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Abstract

The clinical course of losartan potassium/hydrochlorothiazide (Preminent^®)-induced hyponatremia has not been described. We summarized 40 patients with Preminent-induced hyponatremia. The study involved 15 (37.5%) men and 25 (62.5%) women (mean age [SD], 76.4 [8.3] years; range, 55–95). Their sodium levels before Preminent administration were 139.5 (4.9) mEq/L (range, 131–145; reference range, 135–147). The duration from the day of Preminent administration to the day with the lowest sodium level was 59.3 (64.9) days (range, 2–207; median, 24). Most patients for whom this duration was <50 days exhibited progressive symptoms, whereas most of those for whom this duration was >50 days did not exhibit progressive symptoms but exhibited symptoms after fever or appetite loss. The lowest sodium value was 114.4 (8.2) mEq/L (range, 99–133). The duration from the time of Preminent discontinuation to (1) the time of early recovery and (2) the time of final recovery was 6.8 (5.5) days (range, 1–20; median, 5) and 11.6 (7.6) days (range, 2–29; median, 7.5), respectively. Of the 40 patients, 36 (90.0%) achieved full recovery, 1 (2.5%) suffered from after-effects due to central pontine myelinolysis, 1 (2.5%) died, and 2 (5.0%) were unknown. In the analysis of other adverse effects of Preminent and the same adverse effects of other three angiotensin II receptor blocker (ARB)/thiazide combinations, hyponatremia was observed as a primary adverse effect of all ARB/thiazide combinations. However, hyperesthesia dermatitis was reported as an adverse effect of Preminent only.

Keywords

Losartan hydrochlorothiazide Preminent adverse effects hyponatremia

Introduction

Losartan potassium/hydrochlorothiazide has been commercially available since 1995, and it is reported to have good compliance and excellent effects as a depressor.¹ In December 2006, losartan potassium/hydrochlorothiazide was introduced into the Japanese market as Preminent® (Banyu Pharmaceutical Co. Ltd., Tokyo, Japan)—a tablet containing 50 mg of losartan potassium and 12.5 mg of hydrochlorothiazide. Losartan is an angiotensin II receptor blocker (ARB), and hydrochlorothiazide is a diuretic. In Japan, 1 tablet/day of Preminent is approved for the treatment of hypertension.

Since then, Preminent-induced hyponatremia has been often encountered in our clinical practice, but has not been described in the relevant literature (PubMed keywords: Losartan, hydrochlorothazide, and hyponatremia), and therefore, the clinical course has not been described.

Here, we summarize data obtained for 40 patients with Preminent-induced hyponatremia and present a case report. Additionally, we summarize frequently observed adverse effects of Preminent and the same adverse effects of other three ARB/thiazide combinations that have become commercially available in 2009 in Japan.

Methods

First, we accessed the Web site of the Pharmaceuticals and Medical Devices Agency (PMDA).² PMDA is an institution that obtains data on the adverse effects of drugs from all pharmaceutical companies in Japan and shows this information to ensure the appropriate use of drugs. Previous reports on the adverse effects of drugs can be accessed from the PMDA database.³ Previous reports on the adverse effects of Preminent can be accessed from the PMDA database.⁴

Even though this database is available to the public, the information it provides is inadequate for investigating adverse drug effects in detail. Therefore, we requested the PMDA for adverse effect case reports on patients with Preminent-induced hyponatremia, and obtained this information. According to the PMDA reports, 11 and 28 patients experienced hyponatremia as an adverse effect of Preminent in 2007 and 2008, respectively. We analyzed the adverse effect case reports of these 39 patients. Data on patients who experienced adverse effects in 2009 have not yet been summarized in the PMDA and were therefore unavailable.

In addition to the 39 patients, we included a patient with Preminent-induced hyponatremia (Na concentration, 102 mEq/L) whom we encountered in August 2009. As a result, we reviewed the reports of 40 patients with Preminent-induced hyponatremia.

We analyzed (a) the patient characteristics, (b) the duration from the day of Preminent administration to the day when the lowest sodium concentration was recorded, (c) the lowest sodium concentration, (d) the duration from the time when Preminent treatment was discontinued to the time of early recovery, (e) the duration from the time when Preminent treatment was discontinued to the time of final recovery, and (f) the clinical outcome. Early recovery is defined that Na concentration or general condition began to improve. Final recovery is defined that Na concentration or general condition was considered to reach before Preminent administration. Additionally, we summarized (g) frequently observed adverse effects of Preminent from 2006 to 2009 on PMDA Web site.⁴ Further, by using PMDA Web site, we summarized (h) the same adverse effects of other three ARB/thiazide combinations such as valsartan (80 mg)/hydrochlorothiazide (12.5/6.25 mg) (Co-Dio®; Novartis Pharma K.K., Tokyo, Japan),⁵ candesartan (4/8 mg)/hydrochlorothiazide (6.25 mg) (Ecard®; Takeda Pharmaceutical Co. Ltd., Tokyo, Japan),⁶ and telmisartan (40/80 mg)/hydrochlorothiazide (6.25 mg) (Micombi®; Astellas Pharma Inc., Tokyo, Japan)⁷ that have become commercially available in 2009 in Japan.

Results

The findings for the 40 patients are summarized in Table 1 .

Table 1.

The drug adverse effects reports of Preminent-induced hyponatremia^a

Age	Sex	Before Na	Duration 1	The lowest Na	Duration 2	Na at early recovery	Duration 3	Na at final recovery	Clinical outcome
70	F	139	27	128			14	137	Recover
79	M			113	5				Recover
90	F		24		7		6		Recover
72	F		15	120					Recover
87	F		21	115	4	137			Recover
76	F		83	118	5	135	22	140	Recover
66	F		32	116					Recover
68	F		10				15		Recover
88	F		41	107	6				Recover
82	F		207	104			24		Recover
82	F								Unknown
95	F		164	133					Dead
85	F		164	111			6	135	Recover
66	M	143	9	123	1	130	5	139	Recover
64	M		19	109			7	136	Recover
64	F			121					Recover
71	F		94	115	6	133	10	139	Recover
55	M		5	99			19		After-effect
73	F	145	46	116			2	137	Recover
78	F		14	128			7	138	Recover
74	M		120	105		132			Recover
72	M		139	127			7		Recover
82	M		2	114					Recover
85	M		140	118	8	129			Recover
76	F		10	107	4	134			Recover
77	F		19	105	2	129	12		Recover
86	F		33						Unknown
81	M		14	118	2	131			Recover
70	F			111	5	129			Recover
70	F		91						Recover
85	F	138	6	122			6	136	Recover
68	M		196	113	20	124	5	135	Recover
72	M		21	103					Recover
80	M		204	118	14	129	29		Recover
80	M		9				22		Recover
70	F		24	106	16	132	19		Recover
78	M	141	37	120			8		Recover
77	F		19	112	3	130	6		Recover
77	F			113	14				Recover
74	M	131	18	102	1	111	5	132	Recover

^a Na; sodium concentration (mEq/L). Before Na: sodium concentration before Preminent administration. Duration 1: duration from the day of Preminent administration to the day with the lowest sodium concentration. Duration 2: duration from the time when Preminent was discontinued to the time of early recovery. Early recovery is defined that Na concentration or general condition began to improve. Duration 3: duration from the time when Preminent was discontinued to the time of final recovery. Final recovery is defined that Na concentration or general condition is considered to reach before Preminent administration.

Patient characteristics

The mean age of the patients was 76.4 (8.3 SD; range, 55–95 years). Of the 40 patients, 15 (37.5%) were men and 25 (62.5%) were women. The mean sodium concentration before Preminent administration was 139.5 (4.9 SD) mEq/L (range, 131–145 mEq/L; reference range, 135–147 mEq/L), that is, almost within normal limits.

Duration from the day of Preminent administration to the day with the lowest sodium concentration

The mean duration from the day of Preminent administration to the day with the lowest sodium concentration was 59.3 (64.9 SD) days (range, 2–207 days; median, 24 days). This duration was <50 days for 24 of 35 (68.6%) patients and >50 days for 11 of 35 (31.4%) patients. Most patients for whom this duration was <50 days exhibited progressive symptoms, such as general fatigue, muscle weakness, and appetite loss. On the other hand, most of those for whom this duration was >50 days did not exhibit progressive symptoms but exhibited symptoms after fever or appetite loss.

Lowest sodium concentration

The mean lowest sodium concentration was 114.4 (8.2 SD) mEq/L (range, 99–133 mEq/L). A sodium concentration of less than 110–115 mEq/L indicates severe hyponatremia⁸; on this basis, approximately half the patients were considered to be severely hyponatremic.

Duration from the time when Preminent was discontinued to the time of early recovery

The mean duration from the time when Preminent was discontinued to the time of early recovery was 6.8 (5.5 SD) days (range, 1–20 days; median, 5 days). Of the 18 patients, 16 (88.9%) recovered from hyponatremia in 8 days.

Duration from the time when Preminent was discontinued to the time of final recovery

The mean duration from the time when Preminent was discontinued to the time of final recovery was 11.6 (7.6 SD) days (range, 2–29 days; median, 7.5 days). Of the 22 patients, 19 (86.4%) patients recovered from hyponatremia in 5–22 days.

Clinical outcome

Of the 40 patients, 36 (90.0%) achieved full recovery. One patient (2.5%) suffered from after-effects because of central pontine myelinolysis. One patient (2.5%) died but the association between the death and Preminent was unclear. The clinical outcome of two patients (5.0%) was not documented.

Frequently observed adverse effects of Preminent on PMDA Web site

The results are summarized in Table 2 . Hyponatremia and hyperesthesia dermatitis were most frequently observed adverse effects of Preminent. In addition, renal dysfunction, hypokalemia, liver dysfunction, and brain infarction were reported as adverse effects. According to the PMDA database,⁴ no patients exhibit hyponatremia and hyperesthesia dermatitis at the same time as adverse effects of Preminent.

Table 2.

Frequently observed adverse effects of ARB/thiazide combinations on Pharmaceuticals and Medical Devices Agency (PMDA) Web site^a

ARB/thiazide combinations	Preminent	Co-Dio	Ecard	Micombi
Adverse effects	Number of patients
Hyponatremia	56	12	8	1
Hyperesthesia dermatitis	56	0	0	0
Renal dysfunction	29	0	2	0
Hypokalemia	27	3	2	1
Liver dysfunction	22	2	4	0
Brain infarction	16	2	1	0

^a Data of Preminent from 2006 to 2009. Data of Co-Dio, Ecard, and Micombi in 2009. Preminent is composed of losartan and hydrochlorothiazide. Co-Dio is composed of valsartan and hydrochlorothiazide. Ecard is composed of candesartan and hydrochlorothiazide. Micombi is composed of telmisartan and hydrochlorothiazide.

The same adverse effects of other three ARB/thiazide combinations on PMDA Web site

The results are summarized in Table 2. Hyponatremia was observed as a primary adverse effect of other three ARB/thiazide combinations. However, hyperesthesia dermatitis was not reported as an adverse effect of other three ARB/thiazide combinations.

Case report

In July 2009, a 74-year-old man was admitted to the orthopedics department of our hospital, because he was experiencing lumbago and pain in the lower limbs, and thereby could not stand without support.

He had chronic renal failure, hypertension, and lumbar spinal stenosis. In mid-June 2009, his prescription of 160 mg/day of valsartan (Diovan®; Novartis Pharma K.K., Tokyo, Japan) for hypertension was changed to 1 tablet/day of Preminent. Before this change, his blood urea nitrogen (BUN) concentration was 50 mg/dL (reference range, 7–20 mg/dL), creatinine (Cre) concentration, 3.3 mg/dL (reference range, 0.5–1.1 mg/dL), and sodium concentration, 131 mEq/L. After 2–3 days, he began to experience weakness in the muscles of the lower limbs, but could walk. Two weeks later, he began to experience appetite loss. Three weeks from the commencement of Preminent treatment, he began to experience lumbago and pain in the lower limbs, and thereby could not stand without support. Under the situation, his family doctor suspected the exacerbation of lumbar spinal stenosis, and therefore the patient was admitted to the orthopedics department of our hospital.

Lumbar magnetic resonance imaging (MRI) performed on admission revealed no significant differences from the findings obtained before. However, laboratory examinations revealed severe hyponatremia (Na concentration, 102 mEq/L) with increased sodium excretion in the urine (fractional excretion of Na (FENa), 2.7%; reference range, 1.0–2.0%), and rhabdomyolysis (creatine kinase [CK] concentration, 2019 U/L; reference, 30–150 U/L; and CK–muscle/brain [CK–MB], 45 U/L; reference, 0–20 U/L). The levels of adrenocorticotropic hormone (ACTH) was 50.4 pg/mL (reference range, 9.0–52.0 pg/mL); cortisol was 23.3 μg/dL (reference range, 4.5–21.1 μg/dL); plasma rennin activity (PRA) was 21.5 ng/mL/hr (reference range, 0.1–2.0 ng/mL/hr); aldosterone 22.2 ng/dL (reference range, 3.6–24.0 ng/dL); thyroid stimulating hormone (TSH) was 0.28 μU/mL (reference range, 0.35–4.94 μU/mL); free triiodothyronine (FT3) was 1.86 pg/mL (reference range, 1.71–3.71 pg/mL); free thyroxine (FT4) was 1.59 ng/dL (reference range, 0.70–1.48 ng/dL); antidiuretic hormone (ADH) was 1.3 pg/mL (reference range, 0.3–4.2 pg/mL). These endocrinological results were consistent with dehydration probably caused by Preminent.

On the basis of his medical history and laboratory results, we suspected Preminent-induced hyponatremia and hyponatremia-induced rhabdomyolysis.⁹ We discontinued Preminent treatment and administered saline. Thereafter, his hyponatremia, FENa, and rhabdomyolysis improved. Consistent with these improvements, his muscle weakness, lumbago, and pain in the lower limbs improved; therefore, these symptoms were considered to have been induced by hyponatremia and rhabdomyolysis. The patient could eventually stand and walk without support. As for the cause of the hyponatremia, not only Preminent but also the patient’s renal failure might be related to the hyponatremia, because the tubulointerstitial dysfunction deteriorates sodium resorption.

Discussion

Here, we summarized the data of 40 patients with hyponatremia induced by Preminent (Table 1). Clinical practitioners might have better to pay attention to (a) elderly women, (b) especially within 50 days but also after fever or appetite loss. Also, clinical practitioners may take into account (c) severity, (d) early recovery, (e) final recovery, and (f) clinical outcome. In addition, we summarized other adverse effects of Preminent (Table 2) and the same adverse effects of other three ARB/thiazide combinations (Table 2). Further, we presented a case report of severe hyponatremia and hyponatremia-induced rhabdomyolysis.

Losartan potassium/hydrochlorothiazide (Preminent) and hyponatremia

Because losartan potassium is an ARB, it can theoretically cause hyponatremia. However, no reports on the occurrence of losartan potassium-induced hyponatremia are available in literature on PubMed. Moreover, no reports on hyponatremia induced by other ARBs such as varsaltan, candesartan, and telmisartan are available on PubMed. Thus, ARBs may not usually cause hyponatremia.

However, hydrochlorothiazide-induced hyponatremia has been well investigated. Hydrochlorothiazide inhibits the Na/Cl pump in the distal tubule, thereby increasing sodium excretion:¹⁰ A single administration of hydrochlorothiazide can cause hyponatremia.¹¹ These reports indicate that losartan potassium/hydrochlorothiazide can theoretically cause hyponatremia. However, to the best of our knowledge, losartan potassium/hydrochlorothiazide-induced hyponatremia has not been described in literature on PubMed, and therefore the clinical course has not been described. Since most patients in PMDA adverse effects reports are probably Japanese, Japanese might be more susceptible to losartan potassium/hydrochlorothiazide-induced hyponatremia.

Other adverse effects and the same adverse effects of ARB/hydrochlorothiazide combinations

On the basis of the result of other adverse effects of Preminent (Table 2) and the same adverse effects of other three ARB/thiazide combinations (Table 2), clinical practitioners might have better to pay attention to other adverse effects. In particular, as for Preminent, the number of patients who experience hyperesthesia dermatitis was equivalent to the number of patients who experience hyponatremia. However, as for other three ARB/thiazide combinations, hyperesthesia dermatitis was not reported as an adverse effect. The interaction between losartan and hydrochlorothiazide might increase the occurrence of hyperesthesia dermatitis. Since no patient exhibit hyponatremia and hyperesthesia dermatitis at the same time as adverse effects of Preminent, the underling mechanisms of hyponatremia and hyperesthesia dermatitis may be different.

In the four abovementioned ARB/thiazide combinations, the ARBs are different, whereas hydrochlorothiazide is the common component. According to the PMDA database, the adverse effects of hydrochlorothiazide (Dichlotride®; Banyu Pharmaceutical Co. Ltd., Tokyo, Japan)¹² are similar to those of ARB/hydrochlorothiazide combinations. Therefore, we infer that the adverse effects of ARB/hydrochlorothiazide combinations are mainly caused by hydrochlorothiazide and not ARBs.

According to the standard textbook of internal medicine, the usual dose of hydrochlorothiazide is 6.25–50 mg/day.¹⁰ However, higher doses are not recommended because of the associated increased adverse effects.¹⁰ Therefore, we infer that Co-Dio with 6.25 mg of hydrochlorothiazide, Ecard, and Micombi, all of which contain 6.25 mg of hydrochlorothiazide, might be safer than Preminent, which contains 12.5 mg of hydrochlorothiazide. Additional studies are required to analyze the relationship between ARB/thiazide combinations and adverse effects with regard to the dose of hydrochlorothiazide.

The limitation of the present study is described below.

This study only summarized the data from existing reports on adverse drug effects: The study design of the present report is case series. Therefore, it does not provide information regarding the incidence rate of ARB/hydrochlorothiazide-induced hyponatremia and other adverse effects; therefore, the effects of differences in sex, age, and the each ARB/hydrochlorothiazide combinations on hyponatremia and other adverse effects susceptibility are unavailable. However, it was reported that elderly people and women are susceptible to hydrochlorothiazide-induced hyponatremia,¹³ and many of the patients in the present study were elderly women; clinical practitioners might have to pay better attention to results in the present study. Further studies such as cohort studies are needed to determine the incidence rate of ARB/hydrochlorothiazide combinations-induced adverse effects.

Footnotes

Acknowledgements

We thank the PMDA for providing the reports on the adverse drug effects.

This research received no specific grant from any funding agency in the public, commercial, or not for-profit sectors.

We have no conflicts of interest to declare.

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