Analysis of Adverse Drug Reaction Risk in Elderly Patients Using the Japanese Adverse Drug Event Report (JADER) Database

Abstract

In general, the risk of adverse drug reactions (ADRs) is higher in elderly patients than in younger patients. In this study, we performed a comprehensive assessment of the risks of possible drug–ADR combinations in elderly patients using the Japanese Adverse Drug Event Report (JADER) database of the Pharmaceutical and Medical Devices Agency (PMDA, Japan) using the reporting odds ratio (ROR) as an index. Data recorded from April 2004 to September 2015 in the JADER database were downloaded from the PMDA website. The patients were classified into younger (≤69 years old) and elderly (≥70 years old) groups. The ROR and 95% confidence interval (CI) were calculated for all combinations of drugs and ADRs for which there were three or more reports in the database, focusing particularly on the combinations where more than 100 cases had been reported in elderly and younger patients. The most frequently reported drug–ADR combination was methotrexate with interstitial lung disease (646 cases). The combination with the highest ROR was methotrexate with lymphoproliferative disorder (ROR: 484.6, 95% CI: 334.1–702.9). In total, 27 drug–ADR combinations were found to have high risk in elderly patients. In conclusion, the findings of this comprehensive assessment of drug–ADR combinations using the JADER database will be valuable for updating the ADR risks for elderly patients in clinical setting.

In general, the risk of adverse drug reactions (ADRs) is higher in elderly patients compared with younger patients,^1,2) and this is a common clinical problem irrespective of the drug type. Previous studies showed that ADRs is high in ≥65 years old.^3–5) One possible reason is the physiological change elderly patients have undergone, often including a reduction of physiological functions such as renal or hepatic clearance, which can affect the pharmacokinetics and pharmacodynamics of many drugs.⁶⁾ In addition, risks of ADRs in elderly patients increase because of the issue of polypharmacy which is commonly seen in elderly and one of the causes for increasing ADRs.⁷⁾ It is reported that elderly patients taking 5 to 8 drugs at a time were at greater risk of ADRs than those taking 0 to 4 drugs.⁸⁾ Elderly patients often have chronic disease comorbidity requiring many drugs.^9,10) For these reasons, elderly patients generally have higher risks of ADRs.

Drugs that potentially increase ADRs in elderly patients are listed in Beers Criteria¹¹⁾ and in Screening Tool of Older People’s potentially inappropriate Prescriptions (STOPP).¹²⁾ Moreover, the Japan Geriatrics Society has published Guidelines for Medical Treatment and Its Safety in the Elderly 2015.¹³⁾ Many countries have developed databases of ADR information; these can allow research into inappropriate drug usage that can cause ADRs of the clinical use of a drug in advance. In April 2004, Japan’s Pharmaceuticals and Medical Device Agency (PMDA) established a spontaneous reporting system (SRS), the Japanese Adverse Drug Event Report (JADER) database, a unitized large-scale database used to assess the risk of ADRs.¹⁴⁾ Similarly, the United States Food and Drug Administration (FDA) has the FDA Adverse Event Reporting System (FAERS), and the United Kingdom’s Medicines and Healthcare Products Regulatory Agency (MHRA) has its Adverse Event Reporting System.

The reporting odds ratio (ROR)¹⁵⁾ is an index often used for pharmacovigilance analysis to assess the risk of ADRs, especially by the PMDA in Japan. Similar indices include the empirical Bayes geometric mean (EBGM),¹⁶⁾ often used by the FDA, and the proportional reporting ratio (PRR)¹⁷⁾ is often used by MHRA. Previous studies have reported RORs for some drugs and AEs based on information from JADER.^18,19) Umetsu et al.¹⁹⁾ reported RORs for hypoglycemia from a number of hypoglycemic agents (sulfonylurea, meglitinides, biguanides, thiazolidine, alpha-glucosidase inhibitors, and dipeptidyl peptidase-4 inhibitors). Sasaoka et al.²⁰⁾ reported RORs for the association of hand–foot syndrome with anticancer drugs. However, there has been little comprehensive ROR analysis of ADRs for elderly patients based on JADER.

In this study, we performed a comprehensive analysis of the risks for ADRs in elderly patients, using the JADER database to detect developing drugs that pose a high risk for the elderly. RORs for every drug–ADR combination reported in JADER were assessed and compared between elderly and younger patients.

METHODS

Data recorded from April 2004 to September 2015 in the JADER database were downloaded from the PMDA website (http://www.pmda.go.jp/). The database consists of four data tables: patient demographic information (demo), drug information (drug), adverse events (reac), and primary disease (hist). In “Demo” file, the demographic information table stored age in 10-year intervals, such as 60–69 years. In this study, we defined “younger patients” to be those assigned to “Under 10s,” “10s,” “20s,” “30s,” “40s,” “50s,” “60s,” and “elderly patients” to be those assigned to “70s,” “80s,” “90s,” “100s.” There were other codes for age classification such as “first trimester,” “second trimester,” “third trimester,” “newborn,” “infant,” “pediatric,” “youth,” “adult,” “elderly,” “unknown,” and the data from those classes were excluded from the analysis because the actual age ranges were unclear. We could not separate the patients’ age groups at 65 years old, although it is a general definition, because of the limitation of the available data. The patients’ data of 65–69 years old were included in the younger group because our objective was to find the possible risks of drug–ADR combinations in elderly patients and we thought it conservative to exclude the data of 60s from the elderly group as our objective was to find possible risks of drug–ADR combinations in elderly patients.

Adverse events in “Reac” file are coded according to the terminology in the Medical Dictionary for Regulatory Activities (MedDRA).²¹⁾ In “Drug” file, the drug information table assigned the following role codes to each drug: suspected (higiyaku in Japanese), interacting (sougosayou), or concomitant (heiyouyaku). Drug names were changed from the Japanese Accepted Name to the United States Adopted Name based on the Kyoto Encyclopedia of Genes and Genomes (KEGG) drug database (http://www.genome.jp/kegg/).²²⁾ Any adverse events and drug names that were not defined in MedDRA or KEGG were translated by us. We extracted all suspected drugs and ADRs for the elderly and younger patient groups. RORs were calculated with 95% confidence intervals (CIs) from the following equations, with a, b, c, and d defined by the 2×2 table as; a: number of cases which occurred interested AE after using the suspected drug(s), b: number of cases which occurred all other AEs after using the suspected drug(s), c: number of cases which occurred interested AE after using all other drugs, d: number of cases which occurred all other AEs after using all other drugs.   

(1)

  

(2)

The numbers a, b, c, and d were defined not as the count of reports but as the count of the combination of adverse events and drugs.

RORs were calculated for the cases where the number of combinations of all suspected drugs and ADRs was reported more than three times in the elderly patients than in the younger patients. We also defined an index for the difference between elderly and younger (DEY) patients as the difference between the lower limit of the 95% CI in the elderly patients and the upper limit of the 95% CI in the younger patients. We focused, in particular, on the drug–ADR combinations that satisfied the following two conditions: (1) more than 100 cases were reported in the elderly patients and (2) the value of DEY was greater than 1.0. All data analyses were performed using R (version 3.23; downloaded from http://www.r-project.org).²³⁾

RESULTS

In total, 361403 reports were obtained from the JADER database, 124771 for elderly patients, 214641 for younger patients, and 21991 reports that were excluded because the age classifications were unclear. The total number of suspected drugs was 3341 and of ADRs was 7301, with a total of 24392641 combinations of suspected drugs and ADRs. Of these, 21359 combinations were reported more than three times in elderly patients. There were 301168 and 589730 combinations of suspected drugs and ADRs for the elderly and younger patients, respectively.

In some cases, the names of ADRs or drugs were not provided in the Standardized MedDRA queries or the KEGG drug databases, and the names were reported in Japanese. The English expressions for these names are, human red blood cell solution, radiation exposure, hypoglycemia, transfusion-related acute lung injury, pneumocystis pneumonia, pneumatosis intestinalis and infusion-related reaction, and these data were included in the analysis.

Table 1 lists 20 combinations of suspected drugs and ADRs in decreasing order of reported cases in elderly patients. The most frequently reported combination was methotrexate with interstitial lung disease (646 cases). Other ADRs associated with methotrexate were pancytopenia (483 cases) and pneumocystis pneumonia (366 cases). Interstitial lung disease was also associated with other drugs such as gefitinib (515 cases), gemcitabine hydrochloride (414 cases), docetaxel hydrate (358 cases), erlotinib hydrochloride (323 cases), and amiodarone hydrochloride (315 cases). The ROR values are not necessarily higher in elderly patients than younger patients, suggesting that the risks for some drug–ADR combinations are not always high in elderly patients.

Table 1. Combinations of Suspected Drugs and Adverse Drug Reactions*

	Suspected drug	Adverse event	Elderly patients (≥70 years)						Younger patients
			a	b	c	d	ROR	95% CI	a	b	c	d	ROR	95% CI
1	Methotrexate	Interstitial lung disease	646	5159	12355	283008	2.9	2.6–3.1	754	8669	12427	567880	4.0	3.7–4.3
2	Glimepiride	Hypoglycemia	596	802	3200	296570	68.9	61.6–77	190	658	2144	586738	79.0	66.9–93.4
3	Gefitinib	Interstitial lung disease	515	849	12486	287318	14.0	12.5–15.6	493	830	12688	575719	27.0	24.1–30.2
4	Methotrexate	Pancytopenia	483	5322	2377	292986	11.2	10.1–12.4	289	9134	3650	576657	5.0	4.4–5.6
5	Valaciclovir hydrochloride	Acute kidney injury	459	2766	2978	294965	16.4	14.8–18.3	101	1345	4155	584129	10.6	8.6–13
6	Gemcitabine hydrochloride	Interstitial lung disease	414	1408	12587	286759	6.7	6–7.5	408	2297	12773	574252	8.0	7.2–8.9
7	Oxaliplatin	Neutropenia	398	2862	2375	295533	17.3	15.5–19.4	1132	5988	5480	577130	19.9	18.6–21.3
8	Human red blood cell solution (radiation exposure)	Transfusion-related acute lung injury	390	2109	384	298285	143.6	124–166.4	266	1463	627	587374	170.3	146.3–198.4
9	Zoledronic acid hydrate	Osteonecrosis of jaw	383	944	808	299033	150.2	130.9–172.3	488	1166	614	587462	400.4	350.9–457
10	Heparin sodium	Heparin-induced thrombocytopenia	368	966	133	299701	858.4	697.1–1057	510	1286	124	587810	1879.9	1533.4–2304.8
11	Methotrexate	Pneumocystis pneumonia	366	5439	1063	294300	18.6	16.5–21	444	8979	2108	578199	13.6	12.2–15.1
12	Alteplase	Haemorrhagic cerebral infarction	364	699	337	299768	463.2	392.5–546.7	205	375	223	588927	1443.7	1164.4–1790
13	Ribavirin	Anaemia	360	2235	3724	294849	12.8	11.4–14.3	1540	12545	7167	568478	9.7	9.2–10.3
14	Docetaxel hydrate	Interstitial lung disease	358	1677	12643	286490	4.8	4.3–5.4	367	2950	12814	573599	5.6	5–6.2
15	Tegafur, Gimeracil, Oteracil Potassium	Diarrhoea	348	3662	2512	294646	11.1	9.9–12.5	423	4424	5378	579505	10.3	9.3–11.4
16	Iopamidol	Anaphylactic shock	346	938	3561	296323	30.7	27–34.9	442	1340	8867	579081	21.5	19.3–24
17	Human red blood cell solution (radiation exposure)	Blood pressure decreased	344	2155	2560	296109	18.5	16.4–20.8	244	1485	3552	584449	27.0	23.5–31.1
18	Erlotinib hydrochloride	Interstitial lung disease	323	980	12678	287187	7.5	6.6–8.5	429	1184	12752	575365	16.3	14.6–18.3
19	Alendronate sodium hydrate	Osteonecrosis of jaw	319	1281	872	298696	85.3	74.2–98.1	118	748	984	587880	94.2	76.9–115.6
20	Amiodarone hydrochloride	Interstitial lung disease	315	590	12686	287577	12.1	10.5–13.9	188	697	12993	575852	12.0	10.2–14.1

* These combinations are listed in the order of the reported values for a for the elderly patients (a, b, c, and d are defined in text). CI, confidence interval; ROR: reporting odds ratio.

Total number of drug–ADR combinations with DEY greater than 1.0 was 341, and the combinations reported more than 50, 100 or 200 cases in elderly patients were 53, 27, and 9, respectively. Table 2 lists the 27 combinations of suspected drugs and ADRs reported in more than 100 cases in elderly patients for which the DEY index was greater than 1.0 in the descending order of the cases, indicating a higher risk of the ADRs in elderly patients compared with younger patients for these combinations. The combination with the highest DEY was methotrexate with lymphoproliferative disorder (ROR: 484.6, 95% CI: 334.1–702.9, DEY: 158.0). Methotrexate also showed high DEY values with some other ADRs, as shown in Table 2.

Table 2. Combinations of Suspected Drugs and Adverse Drug Reactions Where the Risk was Higher for Elderly Patients (≥70 Years)*

	Suspected drug	Adverse event	Elderly patients (≥70 years)						Younger patients						DEY
			a	b	c	d	ROR	95% CI	a	b	c	d	ROR	95% CI
1	Methotrexate	Pancytopenia	483	5322	2377	292986	11.2	10.1–12.4	289	9134	3650	576657	5.0	4.4–5.6	4.5
2	Valaciclovir hydrochloride	Acute kidney injury	459	2766	2978	294965	16.4	14.8–18.3	101	1345	4155	584129	10.6	8.6–13.0	1.8
3	Methotrexate	Pneumocystis pneumonia	366	5439	1063	294300	18.6	16.5–21.0	444	8979	2108	578199	13.6	12.2–15.1	1.4
4	Ribavirin	Anaemia	360	2235	3724	294849	12.8	11.4–14.3	1540	12545	7167	568478	9.7	9.2–10.3	1.0
5	Iopamidol	Anaphylactic shock	346	938	3561	296323	30.7	27–34.9	442	1340	8867	579081	21.5	19.3–24	3.0
6	Methotrexate	Lymph proliferative disorder	281	5524	31	295332	484.6	334.1–702.9	341	9082	150	580157	145.2	119.7–176.2	158.0
7	Prednisolone	Pneumocystis pneumonia	257	4931	1172	294808	13.1	11.4–15.0	391	11437	2161	575741	9.1	8.2–10.2	1.3
8	Ribavirin	Haemoglobin decreased	251	2344	1768	296805	18.0	15.7–20.6	1123	12962	4115	571530	12.0	11.2–12.9	2.8
9	Methotrexate	Bone marrow failure	241	5564	1092	294271	11.7	10.1–13.5	216	9207	2612	577695	5.2	4.5–6.0	4.2
10	Irinotecan hydrochloride hydrate	Leukopenia	187	2746	1478	296757	13.7	11.7–16.0	313	4582	4200	580635	9.4	8.4–10.6	1.1
11	Allopurinol	Drug reaction with eosinophilia and systemic symptoms	185	2192	716	298075	35.1	29.7–41.5	229	2281	3985	583235	14.7	12.8–16.9	12.8
12	Valaciclovir hydrochloride	Encephalopathy	179	3046	171	297772	102.3	82.7–126.6	79	1367	832	587452	40.8	32.2–51.7	31.0
13	Allopurinol	Stevens-Johnson syndrome	158	2219	1946	296845	10.9	9.2–12.8	137	2373	5452	581768	6.2	5.2–7.3	1.9
14	Carbamazepine	Drug reaction with eosinophilia and systemic symptoms	146	1487	755	298780	38.9	32.3–46.7	780	5314	3434	580202	24.8	22.8–26.9	5.4
15	Methotrexate	Lymphoma	137	5668	163	295200	43.8	34.8–55.0	234	9189	520	579787	28.4	24.3–33.2	1.7
16	Cetuximab	Infusion related reaction	127	871	118	300052	370.8	286.1–480.5	147	1256	396	587931	173.8	142.7–211.6	74.4
17	Infliximab	Pneumocystis pneumonia	127	969	1302	298770	30.1	24.8–36.5	196	3504	2356	583674	13.9	11.9–16.1	8.7
18	Levofloxacin hydrate	Hypoglycemia	126	1455	3670	295917	7.0	5.8–8.4	25	2512	2309	584884	2.5	1.7–3.7	2.1
19	Peginterferon Alfa-2a (Genetical Recombination)	Anaemia	118	986	3966	296098	8.9	7.4–10.8	240	3371	8467	577652	4.9	4.3–5.5	1.8
20	Telaprevir	Haemoglobin decreased	117	570	1902	298579	32.2	26.3–39.5	777	5435	4461	579057	18.6	17.1–20.1	6.2
21	Voglibose	Pneumatosis intestinalis	114	470	186	300398	391.7	305.1–503	28	490	251	588961	134.1	89.8–200.1	104.9
22	Imatinib mesilate	Pleural effusion	113	2112	778	298165	20.5	16.8–25.1	71	3551	1119	584989	10.5	8.2–13.3	3.4
23	Methotrexate	Diffuse large B-cell lymphoma	111	5694	62	295301	92.8	68–126.8	171	9252	233	580074	46	37.7–56.1	11.9
24	Celecoxib	Erythema multiforme	111	1480	1336	298241	16.7	13.7–20.5	96	1191	4583	583860	10.3	8.3–12.7	1.0
25	Human red blood cell solution (radiation exposure)	Pyrexia	106	1666	3468	295928	5.4	4.4–6.6	115	2859	9949	576807	2.3	1.9–2.8	1.6
26	Paroxetine hydrochloride hydrate	Inappropriate antidiuretic hormone secretion	101	1210	649	299208	38.5	31–47.8	45	3247	685	585753	11.9	8.7–16.1	14.9
27	Tacrolimus hydrate	Pneumonia	101	1287	4447	295333	5.2	4.2–6.4	227	8671	6353	574479	2.4	2.1–2.7	1.5

* These combinations were those reported more than 100 times in elderly patients, with a difference greater than 1.0 between the lower limit of the reporting odds ratio (ROR) 95% confidence interval (CI) for the elderly patients and the upper limit of the ROR 95% CI for the younger.

DISCUSSION

In this study, we analyzed the risks of ADRs using the JADER database, focusing especially on risks for elderly patients. We found 27 combinations of drugs and ADRs with a higher risk for elderly patients over 70 years old than for younger patients, of which the greatest difference in risk was found in the combination of methotrexate and lymphoproliferative disorder. This association has previously been reported as a methotrexate associated lymphoproliferative (MTX-associated LPD).²⁴⁾ Although, the mechanism and possible risk factors of MTX-associated LPD remain unclear, some studies have reported its occurrence in elderly patients.^25,26) Further risks with higher RORs associated with methotrexate included diffuse large B-cell lymphoma (111 cases, ROR: 92.8, 95% CI: 68.0–126.8, DEY: 11.9), pancytopenia (483 cases, ROR: 11.2, 95% CI: 10.1–12.4, DEY: 4.5), bone marrow failure (241 cases, ROR: 11.7, 95% CI: 10.1–13.5, DEY: 4.2), lymphoma (137 cases, ROR: 43.8, 95% CI: 34.8–55.0, DEY: 1.7), and pneumocystis pneumonia (366 cases, ROR: 18.6, 95% CI: 16.5–21.0, DEY: 1.4). Methotrexate is a drug that requires careful administration for elderly patients. In total, 3951 reports contained methotrexate as a suspected drug. In most cases, the methotrexate was used to treat rheumatoid arthritis (3387 cases).

Pneumocystis pneumonia was reported as an ADR associated with suspected drugs such as infliximab (127 cases, ROR: 30.1, 95% CI: 24.8–36.5, DEY: 8.7), methotrexate (366 cases, ROR: 18.6, 95% CI: 16.5–21.0, DEY: 1.4), and prednisolone (257 cases, ROR: 13.1, 95% CI: 11.4–15.0, DEY: 1.3). Pneumocystis pneumonia is a type of opportunistic infection resulting from a weakened immune system. In general, elderly patients have defects in T-cell immunity and thus an increased risk of opportunistic infection,²⁷⁾ and care should be taken when using these drugs for elderly patients.

Recently, various analytical methods have been applied to SRS database analyses.^28–30) For example, Fujiwara et al.²⁸⁾ used association analysis to report ADRs for antidepressant drugs such as selective serotonin reuptake inhibitors (SSRI), serotonin–noradrenaline reuptake inhibitors (SNRI) and noradrenergic and specific serotonergic antidepressants (NaSSA) using the association analysis. Narushima et al.²⁹⁾ used a mixed effects logistic model to report ADRs for DPP-4 inhibitors and GLP-1 receptor agonists using a mixed effects logistic model. These analyses may be more sophisticated for data mining; however, in the present study, we used ROR analysis because the objective was a comprehensive evaluation of the risks for all possible drug–ADR combinations. We considered a simpler analysis better for performing the analysis and for understanding the results to meet this objective.

In this study, we have presented a list of drugs posing a high risk for ADRs in elderly patients, but further epidemiological studies are needed to verify the real risk for these ADRs. A further limitation is that the SRS for the JADER database has various biases, such as the lack of a denominator that indicates the total number of patients who received the drugs of interest, as well as missing data and confounding factors.³¹⁾ Moreover, the ROR does not provide a robust indication of signal strength.¹⁵⁾ Despite these limitations, signal analysis using SRS is useful for gaining early and comprehensive information about ADRs.

In conclusion, we undertook a comprehensive assessment of the risk of ADRs in the elderly using the JADER database, and our results have provided a list of possible high-risk combinations of drugs and ADRs. These findings can be used to update information used for prescriptions for elderly patients.

Conflict of Interest

The authors declare no conflict of interest.

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