Real-world analysis of safety, tolerability, and adherence to nirmatrelvir-ritonavir (paxlovid) in primary care COVID-19 outpatients.

This research was a retrospective, cross-sectional, observational study. It was conducted in three government primary healthcare clinics in the Petaling district, Selangor, Malaysia: Klinik Kesihatan Seksyen 7 , Klinik Kesihatan Seksyen 19 , and Klinik Kesihatan Kelana Jaya . These are three out of 59 primary healthcare clinics in Selangor that prescribe Paxlovid in the outpatient pharmacy department and are located in the same district. These primary healthcare clinics were selected due to the highest usage of Paxlovid in the Petaling district. The government primary healthcare clinics offer a wide range of services, including maternal and child healthcare, general outpatient services, and an expanded scope of primary care. Most primary healthcare clinics are staffed by family medicine specialists, medical officers, pharmacists, assistant medical officers, staff nurses, and other primary healthcare professionals. They are also equipped with basic laboratory and radiology services depending on the size of the primary healthcare clinics. During the COVID-19 pandemic, primary healthcare clinics were crucial in managing the outbreak. Selected primary healthcare clinics functioned as COVID-19 Assessment Centres (CACs), contributing significantly to the pandemic response by facilitating early diagnosis, categorising COVID-19 patients for appropriate management, and alleviating pressure on hospital resources. The study population comprised Category 2 COVID-19 patients aged 18 years and older. In accordance with Malaysia’s Clinical Guideline for the Management of Confirmed COVID-19 Cases in Adults and Paediatrics 9 , upon confirmation of COVID-19 infection, patients are categorised into one of five groups as outlined in Table  1 , and the clinical management is guided by these categories. Table 1 Clinical staging of COVID-19. Clinical stage Disease severity 1 Asymptomatic 2 Symptomatic, no pneumonia 3 Symptomatic, pneumonia 4 Symptomatic, pneumonia, requiring supplemental oxygen 5 Critically ill with or without organ failures Clinical staging of COVID-19. The initiation of antiviral therapy in patients categorized as 2 or 3 will be guided by the Eligibility Criteria for Antiviral Therapy detailed in Table  2 , as long as patients do not meet any non-indicated or contraindication criteria, such as being under 18 years of age, having symptoms for more than 5 days, requiring oxygen, being pregnant or breastfeeding, experiencing drug interactions, and having severe renal or liver disease. Patients meeting any of the criteria below will be considered eligible for oral antiviral therapy. Table 2 Eligibility criteria for antiviral therapy (category 2–3). Num Eligibility criteria 1 Age ≥ 60 years old 2 Immunocompromised 3 Any co-morbidity 4 Obesity 5 Current or ex-smoker 6 Unvaccinated or incomplete vaccination Eligibility criteria for antiviral therapy (category 2–3). This study included only category 2 patients who met the specified criteria, as category 3 patients would be referred to a hospital setting for further care. The recommended treatment regimen is expected to evolve as new evidence becomes available. These patients were prescribed Paxlovid between 1 April 2022, and 30 November 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 with incomplete data, where there was no record of whether the patient consumed Paxlovid on day 3 and day 5, were excluded. In this study, an intervention is defined as any medication that was withheld or had dosage adjustments according to COVID-19 drug interactions by the University of Liverpool 8 . Data whether this intervention was complied with was also collected. Paxlovid dosage was determined based on the patient’s renal profile, categorised 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 ≤ 30 ml/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 interactions 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. From a total of 1396 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, and a 50% response distribution. An additional 10% to compensate for potential data gaps in retrospective collection was added giving an estimated sample size of 415. The World Health Organization (WHO) defines ADR as a response to a 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 levels were assessed based on the information documented by pharmacists who dispensed and followed up with patients. Based on the literature review, a medication adherence level of 80% and above is considered optimal 13 . All collected data were entered into a Microsoft Excel spreadsheet and analysed using the Statistical Package for the Social Sciences software (SPSS) version 28.0. Descriptive statistics were used to measure the percentage of total ADRs experienced by patients. A chi-square test analysis was performed to explore the association between the variables.

Our analysis included 415 patients with complete pharmacy records and medical histories who were prescribed Paxlovid from April to November 2022. The demographic and clinical characteristics of the study cohort are presented in Table  3 . 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). Table 3 Demographic data of patients in the study (N = 415). Demographic Number of patients (%) Mean ± SD age (years) 51.5 ± 17.0 Age group   < 60 years old 249 (59.7%)   ≥ 60 years old 166 (40.3%) Gender 205 (49.4%)   Female   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%) a Ethnicity 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. Demographic data of patients in the study (N = 415). a Ethnicity 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. 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), ischaemic 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). 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 was 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 experienced ADRs, 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 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%). 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 30 ml/min and 59 ml/min. These dosing details are summarised in Table  4 . Table 4 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%) ADR adverse drug reaction, BD twice a day. * P value < 0.05 is significant. a Ethnicity from East Malaysia. Prevalence and demographic of patients that experienced and did not experience ADR (N = 415). ADR adverse drug reaction, BD twice a day. * P value < 0.05 is significant. a Ethnicity from East Malaysia. 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 5 outlines the range of ADR encountered by participants in the study. A total of 16 ADRs 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 ADRs 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 ADRs, each reported by 2 individuals (0.5%), were lethargy and dry cough. Table 5 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%) ADR experienced by the study population (N = 415). The evaluation of medication adherence, based on follow-up records by pharmacists, revealed that 402 of the 415 patients consistently adhered to 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 the chi-square analysis, are detailed in Table 6 . 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. 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 6 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%) Gender   Female 199 (49.5%) 6 (46.2%) 0.81   Male 203 (50.5%) 7(53.8%) 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%) Adverse effect   Yes 321 (79.9%) 9 (69.2%) 0.35   No 81 (20.1%) 4 (30.8%) 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%) BD twice a day. P value < 0.05 is significant. The adherent and non-adherent patient characteristic and chi square analysis (N = 415). BD twice a day. P value < 0.05 is significant. Table  7 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 and 10 tablets, 2 patients (15.4%) took between 11 and 20 tablets, and 3 patients (23.1%) took between 21 and 27 tablets. This indicates varying degrees of non-adherence to the 20–30 tablet regimen intended for the 5-day treatment period. Table 7 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%) ADR adverse drug reaction. Non-adherent patients towards nirmatrelvir–ritonavir (Paxlovid) (N = 13). ADR adverse drug reaction. The primary cause for discontinuation of the Paxlovid regimen (Table  7 ) was identified as intolerable ADRs, which accounted for 9 (69.2%) of the cases. The intolerable ADRs include diarrhoea ( n  = 4, 44.4%) dysgeusia ( n  = 3, 33.3%), headache, dizziness, nausea, gastrointestinal discomfort, increase in blood pressure, and difficulty sleeping. Subsequently, dosing uncertainty, forgetfulness and apprehension regarding potential ADRs were each cited by 1 (7.7%) patient, respectively. Moreover, one patient (7.7%) reported improved health status as the rationale for ceasing treatment. 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 8 displays these medications, categorises the type of interaction, tallies the interventions carried out, and adherence to the recommended interventions. Table 8 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 The list of interacting medication, the category of interaction, number of medications intervention and the compliance to recommended intervention (N = 190). 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 with 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 the potential for interaction. The interventions recommended for this group are customised 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, and 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 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 with 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 with the recommended interventions for managing drug interactions with Paxlovid.

Strength and limitation of this study 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. 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, diarrhoea, 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 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 personalised 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.

This study aimed to evaluate the safety, tolerability, and adherence to Paxlovid in managing Category 2 COVID-19 patients in outpatient settings. Our analysis found that 79.5% of patients experienced at least one ADR, with the most commonly reported side effects being dysgeusia, diarrhoea, and body ache. Despite these ADRs, the majority were mild and well tolerated, with no serious adverse events reported. Importantly, adherence to Paxlovid was high, as 96.9% of patients completed the full 5-day treatment regimen. This indicates that while ADRs are common, they generally do not hinder treatment completion. Additionally, 75.3% of patients taking concurrent medications required interventions due to potential drug-drug interactions, highlighting the need for careful medication management. 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 and comparable to the 85% observed in the University of Washington Medicine study 15 . This contrasts sharply with the 22.6% incidence rate of ADRs reported in the EPIC-HR randomised clinical trial 4 , highlighting the potential discrepancies between real-world data and controlled clinical trials. These discrepancies may stem from demographic differences, particularly with a higher proportion of older patients 16 and those with comorbidities in this study, which likely contributed to the elevated ADR prevalence.Real-world data often reflect a broader, more complex patient population, which may explain the difference in ADR rates compared to tightly controlled trial environments. Interestingly, younger patients (under 60 years old) reported slightly more ADRs than older patients. This challenges the conventional belief that elderly patients, due to polypharmacy and comorbidities, are more susceptible to ADRs 17 . This unexpected trend may be explained by the operational dynamic of COVID-19 management in Malaysia, where older patients with severe symptoms are more likely to be escalated to hospital care. 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 hospitalisation. 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. A significant correlation was found between the occurrence of ADRs and the presence of comorbidities. Patients with one or more comorbidities and those taking multiple medications exhibited a higher incidence of ADRs, consistent with broader 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 . Nonetheless, it is crucial to recognise that both the presence of comorbidities and the regimen of multiple medications are independently recognised as risk factors for ADRs 21 – 24 . This finding highlights the need for personalised medication management, particularly for patients with complex health profiles. In this study, the three most prevalent ADRs were identified as dysgeusia, diarrhoea, and body ache. This is consistent with other studies, although variations in the ranking of ADRs were observed across different populations 14 – 16 . Dysgeusia, in particular, was the most commonly reported ADR in all studies. 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 . Future research should investigate the mechanisms underlying dysgeusia and its potential long-term implications for patients. 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 can be hypothesised 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 counselling 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. 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 study, 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. 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 optimising the therapeutic potential of Paxlovid within the ever-evolving landscape of healthcare. The findings of this study have significant implications for clinical practice, especially in Malaysia and similar healthcare environments. The high prevalence of ADRs, while generally mild, indicates a need for improved patient education and support to effectively manage these reactions, ensuring treatment compliance. The study emphasises the vital role of pharmacists in administering Paxlovid, particularly in monitoring ADRs and promoting medication adherence. Interventions led by pharmacists, such as regular follow-ups and adjustments for drug-drug interactions, are crucial for optimising patient outcomes, especially in populations with comorbidities who are often on multiple medications. Furthermore, the findings regarding drug-drug interactions highlight the importance of careful medication management, which could inform the development of protocols for safely administering Paxlovid in resource-limited settings. From a research standpoint, this study highlights the necessity for further investigation into the long-term safety and tolerability of Paxlovid, particularly among diverse patient populations. Future research should aim to validate these findings in larger cohorts and across different geographic regions to enhance the generalisability of the results and refine treatment strategies for COVID-19 in outpatient settings. 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 centres in the Petaling District, Selangor, which may limit the generalisability 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.

As reported by the World Health Organization, the global impact of coronavirus disease (COVID-19) as of 24 December 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 hospitalisation 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 have characteristics such as older age, smoking, and 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 authorised 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 for 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-metabolising enzyme cytochrome P450 (CYP3A4). Therefore, when the combination of both of these drugs is given as a short-term course, it has a high possibility of causing harm from drug-drug interactions with other drugs metabolised 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 these 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 the Evaluation of Protease Inhibition for Covid-19 in High-Risk Patients (EPIC-HR) trial, a phase II and III randomised, placebo-controlled trial in non-hospitalised 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 they are considered non-serious 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 Cases in Adults and Paediatrics 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 include patients aged more than 60 years, immunocompromised individuals, those with any comorbidities, obesity, current or ex-smokers, and those who are unvaccinated or have incomplete vaccination. Patients with any of the mentioned criteria are considered to have a high risk of clinical progression to severe disease. Pharmacists in Malaysia play an important role in managing Paxlovid. The role ranges from inventory management to the monitoring of Paxlovid. In order to monitor patients’ adherence and adverse drug reactions (ADRs), pharmacists are required to follow up on days 3 and 5 through telephone or video calls with all patients. Patients’ responses regarding ADRs and adherence are recorded during the follow-up. During each follow-up, pharmacists will continuously educate and provide additional counselling, if needed, to patients regarding Paxlovid. If a patient is found to have experienced an unusual or severe ADR, the pharmacists will advise the patient to seek medical assistance at the nearest healthcare facility. Furthermore, it is the pharmacists’ responsibility to report ADRs to the National Pharmaceutical Regulatory Agency in Malaysia through manual submission, an online web form or a pharmacy information system 10 . It is important to ensure that all the effort 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 who have been prescribed Paxlovid. Paxlovid being a relatively new antiviral worldwide and made available in Malaysia only in mid 2022, requires continuous research to provide more evidence on the safety, tolerability, and effectiveness of antivirals in specific patient populations, drug combinations, and different healthcare settings 11 . The first aim of this study is to evaluate the prevalence and common ADRs associated with Paxlovid among category 2 COVID-19 patients, thereby assessing the drug’s safety and tolerability. The second aim is to assess the adherence levels of category 2 COVID-19 patients to Paxlovid. Lastly, the study seeks to examine the compliance of healthcare professionals in Malaysia with the 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 optimising patient outcomes during this ongoing global health challenge.