Post-graduate School of Hospital Pharmacy, Sapienza University of Rome, Rome, Italy.
Eur Rev Med Pharmacol Sci. 2021 Apr;25(8):3300-3305. doi: 10.26355/eurrev_202104_25468.
The adalimumab originator Humira® introduced a new citrate-free formulation in 2016, before the patent expiry that occurred in the European Union in October 2018. Some of the adalimumab biosimilars that were subsequently marketed are citrate-free, while others are not. Since citrate as an excipient is associated with pain at the injection site, recent anecdotical reporting in Italy raised the issue of possible prescription biases related to the differences in formulation existing among the various adalimumab products. In this study, we analyzed the data obtained from the 'Rete Nazionale di Farmacovigilanza' (Pharmacovigilance National Network) to investigate whether, and to what extent, the differences in the formulation of the various adalimumab versions had an impact on the rate of injection site reactions reported in Italy in the period 2016-2019.
A search was conducted based on 3 search criteria: (1) time frame; (2) suspected drugs, and (3) adverse reaction type. Reports classified in the System Organ Class "Administration site conditions" were analyzed by year, product, and type of adverse event (whether including or not 'pain'). Data were reported both as absolute numbers, as well as signaling rates, considering the consumption data expressed as defined daily doses (DDD).
We found that: (1) The change in Humira® formulation introduced in august 2016 was followed by a decrease in the reports of injection site reactions (from 45 in 2016 to 12, 12 and 8 in 2017, 2018, and 2019, respectively); (2) after the introduction of biosimilars during 2018, in 2019 a marked shift in reporting toward biosimilars was observed (52 out of 60; 87%).
While the decrease in Humira® reports is consistent with the improved tolerability of the new formulation, the huge increase in biosimilar reporting may be only in part explained by the differences in formulation and cannot be accounted for by a parallel increase in exposure, since 58.3% of total DDDs provided in 2019 were still attributed to Humira®.
阿达木单抗原研药修美乐（Humira®）于 2016 年在专利到期前推出了无枸橼酸盐配方，该专利已于 2018 年 10 月在欧盟到期。随后上市的一些阿达木单抗生物类似药无枸橼酸盐，而另一些则有枸橼酸盐。由于赋形剂枸橼酸盐与注射部位疼痛有关，最近意大利的一些轶事报道提出了与各种阿达木单抗产品之间存在的配方差异相关的可能处方偏见的问题。在这项研究中，我们分析了从“Rete Nazionale di Farmacovigilanza”（药物警戒国家网络）获得的数据，以调查各种阿达木单抗版本的配方差异是否以及在何种程度上影响了 2016 年至 2019 年期间在意大利报告的注射部位反应率。
根据 3 个搜索标准进行了搜索：（1）时间框架；（2）可疑药物；（3）不良反应类型。按年份、产品和不良反应类型（是否包括“疼痛”）对被归类为“用药部位情况”系统器官类别（SOC）的报告进行了分析。数据既以绝对值报告，也以考虑到以限定日剂量（DDD）表示的消费数据的信号率报告。
我们发现：（1）2016 年 8 月推出的修美乐®配方改变后，注射部位反应报告减少（从 2016 年的 45 例减少至 2017 年的 12 例、2018 年的 12 例和 2019 年的 8 例）；（2）2018 年生物类似药上市后，2019 年观察到报告明显转向生物类似药（60 例报告中有 52 例；87%）。
虽然修美乐®报告减少与新配方的耐受性改善一致，但生物类似药报告的大幅增加可能仅部分归因于配方差异，并且不能用暴露量的平行增加来解释，因为 2019 年总 DDD 的 58.3%仍归因于修美乐®。
