Sipuleucel-T is an autologous cellular immunotherapy. It is indicated for the treatment of asymptomatic or minimally symptomatic metastatic castration-resistant prostate cancer. Patients must undergo standard leukapheresis approximately 3 days prior to the scheduled sipuleucel-T infusion date to collect their peripheral blood mononuclear cells; it is important that the patient and physician adhere to the personalized leukapheresis and infusion schedules.
General Administration Information
For storage information, see the specific product information within the How Supplied section.
Safe Handling
-Sipuleucel-T is not tested for transmissible infections diseases. Use universal precautions when handling leukapheresis material or sipuleucel-T.
Route-Specific Administration
Injectable Administration
-Keep the sealed, patient-specific infusion bag inside the insulated polyurethane container, inside the outer cardboard shipping box, until the time of administration.
-The contents of the bag will be clear to opaque, with a white to red color, possibly including shades of light yellow or orange.
Intravenous Administration
-Sipuleucel-T is intended solely for autologous use.
-If the patient is unable to receive a scheduled infusion, they will need to undergo an additional leukapheresis procedure prior to continuing the course of treatment.
-The Final Product Disposition Notification form which contains the disposition status (approved for infusion or rejected), patient identifiers, and expiration date and time, will be sent to the infusion site. Do not use the product until the confirmation of product release is received from Dendreon.
-Premedicate with acetaminophen and an antihistamine (e.g., diphenhydramine) approximately 30 minutes before each infusion.
Intravenous infusion:
-Gently mix to 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 or if clumps remain in the bag.
-Ensure the patient identifiers on the Final Product Disposition Notification and infusion bag match the patient's identity.
-Begin the infusion prior to the expiration date and time on the Final Product Disposition Notification and Product Label.
-Infuse the entire volume in the infusion bag over approximately 60 minutes. Do not use a cell filter.
-Observe the patient for acute infusion reactions for at least 30 minutes after the infusion is complete.
-If an acute infusion reaction occurs, the infusion may be interrupted or slowed, depending on the severity of the reaction. In clinical trials, acute infusion reactions were treated with acetaminophen, intravenous H1 and/or H2 blockers, and low dose meperidine. If the infusion must be interrupted, keep the infusion bag at room temperature. Do not resume the infusion if the sipuleucel-T is at room temperature for more than 3 hours.
Citrate toxicity was reported in 14.8% of men with prostate cancer who received sipuleucel-T and underwent at least 1 leukapheresis procedure compared with 14.2% of men in the control group who received non-activated autologous peripheral blood mononuclear cells in pooled results from 4 randomized studies.
Cerebrovascular events including hemorrhagic and ischemic stroke were reported in 3.5% of men with prostate cancer treated with sipuleucel-T compared with 2.6% of those who received non-activated autologous peripheral blood mononuclear cells without sipuleucel-T in pooled results from 4 randomized trials, although most patients had multiple risk factors for these events. Transient ischemic attacks and strokes were also reported in postmarketing experience with sipuleucel-T; the clinical significance and a causal relationship are uncertain. Use sipuleucel-T with caution in patients with a history of stroke.
Upper respiratory tract infection (6.3% vs. 5.9%) and an influenza-like illness (9.7% vs. 3.6%) were reported more often in men with prostate cancer treated with sipuleucel-T compared with those who received non-activated autologous peripheral blood mononuclear cells without sipuleucel-T in pooled results from 4 randomized trials. Some patients who required central venous catheters developed infections including sepsis, a small number of whom required discontinuation of therapy. Monitor for infectious sequelae in patients with a central venous catheter.
In pooled results from 4 randomized studies, nervous system adverse events that were reported more often in men with prostate cancer treated with sipuleucel-T compared with those who received non-activated autologous peripheral blood mononuclear cells without sipuleucel-T included headache (18.1% vs. 6.6%; grade 3 or 4, 0.7% vs. 0%), dizziness (11.8% vs. 11.2%; grade 3 or 4, 0.3% vs. 0%) and tremor (5% vs. 3%); grade 3 or 4 paresthesias were reported in 0.2% versus 0% of patients, respectively (grade 1 or 2, 14.1% vs. 14.2%). Syncope has been reported in postmarketing experience with sipuleucel-T.
In pooled results from 4 randomized studies, musculoskeletal adverse events that were reported more often in men with prostate cancer treated with sipuleucel-T compared with those who received non-activated autologous peripheral blood mononuclear cells without sipuleucel-T included back pain (29.6% vs. 28.7%; grade 3 or 4, 3% vs. 3%), generalized pain (12.3% vs. 6.6%; grade 3 or 4, 1.2% vs. 1%), myalgia (11.8% vs. 5.6%; grade 3 or 4, 0.5% vs. 0%), neck pain (5.7% vs. 4.6%; grade 3 or 4, 0.5% vs. 0.7%), and muscle spasms (7.7% vs. 5.6%; grade 3 or 4, 0.3% vs. 0%); grade 3 or 4 arthralgia (1.8% vs. 1.7%) and extremity pain (0.8% vs. 0.3%) was also reported more often in the sipuleucel-T arm.
Nausea (21.5% vs. 14.9%; grade 3 or 4, 0.5% vs. 0%) and vomiting (13.3% vs. 7.6%; grade 3 or 4, 0.3% vs. 0%) were reported more often in men with prostate cancer treated with sipuleucel-T compared with those who received non-activated autologous peripheral blood mononuclear cells without sipuleucel-T in pooled results from 4 randomized trials.
Fever (31.3% vs. 9.6%; grade 3 or 4, 1% vs. 1%) and chills (53.1% vs. 10.9%; grade 3 or 4, 2.2% vs. 0%) were reported more often in men with prostate cancer treated with sipuleucel-T compared with those who received non-activated autologous peripheral blood mononuclear cells without sipuleucel-T in pooled results from 4 randomized trials.
Fatigue (41.1% vs. 34.7%; grade 3 or 4, 1% vs. 1.3%) and asthenia (10.8% vs. 6.6%; grade 3 or 4, 1% vs. 0.7%) were reported more often in men with prostate cancer treated with sipuleucel-T compared with those who received non-activated autologous peripheral blood mononuclear cells without sipuleucel-T in pooled results from 4 randomized trials.
Anemia was reported more often in men with prostate cancer treated with sipuleucel-T compared with those who received non-activated autologous peripheral blood mononuclear cells without sipuleucel-T in pooled results from 4 randomized trials (12.5% vs. 11.2%; grade 3 or 4, 0.51.8% vs. 2.3%).
Hematuria was reported more often in men with prostate cancer treated with sipuleucel-T compared with those who received non-activated autologous peripheral blood mononuclear cells without sipuleucel-T in pooled results from 4 randomized trials (7.7% vs. 5.9%; grade 3 or 4, 1% vs. 1%).
Hypertension was reported more often in men with prostate cancer treated with sipuleucel-T compared with those who received non-activated autologous peripheral blood mononuclear cells without sipuleucel-T in pooled results from 4 randomized trials (7.5% vs. 4.6%; grade 3 or 4, 0.5% vs. 0%); hypotension has also been reported in postmarketing experience with sipuleucel-T.
Rash (5.2% vs. 3.3%) and sweating (hyperhidrosis) (5% vs. 1%; grade 3 or 4, 0.2% vs. 0%) were reported more often in men with prostate cancer treated with sipuleucel-T compared with those who received non-activated autologous peripheral blood mononuclear cells without sipuleucel-T in pooled results from 4 randomized trials.
Dyspnea occurred in 8.7% of men with prostate cancer treated with sipuleucel-T compared with 4.6% of those who received non-activated autologous peripheral blood mononuclear cells without sipuleucel-T in pooled results from 4 randomized trials (grade 3 or 4, 1.8% vs. 1%); grade 1 or 2 cough occurred in 5.8% versus 5.6% of patients, respectively.
Acute infusion-related reactions reported within 1 day of infusion occurred in 71.2% of patients treated with sipuleucel-T in controlled clinical trials (grade 3, 3.5%); 1.2% of patients required hospitalization within 1 day of infusion for management of acute infusion reactions. Severe reactions occurred in 0.8% of patients after the first infusion, 2.1% after the second infusion, and 1.3% after the third infusion. Symptoms include headache, dizziness, fatigue, fever/chills, nausea/vomiting, dyspnea, hypoxia, bronchospasm, myalgia, and hypertension. Fever resolved within 2 days in 71.9% of patients and chills within 2 days in 89% of patients. Closely monitor patients with a history of cardiac disease or pulmonary disease. In patients who develop an acute infusion-related reaction, the infusion rate may be decreased or stopped depending on the severity of the reaction. Administer appropriate supportive care as necessary.
Deep vein thrombosis and pulmonary embolism have been reported in postmarketing experience with sipuleucel-T, although most patients had multiple risk factors for these events. The clinical significance and a causal relationship are uncertain. Use sipuleucel-T with caution in patients with a history of thromboembolism.
Myocardial infarction was reported in 0.8% of men with prostate cancer treated with sipuleucel-T compared with 0.3% of those who received non-activated autologous peripheral blood mononuclear cells without sipuleucel-T in pooled results from 4 randomized trials; most patients had multiple risk factors for these events. Myocardial infarction was also reported in postmarketing experience with sipuleucel-T; the clinical significance and a causal relationship are uncertain. Use sipuleucel-T with caution in patients with a history of myocardial infarction.
Acute infusion-related reactions have occurred during treatment with sipuleucel-T. These reactions included, but were not limited to, fever, chills, respiratory events (dyspnea, hypoxia, and bronchospasm), nausea, vomiting, fatigue, hypertension, and tachycardia. Closely monitor patients with a history of cardiac disease or pulmonary disease. In patients who develop an acute infusion-related reaction, the infusion rate may be decreased or stopped depending on the severity of the reaction. Administer appropriate supportive care as necessary.
The concurrent use of chemotherapy or immunosuppressant agents (e.g., systemic corticosteroid therapy) during treatment with sipuleucel-T has not been studied. Sipuleucel-T stimulates the immune system; coadministration with drugs that suppress the immune system may decrease the efficacy or alter the safety profile of sipuleucel-T. Carefully evaluate whether it may be medically appropriate to reduce or discontinue concurrent immunosuppression prior to treatment with sipuleucel-T. Sipuleucel-T is incubated for 2 days prior to release to determine absence of microbial growth; final (7-day) sterility test results are not available at the time of infusion. If the sterility results become positive for microbial contamination after sipuleucel-T has been approved for infusion, Dendreon will notify the treating physician and attempt to identify the microorganism and antimicrobial sensitivities.
The FDA has not assigned a pregnancy category for sipuleucel-T. The only indication at the time of FDA approval was for men; sipuleucel-T is indicated for the treatment of asymptomatic or minimally symptomatic metastatic castrate resistant (hormone refractory) prostate cancer. No studies on the effects of sipuleucel-T on fertility have been conducted.
Use sipuleucel-T with caution in patients with thromboembolic disease or a history of thrombosis. Deep vein thrombosis and pulmonary embolism have been reported in postmarketing experience with sipuleucel-T, although most patients had multiple risk factors for these events. The clinical significance and a causal relationship are uncertain.
Information regarding the safety of breast-feeding for a patient taking sipuleucel-T was not available at the time of FDA approval. The only indication at FDA approval was for men; sipuleucel-T is indicated for the treatment of asymptomatic or minimally symptomatic metastatic castrate resistant (hormone refractory) prostate cancer. Consider the benefits of breast-feeding, the risk of potential infant drug exposure, and the risk of an untreated or inadequately treated condition. If a breast-feeding infant experiences an adverse effect related to a maternally administered drug, healthcare providers are encouraged to report the adverse effect to the FDA.
Myocardial infarction and stroke have been reported in postmarketing experience with sipuleucel-T, although most patients had multiple risk factors for these events. The clinical significance and a causal relationship are uncertain. Use sipuleucel-T with caution in patients with a history of myocardial infarction or stroke.
For the treatment of asymptomatic or minimally symptomatic metastatic, castrate resistant (hormone refractory) prostate cancer:
Intravenous dosage:
Adults: 1 infusion bag (containing a minimum of 50 million autologous CD54+ cells activated with PAP-GM-CSF) IV approximately every 2 weeks for 3 doses. To minimize acute infusion reactions, premedicate with acetaminophen and an antihistamine (e.g., diphenhydramine) 30 minutes prior to the infusion. If an acute infusion reaction occurs during the infusion, sipuleucel-T may need to be interrupted or slowed. Treatment with sipuleucel-T significantly improved median overall survival compared with placebo (25.8 months vs. 21.7 months) in patients with asymptomatic or minimally symptomatic metastatic castrate-resistant prostate cancer (mCRPC) in a multicenter, randomized, double-blind clinical trial. Treatment with sipuleucel-T did not significantly improve the primary endpoint of time to disease progression in patients with mCRPC compared with placebo in a second multicenter, randomized, double-blind clinical trial, although median overall survival was significantly improved (25.9 months vs. 21.4 months); the survival analysis in this study was not prespecified.
Therapeutic Drug Monitoring:
Management of Treatment-Related Toxicity
Infusion-Related Reactions
-Interrupt or slow the rate of infusion and administer appropriate supportive care; in clinical trials, this included acetaminophen, IV H1 and/or H2 blockers, and low-dose IV meperidine.
Maximum Dosage Limits:
-Adults
Maximum dosage limits not defined. Each dose of sipuleucel-T contains the maximum number of cells that can be manufactured from a single leukapheresis procedure. The number of cells in sipuleucel-T does not exceed the number of cells collected from leukapheresis.
-Elderly
Maximum dosage limits not defined. Each dose of sipuleucel-T contains the maximum number of cells that can be manufactured from a single leukapheresis procedure. The number of cells in sipuleucel-T does not exceed the number of cells collected from leukapheresis.
-Adolescents
Safety and efficacy have not been established.
-Children
Safety and efficacy have not been established.
Patients with Hepatic Impairment Dosing
Specific guidelines for dosage adjustments in hepatic impairment are not available; it appears that no dosage adjustments are needed.
Patients with Renal Impairment Dosing
Specific guidelines for dosage adjustments in renal impairment are not available; it appears that no dosage adjustments are needed.
*non-FDA-approved indication
There are no drug interactions associated with Sipuleucel-T products.
Sipuleucel-T is an autologous cellular immunotherapy designed to stimulate T-cell immunity against prostatic acid phosphatase (PAP), an antigen expressed in prostate cancer tissue but not in non-prostate tissue. While the exact mechanism of action is unknown, it is dependent upon the effective presentation of this target antigen to the patient's immune system. The active components of sipuleucel-T are antigen presenting cells (APCs) and PAP-GM-CSF, a recombinant human protein, which consists of PAP linked to granulocyte-macrophage colony-stimulating factor (GM-CSF), an immune cell activator. The APCs within sipuleucel-T are from autologous peripheral blood mononuclear cells, which are obtained during a standard leukapheresis procedure that the patient undergoes approximately 3 days prior to the infusion; they are then activated during a culture period with PAP-GM-CSF. During the culture process, APCs take up and process the recombinant target antigen into smaller peptides that are then displayed on the APC surface. Minimal residual levels of the intact PAP-GM-CSF are detectable in the final sipuleucel-T product. The recombinant antigen is designed to target APCs and may help direct the immune response to PAP. The potency of sipuleucel-T is determined in part by measuring the increased expression of the CD54 molecule on the surface of the APCs after culture with PAP-GM-CSF. CD54, also known as ICAM-1, is a cell surface molecule that plays a role in immunologic interactions between APCs and T-cells, and is considered a marker of immune-cell activation. The final cellular composition of sipuleucel-T is dependent upon the cellular composition of the leukapheresis product. In addition to APCs, the final product contains T cells, B cells, natural killer (NK) cells, and other cells.
Sipuleucel-T is administered by intravenous infusion. It is a dendritic cell product that consists of autologous dendritic-cells loaded with prostatic-acid phosphatase linked to granulocyte-macrophage colony-stimulating factor (PAP-GM-CSF). In a phase 3 controlled clinical trial, 237 patients with prostate cancer were evaluated for the development of humoral and T cell immune responses (proliferative and gamma-interferon ELISPOT) to the target antigens (at baseline and at weeks 6, 14, and 26). IgG and IgM antibody responses against PAP-GM-CSF and against PAP alone were observed through the follow-up period. T cell proliferative and gamma-interferon ELISPOT responses were observed in peripheral blood collected in the follow-up period from patients receiving sipuleucel-T. Responses were not observed in the control group. Some sipuleucel-T patients exhibited a response to PAP antigen alone. The clinical significance of antibody responses is not known. In another trial, the specific T-cell responsiveness against the target antigen was determined in a small group of patients whose cells were processed within 24 hours of collection. The median ratio of the PA2024 (a recombinant fusion protein containing prostatic acid phosphatase and GM-CSF) T-cell stimulation index at 8 weeks versus baseline was approximately eight-fold higher in sipuleucel-T- versus placebo-treated patients.