ARANESP

1 INDICATIONS AND USAGE Aranesp is an erythropoiesis-stimulating agent (ESA) indicated for the treatment of anemia due to: Chronic Kidney Disease (CKD) in patients on dialysis and patients not on dialysis ( 1.1 ). The effects of concomitant myelosuppressive chemotherapy, and upon initiation, there is a minimum of two additional months of planned chemotherapy ( 1.2 ). Limitations of Use Aranesp has not been shown to improve quality of life, fatigue, or patient well-being ( 1.3 ). Aranesp is not indicated for use: In patients with cancer receiving hormonal agents, biologic products, or radiotherapy, unless also receiving concomitant myelosuppressive chemotherapy ( 1.3 ). In patients with cancer receiving myelosuppressive chemotherapy when the anticipated outcome is cure ( 1.3 ). In patients with cancer receiving myelosuppressive chemotherapy in whom the anemia can be managed by transfusion ( 1.3 ). As a substitute for RBC transfusions in patients who require immediate correction of anemia ( 1.3 ). 1.1 Anemia Due to Chronic Kidney Disease Aranesp is indicated for the treatment of anemia due to chronic kidney disease (CKD), including patients on dialysis and patients not on dialysis. 1.2 Anemia Due to Chemotherapy in Patients with Cancer Aranesp is indicated for the treatment of anemia in patients with non-myeloid malignancies where anemia is due to the effect of concomitant myelosuppressive chemotherapy, and upon initiation, there is a minimum of two additional months of planned chemotherapy. 1.3 Limitations of Use Aranesp has not been shown to improve quality of life, fatigue, or patient well-being. Aranesp is not indicated for use: • In patients with cancer receiving hormonal agents, biologic products, or radiotherapy, unless also receiving concomitant myelosuppressive chemotherapy. • In patients with cancer receiving myelosuppressive chemotherapy when the anticipated outcome is cure. • In patients with cancer receiving myelosuppressive chemotherapy in whom the anemia can be managed by transfusion. • As a substitute for RBC transfusions in patients who require immediate correction of anemia.

2 DOSAGE AND ADMINISTRATION Recommended starting dose for patients with CKD on dialysis ( 2.2 ): - 0.45 mcg/kg intravenously or subcutaneously weekly, or - 0.75 mcg/kg intravenously or subcutaneously every 2 weeks - Intravenous route is recommended for patients on hemodialysis Recommended starting dose for patients with CKD not on dialysis ( 2.2 ): - 0.45 mcg/kg intravenously or subcutaneously at 4 week intervals Recommended starting dose for pediatric patients with CKD: - 0.45 mcg/kg intravenously or subcutaneously weekly - patients with CKD not on dialysis may also be initiated at 0.75 mcg/kg every 2 weeks Recommended starting dose for patients with cancer on chemotherapy ( 2.3 ): - 2.25 mcg/kg subcutaneously weekly, or - 500 mcg subcutaneously every 3 weeks 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 Aranesp. 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. 2.2 Patients with 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. No trial has identified a hemoglobin target level, Aranesp dose, or dosing strategy that does not increase these risks. Individualize dosing and use the lowest dose of Aranesp sufficient to reduce the need for RBC transfusions [see Warnings and Precautions ( 5.1 )] . 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 Aranesp 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 Aranesp 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 Aranesp if responsiveness does not improve. For adult patients with CKD on dialysis : Initiate Aranesp 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 Aranesp. The recommended starting dose is 0.45 mcg/kg intravenously or subcutaneously as a weekly injection or 0.75 mcg/kg once every 2 weeks as appropriate. The intravenous route is recommended for patients on hemodialysis. For adult patients with CKD not on dialysis : Consider initiating Aranesp treatment only when the hemoglobin level …

3 DOSAGE FORMS AND STRENGTHS Aranesp is a clear, colorless solution available as: Single - dose vials Injection: 25 mcg, 40 mcg, 60 mcg, 100 mcg, and 200 mcg Single - dose prefilled syringes Injection: 10 mcg/0.4 mL, 25 mcg/0.42 mL, 40 mcg/0.4 mL, 60 mcg/0.3 mL, 100 mcg/0.5 mL, 150 mcg/0.3 mL, 200 mcg/0.4 mL, 300 mcg/0.6 mL, and 500 mcg/1 mL Single - dose vials Injection: 25 mcg, 40 mcg, 60 mcg, 100 mcg, and 200 mcg ( 3 ). Single - dose prefilled syringes Injection: 10 mcg/0.4 mL, 25 mcg/0.42 mL, 40 mcg/0.4 mL, 60 mcg/0.3 mL, 100 mcg/0.5 mL, 150 mcg/0.3 mL, 200 mcg/0.4 mL, 300 mcg/0.6 mL, and 500 mcg/1 mL ( 3 ).

4 CONTRAINDICATIONS Aranesp is contraindicated in patients with: Uncontrolled hypertension [see Warnings and Precautions ( 5.3 )] . Pure red cell aplasia (PRCA) that begins after treatment with Aranesp or other erythropoietin protein drugs [see Warnings and Precautions ( 5.6 )] . Serious allergic reactions to Aranesp [see Warnings and Precautions ( 5.7 )] . Uncontrolled hypertension ( 4 ) Pure red cell aplasia (PRCA) that begins after treatment with Aranesp or other erythropoietin protein drugs ( 4 ) Serious allergic reactions to Aranesp ( 4 )

6 ADVERSE REACTIONS The following clinically significant adverse reactions are discussed in greater detail in other sections of the label: Increased Mortality, Myocardial Infarction, Stroke, and Thromboembolism [see Warnings and Precautions ( 5.1 )] Increased Mortality and/or Increased Risk of Tumor Progression or Recurrence 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 )] Patients with CKD: Adverse reactions in ≥ 10% of Aranesp-treated patients in clinical studies were hypertension, dyspnea, peripheral edema, cough, and procedural hypotension ( 6.1 ). Patients with Cancer Receiving Chemotherapy: Adverse reactions in ≥ 1% of Aranesp-treated patients in clinical studies were abdominal pain, edema, and thrombovascular events ( 6.1 ). To report SUSPECTED ADVERSE REACTIONS, contact Amgen Medical Information at 1-800-77-AMGEN (1-800-772-6436) or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 Clinical Trial Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of other drugs and may not reflect the rates observed in practice. Patients with Chronic Kidney Disease Adult Patients Adverse reactions were determined based on pooled data from 5 randomized, active-controlled studies of Aranesp with a total of 1357 patients (Aranesp 766, epoetin alfa 591). The median duration of exposure for patients receiving Aranesp was 340 days, with 580 patients exposed for greater than 6 months and 360 patients exposed for greater than 1 year. The median (25 th , 75 th percentiles) weight-adjusted dose of Aranesp was 0.50 mcg/kg (0.32, 0.81). The median (range) age for patients administered Aranesp was 62 years (18 to 88). In the Aranesp group, 55% were male, 72% were white, 83% were receiving dialysis, and 17% were not receiving dialysis. Table 5 lists adverse reactions occurring in ≥ 5% of patients treated with Aranesp. Table 5. Adverse Reactions Occurring in ≥ 5% of Patients with CKD Adverse Reaction Patients Treated w ith Aranesp (n = 766) Hypertension 31% Dyspnea 17% Peripheral edema 17% Cough 12% Procedural hypotension 10% Angina pectoris 8% Vascular access complications 8% Fluid overload 7% Rash/Erythema 5% Arteriovenous graft thrombosis 5% Rates of adverse reactions with Aranesp therapy were similar to those observed with other recombinant erythropoietins in these studies. Pediatric Patients Adverse reactions were determined based on pooled data from 2 randomized, controlled trials [see Clinical Studies ( 14.1 )] . In one study, Aranesp was administered to 81 pediatric patients with CKD who had stable hemoglobin concentrations while previously receiving epoetin alfa. In a second study, Aranesp was administered to 114 anemic pediatric patients with CKD receiving or not receiving dialysis for initial treatment of anemia. In these studies, the most frequently reported serious adverse reactions with Aranesp were hypertension and convulsions. The most commonly reported adverse reactions were hypertension, injection site pain, rash, and convulsions. Aranesp administration was discontinued because of injection site pain in 2 patients and hypertension in 3 patients. Patients with Cancer Receiving Chemotherapy Adverse reactions were based on data from a randomized, double-blind, placebo-controlled study of Aranesp in 597 patients (Aranesp 301, placebo 296) with extensive stage small cell lung cancer (SCLC) receiving platinum-based chemotherapy. All patients were white, 64% were male, and the median age was 61 years (range: 28 to 82 years); 25% of the study population were from North America, Western …

8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Risk Summary The limited available data on Aranesp use in pregnant women are insufficient to determine a drug-associated risk of major birth defects or miscarriage. In animal reproductive and developmental toxicity studies, Aranesp increased early post-implantation loss at doses approximating the clinical recommended starting doses [ see Data ] . Consider the benefits and risks of Aranesp for the mother and possible risks to the fetus when prescribing Aranesp to a pregnant woman. 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 2-4% and 15-20%, respectively. Data Animal Data When Aranesp was administered intravenously during organogenesis to pregnant rats (gestational days 6 to 15) and rabbits (gestational days 6 to 18), there was no evidence of embryofetal toxicity or other adverse outcomes at the intravenous doses tested, up to 20 mcg/kg/day. This animal dose level of 20 mcg/kg/day is approximately 20-fold higher than the clinical recommended starting dose, depending on the patient’s treatment indication. Slightly reduced fetal weights were observed when rat and rabbit mothers received doses of 1 mcg/kg or more, causing exaggerated pharmacological effects in both the rat and rabbit dams. This dose of 1 mcg/kg is near the clinical recommended starting dose. While no adverse effects on uterine implantation occurred in animals, in a rat fertility study, there was an increase in early post-implantation loss at doses equal to or greater than 0.5 mcg/kg, administered 3 times weekly. It is not clear whether the increased post-implantation loss reflects a drug effect on the uterine environment or on the conceptus. No significant placental transfer of Aranesp was observed in rats; placental transfer was not evaluated in rabbits. In a peri/postnatal development study, pregnant female rats received Aranesp intravenously every other day from implantation (day 6) throughout pregnancy and lactation (day 23). The lowest dose tested, 0.5 mcg/kg, did not cause fetal toxicity; this dose is approximately equivalent to the clinical recommended starting dose. At maternal doses of 2.5 mcg/kg and higher, pups had decreased fetal body weights, which correlated with a slight increase in the incidence of fetal deaths, as well as delayed eye opening and delayed preputial separation. The offspring (F1 generation) of the treated rats were observed postnatally; rats from the F1 generation reached maturity and were mated; no Aranesp related effects were apparent for their offspring (F2 generation fetuses). 8.2 Lactation Risk Summary There is no information regarding the presence of Aranesp in human milk, the effects on the breastfed child, or the effects on milk production. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for Aranesp and any potential adverse effects on the breastfed child from Aranesp or from the underlying maternal condition. 8.4 Pediatric Use Pediatric Patients with CKD The safety and effectiveness of Aranesp in pediatric patients with CKD receiving and not receiving dialysis have been established in the age groups 1 month to 16 years old. No data are available in pediatric patients less than 1 month old. Use of Aranesp in these age groups is supported by evidence from adequate and well-controlled studies of Aranesp in adults with additional data from a randomized trial evaluating two schedules (weekly and every 2 week dosing) in 114 pediatric patients 1 to 16 years of age receiving darbepoetin alfa, and an observational registry study in 319 pediatric patients < 1 to 16 years of age receiving darbepoetin alfa. Aranesp safety and efficacy wer …

12.1 Mechanism of Action Aranesp stimulates erythropoiesis by the same mechanism as endogenous erythropoietin.

11 DESCRIPTION Darbepoetin alfa is an erythropoiesis-stimulating protein that is produced in Chinese hamster ovary (CHO) cells by recombinant DNA technology. Darbepoetin alfa is a 165-amino acid protein that differs from recombinant human erythropoietin in containing 5 N-linked oligosaccharide chains, whereas recombinant human erythropoietin contains 3 chains. The 2 additional N-glycosylation sites result from amino acid substitutions in the erythropoietin peptide backbone. The approximate molecular weight of darbepoetin alfa is 37,000 daltons. Aranesp (darbepoetin alfa) injection is formulated as a sterile, colorless, preservative-free solution containing polysorbate for intravenous or subcutaneous administration. Each 1 mL contains polysorbate 80 (0.05 mg), sodium chloride (8.18 mg), sodium phosphate dibasic anhydrous (0.66 mg), and sodium phosphate monobasic monohydrate (2.12 mg) in Water for Injection, USP (pH 6.2 ± 0.2).

10 OVERDOSAGE Aranesp overdosage can cause hemoglobin levels above the desired level, which should be managed with discontinuation or reduction of Aranesp dosage and/or with phlebotomy, as clinically indicated [see Clinical Pharmacology ( 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 Store at 36°F to 46°F (2°C to 8°C). Do not freeze. Do not shake. Protect from light; store Aranesp in the carton until use. Do not use Aranesp that has been shaken or frozen. Aranesp is a clear, colorless solution available in the following packages: Single - dose Vial 1 Vial/Pack, 4 Packs/Case 4 Vials/Pack, 10 Packs/Case 200 mcg/1 mL (NDC 55513-006-01) (NDC 55513-006-21) 25 mcg/1 mL (NDC 55513-002-04) 40 mcg/1 mL (NDC 55513-003-04) 60 mcg/1 mL (NDC 55513-004-04) 100 mcg/1 mL (NDC 55513-005-04) Single - dose Prefilled Syringe (SingleJect ® ) with a 27-gauge, 1⁄2-inch needle with an UltraSafe ® Needle Guard that is manually activated to cover the needle during disposal 1 Syringe/Pack, 4 Packs/Case 4 Syringes/Pack, 10 Packs/Case 200 mcg/0.4 mL (NDC 55513-028-01) 10 mcg/0.4 mL (NDC 55513-098-04) 300 mcg/0.6 mL (NDC 55513-111-01) 25 mcg/0.42 mL (NDC 55513-057-04) 500 mcg/1 mL (NDC 55513-032-01) 40 mcg/0.4 mL (NDC 55513-021-04) 60 mcg/0.3 mL (NDC 55513-023-04) 100 mcg/0.5 mL (NDC 55513-025-04) 150 mcg/0.3 mL (NDC 55513-027-04)