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Mircera

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Mircera uses


WARNINGS: ESAs INCREASE THE RISK OF DEATH, MYOCARDIAL INFARCTION, STROKE, VENOUS THROMBOEMBOLISM, THROMBOSIS OF VASCULAR ACCESS, AND TUMOR PROGRESSION OR RECURRENCE

WARNINGS: ESAs INCREASE THE RISK OF DEATH, MYOCARDIAL INFARCTION, STROKE, VENOUS THROMBOEMBOLISM, THROMBOSIS OF VASCULAR ACCESS AND TUMOR PROGRESSION OR RECURRENCE

See full prescribing information for complete boxed warning

Chronic Kidney Disease:


Cancer:


Chronic Kidney Disease


Cancer

Boxed Warning 10/2014
Indications and Usage (1.2) 10/2014
Dosage and Administration (2.1, 2.2) 10/2014
Contraindications (4) 10/2014
Warnings and Precautions

(5.1, 5.2, 5.3, 5.4, 5.6, 5.7, 5.8, 5.9)

10/2014
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1 INDICATIONS AND USAGE

Mircera is an erythropoiesis-stimulating agent indicated for the treatment of anemia associated with chronic kidney disease (CKD in adult patients on dialysis and patients not on dialysis (1.1).

Limitations of Use

Mircera is not indicated and is not recommended for use:


Mircera has not been shown to improve quality of life, fatigue, or patient well-being.

1.1 Anemia Due to Chronic Kidney Disease

Mircera is indicated for the treatment of anemia associated with chronic kidney disease (CKD) in adult patients on dialysis and patients not on dialysis.

1.2 Limitations of Use

Mircera is not indicated and is not recommended:


Mircera has not been shown to improve symptoms, physical functioning or health-related quality of life.

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2 DOSAGE AND ADMINISTRATION

Mircera is administered by subcutaneous or intravenous (IV) injection (2.2).

2.1 Evaluation of Iron Stores and Nutritional Factors

Evaluate the iron status in all patients before and during treatment and maintain iron repletion. Correct or exclude other causes of anemia (e.g., vitamin deficiency, metabolic or chronic inflammatory conditions, bleeding, etc.) before initiating Mircera .

2.2 Patients with Chronic Kidney Disease

Individualize dosing and use the lowest dose of Mircera sufficient to reduce the need for RBC transfusions . In controlled trials, patients experienced greater risks for death, serious adverse cardiovascular reactions, and stroke when administered erythropoiesis-stimulating agents (ESAs) to target a hemoglobin level of greater than 11 g/dL. No trial has identified a hemoglobin target level, ESA dose, or dosing strategy that does not increase these risks. Physicians and patients should weigh the possible benefits of decreasing transfusions against the increased risks of death and other serious cardiovascular adverse events .

For all patients with CKD:

When initiating or adjusting therapy, monitor hemoglobin levels at least weekly until stable, then monitor at least monthly. When adjusting therapy consider hemoglobin rate of rise, rate of decline, ESA responsiveness and hemoglobin variability. A single hemoglobin excursion may not require a dosing change.


Mircera is administered either intravenously (IV) or subcutaneously (SC). When administered SC, Mircera should be injected in the abdomen, arm or thigh.

For Patients with CKD on dialysis:


For Patients with CKD not on dialysis:


Refer patients who self-administer Mircera to the Instructions for Use .

Conversion from Epoetin alfa or Darbepoetin alfa to Mircera in Patients with CKD

Mircera can be administered once every two weeks or once monthly to patients whose hemoglobin has been stabilized by treatment with an ESA. The dose of Mircera, given as a single IV or SC injection, should be based on the total weekly ESA dose at the time of conversion.

Previous Weekly Epoetin alfa Dose (units/week) Previous Weekly Darbepoetin alfa Dose (mcg/week) Mircera Dose
Once Monthly (mcg/month) Once Every Two Weeks (mcg/every two weeks)
< 8000 < 40 120 60
8000 - 16000 40 - 80 200 100
> 16000 > 80 360 180

2.3 Preparation and Administration of Mircera

Mircera is packaged as single-use prefilled syringes. Mircera contains no preservatives. Discard any unused portion. Do not pool unused portions from the prefilled syringes. Do not use the prefilled syringe more than one time.

Always store Mircera prefilled syringes in their original cartons. Vigorous shaking or prolonged exposure to light should be avoided.

Do not mix Mircera with any parenteral solution.

Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration. Do not use any prefilled syringes exhibiting particulate matter or a coloration other than colorless to slightly yellowish.

For administration using the prefilled syringe, the plunger must be fully depressed during injection in order for the needle guard to activate. Following administration, remove the needle from the injection site and then release the plunger to allow the needle guard to move up until the entire needle is covered.

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3 DOSAGE FORMS AND STRENGTHS

Injection: 50, 75, 100, 150, 200, or 250 mcg of Mircera in 0.3 mL solution in single-use prefilled syringes

4 CONTRAINDICATIONS

Mircera is contraindicated in patients with:

5 WARNINGS AND PRECAUTIONS

5.1 Increased Mortality, Myocardial Infarction, Stroke, and Thromboembolism


The design and overall results of the 3 large trials comparing higher and lower hemoglobin targets are shown in Table 2 (Normal Hematocrit Study (NHS), Correction of Hemoglobin Outcomes in Renal Insufficiency (CHOIR) and Trial to Reduce Cardiovascular Events with Aranesp® Therapy (TREAT)).

NHS

(N = 1265)

 CHOIR

(N = 1432)

 TREAT

(N = 4038)
Time Period of Trial 1993 to 1996 2003 to 2006 2004 to 2009
Population CKD patients on hemodialysis with coexisting CHF or CAD, hematocrit 30 ± 3% on epoetin alfa CKD patients not on dialysis with hemoglobin < 11 g/dL not previously administered epoetin alfa CKD patients not on dialysis with type II diabetes, hemoglobin ≤ 11 g/dL
Hemoglobin Target;

Higher vs. Lower (g/dL)

14.0 vs. 10.0 13.5 vs. 11.3 13.0 vs. ≥ 9.0
Median (Q1, Q3)

Achieved Hemoglobin level (g/dL)

12.6 (11.6, 13.3) vs.

10.3 (10.0, 10.7)

 13.0 (12.2, 13.4) vs.

11.4 (11.1, 11.6)

 12.5 (12.0, 12.8) vs.

10.6 (9.9, 11.3)
Primary Endpoint All-cause mortality

or nonfatal MI

 All-cause mortality,

MI, hospitalization for CHF, or stroke

 All-cause mortality,

MI, myocardial ischemia, heart failure, and stroke
Hazard Ratio or Relative Risk (95% CI) 1.28 (1.06 - 1.56) 1.34 (1.03 - 1.74) 1.05 (0.94 - 1.17)
Adverse Outcome for Higher Target Group All-cause mortality All-cause mortality Stroke
Hazard Ratio or Relative Risk (95% CI) 1.27 (1.04 - 1.54) 1.48 (0.97 - 2.27) 1.92 (1.38 - 2.68)

Patients with Chronic Kidney Disease

NHS: A prospective, randomized, open-label study of 1265 patients with chronic kidney disease on dialysis with documented evidence of congestive heart failure or ischemic heart disease was designed to test the hypothesis that a higher target hematocrit (Hct) would result in improved outcomes compared with a lower target Hct. In this study, patients were randomized to epoetin alfa treatment targeted to a maintenance hemoglobin of either 14 ± 1 g/dL or 10 ± 1 g/dL. The trial was terminated early with adverse safety findings of higher mortality in the high hematocrit target group. Higher mortality (35% vs. 29%) was observed for the patients randomized to a target hemoglobin of 14 g/dL than for the patients randomized to a target hemoglobin of 10 g/dL. For all-cause mortality, the HR=1.27; 95% CI (1.04, 1.54); p=0.018. The incidence of nonfatal myocardial infarction, vascular access thrombosis, and other thrombotic events was also higher in the group randomized to a target hemoglobin of 14 g/dL.

CHOIR: In a randomized prospective trial, 1432 patients with anemia due to CKD who were not undergoing dialysis were assigned to epoetin alfa treatment targeting a maintenance hemoglobin concentration of 13.5 g/dL or 11.3 g/dL. The trial was terminated early with adverse safety findings. A major cardiovascular event (death, myocardial infarction, stroke, or hospitalization for congestive heart failure) occurred among 125 (18%) of the 715 patients in the higher hemoglobin group compared to 97 (14%) among the 717 patients in the lower hemoglobin group (HR 1.3, 95% CI: 1.0, 1.7 p=0.03).

TREAT: A randomized, double-blind, placebo-controlled, prospective trial of 4038 patients with: CKD not on dialysis (eGFR of 20 – 60 mL/min), anemia (hemoglobin levels ≤ 11 g/dL), and type 2 diabetes mellitus, patients were randomized to receive either darbepoetin alfa treatment or a matching placebo. Placebo group patients also received darbepoetin alfa when their hemoglobin levels were below 9 g/dL. The trial objectives were to demonstrate the benefit of darbepoetin alfa treatment of the anemia to a target hemoglobin level of 13 g/dL, when compared to a "placebo" group, by reducing the occurrence of either of two primary endpoints: (1) a composite cardiovascular endpoint of all-cause mortality or a specified cardiovascular event (myocardial ischemia, CHF, MI, and CVA) or (2) a composite renal endpoint of all-cause mortality or progression to end stage renal disease. The overall risks for each of the two primary endpoints (the cardiovascular composite and the renal composite) were not reduced with darbepoetin alfa treatment, but the risk of stroke was increased nearly two-fold in the darbepoetin alfa -treated group versus the placebo group: annualized stroke rate 2.1% vs. 1.1%, respectively, HR 1.92; 95% CI: 1.38, 2.68; p < 0.001. The relative risk of stroke was particularly high in patients with a prior stroke: annualized stroke rate 5.2% in the darbepoetin alfa-treated group and 1.9% in the placebo group, HR 3.07; 95% CI: 1.44, 6.54. Also, among darbepoetin alfa-treated subjects with a past history of cancer, there were more deaths due to all causes and more deaths adjudicated as due to cancer, in comparison with the control group.

Patients with Cancer

An increased incidence of thromboembolic reactions, some serious and life-threatening, occurred in patients with cancer treated with ESAs.

In a randomized, placebo-controlled study (Study 1 in Table 3 ) of 939 women with metastatic breast cancer receiving chemotherapy, patients received either weekly epoetin alfa or placebo for up to a year. This study was designed to show that survival was superior when epoetin alfa was administered to prevent anemia (maintain hemoglobin levels between 12 and 14 g/dL or hematocrit between 36% and 42%). This study was terminated prematurely when interim results demonstrated a higher mortality at 4 months (8.7% vs. 3.4%) and a higher rate of fatal thrombotic reactions (1.1% vs. 0.2%) in the first 4 months of the study among patients treated with epoetin alfa. Based on Kaplan-Meier estimates, at the time of study termination, the 12-month survival was lower in the epoetin alfa group than in the placebo group (70% vs. 76%; HR 1.37, 95% CI: 1.07, 1.75; p = 0.012).

Patients Having Surgery

Mircera is not approved for reduction of RBC transfusions in patients scheduled for surgical procedures.

An increased incidence of deep vein thrombosis (DVT) in patients receiving epoetin alfa undergoing surgical orthopedic procedures has been observed. In a randomized controlled study (referred to as the "SPINE" study), 681 adult patients, not receiving prophylactic anticoagulation and undergoing spinal surgery, received epoetin alfa and standard of care (SOC) treatment, or SOC treatment alone. Preliminary analysis showed a higher incidence of DVT, determined by either Color Flow Duplex Imaging or by clinical symptoms, in the epoetin alfa group [16 patients (4.7%)] compared to the SOC group [7 patients (2.1%)]. In addition, 12 patients in the epoetin alfa group and 7 patients in the SOC group had other thrombotic vascular events.

Increased mortality was observed in a randomized placebo-controlled study of epoetin alfa in adult patients who were undergoing coronary artery bypass surgery (7 deaths in 126 patients randomized to epoetin alfa versus no deaths among 56 patients receiving placebo). Four of these deaths occurred during the period of study drug administration and all four deaths were associated with thrombotic events.

5.2 Increased Mortality and/or Increased Risk of Tumor Progression or Recurrence in Patients with Cancer

Mircera is not indicated and is not recommended for use in the treatment of anemia due to cancer chemotherapy. A dose-ranging trial of Mircera in 153 patients who were undergoing chemotherapy for non-small cell lung cancer was terminated prematurely because more deaths occurred among patients receiving Mircera than another ESA.

ESAs resulted in decreased locoregional control/progression-free survival and/or overall survival. These findings were observed in studies of patients with advanced head and neck cancer receiving radiation therapy (Studies 5 and 6), in patients receiving chemotherapy for metastatic breast cancer (Study 1) or lymphoid malignancy (Study 2), and in patients with non-small cell lung cancer or various malignancies who were not receiving chemotherapy or radiotherapy (Studies 7 and 8).

Study/Tumor

(n)

 Hemoglobin Target Achieved Hemoglobin (Median Q1,Q3Q1= 25th percentile; Q3= 75th percentile) Primary Endpoint Adverse Outcome for ESA-containing Arm
Chemotherapy
Cancer Study 1

Metastatic breast

cancer

(n=939)

 12-14 g/dL 12.9 g/dL

12.2, 13.3 g/dL

 12-month overall

survival

 Decreased 12-month survival
Cancer Study 2

Lymphoid malignancy

(n=344)

 13-15 g/dL (M)

13-14 g/dL (F)

 11.0 g/dL

9.8, 12.1 g/dL

 Proportion of patients achieving a hemoglobin response Decreased overall survival
Cancer Study 3

Early breast cancer

(n=733)

12.5-13 g/dL 13.1 g/dL

12.5, 13.7 g/dL

 Relapse-free and overall survival Decreased 3-year relapse-free and overall survival
Cancer Study 4

Cervical cancer

(n=114)

12-14 g/dL 12.7 g/dL

12.1, 13.3 g/dL

 Progression-free and overall survival and locoregional control Decreased 3-year progression-free and overall survival and locoregional control
Radiotherapy Alone
Cancer Study 5

Head and neck

cancer

(n=351)

>15 g/dL (M)

>14 g/dL (F)

 Not available Locoregional progression-free survival (LRPFS) Decreased 5-year locoregional progression-free survival

Decreased overall survival
Cancer Study 6

Head and neck

cancer

(n=522)

14-15.5 g/dL Not available Locoregional disease control (LRC) Decreased locoregional disease control
No Chemotherapy or Radiotherapy
Cancer Study 7

Non-small cell lung cancer

(n=70)

12-14 g/dL Not available Quality of life Decreased overall survival
Cancer Study 8

Non-myeloid malignancy

(n=989)

12-13 g/dL 10.6 g/dL

9.4, 11.8 g/dL

 RBC transfusions Decreased overall survival

Decreased overall survival:

Cancer Study 1 (the "BEST" study) was previously described . Mortality at 4 months (8.7% vs. 3.4%) was significantly higher in the epoetin alfa arm. The most common investigator-attributed cause of death within the first 4 months was disease progression; 28 of 41 deaths in the epoetin alfa arm and 13 of 16 deaths in the placebo arm were attributed to disease progression. Investigator assessed time to tumor progression was not different between the two groups. Survival at 12 months was significantly lower in the epoetin alfa arm (70% vs. 76%, HR 1.37, 95% CI: 1.07, 1.75; p=0.012).

Cancer Study 2 was a Phase 3, double-blind, randomized (darbepoetin alfa vs. placebo) study conducted in 344 anemic patients with lymphoid malignancy receiving chemotherapy. With a median follow-up of 29 months, overall mortality rates were significantly higher among patients randomized to darbepoetin alfa as compared to placebo (HR 1.36, 95% CI: 1.02, 1.82).

Cancer Study 7 was a Phase 3, multicenter, randomized (epoetin alfa vs. placebo), double-blind study, in which patients with advanced non-small cell lung cancer receiving only palliative radiotherapy or no active therapy were treated with epoetin alfa to achieve and maintain hemoglobin levels between 12 and 14 g/dL. Following an interim analysis of 70 of 300 patients planned, a significant difference in survival in favor of the patients on the placebo arm of the trial was observed (median survival 63 vs. 129 days; HR 1.84; p=0.04).

Cancer Study 8 was a Phase 3, double-blind, randomized (darbepoetin alfa vs. placebo), 16-week study in 989 anemic patients with active malignant disease, neither receiving nor planning to receive chemotherapy or radiation therapy. There was no evidence of a statistically significant reduction in proportion of patients receiving RBC transfusions. The median survival was shorter in the darbepoetin alfa treatment group (8 months) compared with the placebo group (10.8 months); HR 1.30, 95% CI: 1.07, 1.57.

Decreased progression-free survival and overall survival:

Cancer Study 3 (the "PREPARE" study) was a randomized controlled study in which darbepoetin alfa was administered to prevent anemia conducted in 733 women receiving neo-adjuvant breast cancer treatment. A final analysis was performed after a median follow-up of approximately 3 years at which time the survival rate was lower (86% vs. 90%, HR 1.42, 95% CI: 0.93, 2.18) and relapse-free survival rate was lower (72% vs. 78%, HR 1.33, 95% CI: 0.99, 1.79) in the darbepoetin alfa-treated arm compared to the control arm.

Cancer Study 4 (protocol GOG 191) was a randomized controlled study that enrolled 114 of a planned 460 cervical cancer patients receiving chemotherapy and radiotherapy. Patients were randomized to receive epoetin alfa to maintain hemoglobin between 12 and 14 g/dL or to transfusion support as needed. The study was terminated prematurely due to an increase in thromboembolic events in epoetin alfa-treated patients compared to control (19% vs. 9%). Both local recurrence (21% vs. 20%) and distant recurrence (12% vs. 7%) were more frequent in epoetin alfa-treated patients compared to control. Progression-free survival at 3 years was lower in the epoetin alfa-treated group compared to control (59% vs. 62%, HR 1.06, 95% CI: 0.58, 1.91). Overall survival at 3 years was lower in the epoetin alfa-treated group compared to control (61% vs. 71%, HR 1.28, 95% CI: 0.68, 2.42).

Cancer Study 5 (the "ENHANCE" study) was a randomized controlled study in 351 head and neck cancer patients where epoetin beta or placebo was administered to achieve target hemoglobins of 14 and 15 g/dL for women and men, respectively. Locoregional progression-free survival was significantly shorter in patients receiving epoetin beta (HR 1.62, 95% CI: 1.22, 2.14, p=0.0008) with a median of 406 days epoetin beta vs. 745 days placebo. Overall survival was significantly shorter in patients receiving epoetin beta (HR 1.39, 95% CI: 1.05, 1.84; p=0.02).

Decreased locoregional control:

Cancer Study 6 (DAHANCA 10) was conducted in 522 patients with primary squamous cell carcinoma of the head and neck receiving radiation therapy randomized to darbepoetin alfa with radiotherapy or radiotherapy alone. An interim analysis on 484 patients demonstrated that locoregional control at 5 years was significantly shorter in patients receiving darbepoetin alfa (RR 1.44, 95% CI: 1.06, 1.96; p=0.02). Overall survival was shorter in patients receiving darbepoetin alfa (RR 1.28, 95% CI: 0.98, 1.68; p=0.08).

5.3 Hypertension

Mircera is contraindicated in patients with uncontrolled hypertension.

In Mircera clinical studies, approximately 27% of patients with CKD, including patients on dialysis and patients not on dialysis, required intensification of antihypertensive therapy. Hypertensive encephalopathy and/or seizures have been observed in patients with CKD treated with Mircera .

Appropriately control hypertension prior to initiation of and during treatment with Mircera. Reduce or withhold Mircera if blood pressure becomes difficult to control. Advise patients of the importance of compliance with antihypertensive therapy and dietary restrictions .

5.4 Seizures

Seizures have occurred in patients participating in Mircera clinical studies. During the first several months following initiation of Mircera, monitor patients closely for premonitory neurologic symptoms. Advise patients to contact their healthcare practitioner for new-onset seizures, premonitory symptoms, or change in seizure frequency.

5.5 Lack or Loss of Hemoglobin Response to Mircera

For lack or loss of hemoglobin response to Mircera, initiate a search for causative factors.

If typical causes of lack or loss of hemoglobin response are excluded, evaluate for PRCA . In the absence of PRCA, follow dosing recommendations for management of patients with an insufficient response to Mircera therapy .

5.6 Pure Red Cell Aplasia

Cases of PRCA and of severe anemia, with or without other cytopenias that arise following the development of neutralizing antibodies to erythropoietin have been reported in the postmarketing setting in patients treated with Mircera. This has been reported predominantly in patients with CKD receiving ESAs by SC administration. PRCA was not observed in clinical studies of Mircera.

PRCA has also been reported in patients receiving ESAs for anemia related to hepatitis C treatment (an indication for which Mircera is not approved).

If severe anemia and low reticulocyte count develop during treatment with Mircera, withhold Mircera and evaluate patients for neutralizing antibodies to erythropoietin . Serum samples should be obtained at least a month after the last Mircera administration to prevent interference of Mircera with the assay. Contact Roche at 1-888-835-2555 to perform assays for binding and neutralizing antibodies. Permanently discontinue Mircera in patients who develop PRCA following treatment with Mircera or other erythropoietin protein drugs. Do not switch patients to other ESAs as antibodies may cross-react .

5.7 Serious Allergic Reactions

Serious allergic reactions, including anaphylactic reactions, angioedema, bronchospasm, tachycardia, pruritus skin rash, urticaria, and Stevens-Johnson syndrome/toxic epidermal necrolysis have been reported in patients treated with Mircera. If a serious allergic or anaphylactic reaction occurs due to Mircera, immediately and permanently discontinue Mircera and administer appropriate therapy.

5.8 Dialysis Management

Therapy with Mircera results in an increase in red blood cells and a decrease in plasma volume, which could reduce dialysis efficiency; patients may require adjustments in their dialysis prescription after initiation of Mircera. Patients receiving Mircera may require increased anticoagulation with heparin to prevent clotting of the extracorporeal circuit during hemodialysis.

5.9 Laboratory Monitoring

Evaluate transferrin saturation and serum ferritin prior to and during Mircera treatment. Administer supplemental iron therapy when serum ferritin is less than 100 mcg/L or when serum transferrin saturation is less than 20% .

The majority of patients with CKD will require supplemental iron during the course of ESA therapy. Following initiation of therapy and after each dose adjustment, monitor hemoglobin weekly until the hemoglobin is stable and sufficient to minimize the need for RBC transfusion. Thereafter, hemoglobin should be monitored at least monthly provided hemoglobin levels remain stable .

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6 ADVERSE REACTIONS

The following serious adverse reactions are discussed in greater detail in other sections of the labeling:


The most common adverse reactions (≥ 10%) are hypertension, diarrhea, nasopharyngitis. (6).

To report SUSPECTED ADVERSE REACTIONS, contact FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

6.1 Clinical Trials Experience

The data described below reflect exposure to Mircera in 2737 patients, including 1451 exposed for 6 months and 1144 exposed for greater than one year. Mircera was studied primarily in active-controlled studies (n=1789 received Mircera, and n=948 received another ESA) and in long-term follow up studies. The population was 18 to 92 years of age, 58% male, and the percentage of Caucasian, Black (including African Americans), Asian and Hispanic patients were 73%, 20%, 5%, and 9%, respectively. Approximately 85% of the patients were receiving dialysis. Most patients received Mircera using dosing regimens of once every two or four weeks, administered SC or IV.

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical studies of Mircera cannot be directly compared to rates in the clinical trials of other drugs and may not reflect the rates observed in practice.

The most commonly reported adverse reactions in ≥10% of patients were hypertension , diarrhea, and nasopharyngitis. The most common adverse reactions that led to treatment discontinuation in the Mircera clinical studies were: hypertension, coronary artery disease, anemia, concomitant termination of other CKD therapy and septic shock. Some of the adverse reactions reported are typically associated with CKD, or recognized complications of dialysis, and may not necessarily be attributable to Mircera therapy. Adverse reaction rates did not importantly differ between patients receiving Mircera or another ESA.

Table 4 summarizes the most frequent adverse reactions (≥ 5%) in patients treated with Mircera.

Adverse Reaction Patients Treated with Mircera

(n=1789)
VASCULAR
Hypertension 13%
Hypotension 5%
GASTROINTESTINAL
Diarrhea 11%
Vomiting 6%
Constipation 5%
INFECTIONS AND INFESTATIONS
Nasopharyngitis 11%
Upper Respiratory Tract Infection 9%
Urinary Tract Infection 5%
NERVOUS SYSTEM
Headache 9%
MUSCULOSKELETAL AND CONNECTIVE TISSUE
Muscle Spasms 8%
Back Pain 6%
Pain in Extremity 5%
INJURY, POISONING AND PROCEDURAL COMPLICATIONS
Procedural Hypotension 8%
Arteriovenous Fistula Thrombosis 5%
Arteriovenous Fistula Site Complication 5%
METABOLISM AND NUTRITION
Fluid Overload 7%
RESPIRATORY, THORACIC AND MEDIASTINAL
Cough 6%

In the controlled trials, the rates of serious adverse reactions did not importantly differ between patients receiving Mircera and another ESA (38% vs. 42%) except for the occurrence of serious gastrointestinal hemorrhage (1.2% vs. 0.2%). Serious hemorrhagic adverse reactions of all types occurred among 5% and 4% of patients receiving Mircera or another ESA, respectively.

6.2 Immunogenicity

As with all therapeutic proteins, there is a potential for immunogenicity. Neutralizing antibodies to Mircera that cross-react with endogenous erythropoietin and other ESAs can result in PRCA or severe anemia . Compared to SC administration, the IV route of administration may lessen the risk for development of antibodies to Mircera.

In 1789 patients treated with Mircera in clinical studies, antibody testing using an enzyme-linked immunosorbent assay (ELISA) was conducted at baseline and during treatment. Antibody development was not detected in any of the patients.

The incidence of antibody formation is highly dependent on the sensitivity and specificity of the assay. Additionally, the observed incidence of antibody (including neutralizing antibody) positivity in an assay may be influenced by several factors including assay methodology, sample handling, timing of sample collection, concomitant medications, and underlying disease. For these reasons, comparison of the incidence of antibodies to Mircera with the incidence of antibodies to other ESAs may be misleading.

6.3 Postmarketing Experience

The following adverse reactions have been identified during postapproval use of Mircera. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

Hypersensitivity

Stevens-Johnson syndrome/toxic epidermal necrolysis has been reported .

Pure Red Cell Aplasia (PRCA)

Cases of PRCA and of severe anemia, with or without other cytopenias that arise following the development of neutralizing antibodies to erythropoietin have been reported in patients treated with Mircera .

7 DRUG INTERACTIONS

No formal drug/drug interaction studies have been performed.

8 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy: Category C

Risk Summary

There are no adequate and well-controlled studies in pregnant women. Mircera should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

Animal Data

When methoxy polyethylene glycol-epoetin beta was administered subcutaneously to rats and rabbits during gestation, bone malformation was observed in both species at 50 mcg/kg once every three days. This effect was observed as missing caudal vertebrae resulting in a thread-like tail in one rat fetus, absent first digit metacarpal and phalanx on each forelimb resulting in absent polex in one rabbit fetus, and fused fourth and fifth cervical vertebrae centra in another rabbit fetus. Dose-related reduction in fetal weights was observed in both rats and rabbits. At doses 5 mcg/kg once every three days and higher, methoxy polyethylene glycol-epoetin beta caused exaggerated pharmacodynamic effects in dams. Once-weekly doses of methoxy polyethylene glycol-epoetin beta up to 50 mcg/kg/dose given to pregnant rats did not adversely affect pregnancy parameters, natural delivery or litter observations. Increased deaths and significant reduction in the growth rate of the F1 generation were observed during lactation and early post weaning period. However, no remarkable effect on reflex, physical and cognitive development or reproductive performance was observed in F1 generation of any dose groups.

8.3 Nursing Mothers

It is not known whether Mircera is excreted into human breast milk. In one study in rats, methoxy polyethylene glycol-epoetin beta was excreted into maternal milk. Because many drugs are excreted in human milk, caution should be exercised when Mircera is administered to a nursing woman.

8.4 Pediatric Use

The safety and efficacy of Mircera in pediatric patients have not been established.

8.5 Geriatric Use

Clinical studies of Mircera did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function and of concomitant disease or other drug therapy.

8.6 Hepatic Impairment

In a study comparing 12 patients with severe (Child-Pugh Classification Grade C) hepatic impairment to 12 healthy volunteers, the single-dose pharmacokinetic disposition of Mircera was not altered in patients with hepatic impairment. No adjustment of the starting dose is necessary in patients with hepatic impairment.

10 OVERDOSAGE

Mircera overdosage can elevate hemoglobin levels above the desired level, which should be managed with discontinuation or reduction of Mircera dosage and/or with phlebotomy, as clinically indicated . Cases of severe hypertension have been observed following overdose with ESAs .

11 DESCRIPTION

Mircera, methoxy polyethylene glycol-epoetin beta, is an ESA which differs from erythropoietin through formation of a chemical bond between either the N-terminal amino group or the ε-amino group of any lysine present in erythropoietin, predominantly Lys52 and Lys45, and methoxy polyethylene glycol (PEG) butanoic acid (approximately 30,000 daltons). This results in a total molecular weight of approximately 60,000 daltons. Mircera is formulated as a sterile, preservative-free protein solution for intravenous or subcutaneous administration.

Injectable solutions of Mircera in prefilled syringes are formulated in an aqueous solution containing sodium phosphate, sodium sulphate, mannitol, methionine and poloxamer 188. The solution is clear, colorless to slightly yellowish and the pH is 6.2 ± 0.2.

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

Mircera is an erythropoietin receptor activator with greater activity in vivo as well as increased half-life, in contrast to erythropoietin. A primary growth factor for erythroid development, erythropoietin is produced in the kidney and released into the bloodstream in response to hypoxia. In responding to hypoxia, erythropoietin interacts with erythroid progenitor cells to increase red cell production. Production of endogenous erythropoietin is impaired in patients with CKD and erythropoietin deficiency is the primary cause of their anemia.

12.2 Pharmacodynamics

Following a single-dose of Mircera in CKD patients, the onset of hemoglobin increase was observed 7 to 15 days following initial dose administration .

12.3 Pharmacokinetics

The pharmacokinetics of Mircera were studied in anemic patients with CKD including patients on dialysis and those not on dialysis. Mircera pharmacokinetics, based on population analyses, were not altered by age, gender, race, or the use of dialysis.

Following an IV administration of Mircera 0.4 mcg/kg body weight to CKD patients receiving peritoneal dialysis, the observed terminal half-life was 134 ± 65 hours (mean ± SD), and the total systemic clearance was 0.49 ± 0.18 mL/hr/kg. Following a SC administration of Mircera 0.8 mcg/kg to CKD patients receiving peritoneal dialysis, the terminal half-life was 139 ± 67 hours. The maximum serum concentrations of Mircera were observed 72 hours (median value) following the SC administration. The absolute bioavailability of Mircera after the SC administration was 62%.

In CKD patients receiving multiple Mircera doses, pharmacokinetics were studied after the first dose and on week 9 and week 19 or 21. Multiple dosing was found to have no effect on clearance, volume of distribution or bioavailability of Mircera. Based on population analyses of the clinical studies, Mircera did not accumulate following administration every four weeks. However, when Mircera was administered every 2 weeks, blood concentrations at steady state increased by 12%.

A comparison of serum concentrations of Mircera measured before and after hemodialysis in 41 patients showed that hemodialysis did not alter serum concentrations.

The single-dose pharmacokinetics of Mircera in patients with severe (Child-Pugh Classification Grade C) hepatic impairment and healthy volunteers were similar.

The site of SC injection (abdomen, arm or thigh) had no clinically important effects on the pharmacokinetics or pharmacodynamics of Mircera in healthy volunteers.

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

No carcinogenicity or genotoxicity studies have been conducted with Mircera. Methoxy polyethylene glycol-epoetin beta did not induce a proliferative response in either the erythropoietin receptor positive cell lines HepG2 and K562 or the erythropoietin receptor negative cell line RT112 in vitro. In addition, using a panel of human tissues, the in vitro binding of methoxy polyethylene glycol-epoetin beta was observed only in bone marrow progenitor cells.

When methoxy polyethylene glycol-epoetin beta was administered subcutaneously to male and female rats prior to and during mating, reproductive performance, fertility, and sperm assessment parameters were not affected.

14 CLINICAL STUDIES

Patients with chronic kidney disease on dialysis: ESA effects on rates of transfusion

In early clinical studies conducted in CKD patients on dialysis, ESAs have been shown to reduce the use of RBC transfusions. These studies enrolled patients with mean baseline hemoglobin levels of approximately 7.5 g/dL and ESAs were generally titrated to achieve a hemoglobin level of approximately 12 g/dL. Fewer transfusions were given during the ESA treatment period when compared to a pre-treatment interval.

In NHS, the yearly transfusion rate was 51.5% in the lower hemoglobin group (10 g/dL) and 32.4% in the higher hemoglobin group (14 g/dL).

Patients with chronic kidney disease not on dialysis: ESA effects on rates of transfusion

In TREAT, a randomized, double-blind trial of 4038 patients with CKD and type 2 diabetes not on dialysis, a post-hoc analysis showed that the proportion of patients receiving RBC transfusions was lower in patients administered an ESA to target a hemoglobin of 13 g/dL compared to the control arm in which the ESA was administered intermittently if hemoglobin concentration decreased to less than 9 g/dL (15% versus 25%, respectively). In CHOIR, a randomized open-label study of 1432 patients with CKD not on dialysis, use of an ESA to target a higher (13.5 g/dL) versus lower (11.3 g/dL) hemoglobin goal did not reduce the use of RBC transfusions. In each trial, no benefits occurred for the cardiovascular or end-stage renal disease outcomes. In each trial, the potential benefit of ESA therapy was offset by worse cardiovascular safety outcomes resulting in an unfavorable benefit-risk profile .

ESA effects on quality of life

Mircera use has not been demonstrated in controlled clinical trials to improve quality of life, fatigue, or patient well-being.

ESA effects on rates of death and other serious cardiac adverse events

Three randomized outcome trials (NHS, CHOIR and TREAT) have been conducted in patients with CKD using Epogen/PROCRIT/Aranesp to target higher vs. lower hemoglobin levels. Though these trials were designed to establish a cardiovascular or renal benefit of targeting higher hemoglobin levels, in all 3 studies, patients randomized to the higher hemoglobin target experienced worse cardiovascular outcomes and showed no reduction in progression to ESRD. In each trial, the potential benefit of ESA therapy was offset by worse cardiovascular safety outcomes resulting in an unfavorable benefit-risk profile .

Other ESA trials

The efficacy and safety of Mircera were assessed in six open-label, multi-center clinical studies that randomized patients to either Mircera or a comparator ESA. Two studies evaluated anemic patients with CKD who were not treated with an ESA at baseline and four studies evaluated patients who were receiving an ESA for treatment of the anemia of CKD. In all studies, patients were assessed as clinically stable at baseline and without evidence of infection or inflammation as determined by history and laboratory data, including C-reactive protein (CRP ≤ 15 mg/L for study 1 and CRP ≤ 30 mg/L for studies 2 to 6). A CRP value above the threshold led to the exclusion of no more than 3% of the screened patients.

In the clinical studies, ESAs were administered to achieve specific hemoglobin levels. Following stabilization of hemoglobin levels (12 g/dL), the median monthly Mircera dose was 150 mcg (range of 97 mcg to 270 mcg).

Patients Not Currently Treated with an ESA

In Study 1 patients who were not receiving dialysis were randomized to Mircera or darbepoetin alfa, administered for 28 weeks. The starting dose of Mircera was 0.6 mcg/kg administered SC once every two weeks and the starting dose of darbepoetin alfa was 0.45 mcg/kg administered SC once a week. In Study 2, patients who were receiving dialysis were randomized to Mircera or another ESA (epoetin alfa or epoetin beta), administered for 24 weeks. The starting dose of Mircera was 0.4 mcg/kg administered IV once every two weeks and the starting dose of the comparator was administered IV three times a week, consistent with the product's recommended dose. In these studies, the observed median dose of Mircera once every two weeks over the course of the correction/evaluation period was 0.6 mcg/kg. Table 5 provides the results of the two studies.

Group

(n)

 Percent Achieving GoalGoal: hemoglobin increase of at least 1 g/dL and to a level of at least 11 g/dL without RBC transfusion; hemoglobin levels were to be maintained within the range of 11 to 13 g/dL. (95% CI) Mean Hemoglobin Change from Baseline (g/dL) RBC Transfusion, %
Study 1
Mircera

(n=162)

 98 (94, 99) 2.1 2.5
Darbepoetin alfa

(n=162)

 96 (92, 99) 2.0 6.8
Study 2
Mircera

(n=135)

 93 (88, 97) 2.7 5.2
Epoetin alfa/beta

(n=46)

 91 (79, 98) 2.6 4.3

Patients Currently Treated with an ESA

Four studies assessed the ability of Mircera to maintain hemoglobin concentrations among patients currently treated with other ESAs. Patients were randomized to receive Mircera administrations either once every two weeks or once every four weeks, or to continue their current ESA dose and schedule. The initial Mircera dose was determined based on the patient's previous weekly ESA dose. As shown in Table 6, treatment with Mircera once every two weeks and once every four weeks maintained hemoglobin concentrations within the targeted hemoglobin range (10 to 13.5 g/dL).

Group

(n)

 Mean Baseline Hemoglobin Evaluation Period Hemoglobin (Mean) Between-group Difference Mircera versus comparator mean hemoglobin difference in the evaluation period; 97.5% CI are shown for studies that compared two Mircera groups to another ESA (Studies 3 and 4) and 95% CI are shown for the other studies.,

g/dL (95% or 97.5% CI)
n/a = not applicable
Study 3
Mircera IV every 2 weeks

(n=223)

 12.0 11.9 0.0 (−0.2, 0.2)
Mircera IV every 4 weeks

(n=224)

 11.9 11.9 0.1 (−0.2, 0.3)
Epoetin alfa/beta IV

(n=226)

 12.0 11.9 n/a
Study 4
Mircera SC every 2 weeks

(n=190)

 11.7 11.7 0.1 (−0.1, 0.4)
Mircera SC every 4 weeks

(n=191)

 11.6 11.5 −0.0 (−0.3, 0.2)
Epoetin beta SC

(n=191)

 11.6 11.5 n/a
Study 5
Mircera IV every 2 weeks

(n=157)

 12.0 12.1 0.2 (−0.0, 0.4)
Darbepoetin alfa IV

(n=156)

 11.9 11.8 n/a
Study 6
Mircera IV/SC every 2 weeks

(n= 68)

 11.8 11.9 0.1 (−0.1, 0.4)
Epoetin alfa IV/SC

(n=168)

 11.9 11.8 0.1 (−0.1, 0.4)

16 HOW SUPPLIED/STORAGE AND HANDLING

16.1 How Supplied

Mircera is available in single-use prefilled syringes. The syringe plungers are designated with unique colors for each dosage strength. The prefilled syringes are supplied with a 27 gauge, ½ inch needle. To reduce the risk of accidental needlesticks after application, each prefilled syringe is equipped with a needle guard that covers the needle during disposal.

Mircera is available in the following pack sizes:

Single Use Prefilled Syringe with a Needle Guard. A 27 Gauge, ½ Inch Needle is also provided:

16.2 Stability and Storage

The recommended storage temperature is at 2°C to 8°C (36°F to 46°F). Do not freeze or shake. Protect from light. Keep Mircera in the original package until use.

Storage of prefilled syringes over the recommended temperature (2°C to 8°C), when necessary, is permissible only for temperatures up to 25°C (77°F) and for no more than 30 days.

17 PATIENT COUNSELING INFORMATION

See Medication Guide and Instructions for Use

Prior to treatment, inform patients of the risks and benefits of Mircera.

Inform patients:


Administer Mircera under the direct supervision of a healthcare provider or, in situations where a patient has been trained to administer Mircera at home, provide instruction on the proper use of Mircera, including instructions to:

MEDICATION GUIDE

Mircera®

(methoxy polyethylene glycol-epoetin beta)

Read this Medication Guide:


This Medication Guide does not take the place of talking to your healthcare provider about your medical condition or your treatment. Talk with your healthcare provider regularly about the use of Mircera and ask if there is new information about Mircera.

What is the most important information I should know about Mircera?

Mircera may cause serious side effects that can lead to death, including:

For people with cancer: Mircera is not for use to treat anemia that is caused by cancer chemotherapy. If you have certain cancers, your tumor may grow faster and you may die sooner if you take Mircera.


See "What are the possible side effects of Mircera?" below for more information.

If you decide to take Mircera, your healthcare provider should prescribe the smallest dose of Mircera that is necessary to reduce your chance of needing red blood cell transfusions.

What is Mircera?

Mircera is a prescription medicine used to treat anemia. People with anemia have a lower-than-normal number of RBCs. Mircera works like the human protein called erythropoietin to help your body make more RBCs. Mircera is used to reduce or avoid the need for RBC transfusion.

Mircera may be used to treat anemia if it is caused by chronic kidney disease (you may or may not be on dialysis).

If your hemoglobin level stays too high or if your hemoglobin goes up too quickly, this may lead to serious health problems which may result in death. These serious health problems may happen if you take Mircera, even if you do not have an increase in your hemoglobin level.

Mircera is not for use for the treatment of anemia:


Mircera has not been proven to improve the quality of life, fatigue, or well-being.

It is not known if Mircera is safe and effective in children.

Who should not take Mircera?

Do not take Mircera if you:


What should I tell my healthcare provider before taking Mircera?

Mircera may not be right for you. Tell your healthcare provider about all of your medical conditions, including if you:


Tell your healthcare provider about all of the medicines you take, including prescription and over-the-counter medicines, vitamins, and herbal supplements.

Know the medicines you take. Keep a list of your medicines with you and show it to your healthcare provider when you get a new medicine.

How should I take Mircera?

What are possible side effects of Mircera?

Mircera may cause serious side effects.


Common side effects of Mircera include:


Tell your healthcare provider if you have any side effect that bothers you or that does not go away.

These are not all of the possible side effects of Mircera. Your healthcare provider can give you a more complete list. Tell your healthcare provider about any side effects that bother you or that do not go away.

Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

How should I store Mircera?


Keep Mircera and all medicines out of the reach of children.

General information about Mircera

Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. Do not use Mircera for a condition for which it was not prescribed. Do not give Mircera to other people, even if they have the same symptoms that you have. It may harm them.

This Medication Guide summarizes the most important information about Mircera. If you would like more information about Mircera, talk with your healthcare provider. You can ask your healthcare provider or pharmacist for information about Mircera that is written for health professionals.

What are the ingredients in Mircera?

Active ingredient: methoxy polyethylene glycol-epoetin beta

Inactive ingredients: sodium phosphate, sodium sulphate, mannitol, methionine and poloxamer 188

This Medication Guide has been approved by the U.S. Food and Drug Administration.

Hoffmann-La Roche Inc.

c/o Genentech USA, Inc.

A Member of the Roche Group

1 DNA Way

South San Francisco, CA 94080-4990

U.S. Govt. Lic. No. 0136

Revised: August 2015

Copyright © 2015 Hoffmann-La Roche Inc. All rights reserved.

Representative sample of labeling :

NDC 0004-0401-09

Mircera®

(methoxy polyethylene glycol-epoetin beta)

50 mcg / 0.3 mL

Sterile Solution

For IV or SC use only

For single use only. Discard unused portion.

Syringe contains 0.3 mL

Single Use Prefilled Syringe with 27 Gauge Needle

KEEP REFRIGERATED

PHARMACIST: Each patient is required to receive the enclosed Medication Guide

Rx only

Roche

10159120

NDC 0004-0402-09

Mircera®

(methoxy polyethylene glycol-epoetin beta)

75 mcg / 0.3 mL

Sterile Solution

For IV or SC use only

For single use only. Discard unused portion.

Syringe contains 0.3 mL

Single Use Prefilled Syringe with 27 Gauge Needle

KEEP REFRIGERATED

PHARMACIST: Each patient is required to receive the enclosed Medication Guide

Rx only

Roche

10159121

NDC 0004-0403-09

Mircera®

(methoxy polyethylene glycol-epoetin beta)

100 mcg / 0.3 mL

Sterile Solution

For IV or SC use only

For single use only. Discard unused portion.

Syringe contains 0.3 mL

Single Use Prefilled Syringe with 27 Gauge Needle

KEEP REFRIGERATED

PHARMACIST: Each patient is required to receive the enclosed Medication Guide

Rx only

Roche

10159122

NDC 0004-0404-09

Mircera®

(methoxy polyethylene glycol-epoetin beta)

150 mcg / 0.3 mL

Sterile Solution

For IV or SC use only

For single use only. Discard unused portion.

Syringe contains 0.3 mL

Single Use Prefilled Syringe with 27 Gauge Needle

KEEP REFRIGERATED

PHARMACIST: Each patient is required to receive the enclosed Medication Guide

Rx only

Roche

10159123

NDC 0004-0405-09

Mircera®

(methoxy polyethylene glycol-epoetin beta)

200 mcg / 0.3 mL

Sterile Solution

For IV or SC use only

For single use only. Discard unused portion.

Syringe contains 0.3 mL

Single Use Prefilled Syringe with 27 Gauge Needle

KEEP REFRIGERATED

PHARMACIST: Each patient is required to receive the enclosed Medication Guide

Rx only

Roche

10159124

NDC 0004-0406-09

Mircera®

(methoxy polyethylene glycol-epoetin beta)

250 mcg / 0.3 mL

Sterile Solution

For IV or SC use only

For single use only. Discard unused portion.

Syringe contains 0.3 mL

Single Use Prefilled Syringe with 27 Gauge Needle

KEEP REFRIGERATED

PHARMACIST: Each patient is required to receive the enclosed Medication Guide

Rx only

Roche

10159125

Mircera pharmaceutical active ingredients containing related brand and generic drugs:


Mircera available forms, composition, doses:


Mircera destination | category:


Mircera Anatomical Therapeutic Chemical codes:


Mircera pharmaceutical companies:


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Frequently asked Questions

Can i drive or operate heavy machine after consuming Mircera?

Depending on the reaction of the Mircera after taken, if you are feeling dizziness, drowsiness or any weakness as a reaction on your body, Then consider Mircera not safe to drive or operate heavy machine after consumption. Meaning that, do not drive or operate heavy duty machines after taking the capsule if the capsule has a strange reaction on your body like dizziness, drowsiness. As prescribed by a pharmacist, it is dangerous to take alcohol while taking medicines as it exposed patients to drowsiness and health risk. Please take note of such effect most especially when taking Primosa capsule. It's advisable to consult your doctor on time for a proper recommendation and medical consultations.

Is Mircera addictive or habit forming?

Medicines are not designed with the mind of creating an addiction or abuse on the health of the users. Addictive Medicine is categorically called Controlled substances by the government. For instance, Schedule H or X in India and schedule II-V in the US are controlled substances.

Please consult the medicine instruction manual on how to use and ensure it is not a controlled substance.In conclusion, self medication is a killer to your health. Consult your doctor for a proper prescription, recommendation, and guidiance.

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Review

sdrugs.com conducted a study on Mircera, and the result of the survey is set out below. It is noteworthy that the product of the survey is based on the perception and impressions of the visitors of the website as well as the views of Mircera consumers. We, as a result of this, advice that you do not base your therapeutic or medical decisions on this result, but rather consult your certified medical experts for their recommendations.

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The information was verified by Dr. Rachana Salvi, MD Pharmacology


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