Evaluating Nirmatrelvir-Ritonavir (Paxlovid®) in Outpatient COVID-19 Treatment: Safety, Tolerability, and Adherence Insights from Primary Healthcare Clinics

doi:10.21203/rs.3.rs-3968833/v1

Objective: This study aims to fill this gap by evaluating the safety, tolerability, and adherence of patients prescribed Paxlovid® in outpatient settings, focusing on its use in managing category 2 COVID-19 patients across three primary healthcare clinics in Selangor, Malaysia.

Design: Retrospective cross-sectional study

Setting: Data were collected from the Paxlovid® pharmacy registry and medical records at Klinik Kesihatan Seksyen 7, Klinik Kesihatan Seksyen 19, and Klinik Kesihatan Kelana Jaya between April 1, 2022, and November 30, 2022.

Participants: This study analysed data from 415 category 2 COVID-19 patients aged ≥18 years old.

Primary and secondary outcomes: Parameters assessed included patient demographics, dosing, current medication, changes in drug regimen, adherence, and ADR. Pharmacists follow-ups were conducted on days 3 and 5 post-medication initiation.

Results: The majority (79.5%) of the cohort experienced ADR, predominantly dysgeusia, diarrhoea, body ache, vomiting, and nausea. Despite these, the ADR were generally well-tolerated, with no severe impacts reported. High adherence was observed, with 96.9% of patients completing the 5-day regimen. The primary reasons for non-adherence included adverse effect intolerability, dosing ambiguity, forgetfulness, concerns about ADR, and perceived health improvement. Notable medications interacting with Paxlovid® were simvastatin, amlodipine, and atorvastatin, and 21.7% of 23 concurrent medications were found not complying to the recommended interventions by the University of Liverpool COVID-19 Drug Interaction database.

Conclusion: Nirmatrelvir-ritonavir (Paxlovid®) demonstrates a high level of safety and tolerability in outpatient COVID-19 patients, with optimal adherence observed. This study underscores the vital role of healthcare professionals in managing Paxlovid® within primary healthcare and highlights the need for broader research and direct patient involvement to enhance treatment strategies against COVID-19.

Paxlovid

COVID-19

adverse drug reactions

As reported by the World Health Organization, the global impact of coronavirus disease (COVID-19) as of December 24, 2023, is staggering, with over 773 million confirmed cases and 6.6 million fatalities [1]. In response to the pandemic's expansive reach, the rapid development and deployment of COVID-19 vaccines have been pivotal. Mass vaccination initiatives have been extensively implemented, with ongoing efforts to inoculate the population. Research conducted by Li et al. underscores the efficacy of these vaccines, demonstrating their substantial role in decreasing the likelihood of hospitalization and mortality due to the virus [2].

Over time, novel therapeutic agents have been discovered aiming to reduce the severity, admission, and mortality of COVID-19 infections, specifically among high-risk populations that has characteristic such as older age, smoking, underlying clinical conditions like cardiovascular diseases, diabetes, obesity, and cancer [3]. A protease inhibitor orally administered nirmatrelvir-ritonavir (Paxlovid^®) combination was introduced in early 2022 [4]. This antiviral combination was reported to reduce the risk of COVID-19 infection related to hospital admission or death by 89% in the Paxlovid^® group as compared to the placebo group [5].

Paxlovid^® is co-packaged as 150-mg and 100-mg tablets, respectively. The authorized dose is 300 mg/100 mg (2 nirmatrelvir tablets and 1 ritonavir tablet) every 12 hours taken with or without food for 5 days. The Emergency Use Authorization (EUA) does not allow the repeat or extended use of Paxlovid^®. The plasma concentration of nirmatrelvir is boosted by ritonavir through a potent and rapid inhibition of the key drug-metabolizing enzyme cytochrome P450 (CYP3A4). Therefore, when the combination of both of this drug is given as a short-term course, it has a high possibility to cause harm from drug-drug interactions with other drugs metabolized through the same pathway [6]. The medications that have interactions with Paxlovid^® need to be withheld, reduced in dosing, or discontinued when used concomitantly [7]. The list of this medications can be found through the website or application called COVID-19 drug interactions by the University of Liverpool [8].

Safety profiles of Paxlovid^® are established via Evaluation of Protease Inhibition for Covid-19 in High-Risk Patients (EPIC-HR) trial, a phase II and III randomized, placebo-controlled trial in non-hospitalized patients at high risk of developing severe COVID-19. The adverse events that were observed in the Paxlovid^® group were dysgeusia, diarrhoea, increased fibrin D-dimer, increased alanine amino transferase, increased headache, decreased creatinine renal clearance, nausea, and vomiting. These adverse events were graded as 1 or 2 where it is considered nonserious and resolved. It was also reported that 2.1% of patients discontinued the drug due to the adverse events [4].

Based on the Clinical Management of Confirmed COVID-19 Case in Adult and Paediatric in Malaysia, a set of scoring systems will be used to identify a certain population who meet the clinical eligibility criteria for Paxlovid^®[9]. This includes patients who are symptomatic for less than 5 days with a clinical category of 2 (symptomatic without pneumonia) or 3 (symptomatic with pneumonia). These patients are then further stratified based on the eligibility criteria which are patients aged more than 60 years old, immunocompromised, any comorbidities, obesity, current or ex-smoker, unvaccinated or incomplete vaccination. Patients with any of the mention criteria is considered to have high risk of clinical progression to severe disease.

Pharmacists play an important role in the managing Paxlovid^®. The role ranges from the point of inventory up to the monitoring of Paxlovid^®. In order to monitor patient’s adherence and adverse drug reaction (ADR), pharmacists are required to follow-up on day 3 and day 5 through telephone or video call of all patients. Patient’s responses of ADR and adherence are recorded during the follow-up. During each follow-up pharmacist will continuously educate and provide additional counselling if needed to patients regarding Paxlovid^®. If a patient was found to have experienced an unusual or severe ADR, the pharmacists will advise patient to seek medical assistance at the nearest healthcare facility. Furthermore, it is the pharmacists’ responsibility to report ADR to the National Pharmaceutical Regulatory Agency through manual submission, online web form or pharmacy information system [10].

It is important to ensure that all the effort that is implemented in managing the COVID-19 pandemic is beneficial to patients. Currently there are still insufficient real-world data available on the safety, tolerability and adherence of patients that has been prescribed with Paxlovid^®. Paxlovid^® being a relatively new antiviral around the world and is only made available in Malaysia in mid of 2022, continuous research is needed to provide more evidence on the safety, tolerability, and effectiveness of antivirals in specific patient populations, drug combinations and different healthcare settings [11].

The study aims to evaluate the safety and tolerability of Paxlovid® in category 2 COVID-19 patients, assess their adherence levels, and determine compliance with recommended interventions from the COVID-19 drug interaction database. This research is vital in the ongoing effort to identify effective COVID-19 treatments. By investigating Paxlovid®, we aim to enhance understanding of its safety, tolerability, and efficacy, thereby guiding healthcare providers in optimizing patient outcomes during this ongoing global health challenge.

2.1 Study Design and Setting

This research was a retrospective, cross-sectional, observational study. It was conducted in three primary healthcare clinics in Petaling district, Selangor, Malaysia: Klinik Kesihatan Seksyen 7, Klinik Kesihatan Seksyen 19, and Klinik Kesihatan Kelana Jaya.

2.2 Patient Population and Data Collection

The study population comprised Category 2 COVID-19 patients aged 18 years and older. These patients were prescribed Paxlovid® between April 1, 2022, and November 30, 2022. A comprehensive dataset was generated from a detailed review of electronic and manual patient records. Key data points included demographic details (age, gender, race, comorbidities, vaccination status), Paxlovid® dosing and regimen, interaction-based medication adjustments, patient outcomes, adherence, and ADR. Data from day 3 and day 5 post-Paxlovid® initiation were meticulously collected to monitor treatment response and adherence. Patient records of incomplete data where no record of whether patient consumed Paxlovid^® or not on day 3 and day 5 were excluded. In this study an intervention is defined as any medication that was withheld or had dosage adjustment according to COVID-19 drug interactions by the University of Liverpool [8]. Data whether this intervention was complied to was also collected.

2.3 Paxlovid® Administration

Paxlovid® dosage was determined based on the patient’s renal profile, categorized as follows: patients with estimated glomerular filtration rate (eGFR) ≥ 60 ml/min required three tablets twice daily, eGFR 30–59 ml/min required two tablets twice daily, and eGFR ≤ 30ml/min was a contraindication for Paxlovid® use [9]. Pharmacists provided comprehensive counselling to patients or caregivers on various aspects of Paxlovid® usage (indication, dosing, frequency, time of administration, dosing adjustments or withholding drugs that have interaction with Paxlovid®, management of missed doses, ADR, storage, and any related precautions). Pharmacists conducted follow-ups on days 3 and 5 post-initiation via different communication modes (face to face, video call or phone call), documenting ADR and adherence.

2.4 Sample Size Determination

From a total of 1,396 patients prescribed Paxlovid® across the health clinics (Klinik Kesihatan Seksyen 7, n = 241, Klinik Kesihatan Kelana Jaya, n = 644 and Klinik Kesihatan Seksyen 19, n = 511) on 30th November 2022, a sample size of 377 was calculated using Raosoft®. This figure accounted for a 95% confidence level, a 5% margin of error, a 50% response distribution. An additional 10% to compensate for potential data gaps in retrospective collection were added giving an estimated sample size of 415.

2.5 Adverse Drug Reaction and Medication Adherence Assessment

The World Health Organization (WHO) defines ADR as a response to drug that is noxious and unintended and occurs at doses normally used in people for the prophylaxis, diagnosis and treatment of a disease [12]. Medication adherence level was assessed based on the information documented by pharmacists who dispensed and followed up with patients. Based on literature review, medication adherence level of 80% and above is considered optimal [13].

2.6 Data Analysis

All collected data were entered into Microsoft Excel spreadsheet and analysed using Statistical Package for the Social Sciences software (SPSS) version 28.0. Descriptive statistics were used to measure the percentage of total ADR experienced by patients. A chi-square test analysis was performed to explore the association between the variables.

3.1 Patient Demographics and Clinical Characteristics

Our analysis included 415 patients with complete pharmacy records and medical histories prescribed Paxlovid® from April to November 2022. The demographic and clinical characteristics of the study cohort are presented in Table 1. The mean age of participants was 51.5 years (SD ± 17.0 years), distributed into two age groups: below 60 years (60.0%, n = 249) and 60 years or older (40.0%, n = 166). The gender distribution was nearly balanced, with 50.6% male (n = 210) and 49.4% female (n = 205) participants. The ethnic composition was predominantly Malay (62.9%, n = 261), followed by Chinese (23.9%, n = 99), Indian (11.1%, n = 46), and other ethnicities from East Malaysia (2.2%, n = 9).

3.2 Comorbidities and Concurrent Medication Usage

The study population had an average of 1.1 comorbidities (SD ± 1.3). More than half (54.5%, n = 226) presented with at least one comorbidity, while 45.5% (n = 189) had no documented medical history. Hypertension was the most prevalent comorbidity (33.0%, n = 137), followed by dyslipidaemia (28.0%, n = 116), diabetes mellitus (21.9%, n = 91), ischemic heart disease (9.9%, n = 41), and asthma (8.0%, n = 33). Additionally, a subset of patients presented with multiple coexisting medical conditions.

Concerning concurrent medication use, 48.2% (n = 200) of the patients were not on any medication, while 51.8% (n = 215) were taking at least one concurrent medication. The distribution of patients based on the number of concurrent medications was as follows: 1–4 medications (38.1%, n = 158), 5–9 medications (11.8%, n = 49), and 10 or more medications (1.9%, n = 8).

Table 1

Demographic data of patients in the study (N = 415)
Demographic		Number of patients (%)
Mean ± SD age		51.5 ± 17.0
Age group	< 60 years old	249 (59.7%)
	≥ 60 years old	166 (40.3%)
Gender	Female	205 (49.4%)
	Male	210 (50.6%)
Ethnicity	Malay	261 (62.9%)
	Chinese	99 (23.9%)
	Indian	46 (11.1%)
	Others^a	9 (2.2%)
Mean ± SD number of comorbidities		1.1 ± 1.3
No comorbidities		189 (45.5%)
With comorbidities		226 (54.5%)
Type of comorbidity	Hypertension	137 (33.0%)
	Dyslipidaemia	116 (28.0%)
	Diabetes mellitus	91 (21.9%)
	Ischemic heart disease	41 (9.9%)
	Asthma	33 (8.0%)
	Chronic kidney disease	16 (3.9%)
	Obesity	12 (2.9%)
	Benign prostate hyperplasia	10 (2.4%)
	Cancer	6 (1.4%)
	Others^b	20 (4.3%)
Mean ± SD number of concurrent medications		1.8 ± 2.6
Number of concurrent medications	No medications	200 (48.2%)
	1–4 medications	158 (38.1%)
	5–9 medications	49 (11.8%)
	≥ 10 medications	8 (1.9%)
^aEthnicity from Sabah and Sarawak
^b Rheumatoid arthritis, erectile dysfunction, hyperthyroid, heart failure, glaucoma, adenomyosis, ulcerative colitis, lumbar spondylosis, bilateral knee osteoarthritis, fatty liver, left bundle branch block, thalassemia intermedia, lumbar spondylosis, polycystic ovarian syndrome, gastroesophageal reflux disease, anxiety, and Parkinson’s disease

3.3 Prevalence and Demographics of adverse drug reactions

Pharmacist follow-up on days 3 and 5 revealed that 330 out of 415 patients experienced at least one adverse effect, giving a prevalence rate of 79.5% whereas 85 (20.5%) patients did not experience any adverse effect. In the group of patients who experienced ADR, the age group of < 60 years old consists of 59.4% (n = 196) while ≥ 60 years old is 40.6% (n = 134). Female patients experienced more ADR (n = 167,50.6%) as compared to male patients (n = 163, 49.4%). The ethnicity of patients that experienced ADR were mostly Malay (n = 211, 63.9%), followed by Chinese (n = 72, 21.8%), Indian (n = 40, 12.1%) and others (n = 7, 2.1%). In addition, within the group of patients that experience ADR patients with comorbidities were shown to experience more ADR (n = 196, 59.4%) as compared to patients without comorbidities (n = 134, 40.6%). Furthermore, patients who were prescribed with at least one concurrent medication were found to experience more ADR (n = 185, 56.1%) in comparison with patients without any medication (n = 145, 43.9%).

3.4 Paxlovid® Dosing

Among the 415 patients in the study, the standard Paxlovid® regimen of three tablets twice daily for five days was administered to 399 patients (96.1%). A reduced dose of two tablets twice daily was prescribed for 16 patients (3.9%), specifically those with an eGFR between 30ml/min and 59 ml/min. These dosing details are summarised in Table 2.

A chi-square test was conducted to examine potential associations between experiencing ADR and various independent variables such as age, gender, ethnicity, Paxlovid® dosing, number of concurrent medications, and comorbidities. The analysis, conducted at a 95% confidence level, indicated that comorbidities (p = 0.01) were significantly associated with experiencing ADR from Paxlovid®. Other variables did not show significant associations in this analysis.

Table 2

Prevalence and demographic of patients that experienced and did not experience ADR (N = 415)
Demographic		Experienced ADR (N = 330) (%)	No ADR (N = 85) (%)	P value (chi-square analysis)
Adverse effect		330 (79.5%)	85 (20.5%)
Age	< 60 years old	196 (59.4%)	53 (62.5%)	0.07
	≥ 60 years old	134 (40.6%)	32 (37.6%)
Gender	Female	167 (50.6%)	38 (44.7%)	0.33
	Male	163 (49.4%)	47 (55.3%)
Ethnicity	Malay	211 (63.9%)	50 (58.8%)	0.20
	Chinese	72 (21.8%)	27 (31.8%)
	Indian	40 (12.1%)	6 (7.1%)
	Others^a	7 (2.1%)	2 (2.4%)
Comorbidities	No comorbidity	134 (40.6%)	55 (64.7%)	0.01*
	With comorbidities	196 (59.4%)	30 (35.2%)
Concurrent medication	No medication	145 (43.9%)	55 (64.7%)	0.38
	With medication	185 (56.1%)	30 (35.3%)
Paxlovid® dosing	3 tablet BD	318 (96.4%)	81 (95.3%)	0.65
	2 tablet BD	12 (3.6%)	4 (4.7%)
^a Ethnicity from East Malaysia
*P value < 0.05 is significant

Abbreviations: ADR – adverse drug reaction; BD - twice a day

Table 3 outlines the range of ADR encountered by participants in the study. A total 16 ADR were reported. The most prevalent reaction was dysgeusia, with 273 patients (65.8%) reporting this issue. This was followed by diarrhoea, affecting 105 patients (25.3%), and body ache, reported by 73 individuals (17.6%). Other noted ADR included vomiting (21 cases, 5.1%), nausea (11 cases, 2.7%), headache (9 cases, 2.2%), dizziness (8 cases, 1.9%), and high blood pressure (4 cases, 1.0%). Additional ADR, each reported by 2 individuals (0.5%), were lethargy and dry cough.

Table 3: ADR experienced by the study population (N=415)

Adverse drug reaction	Number of patients (%)
Dysgeusia	273 (65.8%)
Diarrhoea	105 (25.3%)
Body ache	73 (17.6%)
Vomiting	21 (5.1%)
Nausea	11 (2.7%)
Headache	9 (2.2%)
Dizziness	8 (1.9%)
High blood pressure	4 (1.0%)
Lethargy	2 (0.5%)
Dry cough	2 (0.5%)
Urticaria	1 (0.2%)
Dry mouth	1 (0.2%)
Gastrointestinal discomfort	1 (0.2%)
Loss of appetite	1 (0.2%)
Shivering	1 (0.2%)
Difficulty in sleeping	1 (0.2%)

3.5 Medication Adherence

The evaluation of medication adherence, based on follow-up records by pharmacists, revealed that 402 of the 415 patients consistently adhered the prescribed dosage of Paxlovid®, translating to a prevalence rate of 96.9%. The characteristics of both adherent and non-adherent patients, along with the results of chi-square analysis, are detailed in Table 4. Within the cohort adhering to the Paxlovid® regimen, 60.2% (242 patients) were under 60 years old, while 39.8% (160 patients) were 60 years or older. The gender distribution was nearly even, with males representing 50.5% (203 patients) and females 49.5% (199 patients). Ethnically, the majority were Malay (62.9%, 253 patients), followed by Chinese (24.1%, 97 patients), Indian (10.7%, 43 patients), and Others (2.2%, 9 patients). Regarding health conditions, 54.5% (219 patients) had comorbidities, while 45.5% (183 patients) did not. Adverse drug reactions (ADRs) were reported by 79.9% (321 patients), whereas 20.1% (81 patients) did not report any ADRs. In terms of medication, 61.2% (246 patients) were not taking any concurrent medications, while 38.8% (156 patients) were on at least one other medication. The prescribed dosage of Paxlovid® was predominantly 3 tablets twice daily for five days, 96.3% (387 patients), with a smaller group, 3.7% (15 patients), prescribed 2 tablets twice daily for the same duration. The chi-square analysis comparing adherent and non-adherent groups across these variables did not reveal statistically significant differences.

Table 5 illustrates the tablet consumption patterns and the reasons for non-adherence among patients. According to the prescription guidelines, patients were expected to take 20 tablets over 5 days when prescribed 2 tablets twice daily, and 30 tablets when prescribed 3 tablets twice daily. However, within the non-adherent patient group, observations were as follows: 2 patients (15.4%) did not consume any of the prescribed medication, 6 patients (46.2%) took between 1 to 10 tablets, 2 patients (15.4%) took between 11 to 20 tablets, and 3 patients (23.1%) took between 21 to 27 tablets. This indicates varying degrees of non-adherence to the 20-30 tablet regimen intended for the 5-day treatment period.

The primary cause for discontinuation of the Paxlovid^® regimen (Table 5) was identified as intolerable ADR, which accounted for 9 (69.2%) of the cases. The intolerable ADR include diarrhoea (n=4, 44.4%) dysgeusia (n=3, 33.3%), headache, dizziness, nausea, gastrointestinal discomfort, increased in blood pressure, and difficulty in sleeping. Subsequently, dosing uncertainty, forgetfulness and apprehension regarding potential ADR were each cited by 1 (7.7%) patient, respectively. Moreover, one patient (7.7%) reported improved health status as the rationale for ceasing treatment.

Table 4: The adherent and non-adherent patient characteristic and chi square analysis (N=415)

Demographic		Adherent (N=402) %	Non-adherent (N=13) %	P-value (chi-square analysis)
Adherence level		402 (96.9%)	13 (3.1%)
Age	< 60 years old	242 (60.2%)	7 (53.8%)	0.75
	≥ 60 years old	160 (39.8%)	6 (46.2%)	0.75
Gender	Female	199 (49.5%)	6 (46.2%)	0.81
	Male	203 (50.5%)	7(53.8%)	0.81
Ethnicity	Malay	253 (62.9%)	8 (61.5%)	0.49
	Chinese	97 (24.1%)	2 (15.4%)
	Indian	43 (10.7%)	3 (23.1%)
	Others^a	9 (2.2%)	-
Comorbidities	No comorbidity	183 (45.5%)	6 (46.2%)	0.98
	With comorbidities	219 (54.5%)	7 (53.8%)	0.98
Adverse effect	Yes	321 (79.9%)	9 (69.2%)	0.35
	No	81 (20.1%)	4 (30.8%)	0.35
Concurrent medications	No medications	246 (61.2%)	6 (46.2%)	0.98
	With medication	156 (38.8%)	7 (53.8%)
Paxlovid^® Dosing	3 tablets BD	387 (96.3%)	12 (92.3%)	0.47
	2 tablets BD	15 (3.7%)	1 (7.7%)

P value <0.05 is significant

Abbreviations: BD twice a day

Table 5: Non-adherent patients towards nirmatrelvir-ritonavir (Paxlovid®) (N=13)

Characteristics		Number of patients (%)
Quantity of tablets taken in 5 days	0 tablet	2 (15.4%)
	1-10 tablets	6 (46.2%)
	11-20 tablets	2 (15.4%)
	21-27 tablets	3 (23.1%)
Reasons for non-adherent	Intolerable ADR	9 (69.2%)
	Dosing uncertainty	1 (7.7%)
	Forgetfulness	1 (7.7%)
	Apprehension on potential ADR	1 (7.7%)
	Improved health status	1 (7.7%)

Abbreviations: ADR – adverse drug reaction

3.6 Drug-Drug Interactions

In addressing potential drug interactions with Paxlovid®, healthcare professionals took proactive measures by either withholding or modifying the dosages of the concurrent medications. Out of the 215 patients on at least one other medication, 25 were excluded from subsequent analysis and discussions due to incomplete data regarding these interventions, leaving a cohort of 190 patients. Within this group, a significant majority, 75.3% (143 patients), underwent one or more medication adjustments, while the remaining 24.7% (47 patients) did not necessitate any intervention. It's noteworthy that a single patient could have multiple medications withheld or dosage adjusted simultaneously. The study identified 23 different types of medications taken alongside Paxlovid® that could potentially lead to interactions. Table 6 displays these medications, categorizes the type of interaction, tallies the interventions carried out, and adherence to the recommended interventions.

The interacting medications identified in this study fall into three categories with Paxlovid®, as classified by the University of Liverpool's COVID-19 Drug Interactions database[8]. In the first category, concurrent administration of the medication with Paxlovid® is strongly advised against. The standard recommendation is to avoid co-administration, necessitating the withholding of these drugs. Within this particular interaction category, simvastatin was the most commonly withheld, with all cases (n=58, 100%) complying to this protocol. Similarly, colchicine and salmeterol were each withheld in all instances (n=2, 100% each), and the same was true for alfuzosin and ivabradine, each reported in one instance (n=1, 100%). Compliance was complete in this category, as all recommended interventions were followed, with every identified medication being duly withheld.

The second category includes medications that have a potential for interaction. The interventions recommended for this group are customized based on the particular medication involved. These measures may range from no requirement for dosage change to a reduction in dosage, or even avoiding the co-administration of the interacting drug altogether. The choice of the most suitable intervention is further guided by the physician's evaluation of the patient's clinical symptoms and overall health status. Within this category, certain medications were recommended to be withheld, including atorvastatin (n=58, 100%), rosuvastatin (n=14, 100%), amlodipine (n=8, 11.8%), valsartan (n=7, 87.5%), and clopidogrel (n=4, 100%). Others like dutasteride, tadalafil, and tamsulosin were each withheld in all cases (n=2, 100%), followed by alprazolam, doxazosin, sacubitril, and upadacitinib (each with n=1, 100%).

Conversely, certain medications in this category were subject to dose reduction, particularly amlodipine (n=60, 88.2%), and to a lesser extent, dabigatran, felodipine, nifedipine (each n=1, 100%), and valsartan (n=1, 12.5%). It is noteworthy, however, that the intended interventions for alprazolam and dutasteride were not fully complied with. Instead of the dose adjustment or reduction, these medications were withheld.

The third category includes medications that exhibit have weak interactions with Paxlovid®. For these drugs, the general recommendation is that they can be administered without any need for dose modification. However, the study observed instances where certain medications were either withheld or had their dosage reduced. Specifically, ezetimibe and loratadine were completely withheld (n=3, 100% and n=1, 100%, respectively), and losartan had its dose reduced (n=1, 100%). Despite the guidelines suggesting no need for dose adjustments or withholding these medications due to their weak interaction potential, the study found that these interventions were implemented.

Considering the overall compliance to the recommended interventions for potential drug-drug interactions, the study revealed that, out of the 23 types of medications analysed, five did not follow the recommended intervention guidelines, representing a non-compliance rate of 21.7%. Conversely, a majority of 78.3% (n=18) complied to the recommended interventions for managing drug interactions with Paxlovid®.

Table 6: The list of interacting medication, the category of interaction, number of medications intervention and the compliance to recommended intervention (N=190)

Num.	Medication (number of patients prescribed with the medication)	Category of interaction	Number of patients whose medications were withheld (%)	Number of patients whose medications dose adjusted (%)	University of Liverpool COVID-19 Drug Interactions recommendation [8]	Compliance to recommended intervention
1	Alfuzosin (n=1)	Do not co-administer	1(100%)	0	Contraindicated. Withhold.	Compliant
2	Colchicine (n=2)	Do not co-administer	2 (10%)	0	Contraindicated. Withhold.	Compliant
3	Ivabradine (n=1)	Do not co-administer	1 (100%)	0	Contraindicated. Withhold.	Compliant
4	Salmeterol (n=2)	Do not co-administer	2 (100%)	0	Contraindicated. Withhold.	Compliant
5	Simvastatin (n=58)	Do not co-administer	58 (100%)	0	Contraindicated. Withhold.	Compliant
6	Alprazolam (n=1)	Potential interaction	1 (100%)	0	Consider a lower dose.	Non- compliant
7	Amlodipine (n=68)	Potential interaction	8 (11.8%)	60 (88.2%)	Reduce dose by 50% or take it every other day or withhold and advice patient to monitor for symptoms of hypotension.	Compliant
8	Atorvastatin (n=58)	Potential interaction	58 (100%)	0	Avoid co-administration or use the lowest dose possible dose.	Compliant
9	Clopidogrel (n=4)	Potential interaction	4 (100%)	0	Avoid co-administration.	Compliant
10	Dabigatran (n=1)	Potential interaction	0	1 (100%)	Avoid co-administration or reduce dose	Compliant
11	Doxazosin (n=1)	Potential interaction	1 (100%)	0	No dose adjustment if hypotension occurs stop doxazosin.	Compliant
12	Dutasteride (n=2)	Potential interaction	2 (100%)	0	A reduction of dutasteride dosing frequency can be considered if ADR are noted.	Non- compliant
13	Felodipine (n=1)	Potential interaction	0	1 (100%)	A dose reduction of 50% or taking the dose every other day could be considered, if necessary, to temporarily pause the antihypertensive drug if needed.	Compliant
14	Nifedipine (n=1)	Potential interaction	0	1 (100%)	A dose reduction of 50% or taking the dose every other day could be considered, if necessary, to temporarily pause the antihypertensive drug if needed.	Compliant
15	Rosuvastatin (n=14)	Potential interaction	14 (100%)	0	Avoid co-administration or use the lowest dose possible dose.	Compliant
16	Sacubitril (n=1)	Potential interaction	1 (100%)	0	No dose adjustment if hypotension occurs stop sacubitril.	Compliant
17	Tadalafil (n=2)	Potential interaction	2 (100%)	0	Avoid co-administration or reduce dose.	Compliant
18	Tamsulosin (n=2)	Potential interaction	2 (100%)	0	Avoid co-administration or reduce dose.	Compliant
19	Upadacitinib (n=1)	Potential interaction	1 (100%)	0	Avoid co-administration or reduce dose.	Compliant
20	Valsartan (n=8)	Potential interaction	7 (87.5%)	1(12.5%)	No dose adjustment if hypotension occurs stop valsartan.	Compliant
21	Ezetimibe (n=3)	Potential weak interaction	3 (100%)	0	No dosage adjustment is needed.	Non- compliant
22	Loratadine (n=1)	Potential weak interaction	1 (100%)	0	No dosage adjustment is needed.	Non- compliant
23	Losartan (n=1)	Potential weak interaction	0	1 (100%)	No dosage adjustment is needed.	Non- compliant

In this study, a substantial 79.5% of the participants reported experiencing at least one adverse effect following Paxlovid® administration, a figure significantly higher than the 55.1% (152 out of 276 patients) reported in a local study from Perak, Malaysia [14]. This trend aligns with findings from the University of Washington Medicine, where a notable 85.0% of patients reported ADRs [15]. These numbers starkly contrast with the 22.6% incidence rate of ADRs noted in the Paxlovid® group of the EPIC-HR randomized clinical trial [4]. Such discrepancies in ADR prevalence between real-world studies and clinical trials might be attributable to demographic differences, particularly in age [16]. Notably, the demographic profile of our study participants, with a higher mean age where 40.6% are over 60 years old, and a significant proportion (54.6%) having at least one comorbidity, might have contributed to the elevated ADR prevalence observed, suggesting that real-world application data can differ substantially from controlled trial environments.

In the cohort of patients who experienced ADRs, an intriguing pattern emerged where individuals younger than 60 reported slightly more ADRs compared to their older counterparts. This observation challenges the conventional belief that the elderly is more susceptible to ADRs from drug therapy [17]. Two key factors might elucidate this unexpected trend: study setting in primary healthcare clinics and the distinct course of COVID-19 symptoms in elderly. Primary healthcare clinics, integral to Malaysia's healthcare system, serve as the initial contact point for patients seeking medical attention, playing a pivotal role in the broader healthcare continuum by facilitating referrals to secondary and tertiary care [18]. Specifically, within this framework, COVID-19 Assessment Centres (CAC) have been established to assess and devise home monitoring plans for COVID-19 cases, particularly for those in the initial stages of the infection [19]. According to the protocols set by the Ministry of Health Malaysia [9], patients in category 2 are managed within the primary care setting, while those in categories 3 to 5 necessitate hospitalization. Given the heightened vulnerability of the elderly to COVID-19 and the rapid symptom escalation in the later stages of the disease, they are more likely to be swiftly transitioned to intensive care, often requiring mechanical ventilation [17]. This operational dynamic potentially explains the lower representation of patients above 60 in the study cohort and, consequently, the lower incidence of ADRs reported in this age group. Essentially, the study's setting and the structured approach to COVID-19 patient management may inadvertently skew the age distribution of those experiencing ADRs, offering a fresh perspective on the interaction between age, healthcare system structure, and drug therapy outcomes.

In this study, a pronounced trend was observed where patients with one or more comorbidities and those on multiple medications exhibited a higher incidence of ADRs. The data revealed a significant correlation between the occurrence of ADRs post-Paxlovid® administration and the presence of underlying health conditions. This finding underscores the complexity of patient health profiles and their potential influence on medication tolerance. While specific research focusing on the risk factors contributing to ADRs associated with Paxlovid® is limited, this study's insights align with broader observations in pharmacological research. For instance, the study by Pesko et al. [15] noted that a considerable portion of patients (12 out of 40) who experienced ADRs were taking five or more concurrent medications, suggesting a cumulative burden of medication management on patient health. Furthermore, research evaluating Paxlovid®'s safety and effectiveness in elderly populations highlighted that a vast majority (89.0%) had one or more concurrent health conditions, shedding light on the heightened vulnerability to adverse events in this demographic [17, 20]

These findings collectively point to the intricate interplay between patient comorbidities, polypharmacy, and the risk of ADRs, emphasizing the need for cautious and personalized medication management, especially in populations with complex health profiles. The study contributes to a growing body of evidence, calling for a nuanced understanding of how individual health factors may impact the safety and efficacy of medications like Paxlovid®. The findings of this study may be influenced by the criteria set for initiating antiviral therapy in COVID-19 patients. Specifically, Paxlovid® is prescribed to patients classified in categories 2 or 3, particularly those with any form of comorbidity. As a result, patients with comorbid conditions are often on multiple medications, which might account for the observed trends. Nonetheless, it's crucial to recognize that both the presence of comorbidities and the regimen of multiple medications are independently recognized as risk factors for adverse drug reactions (ADRs) [21-24].

In this study, the three most prevalent adverse drug reactions (ADRs) were identified as dysgeusia, diarrhea, and body ache. This finding contrasts slightly with another local study, which pinpointed dysgeusia, diarrhea, along with nausea and vomiting as the most commonly reported ADRs [14]. Additionally, research from the University of Washington Medicine in the USA reported dysgeusia, diarrhea, and headache as the top ADRs [15]. Moreover, an Italian study observed dysgeusia, diarrhea, and bloating to be the foremost adverse effects experienced by participants [16]. This variation in the top ADRs across different studies underscores the diverse manifestation of adverse reactions in distinct populations and settings.

In all four studies, dysgeusia emerged as the most commonly documented adverse effect. Recent post-marketing analyses have shed light on a possible mechanism for this distinctive altered taste sensation, especially when it diverges markedly from typical symptoms associated with COVID-19. This unique side effect is thought to be specifically associated with nirmatrelvir[25].To delve deeper into this occurrence, future research should focus on uncovering the pathophysiological processes behind this phenomenon. Such studies should not only strive to understand the immediate effects but also explore the possible long-term health implications for individuals experiencing dysgeusia after using Paxlovid®. Undertaking these research initiatives is crucial for unraveling the complexities of this adverse effect and enhancing our overall grasp of its implications for patient health and quality of life.

This study's results indicate that a significant portion of patients adhered to the full Paxlovid® treatment regimen. This observation aligns with findings from a similar local study by Chew et al. [14] , which reported a high adherence rate, with 93.8% (n=259) of patients following the prescribed Paxlovid® schedule. Likewise, research conducted in Italy assessed medication adherence based on the count of returned tablets at the end of the treatment, revealing that 94.6% (n=475) of patients completed the prescribed course [16]. These consistent findings across all three studies highlight a notable trend of robust medication adherence among the study cohorts. It is reasonable to deduce that patient adherence to Paxlovid® is commendably high, exceeding the 80% threshold as indicated by previous research concerning medication adherence [16]. It can be hypothesized that the substantial role of pharmacists significantly contributes to this high adherence rate among patients. In the context of this study, patients benefited from the expert guidance and advice of pharmacists, who offered a thorough understanding of Paxlovid® and its usage. A systematic review by Rajiah et al. [26], has underscored the positive impact of pharmacist-led patient counseling during medication dispensing on enhancing adherence to treatment protocols. This interaction between pharmacists and patients evidently bolsters adherence, showcasing pharmacists as key healthcare figures who not only dispense medication but also educate and engage patients in managing their health effectively.

Additionally, the structure of Paxlovid® treatment—a short, 5-day course coupled with diligent pharmacist oversight—likely facilitates optimal adherence levels. This observation is supported by a systematic review suggesting that strategies to improve medication adherence tend to be more successful with short-term treatments as opposed to the long-term management of chronic conditions [27]. Therefore, the combined influence of pharmacist intervention and the brief nature of the treatment regimen appears instrumental in achieving high levels of patient adherence to Paxlovid®.

The presence of the ritonavir component is responsible for the intricate interplay of drug interactions in Paxlovid^®. This component is associated with an extensive range of drug interactions, thereby constraining its safe utilization, particularly in the elderly population with multiple medication use [28]. Within this study's cohort of patients receiving prescriptions, a substantial proportion of 75.3% (n=143) exhibited drug-drug interactions with Paxlovid^® that necessitated intervention. This percentage is higher than the results of another study, which indicated that 68.0% (n=3,869) of patients were prescribed medications with potential interactions with Paxlovid^® [29]. In this study, within the medications falling under the high-risk interaction category, simvastatin, a lipid lowering agent, was the most prevalent. An intervention was undertaken by withholding the medication as Paxlovid^® could increase the concentration of simvastatin by 100-fold which would lead to the risk of severe toxicity and rhabdomyolysis [6, 8].

Ritonavir, a component of Paxlovid®, plays a pivotal role in the complex dynamics of drug interactions associated with the medication. Its propensity for extensive drug interactions poses challenges for safe administration, especially among older adults who are often on multiple medications [28]. In this study, a notable 75.3% (n=143) of the patient cohort faced drug-drug interactions with Paxlovid® that required proactive management. This incidence surpasses that reported in another research, where 68.0% (n=3,869) of patients were identified as taking medications potentially interacting with Paxlovid® [29]. Notably, within the category of high-risk interactions, simvastatin was most frequently implicated. To mitigate the risk of severe toxicity and rhabdomyolysis, an intervention strategy was adopted, which involved temporarily discontinuing simvastatin due to Paxlovid®'s potential to significantly increase its concentration by up to 100-fold [8]. This underscores the critical need for meticulous medication management and patient monitoring when administering treatments with complex interaction profiles like Paxlovid®.

In the category of medications with potential interactions with Paxlovid®, amlodipine—a calcium channel blocker used to treat hypertension or angina—was the most commonly prescribed. To mitigate risks, the dosage of amlodipine was either adjusted or the medication was temporarily discontinued, as Paxlovid® is known to potentially double the concentration of amlodipine [8]. Additionally, the combination of Paxlovid® with atorvastatin could lead to increased atorvastatin levels; hence, all atorvastatin prescriptions in this study were suspended. Moreover, the majority of the medications identified as interacting with Paxlovid® in this study were managed in accordance with the recommended guidelines outlined in the COVID-19 drug interactions database [8], demonstrating a high level of compliance with established intervention protocols.

While the complexity of certain drug-drug interactions is acknowledged, it's important to underscore that these challenges shouldn't deter the use of Paxlovid®. Notably, a substantial proportion of these interactions are manageable with proper oversight [6]. In the realm of medication safety, thorough medication reconciliation plays a pivotal role, especially in the context of drug-drug interactions. This process is of paramount importance as it equips healthcare professionals with a complete understanding of potential interactions. Armed with this knowledge, practitioners can navigate and manage drug-drug interactions effectively and securely, ensuring that patients not only receive the best possible care but also have minimized risk exposure.

The management of drug-drug interactions associated with Paxlovid^® transcends a mere recognition of these interactions; it encompasses a holistic evaluation of risks and benefits, extends its impact beyond healthcare settings, thrives on interprofessional collaboration, and tailors interventions to the specific needs of vulnerable patient groups. This comprehensive approach safeguards patient well-being while optimizing the therapeutic potential of Paxlovid^® within the ever-evolving landscape of healthcare.

The outcomes of this study need to be considered within the context of certain limitations. Firstly, as a retrospective observational study, data were gathered from pharmacy and medical records in primary healthcare clinics, without direct patient or caregiver engagement during follow-up on days 3 and 5. Consequently, the research team's insights were confined to the information available in these records. Secondly, the analysis faced challenges due to incomplete data about the implementation of medication interventions for managing drug-drug interactions with Paxlovid®, leading to the exclusion of 25 patients from the potential drug-drug interaction analysis. Thirdly, the study was conducted in three primary healthcare centers in the Petaling District, Selangor, which may limit the generalizability of the findings to a wider COVID-19 population due to the relatively small sample size. Lastly, the COVID-19 vaccination status of the study participants was not included in the analysis due to the unavailability of data from one of the primary healthcare clinics, attributed to technical issues.

The study included data from three different primary health clinics
Patients self-reported their side effects and adherence status. These rates may be overestimated or underestimated.
Study's retrospective nature require cautious interpretation of findings.

This study successfully met its objectives, revealing that 79.5% of the 415 COVID-19 patients treated with nirmatrelvir-ritonavir (Paxlovid®) experienced adverse drug reactions (ADRs). The most common ADRs identified were dysgeusia, diarrhea, body ache, vomiting, and nausea. Importantly, the ADRs reported were generally well tolerated, with no severe adverse reactions observed among the study participants. The safety and tolerability of nirmatrelvir-ritonavir (Paxlovid®) were evident, as the vast majority of patients (96.9%) successfully completed the 5-day treatment regimen. However, a small fraction (3.1%) of the patients did not adhere to the recommended treatment protocol.

This study illuminates the crucial role of healthcare professionals in managing Paxlovid® treatment, particularly in navigating its complex drug-drug interactions within a primary healthcare context. The high medication adherence rates and proactive management of interactions underscore the importance of personalized healthcare approaches, especially for patients with multiple comorbidities. However, the study's retrospective nature and its limited scope necessitate cautious interpretation of the findings. It highlights the need for further, more comprehensive research to validate these findings and enhance the understanding of Paxlovid®'s real-world impact. Moving forward, expanding the research scope and incorporating direct patient engagement will be pivotal in refining treatment strategies and ensuring optimal patient care in the ongoing battle against COVID-19.

Ethical Considerations

The study adhered to the Declaration of Helsinki and Malaysian Good Clinical Practice Guidelines. Necessary approvals were obtained from the Selangor State Health Director, the Chief Pharmacist of the Petaling District Health Office (JKNS/KA/Q-712/04-01 Jld 23(20)), and ethics committees of Universiti Teknologi MARA (600-FF(RES.5/4)) and the Medical Research and Ethics Committee, Malaysia (23-00714-L4T).

Consent to Participate declarations

The research gathered retrospective data from three primary health clinics and did not necessitate patient consent. Patient identifiers were not collected. Due to retrospective nature of the study need for informed consent of patients was exempted by ethics committees of Universiti Teknologi MARA (600-FF(RES.5/4)) and the Medical Research and Ethics Committee, Malaysia (23-00714-L4T).

Clinical trial details

Not applicable

Funding

This research received no specific grant from any funding agency in the public, commercial or not-for-profit sectors

Acknowledgments

We thank the staff for all three health clinics for the cooperation in accommodating the research. We would also like to thank the Director General of Health Malaysia for his permission to publish this article.

The authors did not receive support from any organization for the submitted work. All authors certify that they have no affiliations with or involvement in any organization or entity with any financial interest or non-financial interest in the subject matter or materials discussed in this manuscript.

Author contributions

All authors contributed to the study conception and design. Material preparation, data collection and analysis were performed by Zahirah Zaharuddin as part of her dissertation, supervised by Mahmathi Karuppannan and Nur Sabiha Md Hussin. The first draft of the manuscript was written by Zahirah Zaharuddin and all authors commented on previous versions of the manuscript. All authors read and approved the final manuscript.

Data availability Statement

The datasets used and/or analysed during the current study available from the corresponding author on reasonable request.

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No competing interests reported.

Evaluating Nirmatrelvir-Ritonavir (Paxlovid®) in Outpatient COVID-19 Treatment: Safety, Tolerability, and Adherence Insights from Primary Healthcare Clinics

Status:

Journal Publication

Version 1

Abstract

Introduction

Method

2.1 Study Design and Setting

2.2 Patient Population and Data Collection

2.3 Paxlovid® Administration

2.4 Sample Size Determination

2.5 Adverse Drug Reaction and Medication Adherence Assessment

2.6 Data Analysis

Results

3.1 Patient Demographics and Clinical Characteristics

3.2 Comorbidities and Concurrent Medication Usage

3.3 Prevalence and Demographics of adverse drug reactions

3.4 Paxlovid® Dosing

Discussion

Strength and limitation of this study

Conclusion

Declarations

References

Additional Declarations

Status:

Journal Publication

Version 1