MEDICAL POLICY
POLICY TITLE
IRON REPLACEMENT PRODUCTS INCLUDING FERUMOXYTOL (FERAHEME®)
AND FERRIC CARBOXYMALTOSE INJECTION (INJECTAFER®)
POLICY NUMBER
MP-2.146
Original Issue Date (Created):
8/1/2010
Most Recent Review Date (Revised): 11/29/2016
Effective Date:
POLICY
RATIONALE
DISCLAIMER
POLICY HISTORY
1/1/2017
PRODUCT VARIATIONS
DEFINITIONS
CODING INFORMATION
DESCRIPTION/BACKGROUND
BENEFIT VARIATIONS
REFERENCES
I. POLICY
Ferumoxytol (Feraheme®)
Ferumoxytol (Feraheme®) may be considered medically necessary for the treatment of iron
deficiency anemia in adult patients with chronic kidney disease (CKD).
Ferric Carboxymaltose Injection (Injectafer®)
Ferric carboxymaltose injection (Injectafer®) may be considered medically necessary for the
treatment of iron deficiency anemia in adult patients:
 who have intolerance to oral iron or have had unsatisfactory response to oral iron; or
 who have non–dialysis-dependent chronic kidney disease.
Cross-reference:
MP-2.103 Off-Label Use of Medications
II. PRODUCT VARIATIONS
TOP
This policy is applicable to all programs and products administered by Capital BlueCross unless
otherwise indicated below.
Note for Medicare Advantage:
FDA approved drugs used for indications other than what is indicated on the FDA approved
product label may be covered under Medicare if it is determined that the use is medically
accepted, taking into consideration the Medicare recognized national drug compendia,
authoritative medical literature and/or accepted standards of medical practice.” Refer to
Page 1
MEDICAL POLICY
POLICY TITLE
IRON REPLACEMENT PRODUCTS INCLUDING FERUMOXYTOL (FERAHEME®)
AND FERRIC CARBOXYMALTOSE INJECTION (INJECTAFER®)
POLICY NUMBER
MP-2.146
Medicare Benefit Policy Manual (100-2, Chapter 15, Section 50.4.2- Unlabeled Use of Drug).
http://www.cms.gov/manuals/Downloads/bp102c15.pdf
III. DESCRIPTION/BACKGROUND
TOP
Ferumoxytol (Feraheme®)
Ferumoxytol (Feraheme®) is an iron replacement product indicated for the treatment of iron
deficiency anemia in adult patients with chronic kidney disease (CKD). Anemia is highly
prevalent in the CKD population and is nearly universal in patients with CKD on hemodialysis.
Iron deficiency is a common cause of anemia in CKD patients and may be the result of poor iron
absorption, blood loss and increased erythropoiesis after use of erythropoiesis-stimulating agents
(ESAs).
Ferumoxytol is a novel iron oxide nanoparticle with a polyglucose sorbitol carboxymethlether
coating designed to minimize immunological sensitivity. The molecular weight of ferumoxytol
is above the permeability cutoff of standard hemodialysis membranes; therefore, it is not
removed from plasma dialysis and can be administered any time during hemodialysis.
Safety Information
Patients should not use ferumoxytol (Feraheme®) if they have ever had an allergic reaction to an
injectable form of iron (including ferumoxytol), or if they have: iron load syndrome; or any type
of anemia that is not caused by iron deficiency. Ferumoxytol (Feraheme®) can alter magnetic
resonance imaging (MRI) studies and may cause hypotension. Patients should be monitored for
signs and symptoms of hypotension following each administration of ferumoxytol (Feraheme®).
Patients should be observed for signs and symptoms of hypersensitivity during and after
ferumoxytol (Feraheme®) administration for at least 30 minutes and until clinically stable
following completion of each administration.
Ferumoxytol (Feraheme®) General Administration Information According to the FDA, the
recommended dose is an initial 510 mg intravenous injection followed by a second 510 mg
intravenous injection 3 to 8 days later. The recommended dose may be re-administered to
patients with persistent or recurrent iron deficiency anemia. The following hematologic response
(hemoglobin, ferritin, iron and transferrin saturation) should be evaluated at least once a month
following the second ferumoxytol (Feraheme®) injection.
Page 2
MEDICAL POLICY
POLICY TITLE
IRON REPLACEMENT PRODUCTS INCLUDING FERUMOXYTOL (FERAHEME®)
AND FERRIC CARBOXYMALTOSE INJECTION (INJECTAFER®)
POLICY NUMBER
MP-2.146
Ferric Carboxymaltose Injection (Injectafer®)
Injectafer® (ferric carboxymaltose injection) is the first non-dextran IV iron approved for the
treatment of adult patients with iron deficiency anemia (IDA) of various etiologies in addition to
use in non-dialysis dependent CKD patients. A single dose of up to 750 mg of Injectafer® can be
administered undiluted as an IV push injection at a rate of 100 mg/minute or as an IV infusion in
up to 250 mL 0.9 % Sodium Chloride Injection, USP, over at least 15 minutes.
IV. RATIONALE
TOP
Ferumoxytol (Feraheme®)
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 510 mg intravenous single doses
and oral iron (ferrous fumarate) 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 for Trial 1, 2, and 3.
Page 3
MEDICAL POLICY
POLICY TITLE
IRON REPLACEMENT PRODUCTS INCLUDING FERUMOXYTOL (FERAHEME®)
AND FERRIC CARBOXYMALTOSE INJECTION (INJECTAFER®)
POLICY NUMBER
MP-2.146
Table 2: Changes from Baseline to Day 35 in Hemoglobin, Transferrin Saturation and Ferritin (Intent to Treat Population)
ENDPOINT
Trial 1
Non-Dialysis CKD
Feraheme
Oral Iron
n = 226
n = 77
Feraheme
n = 228
Trial 2
Non-Dialysis CKD
Oral Iron
n = 76
Trial 3
CKD on Dialysis
Feraheme
Oral Iron
n = 114
n = 116
Baseline Hgb
(mean ± SD, g/dL)
9.9
± 0.8
9.9
± 0.7
10.0
± 0.7
10.0
± 0.8
10.6
± 0.7
10.7
± 0.6
Hgb change from
Baseline at Day 35
(mean ± SD, g/dL)
1.2*
± 1.3
0.5
± 1.0
0.8*
± 1.2
0.2
± 1.0
1.0*
± 1.1
0.5
± 1.1
Baseline TSAT
(mean ± SD, %)
9.8
± 5.4
10.4
± 5.2
11.3
± 6.1
10.1
± 5.5
15.7
± 7.2
15.9
± 6.3
TSAT change from
Baseline at Day 35
(mean ± SD, %)
9.2
± 9.4
0.3
± 4.7
9.8
± 9.2
1.3
± 6.4
6.4
± 12.6
0.6
± 8.3
Baseline ferritin
(mean ± SD, ng/mL)
123.7
± 125.4
146.2
± 136.3
146.1
± 173.6
143.5
± 144.9
340.5
± 159.1
357.6
± 171.7
Ferritin change from
Baseline at Day 35
(mean ± SD, ng/mL)
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 510 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
for patients with an increase in hemoglobin was 0.86 (± 0.68) g/dL and was 0.5 (± 0.8) g/dL for
all patients.
Ferric Carboxymaltose Injection (Injectafer®)
The safety and efficacy of Injectafer for treatment of iron deficiency anemia were evaluated in
two randomized, open-label, controlled clinical trials (Trial 1 and Trial 2). In these two trials,
Injectafer was administered at a dose of 15 mg/kg body weight up to a maximum single 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.
Trial 1: Iron Deficiency Anemia in Patients Who Are Intolerant to Oral Iron or Have Had
Unsatisfactory Response to Oral Iron
Trial 1 was a randomized, open-label, controlled clinical study in patients with 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 day oral iron run-in period. Inclusion criteria prior to
randomization included hemoglobin (Hb) <12 g/dL, ferritin ≤100 ng/mL or ferritin ≤300 ng/mL
when transferrin saturation (TSAT) ≤30%. Cohort 1 subjects were randomized to Injectafer or
Page 4
MEDICAL POLICY
POLICY TITLE
IRON REPLACEMENT PRODUCTS INCLUDING FERUMOXYTOL (FERAHEME®)
AND FERRIC CARBOXYMALTOSE INJECTION (INJECTAFER®)
POLICY NUMBER
MP-2.146
oral iron for 14 more days. Cohort 2 subjects were randomized to Injectafer or another IV iron
per standard of care [90% of subjects received iron sucrose]. The mean age of study patients was
43 years (range, 18 to 94); 94% were female; 42% were Caucasian, 32% were African American,
24% were Hispanic, and 2% were other races. The primary etiologies of iron deficiency anemia
were heavy uterine bleeding (47%) and gastrointestinal disorders (17%).
T ab le 2. M ean C hange In H em oglobin F ro m B aseline to th e H ighest V alue
Betiveen D ay 35 or T im e of: intervention (M odified In te n t-to T re a t P opulation)
H em oglobin (g/dL)
C oh o rt 1
C o h o rt 2
M ean (SD)
In ject afer
O ral Iro n
Injectafer
IV S C a
(N=244)
^=251)
(N=245)
(N=237)
Baseline
10.6 (1.0)
10.6 (1.0)
9.1 (1.6)
9.0 (1.5)
Highest Value
Change (from baseline to
highest value)
12.2 (1.1)
11.4 (1.2)
12.0 (1.2)
11.2 (1.3)
1.6 (1.2)
0 .‫( ج‬0 .‫)ج‬
2.9 (1.6)
2.2 (1.3)
o . c 01
p-value
SD=standard d e la tio n ‫ ؛‬٥: Infravenous iron per standard of care
0.0()1
Increases from baseline in mean ferritin (264.2 ± 224.2 ng/mL in Cohort 1 and 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.
Trial 2: Iron Deficiency Anemia in Patients with Non–Dialysis-Dependent Chronic Kidney
Disease
Trial 2 was a randomized, open-label, controlled clinical study in patients with non–dialysisdependent chronic kidney disease. Inclusion criteria included hemoglobin (Hb) ≤11.5 g/dL,
ferritin ≤100 ng/mL or ferritin ≤300 ng/mL when transferrin saturation (TSAT) ≤30%. Study
patients were randomized to 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 African American,
18% Hispanics, and 2% were other races.
Table 3 shows the baseline and the change in hemoglobin from baseline to highest value between
baseline and Day 56 or time of intervention.
Page 5
MEDICAL POLICY
POLICY TITLE
IRON REPLACEMENT PRODUCTS INCLUDING FERUMOXYTOL (FERAHEME®)
AND FERRIC CARBOXYMALTOSE INJECTION (INJECTAFER®)
POLICY NUMBER
MP-2.146
T a b le 5. M e a n C h a n g e In H em oglobin F ro m B aseline to th e H ig h est V alu e
B e tw e e n B a s e lin e a n d D a y 5 6 or T h n e o f I n te r v e n tio n (ftlo d ifie d I n t e n t - t o T r e a t
P o p u la tio n )
H em o g lo b in (g/dL)
M e a n (SD)
In je c t afer
tfj=1249)
^=1244)
Baseline
10.3 (0.8)
10.3 (0.8)
H ighest Value
11.4 (1.2)
11.3 (1.1)
1.1 (1.0)
0 .9 (0 .9 2 )
Change (from baseline to highest
value)
T re ato e n t Difference (95% Cl)
١ enofer
0 .2 1 (0 .1 3 0 .2 8 )
Increases from baseline in mean ferritin (734.7 ± 337.8 ng/mL), and transferrin saturation (30 ± 17%)
were observed at Day 56 in Injectafer-treated patients.
V. DEFINITIONS
TOP
IRON DEFICIENCY ANEMIA- The most common known form of nutritional disorder in the world,
iron deficiency results in anemia because iron is necessary to make hemoglobin, key molecule in
red blood cells responsible for the transport of oxygen. In iron deficiency anemia, the red cells
appear abnormal and are unusually small (microcytic) and pale (hypochromic). The pallor of the
red cells reflects their low hemoglobin content.
CHRONIC KIDNEY DISEASE- Chronic kidney disease (CKD), also known as chronic renal disease,
is a progressive loss of renal function over a period of months or years. The symptoms of
worsening kidney function are unspecific, and might include feeling generally unwell and
experiencing a reduced appetite.
VI. BENEFIT VARIATIONS
TOP
The existence of this medical policy does not mean that this service is a covered benefit under
the member's contract. Benefit determinations should be based in all cases on the applicable
contract language. Medical policies do not constitute a description of benefits. A member’s
individual or group customer benefits govern which services are covered, which are excluded,
and which are subject to benefit limits and which require preauthorization. Members and
Page 6
MEDICAL POLICY
POLICY TITLE
IRON REPLACEMENT PRODUCTS INCLUDING FERUMOXYTOL (FERAHEME®)
AND FERRIC CARBOXYMALTOSE INJECTION (INJECTAFER®)
POLICY NUMBER
MP-2.146
providers should consult the member’s benefit information or contact Capital for benefit
information.
VII. DISCLAIMER
TOP
Capital’s medical policies are developed to assist in administering a member’s benefits, do not constitute medical
advice and are subject to change. Treating providers are solely responsible for medical advice and treatment of
members. Members should discuss any medical policy related to their coverage or condition with their provider
and consult their benefit information to determine if the service is covered. If there is a discrepancy between this
medical policy and a member’s benefit information, the benefit information will govern. Capital considers the
contained in this medical policy to be proprietary and it may only be disseminated as permitted by law.
VIII. CODING INFORMATION
TOP
Note: This list of codes may not be all-inclusive, and codes are subject to change at any time. The
identification of a code in this section does not denote coverage as coverage is determined by
the terms of member benefit information. In addition, not all covered services are eligible for
separate reimbursement.
Ferumoxytol (Feraheme®) is covered when medically necessary:
HCPCS
Code
Q0138
Q0139
Description
Injection, ferumoxytol, for treatment of iron deficiency anemia, 1 mg (non-ESRD use)
Injection, ferumoxytol, for treatment of iron deficiency anemia, 1 mg (for ESRD on dialysis)
The following diagnosis codes are considered medically necessary for Q0138 and Q0139:
ICD-10-CM
Diagnosis
Description
Code*
D63.1
Anemia in chronic kidney disease
I20.0
Hypertensive chronic kidney disease with stage 5 chronic kidney disease or end stage renal
disease
I12.9
Hypertensive chronic kidney disease with stage 1 through stage 4 chronic kidney disease, or
unspecified chronic kidney disease
N18.1
Chronic kidney disease, stage 1
N18.2
Chronic kidney disease, stage 2 (mild)
Page 7
MEDICAL POLICY
POLICY TITLE
IRON REPLACEMENT PRODUCTS INCLUDING FERUMOXYTOL (FERAHEME®)
AND FERRIC CARBOXYMALTOSE INJECTION (INJECTAFER®)
POLICY NUMBER
MP-2.146
ICD-10-CM
Diagnosis
Code*
N18.3
N18.4
N18.5
N18.6
N18.9
Description
Chronic kidney disease, stage 3 (moderate)
Chronic kidney disease, stage 4 (severe)
Chronic kidney disease, stage 5
End stage renal disease
Chronic kidney disease, unspecified
*If applicable, please see Medicare LCD or NCD for additional covered diagnoses.
Ferric Carboxymaltose Injection (Injectafer®) is covered when medically necessary:
HCPCS
Code
J1439
Description
Injection, ferric carboxymaltose, 1 mg
The following diagnosis codes are considered medically necessary for J1439:
ICD-10
Diagnosis
Code*
D50.8
D50.9
D63.1
I12.9
N18.1
N18.2
N18.3
N18.4
N18.9
Description
Other iron deficiency anemias
Iron deficiency anemia, unspecified
Anemia in chronic kidney disease
Hypertensive chronic kidney disease with stage 1 through stage 4 chronic kidney disease, or
unspecified chronic kidney disease
Chronic kidney disease, stage 1
Chronic kidney disease, stage 2 (mild)
Chronic kidney disease, stage 3 (moderate)
Chronic kidney disease, stage 4 (severe)
Chronic kidney disease, unspecified
*If applicable, please see Medicare LCD or NCD for additional covered diagnoses.
Page 8
MEDICAL POLICY
POLICY TITLE
IRON REPLACEMENT PRODUCTS INCLUDING FERUMOXYTOL (FERAHEME®)
AND FERRIC CARBOXYMALTOSE INJECTION (INJECTAFER®)
POLICY NUMBER
MP-2.146
IX. REFERENCES
TOP
Balakrishnan VS, Rao M, Kausz AT, et al. Physicochemical properties of ferumoxytol, a new
intravenous iron preparation. Eur J Clin Invest. 2009;39(6):489-496.
Berns J. Use of iron preparations in hemodialysis patients. In: UpToDate Online Journal
[serial online]. Waltham, MA: UpToDate; updated December 16, 2015. Website] :
www.uptodate.com . Accessed September 13, 2016.
Centers for Medicare and Medicaid Services (CMS) Medicare Benefit Policy Manual.
Publication 100-02. Chapter 15. Section 50.4.2. Unlabeled Use of Drug. Effective
10/01/03. [Website]: http://www.cms.gov/manuals/Downloads/bp102c15.pdf . Accessed July
15, 2015.
Centers for Medicare and Medicaid Services (CMS) Medicare Benefit Policy Manual.
Publication 100-02. Chapter 15. Sections 50, 50.4.1, 50.4.3. Drugs and Biologicals.
Effective 10/01/03. [Website]: http://www.cms.gov/manuals/Downloads/bp102c15.pdf .
Accessed September 13, 2016.
Centers for Medicare and Medicaid Services (CMS) Medicare Benefit Policy Manual.
Publication 100-02. Chapter 15. Section 50.4.2. Unlabeled Use of Drug. Effective
10/01/03. [Website]: http://www.cms.gov/manuals/Downloads/bp102c15.pdf . Accessed
May 31, 2016Ferumoxytol (Feraheme) prescribing information. Revised March 2015.
Feraheme [Website]: http://www.feraheme.com/. Accessed September 13, 2016.
Ferric Carboxymaltose Injection (Injectafer®) prescribing information. July 2013. [Website]:
http://www.injectafer.com/ Accessed September 13, 2016.
Mosby’s Medical Nursing & Allied Health Dictionary, 6th edition.
Provenzano R, Schiller B, Rao M, Coyne D, Brenner L, Pereira BJG. Ferumoxytol as an
intravenous iron replacement therapy in hemodialysis patients. Clin J Am Soc Nephrol.
2009; 4(2):386-393.
Singh A, Patel T, Hertel J, Bernardo M, Kausz A, Brenner L. Safety of ferumoxytol in patients
with anemia and CKD. Am J Kidney Dis. 2008;52(5):907-915.
Spinowitz BS, Kausz AT, Baptista J, Noble SD, Sothinathan R, Bernardo MV, Brenner L,
Pereira BJG. Ferumoxytol for treating iron deficiency anemia in CKD
J Am Soc Nephrol. 2008;19(8):1599-1605.
Gozzard D. When is high-dose intravenous iron repletion needed? Assessing new treatment
options. Drug Des Devel Ther. 2011 Jan 20;5:51-60.
Page 9
MEDICAL POLICY
POLICY TITLE
IRON REPLACEMENT PRODUCTS INCLUDING FERUMOXYTOL (FERAHEME®)
AND FERRIC CARBOXYMALTOSE INJECTION (INJECTAFER®)
POLICY NUMBER
MP-2.146
X. POLICY HISTORY
MP 2.146
TOP
CAC 3-10-10 New policy. Medically necessary for the treatment of iron
deficiency anemia in adult patients with chronic kidney disease (CKD). References
added.
CAC 10-25-11 Consensus Review
CAC 10-30-12 Consensus review. References updated; no changes to policy
statements. Codes reviewed 10/31/12
CAC 11/26/13 Consensus. No change to policy statements. References
updated.
CAC 9/30/14 Minor revision. Policy title changed to: Iron Replacement
Products Including ferumoxytol (Feraheme®) and ferric carboxymaltose
injection (Injectafer®) to include new iron replacement drug Ferric
carboxymaltose (Injectafer). Ferric carboxymaltose injection (Injectafer®)
may be considered medically necessary for the treatment of iron deficiency
anemia in adult patients who have intolerance to oral iron or have had
unsatisfactory response to oral iron; or who have non–dialysis-dependent
chronic kidney disease. Policy coding reviewed. Broke out codes.
CAC 9/29/15 Consensus review. No change to policy statements.
References and rationale reviewed. Added Medicare variation to reference
NCD 110.10 Intravenous Iron Therapy. Coding reviewed.
1/7/16 Admin correction. Administrative coding correction only.
6/1/16 Administrative change. Removed Medicare variation referencing
NCD 110.10. The NCD only addresses Venofer and Ferrlecit but not
Feraheme and Injectafer.
CAC 11/29/16 Consensus review. No change to policy statements.
References and rationale reviewed. Coding reviewed. Variation
reformatting.
Top
Health care benefit programs issued or administered by Capital BlueCross and/or its subsidiaries, Capital Advantage Insurance
Company®, Capital Advantage Assurance Company® and Keystone Health Plan® Central. Independent licensees of the
BlueCross BlueShield Association. Communications issued by Capital BlueCross in its capacity as administrator of programs
and provider relations for all companies.
Page 10