Mircera

Indication and Usage ( 1 ) 04/2024 Dosage and Administration ( 2.2 ) 04/2024

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 adult patients not on dialysis ( 1.1 ). • pediatric patients 3 months to 17 years of age on dialysis or not on dialysis who are converting from another ESA after their hemoglobin level was stabilized with an ESA ( 1.1 ). Limitations of Use Mircera is not indicated and is not recommended for use: • In the treatment of anemia due to cancer chemotherapy ( 5.2 ). • As a substitute for RBC transfusions in patients who require immediate correction of anemia ( 12.2 ). 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 adult patients not on dialysis. • pediatric patients 3 months to 17 years of age on dialysis or not on dialysis who are converting from another ESA after their hemoglobin level was stabilized with an ESA. 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.

2 DOSAGE AND ADMINISTRATION Mircera is administered by subcutaneous or intravenous injection ( 2.2 ). Adult Patients • Initial Treatment: (patients not currently treated with an ESA): • CKD patients on dialysis: 0.6 mcg/kg body weight administered once every two weeks ( 2.2 ). • CKD patients not on dialysis: 1.2 mcg/kg body weight administered once every month as a single subcutaneous injection. Alternatively, a starting dose of 0.6 mcg/kg body weight may be administered once every two weeks as a single intravenous or subcutaneous injection ( 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 ). Pediatric Patients • Conversion from another ESA: dosed once every 4 weeks based on total weekly epoetin alfa or darbepoetin alfa dose at time of conversion ( 2.2 ). • In patients less than 6 years of age, maintain the same route of administration as the previous ESA when switching from another ESA to Mircera. 2.1 Important Dosing Information Evaluation of Iron Stores and Nutritional Factors Evaluate the iron status in all patients before and during 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. Monitoring of Response to Therapy 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 )]. Following initiation of therapy and after each dose adjustment, monitor hemoglobin weekly until the hemoglobin level is stable and sufficient to minimize the need for RBC transfusion. Individualization of Dosing Individualize 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 for adult patients. 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 )] . 2.2 For Adult Patients with CKD Prefilled syringes are not designed for administration of partial doses. Round doses to the closest dose achievable with the prefilled syringes. 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 approximately 25% to the closest dose achievable with the prefilled syringes to reduce rapid responses. • If the hemoglobin continues to rise following a dose reduction, discontinue Mircera until the hemoglobin level begins to decrease, at which point therapy should be restarted with a dose that is approximately 25% below the previously administered dose. • 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 approximately 25% to the closest dose achievable with the prefilled syringes. • For patients who do not respond adequately over a 12-week escalation perio …

3 DOSAGE FORMS AND STRENGTHS Injection: 30 mcg, 50 mcg, 75 mcg, 100 mcg, 120 mcg, 150 mcg, 200 mcg, or 250 mcg in 0.3 mL clear, colorless to slightly yellowish solution in single-dose prefilled syringes Injection: 360 mcg in 0.6 mL clear, colorless to slightly yellowish solution in single-dose prefilled syringes • Injection: 30 mcg, 50 mcg, 75 mcg, 100 mcg, 120 mcg, 150 mcg, 200 mcg, or 250 mcg in 0.3 mL solution in single-dose prefilled syringes ( 3 ). • Injection: 360 mcg in 0.6 mL solution in single-dose prefilled syringes ( 3 ).

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) [see Warnings and Precautions ( 5.7 , 5.8 )] . • 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 ).

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 )] • Severe Cutaneous Reactions [see Warnings and Precautions ( 5.8 )] 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 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. Adult Patients 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 subcutaneously or intravenously. 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 6 summarizes the most frequent adverse reactions (≥5%) in patients treated with Mircera. Table 6: Adverse Reactions Occurring in ≥ 5% of CKD Patients BODY SYSTEM 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. Pediatric Patients In an open-label, multiple dose study, 64 pediatric patients (ages 5 to 17 years) with CKD who were on hemodialysis and who had stable hemoglobin levels while previously receiving another ESA (epoetin alfa/beta or darbepoetin alfa) were then converted to Mircera administered …

8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Risk Summary Available data from a small number of published case reports and postmarketing experience with Mircera use in pregnancy are insufficient to identify a drug associated risk of major birth defects, miscarriage, or adverse maternal or fetal outcomes. Chronic kidney disease is associated with maternal and embryo-fetal risks (see Clinical Considerations) . In animal reproduction studies, administration of methoxy polyethylene glycol-epoetin beta to rats and rabbits during pregnancy and lactation adversely affected offspring at doses 17-fold and greater than the recommended human dose (see Data) . The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risks of major birth defects and miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively. Clinical Considerations Disease Associated Maternal and/or Embryo-Fetal Risk Pregnancy in women with chronic kidney disease has been associated with adverse outcomes including hypertension, pre-eclampsia, miscarriage, premature birth, low-birth-weight, polyhydramnios, and intrauterine growth restriction. Data When methoxy polyethylene glycol-epoetin beta was administered subcutaneously to rats and rabbits during gestation (including the period of organogenesis), bone malformation was observed in both species at 50 mcg/kg once every three days (corresponding to 500 mcg/kg/month or 417-fold the recommended human dose) in studies of embryo-fetal development. 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, corresponding to 50 mcg/kg/month or 42-fold the recommended human dose, 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 (corresponding to 200 mcg/kg/month or 167-fold the recommended human dose) given to pregnant and lactating rats did not adversely affect pregnancy parameters, natural delivery or litter observations in a study of pre-and postnatal development. Increased deaths and significant reduction in the growth rate of the F1 generation were observed during lactation and early post weaning period at 20 and 50 mcg/kg/dose, corresponding to 80 and 200 mcg/kg/month or 67- and 167-fold the recommended human dose. A significant reduction in the growth rate of the F1 generation was evident already at 5 mcg/kg/dose, corresponding to 20 mcg/kg/month or 17-fold the recommended human dose. However, no remarkable effect on reflex, physical and cognitive development or reproductive performance was observed in F1 generation of any dose groups. The dose level not causing any adverse effect on dams or offspring was not determined. 8.2 Lactation Risk Summary There are no data on the presence of methoxy polyethylene glycol-epoetin beta in human milk, the effects on the breastfed child, or the effects on milk production. However, endogenous erythropoietin is present in human milk. In rats, methoxy polyethylene glycol-epoetin beta was present in maternal milk (see Data) . When a drug is present in animal milk, it is likely that the drug will be present in human milk. The lack of clinical data during lactation precludes a clear determination of the risk of Mircera to a child during lactation. Therefore, the developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for Mircera and any pote …

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.

11 DESCRIPTION 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 Lys 52 and Lys 45 , and methoxy polyethylene glycol (PEG) butanoic acid (approximately 30,000 daltons). This results in a total molecular weight of approximately 60,000 daltons. Methoxy polyethylene glycol-epoetin beta is produced in Chinese hamster ovary (CHO) cells using recombinant DNA technology. Mircera is formulated as a sterile, preservative-free protein solution for intravenous or subcutaneous administration. Mircera (methoxy polyethylene glycol-epoetin beta) injection is supplied in prefilled syringes (30 mcg, 50 mcg, 75 mcg, 100 mcg, 120 mcg, 150 mcg, 200 mcg, or 250 mcg in 0.3 mL) and formulated in an aqueous solution containing mannitol (9 mg), methionine (0.447 mg), poloxamer 188 (0.03 mg), sodium phosphate monobasic monohydrate (0.414 mg), and sodium sulfate (1.704 mg). Mircera 360 mcg in 0.6 mL is formulated in an aqueous solution containing mannitol (18 mg), methionine (0.894 mg), poloxamer 188 (0.06 mg), sodium phosphate monobasic monohydrate (0.828 mg), and sodium sulfate (3.408 mg). The solution is clear, colorless to slightly yellowish and the pH is 6.2 ± 0.2.

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 [see Pharmacodynamics ( 12.2 )]. Cases of severe hypertension have been observed following overdose with ESAs [see Warnings and Precautions ( 5.3 )].

16 HOW SUPPLIED/STORAGE AND HANDLING 16.1 How Supplied Mircera (methoxy polyethylene glycol-epoetin beta) injection is available in single-dose prefilled syringes. The syringe plungers are designated with unique colors for each dosage strength. The prefilled syringes are supplied with a 27 gauge, 1⁄2 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-Dose Prefilled Syringe with a Needle Guard A 27 Gauge, 1⁄2 inch Needle is also provided: One Prefilled Syringe/Pack NDC number 30 mcg/0.3 mL NDC 59353-400-09 50 mcg/0.3 mL NDC 59353-401-09 75 mcg/0.3 mL NDC 59353-402-09 100 mcg/0.3 mL NDC 59353-403-09 120 mcg/0.3 mL NDC 59353-407-09 150 mcg/0.3 mL NDC 59353-404-09 200 mcg/0.3 mL NDC 59353-405-09 250 mcg/0.3 mL NDC 59353-406-09 360 mcg/0.6 mL NDC 59353-408-09 16.2 Storage Store Mircera refrigerated 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.