PROVENGE Dispersion for infusion Ref.[50325] Active ingredients: Sipuleucel-T

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 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 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).

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).

No interaction studies have been performed with Provenge.

Provenge is 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).

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.

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.

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, staphylococcal 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). Within each frequency grouping, adverse reactions are presented in order of decreasing seriousness.

Table 1. Adverse reactions from clinical studies and post-marketing reports:

^* Primarily associated with the leukapheresis procedure

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.

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 associated with 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. Adverse 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.

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