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158 Biol. Pharm. Bull. 41, 158–162 (2018) Vol. 41, No. 2 Regular Article

Association between Concomitant Use of Acyclovir or Valacyclovir with NSAIDs and an Increased Risk of Acute Kidney Injury: Data Mining of FDA Adverse Event Reporting System Zhihua Yue,*,a Jinhai Shi,b Haona Li,c and Huiyi Lia a Chinese Pharmacopoeia Commission; No. 11 Fahua Nanli, Dongcheng District, Beijing 100061, P. R. China: b Tianjin International Joint Academy of Biotechnology & Medicine; Tianjin 300475, China: and c Huaihe Hospital of Henan University; Kaifeng 475000, China. Received July 9, 2017; accepted November 9, 2017; advance publication released online November 28, 2017

Nonsteroidal anti-inflammatory drugs (NSAIDs) are likely to be used concomitantly with acyclovir or valacyclovir in clinical practice, but the study on the safety of such combinations was seldom reported. The objective of the study was to investigate reports of acute kidney injury (AKI) events associated with the concomitant use of oral acyclovir or valacyclovir with an NSAID by using the United States Food and Drug Administration (FDA) Adverse Event Reporting System (AERS) database between January 2004 and June 2012. The frequency of AKI events in patients while simultaneously taking either acyclovir or valacyclovir and an NSAID was compared using the Chi-square test. The effect of concomitant use of acyclovir or valacy- clovir and individual NSAIDs on AKI was analyzed by the reporting odds ratio (ROR). The results showed that AKI was reported as the adverse event in 8.6% of the 10923 patients taking valacyclovir compared with 8.7% of the 2556 patients taking acyclovir (p NS). However, AKI was significantly more frequently reported in patients simultaneously taking valacyclovir and an NSAID (19.4%) than in patients simultaneously tak- ing acyclovir and an NSAID (10.5%) (p<0.01). The results also suggested that increased risk of AKI was likely associated with the concomitant use of valacyclovir and some NSAIDs such as loxoprofen, , , , or . The case series from the AERS indicated that compared with acyclovir, valacyclovir is more likely to be affected by NSAIDs, and the concomitant use of valacyclovir with some NSAIDs might be associated with increased risk of AKI. The drug interactions with this specific com- bination of medications are worth exploring further. Key words acyclovir; valacyclovir; nonsteroidal anti-inflammatory drug (NSAID); acute kidney injury; data mining; FDA Adverse Event Reporting System (FAERS)

Acyclovir and valacyclovir (the L-valyl ester of acyclovir, frequency of AKI adverse events in patients taking both acy- converted into acyclovir in vivo) are widely used to treat clovir or valacyclovir and an NSAID, and the differences of herpes simplex virus (HSV) and herpes zoster virus (HZV) drug interactions between acyclovir and valacyclovir. infections. Clinical trials have shown that acyclovir and vala- cyclovir can lessen the symptoms of the infection and reduce METHODS the formation of new lesions.1,2) Whereas nonsteroidal anti-inflammatory drugs (NSAIDs) We used the public release of the FDA’s Adverse Event are commonly used for the treatment of acute or chronic con- Reporting System (AERS) database6) which covers the period ditions where pain and inflammation are present. Due to the from January 2004 to June 2012. The AERS contains reports current use profile of NSAIDs, either as prescription or OTC of adverse drug events spontaneously submitted by physicians, drugs, NSAIDs are likely to be used concomitantly with acy- pharmacists, other health care professionals, manufacturers, clovir or valacyclovir in clinical practice such as rheumatoid and consumers from the U.S. and other countries. From the arthritis and herpes zoster virus infection, while the study on first quarter (Q1) of 2004 through the second quarter (Q2) of the safety of such combinations was hardly reported. 2012, tables including demographic information—DEMO file; It is known that both oral acyclovir (or valacyclovir) and drug information—DRUG file and adverse events coded ac- NSAIDs have the potential to affect kidney function, and in cording to the Medical Dictionary for Regulatory Activities rare instances these drugs may cause more severe renal con- (MedDRA) terminology—REAC file for the reported drugs ditions such as acute kidney injury (AKI).3,4) Our previous were considered. A unique ISR number allows linking all research has revealed that the concomitant use of loxoprofen information from different tables. As the AERS database has (a non-selective NSAID) and valacyclovir might lead to an in- some duplicate reports, we removed the older ones from dupli- crease in reports of AKI.5) However, it is not known whether cate reports by sorting case identification numbers.7) the combination therapy of other NSAIDs with acyclovir or All reports containing oral acyclovir or valacyclovir were valacyclovir is associated with increased risk of AKI, and we included in the analysis, no matter whether the drug was also need to know the differences of drug interactions be- reported as suspect (“Primary Suspect Drug (PS)” or “Sec- tween acyclovir and valacyclovir. ondary Suspect Drug (SS)”), interacting (“I”) or concomitant In the present study, we examined the United States Food (“C”) in causing the adverse event. We excluded intravenous and Drug Administration (FDA) database to determine the acyclovir because our focus was on outpatient-dispensed

* To whom correspondence should be addressed. e-mail: [email protected] © 2018 The Pharmaceutical Society of Vol. 41, No. 2 (2018) Biol. Pharm. Bull. 159 preparations. 2556 patients who had an adverse event while taking acyclo- The number of patients with adverse events while simulta- vir. It revealed that patients who had an adverse event while neously taking either acyclovir or valacyclovir and an NSAID taking valacyclovir were significantly more likely to also be was determined. We selected the most widely used NSAIDs taking an NSAID than were patients who had an adverse as following: derivatives (, , event while taking acyclovir (RR 1.4, 95% confidence inter- , flurbiprofen, loxoprofen and ), acetic vals 1.2 to 1.6, p<0.001). Although there were no statistically acid derivatives (diclofenac, indomethacin, ketorolac, , significant differences in patients who had an adverse event etodolac, and ) enolic acid derivatives i.e. while taking valacyclovir in combination with de- (, piroxicam, lornoxicam and ) rivatives and those who taking acyclovir in combination with and selective (COX)-2 inhibitors i.e. Coxibs acetic acid derivatives (p=0.100). ( and ). was excluded in this study The characteristics of the patients with adverse events while because many people take aspirin for disease prevention. simultaneously taking either acyclovir or valacyclovir and an The Standard MedDRA Queries (SMQs) are groupings of NSAID were examined in greater detail. As shown in Table PT terms, which relate to defined medical conditions or areas 2, the proportion of female patients in valacyclovir/NSAID of interest.8) In this study, acute kindey injury (AKI) cases group (n=822, 71.2%) appeared higher than that in acyclovir/ were represented by 17 narrow Preferred Terms (PTs) in the NSAID group (n=100, 50.0%). There were no significantly SMQ [20000003]: “Acute phosphate nephropathy,” “Acute differences in the proportion of patients of each age stage prerenal failure,” “Anuria,” “Azotaemia,” “Continuous haemo- between valacyclovir/NSAID group and acyclovir/NSAID diafiltration,” “Dialysis,” “Haemodialysis,” “Neonatal anuria,” group. The majority of reports came from United States and “Nephropathy toxic,” “Oliguria,” “Peritoneal dialysis,” “Pre- was posted by health professionals. renal failure,” “Renal failure,” “Renal failure acute,” “Renal When considering AKI adverse effects, we found that AKI failure neonatal,” “Renal impairment” and “Renal impairment was significantly more frequently reported in valacyclovir/ neonatal.” Non-cases were defined as reports that did not con- NSAID group than in acyclovir/NSAID group (19.4 versus tain such PTs. 10.5%; p=0.003). The effect of concomitant use of acyclovir or valacyclovir The frequency of AKI in the patients taking either acyclo- and individual NSAIDs on AKI was analyzed by the reporting vir or valacyclovir in combination with individual NSAIDs odds ratio (ROR) which was based of case/non-case meth- was determined. As shown in Table 3, AKI event was signifi- odology.9,10) ROR estimates >1 depict exposure-event safety cantly more frequently reported in the combination therapy of signals and was considered reliable if the number of cases was valacyclovir/loxoprofen compared with AKI event in the com- >3. bination therapy of acyclovir/loxoprofen (45.8 versus 18.9%; Frequencies for categorical variables were compared using p=0.002). In addition, AKI was also frequently reported in the Chi-square test, and a p value <0.05 was considered sta- the combination therapy of valacyclovir/diclofenac (n=37, tistically significant. The statistical analysis was performed 25.2%), valacyclovir/etodolac (n=12, 36.4%), valacyclovir/ke- using R version 2.15.2 software. torolac (n=5, 23.8%), valacyclovir/piroxicam (n=5, 33.3%) or valacyclovir/lornoxicam (n=4, 50.0%), although there were no RESULTS statistically significant differences in AKI events between the groups, which was likely due to the small number of events From January 2004 to June 2012, AERS included almost 3 overall. million case reports. A total of 2556 patients were reported to Furthermore, we studied the effect of concomitant use of have had an adverse event while taking acyclovir and a total valacyclovir and individual NSAIDs on AKI using RORs. We of 10923 patients were reported to have had an adverse event found concomitant use of certain NSAIDs (such as loxopro- while taking valacyclovir. AKI was reported as the adverse fen, diclofenac etodolac, ketorolac, piroxicam or lornoxicam) event in 8.7% of the 2556 patients taking acyclovir compared and valacyclovir might be suggestive of drug interactions. As with 8.6% of the 10923 patients taking valacyclovir (p=NS). shown in Table 4, patients who used valacyclovir and those The number of patients with adverse events while simulta- individual NSAIDs concomitantly had significantly higher neously taking either acyclovir or valacyclovir and an NSAID RORs for the risk of AKI than patients who used the NSAID was shown in Table 1. Coadministration of an NSAID was or valacyclovir alone. No interaction was observed between noted in 10.6% of the 10923 patients who had an adverse use of valacyclovir and other NSAIDs (data was not shown). event while taking valacyclovir, compared with 7.8% of the

Table 1. Percentage of Patients with an Adverse Event While Taking Either Acyclovir or Valacyclovir Who Were Also Taking an NSAID

Acyclovir (n=2556) Valacyclovir (n=10923) Exposure p Value n % n %

Patients taking NSAIDs concomitantly* 200 7.8 1155 10.6 <0.001 Propionic acid derivatives 128 5.0 705 6.5 0.006 Acetic acid derivatives 45 1.8 250 2.3 0.100 Enolic acid derivatives (Oxicams) 11 0.4 91 0.8 0.034 Selective COX-2 inhibitors (Coxibs) 33 1.3 227 2.1 0.009

* Numbers add up to greater than the total taking any NSAID because some patients were taking more than one NSAID. 160 Biol. Pharm. Bull. Vol. 41, No. 2 (2018)

Table 2. Comparison of Patients Who Had an Adverse Event While Taking Either Acyclovir or Valacyclovir in Combination with an NSAID

Acyclovir/NSAID (n=200) Valacyclovir/NSAID (n=1155) p Value n % n %

Sex Female 100 50.0 822 71.2 <0.001 Male 90 45.0 316 27.4 <0.001 Sex missing 10 5.0 17 1.5 <0.001 Age stage <45 45 22.5 220 19.0 0.256 45–64 68 34.0 385 33.3 0.854 ≥65 48 24.0 345 29.9 0.091 Age missing 39 19.5 205 17.7 0.552 Reporter country United states 89 44.5 616 53.3 0.021 Japan 54 27.0 339 29.4 0.499 Other 42 21.0 79 6.8 <0.001 Reporter country missing 22 11.0 128 11.1 0.973 Type of reporter Physician or pharmacist 118 59.0 604 52.3 0.079 Other health professional 28 14.0 145 12.6 0.572 Consumer 35 17.5 264 22.9 0.092 Lawyer 5 2.5 50 4.3 0.226 Reporter missing 14 7.0 92 8.0 0.639 Adverse drug reactions Acute kidney injury 21 10.5 224 19.4 0.003

Table 3. The Frequency of AKI in the Patients Taking Either Acyclovir or Valacyclovir in Combination with Individual NSAIDs

Acyclovir/NSAID Valacyclovir/NSAID Concomitant use of NSAIDs p Value AKI/all cases* % AKI/all cases* %

Propionic acid derivatives 15/128 11.7 156/705 22.1 0.006 Ibuprofen 4/59 6.8 21/287 7.3 0.885 Naproxen 1/26 3.8 9/157 5.7 0.695 Ketoprofen 3/10 30.0 2/17 11.8 0.239 2/8 25.0 2/8 25.0 1.000 Loxoprofen 7/37 18.9 124/271 45.8 0.002 Oxaprozin 0/0 n.a. 1/6 20.0 n.a. Acetic acid derivatives 6/45 13.3 55/250 22.0 0.186 Diclofenac 3/25 12.0 37/147 25.2 0.150 Indomethacin 0/8 0 1/20 5.0 n.a. Sulindac 0/1 0 0/9 0 n.a. Ketorolac 2/7 28.6 5/21 23.8 0.801 Etodolac 1/6 16.7 12/33 36.4 0.347 Nabumetone 1/1 100.0 2/26 7.7 0.188 Tolmetin 0/0 n.a. 0/1 0 n.a. Enolic acid derivatives (Oxicams) 0/11 0 19/91 20.9 n.a. Meloxicam 0/7 0 10/68 14.7 n.a. Piroxicam 0/4 0 5/15 33.3 n.a. Lornoxicam 0/0 n.a. 4/8 50.0 n.a. Tenoxicam 0/0 n.a. 1/1 100.0 n.a. Selective COX-2 inhibitors (Coxibs) 3/33 9.1 18/227 7.9 0.819 Celecoxib 2/24 8.3 12/157 7.6 0.906 Rofecoxib 1/10 10.0 9/80 11.3 0.906

n.a., not available. * More cases are noted than the total number of reports as some patients were taking more than one NSAID. Vol. 41, No. 2 (2018) Biol. Pharm. Bull. 161

Table 4. The Effect of Concomitant Use of Valacyclovir and Individual NSAIDs on AKI Analyzed by Reporting Odds Ratios (RORs)

Exposure AKI cases Non-cases ROR (95% CI)

Neither valacyclovir nor loxoprofen 78671 2902260 1 Valacyclovir no loxoprofen 815 9837 3.06 (2.84–3.28) Loxoprofen no valacyclovir 404 5809 2.57 (2.32–2.84) Concomitant of valacyclovir and loxoprofen 124 147 31.12 (24.50–39.52)

Neither valacyclovir nor diclofenac 77333 2885492 1 Valacyclovir no diclofenac 902 9874 3.41 (3.18–3.65) Diclofenac no valacyclovir 1742 22577 2.88 (2.74–3.02) Concomitant of valacyclovir and diclofenac 37 110 12.55 (8.65–18.22)

Neither valacyclovir nor ketorolac 78826 2905488 1 Valacyclovir no ketorolac 934 9968 3.45 (3.23–3.69) Ketorolac no valacyclovir 249 2581 3.56 (3.12–4.05) Concomitant of valacyclovir and ketorolac 5 16 11.52 (4.22–31.44)

Neither valacyclovir nor etodolac 78897 2904858 1 Valacyclovir no etodolac 927 9963 3.43 (3.20–3.67) Etodolac no valacyclovir 178 3211 2.04 (1.75–2.37) Concomitant of valacyclovir and etodolac 12 21 21.04 (10.35–42.76)

Neither valacyclovir nor piroxicam 78942 2905944 1 Valacyclovir no piroxicam 934 9974 3.45 (3.22–3.69) Piroxicam no valacyclovir 133 2125 2.30 (1.93–2.75) Concomitant of valacyclovir and piroxicam 5 10 18.41 (6.29–53.85)

Neither valacyclovir nor lornoxicam 79059 2907750 1 Valacyclovir no lornoxicam 935 9980 3.45 (3.22–3.69) Lornoxicam no valacyclovir 16 319 1.84 (1.12–3.05) Concomitant of valacyclovir and lornoxicam 4 4 36.78 (9.20–147.07)

DISCUSSION showed that the chance of AKI being reported was slightly in- creased in patients who used these individual NSAIDs or va- It is considered that valacyclovir enhances acyclovir bio- lacyclovir alone, but the reporting rate was much higher when availability compared with orally administered acyclovir,11) the NSAID and valacyclovir were used concomitantly. For this and the efficacy and side effect profiles for oral acyclovir and reason, the strong association between the concomitant use of valacyclovir are quite similar.12–14) While it has been reported these NSAIDs with valacyclovir and AKI therefore was sug- that there are some differences in drug interactions for acyclo- gestive of an interaction. vir and valacyclovir. For example, valacyclovir is more likely The mechanism underlying this suspected interaction re- to be affected by cimetidine,15) while phenytoin and valproic mains to be explained. It has been reported that valacyclovir is acid are more likely to have their effectiveness reduced by a substrate of organic anion transporter 1 (OAT1), OAT2 and acyclovir.16) OAT3.17–19) NSAIDs such as diclofenac in vitro inhibit OAT1 In this study, we reviewed adverse events reported to the and OAT3, and it might increase plasma valacyclovir concen- FDA in patients receiving either oral acyclovir or valacyclovir trations by inhibiting the OAT-mediated tubular secretion of along with an NSAID. Although there were no differences valacyclovir.20) An increase in the levels of valacyclovir might in AKI adverse events between patients taking valacyclovir lead to increased occurrence of AKI.21) Nevertheless, we did (8.6%) and those taking acyclovir (8.7%), we found that AKI not find the association between the concomitant use of vala- was significantly more frequently reported in patients simul- cyclovir with some other NSAIDs such as ibuprofen, naproxen taneously taking valacyclovir and an NSAID (19.4%) than or celecoxib and the increased occurrence of AKI. The rea- in patients simultaneously taking acyclovir and an NSAID sons why AKI adverse effects involving drug interactions (10.5%) ( p<0.01). It’s revealed that compared with acyclovir, might vary between certain individual NSAIDs are not clear. valacyclovir is more likely to be affected by NSAIDs. The main strength of the present study was the use of FDA Our previous research has revealed that the concomitant use AERS database, which collected standardized information on of valacyclovir and loxoprofen might lead to an increase in adverse reactions related to drug use in a “real-world” popula- reports of AKI.5) In this study, it is revealed that concomitant tion. The database also provides a rich opportunity to detect use of valacyclovir and some other NSAIDs such as diclof- novel post-marketed drug interaction adverse effects since in enac, etodolac, piroxicam, ketorolac or lornoxicam might also clinical trials patients on multiple drugs are usually excluded. be associated with increased occurrence of AKI. 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