SIPULEUCEL-T: 4,606 Adverse Event Reports & Safety Profile

PROVENGE (sipuleucel-T) is an autologous cellular immunotherapy available as a suspension for intravenous infusion. PROVENGE consists of autologous peripheral blood mononuclear cells, including antigen presenting cells (APCs), that have been activated during a defined culture period with a recombinant human protein, PAP-GM-CSF, consisting of prostatic acid phosphatase (PAP), an antigen expressed in prostate cancer tissue, linked to granulocyte-macrophage colony-stimulating factor (GM-CSF), an immune cell activator. Each dose of PROVENGE contains a minimum of 50 million autologous CD54 + cells activated with PAP-GM-CSF, suspended in 250 mL of Lactated Ringer's Injection, USP. The active components of PROVENGE are autologous APCs and PAP-GM-CSF. During culture, the recombinant antigen can bind to and be processed by APCs into smaller protein fragments. The recombinant antigen is designed to target APCs, and may help direct the immune response to PAP. Minimal residual levels of the intact PAP-GM-CSF are detectable in the final PROVENGE product. The patient's peripheral blood mononuclear cells are obtained via a standard leukapheresis procedure approximately 3 days prior to the infusion date. Due to the autologous nature of PROVENGE, it is important that the patient and physician adhere to the personalized leukapheresis and infusion schedules. The cellular composition of PROVENGE is dependent on the composition of cells obtained from the patient's leukapheresis. In addition to APCs, the final product contains T cells, B cells, natural killer (NK) cells, and other cells. The number of cells present and the cellular composition of each PROVENGE dose will vary. The potency of PROVENGE is in part determined by measuring the increased expression of the CD54 molecule, also known as ICAM-1, on the surface of APCs after culture with PAP-GM-CSF. CD54 is a cell surface molecule that plays a role in the immunologic interactions between APCs and T cells, and is considered a marker of immune cell activation. In-process and final sterility tests are initiated prior to shipping, but the final results are not available for up to 7 days. PROVENGE is released for shipping based on acceptable results from 2-day incubation of the in-process sterility test.

AND USAGE PROVENGE ® (sipuleucel-T) is an autologous cellular immunotherapy indicated for the treatment of asymptomatic or minimally symptomatic metastatic castrate-resistant (hormone-refractory) prostate cancer. PROVENGE is an autologous cellular immunotherapy indicated for the treatment of asymptomatic or minimally symptomatic metastatic castrate-resistant (hormone-refractory) prostate cancer. ( 1 )

AND ADMINISTRATION For autologous use only. For intravenous use only. For autologous use only. For intravenous use only.

Administer

3 doses at approximately 2-week intervals. ( 2.1 ) Premedicate patients with oral acetaminophen and an antihistamine such as diphenhydramine. ( 2.2 ) Before infusion, confirm that the patient's identity matches the patient identifiers on the infusion bag. ( 2.2 ) Infuse PROVENGE intravenously over a period of approximately 60 minutes.

Do Not

Use a Cell Filter. ( 2.2 ) Interrupt or slow infusion for acute infusion reactions, depending on the severity of the reaction. ( 2.2 )

2.1 Dose Each dose of PROVENGE contains a minimum of 50 million autologous CD54 + cells activated with PAP-GM-CSF [ see Description ( 11 ) ]. The recommended course of therapy for PROVENGE is 3 complete doses, given at approximately 2-week intervals. In controlled clinical trials, the median dosing interval between infusions was 2 weeks (range 1 to 15 weeks); the maximum dosing interval has not been established. If, for any reason, the patient is unable to receive a scheduled infusion of PROVENGE, the patient will need to undergo an additional leukapheresis procedure prior to continuing a course of treatment. Advise patients of this possibility prior to initiating treatment.

2.2 Administration Do not use PROVENGE until confirmation of product release is received from Dendreon. Dendreon will send the Final Product Disposition Notification form containing the patient identifiers, expiration date and time, and the disposition status (approved for infusion or rejected), to the infusion site. Infusion must begin prior to the expiration date and time indicated on the Final Product Disposition Notification form and Product Label. Do not use expired PROVENGE. Keep the sealed, patient-specific PROVENGE infusion bag within the insulated polyurethane container inside the outer cardboard shipping box until the time of administration. To minimize potential acute infusion reactions, premedicate the patients orally with acetaminophen and an antihistamine, such as diphenhydramine, approximately 30 minutes prior to administration of PROVENGE. Administration steps: Remove the infusion bag from the insulated polyurethane container and inspect the bag for signs of leakage or external damage. Contents of the bag will be clear to opaque, with a white to red color, including shades of off-white, cream, light yellow and orange. Remove the infusion bag from the insulated polyurethane container and inspect the bag for signs of leakage or external damage. Contents of the bag will be clear to opaque, with a white to red color, including shades of off-white, cream, light yellow and orange. Gently mix and resuspend the contents of the bag, inspecting for clumps and clots. Small clumps of cellular material should disperse with gentle manual mixing. Do not administer if the bag leaks during handling, is damaged, or if clumps remain in the bag. Match the patient's identity with the patient identifiers on the Final Product Disposition Notification form and the PROVENGE infusion bag. Infuse the entire volume of the PROVENGE infusion bag intravenously over approximately 60 minutes. Do not use a cell filter. Observe the patient for acute infusion reactions for at least 30 minutes following each infusion. If acute infusion reactions occur, such as chills, fatigue, fever, nausea, and joint ache, interrupt or slow the infusion and administer appropriate medical treatment as needed. In controlled clinical trials, symptoms of acute infusion reactions were treated with acetaminophen, intravenous H1 and/or H2 blockers, and low-dose intravenous meperidine. If the infusion is interrupted, keep the PROVENGE infusion bag at room temperature. Do not resume infusion if the PROVENGE infusion bag has been at room temperature for more than 3 hours.

None. None. ( 4 )

REACTIONS The most common adverse reactions reported in clinical trials (≥ 15% of patients receiving PROVENGE) were chills, fatigue, fever, back pain, nausea, joint ache, and headache. The most common adverse reactions (incidence ≥ 15%) are chills, fatigue, fever, back pain, nausea, joint ache, and headache. ( 6 ) To report SUSPECTED ADVERSE REACTIONS, contact Dendreon Pharmaceuticals LLC at 1-877-336-3736 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 trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. The safety evaluation of PROVENGE is based on 601 prostate cancer patients in the PROVENGE group who underwent at least 1 leukapheresis procedure in four randomized, controlled clinical trials. The control group (n = 303) received non-activated autologous peripheral blood mononuclear cells. Patients received 3 infusions of PROVENGE or control every other week over a period of 4 weeks. Almost all (98.3%) patients in the PROVENGE group and 96% in the control group reported an adverse event.

In

67.4% of patients in the PROVENGE group, these adverse events were mild or moderate in severity. Severe (Grade 3) and life-threatening (Grade 4) adverse events were reported in 23.6% and 4% of patients in the PROVENGE group compared with 25.1% and 3.3% of patients in the control group. Fatal (Grade 5) adverse events were reported in 3.3% of patients in the PROVENGE group compared with 3.6% of patients in the control group. The most common (≥ 2%)

Grade

3-5 adverse events reported in the PROVENGE group were back pain and chills. Serious adverse events were reported in 24% of patients in the PROVENGE group and 25.1% of patients in the control group. Serious adverse events in the PROVENGE group included acute infusion reactions [ see Warnings and Precautions ( 5.1 ) ], cerebrovascular events [ see Warnings and Precautions ( 5.3 ) ], and single case reports of eosinophilia, rhabdomyolysis, myasthenia gravis, myositis, and tumor flare. PROVENGE was discontinued in 1.5% of patients in Study 1 due to adverse events. Some patients who required central venous catheters for treatment with PROVENGE developed infections, including sepsis. A small number of these patients discontinued treatment as a result. Monitoring for infectious sequelae in patients with central venous catheters is recommended. Each dose of PROVENGE requires a standard leukapheresis procedure approximately 3 days prior to the infusion. Adverse events that were reported ≤ 1 day following a leukapheresis procedure in ≥ 5% of patients in controlled clinical trials included citrate toxicity (14.2%), oral paresthesia (12.6%), paresthesia (11.4%), and fatigue (8.3%).

Table

1 provides the frequency and severity of adverse events reported in ≥ 5% of patients in the PROVENGE group of randomized, controlled trials of men with prostate cancer. The population included 485 patients with metastatic castrate-resistant prostate cancer and 116 patients with non-metastatic androgen-dependent prostate cancer who were scheduled to receive 3 infusions of PROVENGE at approximately 2-week intervals. The population was age 40 to 91 years (median 70 years), and 90.6% of patients were Caucasian.

Table

1 Incidence of Adverse Events Occurring in ≥ 5% of Patients Randomized to PROVENGE PROVENGE (N = 601) Control * (N = 303)

All

Grades n (%)

Grade

3-5 n (%)

All

Grades n (%)

Grade

3-5 n (%)

Any Adverse Event

591 (98.3) 186 (30.9) 291 (96.0) 97 (32.0) * Control group received non-activated autologous peripheral blood mononuclear cells.

Chills

319 (53.1) 13 (2.2) 33 (10.9) 0 (0.0)

Fatigue

247 (41.1) 6 (1.0) 105 (34.7) 4 (1.3)

Fever

188 (31.3) 6 (1.0) 29 (9.6) 3 (1.0) Back pain 178 (29.6) 18 (3.0) 87 (28.7) 9 (3.0)

Nausea

129 (21.5) 3 (0.5) 45 (14.9) 0 (0.0) Joint ache 118 (19.6) 11 (1.8) 62 (20.5) 5 (1.7)

Headache

109 (18.1) 4 (0.7) 20 (6.6) 0 (0.0) Citrate toxicity 89 (14.8) 0 (0.0) 43 (14.2) 0 (0.0)

Paresthesia

85 (14.1) 1 (0.2) 43 (14.2) 0 (0.0)

Vomiting

80 (13.3) 2 (0.3) 23 (7.6) 0 (0.0)

Anemia

75 (12.5) 11 (1.8) 34 (11.2) 7 (2.3)

Constipation

74 (12.3) 1 (0.2) 40 (13.2) 3 (1.0)

Pain

74 (12.3) 7 (1.2) 20 (6.6) 3 (1.0) Paresthesia oral 74 (12.3) 0 (0.0) 43 (14.2) 0 (0.0) Pain in extremity 73 (12.1) 5 (0.8) 40 (13.2) 1 (0.3)

Dizziness

71 (11.8) 2 (0.3) 34 (11.2) 0 (0.0) Muscle ache 71 (11.8) 3 (0.5) 17 (5.6) 0 (0.0)

Asthenia

65 (10.8) 6 (1.0) 20 (6.6) 2 (0.7)

Diarrhea

60 (10.0) 1 (0.2) 34 (11.2) 3 (1.0) Influenza-like illness 58 (9.7) 0 (0.0) 11 (3.6) 0 (0.0) Musculoskeletal pain 54 (9.0) 3 (0.5) 31 (10.2) 3 (1.0)

Dyspnea

52 (8.7) 11 (1.8) 14 (4.6) 3 (1.0) Edema peripheral 50 (8.3) 1 (0.2) 31 (10.2) 1 (0.3) Hot flush 49 (8.2) 2 (0.3) 29 (9.6) 1 (0.3)

Hematuria

46 (7.7) 6 (1.0) 18 (5.9) 3 (1.0) Muscle spasms 46 (7.7) 2 (0.3) 17 (5.6) 0 (0.0)

Hypertension

45 (7.5) 3 (0.5) 14 (4.6) 0 (0.0)

Anorexia

39 (6.5) 1 (0.2) 33 (10.9) 3 (1.0) Bone pain 38 (6.3) 4 (0.7) 22 (7.3) 3 (1.0) Upper respiratory tract infection 38 (6.3) 0 (0.0) 18 (5.9) 0 (0.0)

Insomnia

37 (6.2) 0 (0.0) 22 (7.3) 1 (0.3) Musculoskeletal chest pain 36 (6.0) 2 (0.3) 23 (7.6) 2 (0.7)

Cough

35 (5.8) 0 (0.0) 17 (5.6) 0 (0.0) Neck pain 34 (5.7) 3 (0.5) 14 (4.6) 2 (0.7) Weight decreased 34 (5.7) 2 (0.3) 24 (7.9) 1 (0.3) Urinary tract infection 33 (5.5) 1 (0.2) 18 (5.9) 2 (0.7)

Rash

31 (5.2) 0 (0.0) 10 (3.3) 0 (0.0)

Sweating

30 (5.0) 1 (0.2) 3 (1.0) 0 (0.0)

Tremor

30 (5.0) 0 (0.0) 9 (3.0) 0 (0.0)

6.2 Postmarketing Experience The following adverse reactions have been identified during post-approval use of PROVENGE. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Nervous system disorders : syncope, transient ischemic attack, strokes <span class="opacity-50 text-xs">[see Warnings and Precautions ( 5.1 , 5.3 )]</span> Vascular disorders : hypotension <span class="opacity-50 text-xs">[see Warnings and Precautions ( 5.1 )]</span> Cardiovascular disorders : myocardial infarction <span class="opacity-50 text-xs">[see Warnings and Precautions ( 5.3 )]</span> Thromboembolic disorders: deep venous thrombosis and pulmonary embolism <span class="opacity-50 text-xs">[see Warnings and Precautions ( 5.2 )]</span>

AND PRECAUTIONS Acute infusion reactions may occur. If reactions occur, decrease the rate or stop the infusion and administer appropriate medical treatment. ( 5.1 ) Syncope and hypotension have also been observed. Closely monitor patients with cardiac or pulmonary conditions. ( 5.1 ) PROVENGE should be used with caution in patients with risk factors for thromboembolic events. ( 5.2 ) PROVENGE is not tested for transmissible infectious diseases and may transmit diseases to health care professionals handling the product. Universal precautions should be followed. ( 5.4 ) Concomitant use of chemotherapy and immunosuppressive medications with PROVENGE has not been studied. ( 5.5 )

5.1 Acute Infusion Reactions Acute infusion reactions (reported within 1 day of infusion) may occur and include nausea, vomiting, fatigue, fever, rigor or chills, respiratory events (dyspnea, hypoxia, and bronchospasm), syncope, hypotension, hypertension, and tachycardia. Acute infusion reactions (reported within 1 day of infusion) may occur and include nausea, vomiting, fatigue, fever, rigor or chills, respiratory events (dyspnea, hypoxia, and bronchospasm), syncope, hypotension, hypertension, and tachycardia. In controlled clinical trials, 71.2% of patients in the PROVENGE group developed an acute infusion reaction. The most common events (≥ 20%) were chills, fever, and fatigue.

In

95.1% of patients reporting acute infusion reactions, the reactions were mild or moderate. Fevers and chills generally resolved within 2 days (71.9% and 89%, respectively). In controlled clinical trials, 71.2% of patients in the PROVENGE group developed an acute infusion reaction. The most common events (≥ 20%) were chills, fever, and fatigue.

In

95.1% of patients reporting acute infusion reactions, the reactions were mild or moderate. Fevers and chills generally resolved within 2 days (71.9% and 89%, respectively). In controlled clinical trials, severe (Grade 3) acute infusion reactions were reported in 3.5% of patients in the PROVENGE group. Reactions included chills, fever, fatigue, asthenia, dyspnea, hypoxia, bronchospasm, dizziness, headache, hypertension, muscle ache, nausea, and vomiting. The incidence of severe events was greater following the second infusion (2.1% vs. 0.8% following the first infusion), and decreased to 1.3% following the third infusion. Some (1.2%) patients in the PROVENGE group were hospitalized within 1 day of infusion for management of acute infusion reactions.

No Grade

4 or 5 acute infusion reactions were reported in patients in the PROVENGE group. In controlled clinical trials, severe (Grade 3) acute infusion reactions were reported in 3.5% of patients in the PROVENGE group. Reactions included chills, fever, fatigue, asthenia, dyspnea, hypoxia, bronchospasm, dizziness, headache, hypertension, muscle ache, nausea, and vomiting. The incidence of severe events was greater following the second infusion (2.1% vs. 0.8% following the first infusion), and decreased to 1.3% following the third infusion. Some (1.2%) patients in the PROVENGE group were hospitalized within 1 day of infusion for management of acute infusion reactions.

No Grade

4 or 5 acute infusion reactions were reported in patients in the PROVENGE group. Closely monitor patients with cardiac or pulmonary conditions. In the event of an acute infusion reaction, decrease the infusion rate or stop the infusion, depending on the severity of the reaction. Administer appropriate medical treatment as needed. [ ] Closely monitor patients with cardiac or pulmonary conditions. In the event of an acute infusion reaction, decrease the infusion rate or stop the infusion, depending on the severity of the reaction. Administer appropriate medical treatment as needed. [ See Dosage and Administration ( 2.2 ) ]

5.2 Thromboembolic Events Thromboembolic events, including deep venous thrombosis and pulmonary embolism, can occur following infusion of PROVENGE. The clinical significance and causal relationship are uncertain. Most patients had multiple risk factors for these events. PROVENGE should be used with caution in patients with risk factors for thromboembolic events. Thromboembolic events, including deep venous thrombosis and pulmonary embolism, can occur following infusion of PROVENGE. The clinical significance and causal relationship are uncertain. Most patients had multiple risk factors for these events. PROVENGE should be used with caution in patients with risk factors for thromboembolic events.

5.3 Vascular Disorders : In controlled clinical trials, cerebrovascular events (hemorrhagic and ischemic strokes) were observed in 3.5% of patients in the PROVENGE group compared with 2.6% of patients in the control group. In the postmarketing setting, cerebrovascular events, including transient ischemic attacks, have been observed following infusion of Provenge. The clinical significance and causal relationship are uncertain. Most patients had multiple risk factors for these events. Cerebrovascular disease : In controlled clinical trials, cerebrovascular events (hemorrhagic and ischemic strokes) were observed in 3.5% of patients in the PROVENGE group compared with 2.6% of patients in the control group. In the postmarketing setting, cerebrovascular events, including transient ischemic attacks, have been observed following infusion of Provenge. The clinical significance and causal relationship are uncertain. Most patients had multiple risk factors for these events. : In controlled clinical trials, myocardial infarctions were observed in 0.8% of patients in the PROVENGE group compared with 0.3% of patients in the control group. In the postmarketing setting, myocardial infarctions have been observed following infusion of Provenge. The clinical significance and causal relationship are uncertain. Most patients had multiple risk factors for these events. Cardiovascular disorders : In controlled clinical trials, myocardial infarctions were observed in 0.8% of patients in the PROVENGE group compared with 0.3% of patients in the control group. In the postmarketing setting, myocardial infarctions have been observed following infusion of Provenge. The clinical significance and causal relationship are uncertain. Most patients had multiple risk factors for these events.

5.4 Handling Precautions for Control of Infectious Disease PROVENGE is not tested for transmissible infectious diseases. Therefore, patient leukapheresis material and PROVENGE may carry the risk of transmitting infectious diseases to health care professionals handling the product. Accordingly, health care professionals should employ universal precautions when handling leukapheresis material or PROVENGE.

5.5 Concomitant Chemotherapy or Immunosuppressive Therapy Use of either chemotherapy or immunosuppressive agents (such as systemic corticosteroids) given concurrently with the leukapheresis procedure or PROVENGE has not been studied. PROVENGE is designed to stimulate the immune system, and concurrent use of immune-suppressive agents may alter the efficacy and/or safety of PROVENGE. Therefore, evaluate patients carefully to determine whether it is medically appropriate to reduce or discontinue immunosuppressive agents prior to treatment with PROVENGE.

5.6 Product Safety Testing PROVENGE is released for infusion based on the microbial and sterility results from several tests: microbial contamination determination by Gram stain, endotoxin content, and in-process sterility with a 2-day incubation to determine absence of microbial growth. The final (7-day incubation) sterility test results are not available at the time of infusion. If the sterility results become positive for microbial contamination after PROVENGE has been approved for infusion, Dendreon will notify the treating physician. Dendreon will attempt to identify the microorganism, perform antibiotic sensitivity testing on recovered microorganisms, and communicate the results to the treating physician. Dendreon may request additional information from the physician in order to determine the source of contamination.

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