Provenge Drug Information

® (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.

Dose Each dose of

PROVENGE contains a minimum of 50 million autologous CD54 + cells activated with PAP-GM-CSF. 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.

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.

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, cerebrovascular events, 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 591 186 291 97 * Control group received non-activated autologous peripheral blood mononuclear cells. Chills 319 13 33 0 Fatigue 247 6 105 4 Fever 188 6 29 3 Back pain 178 18 87 9 Nausea 129 3 45 0 Joint ache 118 11 62 5 Headache 109 4 20 0 Citrate toxicity 89 0 43 0 Paresthesia 85 1 43 0 Vomiting 80 2 23 0 Anemia 75 11 34 7 Constipation 74 1 40 3 Pain 74 7 20 3 Paresthesia oral 74 0 43 0 Pain in extremity 73 5 40 1 Dizziness 71 2 34 0 Muscle ache 71 3 17 0 Asthenia 65 6 20 2 Diarrhea 60 1 34 3 Influenza-like illness 58 0 11 0 Musculoskeletal pain 54 3 31 3 Dyspnea 52 11 14 3 Edema peripheral 50 1 31 1 Hot flush 49 2 29 1 Hematuria 46 6 18 3 Muscle spasms 46 2 17 0 Hypertension 45 3 14 0 Anorexia 39 1 33 3 Bone pain 38 4 22 3 Upper respiratory tract infection 38 0 18 0 Insomnia 37 0 22 1 Musculoskeletal chest pain 36 2 23 2 Cough 35 0 17 0 Neck pain 34 3 14 2 Weight decreased 34 2 24 1 Urinary tract infection 33 1 18 2 Rash 31 0 10 0 Sweating 30 1 3 0 Tremor 30 0 9 0

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 Vascular disorders : hypotension Cardiovascular disorders : myocardial infarction Thromboembolic disorders: deep venous thrombosis and pulmonary embolism

Each PROVENGE infusion comprises the maximum number of cells that can be manufactured from a single leukapheresis procedure. The number of cells in PROVENGE does not exceed the number of cells collected from the leukapheresis. There are no known instances of overdosage from either a single infusion or a full course of therapy with PROVENGE.