Efficacy of administrative intervention for neurosurgical patients with off-label use of alprostadil lipid microsphere

Alprostadil is a stable prostaglandin E1 analogue with anti-platelet aggregation, peripheral vascular smooth muscle relaxation, anti-oxidation, endothelium protection, and liver cell membrane stabilization activities1,2,3,4,5. Based on this, alprostadil has been used successfully for the treatment of critical leg ischemia, angiospastic disorders, Raynaud’s phenomenon, diabetic peripheral neuropathy, diabetic foot, liver transplantation, etc. by intravenous or intraarterial administration6,7,8,9,10. Unfortunately, the conventional alprostadil formulation is rapidly metabolized, resulting in an extremely short half-life of 3–5 min; moreover, its dosage is high in clinical practice thus frequently inducing adverse events. To address these problems, the alprostadil liposome microsphere injection (Lipo-PGE1) was originally produced by Mitsubishi Pharmaceutical Co., Ltd. in Tanabe, Japan. Lipo-PGE1 could accumulate in inflammatory lesions and diseased vessels due to the enhanced permeability and retention (EPR) effect of lipid microspheres, which significantly reduces the dose of alprostadil and thus minimizes toxic side effects11,12,13. For example, when Lipo-PGE1 was used to improve microcirculation, its dosage was only a few tenths of the dosage of conventional formulation, while the drug concentration in the lesions could reach up to 10–20 times than that of conventional formulation. Lipo-PGE1 also can control the drug release and prolong drug retention time in vivo to 12–24 hours14.

In China, the first generic Lipo-PGE1 became commercially available in 1998. Subsequently, more than ten generic Lipo-PGE1s were put on the market, including injection and dried emulsion for injection. As an adjuvant drug, the Lipo-PGE1 has been reported to be used widely in the clinic for 871 kinds of diseases, including cerebral infarction, diabetes, chronic nephropathy, essential hypertension, sudden deafness, fractures, intervertebral disc disease, chronic obstructive pulmonary disease, etc15. However, in China, the summary of product characteristics of generic Lipo-PGE1 contains only 4 indications, namely limb ulcer caused by chronic arterial occlusion disease (thromboangiitis obliterans, occlusive arterial sclerosis, etc.) and resting limb pain caused by tiny blood circulation obstacle, improvement of microcirculation of heart head blood-vessel, antithrombotic therapy after organ transplantation, arterial catheter dependence of congenital heart disease, and aid in the treatment of chronic hepatitis. The term “off-label” use refers to use of a drug that is not included in the package insert (approved labeling) for that drug. In this case, the prescriptions for off-label indications use are common in clinical practice. In addition to this, the inappropriate dose, menstruum, administration route, and contraindications are also frequently found in prescriptions.

Currently, the phenomenon of non-indication or off-label drug use is common all over the world16,17,18,19,20. Eleven countries have regulations on the off-label drug use, namely America, England, Germany, Italy, Netherland, Australia, New Zealand, South Africa, India, Japan, and China21. Accordingly, off-label drug use has its rationality and necessity. In 2015, the “off-label drug use expert consensus” was formed to protect patients and avoid the risk for hospitals and healthcare workers in China. Meanwhile, the Health and Family Planning Commissions of Beijing, Guangdong, Yunnan, and Sichuan Provinces listed Lipo-PGE1 in the catalogue of adjuvant drugs regulation. Despite these expert consensuses, regulatory policies, and local enforcement regulations, the use of Lipo-PGE1 is still far from optimal. A study showed that 65.41% of patients received Lipo-PGE1 treatment with off-label indications, 99.85% of patients used drug with an unreasonable dosage, and 0.39% of patients with contraindications to drug22. Another study revealed that off-label Lipo-PGE1 use was found in 25 out of 36 clinical departments in a tertiary hospital in China23.

Analogously, the inappropriate use of Lipo-PGE1 is ubiquitous in the Affiliated Hospital of Southwest Medical University, located in Luzhou, China. There are two kinds of Lipo-PGE1s produced by different manufacturers in the hospital, namely alprostadil injection (10 μg, 93 RMB) and alprostadil dried emulsion for injection (5 μg, 79 RMB). Our previous investigation demonstrated that the sales of Lipo-PGE1 (88.75% alprostadil dried emulsion for injection and 11.25% alprostadil injection) ranked first among thousands of drugs in the hospital, and from 2014 to 2017, the prescription rate of Lipo-PGE1 for inpatients in the hospital increased annually, which were 4.25%, 10.05%, 12.53%, and 13.63%, respectively. In 2017, the top three departments in the prescription rate of Lipo-PGE1 were cardiovasology, infectious gastroenterology, and neurosurgery. It should be noted that, from 2015 to 2017, the prescription rates of neurosurgery were 28.82% (3351/11,627), 44.54% (6068/13,623), and 49.97% (9148/18,307), respectively, which had been at the forefront of 45 departments. Moreover, for Lipo-PGE1 treatment, most patients in cardiovasology and infectious gastroenterology may have indications, while most patients in neurosurgery may have no indications, and some patients, instead, may have contraindications (intracranial hemorrhage).

The above problems have drawn great attention from the Hospital Pharmacy Administration and Therapeutics Committee (HPATC), and a range of interventions have been implemented to address these issues. Our previous study had confirmed that the real-time interventions of clinical pharmacist promoted the rational use of prophylactic acid suppressants and resulted in favorable economic outcomes24. However, the number of clinical pharmacists is seriously insufficient due to the increase of clinical beds, so an administrative intervention was implemented here for neurosurgery to decrease the inappropriate uses and the costs of Lipo-PGE1 from January 1, 2018 to December 31, 2018. Importantly, to the best of our knowledge, there is no related report. The purpose of this self-controlled study was to evaluate the clinical and economic impacts of administrative intervention and thus promote the rational use of Lipo-PGE1 in neurosurgical patients in a Chinese tertiary teaching hospital.

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