ARANESP

Human erythropoietin with 2 aa substitutions to enhance glycosylation (5 N-linked chains), 165 residues (MW=37 kD).

Produced in

Chinese hamster ovary (CHO) cells by recombinant DNA technology.

For the treatment of anemia (from renal transplants or certain HIV treatment)

Darbepoetin alfa is used in the treatment of anemia.

It is involved in the regulation of erythrocyte differentiation and the maintenance of a physiological level of circulating erythrocyte mass.

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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.

Cases of severe hypertension have been observed following overdose with ESAs.

Aranesp is contraindicated in patients with

Uncontrolled hypertension.

Pure red cell aplasia (PRCA) that begins after treatment with Aranesp or other erythropoietin protein drugs.

Serious allergic reactions to

Uncontrolled hypertension

Pure red cell aplasia (PRCA) that begins after treatment with Aranesp or other erythropoietin protein drugs Serious allergic reactions to Aranesp.

• 0.45 mcg/kg intravenously or subcutaneously weekly, or.

• 0.75 mcg/kg intravenously or subcutaneously every 2 weeks.

• 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.

• 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.

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.

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.

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.

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 is less than 10 g/dL and the following considerations apply: ° The rate of hemoglobin decline indicates the likelihood of requiring a RBC transfusion and, ° Reducing 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 Aranesp, and use the lowest dose of Aranesp sufficient to reduce the need for RBC transfusions.

The recommended starting dose is 0.45 mcg/kg body weight intravenously or subcutaneously given once at four week intervals as appropriate.

For pediatric patients with CKD

Initiate Aranesp treatment when the hemoglobin level is less than 10 g/dL.

If the hemoglobin level approaches or exceeds 12 g/dL, reduce or interrupt the dose of Aranesp.

The recommended starting dose for pediatric patients (less than 18 years) is 0.45 mcg/kg body weight administered as a single subcutaneous or intravenous injection once weekly; patients not receiving dialysis may be initiated at a dose of 0.75 mcg/kg once every 2 weeks.

When treating patients who have chronic kidney disease and cancer, physicians should refer to Warnings and Precautions.

Conversion from Epoetin alfa to Aranesp in patients with CKD on dialysis Aranesp is administered less frequently than epoetin alfa.

Aranesp once weekly in patients who were receiving epoetin alfa to 3 times weekly.

Aranesp once every 2 weeks in patients who were receiving epoetin alfa once weekly.

Estimate the starting weekly dose of

Aranesp for adults and pediatric patients on the basis of the weekly epoetin alfa dose at the time of substitution.

Maintain the route of administration (intravenous or subcutaneous injection).

Table 1.

Doses (mcg/week) for Patients with CKD on Dialysis Based on Previous Epoetin alfa Dose (Units/week) Previous Weekly Epoetin alfa Dose (Units/week) Aranesp Dose (mcg /week ) Adult Pediatric < 1,500 6.25 1,500 to 2,499 6.25 6.25 2,500 to 4,999 12.5 10 5,000 to 10,999 25 20 11,000 to 17,999 40 40 18,000 to 33,999 60 60 34,000 to 89,999 100 100 ≥ 90,000 200 200 For pediatric patients receiving a weekly epoetin alfa dose of < 1,500 Units/week, the available data are insufficient to determine an Aranesp conversion dose.

Conversion from Epoetin alfa to Aranesp in patients with CKD not on dialysis Refer to Table 1.

The dose conversion depicted in

Table 1 does not accurately estimate the once monthly dose of Aranesp. 2.3 Patients on Cancer Chemotherapy Initiate Aranesp in patients on cancer chemotherapy only if the hemoglobin is less than 10 g/dL, and if there is a minimum of two additional months of planned chemotherapy.

Use the lowest dose of Aranesp necessary to avoid RBC transfusions.

The recommended starting dose and schedules are: 2.25 mcg/kg every week subcutaneously until completion of a chemotherapy course. 500 mcg every 3 weeks subcutaneously until completion of a chemotherapy course.

Table 2.

Dose Adjustment Dose Adjustment Weekly Schedule

Every 3 Week Schedule If hemoglobin increases greater than 1 g/dL in any 2-week period or If hemoglobin reaches a level needed to avoid RBC transfusion Reduce dose by 40% Reduce dose by 40% If hemoglobin exceeds a level needed to avoid RBC transfusion Withhold dose until hemoglobin approaches a level where RBC transfusions may be required Reinitiate at a dose 40% below the previous dose Withhold dose until hemoglobin approaches a level where RBC transfusions may be required Reinitiate at a dose 40% below the previous dose If hemoglobin increases by less than 1 g/dL and remains below 10 g/dL after 6 weeks of therapy Increase dose to 4.5 mcg/kg/week No dose adjustment If there is no response as measured by hemoglobin levels or if RBC transfusions are still required after 8 weeks of therapy Following completion of a chemotherapy course Discontinue Aranesp Discontinue Aranesp 2.4 Preparation and Administration The needle cover of the prefilled syringe contains dry natural rubber (a derivative of latex), which may cause allergic reactions.

Do not shake.

Do not use

Aranesp that has been shaken or frozen.

Protect vials and prefilled syringes from light.

Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration.

Do not use any vials or prefilled syringes exhibiting particulate matter or discoloration.

Discard unused portion of

Aranesp in vials or prefilled syringes.

Do not re-enter vial.

Do not dilute

Aranesp and do not administer in conjunction with other drug solutions.

Training should aim to demonstrate to those patients and caregivers how to measure the dose of Aranesp, and the focus should be on ensuring that a patient or caregiver can successfully perform all of the steps in the Instructions for Use for a prefilled syringe.

If a patient or caregiver is not able to demonstrate that they can measure the dose and administer the product successfully, you should consider whether the patient is an appropriate candidate for self-administration of Aranesp or whether the patient would benefit from a different Aranesp presentation.

If a patient or caregiver experiences difficulty measuring the required dose, especially if it is other than the entire contents of the Aranesp prefilled syringe, use of the Aranesp vial may be considered.

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, ½-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).

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.

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.

Aranesp was administered intravenously during organogenesis to pregnant rats (gestational days to 15) and rabbits (gestational days 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).

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 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 were similar between adults and pediatric patients with CKD receiving and not receiving dialysis when Aranesp was used for initial treatment of anemia or patients were transitioned from treatment with epoetin alfa to Aranesp.

Pediatric Patients with Cancer The safety and efficacy of Aranesp in pediatric patients with cancer have not been established.

Of the 1801 patients with CKD in clinical studies of Aranesp, 44% were age and over, while 17% were age and over.

Of the 873 patients in clinical studies receiving Aranesp and concomitant cancer chemotherapy, 45% were age and over, while 14% were age and over.

No differences in safety or efficacy were observed between older and younger patients.