Improving Rare Medication Recommendation with Counterfactual Data Augmentation and Large Language Models

AI-based medication recommendation systems have attracted substantial attention due to their potential to enhance patient safety and therapeutic outcomes. Despite the clinical importance of accurately recommending rarely prescribed medications (rare-meds), we observe that most existing methods show significantly lower predictive performance for rare-meds. We attribute this issue to two intrinsic limitations: (a) the inherent scarcity of data for rare-meds and (b) limited consideration of co-recommended medications. To address these limitations, we propose GenRxR, a novel framework based on large language models (LLMs). GenRxR leverages the medical knowledge and clinical reasoning capability of LLMs to generate counterfactual medical data, mitigating the data scarcity issue for rare-meds. It also integrates an LLM into the medication recommendation process to model relationships among co-recommended medications. To further enhance the clinical reasoning, we introduce an instruction tuning step that aligns the LLM's capability with the recommendation task, enabling better handling of clinical context, including rare-meds cases. In our experiments, we show that GenRxR outperforms 14 (including 5 LLM-based) baselines in most cases. Specifically, it achieves up to 30.9% higher predictive performance for rare-meds than the strongest baseline.