Provenge - summary of medicine characteristics

2. QUALITATIVE AND QUANTITATIVE COMPOSITION2.1 General description

Autologous peripheral blood mononuclear cells activated with PAP-GM-CSF (Sipuleucel-T).

2.2 Qualitative and quantitative composition

One bag contains autologous peripheral blood mononuclear cells activated with PAP-GM-CSF (prostatic acid phosphatase-granulocyte macrophage-colony stimulating f of 50 × 106 autologous CD54+ cells.

The cellular composition and the cell number per dose of Provenge will vary according to the patient’s leu­kapheresis. In addition to antigen presenting cells (APCs), the final product thus contains T cells, B cells, natural killer (NK) cells, and other cells.

Excipients with known effect

This medicinal product contains approximately 800 mg of sodium and 45 mg of potassium per infusion.

For the full list of excipients, see section 6.

3. PHARMACEUTICAL FORM

Dispersion for infusion.

The dispersion is slightly clou

4. CLINICAL PARTICULARS4.1 Therapeutic indications

Provenge is indicated for treatment of asymptomatic or minimally symptomatic metastatic (nonvisceral) castrate resistant prostate cancer in male adults in whom chemotherapy is not yet clinically indicated.

4.2 Posology and method of administration

Provenge must be administered under the supervision of a physician experienced in the medical treatment of prostate cancer and in an environment where availability of resuscitation equipment must be ensured.

Posology

One dose of Provenge contains a minimum of 50 × 106 autologous CD54+ cells activated with PAP-GM-CSF, suspended in 250 mL of Lactated Ringer’s Injection, in a sealed, patient-specific polyolefin bag.

ent is required in the elderly population.

Patients with hepatic impairment

Provenge has not been investigated in patients with hepatic impairment. No specific dose recommendation can be provided in these patients.

Patients with renal impairment and/or hyperkalaemia and/or on a controlled potassium diet Provenge has not been investigated in patients with renal impairment. The potassium content per infusion should be taken into account if administered to patients with renal impairment and/or those on a controlled potassium diet. Hyperkalaemia should be corrected prior to Provenge administration (see section 4.4).

Paediatric population

There is no relevant use of Provenge in the paediatric population in children and adolescents less than 18 years of age in the indication of asymptomatic or minimally symptomatic metastatic (non-visceral) castrate resistant prostate cancer in male adults in whom chemotherapy is not yet clinically indicated.

Method of administration

Provenge is solely intended for autologous use via intravenous infusion.

Provenge should be infused intravenously over a period of approximately 60 minutes. The entire volume of the bag should be infused. A cell filter should not be used. Vital signs should be taken at least 30 minutes prior to and 30 minutes following each infusion. Patients should be observed for at least 30 minutes following each infusion. For patients with cardiovascular disease or those at risk for cardiac ischaemia, physicians should consider observing patients for at least 60 minutes following each infusion with vital signs taken at 30 minutes and 60 minutes following the infusion.

If the infusion of Provenge must be interrupted, it should not be resumed if the infusion held at room temperature (25°C) for more than 3 hours.

Precautions to be taken before handling or administering the medicinal produ

Provenge is not tested for transmissible infectious diseases and hence may car risk of transmitting infectious diseases to healthcare professionals handling the product. Appropriate precautions should be employed when handling Provenge (see section 4.4).

It must be ensured that the APPROVED Final Product Disposition Notification form has been received from the marketing authorisation holder and the product has not expired (see section 6.6).

Before infusion, it must be confirmed that the patient’s identity matches the essential unique patient information on the Provenge bag and on the Final Product Disposition Notification form.

The bag should be removed from the insulated polyurethane container and inspected for leaks, external damage, foreign particulate matter, or clumps/clots.

Contents of the bag will be slightly cloudy, with a cream to pink colour. Gently mix and re-suspend the contents of the bag, inspecting for particles, clumps or clots. Small clumps of cellular material should disperse with gentle manual mixing.

Do not administer if the bag leaks during handling or if particles or clumps remain in the bag.

For full instructions on the preparation and handling of Provenge, see section 6.6.

Hypersensitivity to the active substances or to any of the excipients listed in section 6.1.

4.4 Special warnings and precautions for use

General

Provenge is intended solely for autologous use and should under no circumstances be administered to other patients. Prior to infusion, it must be confirmed that the patient’s identity matches the essential unique patient information on the Provenge bag and on the Final Product Disposition Notification form (see sections 4.2 and 6.6).

Acute infusion reactions

Acute infusion reactions have been observed in patients treated with Provenge. Acute infusion reactions (reported within 1 day of infusion) included, but were not limited to, fever, chills, respiratory events (dyspnoea, hypoxia, and bronchospasm), nausea, vomiting, fatigue, hypertension, and tachycardia. In the event of an acute infusion reaction, the infusion rate may be decreased, or the infusion stopped, depending on the severity of the reaction. Appropriate medical therapy should be administered as needed.

In controlled clinical trials, 23.8% of patients treated with Provenge required opioids (a single dose of pethidine) on the day of infusion for infusion reactions (see sections 4.2 and 4.8).

Patients with cardiac or pulmonary conditions should be closely monitored (see section 4.8).

Infection

Patients with positive serology tests for human immunodeficiency virus [HIV] 1 and 2, human T cell lymphotropic virus [HTLV] 1, and hepatitis B and C were excluded from controlled clinical trials. No data are available for these patients.

Provenge should be delayed in patients with active systemic infection until resolution. Serious infections including sepsis have been observed in patients treated with Provenge. Some serious infections and sepsis were related to the use of central venous catheters (CVCs). To reduce the risk of catheter-related infections, CVCs should be considered only for patients with poor peripheral venous access. These patients should be closely monitored for signs and symptoms of infection.

Embolic and thrombotic events

Provenge should be used with caution in patients with a history of embolic and thrombotic disorders.

Cerebrovascular disease

In controlled clinical trials, cerebrovascular events (hemorrhagic and ischaemic strokes) were observed in 3.5% of patients in the Provenge group compared with 2.6% of patients in the control group. The clinical significance is uncertain. .

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. The clinical significance is uncertain.

Immunocompromised patients

Provenge should be used with caution in immunocompromised patients in general including patients taking systemic immunosuppressive therapy, after careful consideration of the potential risk-benefit on an individiual basis. No data are available for these patients.

Microbiological testing

Provenge is released foi 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 will not be available at the time of infusion. If the sterility results become positive for microbial contamination after Provenge has been approved for infusion, the marketing authorisation holder will notify the treating physician and may request additional information from the physician in order to determine the source of contamination. The physician should monitor and/or treat the patient as appropriate.

Handling precautions for control of infectious disease

Provenge is prepared from human blood of the specific patient and is not tested for transmissible infectious agents. Patient leukapheresis material is tested for transmissible infectious agents in line with applicable member state requirements. However, as Provenge is an autologous product, a positive test does not preclude the manufacture of the product. Therefore, patient leukapheresis material and Provenge may carry the risk of transmitting infectious viruses (HIV 1 and 2, hepatitis B and C) to healthcare professionals handling the product. Accordingly, healthcare professionals should employ appropriate precautions when handling leukapheresis material or Provenge.

Additionally, there is the small possibility/risk of transmitting infectious viruses to a patient if he is not the intended recipient of the product. Hence it is important that the procedures for handling and administering the product are precisely followed (see section 6.6). It is strongly recommended that upon completion of each Provenge infusion, the patient specific label on the infusion bag, which contains the patient name, product name, and chain of identity (COI) product lot number, is removed and adhered to the patient file in order to maintain a link between the patient and the lot of the product.

Cases in which Provenge cannot be infused

In some cases, the patient may be unable to receive a scheduled infusion of Provenge. This may be due to release criteria not being met during manufacturing, the expiration time being exceeded, or the patient being unable to meet the scheduled infusion time. In such cases, the patient may need to undergo an additional leukapheresis procedure if the treatment is to be continued. It is recommended that the minimum interval between leukapheresis procedures should not be less than 2 weeks. In controlled clinical trials, 25.4% of patients treated with Provenge required more than 3 leukapheresis procedures in order to receive 3 infusions. In post-marketing experience of greater than 5,000 patients treated, this incidence is approximately 19% (see section 4.2). :<w

Immunisations

The risks and benefits of vaccinating patients during the course of treatment with Provenge have not been studied. Therefore, vaccinations with live attenuated or inactivated vaccines whilst receiving Provenge should be carefully considered.

Educational materials

All physicians who intend to prescribe Provenge must review the educational materials and sign the training verification form. Physicians must provide the educational materials to the patient as well as the package leaflet and the Patient Alert Card.

Sodium and potassium content

This medicinal product contains approximately 800 mg sodium per infusion. To be taken into consideration by patients on a controlled sodium diet. The product also contains approximately 45 mg potassium per infusion. To be taken into consideration by patients with reduced kidney function or patients on a controlled potassium diet.

Patients with renal impairment and/or hyperkalaemia

The content of sodium and potassium per infusion should be taken into account if administered in patients with cardiovascular diseases and/or renal impairment. Hyperkalaemia should be corrected prior to Provenge administration (see section 4.2).

4.5 Interaction with other medicinal products and other forms of interaction

No interaction studies have been performed with Provenge.

Provengeis designed to stimulate the immune system. Immunocompromised patients and patients taking systemic immunosuppressive therapy were excluded from controlled clinical trials. Concurrent use of immunosuppressive agents (such as systemic corticosteroids) may alter its efficacy and/or safety. Therefore, concurrent use of immunosuppressive agents (such as systemic corticosteroids) should be avoided during Provenge treatment. Patients should be carefully evaluated to determine whether it is medically appropriate to discontinue immunosuppressive agents prior to treatment with Provenge (see section 4.4).

4.6 Fertility, pregnancy and lactation

Pregnancy

Provenge is not intended for use in women.

Breast-feeding

Provenge is not intended for use in women.

Fertility

Effect on male fertility is not known.

Conventional reproductive and development toxicity studies are not considered relevant given the nature and the intended clinical use of this autologous cell therapy product.

4.7 Effects on ability to drive and use machines

Provenge has moderate influence on the ability to drive and use machines, as it may cause fatigue, dizziness, syncope, chills, and headache. Patients should be advised not to drive or use machines if they experience these symptoms following their infusion.

4.8 Undesirable effects

Summary of safety profile

The safety evaluation of Provenge is based on data from 601 prostate cancer patients in four randomized, controlled clinical trials (3 studies in metastatic castrate resistant prostate cancer and 1 study in androgen dependent prostate cancer) and post-marketing surveillance.

Serious adverse reactions include acute infusion reactions, catheter sepsis, bacteraemia, myocardial infarction, and cerebrovascular events.

The most commonly reported adverse reactions are chills, fatigue, pyrexia, nausea, arthralgia, headache, and vomiting.

In the pivotal randomised controlled study (D9902B, IMPACT, see section 5.1) Provenge was discontinued in 1.5% of patients due to adverse reactions. Some patients developed infection, including sepsis. Infections due to contaminated product also occurred in some patients. A small number of these patients discontinued treatment as a result.

Tabulated list of adverse reactions

The following list of adverse reactions is based on experience from clinical trials and on postmarketing experience and are displayed by system organ class and frequency of occurrence: very common (>1/10), common (>1/100 to <1/10), uncommon (>1/1,000 to <1/100), rare (>1/10,000 to <1/1,000), very rare (<1/10,000), and not known (cannot be estimated from the available data). adverse reactions are presented in order of decreasing seriousness.

Table 1

Adverse reactions from clinical studies and post-marketing reports

Description of selected adverse reactions

Acute infusion reactions

In controlled clinical trials, 71.2% of patients in the Provenge group developed an acute infusion reaction. The most common reactions (> 20%) were chills, fever, and fatigue. In 95.1% of patients reporting acute infusion reactions, the events were mild or moderate. Fevers and chills generally resolved within 2 days (71.9% and 89.0%, 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, dyspnoea, hypoxia, bronchospasm, dizziness, headache, hypertension, muscle ache, nausea, and vomiting. The incidence of severe reactions 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, 23.8% of patients in the Provenge group required opioids (a single dose of pethidine) on the day of infusion for infusion reactions compared with 2.4% of patients in control group (see sections 4.2 and 4.4).

In the post-marketing setting, serious acute infusion reactions involving hypotension and syncope have been reported. Some have resulted in hospitalization.

Patients should be informed of the possibility of late onset reactions and instructed to contact their physician if symptoms of dyspnoea, bronchospasm, dizziness, rash, or pyrexia occur.

pX

Infection

In controlled clinical trials, infection occurred in 27.5% of subjects in the Provenge group and 27.7% of subjects in the control group. Serious infections occurred in 4.7% of subjects in the Provenge group and 4.0% of subjects in the control group. The most frequently occurring serious infections in the Provenge group were catheter sepsis (0.7%), staphylococcal bacteraemia (0.7%), sepsis (0.7%), staphylococcal sepsis (0.5%), and pneumonia (0.5%).

Reports of serious infection have been received in post-marketing surveillance including devicerelated infection, device-related sepsis, pneumonia, sepsis, bacteraemia, and urinary tract infection.

Adverse reactions associate d m ith leukapheresis

Each dose of Provenge requires a standard leukapheresis procedure approximately 3 days prior to the infusion. Citrate is generally the preferred anticoagulant used during leukapheresis and can result in hypocalcaemia Adv else reactions that were reported most commonly < 1 day following a leukapheresis procedure in controlled clinical trials included citrate toxicity (14.6%), oral paraesthesia (12.0%), and paraesthesia (11.1%). Additional adverse reactions that were seen commonly < 1 day following a leukapheresis procedure in controlled clinical trials included fatigue (5.5%), muscle spasm (4.0%), chills (3.0%), dizziness (2.8%), and anaemia (2.8%). Additionally, there have been reports of thrombocytopenia received in spontaneous post-marketing reporting that have been temporally associated with leukapheresis.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the national reporting system listed in Appendix V.

4.9 Overdose

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 from the leukapheresis. There are no known instances of overdose from either a single infusion or a full course of therapy with Provenge.

5. PHARMACOLOGICAL PROPERTIES5.1 Pharmacodynamic properties

Pharmacotherapeutic group: Immunostimulants, other immunostimulants, ATC code: L03AX17.

Mechanism of action

Provenge is an autologous cellular immunotherapy designed to induce an immune response targeted against prostatic acid phosphatase (PAP), an antigen expressed in most prostate cancers. Peripheral blood mononuclear cells collected from the patients are cultured with PAP-GM-CSF, a fusion protein consisting of PAP linked to granulocyte-macrophage colony-stimulating factor (GM-CSF) an immune cell activator. During ex vivo culture with PAP-GM-CSF, activated APCs (antigen presenting cells) take up and process the recombinant target antigen into peptides that are then presented to T cells. Product characterization shows that PAP and PAP-GM-CSF fusion protein-specific T cells are generated during treatment and are detected in the peripheral blood of patients after treatment with Provenge.

virtue of increased surface CD54 expression after culture with P and costimulatory molecule essential in the formation of the        ogical synapse between an APC

and a T cell. The degree of CD54 upregulation correlates wi verall survival in the randomised controlled clinical trials carried out with Provenge in metastatic castrate resistant prostate cancer. In clinical study D9902B (IMPACT), 237 out of the 512 patients randomized were evaluated for the development of humoral or cellular immune responses (T cell proliferation and gamma-interferon (yIFN) ELISPOT) to the target antigens at baseline, and at Weeks 6, 14, and 26. Antibody (IgM and IgG) responses against both PAP-GM-CSF and the PAP antigens were observed in the Provenge group through the follow up period. T cel. prooliferative and yIFN ELISPOT responses to PAP and PAP-GM-CSF were observed in cells collected from peripheral blood of patients through the follow-up period in the Provenge treatment group but not in controls. There was a correlation between cellular or antibody responses to PAP or PAP-GM-CSF in the Provenge group and improved survival. Neutralising antibody responses to GM-CSF were transient.

Clinical efficacy and safety

The efficacy and safety of Provenge in patients with asymptomatic or minimally symptomatic metastatic castrate resistant prostate cancer were studied in three similar Phase III, randomised, double-blind, controlled, multicentre trials: D9902B (IMPACT), D9901, and D9902A. The patients enrolled in these trials had failed surgical or medical castration (e.g. luteinising hormone-releasing hormone [LHRH] agonist or gonadotropin-releasing hormone [GnRh] antagonist) therapies and had metastatic disease in the soft tissue and/or bone. Patients did not require opioid analgesics for pain management and the majority had not received prior chemotherapy.

Following randomization, patients from both treatment groups underwent a series of 3 leukapheresis procedures (at approximately 2 week intervals, range 1 to 15 weeks). Each leukapheresis was followed approximately 3 days later by infusion of Provenge or control. The control was nonactivated autologous peripheral blood mononuclear cells. Following disease progression, patients were treated at the physician’s dis­cretion with other anti-cancer interventions. Patients in the control group could enrol in an open-label protocol and receive an investigational autologous cellular therapy manufactured from cells cryopreserved at the time the control product was prepared.

IMPACT study

The IMPACT study was a randomised, double-blind, controlled, multicentre trial in patients with asymptomatic or minimally symptomatic metastatic castrate resistant prostate cancer. Eligible patients had metastatic disease in the soft tissue and/or bone with current or historical evidence of disease progression concomitant with surgical or medical castration, as evidenced by progression of serum prostate specific antigen (PSA) and/or bone or soft tissue disease, and an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1. Exclusion criteria included visceral (liver, lung, or brain) metastases, malignant pleural effusions or malignant ascites, pathologic long bone fractures, imminent pathologic long-bone fractures (cortical erosion on radiography >50%), spinal cord compression, moderate to severe prostate cancer-related pain and use of narcotics for cancer-related pain, and treatment with chemotherapy at least 3 months prior to randomisation. The primary endpoint was overall survival. Secondary endpoints included time to objective disease progression, time to clinical progression, and PSA doubling time (PSADT).

A total of 512 patients were randomised in a 2:1 ratio to receive Provenge (n=341) or control (n= The median age was 71, 90% of the patients were Caucasian, and all had a life expectancy of at le 6 months. Thirty-five percent of patients had undergone radical prostatectomy, 54% had received local radiotherapy, and 82% had received combined androgen blockade. All patients had testosterone levels < 50 ng/mL. Forty-eight percent of patients were receiving bisphosphonates and 18% had received prior chemotherapy, including docetaxel. Eighty-two percent of patients had an ECOG performance status of 0; 75% had a Gleason sum < 7; 44% had bone and Soft tissue disease; 48% had bone-only disease; 7% had soft tissue-only disease; and 43% had greater than ten bony metastases.

A statistically significant improvement in overall survival was seen in patients treated with Provenge, with a 22.5% reduction in the risk of death compared with control (see Table 2 and Figure 1). Of the control arm patients, 64% crossed over to receive an investigational autologous cellular immunotherapy manufactured from cells cryopreserved at the time the control was manufactured; patients were not randomised to subsequent autologous cellular immunotherapy.

A retrospective subgroup analysis has suggested a greater Provenge treatment effect in patients with a baseline PSA < 22.1 ng/mL [HR= 0.521 (95% CI: 0.309, 0.879)]. Intermediate results were observed in patients with baseline PSA > 22.1 to 50.1 ng/mL [HR=0.685 (95% CI: 0.431, 1.088)] and patients with baseline PSA > 50.1 to 134.1 ng/mL [HR=0.819 (95% CI: 0.532, 1.262)]. A smaller treatment effect was observed in those with baseline PSA > 134.1 ng/mL [HR=0.853 (95% CI: 0.554, 1.315)].

Analyses of time to objective disease progression, time to clinical progression, or PSA doubling time (PSADT) did not meet statistical significance.

Supportive studies

Study D9901 was a randomised, double-blind, controlled, multicentre trial in patients with metastatic castrate resistant prostate cancer and no cancer-related pain. The primary endpoint was time to disease progression, which did not reach statistical significance. Overall survival was not a study endpoint but a pre-specified analysis. Patients treated with Provenge had a statistically significant survival advantage compared with control.

A third study, D9902A, similar in design to study D9901, was terminated prior to completion of planned accrual based on the time to disease progression results in study D9901. The primary endpoint was time to disease progression and the secondary endpoint was overall survival. Neither endpoint met statistical significance.

Summary of study results

Table 2 presents overall survival results observed in IMPACT, study D9901, and study D9902A.

Table 2

Summary of overall survival (all patients as randomized)

bisphosphonate use, number of bone metastases, and primary Gleason grade.

b Hazard ratio based on the unadjusted Cox Model.

c p-value based on a log-rank test.

Abbreviations: CI = confidence interval.

Paediatric population

The European Medicines Agency has waived the obligation to submit the results of studies with Provenge in all subsets of the paediatric population in the treatment of prostate cancer (see section 4.2 for information on paediatric use).

5.2 Pharmacokinetic properties

Provenge is an autologous cellular therapy. The nature of Provenge is such that conventional studies on pharmacokinetics, absorption, distribution, metabolism, and elimination are not applicable.

5.3 Preclinical safety data

Conventional toxicology, carcinogenicity, mutagenicity, and reproductive toxicity studies have not been performed.

6. QUALITY PARTICULARS6.1 List of excipients

6.2 Incompatibilities

In the absence of compatibility studies, this medicinal product must not be mixed with other medicinal products.

6.3 Shelf life

In the insulated container 18 hours.

After removal from the insulated container

The medicinal product should be used immediately. If not used immediately, in-use storage times and conditions should not exceed 3 hours at room temperature (25°C).

6.4 Special precautions for storage

6.5 Nature and contents of container and special equipment for use, administration or implantation

6.6 Special precautions for disposal and other handling

Provenge is intended solely for autologous use. The identity of the patient must essential unique patient information on the infusion bag and the Final Product D Notification form prior to infusion.

Provenge is not tested for transmissible infectious agents. Patient leukapheresis material is tested for transmissible infectious agents in line with applicable member state requirements. However, as it is

an autologous product, a positive test does not preclude the manufact patient leukapheresis material and Provenge may carry the risk of t healthcare professionals handling the product. Accordingly, he appropriate precautions when handling leukapheresis material o

Handling instructions

Before handling or administering Provenge

• • Provenge is shipped directly to the medical facility where the infusion will be administered. The infusion bag is placed inside an insulated polyurethane container and packed in a shipping box. The insulated c iner and the gel packs within are designed to maintain the appropriate transportation age temperature of Provenge until infusion. Do not irradiate.
• • The outer shipping box should be opened to verify the product and patient-specific labels located on the top of the insulated container. Do not remove this insulated container from the shipping box, or open the lid of the insulated container, until the patient is ready for infusion.

Take care to ensure aseptic handling when preparing the infusion.

What to check prior to infusion

• • It must be ensured that the Final Product Disposition Notification form containing the patient identifiers, expiration date and time, and the disposition status (approved for infusion or rejected), has been received from the marketing authorisation holder.
• • It must be ensured that the patient’s identity matches the essential unique patient information on the Provenge bag and on the Final Product Disposition form.
• • Once the patient is prepared for infusion and the APPROVED Final Product Disposition Notification form has been received, the Provenge bag should be removed from the insulated container and inspected for leaks, external damage, foreign particulate matter, or clumps/clots.
• • Contents of the bag will be slightly cloudy, with a cream to pink colour. Gently mix and re-suspend the contents of the bag, inspecting for clumps and clots. Small clumps of cellular material should disperse with gentle manual mixing.
• • If the Provenge bag leaks, is damaged, or if particles or clumps remain in the bag after gentle manual mixing, the product must not be used.

Administration

• • Infusion must begin prior to the expiration date and time indicated on the Final Product Disposition Notification form and bag label. Do not initiate infusion of expired Provenge.
• • Only one of the 2 spike ports should be used and should not be opened prior to administration in order to avoid contamination.

Provenge is infused over a period of approximately 60 minutes through a large bore needle appropriate for transfusion of red blood cells. This peripheral delivery system is commonly used in clinical practice for the transfusion of blood components. Do not use a cell filter for infusion. The entire volume of the infusion bag should be used.

If the infusion of Provenge must be interrupted, it should not be resumed if the infusion bag has been held at room temperature (25°C) for more than 3 hours.

After the infusion

• • Upon completion of the infusion, the patient specific label on the infusion bag should removed and adhered to the patient file.
• • Any unused product or waste material should be disposed of in accordance with local requirements.

7. MARKETING AUTHORISATION HOLDER

Dendreon UK Limited 41 Chalton Street

London, NW1 1JD United Kingdom

Tel: (0)20 7554 2222

Fax: (0)20 7554 2201

8. MARKETING AUTHORISATION NUMBER(S)

EU/1/13/867/001