Darbepoetin Alfa (Polysorbate 80)

1.1 Anemia Due to Chronic Kidney Disease

Darbepoetin Alfa (Polysorbate 80) 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

Darbepoetin Alfa (Polysorbate 80) 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

Darbepoetin Alfa (Polysorbate 80) has not been shown to improve quality of life, fatigue, or patient well-being.

Darbepoetin Alfa (Polysorbate 80) 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.

• As a substitute for RBC transfusions in patients who require immediate correction of anemia.

Darbepoetin Alfa (Polysorbate 80) (Darbepoetin Alfa (Polysorbate 80)) is a man-made form of a protein that helps your body produce red blood cells. This protein may be reduced when you have kidney failure or use certain medications. When fewer red blood cells are produced, you can develop a condition called anemia.

Darbepoetin Alfa (Polysorbate 80) is used to treat anemia caused by chemotherapy or chronic kidney disease.

Darbepoetin Alfa (Polysorbate 80) is available to cancer patients only under a special program called APPRISE. You must be registered in the program and understand the risks and benefits of taking this medicine.

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 Darbepoetin Alfa (Polysorbate 80).

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, Darbepoetin Alfa (Polysorbate 80) dose, or dosing strategy that does not increase these risks. Individualize dosing and use the lowest dose of Darbepoetin Alfa (Polysorbate 80) 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 Darbepoetin Alfa (Polysorbate 80) 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 Darbepoetin Alfa (Polysorbate 80) 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 Darbepoetin Alfa (Polysorbate 80) if responsiveness does not improve.

For Adult Patients With CKD on Dialysis:

• Initiate Darbepoetin Alfa (Polysorbate 80) 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 Darbepoetin Alfa (Polysorbate 80).
• 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 Darbepoetin Alfa (Polysorbate 80) 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 Darbepoetin Alfa (Polysorbate 80), and use the lowest dose of Darbepoetin Alfa (Polysorbate 80) 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 Darbepoetin Alfa (Polysorbate 80) 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 Darbepoetin Alfa (Polysorbate 80)
• The recommended starting dose for pediatric patients (less than18 years) is 0.45 mcg/kg body weight administered as a single subcutaneous or intravenous injection once weekly; patients not receiving dialysis may also 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.

Refer patients who self-administer Darbepoetin Alfa (Polysorbate 80) to the Instructions for Use.

Conversion From Epoetin Alfa To Darbepoetin Alfa (Polysorbate 80) In Patients With CKD on Dialysis

Darbepoetin Alfa (Polysorbate 80) is administered less frequently than epoetin alfa.

• Administer Darbepoetin Alfa (Polysorbate 80) once weekly in patients who were receiving epoetin alfa 2 to 3 times weekly.
• Administer Darbepoetin Alfa (Polysorbate 80) once every 2 weeks in patients who were receiving epoetin alfa once weekly.

Estimate the starting weekly dose of Darbepoetin Alfa (Polysorbate 80) 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: Estimated Darbepoetin Alfa (Polysorbate 80) Starting Doses (mcg/week) for Patients with CKD on Dialysis Based on Previous Epoetin alfa Dose (Units/week)

Conversion from Epoetin alfa to Darbepoetin Alfa (Polysorbate 80) 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 Darbepoetin Alfa (Polysorbate 80).

Patients On Cancer Chemotherapy

Initiate Darbepoetin Alfa (Polysorbate 80) 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 Darbepoetin Alfa (Polysorbate 80) necessary to avoid RBC transfusions.

Recommended Starting Dose

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

Dose Adjustment

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 Darbepoetin Alfa (Polysorbate 80) 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 Darbepoetin Alfa (Polysorbate 80) in vials or prefilled syringes. Do not re-enter vial.
• Do not dilute Darbepoetin Alfa (Polysorbate 80) and do not administer in conjunction with other drug solutions.

How supplied

Dosage Forms And Strengths

Darbepoetin Alfa (Polysorbate 80) is available as a polysorbate-containing solution.

• Single-dose vials: 25, 40, 60, 100, 200, 300, and 500 mcg Darbepoetin Alfa (Polysorbate 80)/1 mL, and 150 mcg Darbepoetin Alfa (Polysorbate 80)/0.75 mL
• Single-dose prefilled syringes: 10 mcg Darbepoetin Alfa (Polysorbate 80)/0.4 mL, 25 mcg Darbepoetin Alfa (Polysorbate 80)/0.42 mL, 40 mcg Darbepoetin Alfa (Polysorbate 80)/0.4 mL, 60 mcg Darbepoetin Alfa (Polysorbate 80)/0.3 mL, 100 mcg Darbepoetin Alfa (Polysorbate 80)/0.5 mL, and 150 mcg Darbepoetin Alfa (Polysorbate 80)/0.3 mL, 200 mcg Darbepoetin Alfa (Polysorbate 80)/0.4 mL, 300 mcg Darbepoetin Alfa (Polysorbate 80)/0.6 mL, and 500 mcg Darbepoetin Alfa (Polysorbate 80)/1 mL

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 Darbepoetin Alfa (Polysorbate 80) in the carton until use.

Do not use Darbepoetin Alfa (Polysorbate 80) that has been shaken or frozen.

Darbepoetin Alfa (Polysorbate 80) is available in the following packages:

Single-dose Vial

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

Manufactured by: Amgen Inc., One Amgen Center Drive, Thousand Oaks, CA 91320-1799 U.S.A. Revised: July 2015

See also:
What is the most important information I should know about Darbepoetin Alfa (Polysorbate 80)?

You should not use this medication if you have untreated or uncontrolled high blood pressure, if you are allergic to Darbepoetin Alfa (Polysorbate 80) or epoetin alfa (Epogen or Procrit), or if you have ever had pure red cell aplasia (PRCA, a type of anemia) caused by using either of these two drugs.

Before using Darbepoetin Alfa (Polysorbate 80), tell your doctor if you have heart disease, congestive heart failure, high blood pressure, kidney disease, a blood cell or clotting disorder, cancer, a seizure disorder, a latex allergy, or a history of stroke, heart attack, or blood clots.

This medicine can increase your risk of life-threatening heart or circulation problems, including heart attack or stroke. This risk will increase the longer you use Darbepoetin Alfa (Polysorbate 80). Darbepoetin Alfa (Polysorbate 80) may also shorten remission time or survival time in some people with certain types of cancer. Talk with your doctor about the risks and benefits of using Darbepoetin Alfa (Polysorbate 80).

Seek emergency medical help if you have symptoms of heart or circulation problems, such as chest pain or heavy feeling, pain spreading to the arm or shoulder, shortness of breath, slurred speech, or problems with vision or balance.

To be sure this medication is helping your condition, your blood may need to be tested often. Your blood pressure will also need to be checked. Visit your doctor regularly.

Contact your doctor if you feel light-headed or unusually weak or tired. These may be signs that your body has stopped responding to Darbepoetin Alfa (Polysorbate 80).

Some women using Darbepoetin Alfa (Polysorbate 80) have started having menstrual periods, even after not having a period for a long time due to a medical condition. You may be able to get pregnant if your periods restart. Talk with your doctor about the need for birth control.

Use Darbepoetin Alfa (Polysorbate 80) (polysorbate 80) as directed by your doctor. Check the label on the medicine for exact dosing instructions.

• Darbepoetin Alfa (Polysorbate 80) (polysorbate 80) comes with an extra patient information sheet called a Medication Guide. Read it carefully. Read it again each time you get Darbepoetin Alfa (Polysorbate 80) (polysorbate 80) refilled.
• Darbepoetin Alfa (Polysorbate 80) (polysorbate 80) is usually given as an injection at your doctor's office, hospital, or clinic. If you will be using Darbepoetin Alfa (Polysorbate 80) (polysorbate 80) at home, a health care provider will teach you how to use it. Be sure you understand how to use Darbepoetin Alfa (Polysorbate 80) (polysorbate 80). Follow the procedures you are taught when you use a dose. Contact your health care provider if you have any questions.
• Do not use Darbepoetin Alfa (Polysorbate 80) (polysorbate 80) if it contains particles, is cloudy or discolored, or if the vial is cracked or damaged.
• Do not shake Darbepoetin Alfa (Polysorbate 80) (polysorbate 80). Do not use Darbepoetin Alfa (Polysorbate 80) (polysorbate 80) if it has been shaken.
• Do not use Darbepoetin Alfa (Polysorbate 80) (polysorbate 80) if it has been frozen.
• Do not dilute or mix Darbepoetin Alfa (Polysorbate 80) (polysorbate 80) with any other solutions or medicines.
• Discard any unused portion of medicine left in the vial or syringe.
• Use only disposable syringes and needles. Use the syringes and needles only once and dispose of them in a puncture-proof container as instructed by your health care provider.
• Choose a new site each time you inject Darbepoetin Alfa (Polysorbate 80) (polysorbate 80). Do not inject into an area that is tender, red, bruised, hard, swollen, or has scars or stretch marks.
• Keep this product, as well as syringes and needles, out of the reach of children and pets. Do not reuse needles, syringes, or other materials. Ask your health care provider how to dispose of these materials after use. Follow all local rules for disposal.
• If you miss a dose of Darbepoetin Alfa (Polysorbate 80) (polysorbate 80), contact your doctor right away.

Ask your health care provider any questions you may have about how to use Darbepoetin Alfa (Polysorbate 80) (polysorbate 80).

Use: Labeled Indications

Anemia due to chemotherapy in patients with cancer: Treatment of anemia in patients with nonmyeloid malignancies when anemia is due to the effect of concomitant myelosuppressive chemotherapy, and upon initiation, there is a minimum of 2 additional months of planned chemotherapy.

Anemia due to chronic kidney disease: Treatment of anemia due to chronic kidney disease, including patients on dialysis and patients not on dialysis.

Limitations of use: Darbepoetin Alfa (Polysorbate 80) has not demonstrated improved quality of life, fatigue, or well-being. Darbepoetin Alfa (Polysorbate 80) is not indicated for use under the following conditions:

- Cancer patients receiving hormonal therapy, therapeutic biologic products, or radiation therapy unless also receiving concurrent myelosuppressive chemotherapy

- Cancer patients receiving myelosuppressive chemotherapy when the expected outcome is curative

- Cancer patients receiving myelosuppressive chemotherapy when anemia can be managed by transfusion

- As a substitute for red blood cell (RBC) transfusion in patients requiring immediate correction of anemia

Off Label Uses

Myelodysplastic syndromes, lower-risk (symptomatic anemia management)

Data from 4 studies, a meta-analysis, and a systematic review support the use of Darbepoetin Alfa (Polysorbate 80) (initially as a single agent and then in combination with growth-colony stimulating factor after single-agent failure) in the management of anemia in patients with lower-risk myelodysplastic syndromes.

Based on guidelines from the American Society of Clinical Oncology (ASCO) and the American Society of Hematology (ASH) for management of cancer-associated anemia with erythropoiesis-stimulating agents, erythropoiesis-stimulating agents may be an option for management of anemia in patients with lower-risk myelodysplastic syndromes who have an erythropoietin level ≤500 mU/mL.

See also:
What other drugs will affect Darbepoetin Alfa (Polysorbate 80)?

No formal drug interaction studies have been conducted with Darbepoetin Alfa (Polysorbate 80).

See also:
What are the possible side effects of Darbepoetin Alfa (Polysorbate 80)?

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

• Increased Mortality, Myocardial Infarction, Stroke, and Thromboembolism
• Increased Mortality and/or Increased Risk of Tumor Progression or Recurrence in Patients with Cancer
• Hypertension
• Seizures
• PRCA
• Serious allergic reactions

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 Darbepoetin Alfa (Polysorbate 80) with a total of 1357 patients (Darbepoetin Alfa (Polysorbate 80) 766, epoetin alfa 591). The median duration of exposure for patients receiving Darbepoetin Alfa (Polysorbate 80) was 340 days, with 580 patients exposed for greater than 6 months and 360 patients exposed for greater than 1 year. The median (25th, 75th percentiles) weight-adjusted dose of Darbepoetin Alfa (Polysorbate 80) was 0.50 mcg/kg (0.32, 0.81). The median (range) age for patients administered Darbepoetin Alfa (Polysorbate 80) was 62 years (18 to 88). In the Darbepoetin Alfa (Polysorbate 80) group, 55% were male, 72% were white, 83% were receiving dialysis, and 17% were not receiving dialysis. Table 4 lists adverse reactions occurring in ≥ 5% of patients treated with Darbepoetin Alfa (Polysorbate 80).

Table 4: Adverse Reactions Occurring in ≥ 5% of Patients with CKD

Rates of adverse reactions with Darbepoetin Alfa (Polysorbate 80) 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. In one study, Darbepoetin Alfa (Polysorbate 80) was administered to 81 pediatric patients with CKD who had stable hemoglobin concentrations while previously receiving epoetin alfa. In a second study, Darbepoetin Alfa (Polysorbate 80) 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 Darbepoetin Alfa (Polysorbate 80) were hypertension and convulsions. The most commonly reported adverse reactions were hypertension, injection site pain, rash, and convulsions. Darbepoetin Alfa (Polysorbate 80) 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 Darbepoetin Alfa (Polysorbate 80) in 597 patients (Darbepoetin Alfa (Polysorbate 80) 301, placebo 296) with extensive stage small cell lung cancer (SCLC) receiving platinumbased 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 Europe, and Australia. Patients received Darbepoetin Alfa (Polysorbate 80) at a dose of 300 mcg or placebo weekly for 4 weeks then every 3 weeks for a total of 24 weeks, and the median duration of exposure was 19 weeks (range: 1 to 26 weeks).

Adverse reactions were also based on data from 7 randomized, double-blind, placebo-controlled studies, including the SCLC study described above, that enrolled 2112 patients (Darbepoetin Alfa (Polysorbate 80) 1203, placebo 909) with non-myeloid malignancies. Most patients were white (95%), male (52%), and the median age was 63 years (range: 18 to 91 years); 73% of the study population were from North America, Western Europe, and Australia. Dosing and schedules varied by study from once weekly to once every 4 weeks, and the median duration of exposure was 12 weeks (range: 1 to 27 weeks).

Table 5: Thrombovascular Adverse Reactions in Patients Receiving Chemotherapy

In addition to the thrombovascular adverse reactions, abdominal pain and edema occurred at a higher incidence in patients taking Darbepoetin Alfa (Polysorbate 80) compared to patients on placebo. Among all placebo-controlled studies, abdominal pain (13.2% vs. 9.4%) and edema (12.8% vs. 9.7%) were reported more frequently in patients receiving Darbepoetin Alfa (Polysorbate 80) compared to the placebo group. In the SCLC study the incidence of abdominal pain (10.3% vs. 3.4%) and edema (5.6% vs. 5.1%) in the Darbepoetin Alfa (Polysorbate 80)-treated patients compared to those receiving placebo.

Postmarketing Experience

Because postmarketing reporting of adverse reactions is voluntary and from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

The following adverse reactions have been identified during postmarketing use of Darbepoetin Alfa (Polysorbate 80):

• Seizures
• PRCA
• Serious allergic reactions

Immunogenicity

As with all therapeutic proteins, there is a potential for immunogenicity. Neutralizing antibodies to Darbepoetin Alfa (Polysorbate 80) that cross-react with endogenous erythropoietin and other ESAs can result in PRCA or severe anemia (with or without other cytopenias).

In clinical studies, the percentage of patients with antibodies to Darbepoetin Alfa (Polysorbate 80) was examined using the Biacore® assay. Sera from 1501 patients with CKD and 1159 patients with cancer were tested. At baseline, prior to Darbepoetin Alfa (Polysorbate 80) treatment, binding antibodies were detected in 59 patients (4%) with CKD and 36 patients with cancer (3%). During Darbepoetin Alfa (Polysorbate 80) therapy (range: 22 to 177 weeks), a follow-up sample was taken. One additional patient with CKD and 8 additional patients with cancer developed antibodies capable of binding Darbepoetin Alfa (Polysorbate 80). In two studies of pediatric patients with CKD aged 2-16, 20 of 111 patients with CKD (18%) receiving dialysis and 6 of 69 patients (9%) not receiving dialysis had anti-ESA antibodies at baseline. During therapy, 4 additional patients receiving dialysis and 4 additional patients not receiving dialysis developed antibodies capable of binding Darbepoetin Alfa (Polysorbate 80).

None of the patients had antibodies capable of neutralizing the activity of Darbepoetin Alfa (Polysorbate 80) or endogenous erythropoietin at baseline or at end of study. No clinical sequelae consistent with PRCA were associated with the presence of these antibodies.

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

Darbepoetin Alfa (Polysorbate 80) with the incidence of antibodies to other products may be misleading.

One syringe (0.5 mL) contains the following ingredients: See Table 1.

The active ingredient of this product, Darbepoetin Alfa (Polysorbate 80) (genetical recombination), is produced in Chinese hamster ovary cells.

Darbepoetin Alfa (Polysorbate 80) is a glycoprotein (molecular weight: ca. 36,000) consisting of 165 amino acid residues (C₈₀₀H₁₃₀₀N₂₂₈O₂₄₄S₅, molecular weight: 18,176.59). It is produced in Chinese hamster ovary cells transfected with cDNA of human hepatic cell-derived erythropoietin, which was transformed to change 5 amino acid residues.

Excipients/Inactive Ingredients: Polysorbate 80, L-methionine, sodium dihydrogen phosphate dihydrate, sodium chloride, dibasic sodium phosphate hydrate, water for injection.