A descriptive analysis of drug related problems identified when prescribing the COVID-19 antiviral drug Paxlovid®

doi:10.21203/rs.3.rs-4973191/v1

Background

Paxlovid® is the only licensed oral COVID − 19 antiviral containing nirmatrelvir and ritonavir. Ritonavir is a potent inhibitor of cytochrome P450 enzymes resulting in clinically significant drug-drug interactions (DDIs).

Aim

To describe the frequency, type, and severity of detected drug related problems (DRPs) with Paxlovid®

Method

This study involved a retrospective, quantitative data analysis. All patients prescribed Paxlovid® in a public hospital in Vienna, were included. Data was collected from the patients’ records and recorded on a customised and piloted data collection form. Any DRPs were also noted. The severity of DDIs was classified using an established checker tool.

Results

122 of 140 (87.1%) patients required interventions to prevent DRPs; 63.6% of cases required intervention by the pharmacist at dispensing. The most common DRPs were DDIs (57.1%). In 24.3% of cases both renal impairment and DDIs were noted. 313 DDIs were recorded in 114 patients; in 24 patients, the interactions recorded were severe. In 3 patients (2.1%), Paxlovid® was prescribed despite being contraindicated due to severe renal impairment requiring pharmacist intervention.

Conclusion

This study demonstrated that numerous DRPs involving Paxlovid® were identified by the pharmacist following prescribing. Pharmacists’ involvement in prescribing highly interacting drugs such as Paxlovid® is beneficial to enhance patient safety.

Pharmacist screening for drug related problems at the point of dispensing is likely to increase patient safety and mitigate risk associated with high-risk drugs.
The study confirms that a strong focus needs to be placed on reviewing the patients´ renal function and adjusting dosing accordingly both as part of the prescribing and screening processes.

The development of vaccines was a significant milestone in the fight against the coronavirus (COVID-19). However, immunosuppressed patients do not respond adequately to the vaccine and require additional protection [1].

Various treatments preventing the progression of COVID-19 [2] require intravenous administration making accessibility challenging. Paxlovid®, a combination of nirmatrelvir and ritonavir, is the only preparation available orally to treat COVID-19 that is licensed in Europe enhancing accessibility for outpatients.

Use of Paxlovid® maybe challenging due to ritonavir's potent inhibition of Cytochrome P450 enzymes, leading to numerous drug interactions [3-6]. Additionally, nirmatrelvir, when administered in combination with ritonavir, is renally excreted unchanged requiring dose adjustments in patients with moderate renal impairment (eGFR ≤ 60 ml/min) [3]. In patients with severe renal impairment (eGFR < 30 ml/min), Paxlovid® is contraindicated [3,7]. Therefore, a comprehensive medication review is imperative for every patient prescribed Paxlovid®.

In view of the above, pharmacists in some countries such as the US and Canada have been authorized to prescribe and dispense Paxlovid® to enhance patient safety [8,9]. In Austria, only doctors can prescribe Paxlovid® [10]. Nevertheless, pharmacists can play an important role in ensuring patient safety by conducting medication reviews and providing support during the prescribing process. A pharmaceutical service involving medication reviews of all patients on Paxlovid® was introduced in an Austrian public hospital (Figure 1).

Figure 1 placed here

Aim

The aim was to describe the frequency, type, and severity of detected DRPs with Paxlovid®

Ethics approval

The study was approved by the Ethics Committees of Robert Gordon University (1st Feb 2023/S331) and the City of Vienna (10th Mar 2023/EK23-028-VK).

A retrospective, single centre, descriptive data analysis was performed in a 750-bed-capacity public hospital in Vienna, Austria. Inpatients who tested positive for COVID-19 and prescribed Paxlovid® were included and identified through the hospital software system. Demographic details of patients prescribed Paxlovid® between September 2022 to March 2023 were collected and recorded in a customized and anonymized Data Collection Tool (DCT) [See Appendix I]. The DCT developed was piloted using 10 patient records where the data was collected by two clinical pharmacists (AS, RC) and independently checked for consistency by a third (GS). Cohen´s kappa statistic was used to check for inter-rater reliability [11] which was 100% for every component. Other information collected included any DDIs identified together with the degree of severity of the interaction as per University of Liverpool interaction checker [12, 13]. Descriptive statistics were generated and supported by Excel.

Participant characteristics

140 patients were prescribed Paxlovid® during the data collection period with 58 males and a median age of 75.2 years (range 24 - 101 years). All had a medication review performed by a trained clinical pharmacist. The median number of concomitantly used drugs per patient was 9.8 (ranging 1 - 23) with an average of 2.2 (± 1.8) interactions with Paxlovid® per patient. Table 1 summarises the characteristics of patients included.

Table 1 placed here

Analysis of all patients prescribed Paxlovid® during the study period indicated that in 12.9% (18 of 140 patients) of patients, no drug related problem (DRP) was identified and therefore no intervention was required. In the other 87.1% (122 of 140) of cases DRPs were identified. In 33 cases these actions were performed by the prescribers at prescribing stage. In 89 (63.6%) cases the required action was not identified at the point of prescribing but during the pharmaceutical medication analysis after Paxlovid® was ordered in the pharmacy.

The nature of the DRPs identified were as follows: in 5.7% (n=8) of patients, a dose reduction of Paxlovid® was recommended or Paxlovid® contraindicated due to the patient´s renal function; in 57.1% (n=80) drug-drug interactions (DDIs) were identified. In 24.3% (n=34) of all cases renal impairment and DDIs were noted.

Drug-drug interactions and required interventions

Multiple interactions were identified in individuals due to polypharmacy resulting in a total of 313 DDIs identified in 114 patients (81.4%). Sixty-eight drugs were accountable for these DDIs (see Table 2), with nine drugs having the potential to cause severe interactions with Paxlovid® (red). In three cases where Paxlovid® was contraindicated due to severe renal impairment no extended medication review was conducted. In 24 out of 114 patients where interactions were identified at least one was severe (red) interaction, in 86 patients, at least one possible (orange) interaction was identified, while in 4 patients at least one mild (yellow) interaction was identified.

For each of the 313 identified interactions an intervention was recommended based on guidance available in the Liverpool interaction checker. These included the prescribing of a different COVID-19 medication (n = 5; 1.6%), the temporary withdrawal of the patient’s regular medication [118 interactions (37.7 %)] during Paxlovid® administration, dose adjustment to the regular medication [33 interactions (10.5 %)] and closer patient monitoring including blood pressure, ECG or drug monitoring [109 interactions (34.8 %)].

Table 2 placed here

Paxlovid® in patients with decreased renal function

39 out of the 140 screened patients (27.9%) had moderate renal impairment (30 ≤ eGFR < 60 ml/min) requiring a dose reduction of Paxlovid®. This had been considered in 14 cases by the prescribing physician but was highlighted and recommended by the designated clinical pharmacists in the other 25 cases. Three out of 140 (2.1%) had severe renal impairment (eGFR < 30 ml/min) with Paxlovid® prescribed despite the contraindication with an alternative recommended by the pharmacist during the screening process.

Statement of key findings

This study shows that interventions were still required in most of the prescriptions for Paxlovid® screened by the pharmacists, even though screening had routinely been conducted at the point of prescribing. These findings confirm those in the literature which also suggest that collaboration of medical doctors and pharmacists and involvement of clinical pharmacists in screening can lead to reduced rates of DRPs in hospital as well as in community settings [14–16].

Strengths and weaknesses

The strength of the study lies in the way data was obtained with data concerning DDIs collected and rated separately for each drug. The fact that pharmacists in Austria are independent from prescribing decisions ensures objectivity during the screening process. Limitations of this study include the study’s small sample size and the monocentric setting limiting the generalizability of the results and the lack of comparable published data since the drug is relatively new.

Interpretation

The results of our study are highly relevant in the context of a US retrospective, observational cohort study that concluded that approximately one third of patients treated with ritonavir-containing COVID therapy may be at risk of major or contraindicated drug-drug interactions requiring a skilled assessment of possible DDIs before prescribing and dispensing the drug [17]. This is particularly relevant in elderly, patients with comorbidities and women [17].

A retrospective review of a pharmacist-led dispensing service conducted in a US community pharmacy setting highlighted the ability of pharmacists to identify and address DRPs involving oral COVID-19 drugs [18] with one or more significant DRPs identified in 78% of Paxlovid® prescriptions at the point of dispensing [18]. Most interventions identified involved DDIs with HMG-CoA reductase inhibitors, calcium channel blockers, fluticasone nasal sprays, benzodiazepines, antiplatelet therapies and alpha-blockers [18]. A study reporting a pharmacy service in an ambulatory care setting identified HMG-CoA reductase inhibitors, Tamsulosin, Trazodone, Amlodipine and Apixaban among the top 10 most frequent drugs to interact with Paxlovid® [19]. Apart from fluticasone nasal spray, the drugs identified are like those in our study.

The average number of identified possible DDIs with Paxlovid ® per patient was slightly higher in our study (2.2 ± 1.8) compared to that published by Portman and Scolese (1.7 ± 1.3) [19]. The reason for the deviation is potentially since all possible DDIs were considered in our study while Portman and Scolese only included ´significant drug interactions´ [19]. Nevertheless, a similar number of patients were found to have at least one significant interaction with Paxlovid® (80% of patients compared to 81.4% in our study) [19].

Evidence indicates that physicians do not always sufficiently take the patient´s renal function into account when prescribing [14, 20–22]. For example, a study by Hassan et al showed that the involvement of a pharmacist on ward rounds led to increased consideration of relevant dose adjustments due to impaired renal function [20]. Similarly, in a retrospective review by Kieck et al, dose reduction of Paxlovid® in patients with decreased renal function was not considered by the prescriber but only subsequently implemented by the pharmacists [18]. Likewise, in our study, patients’ doses of Paxlovid® were not reduced in response to the patient’s renal function, but adjusted only following recommendations by the pharmacists and after the prescription had been issued and during the screening process.

In conclusion, it is recommended that pharmacists are routinely involved in the process of prescribing highly interactive drugs such as Paxlovid®. Considering the final draft guidance from the National Institute for Health and Care Excellence (NICE) suggesting an extension of the list of categories of patients who test positive for COVID-19 and who should be considered for Paxlovid®, there is a likelihood of an increased use of the drug [24]. Results are even more significant in view of draft legislation presented by the Austrian Parliament suggesting the legalisation of certain changes in a patient`s medication by hospital pharmacists following medical instruction [23].

Funding

The authors declare that no funds, grants, or other support were received during the preparation of this manuscript.

Conflict of Interests

The authors declare that they have no conflict of interest.

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Table 1: Characteristics of patients included in the study (n=140)

Characteristics
Gender	N (%)
male	58 (41)
female	82 (59)
Age, mean ± SD	75.2 ± 14.1
Renal function (eGFR), mean ± SD	71.6 ± 22.1
Renal function n (%)
Normal renal function¹ or mild impairment²	98 (70.0)
Moderate impairment³	39 (27.9)
Severe impairment⁴	3 (2.1)
Concomitant Drugs and Interactions
Concomitantly used drugs per patient (n), mean ± SD	9.8 ± 5.0
Interactions identified per patient (n), mean ± SD	2.2 ± 1.8
eGFR… estimated glomerular filtration rate ¹ eGFR ≥ 90 ml/min ² eGFR ≥ 60 to < 90 ml/min ³ eGFR ≥ 30 to < 60 mL/min ⁴eGFR < 30 ml/min

Table 2 Number of detected interactions per drug of the 20 most frequently found interacting drugs (N= in 239 out of the 313 DDIs identified; multiple interactions per patient were possible due to polypharmacy)

Drug	Number of interactions (%)
Severe (red) interactions	19 (6.1)
Quetiapine	9 (2.9)
Triazolam	6 (1.9)
Simvastatin	4 (1.3)
Possible (orange) interactions	177 (56.6)
Metamizole	50 (16.0)
Amlodipine	29 (9.3)
Atorvastatin	27 (8.6)
Trazodone	12 (3.8)
Rosuvastatin	10 (3.2)
Valsartan	9 (2.9)
Tamsulosin	9 (2.9)
Edoxaban	8 (2.6)
Dihydrocodeine	6 (1.9)
Doxazosin	6 (1.9)
Apixaban	6 (1.9)
Alprazolam	5 (1.6)
Possible weak (yellow) interactions	43 (13.7)
Hydromorphone	20 (6.4)
Diosmin	7 (2.2)
Mirtazapine	6 (1.9)
Ezetimibe	5 (1.6)
Macrogol	5 (1.6)

Appendices.docx

A descriptive analysis of drug related problems identified when prescribing the COVID-19 antiviral drug Paxlovid®

Status:

Version 1

Abstract

Figures

Impact on Practice

Introduction

Method

Results

Participant characteristics

Drug-drug interactions and required interventions

Paxlovid® in patients with decreased renal function

Discussion

Statement of key findings

Strengths and weaknesses

Interpretation

Conclusion

Declarations

Funding

Conflict of Interests

References

Tables

Supplementary Files

Status:

Version 1