What’s Known

Transplanted patients with coronavirus-disease-2019 are more likely to develop drug-related problems due to their polypharmacy and pharmacokinetic alteration.

What’s New

The study shows that drug-related problems had high-frequency (69% of such patients). Patients with polypharmacy have 1.8 times more drug-related problems. The most frequently reported drug-related problems were those related to treatment effectiveness.

Introduction

On March 11, 2020, the world health organization (WHO) declared the outbreak of Coronavirus Disease 2019 (COVID-19) a “pandemic” worldwide. According to epidemiological updates from WHO, on Feb. 28, 2022, 434,154,739 cases were confirmed worldwide, causing 5,944,342 deaths. ^{1 , 2} Patients receiving solid organ transplantation (SOT) seem to be at a higher risk of COVID-19 due to long-term use of immunosuppressive agents and additional coexisting medical comorbidities. ^{3 , 4} Since no definitive and effective treatment for COVID-19 has yet been registered, in vitro evidence or successful experiences in managing affected patients are significant sources of information. Several antiviral and immunomodulatory drugs have been developed to be evaluated in clinical trials. The chloroquine/hydroxychloroquine, remdesivir, favipiravir, umifenovir, protease inhibitors (PIs) such as lopinavir/ritonavir, interferons are some of the compounds that have been investigated in these studies. ^{5 , 6} When it comes to transplanted patients with COVID-19, maintaining the balance between decelerating viral disease and the function of the graft via a proper degree of immunosuppressive modulation acts as a double-edged sword. ^{7 , 8} Additionally, combining the aforementioned medications with immunosuppressive agents causes various pharmacokinetic and pharmacodynamic interactions, which can sometimes lead to dangerous and even life-threatening drug-related problems (DRPs). ⁹

The pharmaceutical care network of Europe (PCNE) defines DRP as “an event or circumstance involving drug therapy that actually or potentially interferes with desired health outcomes”. ^{10 , 11} DRPs seem to induce harm to patients, increase healthcare costs, lengthen hospitalization time, and reduce the quality of life and potentially patients’ survival. Therefore, identifying, reducing, and preventing DRPs are critical steps carried out precisely by pharmaceutical care services. In order to optimize the medication therapy and reduce re-hospitalization, the pharmacists should review the medications, identify the patients at risk of DRPs, and improve drug regimens. ¹¹ PCNE provides a practical classification system that enables clinical pharmacists to identify DRPs in adverse drug reactions (ADRs), drug selection, dose, usage process, and interactions among several classifications with different focuses. It also helps the pharmacotherapy services in determining the root causes of problems, leading to timely interventions. ¹⁰ Patients with SOT are more likely to develop DRPs as a result of coexisting morbidity-related polypharmacy, pharmacokinetics or pharmacodynamics changes, and immune response alterations. ¹¹

Clinical pharmacists are specifically trained in pharmacotherapy evaluation and are able to identify and prevent DRPs. Many studies indicated that involving clinical pharmacists in a multidisciplinary team and implementing comprehensive medication management might reduce healthcare expenditures, as well as improving drug safety. ^{12 - 14} In this critical situation of COVID-19 control, pharmacists are extremely influential as members of the healthcare team. A published review study assessed the role of pharmacists in the COVID-19 crisis and found that pharmacists are effectively involved in different areas such as infection control, drug supply, patient care, and support for healthcare professionals. ¹⁵ Elbeddini and others also investigated the role of pharmacists in the use of telemedicine as the most accessible primary care provider in Canada. ¹⁶ Consequently, clinical pharmacists play a vital role in managing polypharmacy conditions in such transplant patients with COVID-19.

Although it has been more than a year since the outbreak of COVID-19, and the global vaccination has begun, the world is faced with emerging variants, and the disease and its treatment-related complications still continue to plague the world. Hence, this study aimed to evaluate the drug-related problems and clinical pharmacists’ interventions in managing transplant patients and candidates for transplantation with COVID-19 at tertiary referral solid organ transplant hospital.

Patients and Methods

Study Design, Setting, and Patients

A cross-sectional study was conducted from March 2020 to April 2021 at Shiraz Organ Transplant Hospital, the largest referral center for solid organ transplants in the Middle East and Asia, which is affiliated with Shiraz University of Medical Sciences, Shiraz, Iran. The study was approved by the Ethics Committee of Shiraz University of Medical Sciences (#IR.SUMS.REC.1399.398). All the protocols conformed to the ethical guidelines of the Helsinki Declaration (1975). Written informed consent was obtained from all the participants. With the outbreak of COVID-19, a 30-bed intensive care unit was set up for adult transplanted patients or candidates for transplantation with confirmed COVID-19. Based on clinical presentations, radiographic findings, or positive real-time polymerase chain reaction (RT-PCR) tests, the transplanted patients or candidates for transplantation, whose COVID-19 infection was confirmed, were recruited to study. Patients who stayed for less than 48 hours or died during the study were excluded. A multidisciplinary team of internal medicine and infectious diseases specialists as supervisors, pulmonologists, transplant surgeons, and a clinical pharmacist evaluated and managed the patients on a daily basis based on the published international and regional guidelines by scientific communities related to transplantation. ^{2 , 7 , 17} Through the patients’ medical records, a clinical pharmacist carefully gathered all the demographic characteristics, length of hospitalization, clinical outcomes, and medications.

Drug-related Problems Identification

The medications of hospitalized patients were reviewed by a clinical pharmacist. All drug regimens information were individually recorded, including name, dosage form, drug class, indication, dosage, and interval. The clinical and laboratory data, such as plasma level of immunosuppressive agents, renal and hepatic function status, and the ADR of antiviral regimens (according to the Naranjo ADR probability scale), ¹⁸ were also continuously monitored, until the patient was hospitalized. Furthermore, the drug-drug interactions were identified using Micromedex online software (Micromedex^® version 4.4, Ann Arbor, Michigan, United States drug interaction software mobile app available online with limited access). Polypharmacy, which is defined as regimens containing five or more drugs together, ^{11 , 19} was also considered. The nature and incidence of DRPs were determined by evaluating patients’ pharmacotherapy in terms of indication, dosage, safety, and efficacy using PCNE classification (Version 8.01). ²⁰

PNCE Classification

PCNE classification is a well-structured tool that provides relevant information on documented DRPs. ²¹ To determine the nature and number of DRPs in Version 8.01, five main domains must be evaluated.The five domains are as follows:

1. • “Problems”: Defines as an unexpected event that can occur in the following three categories: “treatment effectiveness,” “treatment safety or ADR,” and “others” such as “treatment cost-effectiveness or unnecessary drug treatment.”
2. • “Causes”: Identifies the causes of DRP in eight sub-domains, such as “drug selection,” “drug form,” “dose selection,” “treatment duration,” “dispensing,” “drug use process,” “patient-related,” and “other” such as “inappropriate drug monitoring”
3. • “Planned Interventions”: Record the pharmacist’s level of intervention to prevent or correct the DRPs.
4. • “Intervention acceptance”: Describes the acceptance status of intervention.
5. • “Status of the DRP”: Explains the outcome of DRPs, and indicates whether the problem status is “unknown”, “solved”, “partially solved”, or “not solved”. ²⁰

Clinical Pharmacist Interventions

Clinical pharmacist interventions were referred to all recommendations proposed by a clinical pharmacist at any stage of the pharmacotherapy process that influenced management plans. Based on the laboratory tests and the patient’s clinical condition, the clinical pharmacist has daily reviewed all medication orders for patients in terms of drug-drug interactions, ADR, dose adjustment based on renal and hepatic functions, and dose adjustment of immunosuppressive agents according to their plasma levels. For early DRPs prevention, the recommendations were developed through discussions with health care professionals at the drug prescription phase. Moreover, additional interventions were presented, either verbally or in the patient’s clinical file, at the prescriber, patient, and drug levels during daily monitoring and rounds. The reasons for accepting or rejecting the clinical pharmacist’s recommendation have also been noted. The acceptance rate was calculated based on the intervention agreement at the prescriber level.

Statistical Analysis

Statistical analysis was performed using SPSS Version 25.0 (Armonk, NY, USA: IBM Corp.). The frequency of each type of DRP and the prescriber’s acceptance rate were determined using descriptive statistics. The continuous variables were reported as mean±SD, and the categorical data were reported as percentages or frequencies. The potential risk factor of DRPs was determined using univariate and multivariate logistic regression analysis. Results were reported as odds ratios (ORs) with 95% CIs. P values less than 0.05 were considered statistically significant.

Results

During the study period, 631 individuals with COVID-19 clinical manifestations (39%) or a positive SARS-CoV-2 PCR test (61%) were recruited for final analysis; of which 232 patients (36.76%) were transplanted (133 kidney transplant recipients, 92 liver transplant recipients, three isolated small bowel transplant recipients, three multi-visceral transplants, and one Simultaneous pancreas-kidney (SPK) transplant recipient), and 399 patients were candidates for transplantation. The demographic characteristics of these participants are summarized in table 1. More than half of the patients (63.07%) were male. The most prevalent underlying comorbidities were Cirrhosis (23.99%), diabetes mellitus (21.12%), hypertension (20.53%), and end-stage renal disease (ESRD) (19.69%). Each patient had an average of 3.71±1.10 underlying disease.

The clinical pharmacist has reviewed 11770 medication orders. On average, each patient took 5.01±3.30 drugs. Immunosuppressants (52%), antivirals and antibiotics (31%), and antihypertension (11%), were the top three prescribed drug classes. The clinical outcomes of patients and treatment options are presented in table 2. COVID-19 therapeutic management included high doses of steroids (36.67%), remdesivir (29.34%), the combination of hydroxychloroquine and lopinavir-ritonavir (13.26%), followed by tocilizumab (10.58%), the combination of hydroxychloroquine and azithromycin (5.36%), and favipiravir (4.80%), respectively. The most commonly used immunosuppressive regimens among transplanted patients were tacrolimus-based.

According to the polypharmacy definition, 429 individuals (67.99%) were in this category, however, the rate of polypharmacy was not statistically different between transplanted patients and transplant candidates (P=0.22). A total of 639 DRPs were identified from 69% of the studied patients. The mean DRPs for each patient was 1.01±1. The most commonly found types of DRPs were those related to treatment effectiveness (34.12%), ADR (33.02%), and unnecessary drug treatment (17.68%). The identified DRPs, causes, and interventions according to the PCNE classification (Version 8.01) are summarized in table 3.

Based on the PCNE classification, 724 causes of DRPs were identified. The most common causes of DRPs were drug selection (27.49%), followed by patient-related causes (17.82%), drug use process (16.85%), dispensing (13.54%), and dose selection causes (12.02%). The majority of patients received an inappropriate combination of drugs or drugs and herbal medications (9.81%). Patients who administered/used drugs incorrectly (8.29%), were primarily responsible for patient-related causes. Furthermore, the majority of cases were related to drugs under-administration (7.87%) throughout the drug use process (table 3). Individuals with at least one DRP (n=82) had a significantly greater mortality rate (P<0.001) than patients without any DRPs (n=31).

A significant association between hydroxychloroquine intake, transplantation, polypharmacy, and comorbid diseases more than three with the DRPs in transplant patients or candidates for transplantation with COVID-19 was found by applying multivariable logistic regression. Table 4 summarizes the DRPs risk factors in these groups. Patients, who received five or more drugs (polypharmacy), were 2.03 times more susceptible to develop DRPs. The transplanted people were at a higher risk of DRPs than candidates for transplantation, and the existence of three or more comorbidities significantly increased the probability of such problems.

A clinical pharmacist performed 982 interventions at different levels of PCNE classification. As indicated in table 3, the majority of the interventions occurred at the prescriber level (71.08%), then at the drug level (16.80%), and finally at the patient level (12.12%). $\underset{\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_}{\mathrm{Supplementary\; file\; 1}}$ contains several examples of interventions. In transplant patients, the most common intervention was dose adjustment of calcineurin inhibitors (CNIs) in combination with antivirals. A total of 801 interventions were accepted (81.56%), with 659 (67.11%) of them being fully implemented. The most accepted interventions were dose selection, drug selection, and treatment duration, respectively. The primary reason for the physicians’ refusal of clinical pharmacist recommendations was the absence of clinical relevance and/or the rarity of clinical ADRs associated with these drug-drug interactions. After implementing the interventions, 61.21% of the problems were solved, while 22.91% were not solved.

Discussion

To the best of our knowledge, this is the first study to investigate the DRPs and clinical pharmacy interventions in transplanted patients and transplant candidates with COVID-19. The present study shows a high-frequency of DRPs in the management of transplanted patients and candidates for transplantation with COVID-19. Drug-related problems are significant public health concerns in patients’ pharmacotherapy, especially in those with chronic diseases. DRPs have always been a problem for transplanted patients or candidates due to comorbidity associated with polypharmacy and pharmacokinetic changes.

For many years, clinical pharmacists have been providing valuable advice to optimize patients’ pharmacotherapy and improve clinical and economic outcomes. Due to their polypharmacy status, their collaboration in a multidisciplinary team is critical in managing patients, especially those with chronic diseases. ²² Since the beginning of the SARS-CoV-2 outbreak, pharmacists have played a key role in various areas, including drug distribution, drug information, pharmaceutical care development, and drug registration research. ¹⁵ The lack of definitive treatment, the existence of numerous morbidities, and prolonged ICU stays have doubled the importance of proper pharmacotherapy, especially in transplant patients for whom the immunosuppressant receiving and clinical condition should be balanced. The high acceptance rate of the present study reflects a long-standing and trustworthy relationship between clinical pharmacists and multidisciplinary teams. Since the inception of our center, a board-certified clinical pharmacist with extensive knowledge of organ transplantation has offered his recommendation and provided trustworthy cooperation.

We found a rather high frequency of DRPs in 69% of the studied patients with a mean of 1.01±1, while two other studies at the internal medicine ward in Turkey ²³ and among admitted geriatric patients in Ethiopia ¹¹ reported the average value of 1.63 and 1.90, respectively. These discrepancies might be attributed to differences in study designs, study populations, and study duration. There are various criteria for identifying and classifying the DRPs, and those studies that used the PCNE standards found more DRPs due to their multiple sub-domains of classification. Furthermore to date, no DRPs analysis has been performed in COVID-19 patients to be compared. 

According to our findings, the most common subset of DRPs was treatment effectiveness (34.12%). The appropriate drug selection in the COVID-19 population varies depending on the stages of the disease (viral or inflammatory). For example, taking corticosteroids during the viral phase leads to more virus replication and worsens the patients’ condition. On the other hand, the late start of antiviral drugs, especially in the fourth week of infection, can be ineffective. ^{24 , 25} In studies in Ethiopia (10%) ²⁶ and India (40.6%), ²⁷ ineffective drug treatment contributed to a lower proportion of DRPs, while a Canadian (51.3%) ²⁸ research indicated more ineffective drug therapy.

According to our findings, ADR is the second most frequent subtype of DRPs (33.02%). In contrast, studies conducted in Ethiopia (2%), ²⁶ Canada (6.8%), ²⁸ and Singapore (25%) ²⁹ indicated lower ADR of all DRPs. In comparison to a study by Sun and others, we consider the usage of some antivirals for COVID-19 management, such as hydroxychloroquine and lopinavir-ritonavir, as our complicating drugs. In patients with COVID-19, the length of hospital stay, the amount of the hospital drugs used, underlying diseases, and receiving lopinavir-ritonavir are all the risk factors for ADRs. ³⁰

Drug selection causes accounted for 27.49% of all DRPs causes, especially in the subset of inappropriate combination therapy (9.81%). The most common inappropriate combination therapy was hydroxychloroquine with remdesivir or non-vitamin K antagonist oral anticoagulants (NOACs) with PIs. Changes in serum levels of the CNI class by PIs (tacrolimus with lopinavir-ritonavir) and hydroxychloroquine (cyclosporine with hydroxychloroquine) were among the most commonly observed pharmacokinetic interactions. 

According to our findings, polypharmacy, the existence of more than three comorbidities, transplantation, and receiving hydroxychloroquine are all substantial risk factors for developing DRPs. The transplanted population frequently experienced polypharmacy due to post-transplant complications, multiple immunosuppressive regimens, and receiving prophylactic antimicrobial agents. In confirmation, a study by Shafiekhani and colleagues mentioned that each kidney transplant recipient received approximately 11 medications, ¹³ and some other studies have also identified polypharmacy and comorbidity as the risk factors for DRPs. ^{31 , 32} Besides, Eichenberger and others reported that transplant patients are more prone to develop DRPs. ²²

In the present study, more than 81.56% of the clinical pharmacist interventions were approved, while approximately 67.11% were fully implemented. In this research, the most common intervention performed by the clinical pharmacist was dose adjustment of CNIs in transplant patients taking antivirals. Considering previous research, simultaneous use of CNIs, especially tacrolimus and PIs, can significantly increase tacrolimus blood levels, and a 1/20th–1/50th reduction in daily dose is recommended when starting or changing PI therapy. ³³ Cyclosporine plasma levels are also increased when PIs and hydroxychloroquine are used simultaneously. ² In severe cases of COVID-19 with significant extensive lung involvement, it is also recommended to discontinue the other immunosuppressant class, mTOR inhibitors (e.g., everolimus), due to their pulmonary side effects such as pneumonitis and interstitial lung disease. ³⁴

Additionally, with the introduction of emergent therapeutic options such as interleukin-6 antagonists, i.e., tocilizumab, a number of pharmacotherapeutic issues should be considered. These include administration and continuation in patients with hepatic dysfunction or leukopenia, ² for which a clinical pharmacist performed several interventions on dose adjustment or therapy discontinuation in the current study.

On the other hand, since the majority of the prescribed drugs in our study were corticosteroids, and these drugs are used in COVID-19 therapy at higher-than-usual doses, the side effects and adverse effects monitoring should be part of the interventions provided by clinical pharmacists. The side effects and adverse effects of these drugs in their high doses include hypertension, elevated blood sugar levels, and secondary bacterial or fungal infections, which should be monitored. Furthermore, based on the potential interaction (Type X) of everolimus and PIs, it should not be used concurrently with lopinavir-ritonavir. ³⁵ Considering the two clinical conditions in transplant candidates, ESRD or end-stage liver failure, which induced changes in pharmacokinetic and pharmacodynamic parameters, ³⁶ as well as the risk of graft rejection in transplant patients, drug dose adjustment based on clinical status is reasonable. In the current study, clinical pharmacist interventions included dose adjustments of antivirals such as remdesivir, antibiotics, and analgesics such as NSAIDs, as well as a reduction of the maximum daily dose of acetaminophen used for fever control in COVID-19 patients with ESRD, acute tubular necrosis (ATN), or chronic hepatic impairment in hospital settings. Furthermore, since the majority of the studied patients were polypharmacy, clinical pharmacists’ recommendations were critical in reducing drug interactions between antiviral agents and other drugs.

With the emphasis on DRPs among the COVID-19 patients, this study has some limitations that should be noticed. The economic effects and cost-effectiveness of clinical pharmacist’s interventions have not been evaluated. This is a relatively small-scale study from one center with a short duration and no independent clinical panel. A larger study is required to assess the clinical outcomes and DRPs consequences of accepted and rejected clinical pharmacist’s interventions. It is also suggested that future research investigate the relationship between the severity of COVID-19 and the incidence of DRPs.

Conclusion

The present study shows a high-frequency of DRPs in the management of transplanted patients and transplant candidates with COVID-19. DRPs are more common in the transplanted population, and patients with polypharmacy, more than three comorbidities, and hydroxychloroquine regimens are more prone to manifest the problems. The mutual collaboration of clinical pharmacists and physicians is deemed vital in identifying, preventing, and resolving DRPs.

Acknowledgment

The authors would like to express their gratitude to the healthcare personnel of Shiraz Transplantation Hospital for their ongoing efforts to improve the quality of the services.

Authors’ Contribution

S.A: Conception, design of the work, acquisition and analysis of data, drafting and revising the manuscript; F.Sh: Analysis and interpretation of data; revising the manuscript; M.Sh: Conception, design of the work, acquisition, analysis and Interpretation of data, drafting and revising the manuscript. All authors have read and approved the final manuscript and agree to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

Conflict of Interest

None declared.

References

1. Organization WH [Internet]. Coronavirus disease (COVID-2019) situation reports 2020 2020 [cited 20 May 2021]. Available from: https://www.who.int/emergencies/diseases/novel-coronavirus-2019/situation-reports.
2. Mirjalili M, Shafiekhani M, Vazin A. Coronavirus Disease 2019 (COVID-19) and Transplantation: Pharmacotherapeutic Management of Immunosuppression Regimen. Ther Clin Risk Manag. 2020; 16:617-29. Publisher Full Text | DOI | PubMed
3. Fernandez-Ruiz M, Andres A, Loinaz C, Delgado JF, Lopez-Medrano F, San Juan R, et al. COVID-19 in solid organ transplant recipients: A single-center case series from Spain. Am J Transplant. 2020; 20:1849-58. DOI | PubMed
4. Pereira MR, Mohan S, Cohen DJ, Husain SA, Dube GK, Ratner LE, et al. COVID-19 in solid organ transplant recipients: Initial report from the US epicenter. Am J Transplant. 2020; 20:1800-8. Publisher Full Text | DOI | PubMed
5. Sahraei Z, Shabani M, Shokouhi S, Saffaei A. Aminoquinolines against coronavirus disease 2019 (COVID-19): chloroquine or hydroxychloroquine. Int J Antimicrob Agents. 2020; 55:105945. Publisher Full Text | DOI | PubMed
6. Amariles P, Hincapie-Garcia J, Julio Montoya C. Pharmacotherapy for hospitalized patients with COVID-19: Waiting or doing?. Res Social Adm Pharm. 2021; 17:2049. Publisher Full Text | DOI | PubMed
7. Fix OK, Hameed B, Fontana RJ, Kwok RM, McGuire BM, Mulligan DC, et al. Clinical Best Practice Advice for Hepatology and Liver Transplant Providers During the COVID-19 Pandemic: AASLD Expert Panel Consensus Statement. Hepatology. 2020; 72:287-304. Publisher Full Text | DOI | PubMed
8. Shafiekhani M, Shahabinezhad F, Niknam T, Tara SA, Haem E, Mardani P, et al. Evaluation of the therapeutic regimen in COVID-19 in transplant patients: where do immunomodulatory and antivirals stand?. Virol J. 2021; 18:228. Publisher Full Text | DOI | PubMed
9. Bartiromo M, Borchi B, Botta A, Bagala A, Lugli G, Tilli M, et al. Threatening drug-drug interaction in a kidney transplant patient with coronavirus disease 2019 (COVID-19). Transpl Infect Dis. 2020; 22:e13286. Publisher Full Text | DOI | PubMed
10. van Mil F. Drug-related problems: a cornerstone for pharmaceutical care. Journal of the Malta College of Pharmacy Practice. 2005; 10:5-8.
11. Hailu BY, Berhe DF, Gudina EK, Gidey K, Getachew M. Drug related problems in admitted geriatric patients: the impact of clinical pharmacist interventions. BMC Geriatr. 2020; 20:13. Publisher Full Text | DOI | PubMed
12. Rezazadeh A, Hajimiri SH, Kebriaeezadeh A, Gholami K, Hashemian F, Khoshnevisan A, et al. Clinical and economic impact of comprehensive medication management implementation by clinical pharmacists in an intensive care unit: a cost–benefit analysis. Journal of Pharmaceutical Health Services Research. 2021; 12:460-2. DOI
13. Shafiekhani M, Tarighati S, Mirzaei E, Namazi S. Evaluation and management of drug-drug interactions in patients hospitalized in nephrology and post-transplant wards in a teaching hospital. Journal of Pharmaceutical Care. 2020. DOI
14. Shafiekhani M, Moosavi N, Firouzabadi D, Namazi S. Impact of Clinical Pharmacist’s Interventions on Potential Drug-Drug Interactions in the Cardiac Care Units of Two University Hospitals in Shiraz, South of Iran. J Res Pharm Pract. 2019; 8:143-8. Publisher Full Text | DOI | PubMed
15. Visacri MB, Figueiredo IV, Lima TM. Role of pharmacist during the COVID-19 pandemic: A scoping review. Res Social Adm Pharm. 2021; 17:1799-806. Publisher Full Text | DOI | PubMed
16. Elbeddini A, Yeats A. Pharmacist intervention amid the coronavirus disease 2019 (COVID-19) pandemic: from direct patient care to telemedicine. J Pharm Policy Pract. 2020; 13:23. Publisher Full Text | DOI | PubMed
17. Banerjee D, Popoola J, Shah S, Ster IC, Quan V, Phanish M. COVID-19 infection in kidney transplant recipients. Kidney Int. 2020; 97:1076-82. Publisher Full Text | DOI | PubMed
18. Naranjo CA, Busto U, Sellers EM, Sandor P, Ruiz I, Roberts EA, et al. A method for estimating the probability of adverse drug reactions. Clin Pharmacol Ther. 1981; 30:239-45. DOI | PubMed
19. Masnoon N, Shakib S, Kalisch-Ellett L, Caughey GE. What is polypharmacy? A systematic review of definitions. BMC Geriatr. 2017; 17:230. Publisher Full Text | DOI | PubMed
20. Europe PCN. PCNE Classification for Drug-Related Problems V8. 01. 2017. Europe PCN: Benelux; 2018.
21. Koubaity M, Lelubre M, Sansterre G, Amighi K, De Vriese C. Adaptation and validation of PCNE drug-related problem classification v6. 2 in French-speaking Belgian community pharmacies. Int J Clin Pharm 2019; 41:244-50. DOI | PubMed
22. Lin HW, Lin CH, Chang CK, Chou CY, Yu IW, Lin CC, et al. Economic outcomes of pharmacist-physician medication therapy management for polypharmacy elderly: A prospective, randomized, controlled trial. J Formos Med Assoc. 2018; 117:235-43. DOI | PubMed
23. Abunahlah N, Elawaisi A, Velibeyoglu FM, Sancar M. Drug related problems identified by clinical pharmacist at the Internal Medicine Ward in Turkey. Int J Clin Pharm. 2018; 40:360-7. DOI | PubMed
24. Ritchie AI, Singanayagam A. Immunosuppression for hyperinflammation in COVID-19: a double-edged sword?. Lancet. 2020; 395:1111. Publisher Full Text | DOI | PubMed
25. Yousefifard M, Zali A, Ali KM, Neishaboori AM, Zarghi A, Hosseini M, et al. Antiviral Therapy inManagement of COVID-19: a Systematic Review on Current Evidence. Archives of Academic Emergency Medicine. 2020; ;:1-9.
26. Garedow AW, Mulisa Bobasa E, Desalegn Wolide A, Kerga Dibaba F, Gashe Fufa F, Idilu Tufa B, et al. Drug-Related Problems and Associated Factors among Patients Admitted with Chronic Kidney Disease at Jimma University Medical Center, Jimma Zone, Jimma, Southwest Ethiopia: A Hospital-Based Prospective Observational Study. Int J Nephrol. 2019; 2019:1504371. Publisher Full Text | DOI | PubMed
27. Blix HS, Viktil KK, Moger TA, Reikvam A. Characteristics of drug-related problems discussed by hospital pharmacists in multidisciplinary teams. Pharm World Sci. 2006; 28:152-8. DOI | PubMed
28. Greeshma M, Lincy S, Maheswari E, Tharanath S, Viswam S. Identification of drug related problems by clinical pharmacist in prescriptions with polypharmacy: A prospective interventional study. Journal of Young Pharmacists. 2018; 10:460. DOI
29. Joel JJ, Shastry C. A study on drug related problems and pharmacist intervention in patients undergoing haemodialysis in a tertiary care hospital. International Research Journal of Pharmaceutical and Applied Sciences. 2013; 3:263-5.
30. Sun J, Deng X, Chen X, Huang J, Huang S, Li Y, et al. Incidence of Adverse Drug Reactions in COVID-19 Patients in China: An Active Monitoring Study by Hospital Pharmacovigilance System. Clin Pharmacol Ther. 2020; 108:791-7. Publisher Full Text | DOI | PubMed
31. Fathnin FH, Yuniastuti A. The Relation of Drug Amount, Comorbidity, Blood Pressure, and Residential Area to Drug-Related-Problems of Hypertension Patients. Public Health Perspective Journal. 2020; 5
32. Eichenberger PM, Haschke M, Lampert ML, Hersberger KE. Drug-related problems in diabetes and transplant patients: an observational study with home visits. Int J Clin Pharm. 2011; 33:815-23. DOI | PubMed
33. Bickel M, Anadol E, Vogel M, Hofmann WP, von Hentig N, Kuetscher J, et al. Daily dosing of tacrolimus in patients treated with HIV-1 therapy containing a ritonavir-boosted protease inhibitor or raltegravir. J Antimicrob Chemother. 2010; 65:999-1004. Publisher Full Text | DOI | PubMed
34. Dashti-Khavidaki S, Mohammadi K, Khalili H, Abdollahi A. Pharmacotherapeutic considerations in solid organ transplant patients with COVID-19. Expert Opin Pharmacother. 2020; 21:1813-9. DOI | PubMed
35. van Maarseveen EM, Rogers CC, Trofe-Clark J, van Zuilen AD, Mudrikova T. Drug-drug interactions between antiretroviral and immunosuppressive agents in HIV-infected patients after solid organ transplantation: a review. AIDS Patient Care STDS. 2012; 26:568-81. DOI | PubMed
36. Pena MA, Horga JF, Zapater P. Variations of pharmacokinetics of drugs in patients with cirrhosis. Expert Rev Clin Pharmacol. 2016; 9:441-58. DOI | PubMed