Injection, USP in a sealed, patient-specific infusion
`
`bag. (3)
`
` - - - - - - -
`CONTRAINDICATIONS -
`
`
`
` - - - - - - - - -
`
`• None. (4)
`
`
`
`
`- - - - - WARNINGS AND PRECAUTIONS
`
`- - - - ­
`
` • PROVENGE is intended solely for autologous
`
`
`use. (5)
` • Acute infusion reactions have been observed in
`
`
`
`
` patients treated with PROVENGE. 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.
`
`
`Closely monitor patients with cardiac or
`
`pulmonary conditions. (2.8, 5.1)
` • PROVENGE is not routinely tested for
`
`
`
` transmissible infectious diseases and may transmit
`
`diseases to health care professionals handling the
`
`product. Universal precautions should be
`
`followed. (2.3, 5.2)
`• Concomitant use of chemotherapy and
`
`
`immunosuppressive medications with
`
`
`PROVENGE has not been studied. (5.3)
`
`
`
`
` - - - - - - - - ­
`
`- - - - - - - - - ADVERSE REACTIONS
`• The most common adverse reactions (incidence
`
`
`≥ 15%) are chills, fatigue, fever, back pain,
`
`
`nausea, joint ache, and headache. (6.1)
`To report SUSPECTED ADVERSE
`REACTIONS, contact Dendreon Corporation at
`
`
`1-877-336-3736 or FDA at 1-800-FDA-1088 or
`www.fda.gov/medwatch.
`
`See 17 for PATIENT COUNSELING
`INFORMATION and FDA-approved patient
`
`labeling.
`Revision date: Month/Year
`
`HIGHLIGHTS OF PRESCRIBING
`INFORMATION
`These highlights do not include all of the
`information needed to use PROVENGE®
`
`(sipuleucel-T) safely and effectively. See Full
`Prescribing Information for PROVENGE.
`PROVENGE® (sipuleucel-T)
`
`Suspension for Intravenous Infusion
`
`Initial U.S. Approval: 2010
`
`
` - - - - - - ­
`
`
`
`- - - - - - - INDICATIONS AND USAGE
`
`PROVENGE is an autologous cellular
`immunotherapy indicated for the treatment of
`
`asymptomatic or minimally symptomatic metastatic
`castrate resistant (hormone refractory) prostate
`cancer. (1)
`
`
`
`- - - ­
`
`
`
`- - - - - DOSAGE AND ADMINISTRATION
`•
`For Autologous 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.
`
`(2.6)
` • Do not initiate infusion of expired
`
`
`PROVENGE. (2.7)
` • Infuse PROVENGE intravenously over a period of
`
`
`approximately 60 minutes. Do Not Use a Cell
`Filter. (2.7)
`
` • Interrupt or slow infusion for acute infusion
`
`
` reactions, depending on the severity of the
`
`reaction. (2.8)
`
`- - - -
`DOSAGE FORMS AND STRENGTHS - - - -
`
`
` 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
`
`
`
`
`
`
`
`
`
`
`Page 1 of 17
`
`
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`
`
`AVENTIS EXHIBIT 2196
`Mylan v. Aventis IPR2016-00712
`
`

`
`
`
`
`
`
`
`
`
`FULL PRESCRIBING INFORMATION:
`CONTENTS*
`
`
`1
`INDICATIONS AND USAGE
`
`
`
`2 DOSAGE AND ADMINISTRATION
`
`
`
`2.1 Dose and Schedule
`
`2.2
` Premedication
`
`
`2.3 Handling Precautions for Control
`of Infectious Disease
`
`
`2.4 Storage
`2.5 Confirm Product Release Before Infusion
`
`2.6
` Preparation for Infusion
`
`
`2.7 Administration
`
`
`
`2.8 Administration Modification
`
`
`
`for Infusion Reactions
`
`
`
`
`3 DOSAGE FORMS AND STRENGTHS
`
`4 CONTRAINDICATIONS
`
`5 WARNINGS AND PRECAUTIONS
`
`
`
`5.1 Acute Infusion Reactions
`
`
`
`5.2 Handling Precautions for Control
`of Infectious Disease
`
`
`
`5.3 Concomitant Chemotherapy or
`
`
`
`Immunosuppressive Therapy
`
`
`5.4 Product Safety Testing
`
`6 ADVERSE REACTIONS
`
`
`6.1 Clinical Trials Experience
`
`
`
`
`7 DRUG INTERACTIONS
`
`8 USE IN SPECIFIC POPULATIONS
`
`
`8.5 Geriatric
`
`8.6
` Race
`10 OVERDOSAGE
`
`11 DESCRIPTION
`
`12 CLINICAL PHARMACOLOGY
`
`12.1 Mechanism of Action
`
`
`
`13 NONCLINICAL TOXICOLOGY
`
`
`
`13.1 Carcinogenesis, Mutagenesis, Impairment
`
`
`
`
`of Fertility
`14 CLINICAL STUDIES
`
`16 HOW SUPPLIED/STORAGE AND
`
`HANDLING
`17 PATIENT COUNSELING INFORMATION
`
`
`
`* Sections or subsections omitted from the Full
`
`Prescribing Information are not listed.
`
`
`
`
`
`
`
`Page 2 of 17
`
`
`
`
`
`

`
`
`
`FULL PRESCRIBING INFORMATION
`
`
`
`INDICATIONS AND USAGE
`1
`PROVENGE® (sipuleucel-T) is an autologous cellular immunotherapy indicated for the
`treatment of asymptomatic or minimally symptomatic metastatic castrate resistant (hormone
`refractory) prostate cancer.
`
`2
`DOSAGE AND ADMINISTRATION
`For Autologous Use Only.
`For Intravenous Use Only. Do Not Use a Cell Filter.
`Do Not Initiate Infusion of Expired Product.
`
`
`Dose and Schedule
`2.1
`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 if the course of treatment
`is to be continued. Patients should be advised of this possibility prior to initiating treatment.
`
`
`Premedication
`2.2
`
`To minimize potential acute infusion reactions such as chills and/or fever, it is recommended
`that patients be premedicated orally with acetaminophen and an antihistamine such as
`diphenhydramine approximately 30 minutes prior to administration of PROVENGE [see
`Warnings and Precautions (5.1)].
`
`2.3 Handling Precautions for Control of Infectious Disease
`PROVENGE is not routinely 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. Employ universal precautions in
`handling leukapheresis material or PROVENGE. [See How Supplied/Storage and Handling
`(16).]
`
`
`
`
`Page 3 of 17
`
`
`
`
`
`

`
`
`
`
`
`Storage
`2.4
`The PROVENGE infusion bag must remain within the insulated polyurethane container until
`the time of administration. Do not remove the insulated polyurethane container from the
`outer cardboard shipping box. [See How Supplied/Storage and Handling (16).]
`
`
`2.5
`Confirm Product Release Before Infusion
`Do not infuse PROVENGE until confirmation of product release has been received from
`
`Dendreon. Dendreon will send a Cell Product Disposition Form containing the patient
`identifiers, expiration date and time, and the disposition status (approved for infusion or
`rejected), to the infusion site. [See How Supplied/Storage and Handling (16).]
`
`
`2.6
`
`Preparation for Infusion
`
`See How Supplied/Storage and Handling (16) for full handling instructions.
`Confirm Patient Identity
`
`PROVENGE is intended solely for autologous use. Confirm the proper product has been
`received according to the label on the outside of the insulated polyurethane container. Prior
`to PROVENGE infusion, match the patient’s identity with the patient identifiers on the Cell
`Product Disposition Form and the PROVENGE infusion bag.
`
`Inspect the Infusion Bag
`
`Remove the infusion bag from the insulated polyurethane container and inspect the bag for
`signs of leakage. Do not administer if the bag leaks.
`Contents of the bag will be slightly cloudy, with a cream-to-pink color. 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. Do not administer if the bag leaks
`during handling or if clumps remain in the bag.
`
`2.7
`Administration
`
`Infusion must begin prior to the expiration date and time indicated on the Cell Product
`Disposition Form and Product Label. Do not initiate infusion of expired PROVENGE.
`Administer PROVENGE via intravenous infusion over a period of approximately
`60 minutes. Do not use a cell filter. PROVENGE is supplied in a sealed, patient-specific
`
`
`infusion bag; the entire volume of the bag should be infused.
`Observe the patient for at least 30 minutes following each infusion.
`
`Administration Modification for Infusion Reactions
`2.8
`Acute infusion reactions such as chills, fatigue, fever, nausea, and joint ache were frequently
`observed in studies of PROVENGE. To mitigate such reactions, premedication, consisting
`
`
`
`
`Page 4 of 17
`
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`
`
`

`
`
`
`of acetaminophen and an antihistamine such as diphenhydramine, was administered in
`clinical studies prior to infusion.
`In the event of an acute infusion reaction, the infusion may be interrupted or slowed,
`depending on the severity of the reaction. Appropriate medical therapy should be
`administered 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 of PROVENGE must be interrupted, the infusion should not be resumed if the
`PROVENGE infusion bag will be held at room temperature for more than 3 hours. [See How
`Supplied/Storage and Handling (16).]
`
`
`3
`
`Dosage Forms and Strengths
`
`
`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 in a
`sealed, patient-specific infusion bag.
`
`CONTRAINDICATIONS
`
`4
`None.
`
`WARNINGS AND PRECAUTIONS
`5
`PROVENGE is intended solely for autologous use.
`
`
`Acute Infusion Reactions
`5.1
`Acute infusion reactions (reported within 1 day of infusion) included, but were not limited to,
`fever, chills, respiratory events (dyspnea, hypoxia, and bronchospasm), nausea, vomiting,
`fatigue, 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
`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,
`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.
`
`
`
`
`Page 5 of 17
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`
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`
`
`

`
`
`
`Closely monitor patients with cardiac or pulmonary conditions. 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.
`[See Administration Modification for Infusion Reactions (2.8) and How Supplied/Storage and
`
` Handling (16).]
`
`
`5.2 Handling Precautions for Control of Infectious Disease
`PROVENGE is not routinely 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. [See How Supplied/Storage and Handling (16).]
`
`
`Concomitant Chemotherapy or Immunosuppressive Therapy
`5.3
`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
`immunosuppressive agents may alter the efficacy and/or safety of PROVENGE. Therefore,
`patients should be carefully evaluated to determine whether it is medically appropriate to
`reduce or discontinue immunosuppressive agents prior to treatment with PROVENGE.
`
`
` Product Safety Testing
`
`5.4
` 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.
`
`6
`
`ADVERSE REACTIONS
`
`Clinical Trials Experience
`6.1
`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.
`
`
`
`
`
`Page 6 of 17
`
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`

`
`
`
`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 was non-activated autologous peripheral blood
`mononuclear cells.
`Almost all (98.3%) patients in the PROVENGE group and 96.0% in the control group
`reported an adverse event. The most common adverse events, reported in patients in the
`PROVENGE group at a rate ≥ 15%, were chills, fatigue, fever, back pain, nausea, joint ache,
`and headache. 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 4.0% 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 24.0% 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, 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.
`
`
`
`
`Page 7 of 17
`
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`
`
`

`
`
`
`Table 1
`
`Incidence of Adverse Events Occurring in ≥ 5% of Patients Randomized
`to PROVENGE
`
`
`
`
`
`Any Adverse Event
`
`Chills
`Fatigue
`Fever
`Back pain
`Nausea
`Joint ache
`Headache
`Citrate toxicity
`Paresthesia
`Vomiting
`Anemia
`Constipation
`Pain
`Paresthesia oral
`Pain in extremity
`Dizziness
`Muscle ache
`Asthenia
`Diarrhea
`Influenza-like illness
`Musculoskeletal pain
`Dyspnea
`Edema peripheral
`Hot flush
`Hematuria
`
`Muscle spasms
`
`PROVENGE
`
`(N = 601)
`
`All Grades Grade 3-5
`n (%)
`n (%)
`591 (98.3)
`186 (30.9)
`319 (53.1)
`13 (2.2)
`247 (41.1)
`6 (1.0)
`188 (31.3)
`6 (1.0)
`178 (29.6)
`18 (3.0)
`129 (21.5)
`3 (0.5)
`118 (19.6)
`11 (1.8)
`109 (18.1)
`4 (0.7)
`89 (14.8)
`0 (0.0)
`85 (14.1)
`1 (0.2)
`80 (13.3)
`2 (0.3)
`75 (12.5)
`11 (1.8)
`74 (12.3)
`1 (0.2)
`74 (12.3)
`7 (1.2)
`74 (12.3)
`0 (0.0)
`73 (12.1)
`5 (0.8)
`71 (11.8)
`2 (0.3)
`71 (11.8)
`3 (0.5)
`65 (10.8)
`6 (1.0)
`60 (10.0)
`1 (0.2)
`58 (9.7)
`0 (0.0)
`
`54 (9.0)
`3 (0.5)
`52 (8.7)
`11 (1.8)
`50 (8.3)
`1 (0.2)
`49 (8.2)
`2 (0.3)
`46 (7.7)
`6 (1.0)
`46 (7.7)
`2 (0.3)
`
`Control*
`(N = 303)
`
`
`All Grades Grade 3-5
`
`n (%)
`n (%)
`
`291 (96.0)
`97 (32.0)
`33 (10.9)
`0 (0.0)
`105 (34.7)
`4 (1.3)
`29 (9.6)
`3 (1.0)
`87 (28.7)
`9 (3.0)
`45 (14.9)
`0 (0.0)
`62 (20.5)
`5 (1.7)
`20 (6.6)
`0 (0.0)
`43 (14.2)
`0 (0.0)
`43 (14.2)
`0 (0.0)
`23 (7.6)
`0 (0.0)
`34 (11.2)
`7 (2.3)
`40 (13.2)
`3 (1.0)
`20 (6.6)
`3 (1.0)
`43 (14.2)
`0 (0.0)
`40 (13.2)
`1 (0.3)
`34 (11.2)
`0 (0.0)
`17 (5.6)
`0 (0.0)
`20 (6.6)
`2 (0.7)
`34 (11.2)
`3 (1.0)
`11 (3.6)
`0 (0.0)
`31 (10.2)
`3 (1.0)
`14 (4.6)
`3 (1.0)
`31 (10.2)
`1 (0.3)
`29 (9.6)
`1 (0.3)
`18 (5.9)
`3 (1.0)
`17 (5.6)
`0 (0.0)
`
`
`
`
`Page 8 of 17
`
`
`
`
`
`

`
`
`
`
`
`
`
`Any Adverse Event
`Hypertension
`Anorexia
`Bone pain
`Upper respiratory tract
`
` infection
`0 (0.0)
`37 (6.2)
`Insomnia
`2 (0.3)
`36 (6.0)
`Musculoskeletal chest pain
`0 (0.0)
`35 (5.8)
`Cough
`3 (0.5)
`34 (5.7)
`Neck pain
`2 (0.3)
`34 (5.7)
`Weight decreased
`1 (0.2)
`33 (5.5)
`Urinary tract infection
`0 (0.0)
`31 (5.2)
`Rash
`1 (0.2)
`30 (5.0)
`Sweating
`
`0 (0.0)
`30 (5.0)
`Tremor
` * Control was non-activated autologous peripheral blood mononuclear cells.
`
`
`
`
`
`
` PROVENGE
`(N = 601)
`
` All Grades Grade 3-5
`n (%)
`n (%)
`591 (98.3)
`186 (30.9)
`45 (7.5)
`3 (0.5)
`39 (6.5)
`1 (0.2)
`38 (6.3)
`4 (0.7)
`38 (6.3)
`0 (0.0)
`
`Control*
`(N = 303)
`
` All Grades Grade 3-5
`n (%)
`n (%)
`291 (96.0)
`97 (32.0)
`14 (4.6)
`0 (0.0)
`33 (10.9)
`3 (1.0)
`22 (7.3)
`3 (1.0)
`18 (5.9)
`0 (0.0)
`
`22 (7.3)
`23 (7.6)
`17 (5.6)
`14 (4.6)
`24 (7.9)
`18 (5.9)
`10 (3.3)
`3 (1.0)
`9 (3.0)
`
`1 (0.3)
`2 (0.7)
`0 (0.0)
`2 (0.7)
`1 (0.3)
`2 (0.7)
`0 (0.0)
`0 (0.0)
`0 (0.0)
`
`Cerebrovascular Events
`In controlled clinical trials, cerebrovascular events, including 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.
`
`DRUG INTERACTIONS
`7
`No studies of drug interactions have been performed with PROVENGE.
`
`8
`
`USE IN SPECIFIC POPULATIONS
`
`8.5 Geriatric
`In controlled clinical trials, 72.9% of patients (438 of 601) in the PROVENGE group were
`≥ 65 years of age. There were no apparent differences in the safety of PROVENGE between
`patients ≥ 65 years of age and younger patients.
`
`
`
`
`Page 9 of 17
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`

`
`
`
`In a survival analysis of the controlled clinical trials of PROVENGE in metastatic castrate
`resistant prostate cancer, 78.3% of randomized patients (382 of 488) were ≥ 65 years of age.
`The median survival of patients in the PROVENGE group ≥ 65 years of age was 23.4 months
`(95% confidence interval 22.0, 27.1), compared with 17.3 months in the control group (95%
`confidence interval: 13.5, 21.5).
`
`8.6
`Race
`
`In controlled clinical trials, 90.6% of patients were Caucasian, 5.8% were African American,
`and 3.7% were “Other”. Due to the low numbers of non-Caucasian patients in the trials, no
`conclusions can be made regarding the safety or efficacy of PROVENGE by race.
`
`
`10
`OVERDOSAGE
`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.
`
`
`DESCRIPTION
`11
`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. 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 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 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. 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.
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`The potency of PROVENGE is in part determined by measuring the increased expression of
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` 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.
`
`
`12
`
`CLINICAL PHARMACOLOGY
`
`
`12.1 Mechanism of Action
`
`PROVENGE is classified as an autologous cellular immunotherapy. While the precise
`mechanism of action is unknown, PROVENGE is designed to induce an immune response
`targeted against PAP, an antigen expressed in most prostate cancers. During ex vivo culture
`with PAP-GM-CSF, APCs take up and process the recombinant target antigen into small
`peptides that are then displayed on the APC surface.
`In Study 1, 237 out of the 512 patients randomized were evaluated for the development of
`humoral and T cell immune responses (proliferative and gamma-interferon (γIFN) ELISPOT)
`to the target antigens at Baseline, and at Weeks 6, 14, and 26. Antibody (IgM and IgG)
`responses against PAP-GM-CSF and PAP antigen alone were observed through the
`follow-up period in the PROVENGE group. Neutralizing antibody responses to GM-CSF
`were transient. T cell proliferative and γIFN ELISPOT responses to PAP-GM-CSF fusion
`protein were observed in cells collected from peripheral blood of patients through the
`follow-up period in the PROVENGE treatment group but not in controls. In some patients a
`response to PAP antigen alone was observed. No conclusions could be made regarding the
`clinical significance of the observed immune responses.
`
`13
`
`NONCLINICAL TOXICOLOGY
`
`13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
`No carcinogenicity or mutagenicity studies of PROVENGE in animals were conducted. No
`studies on the effects of PROVENGE on fertility have been conducted.
`
`14
`CLINICAL STUDIES
`The effect of PROVENGE on patients with metastatic castrate resistant (hormone refractory)
`prostate cancer was studied in three similar randomized, double-blind, placebo-controlled,
`multicenter trials. Following randomization, patients from both treatment groups underwent
`a series of 3 leukapheresis procedures (at approximately Weeks 0, 2, and 4). Each
`leukapheresis was followed approximately 3 days later by infusion of PROVENGE or
`control. The control was autologous peripheral blood mononuclear cells that had not been
`activated [see Description (11)]. Following disease progression, patients were treated at the
`
`
`physician’s discretion with other anti-cancer interventions.
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`Study 1
`Study 1 was a randomized, double-blind, placebo-controlled, multicenter trial in patients with
`asymptomatic or minimally symptomatic metastatic castrate resistant (hormone refractory)
`prostate cancer. Eligible patients had metastatic disease in the soft tissue and/or bone with
`evidence of progression either at these sites or by serial Prostate Specific Antigen (PSA)
`measurements. Exclusion criteria included visceral (liver, lung, or brain) metastases,
`moderate to severe prostate cancer-related pain, and use of narcotics for cancer-related pain.
`
`A total of 512 patients were randomized in a 2:1 ratio to receive PROVENGE (n=341) or
`control (n=171). The median age was 71, and 90% of the patients were Caucasian.
`Thirty-five percent of patients had undergone radical prostatectomy, 54% had received local
`radiotherapy, and 82% had received combined androgen blockade. All patients had baseline
`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; 58% had primary Gleason scores
`of four or more; 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.
`
`Supportive Studies
`Study 2 was a randomized, double-blind, placebo-controlled, multicenter trial in patients with
`metastatic castrate resistant prostate cancer and no cancer-related pain. The primary
`endpoint was time to disease progression; analysis of the primary endpoint did not reach
`statistical significance. All patients were to be followed for survival; however, the survival
`
`analysis was not pre-specified. A third study, similar in design to Study 2, was terminated
`prior to completion of planned accrual.
`
`Summary of Study Results
`Figure 1 and Table 2 present overall survival results observed in two randomized, Phase 3
`studies of PROVENGE in men with metastatic castrate resistant prostate cancer. The
`survival findings were consistent across multiple subgroups. Analyses of time to disease
`progression did not meet statistical significance in any Phase 3 study of PROVENGE.
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` Figure 1
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`Kaplan-Meier Overall Survival Curve for Study 1
`
`
`Table 2
`
`Summary of Overall Survival
`
` (All Patients as Randomized)
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`
`
`Study 1
`Study 2
`
`Control
`PROVENGE
`PROVENGE
`Control
`
`
`(N=45)
`(N=82)
`(N=171)
`(N=341)
`
`Overall Survival
`
`
`
`
`21.7
`25.8
` Median, months
` 21.4
`
` 25.9
`
`
`
`
`(17.7, 23.8)
`(22.8, 27.7)
`(95% CI)
`
` (12.3, 25.8)
` (20.0, 32.4)
`
`
`
`
` Hazard Ratio
`0.586b (0.388, 0.884)
`0.775a (0.614, 0.979)
`
`(95% CI)
`
`
`0.010c
`0.032a
` p-value
`
`
`
` a Hazard ratio and p-value based on the Cox Model adjusted for PSA (ln) and LDH (ln) and stratified by
`
`
`
`
` bisphosphonate use, number of bone metastases, and primary Gleason grade.
`b Hazard ratio based on the unadjusted Cox Model (not pre-specified).
`
`c p-value based on a log-rank test (not pre-specified).
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`
`Abbreviations: CI = confidence interval.
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`16
`HOW SUPPLIED/STORAGE AND HANDLING
`PROVENGE IS INTENDED SOLELY FOR AUTOLOGOUS USE. PROVENGE is a
`250 mL suspension containing a minimum of 50 million autologous CD54+ cells activated
`with PAP-GM-CSF in Lactated Ringer’s Injection, USP, and supplied in an infusion bag
`labeled for the specific recipient. The identity of the patient must be matched with the
`patient identifiers on the infusion bag and the Cell Product Disposition Form prior to
`infusion. PROVENGE is not routinely 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.
`Handling Instructions:
`
`1. PROVENGE is shipped directly to the infusing provider.
`2. PROVENGE will arrive in a cardboard shipping box with a special insulated
`polyurethane container inside. The insulated container and gel packs within the
`container are designed to maintain the appropriate transportation and storage
`temperature of PROVENGE until infusion.
`
`
`3. Upon receipt, the outer cardboard 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.
`
`4. Do not infuse PROVENGE until confirmation of product release has been received
`from Dendreon. Dendreon will send a Cell Product Disposition Form containing the
`patient identifiers, expiration date and time, and the disposition status (approved for
`infusion or rejected), to the infusion site.
`
`
`5. Infusion must begin prior to the expiration date and time indicated on the Cell
`Product Disposition Form and Product Label. Do not initiate infusion of expired
`PROVENGE. Once the PROVENGE infusion bag is removed from the insulated
`
`container, it should remain at room temperature for no more than 3 hours.
`PROVENGE should not be returned to the shipping container.
`
`
`
`6. Once the patient is prepared for infusion and the Cell Product Disposition Form has
`been received, remove the PROVENGE infusion bag from the insulated container and
`inspect the bag for signs of leakage. Contents of the bag will be slightly cloudy, with
`a cream-to-pink color. 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. Do not administer if the bag leaks or if clumps remain in the bag.
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`7. Prior to PROVENGE infusion, match the patient’s identity with the patient identifiers
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` on the Cell Product Disposition Form and the PROVENGE infusion bag.
`
`•
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`PATIENT COUNSELING INFORMATION
`17
`Inform the patient or caregiver about the following:
`• The recommended course of therapy for PROVENGE is 3 complete doses. Each infusion
`
`of PROVENGE is preceded by a leukapheresis procedure approximately 3 days prior. It
`is important to maintain all scheduled appointments and arrive at each appointment on
`time because the leukapheresis and infusions must be appropriately spaced and the
`PROVENGE expiration time must not be exceeded.
`If the patient is unable to receive an infusion of PROVENGE, the patient will need to
`undergo an additional leukapheresis procedure if the treatment is to be continued.
`• Counsel the patient on the importance of adhering to preparation instructions for the
`leukapheresis procedure, the possible side effects of leukapheresis, and post-procedure
`care.
`
`If the patient does not have adequate peripheral venous access to accommodate the
`leukapheresis procedure and infusion of PROVENGE, inform the patient about the need
`
`for a central venous catheter. Counsel the patient on the importance of catheter care.
`Instruct the patient to tell their doctor if they are experiencing fevers or any swelling or
`redness around the catheter site, because these symptoms could be signs of an infected
`catheter.
`
`• Report signs and symptoms of acute infusion reactions such as fever, chills, fatigue,
`
`breathing problems, dizziness, high blood pressure, nausea, vomi