after Injectafer dose. In patients with renal anemia red celluptake of radio-labeled iron ranged from 61% to 84% after 24 days Injectaferdose.
12.3 PharmacokineticsAfter administration of a single dose of Injectafer of 100 to 1000 mg of iron iniron deficient patients, maximum iron levels of 37 μg/mL to 333 μg/mL wereobtained respectively after 15 minutes to 1.21 hours post dose. The volume ofdistribution was estimated to be 3 L.The iron injected or infused was rapidly cleared from the plasma, the terminalhalf-life ranged from 7 to 12 hours. Renal elimination of iron was negligible.
13 NONCLINICAL TOXICOLOGY
13.1 Carcinogenesis, Mutagenesis, Impairment of FertilityCarcinogenicity studies have not been performed with ferric carboxymaltose.Ferric carboxymaltose was not genotoxic in the following genetic toxicologystudies: in vitro microbial mutagenesis (Ames) assay, in vitro chromosomeaberration test in human lymphocytes, in vitro mammalian cell mutation assayin mouse lymphoma L5178Y/TK+/- cells, in vivo mouse micronucleus test atsingle intravenous doses up to 500 mg/kg.In a combined male and female fertility study, ferric carboxymaltose wasadministered intravenously over one hour to male and female rats at irondoses of up to 30 mg/kg. Animals were dosed 3 times per week (on Days 0,3, and 7). There was no effect on mating function, fertility or early embryonicdevelopment. The dose of 30 mg/kg in animals is approximately 40% of thehuman dose of 750 mg based on body surface area.
14 CLINICAL STUDIES
The safety and efficacy of Injectafer for treatment of iron deficiency anemiawere evaluated in two randomized, open-label, controlled clinical trials (Trial1 and Trial 2). In these two trials, Injectafer was administered at a dose of15 mg/kg body weight up to a maximum single dose of 750 mg of ironon two occasions separated by at least 7 days up to a cumulative dose of1500 mg of iron.14.1 Trial 1: Iron Deficiency Anemia in Patients Who Are Intolerant to Oral
Iron or Have Had Unsatisfactory Response to Oral IronTrial 1 was a randomized, open-label, controlled clinical study in patientswith iron deficiency anemia who had an unsatisfactory response to oral iron(Cohort 1) or who were intolerant to oral iron (Cohort 2) during the 14 dayoral iron run-in period. Inclusion criteria prior to randomization includedhemoglobin (Hb) <12 g/dL, ferritin ≤ 100 ng/mL or ferritin ≤ 300 ng/mL whentransferrin saturation (TSAT) ≤ 30%. Cohort 1 subjects were randomized toInjectafer or oral iron for 14 more days. Cohort 2 subjects were randomizedto Injectafer or another IV iron per standard of care [90% of subjects receivediron sucrose]. The mean age of study patients was 43 years (range, 18 to94); 94% were female; 42% were Caucasian, 32% were African American,24% were Hispanic, and 2% were other races. The primary etiologies of irondeficiency anemia were heavy uterine bleeding (47%) and gastrointestinaldisorders (17%).Table 2 shows the baseline and the change in hemoglobin from baseline tohighest value between baseline and Day 35 or time of intervention.Table 2. Mean Change in Hemoglobin From Baseline to the HighestValue Between Day 35 or Time of Intervention (Modified Intent‑to‑TreatPopulation)
Hemoglobin (g/dL)Mean (SD)
Cohort 1 Cohort 2Injectafer(N=244)
Oral Iron(N=251)
Injectafer(N=245)
IV SCa
(N=237)
Baseline 10.6 (1.0) 10.6 (1.0) 9.1 (1.6) 9.0 (1.5)
Highest Value 12.2 (1.1) 11.4 (1.2) 12.0 (1.2) 11.2 (1.3)
Change (from baseline tohighest value) 1.6 (1.2) 0.8 (0.8) 2.9 (1.6) 2.2 (1.3)
p-value 0.001 0.001SD=standard deviation; a: Intravenous iron per standard of careIncreases from baseline in mean ferritin (264.2 ± 224.2 ng/mL in Cohort 1and 218.2 ± 211.4 ng/mL in Cohort 2), and transferrin saturation (13 ± 16%in Cohort 1 and 20 ± 15% in Cohort 2) were observed at Day 35 in Injectafer-treated patients.14.2 Trial 2: Iron Deficiency Anemia in Patients with Non‑DialysisDependent Chronic Kidney DiseaseTrial 2 was a randomized, open-label, controlled clinical study in patients withnon-dialysis dependent chronic kidney disease. Inclusion criteria includedhemoglobin (Hb) ≤ 11.5 g/dL, ferritin ≤ 100 ng/mL or ferritin ≤ 300 ng/mLwhen transferrin saturation (TSAT) ≤ 30%. Study patients were randomizedto either Injectafer or Venofer. The mean age of study patients was 67 years(range, 19 to 96); 64% were female; 54% were Caucasian, 26% were AfricanAmerican, 18% Hispanics, and 2% were other races.Table 3 shows the baseline and the change in hemoglobin from baseline tohighest value between baseline and Day 56 or time of intervention.
Table 3. Mean Change in Hemoglobin From Baseline to theHighest Value Between Baseline and Day 56 or Time of Intervention(Modified Intent‑to‑Treat Population)
Hemoglobin (g/dL)Mean (SD)
Injectafer(N=1249)
Venofer(N=1244)
Baseline 10.3 (0.8) 10.3 (0.8)Highest Value 11.4 (1.2) 11.3 (1.1)Change (from baseline to highestvalue) 1.1 (1.0) 0.9 (0.92)
Treatment Difference (95% CI) 0.21 (0.13, 0.28)
Increases from baseline in mean ferritin (734.7 ± 337.8 ng/mL), and transferrinsaturation (30 ± 17%) were observed at Day 56 in Injectafer-treated patients.
16 HOW SUPPLIED/STORAGE AND HANDLING
NDC 0517-0650-01 750 mg iron/15 mL Single-Use Vial Individually boxedNDC 0517-0650-02 750 mg iron/15 mL Single-Use Vial Packages of 2Store at 20°C to 25°C (68°F to 77°F); excursions permitted to 15°C to 30°C(59°F to 86°F). [See the USP controlled room temperature]. Do not freeze.
17 PATIENT COUNSELING INFORMATION
• Question patients regarding any prior history of reactions toparenteral iron products.
• Advise patients of the risks associated with Injectafer.• Advise patients to report any signs and symptoms of hypersensitivity
that may develop during and following Injectafer administration,such as rash, itching, dizziness, lightheadedness, swelling andbreathing problems [see Warnings and Precautions (5)]
Injectafer is manufactured under license from Vifor (International) Inc,Switzerland.
AMERICANREGENT, INC.SHIRLEY, NY 11967
Patient InformationINJECTAFER (ferric carboxymaltose injection)
Please read this information carefully before taking thismedication. This summary does not tell you everythingabout INJECTAFER. Speak with your doctor or healthcareprofessional if there is something you do not understand or ifyou would like to learn more about INJECTAFER. Your doctoror healthcare professional is your best source of informationabout this medicine.What is INJECTAFER?Iron is a mineral that the body needs to produce red bloodcells. When the body does not get enough iron, it cannotproduce the number of normal red blood cells needed to keepyou in good health. This condition is called iron deficiency(iron shortage) or iron deficiency anemia.INJECTAFER is used to treat iron deficiency anemia. Irondeficiency anemia may be caused by several medicalconditions including heavy menstrual bleeding, pregnancy,childbirth, inflammatory bowel disease, other malabsorptiondiseases, bariatric surgery, or chronic kidney disease.General information about using INJECTAFER safely andeffectivelyInjectable iron is administered only by or under the supervisionof your health care professional.Serious or life threatening allergic reactions have beenreported with intravenous iron products. Tell your healthcare professional if you have ever had any unusual or allergicreaction to any IV iron.Patients should report to their healthcare professional anysigns and symptoms of an allergic reaction to INJECTAFER, inparticular rashes, shortness of breath and wheezing.Iron is not easily eliminated from the body, and its build upmay be lead to a condition called iron overload which may beharmful. Certain medical conditions such as liver disease mayalso make you more likely to develop iron overload. Ask yourdoctor or healthcare professional.Who should not take INJECTAFER?You should not be given INJECTAFER if you have anemia thatis not caused by iron deficiency, or if you have iron overload.If you are pregnant or plan to become pregnant please notifyyour doctor or healthcare professional. They will decidewhether it is safe for you to receive INJECTAFER.How should I take INJECTAFER?INJECTAFER is administered intravenously (into your vein) byyour doctor or healthcare professional in two doses.What should I avoid while taking INJECTAFER?You should not take iron supplements by mouth if youare receiving iron injections. Tell your doctor about allthe medicines you take, including prescription and non-prescription medicines, vitamins and herbal supplements.
What are the possible side effects of INJECTAFER?The side effects of INJECTAFER are infrequent, usuallymild and generally do not cause patients to stop treatment.The most common side effects are nausea, injection sitereactions (including pain or bruising at the injection site),asymptomatic reductions in blood phosphorus, flushing,headache, hypertension, dizziness, and increased alanineaminotransferase. Potentially long lasting brown staining ofskin near injection site may occur.These are not all the possible side effects of INJECTAFER. Formore information ask your doctor or healthcare professional.Talk to your doctor if you think you have side effects fromtaking INJECTAFER.
651 S M
L King Jr A
ve • Waukegan, IL 60085 • P
hone 847.336.4200 • Fax 847.360.4924co
mp
lete packag
ing
| ind
ividu
al solu
tion
sS
M
Pro
du
ct Info
rmatio
nS
pecified
Co
lors
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ust:Size:
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roved
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FULL PRESCRIBING INFORMATION
1INDICATIONS AND USAGE
Injectaferis
indicatedfor
thetreatm
entof
irondeficiency
anemia
inadult
patients:•
who
haveintolerance
tooraliron
orhavehad
unsatisfactoryresponse
tooral iron;
•who
havenon-dialysis
dependentchronickidney
disease.2
DOSAGE AND ADMINISTRATION
Forpatients
weighing
50kg
(110lb)or
more:
GiveInjectafer
intwodoses
separatedby
atleast7days.
Giveeach
doseas
750mgfora
totalcumulative
dosenotto
exceed1500
mgofiron
percourse.For
patientsweighing
lessthan
50kg
(110lb):Give
Injectaferin
twodoses
separatedby
atleast7days.Give
eachdose
as15
mg/kg
bodyweightfor
atotalcum
ulativedose
nottoexceed
1500mgofiron
percourse.The
dosageof
Injectaferis
expressedin
mgof
elementaliron.Each
mLof
Injectafercontains
50mgof
elemental
iron.Injectafer
treatment
may
berepeated
ifirondeficiency
anemiareoccurs.
Administer
Injectaferintravenously,either
asan
undilutedslow
intravenouspush
orbyinfusion.W
henadm
inisteringas
aslow
intravenouspush,give
atthe
rateofapproxim
ately100
mg(2
mL)perm
inute.When
administered
viainfusion,dilute
upto
750mgofiron
inno
more
than250
mLofsterile
0.9%sodium
chlorideinjection,USP,such
thattheconcentration
oftheinfusion
isnotless
than2mgofiron
permLand
administeroveratleast15
minutes.
When
addedto
aninfusion
bagcontaining
0.9%sodium
chlorideinjection,
USP,atconcentrationsranging
from2mgto
4mgofiron
permL,Injectafer
solutionisphysically
andchem
icallystable
for72hours
when
storedatroom
temperature.To
maintain
stability,donot
diluteto
concentrationsless
than2mgiron/m
L.Inspect
parenteraldrug
productsvisually
forthe
absenceof
particulatematter
anddiscoloration
priorto
administration.
Theproduct
containsno
preservatives.Each
vialof
Injectaferis
intendedfor
single-useonly.
Anyunused
drugrem
ainingafterinjection
mustbe
discarded.Avoid
extravasationofInjectafersince
browndiscoloration
oftheextravasation
sitemay
belong
lasting.Monitor
forextravasation.Ifextravasation
occurs,discontinue
theInjectaferadm
inistrationatthatsite.
3DOSAGE FORM
S AND STRENGTHS
750mgiron
/15mLsingle-use
vial
4CONTRAINDICATIONS
Hypersensitivityto
Injectaferor
anyof
itscom
ponents[see
Warnings
andPrecautions (5.1)].
5W
ARNINGS AND PRECAUTIONS
5.1Hypersensitivity Reactions
Serioushypersensitivity
reactions,including
anaphylactic-typereactions,
some
ofwhich
havebeen
life-threateningand
fatal,havebeen
reportedin
patientsreceiving
Injectafer.Patients
may
presentw
ithshock,
clinicallysignificant
hypotension,loss
ofconsciousness,
and/orcollapse.
Monitor
patientsfor
signsand
symptom
sof
hypersensitivityduring
andafter
Injectaferadministration
foratleast30m
inutesand
untilclinicallystable
following
completion
ofthe
infusion.Only
administer
Injectaferw
henpersonnel
andtherapies
areim
mediately
availablefor
thetreatm
entof
serioushypersensitivity
reactions.[see
AdverseReactions
(6.1and
6.2)].
HIGHLIGHTS OF PRESCRIBING INFORMATION
These highlights do not include all the information needed to use
Injectafer safely and effectively. See full prescribing information for
Injectafer.INJECTAFER
® (ferric carboxymaltose injection)
For intravenous useInitial U.S. Approval: 2013------------------------------INDICATIONS
ANDUSAGE------------------------------
Injectafer is an iron replacement product indicated for the treatm
ent of irondeficiency anem
ia in adult patients:•
who
haveintolerance
tooraliron
orhavehad
unsatisfactoryresponse
tooral iron;
•who
havenon-dialysis
dependentchronickidney
disease.-------------------------DOSAGE AND ADM
INISTRATION---------------------------Forpatients
weighing
50kg
(110lb)ormore:
GiveInjectaferin
two
dosesseparated
byatleast7
days.Give
eachdose
as750
mgfora
totalcum
ulativedose
of1500mgofiron
percourse.Forpatients
weighing
lessthan
50kg
(110lb):Give
Injectaferintwodoses
separatedby
atleast7days
andgive
eachdose
as15
mg/kg
bodyweight.
Injectafertreatmentm
aybe
repeatedifiron
deficiencyanem
iareoccurs.(2)
FULL PRESCRIBING INFORMATION: CONTENTS*
1INDICATIONS AND USAGE
2DOSAGE AND ADM
INISTRATION3
DOSAGE FORMS AND STRENGTHS
4CONTRAINDICATIONS
5W
ARNINGS AND PRECAUTIONS5.1
HypersensitivityReactions
5.2Hypertension
5.3Laboratory
TestAlterations6
ADVERSE REACTIONS6.1
AdverseReactions
inClinicalTrials
6.2Post-m
arketingExperience
7DRUG INTERACTIONS
8USE IN SPECIFIC POPULATIONS8.1
Pregnancy8.3
NursingMothers
8.4Pediatric
Use8.5
GeriatricUse
--------------------------DOSAGEFORM
SAND
STRENGTHS-----------------------750
mgiron
/15mLsingle-use
vial.(3)-------------------------------CONTRAINDICATIONS---------------------------------Hypersensitivity
toInjectaferorany
ofitsinactive
components.(4)
------------------------WARNINGS AND PRECAUTIONS----------------------------
•Hypersensitivity reactions:Observe
forsignsand
symptom
sof
hypersensitivityduring
andafterInjectaferadm
inistrationforatleast
30minutes
anduntilclinically
stablefollow
ingcom
pletionofeach
administration.(5.1)
•Hypertension:M
onitorpatientsclosely
forsignsand
symptom
sof
hypertensionfollow
ingeach
Injectaferadministration.(5.2)
------------------------------ADVERSE REACTIONS----------------------------------The
mostcom
mon
adversereactions
(≥2%
)arenausea,hypertension,
flushing,hypophosphatemia,and
dizziness(6.1)
To report SUSPECTED ADVERSE REACTIONS, contact American Regent at
1-800-734-9236 or FDA at 1-800-FDA-1088 orwww.fda.gov/m
edwatch.
------------------------USE IN SPECIFIC POPULATIONS----------------------------•
NursingMothers:Exercise
cautionwhen
administered
toanursing
wom
an.(8.3)See 17 for PATIENT COUNSELING INFORM
ATION and FDA-approvedpatient labeling.
Revised: July 2013
10OVERDOSAGE
11DESCRIPTION
12CLINICAL PHARM
ACOLOGY12.1
Mechanism
ofAction12.2
Pharmacodynam
ics12.3
Pharmacokinetics
13NONCLINICAL TOXICOLOGY13.1
Carcinogenesis,Mutagenesis,and
Impairm
entofFertility14
CLINICAL STUDIES14.1
Trial1:IronDeficiency
AnemiainPatients
Who
areIntolerantto
OralIronorHave
HadUnsatisfactory
Responseto
OralIron14.2
Trial2:IronDeficiency
AnemiainPatients
with
Non-DialysisDependentChronic
KidneyDisease
16HOW
SUPPLIED/STORAGE AND HANDLING17
PATIENT COUNSELING INFORMATION
*Sectionsorsubsections
omitted
fromthe
fullprescribinginform
ationare
notlisted.
Inclinicaltrials,serious
anaphylactic/anaphylactoidreactions
were
reportedin
0.1%(2/1775)
ofsubjects
receivingInjectafer.
Otherserious
orsevere
adversereactions
potentiallyassociated
with
hypersensitivitywhich
included,but
notlim
itedto,
pruritus,rash,
urticaria,wheezing,
orhypotension
were
reportedin1.5%
(26/1775)ofthesesubjects.
5.2Hypertension
Inclinicalstudies,hypertension
was
reportedin3.8%
(67/1,775)ofsubjectsin
clinicaltrials
1and
2.Transient
elevationsin
systolicblood
pressure,som
etimes
occurringwith
facialflushing,dizziness,ornauseawere
observedin
6%(106/1,775)
ofsubjects
inthese
twoclinicaltrials.
Theseelevations
generallyoccurred
immediately
afterdosingand
resolvedwithin
30minutes.
Monitor
patientsfor
signsand
symptom
sof
hypertensionfollow
ingeach
Injectaferadministration
[seeDosage and Adm
inistration(2)].
5.3Laboratory Test Alterations
Inthe
24hours
following
administration
ofInjectafer,laboratoryassays
may
overestimate
serumiron
andtransferrin
boundiron
byalso
measuring
theiron
inInjectafer.
6ADVERSE REACTIONS
Thefollow
ingadverse
reactionsare
discussedin
greaterdetail
inother
sectionsofthe
labeling:•
HypersensitivityReactions
[seeW
arnings and Precautions(5.1)]
•Hypertension
[seeW
arnings and Precautions(5.2)]
•Laboratory
TestAlterations[see
Warnings and Precautions
(5.3)]6.1
Adverse Reactions in Clinical TrialsBecause
clinicaltrials
areconducted
underwidely
varyingconditions,
theadverse
reactionrates
observedcannotbe
directlycom
paredto
ratesinother
clinicaltrialsand
may
notreflecttherates
observedinclinicalpractice.
Intworandom
izedclinicalstudies
[Studies1and
2,SeeClinicalStudies
(14)],atotalof1,775
patientswere
exposedto
Injectafer15mg/kg
bodyweightup
toamaxim
umsingle
doseof750
mgofiron
ontwooccasions
separatedby
atleast7days
upto
acum
ulativedose
of1500mgofiron.
Adversereactions
reportedby
≥1%
oftreated
patientsare
shownin
thefollow
ingtable.
Table1.
Adversereactions
reportedin
≥1%
ofStudyPatients
inClinicalTrials
1 and 2
TermInjectafer
(N=1775)%
PooledCom
paratorsa
(N=1783)%
Oraliron
(N=253)%
Nausea7.2
1.81.2
Hypertension3.8
1.90.4
Flushing/HotFlush3.6
0.20.0
BloodPhosphorus
Decrease2.1
0.10.0
Dizziness2.0
1.20.0
Vomiting
1.70.5
0.4Injection
SiteDiscoloration
1.40.3
0.0Headache
1.20.9
0.0Alanine Am
inotransferaseIncrease
1.10.2
0.0
Dysgeusia1.1
2.10.0
Hypotension1.0
1.90.0
Constipation0.5
0.93.2
a Includes oral iron and all formulations of IV iron other than Injectafer
INJECTAFER®
(ferric carboxymaltose injection)
RQ105200
Otheradverse
reactionsreported
by≥
0.5%of
treatedpatients
includeabdom
inalpain,
diarrhea,gam
maglutam
yltransferase
increased,injection
sitepain/irritation,
rash,paraesthesia,
sneezing.Transient
decreasesin
laboratoryblood
phosphoruslevels
(<2mg/dL)have
beenobserved
in27%
(440/1638)patientsinclinicaltrials.
6.2Post-m
arketing ExperienceBecause
thesereactions
arereported
voluntarilyfrom
apopulation
ofuncertainsize,itis
notalways
possibletoreliably
estimate
theirfrequencyorestablish
acausalrelationship
todrug
exposure.Thefollow
ingserious
adversereactions
havebeen
most
commonly
reportedfrom
thepost-m
arketingspontaneous
reportswith
Injectafer:urticaria,
dyspnea,pruritis,
tachycardia,erythem
a,pyrexia,
chestdiscom
fort,chills,
angioedema,
backpain,
arthralgia,and
syncope.One
caseof
hypophosphatemic
osteomalacia
was
reportedin
asubject
who
received500
mgof
Injectaferevery
2weeks
foratotal
of16
weeks.Partialrecovery
followed
discontinuationofInjectafer.
7DRUG INTERACTIONS
Formaldrug
interactionstudies
havenotbeen
performed
with
Injectafer.
8USE IN SPECIFIC POPULATIONS
8.1Pregnancy
PregnancyCategory
CRisk
Summ
aryAdequate
andwell
controlledstudies
inpregnant
wom
enhave
notbeen
conducted.However,anim
alreproductionstudies
havebeen
conductedwith
ferriccarboxymaltose.In
thesestudies,administration
offerriccarboxymaltose
torabbits
duringthe
periodoforganogenesis
causedfetalm
alformations
andincreased
implantation
lossatm
aternallytoxic
dosesofapproxim
ately12%
to23%
ofthehum
anweekly
doseof750
mg(based
onbody
surfacearea).
Theincidence
ofmajor
malform
ationsin
human
pregnancieshas
notbeen
establishedforInjectafer.How
ever,allpregnancies,regardlessofexposure
toany
drug,hasabackground
rateof2
to4%
formajorm
alformations,and
15to
20%forpregnancy
loss.Injectafershouldbe
usedduring
pregnancyonly
ifthe
potentialbenefitjustifiesthe
potentialriskto
thefetus.
Animal Data
Administration
offerric
carboxymaltose
torats
asaone-hour
intravenousinfusion
upto
30mg/kg/day
ironon
gestationdays
6to
17did
notresultinadverse
embryofetalfindings.This
dailydose
inrats
isapproxim
ately40%
ofthehum
anweekly
doseof750
mgbased
onbody
surfacearea.In
rabbits,ferric
carboxymaltose
was
administered
asaone-hour
infusionon
gestationdays
6to
19atiron
dosesof4.5,9,13.5,and
18mg/kg/day.M
alformations
were
seenstarting
atthedaily
doseof9
mg/kg
(23%ofthe
human
weekly
doseof750
mg).Spontaneous
abortionsoccurred
startingatthe
dailyiron
doseof4.5
mg/kg
(12%ofthe
human
weekly
dosebased
onbody
surfacearea).
Pre-implantation
losswas
atthe
highestdose.
Adverseem
bryofetaleffects
were
observedinthe
presenceofm
aternaltoxicity.Apre-and
post-nataldevelopmentstudy
was
conductedinrats
atintravenousdoses
upto
18mg/kg/day
ofiron(approxim
ately23%
oftheweekly
human
doseof750
mgon
abody
surfacearea
basis).Therewere
noadverse
effectson
survivalof
offspring,their
behavior,sexual
maturation
orreproductive
parameters.
8.3Nursing M
othersAstudy
todeterm
ineiron
concentrationsinbreastm
ilkafteradm
inistrationof
Injectafer(n=11)ororalferroussulfate
(n=14)was
conductedin25
lactatingwom
enwith
postpartumiron
deficiencyanem
ia.Mean
breastmilk
ironlevels
were
higherin
lactatingwom
enreceiving
Injectaferthan
inlactating
wom
enreceiving
oralferroussulfate.
8.4Pediatric Use
Safetyand
effectivenesshave
notbeenestablished
inpediatric
patients.8.5
Geriatric UseOfthe
1775subjects
inclinicalstudies
ofInjectafer,50%were
65years
andover,w
hile25%
were
75years
andover.No
overalldifferencesin
safetyor
effectivenesswere
observedbetw
eenthese
subjectsand
youngersubjects,
andother
reportedclinical
experiencehas
notidentified
differencesin
responsesbetw
eenthe
elderlyand
youngerpatients,butgreatersensitivityof
someolderindividuals
cannotberuled
out.
10OVERDOSAGE
Excessivedosages
ofInjectafermay
leadto
accumulation
ofironin
storagesites
potentiallyleading
tohem
osiderosis.Apatientw
horeceived
Injectafer18,000
mg
over6
months
developedhem
osiderosiswith
multiple
jointdisorder,
walking
disabilityand
asthenia.Hypophosphatem
icosteom
alaciawas
reportedin
apatient
who
receivedInjectafer
4000mgover
4months.
Partialrecoveryfollow
eddiscontinuation
ofInjectafer.
[seePost-m
arketingExperience (6.2)].
11DESCRIPTION
Ferriccarboxym
altose,aniron
replacementproduct,is
aniron
carbohydratecom
plexwith
thechem
icalnam
eof
polynucleariron
(III)hydroxide
4(R)-(poly-(1→
4)-O-a
-D-glucopyranosyl)-oxy-2(R
),3(S),5(R
),6-tetrahydroxy-hexanoate.It
hasarelative
molecular
weight
ofapproxim
ately150,000
Dacorresponding
tothe
following
empiricalform
ula:[FeO
x (OH)y (H2 O)z ]n [{(C
6 H10 O
5 )m(C
6 H12 O
7 )}l ]k ,
where
n≈10
3,m≈8,l≈
11,andk≈4
(lrepresentsthe
mean
branchingdegree
oftheligand).
Thechem
icalstructureispresented
below:
651 S M
L King Jr A
ve • Waukegan, IL 60085 • P
hone 847.336.4200 • Fax 847.360.4924co
mp
lete packag
ing
| ind
ividu
al solu
tion
sS
M
Pro
du
ct Info
rmatio
nS
pecified
Co
lors
P/N: J/N:C
ust:Size:
Pro
of A
7/26/2013A
pp
roved
By
Nam
e
DateO
K to PrintN
ew Proof R
equired
This proof is to show size, copy placem
ent andcolor break. Actual colors w
ill be matched on
press to: PMS Book, O
n_Dem
and Solutions FourC
olor Book, On _D
emand Solutions Indichrom
ePlus Book and/or approved C
olor Standards.
258024LU
ITPOLD
PHAR
MAC
EUTIC
ALS INC
Cyan
Magenta
Yellow
Black
FULL PRESCRIBING INFORMATION
1INDICATIONS AND USAGE
Injectaferis
indicatedfor
thetreatm
entof
irondeficiency
anemia
inadult
patients:•
who
haveintolerance
tooraliron
orhavehad
unsatisfactoryresponse
tooral iron;
•who
havenon-dialysis
dependentchronickidney
disease.2
DOSAGE AND ADMINISTRATION
Forpatients
weighing
50kg
(110lb)or
more:
GiveInjectafer
intwodoses
separatedby
atleast7days.
Giveeach
doseas
750mgfora
totalcumulative
dosenotto
exceed1500
mgofiron
percourse.For
patientsweighing
lessthan
50kg
(110lb):Give
Injectaferin
twodoses
separatedby
atleast7days.Give
eachdose
as15
mg/kg
bodyweightfor
atotalcum
ulativedose
nottoexceed
1500mgofiron
percourse.The
dosageof
Injectaferis
expressedin
mgof
elementaliron.Each
mLof
Injectafercontains
50mgof
elemental
iron.Injectafer
treatment
may
berepeated
ifirondeficiency
anemiareoccurs.
Administer
Injectaferintravenously,either
asan
undilutedslow
intravenouspush
orbyinfusion.W
henadm
inisteringas
aslow
intravenouspush,give
atthe
rateofapproxim
ately100
mg(2
mL)perm
inute.When
administered
viainfusion,dilute
upto
750mgofiron
inno
more
than250
mLofsterile
0.9%sodium
chlorideinjection,USP,such
thattheconcentration
oftheinfusion
isnotless
than2mgofiron
permLand
administeroveratleast15
minutes.
When
addedto
aninfusion
bagcontaining
0.9%sodium
chlorideinjection,
USP,atconcentrationsranging
from2mgto
4mgofiron
permL,Injectafer
solutionisphysically
andchem
icallystable
for72hours
when
storedatroom
temperature.To
maintain
stability,donot
diluteto
concentrationsless
than2mgiron/m
L.Inspect
parenteraldrug
productsvisually
forthe
absenceof
particulatematter
anddiscoloration
priorto
administration.
Theproduct
containsno
preservatives.Each
vialof
Injectaferis
intendedfor
single-useonly.
Anyunused
drugrem
ainingafterinjection
mustbe
discarded.Avoid
extravasationofInjectafersince
browndiscoloration
oftheextravasation
sitemay
belong
lasting.Monitor
forextravasation.Ifextravasation
occurs,discontinue
theInjectaferadm
inistrationatthatsite.
3DOSAGE FORM
S AND STRENGTHS
750mgiron
/15mLsingle-use
vial
4CONTRAINDICATIONS
Hypersensitivityto
Injectaferor
anyof
itscom
ponents[see
Warnings
andPrecautions (5.1)].
5W
ARNINGS AND PRECAUTIONS
5.1Hypersensitivity Reactions
Serioushypersensitivity
reactions,including
anaphylactic-typereactions,
some
ofwhich
havebeen
life-threateningand
fatal,havebeen
reportedin
patientsreceiving
Injectafer.Patients
may
presentw
ithshock,
clinicallysignificant
hypotension,loss
ofconsciousness,
and/orcollapse.
Monitor
patientsfor
signsand
symptom
sof
hypersensitivityduring
andafter
Injectaferadministration
foratleast30m
inutesand
untilclinicallystable
following
completion
ofthe
infusion.Only
administer
Injectaferw
henpersonnel
andtherapies
areim
mediately
availablefor
thetreatm
entof
serioushypersensitivity
reactions.[see
AdverseReactions
(6.1and
6.2)].
HIGHLIGHTS OF PRESCRIBING INFORMATION
These highlights do not include all the information needed to use
Injectafer safely and effectively. See full prescribing information for
Injectafer.INJECTAFER
® (ferric carboxymaltose injection)
For intravenous useInitial U.S. Approval: 2013------------------------------INDICATIONS
ANDUSAGE------------------------------
Injectafer is an iron replacement product indicated for the treatm
ent of irondeficiency anem
ia in adult patients:•
who
haveintolerance
tooraliron
orhavehad
unsatisfactoryresponse
tooral iron;
•who
havenon-dialysis
dependentchronickidney
disease.-------------------------DOSAGE AND ADM
INISTRATION---------------------------Forpatients
weighing
50kg
(110lb)ormore:
GiveInjectaferin
two
dosesseparated
byatleast7
days.Give
eachdose
as750
mgfora
totalcum
ulativedose
of1500mgofiron
percourse.Forpatients
weighing
lessthan
50kg
(110lb):Give
Injectaferintwodoses
separatedby
atleast7days
andgive
eachdose
as15
mg/kg
bodyweight.
Injectafertreatmentm
aybe
repeatedifiron
deficiencyanem
iareoccurs.(2)
FULL PRESCRIBING INFORMATION: CONTENTS*
1INDICATIONS AND USAGE
2DOSAGE AND ADM
INISTRATION3
DOSAGE FORMS AND STRENGTHS
4CONTRAINDICATIONS
5W
ARNINGS AND PRECAUTIONS5.1
HypersensitivityReactions
5.2Hypertension
5.3Laboratory
TestAlterations6
ADVERSE REACTIONS6.1
AdverseReactions
inClinicalTrials
6.2Post-m
arketingExperience
7DRUG INTERACTIONS
8USE IN SPECIFIC POPULATIONS8.1
Pregnancy8.3
NursingMothers
8.4Pediatric
Use8.5
GeriatricUse
--------------------------DOSAGEFORM
SAND
STRENGTHS-----------------------750
mgiron
/15mLsingle-use
vial.(3)-------------------------------CONTRAINDICATIONS---------------------------------Hypersensitivity
toInjectaferorany
ofitsinactive
components.(4)
------------------------WARNINGS AND PRECAUTIONS----------------------------
•Hypersensitivity reactions:Observe
forsignsand
symptom
sof
hypersensitivityduring
andafterInjectaferadm
inistrationforatleast
30minutes
anduntilclinically
stablefollow
ingcom
pletionofeach
administration.(5.1)
•Hypertension:M
onitorpatientsclosely
forsignsand
symptom
sof
hypertensionfollow
ingeach
Injectaferadministration.(5.2)
------------------------------ADVERSE REACTIONS----------------------------------The
mostcom
mon
adversereactions
(≥2%
)arenausea,hypertension,
flushing,hypophosphatemia,and
dizziness(6.1)
To report SUSPECTED ADVERSE REACTIONS, contact American Regent at
1-800-734-9236 or FDA at 1-800-FDA-1088 orwww.fda.gov/m
edwatch.
------------------------USE IN SPECIFIC POPULATIONS----------------------------•
NursingMothers:Exercise
cautionwhen
administered
toanursing
wom
an.(8.3)See 17 for PATIENT COUNSELING INFORM
ATION and FDA-approvedpatient labeling.
Revised: July 2013
10OVERDOSAGE
11DESCRIPTION
12CLINICAL PHARM
ACOLOGY12.1
Mechanism
ofAction12.2
Pharmacodynam
ics12.3
Pharmacokinetics
13NONCLINICAL TOXICOLOGY13.1
Carcinogenesis,Mutagenesis,and
Impairm
entofFertility14
CLINICAL STUDIES14.1
Trial1:IronDeficiency
AnemiainPatients
Who
areIntolerantto
OralIronorHave
HadUnsatisfactory
Responseto
OralIron14.2
Trial2:IronDeficiency
AnemiainPatients
with
Non-DialysisDependentChronic
KidneyDisease
16HOW
SUPPLIED/STORAGE AND HANDLING17
PATIENT COUNSELING INFORMATION
*Sectionsorsubsections
omitted
fromthe
fullprescribinginform
ationare
notlisted.
Inclinicaltrials,serious
anaphylactic/anaphylactoidreactions
were
reportedin
0.1%(2/1775)
ofsubjects
receivingInjectafer.
Otherserious
orsevere
adversereactions
potentiallyassociated
with
hypersensitivitywhich
included,but
notlim
itedto,
pruritus,rash,
urticaria,wheezing,
orhypotension
were
reportedin1.5%
(26/1775)ofthesesubjects.
5.2Hypertension
Inclinicalstudies,hypertension
was
reportedin3.8%
(67/1,775)ofsubjectsin
clinicaltrials
1and
2.Transient
elevationsin
systolicblood
pressure,som
etimes
occurringwith
facialflushing,dizziness,ornauseawere
observedin
6%(106/1,775)
ofsubjects
inthese
twoclinicaltrials.
Theseelevations
generallyoccurred
immediately
afterdosingand
resolvedwithin
30minutes.
Monitor
patientsfor
signsand
symptom
sof
hypertensionfollow
ingeach
Injectaferadministration
[seeDosage and Adm
inistration(2)].
5.3Laboratory Test Alterations
Inthe
24hours
following
administration
ofInjectafer,laboratoryassays
may
overestimate
serumiron
andtransferrin
boundiron
byalso
measuring
theiron
inInjectafer.
6ADVERSE REACTIONS
Thefollow
ingadverse
reactionsare
discussedin
greaterdetail
inother
sectionsofthe
labeling:•
HypersensitivityReactions
[seeW
arnings and Precautions(5.1)]
•Hypertension
[seeW
arnings and Precautions(5.2)]
•Laboratory
TestAlterations[see
Warnings and Precautions
(5.3)]6.1
Adverse Reactions in Clinical TrialsBecause
clinicaltrials
areconducted
underwidely
varyingconditions,
theadverse
reactionrates
observedcannotbe
directlycom
paredto
ratesinother
clinicaltrialsand
may
notreflecttherates
observedinclinicalpractice.
Intworandom
izedclinicalstudies
[Studies1and
2,SeeClinicalStudies
(14)],atotalof1,775
patientswere
exposedto
Injectafer15mg/kg
bodyweightup
toamaxim
umsingle
doseof750
mgofiron
ontwooccasions
separatedby
atleast7days
upto
acum
ulativedose
of1500mgofiron.
Adversereactions
reportedby
≥1%
oftreated
patientsare
shownin
thefollow
ingtable.
Table1.
Adversereactions
reportedin
≥1%
ofStudyPatients
inClinicalTrials
1 and 2
TermInjectafer
(N=1775)%
PooledCom
paratorsa
(N=1783)%
Oraliron
(N=253)%
Nausea7.2
1.81.2
Hypertension3.8
1.90.4
Flushing/HotFlush3.6
0.20.0
BloodPhosphorus
Decrease2.1
0.10.0
Dizziness2.0
1.20.0
Vomiting
1.70.5
0.4Injection
SiteDiscoloration
1.40.3
0.0Headache
1.20.9
0.0Alanine Am
inotransferaseIncrease
1.10.2
0.0
Dysgeusia1.1
2.10.0
Hypotension1.0
1.90.0
Constipation0.5
0.93.2
a Includes oral iron and all formulations of IV iron other than Injectafer
INJECTAFER®
(ferric carboxymaltose injection)
RQ105200
Otheradverse
reactionsreported
by≥
0.5%of
treatedpatients
includeabdom
inalpain,
diarrhea,gam
maglutam
yltransferase
increased,injection
sitepain/irritation,
rash,paraesthesia,
sneezing.Transient
decreasesin
laboratoryblood
phosphoruslevels
(<2mg/dL)have
beenobserved
in27%
(440/1638)patientsinclinicaltrials.
6.2Post-m
arketing ExperienceBecause
thesereactions
arereported
voluntarilyfrom
apopulation
ofuncertainsize,itis
notalways
possibletoreliably
estimate
theirfrequencyorestablish
acausalrelationship
todrug
exposure.Thefollow
ingserious
adversereactions
havebeen
most
commonly
reportedfrom
thepost-m
arketingspontaneous
reportswith
Injectafer:urticaria,
dyspnea,pruritis,
tachycardia,erythem
a,pyrexia,
chestdiscom
fort,chills,
angioedema,
backpain,
arthralgia,and
syncope.One
caseof
hypophosphatemic
osteomalacia
was
reportedin
asubject
who
received500
mgof
Injectaferevery
2weeks
foratotal
of16
weeks.Partialrecovery
followed
discontinuationofInjectafer.
7DRUG INTERACTIONS
Formaldrug
interactionstudies
havenotbeen
performed
with
Injectafer.
8USE IN SPECIFIC POPULATIONS
8.1Pregnancy
PregnancyCategory
CRisk
Summ
aryAdequate
andwell
controlledstudies
inpregnant
wom
enhave
notbeen
conducted.However,anim
alreproductionstudies
havebeen
conductedwith
ferriccarboxymaltose.In
thesestudies,administration
offerriccarboxymaltose
torabbits
duringthe
periodoforganogenesis
causedfetalm
alformations
andincreased
implantation
lossatm
aternallytoxic
dosesofapproxim
ately12%
to23%
ofthehum
anweekly
doseof750
mg(based
onbody
surfacearea).
Theincidence
ofmajor
malform
ationsin
human
pregnancieshas
notbeen
establishedforInjectafer.How
ever,allpregnancies,regardlessofexposure
toany
drug,hasabackground
rateof2
to4%
formajorm
alformations,and
15to
20%forpregnancy
loss.Injectafershouldbe
usedduring
pregnancyonly
ifthe
potentialbenefitjustifiesthe
potentialriskto
thefetus.
Animal Data
Administration
offerric
carboxymaltose
torats
asaone-hour
intravenousinfusion
upto
30mg/kg/day
ironon
gestationdays
6to
17did
notresultinadverse
embryofetalfindings.This
dailydose
inrats
isapproxim
ately40%
ofthehum
anweekly
doseof750
mgbased
onbody
surfacearea.In
rabbits,ferric
carboxymaltose
was
administered
asaone-hour
infusionon
gestationdays
6to
19atiron
dosesof4.5,9,13.5,and
18mg/kg/day.M
alformations
were
seenstarting
atthedaily
doseof9
mg/kg
(23%ofthe
human
weekly
doseof750
mg).Spontaneous
abortionsoccurred
startingatthe
dailyiron
doseof4.5
mg/kg
(12%ofthe
human
weekly
dosebased
onbody
surfacearea).
Pre-implantation
losswas
atthe
highestdose.
Adverseem
bryofetaleffects
were
observedinthe
presenceofm
aternaltoxicity.Apre-and
post-nataldevelopmentstudy
was
conductedinrats
atintravenousdoses
upto
18mg/kg/day
ofiron(approxim
ately23%
oftheweekly
human
doseof750
mgon
abody
surfacearea
basis).Therewere
noadverse
effectson
survivalof
offspring,their
behavior,sexual
maturation
orreproductive
parameters.
8.3Nursing M
othersAstudy
todeterm
ineiron
concentrationsinbreastm
ilkafteradm
inistrationof
Injectafer(n=11)ororalferroussulfate
(n=14)was
conductedin25
lactatingwom
enwith
postpartumiron
deficiencyanem
ia.Mean
breastmilk
ironlevels
were
higherin
lactatingwom
enreceiving
Injectaferthan
inlactating
wom
enreceiving
oralferroussulfate.
8.4Pediatric Use
Safetyand
effectivenesshave
notbeenestablished
inpediatric
patients.8.5
Geriatric UseOfthe
1775subjects
inclinicalstudies
ofInjectafer,50%were
65years
andover,w
hile25%
were
75years
andover.No
overalldifferencesin
safetyor
effectivenesswere
observedbetw
eenthese
subjectsand
youngersubjects,
andother
reportedclinical
experiencehas
notidentified
differencesin
responsesbetw
eenthe
elderlyand
youngerpatients,butgreatersensitivityof
someolderindividuals
cannotberuled
out.
10OVERDOSAGE
Excessivedosages
ofInjectafermay
leadto
accumulation
ofironin
storagesites
potentiallyleading
tohem
osiderosis.Apatientw
horeceived
Injectafer18,000
mg
over6
months
developedhem
osiderosiswith
multiple
jointdisorder,
walking
disabilityand
asthenia.Hypophosphatem
icosteom
alaciawas
reportedin
apatient
who
receivedInjectafer
4000mgover
4months.
Partialrecoveryfollow
eddiscontinuation
ofInjectafer.
[seePost-m
arketingExperience (6.2)].
11DESCRIPTION
Ferriccarboxym
altose,aniron
replacementproduct,is
aniron
carbohydratecom
plexwith
thechem
icalnam
eof
polynucleariron
(III)hydroxide
4(R)-(poly-(1→
4)-O-a
-D-glucopyranosyl)-oxy-2(R
),3(S),5(R
),6-tetrahydroxy-hexanoate.It
hasarelative
molecular
weight
ofapproxim
ately150,000
Dacorresponding
tothe
following
empiricalform
ula:[FeO
x (OH)y (H2 O)z ]n [{(C
6 H10 O
5 )m(C
6 H12 O
7 )}l ]k ,
where
n≈10
3,m≈8,l≈
11,andk≈4
(lrepresentsthe
mean
branchingdegree
oftheligand).
Thechem
icalstructureispresented
below:
IN0650ADVIss. 7/2013