What is the annual mortality rate associated with paliperidone (Invega) treatment?

Annual Mortality Rate Associated with Paliperidone Treatment

The annual mortality rate associated with paliperidone (Invega) treatment is not precisely established in the available literature, but based on a Japanese post-marketing surveillance report, approximately 32 deaths occurred among 11,000 patients over a 6-month period, suggesting a significant mortality risk that requires careful monitoring. 1

Mortality Data on Paliperidone

• A Japanese post-marketing surveillance study reported 32 fatal cases among approximately 11,000 patients using paliperidone palmitate (Xeplion/Invega Sustenna) over a 6-month period following its launch in November 2013 1

• The most common causes of death in this surveillance were:

  • Sudden death (12 confirmed cases, 4 suspected cases)
  • Suicide (7 cases)
  • Neuroleptic malignant syndrome (4 cases) 1

• A French pharmacovigilance database study identified 13 deaths and 14 life-threatening events among 473 paliperidone palmitate-related adverse drug reactions reported between 2013 and 2019 2

• Cardiorespiratory symptoms were the predominant cause (17 cases, 63%) of these serious adverse events 2

Timing and Risk Factors for Mortality

• Cardiorespiratory adverse events typically occurred within the first 6 months after treatment initiation (11 out of 17 cases) 2
• Cardiac arrests and sudden unexpected deaths occurred 10-14 days after monthly injections or 11-24 days after three-monthly injections, coinciding with peak plasma concentrations 2
• Metabolic disorders leading to serious outcomes tended to occur later (12-21 months after initiation) 2

Comparative Mortality Risk

• In clinical trials comparing paliperidone palmitate with risperidone long-acting injection, 5 deaths occurred among paliperidone palmitate recipients versus 1 death among risperidone recipients, though this difference was not statistically significant (RR 3.62, CI 0.60 to 21.89) 3
• The mortality risk for patients with schizophrenia (regardless of treatment) is generally 2-3 times higher than the general population, corresponding to a 10-25 year reduction in life expectancy 1
• Natural deaths account for approximately 60% of excess mortality in schizophrenia, with ischemic heart disease being a significant contributor 1

Mechanisms of Mortality Risk

• Supratherapeutic drug concentrations following intramuscular injection may contribute to sudden cardiac deaths 2
• The pharmacokinetic profile of paliperidone palmitate shows peak plasma concentrations approximately 24 hours after dosing with a terminal half-life of about 23 hours 4
• Paliperidone palmitate's release begins as early as day 1 after injection, reaches maximum plasma concentrations at 13 days, and can last for up to 126 days 5

Clinical Implications and Recommendations

• Blood concentration monitoring of paliperidone palmitate may be necessary to prevent supratherapeutic levels and associated risks 2
• Careful cardiovascular assessment before initiating treatment is warranted given the predominance of cardiorespiratory adverse events 2, 1
• Close monitoring is particularly important during the first 6 months of treatment when cardiorespiratory events appear most common 2
• Particular attention should be paid during periods when plasma concentrations are expected to peak (10-14 days after monthly injections) 2

Limitations of Available Data

• There is a lack of large-scale, long-term mortality studies specifically focused on paliperidone
• Most mortality data comes from post-marketing surveillance or pharmacovigilance databases rather than controlled clinical trials 2, 1
• The exact mechanism linking paliperidone to sudden death requires further investigation 2, 1