Introduction
The first conference concerning the Rational Use of Drug (RUD) was held in Nairobi in 1985, where the RUD was defined as “patients receive medications appropriate to their clinical needs, in doses that meet their requirements, for an adequate period, and at the lowest cost to them and their community” [1]. In other words, each individual receives a maximal curative benefit with minimal risk and cost.
Common types of Irrational Use of Drug (IRUD) include the inappropriate use of antibiotics, the overuse of injection when the oral drug would be more appropriate, multiple medicines per prescription, prescribing medicine regardless of clinical guidelines, failure to follow drug orders, and inappropriate self-medication [2]. IRUD is a serious global problem, especially in developing countries. It can greatly impact the patient (adverse drug reaction, drug resistance), the community, and the health system (the wastes of resources) [3]. This issue has a long history in Iran; as the World Health Organization (WHO) reported in 1999, the IRUD concerning factors, such as the economic benefit of, the pressure of patients on physicians for prescribing drugs, legal weaknesses, and self-medication [4].
Medicines account for 20%-60% of healthcare costs in Low- and Middle-Income Countries (LMICs) [5]. In Iran, the analysis of pharmaceutical markets between 1997 and 2010 indicated that medicine consumption sales value growth equaled 28.38% annually; while the annual growth of population was calculated as 1.53% [6]. Another research suggested a 107% increase in pharmaceutical costs from the beginning of the 2001s to the end [7]. 
In response to these rising, the Ministry of Health and Medical Education (MoHME) of Iran has adopted various cost containment strategies, including standard treatment guidelines. The guidelines are managerial interventions to help prescribers make decisions about appropriate interventions for specific clinical conditions. There is growing literature on the impact of some of these techniques on RUD and drug spending. A study indicated that IRUD can lead to higher pharmaceutical expenditures due to the prescription of unnecessarily expensive products [8]. Another study also declared pharmaceutical costs in healthcare could have been reduced by 70% if some managerial strategies had been implemented [9]. In a study in Iran, Rafsanjani et al. declared that implementing restrictive drug protocols, decreased pantoprazole consumption by approximately $1.4 per hospital bed day and a 43% reduction in albumin expenditure [10].
In the first phase of implementing the cost management program in the hospital by the MoHME, Intravenous (IV) pantoprazole and albumin were candidates for cost savings. These drugs are expensive and the costliest medications in hospitals [11]. We will describe the irrationalized use of albumin and IV pantoprazole in hospitals by implementing pharmaceutical guidelines. Albumin is a biological drug with high consumption, i.e., not produced in Iran [12]. It is used to treat patients with hypovolemia (hemodialysis, acute liver failure, & high bilirubin in infants) [13]. There exist some favorable alternatives to albumin, as per the scientific literature, with a cost-reduction approach [14, 15]. Pantoprazole is a proton pump inhibitor prescribed to reduce gastric acid secretion and treat acute peptic ulcers and reflux esophagitis [16]. 
The present study aimed to rationalize and reduce the use of albumin and IV pantoprazole and assess the relevant inappropriate costs. This study was in line with the MoHME of Iran’s policy on health cost management (Health Reform Plan).

Material and Methods
This quasi-experimental study was conducted from January 2016 to October 2018 in two teaching hospitals affiliated with Jahrom University of Medical Sciences, Sothern of Iran. Both hospitals had 200 active beds with 15 medical wards. This project was approved by the Ethics Committee of the MoHME in Iran (Code: IR.JUMS.REC.399.068). 
After conducting the pharmaceutical guidelines [13, 17, 18] by specialist physicians in June 2016, we examined its effects on using these expensive drugs. The implementation of the guidelines include a few steps, as follows: 
1. Training physicians
2. Supervising clinical pharmacists on daily orders according to the relevant indications checklist (appendix 1, 2)
3. Managing data in the prescribing drugs
4. Providing feedback to prescribers
In 3 years (2016-2018), we compared drug consumption data and the created drug costs. For this purpose, we used the pharmaceutical software data of each hospital dedicated to this measure. The study population consisted of all prescriptions at inpatients wards during the period. These prescriptions were related to the numbers of 61377, 63847, and 63877 patients in the studied years, respectively. 
The data collection was performed from January to February 2019. Descriptive statistics were presented as frequencies and mean in tables. Two-Way non-parametric Analysis of Variance (ANOVA) was applied in SPSS to assess the obtained results and compare values in the 3 years. The significance level was set at P<0.05. Besides, the estimated Odds Ratios (ORs) were presented with a 95% Confidence Interval (CI).

Results
The Mean±SD number of patients in the two studied hospitals per month in 2016, 2017, and 2018 were equal to 5114±250, 5320±278, and 5315±524 years, respectively. The minimum and maximum albumin use in the first 6 months of the year 2016 equaled 294 and 397 vials, in sequence, in December. After implementing the albumin guideline, the average drug use was measured as 166 and 167 vials in 2017 and 2018, respectively. Reduced albumin use in the years was approximately 48% and significant (P<0.05). Averagely, approximately 165 vials per month were prescribed appropriately (Table 1).

Annual cost saving from RUD in albumin was estimated to be USD 25000. 
The reduced mean number of pantoprazole vials prescribed for patients in 2017 was calculated as 46%, compared to the previous year. This trend has continued in the following year (2018); we observed a 70% reduction in this respect. Change in the number of drugs prescribed in the study years was determined to be statistically significant (P<0.05). Consuming IV pantoprazole was measured to be 1457 vials and 795 vials per month in 2017 and 2018, respectively; it revealed a significant reduction (P=0.002) (Table 2).

Cost-Saving from RUD in IV pantoprazole was estimated to be USD 16000 in 2017 and USD 25000 in 2018.
Declined albumin and IV pantoprazole prescription patterns used after the intervention are shown in Figure 1.

The majority of prescribed albumin and pantoprazole vials were deemed to have been inappropriate. RUD was consistent in the years after the implementation of guidelines. Cost-saving respecting RUD in albumin and IV pantoprazole were approximately USD 50000 per year. 
Based on trend analysis by joint point regression method, the average monthly changes in albumin consumption in the first 17 months of the study presented a significant decrease of 5% (AMPC=-5; 95%CI: -6.6 to-3.4; P<0.001); it has been then almost constant. The average monthly change of pantoprazole consumption has been decreasing in 28 months. The largest decrease in the 10th to 28th months was approximately 7% (AMPC= -6.8; 95% CI: -7.3 to -6.3; P<0.001). Besides, from the 28th to the 36th month, it was almost constant (Table 3) (Figure 2, 3).


Discussion
The WHO reported that in numerous countries, 30% of patients in public sectors and 40% of patients in private sectors are treated per standard clinical guidelines [19]. Previous studies evaluated the clinical and economic impacts of pharmaceutical guidelines in Iran, suggesting that IRUD for albumin and pantoprazole ranged between 36% and 93% [12, 20, 21]. Albumin and IV pantoprazole IRUD in the studied hospitals, before our intervention (July 2016), has dramatically risen from 48% to 70% in 2015 and 2016, respectively. We attempted to reduce the irrational use of these expensive drugs and their costs by implementing pharmaceutical guidelines. 
The WHO announced that only less than half of all countries are implementing the basic policies required to ensure the appropriate use of medicines [4]. Introducing evidence-based guidelines for the expensive drug, i.e., led to a steady decline in drug use in our study has been followed by implementing the Health Reform Plan in Iran [22]. 
A pre and post-clinical pharmacists’ interventional study was conducted by Vazin et al. to evaluate the use pattern and direct cost of 3 high-cost medications, including albumin and IV pantoprazole in a hospital in Shiraz City, Iran. The obtained results indicated that after the intervention, the administered medication and their cost significantly decreased by 50.76%. Moreover, the direct cost of albumin and IV pantoprazole significantly decreased by 55.8% and 83.92%, respectively [23]. Reduced mean frequency of albumin vial and IV pantoprazole in our study, compared to pre-intervention was measured as 48% and 70%, in sequence. Additionally, these findings were in line with those of a study by Rafsanjani et al. who found that protocol implementation in the hospital ward can decline 19% and 43% in IV pantoprazole and albumin vials prescription, respectively [10]. 
In our interventional study, the use of pharmaceutical guidelines led to the RUM and saving its cost in hospitals. This recommendation was previously made by a few similar studies to reduce IRUD in the world with drug use evaluation. Ala et al. evaluated using albumin in a teaching hospital in Tehran City, Iran. They described how to RUM and its cost-saving with pharmaceutical guidelines [24]. Another study evaluated the pattern of albumin use in a large university-affiliated hospital in Iran; the obtained data highly suggested a mandatory need for education physicians to revise the prescribing strategies for expensive drugs, like albumin [25]. In this regard, promoting rational prescribing with clinical guidelines in Bangladesh [2] and 12 developing countries [26] was reported. 
A cost-saving of USD 50000 annually in the study hospitals by educational and management measures, like pharmacist-led intervention, has resulted in only two expensive drugs. This intervention was performed in another research by Dastan et al. in a tertiary referral hospital in Iran. They introduced an evidence-based guideline for albumin via a pharmacist-led audit and feedback leading to a reduction of USD 38800 [27]. Similar findings announced a USD 77720 cost reduction for three medicines (albumin, IV pantoprazole, IV immune globulin) in a referral hospital in Shiraz City, Iran [23]. The cost reduction revealed a decrease in the antibiotic expenditure of approximately Euro 3.6 million in a study by Piovani and associates [28]. 

Conclusion 
Prescription strategies, such as pharmaceutical guidelines with educational measures, pharmacist-led intervention, monitoring the prescribing drug, and feedback to prescribers can significantly decrease the inappropriate use of expensive drugs and their costs. However, most similar studies focusing on drug cost management were regionally conducted in Iran. Therefore, further studies are required at the national level to allow accurate assessment of the cost-effectiveness of these intervention strategies. In particular, Iran’s health reform plan embodies such a policy.
This study overlooked examining the trend of the two expensive drug use in the studied years, regardless of the number and type of patients in the hospitals that may affect the extent of consumed medications.


Ethical Considerations
Compliance with ethical guidelines
This project was approved by the Ethics Committee of the MoHME in Iran (Code: IR.JUMS.REC.399.068). 

Funding
This study was supported by the Vice-Chancellor for Research, Jahrom University of Medical Sciences.

Authors' contributions
Data collection: Vahid Kohpeima Jahromi, Mohamad Rahmanian; Data analysis: Nader Sharifi; Writing and drafting the manuscript: Vahid Kohpeima Jahromi, Rahim Raoofi; Approval of the final manuscript: All authors.

Conflict of interest
The authors declared no conflict of interest.

Acknowledgments
We would like to thank Mr. Noee, Mr. Zarafshar, and Mr. Faraji managers of pharmaceutical health information systems in studied hospitals for their time in obtaining the data in this project.

References

1. WHO. Promoting rational use of medicines: Core components. Geneva: World Health Organization; 2002. https://apps.who.int/iris/handle/10665/67438
2. Khan MI, Ara N. Promoting rational prescribing among medical practitioners. Bangladesh Med J. 2011; 40(2):6-7. [DOI:10.3329/bmj.v40i2.18495]
3. Okyay RA, Erdoğan A. Self-medication practices and rational drug use habits among university students: A cross-sectional study from Kahramanmaraş, Turkey. PeerJ. 2017; 5:e3990. [DOI:10.7717/peerj.3990] [PMID] [PMCID]
4. World Health Organization. Rational drug use. Report on a regional consultation, Teheran, Islamic Republic of Iran, 22-24 November 1999. Cairo: World Health Organization. Regional Office for the Eastern Mediterranean; 2002. https://apps.who.int/iris/handle/10665/254877
5. World Health Organization. WHO guideline on country pharmaceutical pricing policies. Geneva: World Health Organization; 2020. file:///C:/Users/b.fallahi/Downloads/9789240011878-eng.pdf
6. Kebriaeezadeh A, Koopaei NN, Abdollahiasl A, Nikfar S, Mohamadi N. Trend analysis of the pharmaceutical market in Iran; 1997-2010; policy implications for developing countries. Daru. 2013; 21(1):52. [DOI:10.1186/2008-2231-21-52] [PMID] [PMCID]
7. Ghasemi H, Raeeszadeh M. [Comparison of increase in medication costs and medication funding per capita of the outpatients insured by the Iranian Salamat Insurance in Isfahan, Iran (Persian)]. Health Inf Manage. 2016; 13(2):132-7. http://him.mui.ac.ir/index.php/him/article/view/2467
8. Dumoulin J, Kaddar M, Velásquez G. [Guide d’analyse économique du circuit du médicament (French)]. Genève: Organisation mondiale de la Santé; 2001. https://apps.who.int/iris/bitstream/handle/10665/58658/WHO_DAP_95.2_fre.pdf
9. Barnett A, Creese AL, Ayivor EC. The economics of pharmaceutical policy in Ghana. Int J Health Serv. 1980; 10(3):479-99. [DOI:10.2190/UKU9-4XK5-VYMG-ELB4] [PMID]
10. Rafsanjani ZJ, Kamyab H, Nosrati M, Najafi S, Keshavarz-Bahaghighat H, Sarayani A, et al. CP-166 Impact of guideline implementation on albumin and intravenous pantoprazole expenditure in a referral teaching hospital, Tehran, Iran. Eur J Hosp Pharm. 2017; 24(1):A74-5. [DOI:10.1136/ejhpharm-2017-000640.165]
11. Noormandi A, Karimzadeh I, Mirjalili M, Khalili H. Clinical and economic impacts of clinical pharmacists’ interventions in Iran: A systematic review. Daru. 2019; 27(1):361-78. [DOI:10.1007/s40199-019-00245-8] [PMID] [PMCID]
12. Jahangard-Rafsanjani Z, Javadi MR, Torkamandi H, Alahyari S, Hajhossein Talasaz A, Gholami K. The evaluation of albumin utilization in a teaching university hospital in Iran. Iran J Pharm Res. 2011; 10(2):385-90. [PMID]
13. Boldt J. Use of albumin: An update. Br J Anaesth. 2010; 104(3):276-84. [DOI:10.1093/bja/aep393] [PMID]
14. Schierhout G, Roberts I. Fluid resuscitation with colloid or crystalloid solutions in critically ill patients: A systematic review of randomised trials. BMJ. 1998; 316(7136):961-4. [DOI:10.1136/bmj.316.7136.961] [PMID] [PMCID]
15. Brecher ME, Owen HG, Bandarenko N. Alternatives to albumin: Starch replacement for plasma exchange. J Clin Apher. 1997; 12(3):146-53. [DOI:10.1002/(SICI)1098-1101(1997)12:33.0.CO;2-A] [PMID]
16. Moayyedi P, Eikelboom JW, Bosch J, Connolly SJ, Dyal L, Shestakovska O, et al. Pantoprazole to prevents gastroduodenal events in patients receiving rivaroxaban and/or aspirin in a randomized, double-blind, placebo-controlled trial. Gastroenterology. 2019; 157(2):403-12. [DOI:10.1053/j.gastro.2019.04.041] [PMID]
17. World Health Organization. Technical brief series - brief No 3. Achieving better health outcomes and efficiency gains through rational use of medicine. Geneva: World Health Organization; 2010. http://digicollection.org/hss/documents/s18330en/s18330en.pdf
18. Lu Y, Hernandez P, Abegunde D, Edejer T. The world medicines situation 2011. Medicine expenditures. Geneva: World Health Organization; 2011. https://www.who.int/health-accounts/documentation/world_medicine_situation.pdf
19. Holloway KA. Combating inappropriate use of medicines. Expert Rev Clin Pharmacol. 2011; 4(3):335-48. [DOI:10.1586/ecp.11.14] [PMID]
20. Talasaz AH, Jahangard-rafsanjani Z, Ziaie S, Fahimi F. Evaluation of the pattern of human albumin utilization at a university affiliated hospital. Arch Iran Med. 2012; 15(2):85-7. [PMID]
21. Matos GC, Rozenfeld S, Martins M. Human albumin use at hospitals in the Metropolitan Region of Rio de Janeiro, Brazil. Cad Saude Publica. 2010; 26(5):981-90. [DOI:10.1590/S0102-311X2010000500020] [PMID]
22. Haghdoost AA, Mehrolhassani MH, Khajehkazemi R, Fallah MS, Dehnavieh R. [Monitoring indicators of Iranian health system reform plan (Persian)]. Hakim Res J. 2013; 16(3):171-81. https://www.sid.ir/en/journal/ViewPaper.aspx?ID=354339
23. Vazin A, Karimzadeh I, Karamikhah R, Oveisi Z, Mohseni S, Keykhaee M, et al. Clinical and economical impacts of guideline implementation by the pharmaceutical care unit for high cost medications in a referral teaching hospital. BMC Health Serv Res. 2018; 18(1):815. [DOI:10.1186/s12913-018-3627-3] [PMID] [PMCID]
24. Ala S, Salehifar E, Chalaki V. [Evaluation of albumin use in a teaching hospital (Persian)]. J Mazandaran Univ Med Sci. 2015; 25(129):137-41. http://jmums.mazums.ac.ir/article-1-6266-en.html
25. Kazemi Y, Hadavand N, Hayatshahi A, Torkamandi H, Gholami K, Hadjibabaie M, et al. Albumin utilization in a teaching hospital in Tehran: Time to revise the prescribing strategies. J Pharm Care. 2013; 1(4):127-32. https://jpc.tums.ac.ir/index.php/jpc/article/view/29
26. Hogerzeil HV, Bimo, Ross-Degnan D, Laing RO, Ofori-Adjei D, Santoso B, et al. Field tests for rational drug use in twelve developing countries. Lancet. 1993; 342(8884):1408-10. [DOI:10.1016/0140-6736(93)92760-Q] [PMID]
27. Dastan F, Jamaati H, Emami H, Haghgoo R, Eskandari R, Hashemifard SS, et al. Reducing inappropriate utilization of albumin: The value of pharmacistled intervention model. Iran J Pharm Res. 2018; 17(3):1125-9. [PMID]
28. Piovani D, Clavenna A, Sequi M, Cartabia M, Bortolotti A, Fortino I, et al. Reducing the costs of paediatric antibiotic prescribing in the community by implementing guideline recommendations. J Clin Pharm Ther. 2013; 38(5):373-8. [DOI:10.1111/jcpt.12068] [PMID]