Accurate and safe medication recommendations are critical for effective clinical decision-making, especially in multimorbidity cases. However, existing systems rely on point-wise prediction paradigms that overlook synergistic drug effects and potential adverse drug-drug interactions (DDIs). We propose FLAME, a fine-grained list-wise alignment framework for large language models (LLMs), enabling drug-by-drug generation of drug lists. FLAME formulates recommendation as a sequential decision process, where each step adds or removes a single drug. To provide fine-grained learning signals, we devise step-wise Group Relative Policy Optimization (GRPO) with potential-based reward shaping, which explicitly models DDIs and optimizes the contribution of each drug to the overall prescription. Furthermore, FLAME enhances patient modeling by integrating structured clinical knowledge and collaborative information into the representation space of LLMs. Experiments on benchmark datasets demonstrate that FLAME achieves state-of-the-art performance, delivering superior accuracy, controllable safety–accuracy trade-offs, and strong generalization across diverse clinical scenarios. Our code is available at https://github.com/cxfann/Flame.

Medication recommendation systems have gained significant attention in healthcare as a means of providing tailored and effective drug combinations based on patients' clinical information. However, existing approaches often suffer from fairness issues, as recommendations tend to be more accurate for patients with common diseases compared to those with rare conditions. In this paper, we propose a novel model called Robust and Accurate REcommendations for Medication (RAREMed), which leverages the pretrain-finetune learning paradigm to enhance accuracy for rare diseases. RAREMed employs a transformer encoder with a unified input sequence approach to capture complex relationships among disease and procedure codes. Additionally, it introduces two self-supervised pre-training tasks, namely Sequence Matching Prediction (SMP) and Self Reconstruction (SR), to learn specialized medication needs and interrelations among clinical codes. Experimental results on two real-world datasets demonstrate that RAREMed provides accurate drug sets for both rare and common disease patients, thereby mitigating unfairness in medication recommendation systems. The implementation is available via https://github.com/zzhUSTC2016/RAREMed.

Recommender system usually suffers from severepopularity bias— the collected interaction data usually exhibits quite imbalanced or even long-tailed distribution over items. Such skewed distribution may result from the users’conformityto the group, which deviates from reflecting users’ true preference. Existing efforts for tackling this issue mainly focus on completely eliminating popularity bias. However, we argue that not all popularity bias is evil. Popularity bias not only results from conformity but alsoitem quality, which is usually ignored by existing methods. Some items exhibit higher popularity as they have intrinsic better property. Blindly removing the popularity bias would lose such important signal, and further deteriorate model performance. To sufficiently exploit such important information for recommendation, it is essential to disentangle the benign popularity bias caused by item quality from the harmful popularity bias caused by conformity. Although important, it is quite challenging as we lack an explicit signal to differentiate the two factors of popularity bias. In this paper, we propose to leverage temporal information as the two factors exhibit quite different patterns along the time: item quality revealing item inherent property is stable and static while conformity that depends on items’ recent clicks is highly time-sensitive. Correspondingly, we further propose a novelTime-awareDisEntangled framework (TIDE), where a click is generated from three components namely the static item quality, the dynamic conformity effect, as well as the user-item matching score returned by any recommendation model. Lastly, we conduct interventional inference so that the recommendation can benefit from the benign popularity bias while circumvent the harmful one. Extensive experiments on four real-world datasets demonstrated the effectiveness of TIDE.