Data from FDA - Curated by EPG Health - Last updated 22 March 2018

Indication(s)

1 INDICATIONS AND USAGE Mircera is an erythropoiesis-stimulating agent (ESA) 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: • In the treatment of anemia due to cancer chemotherapy (1.2).

• As a substitute for RBC transfusions in patients who require immediate correction of anemia (1.2) 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: •In the treatment of anemia due to cancer chemotherapy [see Warnings and Precautions (5.2)] •As a substitute for RBC transfusions in patients who require immediate correction of anemia [see Clinical Pharmacology (12.2)] Mircera has not been shown to improve symptoms, physical functioning or health-related quality of life.

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Advisory information

contraindications

4 CONTRAINDICATIONS Mircera is contraindicated in patients with: •Uncontrolled hypertension [see Warnings and Precautions (5.3)] •Pure red cell aplasia (PRCA) that begins after treatment with Mircera or other erythropoietin protein drugs [see Warnings and Precautions (5.6)] •History of serious or severe allergic reactions to Mircera (e.g. anaphylactic reactions, angioedema, bronchospasm, skin rash, and urticaria).

Uncontrolled hypertension (4).

Pure red cell aplasia (PRCA) that begins after treatment with Mircera or other erythropoietin protein drugs (4) • History of serious allergic reactions to Mircera, including anaphylaxis (4).

Adverse reactions

6 ADVERSE REACTIONS The following serious adverse reactions are discussed in greater detail in other sections of the labeling: •Increased Mortality, Myocardial Infarction, Stroke, and Thromboembolism [see Warnings and Precautions (5.1)] •Increased mortality and/or tumor progression in patients with cancer [see Warnings and Precautions (5.2)] •Hypertension [see Warnings and Precautions (5.3)] •Seizures [see Warnings and Precautions (5.4)] •Pure red cell aplasia [see Warnings and Precautions (5.6)] •Serious allergic reactions [see Warnings and Precautions (5.7)] The most common adverse reactions (?

10 %) are hypertension, diarrhea, nasopharyngitis.

(6).

To report SUSPECTED ADVERSE REACTIONS, contact Vifor (International) Inc. at 1-800-576-8295, or 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 can not 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 [see Warnings and Precautions (5.3)], 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.

Table 4 Adverse Reactions Occurring in?

5 % of CKD Patients 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 (with or without other cytopenias) [see Warnings and Precautions (5.6)].

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 [see Warnings and Precautions (5.7)].

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 [see Warnings and Precautions (5.6)].

Usage information

Dosing and administration

2 DOSAGE AND ADMINISTRATION Mircera is administered by subcutaneous (SC) or intravenous (IV) injection (2.2).

• Initial Treatment: 0.6 mcg/ kg body weight administered once every two weeks (2.2).

• Conversion from Another ESA: dosed once monthly or once every two weeks based on total weekly epoetin alfa or darbepoetin alfa dose at time of conversion (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 [see Warnings and Precautions (5.9)].

2.2 Patients with Chronic Kidney Disease Individualize dosing and use the lowest dose of Mircera sufficient to reduce the need for RBC transfusions [see Warnings and Precautions (5.1)].

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 [see Boxed Warning and Clinical Studies (14)].

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.

•Do not increase the dose more frequently than once every 4 weeks.

Decreases in dose can occur more frequently.

Avoid frequent dose adjustments.

•If the hemoglobin rises rapidly (e.g., more than 1 g/dL in any 2-week period), reduce the dose of Mircera by 25 % or more as needed to reduce rapid responses.

•For patients who do not respond adequately, if the hemoglobin has not increased by more than 1 g/dL after 4 weeks of therapy, increase the dose by 25 %.

•For patients who do not respond adequately over a 12-week escalation period, increasing the Mircera dose further is unlikely to improve response and may increase risks.

Use the lowest dose that will maintain a hemoglobin level sufficient to reduce the need for RBC transfusions.

Evaluate other causes of anemia.

Discontinue Mircera if responsiveness does not improve.

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: •Initiate Mircera treatment when the hemoglobin level is less than 10 g/dL. •If the hemoglobin level approaches or exceeds 11 g/dL, reduce or interrupt the dose of Mircera.

•The recommended starting dose of Mircera for the treatment of anemia in adult CKD patients who are not currently treated with an ESA is 0.6 mcg/ kg body weight administered as a single IV or SC injection once every two weeks.

The IV route is recommended for patients receiving hemodialysis because the IV route may be less immunogenic [see Adverse Reactions (6.2)].

•Once the hemoglobin has been stabilized, Mircera may be administered once monthly using a dose that is twice that of the every-two-week dose and subsequently titrated as necessary.

For Patients with CKD not on dialysis: •Consider initiating Mircera treatment only when the hemoglobin level is less than 10 g/dL and the following considerations apply: oThe rate of hemoglobin decline indicates the likelihood of requiring a RBC transfusion and, oReducing the risk of alloimmunization and/or other RBC transfusion-related risks is a goal •If the hemoglobin level exceeds 10 g/dL, reduce or interrupt the dose of Mircera, and use the lowest dose of Mircera sufficient to reduce the need for RBC transfusions.

•The recommended starting dose of Mircera for the treatment of anemia in adult CKD patients who are not currently treated with an ESA is 0.6 mcg/ kg body weight administered as a single IV or SC injection once every two weeks.

•Once the hemoglobin has been stabilized, Mircera may be administered once monthly using a dose that is twice that of the every-two-week dose and subsequently titrated as necessary.

Refer patients who self-administer Mircera to the Instructions for Use [see Patient Counseling Information (17)].

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 (see Table 1).

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.

Table 1 Mircera Starting Doses for Patients

Currently Receiving an ESA 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-dose 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.

See " Instructions for Use " for complete instructions on the preparation and administration of Mircera.

Examine each prefilled syringe for the expiration date.

Do not use Mircera after the expiration date.

Use in special populations

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 pollex 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.

Pregnancy and lactation
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.

Interactions

7 DRUG INTERACTIONS No formal drug/drug interaction studies have been performed.

More information

Category Value
Authorisation number BLA125164
Orphan designation No
Product NDC 59353-407,59353-406,59353-405,59353-404,59353-403,59353-402,59353-401,59353-400,59353-408
Date Last Revised 10-05-2016
Type HUMAN PRESCRIPTION DRUG
RXCUI 758164
Storage and handling 16.2 Stability and Storage The recommended storage temperature is at 2°C to 8°C (36°F to 46°F) in the original carton to protect from light. Do not freeze or shake. The end-user may store the product at room temperature up to 25°C (77°F) in the original carton up to 30 days. Discard after 30 days.
Marketing authorisation holder Vifor (International) Inc.
Warnings

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: • 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 (5.1).

No trial has identified a hemoglobin target level, ESA dose, or dosing strategy that does not increase these risks (5.1).

Use the lowest Mircera dose sufficient to reduce the need for red blood cell (RBC) transfusions (5.1).

Cancer: • Mircera is not indicated and is not recommended for the treatment of anemia due to cancer chemotherapy.

A dose-ranging study of Mircera was terminated early because of more deaths among patients receiving Mircera than another ESA (5.2).

• ESAs shortened overall survival and/or increased the risk of tumor progression or recurrence in clinical studies in patients with breast, non-small cell lung, head and neck, lymphoid, and cervical cancers (5.2).

Chronic Kidney Disease [see Warnings and Precautions (5.1)] • 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.

Use the lowest Mircera dose sufficient to reduce the need for red blood cell (RBC) transfusions.

Cancer [see Warnings and Precautions (5.2)] • Mircera is not indicated and is not recommended for the treatment of anemia due to cancer chemotherapy.

A dose-ranging study of Mircera was terminated early because of more deaths among patients receiving Mircera than another ESA. • ESAs have shown shortened overall survival and/or increased the risk of tumor progression or recurrence in clinical studies in patients with breast, non-small cell lung, head and neck, lymphoid, and cervical cancers.