To determine the efficacy and safety profile of the subcutaneous infusion mode of administration compared to oral levodopa therapy in patients with advanced Parkinson's disease.

Subcutaneous Levodopa-Carbidopa [SC L-C] /Foslevodopa-Foscarbidopa [FL/FC] infusion for Advanced Parkinson's Disease (PD) offers an alternative to oral and invasive treatments, mitigating motor fluctuations by stabilizing levodopa plasma levels.

A systematic screening of PubMed, Embase and Scopus databases was conducted to identify Phase 3 randomized controlled trials (RCTs) and their open, label extensions (OLEs) /post hoc for detailed safety, durability, and clinical benefit analysis.

Two phase 3 RCTs and six additional studies (2 OLEs and four post hocs) were included. The subgroup analysis demonstrated that the SC L-C offered a statistically significant improvement over oral L-C in both "ON" time without troublesome dyskinesia (MD:+1.72 hours, +95%CI [+0.74,+2.70], p=0.0019) and "OFF" time (MD: −1.40hours, +95%CI [-2.33,-0.47], p=0.0028). Conversely, FL/FC showed a neutral effect in its comparison group (MD "ON" time without troublesome dyskinesia: +0.04 hours ,p=0.96 ; MD "OFF" time: 0.20 hours, p=0.40). 

Similar results were seen across the secondary outcome measures with the SC L-C having better improvement and quality of life (PDQ-39 : MD = -3.7 points, p<0.001) and reduced sleep disturbances (PDSS-2 MD = -3.5 points,p<0.001). While the FL/FC group showed non significant changes (p=0.52).

Long-term safety data, primarily from the OLE studies, confirmed sustained motor benefit Over three years (MD “OFF” time: -2.81 h/day). Safety synthesis highlighted Infusion Site Reactions (ISRs) as the most frequent adverse event resulting in discontinuation (10.3 -26.2%) within the first year.

The Subcutaneous mode of administration offers a superior effect compared to the oral L-C for motor control and across quality of life domains. While the subcutaneous mode provides a valuable alternative to oral therapy, further research To confirm long-term efficacy and standardize ISR management is needed.