Long-acting (LA) implantable drug delivery systems (IDDS) offer an effective approach for the management or prevention of chronic conditions by sustained parenteral therapeutic administration. LA IDDS can and improve adherence to treatment regimens by minimizing dosing frequency. However, their clinical deployment is challenged by factors such as, poor drug loading capacity, which limit their lifespan and require repeated surgical replacement for continued therapy. To address these challenges, and by leveraging previous work on nanofluidic systems, a reservoir-based IDDS that enables transcutaneous refilling of solid drug formulations through minimally invasive needle injection is presented. With 1000-fold higher drug loading efficiency, the implant affords minimal volume and aspect ratio suitable for discrete subcutaneous deployment. Key parameters for clinical acceptability, namely, implant safety, access port robustness, and refilling method are systematically evaluated. The implant and refilling procedure are studied in rats and nonhuman primates with therapeutics used clinically for type 2 diabetes and human immunodeficiency virus pre-exposure prophylaxis. The ability to extend drug release and maintain equivalent pharmacokinetics profiles pre- and post-drug refilling is demonstrated. This technology presents a clinically viable LA approach to prolong drug release for lifelong prevention or management of chronic conditions.