PHARMACEUTICAL CARE OF ACNE PATIENTS USING SYSTEMIC RETINOIDS

³çîòðåòè-Abstract Aim. The research aims to study of the issue of pharmaceutical care of acne patients when using systemic retinoids. Materials and Methods. The following methods were used: systematic approach, bibliographic, questionnaire survey, statistical, pharmacoeconomic assessment. The objects of the study: relevant information sources; current standards of pharmacotherapy, instructions for medical use of isotretinoin of the State Register of Medicines of Ukraine (n=4), 14 th edition of the State Drug Formulary; questionnaires of acne patients who use systemic retinoids (n=53); pharmacy quotes for isotretinoin drugs and laboratory quotes for liver biopsy and lipid testing. The subject of the study: appropriate pharmaceutical care of acne patients when using systemic retinoids. Results and Discussion. The results of the questionnaire showed that, despite high awareness, the practice of patients' compliance with the recommendations regarding the use of isotretinoin needs to be optimized, in particular by means of pharmaceutical

patients.As a result of the analysis of current regulatorylegal documents, 6 main guidelines were identified, including 10 key messages of pharmaceutical care.Considering the extremely low level of proper implementation of the Pregnancy Prevention Program when using systemic retinoids (3.7%; 95CI: 0.1-19.0%)and the severity of the consequences of neglecting the recommendations (teratogenic effect), pharmaceutical care should include the issue of effective contraception and pregnancy testing by not only informing but also finding and using other strategies to increase patient compliance with the recommendations, in our opinion.We consider that the discussion with the patient regarding the costs of pharmacotherapy with systemic retinoids (according to the results of our study -from 17919.20 to 25307.50), in addition to the cost of isotretinoin (from 15417.20 to 21550.00),should include the costs of conducting laboratory control of liver tests (from 1530.00 to 2340.00), lipidogram (from 972.00 to 1417.50) and meeting some other individual patient needs.Conclusions.Studying the issue of pharmaceutical care when using systemic retinoids allowed to determine the main guidelines (n=6) and key messages (n=10) that pharmacists can focus on during professional communication with acne patients, which makes it possible to increase the effectiveness and safety of pharmacotherapy.

Introduction
Acne is an inflammatory skin disease that occurs in approximately 9% of the world population (85% of individuals aged 12-24 and 50% of individuals aged 20-29) [10,12].The disease can cause permanent physical scarring, affect patients' self-esteem, increase anxiety levels, and provoke depression and suicidal thoughts [10,12,16].The quality of life of acne patients can be significantly reduced [5,8,10,12,19].The impact of acne, in this aspect, especially with a severe course, can be compared to such diseases as bronchial asthma, epilepsy, diabetes, back pain, and arthritis [5,8,18].
Providing adequate medical care allows the reduction of the clinical signs of acne and improves the quality of life of patients [8], but requires significant financial costs [12].In Germany, in particular, the cost of acne treatment exceeds 400 million euros annually [12,21].Effective treatment methods include the use of systemic retinoids [1,10,16,24,25,29], which, however, is associated with the probability of a number of adverse drug reactions (ADRs) and requires compliance with Risk Management Programs [1,4,15,24,25,29].In particular, prevention of the teratogenic effect of systemic retinoids, when used by female patients of childbearing age, requires effective contraception ì³çàö³¿, çîêðåìà øëÿõîì ôàðìàöåâòè÷íî¿ îï³êè, ÿêó, çà îö³íêàìè ïàö³ºíò³â, áóëî íàäàíî ëèøå ó 30,2% (95Ä²: 18,3-44,3%) âèïàäê³â.13,22].After the implementation of the iPLEDGE Program in the USA, the number of female patients who simultaneously use oral isotretinoin with contraceptives has increased significantly.Subsequently, study results have shown a reduction in the number of pregnancies, abortions and birth defects, as the Program improved access to effective long-term and emergency contraceptives [22].However, despite participating in the Program, about 150 women taking isotretinoin become pregnant every year [16,22].This problem has not been solved in European countries yet.Despite the implementation of PPP, some female patients become pregnant within the first 30 days after stopping isotretinoin.However, it is known that with the implementation of more stringent requirements, the fear of teratogenic risks in female patients increases more than the actual avoidance of the effect of isotretinoin on pregnancy.At the same time, according to the FDA, due to failure to meet requirements of the Program, 40% of isotretinoin prescriptions are rejected by pharmacists, which leads to interruption or termination of pharmacotherapy (PT).Determining effective measures to improve the situation requires further research [22].
In general, according to the data of the systematic review, serious ADRs to isotretinoin, which require discontinuation of its use, occur in 3.2% of cases but others manifest quite often [29].The probability of statistically significant changes in the average values of some laboratory tests, associated with the use of isotretinoin [17], including lipid level (15-25%) and liver tests (15%) [15], which require laboratory control, has been proven [17].The most frequently reported ADR to isotretinoin is dry lips, which is observed in almost all patients (90-100%) [15,16,22], dry skin occurs very often (72-95%) [22].Dry eyes and blepharoconjunctivitis are possible manifestations of an ADR (14-40%) [15,16].The described ADRs are well tolerated and easily managed [22].However, it is necessary to prepare the patient for their appearance even before starting treatment by offering appropriate care for the skin or mucous membranes [30].It should be noted that the activities of the described Risk Management Programs and the management of ADRs to isotretinoin include the involvement of pharmacists [11,13,22].In addition, in the USA, Canada, and Great Britain, for at least 10 years, the model of management of acne by pharmacists according to a standardized protocol with the use of prescription drugs in particular, has been successfully used [2].However, the results of the conducted systematic review in general demonstrate a low level of assessment of the compliance of the use of drugs with the specified requirements and counseling of patients when dispensing drugs due to insufficient awareness of pharmacists with the potential risks of oral use of isotretinoin [22].In Ukraine, a Pharmacist's protocol for "Prevention and symptomatic treatment of acne" has been approved, however, only retinoids for local use are included in it [20].Research on pharmaceutical care (PC) of patients with acne conducted in our country is also mostly related to symptomatic treatment and shows a low level of provision [27,28].According to the results of a survey conducted among pharmacists, 40% of them inform patients about the risks of ADRs to anti-acne drugs [28].According to the conducted survey among teenage girls and women only 50% received recommendations on the use of anti-acne drugs from pharmacists -every second [27].
Therefore, the aim of our study was to study the issue of PC in patients with acne when using systemic retinoids.

Material and Methods
The following methods were used: systematic approach, bibliographic, questionnaire survey, statistical, pharmacoeconomic assessment.
The objects of study: relevant information sources; current standards of PT -the evidencebased clinical guideline for the treatment of acne [1], instructions for medical use of isotretinoin of the State Register of Medicines of Ukraine (n=4) (as of April 2023) [25], 14th edition of the State Drug Formulary [24]; questionnaires of acne patients who use systemic retinoids (n=53); pharmacy quotes for isotretinoin [26] and laboratory quotes for liver tests and lipid testing (Fig. 1).The subject of the study: appropriate PC of acne patients when using systemic retinoids.
An anonymous online survey was conducted in the period of March 22 and June 23, 2023 among acne patients according to a single protocol using Google Forms.The criterion for the inclusion of questionnaires in the research was the use by adult patients (≥18 years) of isotretinoin of the systemic retinoid group.Survey results are presented as percentages and 95% confidence interval (CI) calculated according to the Clopper-Pearson method (exact) in the SPSS Trial program.
Calculations of the cost of PT with isotretinoin were carried out based on the recommendations of the current evidence-based clinical guideline for the treatment of acne -at a dosage of 0.5-2.0mg/kg/day for 5 months / 20-week course [1] and the availability of oral forms of medicines for dispensing from pharmacies -Acnetin 8 and 16 mg No.30 (as of April 2023) [26].Taking into account the dosage of drugs presented on the pharmaceutical market, calculations were made for a patient weighing 70 kg, who was prescribed The cost of laboratory monitoring was calculated according to the price offers of the official websites of 4 laboratory networks (Eskulab, Medis, Sinevo, Unilab) that provide services in Lviv.The least and most expensive quotes for liver tests and lipidograms were selected from all those proposed (as of April 17, 2023).

Results
Analyzing current evidence-based clinical practice guidelines for acne treatment [1], instructions for medical use of isotretinoin (n=4) as the only representative of systemic retinoids of the State Register of Medicines of Ukraine [25], the State Drug Formulary [24] and some other sources made it possible to identify 6 main guidelines and key messages of PC for patients (Table 1).
To study the awareness of patients regarding these messages and to determine the extent of their following the recommendations, a questionnaire survey was conducted.According to the findings, the use of isotretinoin lasted from 1 week to 26 months.In 84.9% of cases, systemic retinoids were prescribed in private hospitals, 11.3% -in state-communal ones, and another 3.8% of patients started taking drugs after an online consultation.The age of the respondents was 18-36 years.The number of surveyed women (94.3%) significantly outnumbered men (5.7%).Residents of the Western region of Ukraine (Volyn, Ivano-Frankivsk, Lviv, Rivne, Ternopil, Chernivtsi regions) amounted to 56.6%, among them a significant share from the Lviv region -43.4%.The rest of the respondents during the period of PT were in the Northern (Zhytomyr, Kyiv, Sumy regions) -13.2%, the Eastern (Donetsk, Kharkiv regions) -9.4%, the Central (Dnipropetrovsk region) -5.7%, the Southern region (Mykolaiv, Odesa region) -5.7% or outside Ukraine -9.4%.According to the answers received in the survey, the informing of 30.2% (95CI: 18.3-44.3%) of patients regarding the risks of using systemic retinoids and requirements for monitoring PT was done by physicians and pharmacists.In 58.5% of cases, patients claimed that they were informed by the physician, however, the pharmacist did not do this.Another 11.3% of patients reported that they did not receive such information from the physician or the pharmacist.
Patients' awareness of the probability of statistically significant isotretinoin-associated changes in mean values of liver tests and lipid levels was sufficiently high (94.3%;95CI: 84.3-98.8%).However, the results of the survey showed a lower level of compliance with the

Stage І
Determining the main guidelines and formulating key messages of PC messages for patients when using systemic retinoids Evidence-based clinical guideline for the treatment of acne [1] Instructions for medical use of isotretinoin (n=4) as the only representative of systemic retinoids of the State Register of Medicines of Ukraine [25] The State Drug Formulary [24] Other sources [9,10,12,29] Guidelines recommendations for laboratory monitoring of liver functions and lipid profile compared to awareness.According to respondents, it amounted to 90.5%.However, the results of comparing the frequency of laboratory control and the duration of PT with systemic retinoids compliance with the standards presented in the clinical guidelines and instructions for the medical use of isotretinoin (before the start of PT, 1 month after the start of PT, and thereafter every 3 months), only at the level of 67.9% (95CI: 53.7-80.1%).Accordingly, 22.6% of patients did not perform laboratory control frequently enough (Table 2).As evidenced by the results of our study, 98.1% (95CI: 89.9-100.0%) of patients are aware of the risks of teratogenic effects of systemic retinoids.One case (1.9%) of isotretinoin use during 14 months by a patient who was unaware of the risk of fetal malformations when using this drug during pregnancy was identified.
A little more than half of the surveyed women (n=27) reported using contraceptives while taking isotretinoin to prevent its teratogenic effect.Among them, we studied compliance with the requirements of the PPP.With 100.0%awareness of the teratogenic effect of isotretinoin, appropriate reliable contraception was found in 18.5% (95CI: 6.3-38.1%) of patients.In 63.0% of cases, the methods of contraception used were insufficient.In another 18.5% of cases, we could not assess the reliability of contraception, as the women did not indicate the specific means used.At the same time, 22.2% (95CI: 8.6-42.3%) of patients confirmed having >1 test to rule out pregnancy before and during PT, another 51.9% did the test 1 time, respectively, and 25.9% of women did not follow this recommendation at all.Thus, there were no comments on compliance with the requirements of the PPP in only 3.7% (95CI: 0.1-19.0%) of cases (Table 3).
The conducted survey enabled the

No. Pharmaceutical care messages I Advisability of use 1.
Oral use of the systemic retinoid isotretinoin, given its high efficacy, is recommended for the treatment of severe nodular acne (strength of recommendation -A, quality of evidence -І) [1,10,24,25,29] As a consensus solution, the use of systemic retinoids is also considered appropriate for less severe acne, resistant to treatment, or for acne that creates physical or "psychological" scars [1,24,25] II Laboratory monitoring 2.
Laboratory control of the level of liver enzymes and lipids should be carried out before the start of PT, 1 month after the start of PT, and thereafter every 3 months [1,24,25] III Pregnancy Prevention Program 3.
Providing effective contraception continuously for 1 month before the start of PT, during the entire period of PT, and for 1 month after the end of PT [24,25] The use of at least one highly effective method of contraception that does not depend on the user, or at the same time 2 complementary methods of contraception that depend on the user [25] 4.
Carrying out a pregnancy test before PT, during PT (preferably monthly), and 1 month after the end of PT [24,25] IV Warnings 5.
Avoid excessive exposure to sunlight or UV rays [24,25] V Elimination / relief of ADR manifestations 8.
To prevent the manifestations of photosensitization, it is recommended to use protective means with SPF of at least 15 [25] 9.
To reduce dryness of the skin and lips, it is recommended to use moisturizing ointments, body creams, lip balm [25] 10.In the dry mucous membrane of the eye, it is recommended to use applications of moisturizing eye ointment or artificial tears [25] In case of intolerance to contact lenses during PT, it is recommended to use glasses [25] VI The cost of pharmacotherapy  definition of the level of awareness in patients regarding the warnings related to PT with systemic retinoids.83.0% (95CI: 70.2-91.9%) of respondents were informed about the need to abstain from donating blood.Accordingly, 17.0% of patients did not know that they could not be blood donors during drug use and within 1 month after the end of PT. 96.2% (95CI: 87.0-99.5%) of patients knew about warnings about drinking alcohol while taking medication, and 3.8% did not.All surveyed patients confirmed awareness of the need to avoid exposure to sunlight or UV rays.
According to the results of the study on the issue of preventing ADRs to systemic retinoids, it was established that to avoid the manifestations of photosensitization, out of 100.0% of informed patients, only 92.5% used protective means with SPF (95CI: 81.8-97.9%).All surveyed patients were also aware of such ADRs to prescribed medications as dryness of the skin and mucous membranes of the nose, eyes, and lips.Among the respondents, 98.1% (95CI: 89.9-100.0%)observed dry lips and used means to eliminate/relieve the manifestations of ADRs.60.4% of patients reported dry eyes, among them 5.7% wore contact lenses.26.4% of respondents (95CI: 15.3-40.3%)used means to eliminate / relieve dry eyes (Table 4).
In order to establish the costs of PT with systemic retinoids, we calculated the cost of using isotretinoin at the minimum dosage of 0.57 mg/kg/day for 5 months, which is the minimum duration of taking the drug recommended by clinical guidelines.The cost of PT with isotretinoin ranged from 15417.20 to 21550.00.Proper PT with systemic retinoids involves laboratory monitoring of liver functions and lipid profile of all patients, the frequency of which is higher in months I and II compared to III-V and subsequent months of treatment.The cost of laboratory control of liver tests during 5 months of isotretinoin PT ranged from 1530.00 to 2340.00 and lipidograms -from 972.00 to 1417.50.Thus, the costs calculated for 5 months of PT are equal to the cost of the minimum course of isotretinoin use at its minimum dosage and the cost of the minimum frequency of laboratory control -from 17919.20 to 25307.50 (Table 5).

Discussion
As evidenced by the results of our survey, only 30.2% of patients were informed by pharmacists about the risks of using systemic retinoids and the requirements for PT monitoring.Therefore, in our opinion, the real practice of providing PC to patients administrating retinoids is not widespread, which confirms the relevance of studying this issue.
In the absence of approved standards for the PC of patients administrating systemic retinoids in Ukraine, the first stage of our research consisted of the analysis of current regulatory documents and other sources to determine the main directions of PC.As a result, 6 guidelines were established, including 10 key messages of PC, the first of which concerns the expediency of using retinoids.When prescribing systemic retinoids, physicians quite often encounter patients refusing to take isotretinoin (non-compliance), which is explained by the problem of so-called retinoidophobia [30].Information sources available to patients present oral isotretinoin as a dangerous drug, without specifying that the only real ADR of concern is teratogenicity in patients of childbearing age, for which there is a Risk Management Program [4].Other ADRs can usually be easily prevented and / or eliminated [4,16].Considering the high effectiveness of oral isotretinoin in treating acne [1,10,24,25,29], the primary task of the pharmacist in providing PC is to support the patient in the agreed decision recommended by the physician to take systemic retinoids.It should be taken into account that the stability of the clinical effect and low risk of relapse can only be guaranteed by the long-term use of drugs in the full course dosage calculated by the physician [1,30].
The degree of patient following the doctor's prescriptions has a significant impact on the results of treatment [7], however, the results of some studies show a low level of adherence to drugs used for acne [7,23].for increasing adherence is the use of a strategy of reminding patients to take medications, increasing the frequency of visits to healthcare professionals, avoiding complex PT regimens, taking into account patient satisfaction, successfully managing ADRs, and adjusting other factors that may affect adherence [23].
As a PC guideline, we have considered the pharmacist's participation in ensuring proper laboratory monitoring of the level of liver enzymes and lipids.Since laboratory tests are usually related to the diagnostic process, these questions rarely arise in the area of professional competence of the pharmacist.However, when using isotretinoin, laboratory monitoring is carried out for the prevention and timely detection of ADRs, which justifies the feasibility of including this issue as a component of the PC.The results of the patient survey regarding the laboratory monitoring of liver functions and lipid profile on systemic retinoid administration at the second stage of the study showed a fairly high level of awareness (94.3%), but the level of compliance with the recommendations turned out to be lower (67.9%).In our opinion, studying the reasons for patients' non-compliance with recommendations is important for the proper provision of PC.It was found that 5.7% of patients did not know that the use of retinoids can cause a change in laboratory parameters and did not perform monitoring.Thus, such patients need to be informed about the predicted ADRs to isotretinoin and PT monitoring.However, among patients who knew about this ADR, 22.6% did not conduct monitoring often enough, and 3.8% did not conduct it at all.We believe that the reason may be an increase in patient costs associated with monitoring [3].We consider that counseling the patient about future expenses, by the monitoring regime recommended by the physician, before starting PT will help to solve the problem.Besides, conducting laboratory monitoring can cause the patient psychological discomfort due to the need for blood tests, inconvenience due to missing work or studying [3], which should also be taken into account when providing PC.
A difficult task of providing PC to female patients of childbearing age is to facilitate compliance with the requirements of the PPP.According to the  Therefore, PC when using systemic retinoids must necessarily include the issue of effective contraception and conducting pregnancy tests by not only informing but also finding and using other strategies to increase patient compliance.The next PC guideline concerns warnings in PT with systemic retinoids.According to the results of our survey of uninformed patients were found concerning 2 of the 3 warnings included in the key messages of PC. 17.0% of patients did not know about the need to avoid donating blood, and 3.8% about the need to refrain from drinking alcohol.We think that these issues should be discussed with patients within the PC.
The provision of PC to prevent, eliminate, or relieve the manifestations of ADRs is another of the guidelines considered by us.According to the results of the survey, 7.5% of patients did not use protective means against UV rays.The appearance of such ADRs to retinoids as sunburn directly depends on the actions of the patient [30].Therefore, within PC, patients should be taught to use sunscreen while in the sun, as well as to reapply it every 2 hours and after swimming or intense sweating [4].98.1% of patients observed dry lips and used means to eliminate / relieve their manifestations.Dry eyes occurred in 60.4% of the respondents, but only 26.4% used the means to eliminate / relieve ADRs.The use of therapeutic cosmetics for the needs of the patient helps to reduce the manifestations of ADRs, thus increasing treatment adherence, which contributes to achieving better therapeutic effectiveness and a higher quality of life [4,7].It should be noted that the results of studies on the influence of ADRs on the level of adherence are somewhat contradictory.Minimizing ADRs is seen as a way to increase medication adherence, while ADRs to isotretinoin can remind patients of the need to take medication [23].
Cost is an important criterion for choosing medications.Depending on the ability to cover medication costs through public, private insurance, or personal funds, drug availability will vary for an individual patient.If the issue of cost is neglected, patients in pharmacies can ask for a change in the prescription of drugs or refuse to purchase them [6].When conducting a bibliographic search, we did not find regulatory documents or publications on the cost of PT with systemic retinoids in Ukraine, which prompted us to conduct a pharmacoeconomic evaluation of their use as a separate stage of research.
In addition to the cost of isotretinoin, the cost of systemic retinoid PT has other components.Because laboratory monitoring of liver function and lipid profile is indicated in all patients using systemic retinoids, we included these costs in the calculation of the cost of the treatment regimen.However, depending on the needs of the individual patient, the cost of treatment will also include the cost of contraceptives, pregnancy tests, protection against UV rays, moisturizing and protection of the skin and mucous membranes, etc.In case of an unsatisfactory response, the period of PT can be extended.In this case, the cost of each subsequent month will be equal to the costs calculated for 1 month for III-V months of treatment.The cost of PT will also increase with the need to increase the dosage of isotretinoin [1].We think that all this should be discussed with the patient within the framework of PC.
Defined guidelines and messages of PC concerning systemic retinoid administration are not comprehensive, which we consider a limitation of the conducted research.Issues related to mood disorders [1,4,22], laser treatment, peeling, dermabrasion, waxing [1,4], thinning of hair [14,30], adherence [1,7,23], assessment of health-related quality of life [5,8,19], etc., may be important for a specific patient.Regarding the pharmacoeconomic evaluation of PT, based on a single calculation methodology for the entire territory of Ukraine, we were guided by the availability and cost of drugs and laboratory monitoring in Lviv, which may differ slightly from other regions.

Conclusions
1. Studying the issue of pharmaceutical care during the use of systemic retinoids enabled determination the main guidelines (n=6) and key messages (n=10) that pharmacists can focus on during professional communication with acne patients, which makes it possible to increase the effectiveness and safety of pharmacotherapy.
2. The results of the study of patients' compliance with the recommendations related to the use of isotretinoin showed that, despite high awareness, the practice of using systemic retinoids needs optimization, in particular through pharmaceutical care, which, according to patients, was provided only in 30.2% (95CI: 18.3-44.3%) of cases.

3 .
Given the very low level of proper implementation of the Pregnancy Prevention Program when using systemic retinoids (3.7%; 95CI: 0.1-19.0%)and the severity of the consequences of neglecting the recommendations, pharmaceutical care should include issues of effective contraception and conducting pregnancy tests by not only informing but also by finding and using other strategies to increase patient compliance, in our opinion.4. We consider that the discussion with the patient of the costs of pharmacotherapy with systemic retinoids (according to the results of our studyfrom 17919.20 to 25307.50), in addition to the cost of isotretinoin (from 15417.20 to 21550.00),should include the costs of conducting laboratory control of liver tests (from 1530.00 to 2340.00), lipidogram (from 972.00 to 1417.50), and meeting some other individual patient needs.

Table 1
The main guidelines and key messages of PC of patients when using systemic retinoids

Table 2
Laboratory monitoring during the use of systemic retinoids

Table 3
Following the Pregnancy Prevention Program during the use of systemic retinoids

Table 4
Manifestations of dry skin and mucous membranes as ADR of systemic retinoids

Table 5
The cost of isotretinoin* PT with proper laboratory control * PT of a patient weighing 70 kg at the isotretinoin dosage of 0.57 mg/kg/day, 2 capsules 16 mg + 1 capsule 8 mg