Fera heme™
`ferui:n_oxy~ol ~
`m1ect10n
`
`HIGHLIGHTS OF PRESCRIBING INFORMATION
`These highlights do not include all the information needed to use Feraheme
`safely and effectively. See full prescribing information for Feraheme.
`
`FERAHEME® (ferumoxytol) Injection
`For Intravenous {IV) use
`Initial U.S. Approval: 2009
`
`--------RECENT MAJOR CHANGES--------
`Boxed Warning
`03/2015
`Dosage and Administration (2)
`03/2015
`Warnings and Precautions,
`Serious Hypersensitivity Reactions (5.1)
`
`03/2015
`
`WARNING: RISK FOR SERIOUS
`HYPERSENSITIVITY/ ANAPHYLAXIS REACTIONS
`See full prescribing information for complete boxed warning.
`
`Fatal and serious hypersensitivity reactions including anaphylaxis have
`occurred in patients receiving Feraheme. Initial symptoms may include
`hypotension, syncope, unresponsiveness, cardiac/cardiorespiratory arrest.
`• Only administer Feraheme when personnel and therapies are
`immediately available for the treatment of anaphylaxis and
`other hypersensitivity reactions. (5.1)
`• Observe for signs or symptoms of hypersensitivity reactions
`during and for at least 30 minutes following Feraheme infusion
`including monitoring of blood pressure and pulse during and
`after Feraheme administration. (5.1)
`• Hypersensitivity reactions have occurred in patients in whom a
`previous Feraheme dose was tolerated. (5.1)
`
`--------INDICATIONS AND USAGE-------(cid:173)
`Feraheme is an iron replacement product indicated for the treatment of iron
`deficiency anemia in adult patients with chronic kidney disease (CKD). (1)
`
`FULL PRESCRIBING INFORMATION: CONTENTS*
`
`INDICATIONS AND USAGE
`1
`2 DOSAGE AND ADMINISTRATION
`3 DOSAGE FORMS AND STRENGTHS
`4 CONTRAINDICATIONS
`5 WARNINGS AND PRECAUTIONS
`5.1
`Serious Hypersensitivity Reactions
`5.2
`Hypotension
`5.3
`Iron overload
`5.4
`Magnetic Resonance (MR) Imaging
`6 ADVERSE REACTIONS
`6.1
`Adverse Reactions in Clinical Studies
`6.2
`Postmarketing Experience
`7 DRUG INTERACTIONS
`8 USE IN SPECIFIC POPULATIONS
`8.1
`Pregnancy
`8.3
`Nursing Mothers
`8.4
`Pediatric Use
`8.5
`Geriatric Use
`
`-------DOSAGE AND ADMINISTRATION-------
`• The recommended dose of Feraheme is an initial 51 O mg dose
`followed by a second 510 mg dose 3 to 8 days later.
`• Administer Feraheme as an intravenous infusion in 50-200 ml
`0.9% Sodium Chloride Injection, USP or 5% Dextrose Injection,
`USP over at least 15 minutes
`
`------DOSAGE FORMS AND STRENGTHS-----(cid:173)
`Injection: 51 o mg iron per17 ml (30 mg per ml) in single use vials. (3)
`--------CONTRAINDICATIONS--------
`• Known hypersensitivity to Feraheme or any of its components.
`• History of allergic reaction to any intravenous iron product
`
`-------WARNINGS AND PRECAUTIONS-------
`• Greater risk of anaphylaxis in patients with multiple drug allergies. (5.1 ).
`• Hypotension: Feraheme may cause hypotension. Monitor for signs and
`symptoms of hypotension following each administration of Feraheme. (5.2)
`• Iron Overload: Regularly monitor hematologic responses during Feraheme
`therapy. Do not administer Feraheme to patients with iron overload. (5.3)
`• Magnetic Resonance Imaging: Feraheme can alter magnetic resonance
`imaging (MRI) studies. (5.4)
`
`---------ADVERSE REACTIONS-------(cid:173)
`The most common adverse reactions(~ 2%) following the administration of
`Feraheme are diarrhea, nausea, dizziness, hypotension, constipation, and
`peripheral edema. (6.1)
`
`To report SUSPECTED ADVERSE REACTIONS with Feraheme, contact AMAG
`Pharmaceuticals, Inc. at 1-877-411-2510, or FDA at 1-800-FDA-1088 or
`www.fda.gov/medwatch.
`
`See 17 for PATIENT COUNSELING INFORMATION and FDA-approved
`patient labeling
`
`Revised: 03/2015
`
`10 OVER DOSAGE
`11 DESCRIPTION
`12 CLINICAL PHARMACOLOGY
`12.1 Mechanism of Action
`12.2 Pharmacodynamics
`12.3 Pharmacokinetics
`13 NONCLINICAL TOXICOLOGY
`13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
`14 CLINICAL STUDIES
`16 HOW SUPPLIED/STORAGE AND HANDLING
`16.1 How Supplied
`16.2 Stability and Storage
`17 PATIENT COUNSELING INFORMATION
`
`*Sections or subsections omitted from the full prescribing information are not listed.
`
`Pharmacosmos, Exh. 1031, p. 1
`
`

`

`FULL PRESCRIBING INFORMATION
`
`WARNING: RISK FOR SERIOUS HYPERSENSITIVITY/ANAPHYLAXIS REACTIONS
`Fatal and serious hypersensitivity reactions including anaphylaxis have occurred
`in patients receiving Feraheme. Initial symptoms may include hypotension,
`syncope, unresponsiveness, cardiac/cardiorespiratory arrest.
`• Only administer Feraheme when personnel and therapies are immediately
`available for the treatment of anaphylaxis and other hypersensitivity reactions
`[see Warnings and Precautions (5.1)].
`• Observe for signs or symptoms of hypersensitivity reactions during and for at
`least 30 minutes following Feraheme infusion including monitoring of blood
`pressure and pulse during and after Feraheme administration (see Warnings
`and Precautions (5.1)].
`• Hypersensitivity reactions have occurred in patients in whom a previous
`Feraheme dose was tolerated [see Warnings and Precautions (5.1)].
`
`INDICATIONS AND USAGE
`Feraheme is indicated for the treatment of iron deficiency anemia in adult patients with
`chronic kidney disease (CKD).
`
`DOSAGE AND ADMINISTRATION
`2
`The recommended dose of Feraheme is an initial 510 mg dose followed by a second 510 mg
`dose 3 to 8 days later. Administer Feraheme as an intravenous infusion in 50-200 ml 0.9%
`Sodium Chloride Injection, USP or 5% Dextrose Injection, USP over at least 15 minutes.
`Aclminister while the patient is in a reclined or semi-reclined position.
`
`Feraheme, when added to intravenous infusion bags containing either 0.9% Sodium Chloride
`Injection, USP (normal saline), or 5% Dextrose Injection, USP, at concentrations of 2-8 mg
`elemental iron per ml, should be used immediately but may be stored at controlled room
`temperature (25°C ± 2°C) for up to 4 hours.
`
`The dosage is expressed in terms of mg of elemental iron, with each ml of Feraheme
`containing 30 mg of elemental iron. Evaluate the hematologic response (hemoglobin, ferritin,
`iron and transferrin saturation) at least one month following the second Feraheme infusion.
`Tl1e recommended Feraheme dose may be readministered to patients with persistent or
`recurrent iron deficiency anemia.
`
`For patients receiving hemodialysis, administer Feraheme once the blood pressure is stable
`and the patient has completed at least one hour of hemodialysis. Monitor for signs and
`symptoms of hypotension following each Feraheme infusion.
`
`Allow at least 30 minutes between administration of Feraheme and administration of other
`medications that could potentially cause serious hypersensitivity reactions and/or
`liypotension, such as chemotherapeutic agents or monoclonal antibodies.
`
`Inspect parenteral drug products visually for the absence of particulate matter and
`discoloration prior to administration.
`
`3
`
`DOSAGE FORMS AND STRENGTHS
`
`I Feraheme Injection is available in single use vials. Each vial contains 510 mg of elemental
`
`iron in 17 ml (30 mg per ml).
`
`CONTRAINDICATIONS
`4
`Feraheme is contraindicated in patients with:
`
`• Known hypersensitivity to Feraheme or any of its components
`• History of allergic reaction to any intravenous iron product
`
`5
`
`WARNINGS AND PRECAUTIONS
`
`Serious Hypersensitivity Reactions
`5.1
`Fatal and serious hypersensitivity reactions including anaphylaxis, presenting with
`cardiac/cardiorespiratory arrest, clinically significant hypotension, syncope, or
`unresponsiveness have occurred in patients receiving Feraheme (see Boxed Warning].
`Other adverse reactions potentially associated with hypersensitivity have occurred
`(pruritus, rash, urticaria, and wheezing). These reactions have occurred following the first
`dose or subsequent doses in patients in whom a previous Feraheme dose was tolerated.
`
`Patients with a history of multiple drug allergies may have a greater risk of anaphylaxis
`with parenteral iron products. Carefully consider the potential risks and benefits before
`administering Feraheme to these patients.
`
`Only administer Feraheme when personnel and therapies are immediately available for
`the treatment of anaphylaxis and other hypersensitivity reactions. Closely observe patients
`for signs and symptoms of hypersensitivity including monitoring of blood pressure and
`pulse during and after Feraheme administration for at least 30 minutes and until
`clinically stable following completion of each infusion [see Adverse Reactions (6.2)].
`
`In clinical studies predominantly in patients with CKD, serious hypersensitivity reactions
`were reported in 0.2% (3/1,726) of subjects receiving Feraheme. Other adverse
`reactions potentially associated with hypersensitivity (e.g., pruritus, rash, urticaria or
`wheezing) were reported in 3. 7% (63/1, 726) of these subjects. In other trials excluding
`patients with Stages 4 and 5 CKD, moderate to severe hypersensitivity reactions were
`reported in 2.6% (26/1014) of patients treated with Feraheme.
`
`In the post-marketing experience, fatal and serious anaphylactic type reactions
`presenting with cardiac/ cardiorespiratory arrest, clinically significant hypotension,
`syncope, and unresponsiveness have been reported. Elderly patients with multiple or
`serious co-morbidities who experience hypersensitivity reactions and/or hypotension
`following administration of Feraheme may have more severe outcomes (see Boxed
`Warning, Adverse Reactions (6.2) and Use in Specific Populations (8.5)].
`
`Hypotension
`5.2
`Severe adverse reactions of clinically significant hypotension have been reported. In
`clinical studies, hypotension was reported in 1.9% (33/1,726) of subjects, including
`three patients with serious hypotensive reactions. Hypotension has also been reported
`in the post-marketing experience [see Adverse Reactions from Post-marketing
`Spontaneous Reports (6.2)]. Monitor patients for signs and symptoms of hypotension
`following each Feraheme administration [see Dosage and Administration (2) and
`Warnings and Precautions (5.1)].
`
`Iron Overload
`5.3
`Excessive therapy with parenteral iron can lead to excess storage of iron with the
`possibility of iatrogenic hemosiderosis. Regularly monitor the hematologic response
`during parenteral iron therapy [see Dosage and Administration {2)]. Do not administer
`Feraheme to patients with iron overload.
`
`In the 24 hours following administration of Feraheme, laboratory assays may
`overestimate serum iron and transferrin bound iron by also measuring the iron in the
`Feraheme complex.
`
`5.4 Magnetic Resonance (MR) Imaging
`Administration of Feraheme may transiently affect the diagnostic ability of MR imaging.
`Anticipated MR imaging studies should be conducted prior to the administration of
`Feraheme. Alteration of MR imaging studies may persist for up to 3 months following
`the last Feraheme dose. If MR imaging is required within 3 months after Feraheme
`administration, use T1- or proton density-weighted MR pulse sequences to minimize
`the Feraheme effects; MR imaging using T2-weighted pulse sequences should not
`be performed earlier than 4 weeks after the administration of Feraheme. Maximum
`alteration of vascular MR imaging is anticipated to be evident for 1 - 2 days following
`Feraheme administration [see Clinical Pharmacology (12.3)].
`
`Feraheme will not interfere with X-ray, computed tomography (CT), positron emission
`tomography (PET), single photon emission computed tomography (SPECT), ultrasound
`or nuclear medicine imaging.
`
`ADVERSE REACTIONS
`6
`Feraheme administration may cause serious hypersensitivity reactions and hypotension
`(see Warnings and Precautions (5.1),(5.2)].
`
`In clinical studies, 1,726 subjects were exposed to Feraheme; 1,562 of these had CKD
`and 164 did not have CKD. Of these subjects 46% were male and the median age was
`63 years (range of 18 to 96 years).
`
`Because clinical trials are conducted under widely varying conditions, adverse reaction
`rates observed in the clinical trials of a drug may not reflect the rates observed in practice.
`
`Adverse Reactions in Clinical Studies
`6.1
`Across the three randomized clinical trials [Trial 1, 2, and 3, see Clinical Studies (14)],
`a total of 605 patients were exposed to two injections of 51 O mg of Feraheme and a
`total of 280 patients were exposed to 200 mg/day of oral iron for 21 days. Most patients
`received their second Feraheme injection 3 to 8 days after the first injection.
`
`Adverse reactions related to Feraheme and reported by ~ 1 % of Feraheme-treated
`patients in the randomized clinical trials are listed in Table 1. Diarrhea (4.0%),
`constipation (2.1 %) and hypertension (1.0%) have also been reported in
`Feraheme-treated patients.
`
`Pharmacosmos, Exh. 1031, p. 2
`
`

`

`Table 1: Adverse Reactions to Feraheme Reported in ~1 % of Patients with CKD
`
`Adverse Reactions
`
`Nausea
`
`Dizziness
`
`Hypotension
`
`Peripheral Edema
`
`Headache
`
`Edema
`
`Vomiting
`
`Abdominal Pain
`
`Chest Pain
`
`Cough
`
`Pruritus
`
`Pyrexia
`
`Back Pain
`
`Muscle Spasms
`
`Dyspnea
`
`Rash
`
`Feraheme
`2 x 510 mg
`(n = 605)
`3.1%
`
`Oral Iron
`(n = 280)
`7.5%
`
`2.6%
`
`2.5%
`
`2.0%
`
`1.8%
`
`1.5%
`
`1.5%
`
`1.3%
`
`1.3%
`
`1.3%
`
`1.2%
`
`1.0%
`
`1.0%
`
`1.0%
`
`1.0%
`
`1.0%
`
`1.8%
`
`0.4%
`
`3.2%
`
`2.1%
`
`1.4%
`
`5.0%
`
`1.4%
`
`0.7%
`
`1.4%
`
`0.4%
`
`0.7%
`
`0%
`
`1.4%
`
`1.1%
`
`0.4%
`
`In clinical trials, adverse reactions leading to treatment discontinuation and occurring
`in ;;:: 2 Feraheme-treated patients included hypotension, infusion site swelling, increased
`serum ferritin level, chest pain, diarrhea, dizziness, ecchymosis, pruritus, chronic renal
`failure. and urticaria.
`
`Following completion of the controlled phase of the trials, 69 patients received two
`additional 51 O mg intravenous injections of Feraheme (for a total cumulative dose
`of 2.04 g). Adverse reactions following this repeat Feraheme dosing were similar in
`character and frequency to those observed following the first two intravenous injections.
`
`In a placebo-controlled, cross-over trial, 713 patients with CKD received a single
`51 O mg dose of Feraheme. Adverse reactions reported by these patients were
`similar in character and frequency to those observed in other clinical trials.
`
`Postmarketing Experience
`6.2
`Because adverse reactions are reported voluntarily from a population of uncertain size,
`it is not always possible to reliably estimate their frequency or establish a causal
`relationship to drug exposure.
`
`The following serious adverse reactions have been reported from the post-marketing
`experience with Feraheme: fatal, life-threatening, and serious anaphylactic-type
`reactions, cardiac/cardiorespiratory arrest, clinically significant hypotension, syncope,
`unresponsiveness, loss of consciousness, tachycardia/rhythm abnormalities,
`angioedema, ischemic myocardial events, congestive heart failure, pulse absent, and
`cyanosis. These adverse reactions have usually occurred within 30 minutes after the
`administration of Feraheme. Reactions have occurred following the first dose or
`subsequent doses of Feraheme.
`
`DRUG INTERACTIONS
`7
`Drug-drug interaction studies with Feraheme were not conducted. Feraheme may
`reduce the absorption of concomitantly administered oral iron preparations.
`
`8
`
`USE IN SPECIFIC POPULATIONS
`
`Pregnancy
`8.1
`Pregnancy Category C
`
`There are no studies of Feraheme in pregnant women. In animal studies, ferumoxytol
`caused fetal malformations and decreased fetal weights at maternally toxic doses of
`6 times the estimated human daily dose. Use Feraheme during pregnancy only if the
`potential benefit justifies the potential risk to the fetus.
`
`Administration of ferumoxytol during organogenesis, at doses of 31.6 mg Fe/kg/day
`in rats and 16.5 mg Fe/kg/day in rabbits, did not result in maternal or fetal effects.
`These doses are approximately 2 times the estimated human daily dose based on
`body surface area. In rats, administration of ferumoxytol during organogenesis at a
`maternally toxic dose of 100 mg Fe/kg/day, approximately 6 times the estimated human
`daily dose based on body surface area, caused a decrease in fetal weights. In rabbits,
`administration of ferumoxytol during organogenesis at a maternally toxic dose of
`45 mg Fe/kg/day, approximately 6 times the estimated human daily dose based
`on body surface area, was associated with external and/or soft tissue fetal
`malformations and decreased fetal weights.
`
`Nursing Mothers
`8.3
`It is not known whether Feraheme is present in human milk. Because many drugs are
`excreted in human milk and because of the potential for adverse reactions in nursing
`infants, a decision should be made whether to discontinue nursing or to avoid
`Feraheme, taking into account the importance of Feraheme to the mother and the
`known benefits of nursing.
`
`Pediatric Use
`8.4
`The safety and effectiveness of Feraheme in pediatric patients (less than 18 years old)
`have not been established.
`
`Geriatric Use
`8.5
`In controlled clinical trials, 330 patients 2: 65 years of age were treated with Feraheme.
`No overall differences in safety and efficacy were observed between older and younger
`patients in these trials, but greater sensitivity of older individuals cannot be ruled out.
`In general, dose administration to an elderly patient should be cautious, reflecting the
`greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant
`disease or other drug therapy. Elderly patients with multiple or serious co-morbidities
`who experience hypersensitivity reactions and/or hypotension following administration
`of Feraheme may have more severe outcomes. The potential risks and benefits of
`Feraheme administration should be carefully considered in these patients [see Dosage
`and Administration (2) Serious Hypersensitivity Reactions (5. 1) and Clinical Studies (14]].
`
`OVER DOSAGE
`10
`Limited data are available regarding overdosage of Feraheme in humans.
`
`Excessive dosages of Feraheme may lead to accumulation of iron in storage sites
`potentially leading to hemosiderosis. Do not administer Feraheme to patients with
`iron overload [Warnings and Precautions (5.3}].
`
`DESCRIPTION
`11
`Feraheme, an iron replacement product, is a non-stoichiometric magnetite
`(superparamagnetic iron oxide) coated with polyglucose sorbitol carboxymethylether.
`The overall colloidal particle size is 17-31 nm in diameter. The chemical formula of
`Feraheme is Fe,,81p8152-C11119H1868p9933Na4, 4 with an apparent molecular weight of
`750 kDa.
`
`Feraheme Injection is an aqueous colloidal product that is formulated with mannitol.
`It is a black to reddish brown liquid, and is provided in single use vials containing
`51 O mg of elemental iron. Each ml of the sterile colloidal solution of Feraheme
`Injection contains 30 mg of elemental iron and 44 mg of mannitol, and has low
`bleomycin-detectable iron. The formulation is isotonic with an osmolality of
`270-330 mOsm/kg. The product contains no preservatives, and has a pH of 6 to 8.
`
`12
`
`CLINICAL PHARMACOLOGY
`
`12.1 Mechanism of Action
`Feraheme consists of a superparamagnetic iron oxide that is coated with a
`carbohydrate shell, which helps to isolate the bioactive iron from plasma components
`until the iron-carbohydrate complex enters the reticuloendothelial system macrophages
`of the liver, spleen and bone marrow. The iron is released from the iron-carbohydrate
`complex within vesicles in the macrophages. Iron then either enters the intracellular
`storage iron pool (e.g., ferritin) or is transferred to plasma transferrin for transport
`to erythroid precursor cells for incorporation into hemoglobin.
`
`12.2 Pharmacodynamics
`
`Cardiac Electrophysiology
`In a randomized, positive- and placebo-controlled, parallel-group study, healthy subjects
`received a supratherapeutic regimen of Feraheme (1.02 g given as two 51 O mg doses
`within 24 hours), placebo or a single dose of 400 mg moxifloxacin (positive control).
`Results demonstrated no effect of Feraheme on QT interval durations. No clinically
`meaningful effect of Feraheme on heart rate was observed.
`
`Pharmacosmos, Exh. 1031, p. 3
`
`

`

`12.3 Pharmacokinetics
`The pharmacokinetic (PK) behavior of Feraheme has been examined in healthy
`subjects and in patients with CKD stage 50 on hemodialysis. Feraheme exhibited
`dose-dependent, capacity-limited elimination from plasma with a halt lite of
`approximately 15 hours in humans. The clearance (CL) was decreased by increasing
`the dose of Feraheme. Volume of distribution (Vd) was consistent with plasma volume,
`and the mean maximum observed plasma concentration (Cm.,) and terminal half-lite (t, 1
`values increased with dose. The estimated values of CL and Vd following two
`51 o mg doses of Feraheme administered intravenously within 24 hours were
`69.1 mUhr and 3.16 L, respectively. The C"'ax and time of maximum concentration (t11J
`were 206 mcg/mL and 0.32 hr, respectively. Rate of infusion had no influence
`on Feraheme PK parameters. No gender differences in Feraheme PK parameters
`were observed. Feraheme is not removed by hemodialysis.
`
`,)
`
`13
`
`NONCLINICAL TOXICOLOGY
`
`13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
`Ferumoxytol was not tested tor carcinogenic effects. In standard genotoxicity tests,
`ferumoxytol showed no evidence of mutagenic activity in an in vitro Ames test or
`clastogenic activity in either an in vitro chromosomal aberration assay or an in vivo
`micronucleus assay.
`
`No adverse effects on fertility or general reproductive performance were noted
`in animal studies. Ferumoxytol had no effect on male or female fertility or general
`reproductive function in rats.
`
`CLINICAL STUDIES
`14
`The safety and efficacy of Feraheme for the episodic treatment of iron deficiency
`anemia in patients with CKD were assessed in three randomized, open-label, controlled
`clinical trials (Trial 1, 2 and 3). These trials also included an uncontrolled, follow-up
`phase in which patients with persistent iron deficiency anemia could receive two
`additional 510 mg intravenous injections of Feraheme. The major efficacy results
`from the controlled phase of each study are shown in Table 2.
`
`In all three trials, patients with CKD and iron deficiency anemia were randomized to
`treatment with Feraheme or oral iron. Feraheme was administered as two 51 O mg
`intravenous single doses and oral iron (ferrous tumarate) was administered as a total
`daily dose of 200 mg elemental iron daily for 21 days. The major trial outcomes
`assessed the change in hemoglobin from baseline to Day 35. Trial 1 and 2 enrolled
`patients with non-dialysis dependent CKD and Trial 3 enrolled patients who were
`undergoing hemodialysis.
`
`In Trial 1, the mean age of patients was 66 years (range, 23 to 95); 60% were female;
`65% were Caucasian, 32% were Black, and 2% were other races. In the Feraheme and
`oral iron groups, 42% and 44% of patients, respectively, were receiving erythropoiesis
`stimulating agents (ESAs) at baseline.
`
`In Trial 2, the mean age of patients was 65 years (range, 31 to 96); 61 % were female;
`58% were Caucasian, 35% were Black, and 7% were other races. In the Feraheme
`and oral iron groups, 36% and 43% of patients, respectively, were receiving ESAs
`at baseline.
`
`In Trial 3, the mean age of patients was 60 years (range, 24 to 87); 43% were female;
`34% were Caucasian, 59% were Black, and 7% were other races. All patients were
`receiving ESAs.
`
`Table 2 shows the Baseline and mean change to Day 35 in hemoglobin (Hgb, g/dL),
`transferrin saturation (TSAT, %) and ferritin (ng/mL) in each treatment group tor
`Trial 1, 2, and 3.
`
`AMAG Pharmaceuticalss, Inc.
`1100 Winter Street
`Waltham, MA 02451
`
`AMAG Pharmaceuticals, Feraheme, and the logo designs presented in this material
`are trademarks of AMAG Pharmaceuticals, Inc.
`©2015 AMAG Pharmaceuticals, Inc. DR-0627-0315
`
`Table 2: Changes from Baseline to Day 35 in Hemoglobin, Transferrin Saturation
`and Ferritin (Intent to Treat Population)
`
`Trial 2
`Trial 1
`Non-Dialysis CKD Non-Dialysis CKD
`
`Trial 3
`CKD on Dialysis
`
`ENDPOINT
`
`Feraheme
`
`n = 226
`
`Baseline Hgb
`(mean ± SD, g/dL)
`
`9.9
`± 0.8
`
`Oral
`Iron
`n = 77
`
`9.9
`± 0.7
`
`Feraheme
`
`n = 228
`
`10.0
`± 0.7
`
`Oral
`Iron
`n = 76
`
`10.0
`± 0.8
`
`Feraheme
`
`n = 114
`
`Oral
`Iron
`n = 116
`
`10.6
`± 0.7
`
`10.7
`± 0.6
`
`0.5
`± 1.1
`
`15.9
`± 6.3
`
`1.2*
`± 1.3
`
`0.5
`± 1.0
`
`0.8*
`± 1.2
`
`0.2
`± 1.0
`
`1.0*
`± 1.1
`
`9.8
`± 5.4
`
`9.2
`± 9.4
`
`10.4
`± 5.2
`
`0.3
`± 4.7
`
`11.3
`± 6.1
`
`10.1
`± 5.5
`
`15.7
`± 7.2
`
`9.8
`±9.2
`
`1.3
`± 6.4
`
`6.4
`± 12.6
`
`0.6
`± 8.3
`
`Hgb change from
`Baseline at Day 35
`(mean ±SD, g/dL)
`
`Baseline TSAT
`(mean ± SD, %)
`
`TSAT change from
`Baseline at Day 35
`(mean ± SD,%)
`
`Baseline ferritin
`(mean± SD,
`ng/mL)
`
`Ferritin change
`from Baseline at
`Day 35
`(mean± SD,
`ng/ml)
`
`340.5
`143.5
`146.1
`146.2
`123.7
`± 125.4 ± 136.3 ± 173.6 ± 144.9 ± 159.1
`
`357.6
`± 171.7
`
`300.7
`± 214.9
`
`0.3
`:!: 82.0
`
`381.7
`± 278.6
`
`6.9
`:!: 60.1
`
`233.9
`± 207.0
`
`-59.2
`:!: 106.2
`
`• p:::0.001 for main efficacy endpoint
`Following completion of the controlled phase of each of the Phase 3 trials, patients
`who were iron deficient and anemic could receive two additional 51 O mg intravenous
`injections of Feraheme for a total cumulative dose of 2.04 g. Overall, 69 patients
`received two additional 510 mg intravenous injections of Feraheme, and on Day 35
`following these additional injections, the majority of these patients (70%) experienced an
`increase in hemoglobin and iron parameters (TSAT and ferritin). The mean change (±SD)
`in hemoglobin level from the retreatment baseline tor patients with an increase
`in hemoglobin was 0.86 (± 0.68) g/dl and was 0.5 (± 0.8) g/dL for all patients.
`
`16
`
`HOW SUPPLIED/STORAGE AND HANDLING
`
`16.1 How Supplied
`Feraheme is available in single use vials in the following package sizes (Table 3).
`
`Table 3: Feraheme Packaging Description
`
`NOC Code
`
`Dose I Total volume per vial
`
`Vials I Carton
`
`NOC 59338-775-01
`
`510mg/17 ml
`
`NOC 59338-775-10
`
`510mg/17mL
`
`1
`
`10
`
`16.2 Stability and Storage
`Store at 20° to 25°C (68° to 77°F). Excursions permitted to 15° - 30°C (59° - 86°F) [see
`USP controlled room temperature].
`
`PATIENT COUNSELING INFORMATION
`17
`Refer patients to the FDA approved Patient Package Insert.
`Prior to Feraheme administration:
`• Question patients regarding a history of allergy to intravenous iron or any medications.
`• Advise patients of the serious risks associated with Feraheme.
`• Advise patients to immediately report any signs and symptoms of hypersensitivity that
`may develop during and following Feraheme administration, such as rash, itching,
`dizziness, lightheadedness, swelling and breathing problems. Advise patients to seek
`immediate medical attention if these occur [see Warnings and Precautions (SA.
`
`U.S Patents: 6,599,498 B1; 7,553,479 82; 7,871,597 B2; 8,501, 158 B2
`Distributed by: AMAG Pharmaceuticals, Inc. Waltham, MA 02451
`
`Pharmacosmos, Exh. 1031, p. 4
`
`