Sipuleucel-T

Sipuleucel-T 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.

Sipuleucel-T 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.

Sipuleucel-T should be used with caution in patients with a history of embolic and thrombotic disorders.

Autologous peripheral blood mononuclear cells activated with PAP-GM-CSF (Sipuleucel-T) are not intended for use in women.

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

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

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 sipuleucel-T 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 sipuleucel-T 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 sipuleucel-T 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 sipuleucel-T group.

In controlled clinical trials, 23.8% of patients in the sipuleucel-T 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.

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 sipuleucel-T group and 27.7% of subjects in the control group. Serious infections occurred in 4.7% of subjects in the sipuleucel-T group and 4.0% of subjects in the control group. The most frequently occurring serious infections in the sipuleucel-T 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 sipuleucel-T 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.