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`ARANESP(cid:228)
`(darbepoetin alfa)
`For Injection
`
`DESCRIPTION
`Aranesp(cid:212)
` is an erythropoiesis stimulating protein, closely related to erythropoietin, that
`is produced in Chinese hamster ovary (CHO) cells by recombinant DNA technology.
`Aranesp(cid:212)
` 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 (Egrie 2001). The 2 additional N-glycosylation
`sites result from amino acid substitutions in the erythropoietin peptide backbone. The
`additional carbohydrate chains increase the approximate molecular weight of the
`glycoprotein from 30,000 to 37,000 daltons. Aranesp(cid:212)
` is formulated as a sterile,
`colorless, preservative-free protein solution for intravenous (IV) or subcutaneous (SC)
`administration.
`Single-dose vials are available containing 25, 40, 60, 100, 150, 200, 300, or 500 mcg of
`Aranesp(cid:212)
`. Two formulations contain excipients as follows:
`Polysorbate solution contains 0.05 mg polysorbate 80, 2.12 mg sodium phosphate
`monobasic monohydrate, 0.66 mg sodium phosphate dibasic anhydrous, and
`8.18 mg sodium chloride in Water for Injection, USP (per 1 mL) at pH 6.2 –
` 0.2.
`Albumin solution contains 2.5 mg albumin (human), 2.23 mg sodium phosphate
`monobasic monohydrate, 0.53 mg sodium phosphate dibasic anhydrous, and 8.18 mg
`sodium chloride in Water for Injection, USP (per 1 mL) at pH 6.0 –
` 0.3.
`
`CLINICAL PHARMACOLOGY
`Mechanism of Action
`Aranesp(cid:212)
` stimulates erythropoiesis by the same mechanism as endogenous
`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 progenitor stem cells to increase red
`cell production. Production of endogenous erythropoietin is impaired in patients with
`chronic renal failure (CRF), and erythropoietin deficiency is the primary cause of their
`anemia. Increased hemoglobin levels are not generally observed until 2 to 6 weeks after
`initiating treatment with Aranesp(cid:212)
` (see DOSAGE AND ADMINISTRATION: Dose
`Adjustment). In patients with cancer receiving concomitant chemotherapy, the etiology
`of anemia is multifactorial.
`
`Amgen Thousand Oaks
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`Ex. 1029 - Page 1 of 22
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`AMGEN INC.
`Exhibit 1029
`
`

`
`Amgen
`darbepoetin alfa
`
`
`
`Page 1 of 21
`
`ARANESP(cid:228)
`(darbepoetin alfa)
`For Injection
`
`DESCRIPTION
`Aranesp(cid:212)
` is an erythropoiesis stimulating protein, closely related to erythropoietin, that
`is produced in Chinese hamster ovary (CHO) cells by recombinant DNA technology.
`Aranesp(cid:212)
` 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 (Egrie 2001). The 2 additional N-glycosylation
`sites result from amino acid substitutions in the erythropoietin peptide backbone. The
`additional carbohydrate chains increase the approximate molecular weight of the
`glycoprotein from 30,000 to 37,000 daltons. Aranesp(cid:212)
` is formulated as a sterile,
`colorless, preservative-free protein solution for intravenous (IV) or subcutaneous (SC)
`administration.
`Single-dose vials are available containing 25, 40, 60, 100, 150, 200, 300, or 500 mcg of
`Aranesp(cid:212)
`. Two formulations contain excipients as follows:
`Polysorbate solution contains 0.05 mg polysorbate 80, 2.12 mg sodium phosphate
`monobasic monohydrate, 0.66 mg sodium phosphate dibasic anhydrous, and
`8.18 mg sodium chloride in Water for Injection, USP (per 1 mL) at pH 6.2 –
` 0.2.
`Albumin solution contains 2.5 mg albumin (human), 2.23 mg sodium phosphate
`monobasic monohydrate, 0.53 mg sodium phosphate dibasic anhydrous, and 8.18 mg
`sodium chloride in Water for Injection, USP (per 1 mL) at pH 6.0 –
` 0.3.
`
`CLINICAL PHARMACOLOGY
`Mechanism of Action
`Aranesp(cid:212)
` stimulates erythropoiesis by the same mechanism as endogenous
`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 progenitor stem cells to increase red
`cell production. Production of endogenous erythropoietin is impaired in patients with
`chronic renal failure (CRF), and erythropoietin deficiency is the primary cause of their
`anemia. Increased hemoglobin levels are not generally observed until 2 to 6 weeks after
`initiating treatment with Aranesp(cid:212)
` (see DOSAGE AND ADMINISTRATION: Dose
`Adjustment). In patients with cancer receiving concomitant chemotherapy, the etiology
`of anemia is multifactorial.
`
`Amgen Thousand Oaks
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`Ex. 1029 - Page 2 of 22
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`

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`Amgen
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`Page 2 of 21
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`Pharmacokinetics
`The pharmacokinetics of Aranesp(cid:212)
` were studied in patients with chronic renal failure
`and cancer patients receiving chemotherapy.
`Over the therapeutic range of 0.45 to 4.5 mcg/kg, pharmacokinetic measures (Cmax,
`half-life, AUC) were linear with respect to dose and no evidence of accumulation was
`observed beyond an expected < 2-fold increase in blood levels when compared to the
`initial dose.
`Following subcutaneous (SC) administration, absorption is slow and rate limiting. The
`observed half-life in CRF patients, which reflected the rate of absorption, was 49 hours
`(range: 27 to 89 hours). Following IV administration to these patients, Aranesp(cid:212)
` serum
`concentration-time profiles are biphasic, with a distribution half-life of approximately
`1.4 hours and the mean terminal half-life of 21 hours. Post SC administration, CRF
`patients’ peak concentrations occur at 34 hours (range: 24 to 72 hours) whereas cancer
`patients’ peak concentrations are at 90 hours (range: 71 to 123 hours).
`When administered by IV administration, the terminal half-life of Aranesp(cid:212)
` is
`approximately 3-fold longer than Epoetin alfa. The bioavailability of Aranesp(cid:212)
` as
`measured in CRF patients after SC administration is 37% (range: 30% to 50%).
`
`CLINICAL STUDIES
`Throughout this section of the package insert, the Aranesp(cid:212)
` study numbers associated
`with the nephrology and cancer clinical programs are designated with the letters “N” and
`“C”, respectively.
`Chronic Renal Failure Patients
`The safety and effectiveness of Aranesp(cid:212)
` have been assessed in multicenter studies.
`Two studies evaluated the safety and efficacy of Aranesp(cid:212)
` for the correction of anemia
`in adult patients with CRF, and 2 studies assessed the ability of Aranesp(cid:212)
` to maintain
`hemoglobin concentrations in adult patients with CRF who had been receiving other
`recombinant erythropoietins.
`De Novo Use of Aranesp(cid:228)
`In 2 open-label studies, Aranesp(cid:212)
` or Epoetin alfa were administered for the correction of
`anemia in CRF patients who had not been receiving prior treatment with exogenous
`erythropoietin. Study N1 evaluated CRF patients receiving dialysis; Study N2 evaluated
`patients not requiring dialysis (predialysis patients). In both studies, the starting dose of
`Aranesp™ was 0.45 mcg/kg administered once weekly. The starting dose of Epoetin alfa
`was 50 U/kg 3 times weekly in Study N1 and 50 U/kg twice weekly in Study N2. When
`necessary, dosage adjustments were instituted to maintain hemoglobin in the study target
`range of 11 to 13 g/dL. (Note: The recommended hemoglobin target is lower than the
`target range of these studies. See DOSAGE AND ADMINISTRATION: General for
`
`Amgen Thousand Oaks
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`recommended clinical hemoglobin target.) The primary efficacy endpoint was the
`proportion of patients who experienced at least a 1.0 g/dL increase in hemoglobin
`concentration to a level of at least 11.0 g/dL by 20 weeks (Study N1) or 24 weeks
`(Study N2). The studies were designed to assess the safety and effectiveness of
`Aranesp(cid:212)
`, but not to support conclusions regarding comparisons between the two
`products.
`In Study N1, the hemoglobin target was achieved by 72% (95% CI: 62%, 81%) of the
`90 patients treated with Aranesp(cid:212)
` and 84% (95% CI: 66%, 95%) of the 31 patients
`treated with Epoetin alfa. The mean increase in hemoglobin over the initial 4 weeks of
`Aranesp(cid:212)
` treatment was 1.10 g/dL (95% CI: 0.82 g/dL, 1.37 g/dL).
`In Study N2, the primary efficacy endpoint was achieved by 93% (95% CI: 87%, 97%)
`of the 129 patients treated with Aranesp(cid:212)
` and 92% (95% CI: 78%, 98%) of the
`37 patients treated with Epoetin alfa. The mean increase in hemoglobin from baseline
`through the initial 4 weeks of Aranesp(cid:212)
` treatment was 1.38 g/dL (95% CI: 1.21 g/dL,
`1.55 g/dL).
`Conversion From Other Recombinant Erythropoietins
`Two studies (Studies N3 and N4) were conducted in adult patients with CRF who had
`been receiving other recombinant erythropoietins and compared the abilities of
`Aranesp(cid:212)
` and other erythropoietins to maintain hemoglobin concentrations within a
`study target range of 9 to 13 g/dL. (Note: The recommended hemoglobin target is lower
`than the target range of these studies. See DOSAGE AND ADMINISTRATION: General
`for recommended clinical hemoglobin target.) CRF patients who had been receiving
`stable doses of other recombinant erythropoietins were randomized to Aranesp(cid:212)
`, or to
`continue with their prior erythropoietin at the previous dose and schedule. For patients
`randomized to Aranesp(cid:212)
`, the initial weekly dose was determined on the basis of the
`previous total weekly dose of recombinant erythropoietin. Study N3 was a double-blind
`study conducted in North America, in which 169 hemodialysis patients were randomized
`to treatment with Aranesp(cid:212)
` and 338 patients continued on Epoetin alfa. Study N4 was
`an open-label study conducted in Europe and Australia in which 347 patients were
`randomized to treatment with Aranesp(cid:212)
` and 175 patients were randomized to continue
`on Epoetin alfa or Epoetin beta. Of the 347 patients randomized to Aranesp(cid:212)
`, 92% were
`receiving hemodialysis and 8% were receiving peritoneal dialysis.
`In Study N3, a median weekly dose of 0.53 mcg/kg Aranesp(cid:212)
` (25th, 75th percentiles:
`0.30, 0.93 mcg/kg) was required to maintain hemoglobin in the study target range. In
`Study N4, a median weekly dose of 0.41 mcg/kg Aranesp(cid:212)
` (25th, 75th percentiles: 0.26,
`0.65 mcg/kg) was required to maintain hemoglobin in the study target range.
`
`
`Amgen Thousand Oaks
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`Ex. 1029 - Page 4 of 22
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`Page 4 of 21
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`Cancer Patients Receiving Chemotherapy
`The safety and effectiveness of Aranesp(cid:212)
` in reducing the requirement for red blood cell
`(RBC) transfusions in patients undergoing chemotherapy were assessed in a randomized,
`placebo-controlled, double-blind, multinational study (C1). This study was conducted in
`anemic (Hgb = 11 g/dL) patients with advanced, small cell or non-small cell lung cancer,
`who received a platinum-containing chemotherapy regimen. Patients were randomized to
`receive Aranesp(cid:212)
` 2.25 mcg/kg (n = 156) or placebo (n = 158) administered as a single
`weekly SC injection for up to 12 weeks. The dose was escalated to 4.5 mcg/kg/week at
`week six, in subjects with an inadequate response to treatment, defined as less than
`1 g/dL hemoglobin increase. There were 67 patients in the Aranesp(cid:212)
` arm who had their
`dose increased from 2.25 to 4.5 mcg/kg/week, at any time during the treatment period.
`Efficacy was determined by a reduction in the proportion of patients who were transfused
`over the 12 week treatment period. A significantly lower proportion of patients in the
`Aranesp(cid:212)
` arm, 26% (95% CI: 20, 33) required transfusion compared to 60% (95% CI:
`52, 68) in the placebo arm (Kaplan-Meier estimate of proportion; p < 0.001 by Cochran -
`Mantel - Haenszel test). Of the 67 patients who received a dose increase, 28% had a 2
`g/dL increase in hemoglobin over baseline, generally occurring between weeks 8 to 13.
`Of the 89 patients who did not receive a dose increase, 69% had a 2 g/dL increase in
`hemoglobin over baseline, generally occurring between weeks 6 to 13.
`Studies were conducted that evaluated doses of Aranesp(cid:212)
` ranging from 0.5 mcg/kg to
`8.0 mcg/kg administered weekly. Data from these studies indicate that there is a dose
`response relationship with respect to hemoglobin response. The minimally effective
`starting dose with respect to reducing transfusion requirements was 1.5 mcg/kg/week
`with a plateau observed at 4.5 mcg/kg/week.
`
`
`
`INDICATIONS AND USAGE
`Aranesp(cid:212)
` is indicated for the treatment of anemia associated with chronic renal failure,
`including patients on dialysis and patients not on dialysis, and for the treatment of anemia
`in patients with non-myeloid malignancies where anemia is due to the effect of
`concomitantly administered chemotherapy.
`
`CONTRAINDICATIONS
`Aranesp(cid:212)
` is contraindicated in patients with:
`• Uncontrolled hypertension
`• Known hypersensitivity to the active substance or any of the excipients
`
`
`
`Amgen Thousand Oaks
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`Ex. 1029 - Page 5 of 22
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`Page 5 of 21
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`WARNINGS
`Cardiovascular Events, Hemoglobin, and Rate of Rise of Hemoglobin
`Aranesp(cid:212)
` and other erythropoietic therapies may increase the risk of cardiovascular
`events, including death. The higher risk of cardiovascular events may be associated with
`higher hemoglobin and/or higher rates of rise of hemoglobin. The hemoglobin level
`should be managed carefully to avoid exceeding a target level of 12 g/dL.
`In a clinical trial of Epoetin alfa (rHuEPO) treatment in hemodialysis patients with
`clinically evident cardiac disease, patients were randomized to a target hemoglobin of
`either 14 –
` 1 g/dL or 10 –
` 1 g/dL (Besarab 1998). Higher mortality (35% versus 29%)
`was observed in the 634 patients randomized to a target hemoglobin of 14 g/dL than in
`the 631 patients assigned a target hemoglobin of 10 g/dL. The reason for the increased
`mortality observed in this study is unknown; however, the incidence of nonfatal
`myocardial infarction, vascular access thrombosis, and other thrombotic events was also
`higher in the group randomized to a target hemoglobin of 14 g/dL.
`In patients treated with Aranesp(cid:212)
` or other recombinant erythropoietins in Aranesp(cid:212)
`
`clinical trials, increases in hemoglobin greater than approximately 1.0 g/dL during any
`2-week period were associated with increased incidence of cardiac arrest, neurologic
`events (including seizures and stroke), exacerbations of hypertension, congestive heart
`failure, vascular thrombosis/ischemia/infarction, acute myocardial infarction, and fluid
`overload/edema. It is recommended that the dose of Aranesp(cid:212)
` be decreased if the
`hemoglobin increase exceeds 1.0 g/dL in any 2-week period, because of the association
`of excessive rate of rise of hemoglobin with these events.
`
`Hypertension
`Patients with uncontrolled hypertension should not be treated with Aranesp(cid:212)
`; blood
`pressure should be controlled adequately before initiation of therapy. Blood pressure
`may rise during treatment of anemia with Aranesp(cid:212)
` or Epoetin alfa. In Aranesp(cid:212)
`
`clinical trials, approximately 40% of patients with CRF required initiation or
`intensification of antihypertensive therapy during the early phase of treatment when the
`hemoglobin was increasing. Hypertensive encephalopathy and seizures have been
`observed in patients with CRF treated with Aranesp(cid:212)
` or Epoetin alfa.
`Special care should be taken to closely monitor and control blood pressure in patients
`treated with Aranesp(cid:212)
`. During Aranesp(cid:212)
` therapy, patients should be advised of the
`importance of compliance with antihypertensive therapy and dietary restrictions. If blood
`pressure is difficult to control by pharmacologic or dietary measures, the dose of
`Aranesp(cid:212)
` should be reduced or withheld (see DOSAGE AND ADMINISTRATION:
`Dose Adjustment). A clinically significant decrease in hemoglobin may not be observed
`for several weeks.
`
`
`Amgen Thousand Oaks
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`Ex. 1029 - Page 6 of 22
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`Page 6 of 21
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`
`
`Seizures
`Seizures have occurred in patients with CRF participating in clinical trials of Aranesp(cid:212)
`and Epoetin alfa. During the first several months of therapy, blood pressure and the
`presence of premonitory neurologic symptoms should be monitored closely. While the
`relationship between seizures and the rate of rise of hemoglobin is uncertain, it is
`recommended that the dose of Aranesp(cid:212)
` be decreased if the hemoglobin increase
`exceeds 1.0 g/dL in any 2-week period.
`
`Thrombotic Events
`An increased incidence of thrombotic events has been observed in patients treated with
`erythropoietic agents. In patients with cancer who received Aranesp(cid:212)
`, pulmonary
`emboli, thrombophlebitis and thrombosis occurred more frequently than in placebo
`controls (see ADVERSE REACTIONS: Cancer Patients Receiving Chemotherapy,
`Table 4).
`
`Pure Red Cell Aplasia
`Pure red cell aplasia (PRCA), in association with neutralizing antibodies to native
`erythropoietin has been observed in patients treated with recombinant erythropoietins.
`This has been reported predominantly in patients with CRF. PRCA has been reported in
`a limited number of subjects exposed to other recombinant erythropoietin products prior
`to exposure to Aranesp(cid:212)
` therefore, the contribution of Aranesp(cid:212)
` to the development of
`PRCA is unclear. Any patient with loss of response to Aranesp(cid:212)
` should be evaluated for
`the etiology of loss of effect (See PRECAUTIONS: General). Aranesp(cid:212)
` should be
`discontinued in any patient with evidence of PRCA and the patient evaluated for the
`presence of binding and neutralizing antibodies to Aranesp(cid:212)
`, native erythropoietin, and
`any other recombinant erythropoietin administered to the patient. Amgen may be
`contacted to assist in this evaluation. In patients with PRCA secondary to neutralizing
`antibodies to erythropoietin, Aranesp(cid:212)
` should not be administered.
`
`Albumin (Human)
`Aranesp(cid:212)
` is supplied in 2 formulations with different excipients, one containing
`polysorbate 80 and another containing albumin (human), a derivative of human blood
`(see DESCRIPTION). Based on effective donor screening and product manufacturing
`processes, Aranesp(cid:212)
` formulated with albumin carries an extremely remote risk for
`transmission of viral diseases. A theoretical risk for transmission of Creutzfeldt-Jakob
`disease (CJD) also is considered extremely remote. No cases of transmission of viral
`diseases or CJD have ever been identified for albumin.
`.
`
`Amgen Thousand Oaks
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`Ex. 1029 - Page 7 of 22
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`Page 7 of 21
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`PRECAUTIONS
`General
`The safety and efficacy of Aranesp(cid:212)
` therapy have not been established in patients with
`underlying hematologic diseases (e.g., hemolytic anemia, sickle cell anemia, thalassemia,
`porphyria).
`
`Lack or Loss of Response to Aranesp(cid:228)
`
`A lack of response or failure to maintain a hemoglobin response with Aranesp(cid:212)
` doses
`within the recommended dosing range should prompt a search for causative factors.
`Deficiencies of folic acid or vitamin B12 should be excluded or corrected. Depending on
`the clinical setting, intercurrent infections, inflammatory or malignant processes,
`osteofibrosis cystica, occult blood loss, hemolysis, severe aluminum toxicity, and bone
`marrow fibrosis may compromise an erythropoietic response. In the absence of another
`etiology, the patient should be evaluated for evidence of pure red cell aplasia and sera
`should be tested for the presence of antibody to recombinant erythropoietins.
`Hematology
`Sufficient time should be allowed to determine a patient’s responsiveness to a dosage of
`Aranesp(cid:212)
` before adjusting the dose. Because of the time required for erythropoiesis and
`the red cell half-life, an interval of 2 to 6 weeks may occur between the time of a dose
`adjustment (initiation, increase, decrease, or discontinuation) and a significant change in
`hemoglobin.
`In order to prevent the hemoglobin from exceeding the recommended target (12 g/dL) or
`rising too rapidly (greater than 1.0 g/dL in 2 weeks), the guidelines for dose and
`frequency of dose adjustments should be followed (see WARNINGS, DOSAGE AND
`ADMINISTRATION: Dose Adjustment).
`Allergic Reactions
`There have been rare reports of potentially serious allergic reactions including skin rash
`and urticaria associated with Aranesp(cid:212)
`. Symptoms have recurred with rechallenge,
`suggesting a causal relationship exists in some instances. If a serious allergic or
`anaphylactic reaction occurs, Aranesp(cid:212)
` should be immediately and permanently
`discontinued and appropriate therapy should be administered.
`
`Patients With CRF Not Requiring Dialysis
`Patients with CRF not yet requiring dialysis may require lower maintenance doses of
`Aranesp(cid:212)
` than patients receiving dialysis. Though predialysis patients generally receive
`less frequent monitoring of blood pressure and laboratory parameters than dialysis
`patients, predialysis patients may be more responsive to the effects of Aranesp(cid:212)
`, and
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`require judicious monitoring of blood pressure and hemoglobin. Renal function and fluid
`and electrolyte balance should also be closely monitored.
`Dialysis Management
`Therapy with Aranesp(cid:212)
` results in an increase in RBCs and a decrease in plasma volume,
`which could reduce dialysis efficiency; patients who are marginally dialyzed may require
`adjustments in their dialysis prescription.
`
`Growth Factor Potential
`Aranesp(cid:212)
` is a growth factor that primarily stimulates RBC production. The possibility
`that Aranesp(cid:212)
` can act as a growth factor for any tumor type, particularly myeloid
`malignancies, has not been evaluated. In the randomized, placebo-controlled study in
`314 subjects with advanced lung cancer, there were no statistically significant differences
`in time-to-progression (TTP) or overall survival (OS) observed, however the study was
`not designed to detect or exclude clinically meaningful differences in either TTP or OS.
`
`Laboratory Tests
`After initiation of Aranesp(cid:212)
` therapy, the hemoglobin should be determined weekly until
`it has stabilized and the maintenance dose has been established (see DOSAGE AND
`ADMINISTRATION). After a dose adjustment, the hemoglobin should be determined
`weekly for at least 4 weeks until it has been determined that the hemoglobin has
`stabilized in response to the dose change. The hemoglobin should then be monitored at
`regular intervals.
`In order to ensure effective erythropoiesis, iron status should be evaluated for all patients
`before and during treatment, as the majority of patients will eventually require
`supplemental iron therapy. Supplemental iron therapy is recommended for all patients
`whose serum ferritin is below 100 mcg/L or whose serum transferrin saturation is
`below 20%.
`
`Information for Patients
`Patients should be informed of the possible side effects of Aranesp(cid:212)
` and be instructed to
`report them to the prescribing physician. Patients should be informed of the signs and
`symptoms of allergic drug reactions and be advised of appropriate actions. Patients
`should be counseled on the importance of compliance with their Aranesp(cid:212)
` treatment,
`dietary and dialysis prescriptions, and the importance of judicious monitoring of blood
`pressure and hemoglobin concentration should be stressed.
`If it is determined that a patient can safely and effectively administer Aranesp(cid:212)
` at home,
`appropriate instruction on the proper use of Aranesp(cid:212)
` should be provided for patients
`and their caregivers, including careful review of the “Information for Patients and
`Caregivers” insert. Patients and caregivers should also be cautioned against the reuse of
`needles, syringes, or drug product, and be thoroughly instructed in their proper disposal.
`
`Amgen Thousand Oaks
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`Ex. 1029 - Page 9 of 22
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`A puncture-resistant container for the disposal of used syringes and needles should be
`made available to the patient.
`
`Drug Interactions
`No formal drug interaction studies of Aranesp(cid:212)
`
` have been performed.
`
`Carcinogenesis, Mutagenesis, and Impairment of Fertility
`Carcinogenicity: The carcinogenic potential of Aranesp(cid:212)
` has not been evaluated in
`long-term animal studies. Aranesp(cid:212)
` did not alter the proliferative response of non-
`hematological cells in vitro or in vivo. In toxicity studies of approximately 6 months
`duration in rats and dogs, no tumorigenic or unexpected mitogenic responses were
`observed in any tissue type. Using a panel of human tissues, the in vitro tissue binding
`profile of Aranesp(cid:212)
` was identical to Epoetin alfa. Neither molecule bound to human
`tissues other than those expressing the erythropoietin receptor.
`Mutagenicity: Aranesp(cid:212)
` was negative in the in vitro bacterial and CHO cell assays to
`detect mutagenicity and in the in vivo mouse micronucleus assay to detect clastogenicity.
`Impairment of Fertility: When administered intravenously to male and female rats
`prior to and during mating, reproductive performance, fertility, and sperm assessment
`parameters were not affected at any doses evaluated (up to 10 mcg/kg/dose, administered
`3 times weekly). An increase in post implantation fetal loss was seen at doses equal to or
`greater than 0.5 mcg/kg/dose, administered 3 times weekly.
`
`Pregnancy Category C
`When Aranesp(cid:212)
` was administered intravenously to rats and rabbits during gestation, no
`evidence of a direct embryotoxic, fetotoxic, or teratogenic outcome was observed at
`doses up to 20 mcg/kg/day. The only adverse effect observed was a slight reduction in
`fetal weight, which occurred at doses causing exaggerated pharmacological effects in the
`dams (1 mcg/kg/day and higher). No deleterious effects on uterine implantation were
`seen in either species. No significant placental transfer of Aranesp(cid:212)
` was observed in
`rats. An increase in post implantation fetal loss was observed in studies assessing fertility
`(see PRECAUTIONS: Carcinogenesis, Mutagenesis, and Impairment of Fertility:
`Impairment of Fertility).
`Intravenous injection of Aranesp(cid:212)
` to female rats every other day from day 6 of gestation
`through day 23 of lactation at doses of 2.5 mcg/kg/dose and higher resulted in offspring
`(F1 generation) with decreased body weights, which correlated with a low incidence of
`deaths, as well as delayed eye opening and delayed preputial separation. No adverse
`effects were seen in the F2 offspring.
`There are no adequate and well-controlled studies in pregnant women. Aranesp(cid:212)
` should
`be used during pregnancy only if the potential benefit justifies the potential risk to the
`fetus.
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`Nursing Mothers
`It is not known whether Aranesp(cid:212)
` is excreted in human milk. Because many drugs are
`excreted in human milk, caution should be exercised when Aranesp(cid:212)
` is administered to a
`nursing woman.
`
`Pediatric Use
`The safety and efficacy of Aranesp(cid:212)
`
` in pediatric patients have not been established.
`
`Geriatric Use
`Of the 1598 CRF patients in clinical studies of Aranesp(cid:212)
`, 42% were age 65 and over,
`while 15% were 75 and over. Of the 873 cancer patients in clinical studies receiving
`Aranesp(cid:212)
` and concomitant chemotherapy, 45% were age 65 and over, while 14%
`were 75 and over. No overall differences in safety or efficacy were observed between
`older and younger patients.
`
`ADVERSE REACTIONS
`General
`Because clinical trials are conducted under widely varying conditions, adverse reaction
`rates observed in the clinical trials of Aranesp(cid:212)
` cannot be directly compared to rates in
`the clinical trials of other drugs and may not reflect the rates observed in practice.
`
`Chronic Renal Failure Patients
`In all studies, the most frequently reported serious adverse reactions with Aranesp(cid:212)
` were
`vascular access thrombosis, congestive heart failure, sepsis, and cardiac arrhythmia. The
`most commonly reported adverse reactions were infection, hypertension, hypotension,
`myalgia, headache and diarrhea, (see WARNINGS: Cardiovascular Events, Hemoglobin,
`and Rate of Rise of Hemoglobin/Hypertension). The most frequently reported adverse
`reactions resulting in clinical intervention (e.g., discontinuation of Aranesp(cid:212)
`, adjustment
`in dosage, or the need for concomitant medication to treat an adverse reaction symptom)
`were hypotension, hypertension, fever, myalgia, nausea, and chest pain.
`The data described below reflect exposure to Aranesp(cid:212)
` in 1598 CRF patients,
`including 675 exposed for at least 6 months, of whom 185 were exposed for greater than
`1 year. Aranesp(cid:212)
` was evaluated in active-controlled (n = 823) and uncontrolled studies
`(n = 775).
`The rates of adverse events and association with Aranesp(cid:212)
` are best assessed in the
`results from studies in which Aranesp(cid:212)
` was used to stimulate erythropoiesis in patients
`anemic at study baseline (n = 348), and, in particular, the subset of these patients in
`randomized controlled trials (n = 276). Because there were no substantive differences in
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`the rates of adverse reactions between these subpopulations, or between these
`subpopulations and the entire population of patients treated with Aranesp(cid:212)
`, data from all
`1598 patients were pooled.
`The population encompassed an age range from 18 to 91 years. Fifty-seven percent of
`the patients were male. The percentages of Caucasian, Black, Asian, and Hispanic
`patients were 83%, 11%, 3%, and 1%, respectively. The median weekly dose of
`Aranesp(cid:212)
` was 0.45 mcg/kg (25th, 75th percentiles: 0.29, 0.66 mcg/kg).
`Some of the adverse events reported are typically associated with CRF, or recognized
`complications of dialysis, and may not necessarily be attributable to Aranesp(cid:212)
` therapy.
`No important differences in adverse event rates between treatment groups were observed
`in controlled studies in which patients received Aranesp(cid:212)
` or other recombinant
`erythropoietins.
`The data in Table 1 reflect those adverse events occurring in at least 5% of patients
`treated with Aranesp(cid:212)
`.
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`Table 1. Adverse Events Occurring in ‡ 5% of CRF Patients
`Patients Treated With
`Aranesp(cid:212)
` (n = 1598)
`
`7%
`
`11%
`9%
`9%
`7%
`6%
`6%
`6%
`6%
`6%
`5%
`
`23%
`22%
`10%
`8%
`8%
`6%
`
`16%
`8%
`
`16%
`15%
`14%
`12%
`5%
`
`21%
`11%
`10%
`8%
`
`Event
`APPLICATION SITE
`
`Injection Site Pain
`BODY AS A WHOLE
`
`Peripheral Edema
`
`Fatigue
`
`Fever
`
`Death
`
`Chest Pain, Unspecified
`
`Fluid Overload
`
`Access Infection
`
`Influenza-like Symptoms
`
`Access Hemorrhage
`
`Asthenia
`CARDIOVASCULAR
`
`Hypertension
`
`Hypotension
`
`Cardiac Arrhythmias/Cardiac Arrest
`
`Angina Pectoris/Cardiac Chest Pain
`
`Thrombosis Vascular Access
`
`Congestive Heart Failure
`CNS/PNS
`
`Headache
`
`Dizziness
`GASTROINTESTINAL
`
`Diarrhea
`
`Vomiting
`
`Nausea
`
`Abdominal Pain
`
`Constipation
`MUSCULO-SKELETAL
`
`Myalgia
`
`Arthralgia
`
`Limb Pain
`
`Back Pain
`
`(Continued)
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`Table 1. Adverse Events Occurring in ‡ 5% of CRF Patients (Continued)
`Patients Treated With Aranesp(cid:212)
`
`(n = 1598)
`Event
`
`RESISTANCE MECHANISM
`Infectiona
`27%
`
`
`
`
`RESPIRATORY
`14%
`
`Upper Respiratory Infection
`12%
`
`Dyspnea
`10%
`
`Cough
`6%
`
`Bronchitis
`
`
`
`SKIN AND A