J Clin Med Res

Journal of Clinical Medicine Research, ISSN 1918-3003 print, 1918-3011 online, Open Access

Article copyright, the authors; Journal compilation copyright, J Clin Med Res and Elmer Press Inc

Journal website https://www.jocmr.org

Original Article

Volume 13, Number 2, February 2021, pages 92-100

Clinical Practice Changes After Post-Market Safety Reports on Desmopressin Orally Disintegrating Tablet in Japan: A Single-Center Retrospective Study

Figure 1. Type of desmopressin according to the date starting treatment for CDI. The percentage of patients who received desmopressin ODT as initial desmopressin therapy was continuously increased. The numbers of patients who started each therapy are indicated in the column (black: patients who started treatment with desmopressin ODT; gray: patients who started treatment with desmopressin spray; white: patients who started treatment with desmopressin nasal drop). CDI: central diabetes insipidus; ODT: orally disintegrating tablet.

Figure 2. Comparison of dose ratios of oral to intranasal desmopressin between patients switching before October 2014 and those switching after November 2014. (a) The ratios of oral to intranasal desmopressin dose. Patients were divided into two groups; patients switching from intranasal desmopressin to desmopressin ODT before October 2014 (gray line) and patients switching after November 2014 (black line). More gradual titration but increased final dose is shown in patients switching after November 2014 (dose ratio: the ratio of oral to nasal desmopressin dose; error bar: standard error). (b) The relative dose per initial oral desmopressin dose. The relative doses 9 and 12 months after switching from intranasal desmopressin to ODT were significantly higher in patients switching after November 2014 (gray bar: patients switching from intranasal desmopressin to desmopressin ODT from April 2012 to October 2014; black bar: patients switching from intranasal desmopressin to desmopressin ODT from November 2014 to March 2019; error bar: standard error; *P < 0.05). (c) The increment of desmopressin ODT dose from initiation. The increments 9 and 12 months after switching from intranasal desmopressin to ODT were significantly higher in patients switching after November 2014 (gray bar: patients switching from intranasal desmopressin to desmopressin ODT from April 2012 to October 2014; black bar: patients switching from intranasal desmopressin to desmopressin ODT from November 2014 to March 2019; error bar: standard error; *P < 0.05). ODT: orally disintegrating tablet.

**Table 1.** Characteristics of CDI Patients Who Switched From Intranasal Desmopressin to Desmopressin ODT
	All patients	Patients switching before October 2014	Patients switching after November 2014	P value
The numbers of patients treated with replacement therapy of anterior pituitary hormones are indicated in parentheses. CDI: central diabetes insipidus; ODT: orally disintegrating tablet; GH: growth hormone; TSH: thyroid-stimulating hormone; ACTH: adrenocorticotropic hormone; LH: luteinizing hormone; FSH: follicle-stimulating hormone.
Number of patients (male/female)	50	34	16
Male/female	20/30	12/22	8/8	0.32
Age (years)	51.2 ± 2.8	50.9 ± 3.5	51.9 ± 5.0	0.88
Blood pressure (systolic/diastolic) (mm Hg)	117.8 ± 3.0/71.4 ± 2.2	117.0 ± 3.6/70.9 ± 2.8	119.5 ± 5.3/72.8 ± 3.6	0.69/0.74
Body mass index (kg/m²)	24.6 ± 0.7	24.7 ± 0.98	24.6 ± 1.12	0.55
Smoking (never/ex/current) (%)	68.0/16.0/16.0	64.7/17.7/17.7	75.0/12.5/12.5	0.77
Urine volume (mL/day)	2,304 ± 282	2,140 ± 266	2,693 ± 732	0.71
Etiology
Craniopharyngioma	15	11	4	0.43
Rathke cleft cyst	7	4	3	0.86
Inflammation	7	4	3	0.86
Germ cell tumor of CNS	7	4	3	0.86
Idiopathic	3	3	0	0.31
Sarcoidosis	3	3	0	0.31
Pituitary adenoma	3	1	2	0.24
Langerhans cell histiocytosis	2	2	0	0.46
Eosinophilic granulomatosis	1	1	0	0.68
Cerebral apoplexy due to subarachnoid hemorrhage	1	1	0	0.68
Empty sella	1	0	1	0.32
Anterior pituitary deficiency	41 (28)	27 (17)	14 (11)	0.49 (0.21)
GH	27 (7)	18 (5)	8 (2)	0.85 (0.60)
TSH	34 (24)	20 (12)	14 (12)	0.04 (0.01)
ACTH	31 (23)	19 (13)	12 (10)	0.19 (0.11)
LH	32 (5)	20 (3)	12 (2)	0.27 (0.82)
FSH	25 (5)	16 (3)	9 (2)	0.54 (0.82)
Serum sodium < 135 mEq/L	14 (28.0%)	9 (26.5%)	5 (31.3%)	0.75
Serum sodium < 130 mEq/L	6 (12.0%)	4 (11.8%)	2 (12.5%)	0.94

Table 1. Characteristics of CDI Patients Who Switched From Intranasal Desmopressin to Desmopressin ODT

All patients

Patients switching before October 2014

Patients switching after November 2014

P value

The numbers of patients treated with replacement therapy of anterior pituitary hormones are indicated in parentheses. CDI: central diabetes insipidus; ODT: orally disintegrating tablet; GH: growth hormone; TSH: thyroid-stimulating hormone; ACTH: adrenocorticotropic hormone; LH: luteinizing hormone; FSH: follicle-stimulating hormone.

Number of patients (male/female)

Male/female

20/30

12/22

8/8

0.32

Age (years)

51.2 ± 2.8

50.9 ± 3.5

51.9 ± 5.0

0.88

Blood pressure (systolic/diastolic) (mm Hg)

117.8 ± 3.0/71.4 ± 2.2

117.0 ± 3.6/70.9 ± 2.8

119.5 ± 5.3/72.8 ± 3.6

0.69/0.74

Body mass index (kg/m²)

24.6 ± 0.7

24.7 ± 0.98

24.6 ± 1.12

0.55

Smoking (never/ex/current) (%)

68.0/16.0/16.0

64.7/17.7/17.7

75.0/12.5/12.5

0.77

Urine volume (mL/day)

2,304 ± 282

2,140 ± 266

2,693 ± 732

0.71

Etiology

Craniopharyngioma

0.43

Rathke cleft cyst

0.86

Inflammation

0.86

Germ cell tumor of CNS

0.86

Idiopathic

0.31

Sarcoidosis

0.31

Pituitary adenoma

0.24

Langerhans cell histiocytosis

0.46

Eosinophilic granulomatosis

0.68

Cerebral apoplexy due to subarachnoid hemorrhage

0.68

Empty sella

0.32

Anterior pituitary deficiency

41 (28)

27 (17)

14 (11)

0.49 (0.21)

27 (7)

18 (5)

8 (2)

0.85 (0.60)

TSH

34 (24)

20 (12)

14 (12)

0.04 (0.01)

ACTH

31 (23)

19 (13)

12 (10)

0.19 (0.11)

32 (5)

20 (3)

12 (2)

0.27 (0.82)

FSH

25 (5)

16 (3)

9 (2)

0.54 (0.82)

Serum sodium < 135 mEq/L

14 (28.0%)

9 (26.5%)

5 (31.3%)

0.75

Serum sodium < 130 mEq/L

6 (12.0%)

4 (11.8%)

2 (12.5%)

0.94

**Table 2.** The Comparison Between Patients With and Without Hyponatremia in the Early Phase
	Na ≥ 135 mEq/L (n = 36)	Na < 135 mEq/L (n = 14)	Na < 130 mEq/L (n = 6)	P value
The left value of P value indicates the comparison between Na ≥ 135 mEq/L and Na < 135 mEq/L. The right value of P value indicates the comparison between Na ≥ 135 mEq/L and Na < 130 mEq/L. The model comparison of ODT/intranasal dose ratio after adjusting age between Na ≥ 135 mEq/L and Na < 135 mEq/L was not established. GH: growth hormone; TSH: thyroid-stimulating hormone; ACTH: adrenocorticotropic hormone; LH: luteinizing hormone; FSH: follicle-stimulating hormone; ODT: orally disintegrating tablet.
Age (years)	49.1 ± 3.1	56.6 ± 6.1	56.8 ± 9.7	0.23/0.37
Male/female	14/22	6/8	3/3	0.80/0.67
Anterior pituitary deficiency	28 (77.8%)	13 (92.9%)	5 (83.3%)	0.21/0.76
GH	17 (47.2%)	10 (71.4%)	4 (66.7%)	0.12/0.38
TSH	23 (63.9%)	11 (78.6%)	5 (83.3%)	0.32/0.35
ACTH	22 (61.1%)	9 (64.3%)	4 (66.7%)	0.84/0.80
LH	20 (55.6%)	12 (85.7%)	5 (83.3%)	0.04/0.20
FSH	16 (44.4%)	9 (64.3%)	3 (50.0%)	0.21/0.80
Intranasal desmopressin (µg)	6.34 ± 0.57	7.14 ± 1.13	5.21 ± 1.14	0.52/0.53
Desmopressin ODT (µg)	130.6 ± 10.0	169.3 ± 46.6	215.0 ± 108.6	0.99/0.72
ODT/intranasal dose ratio	20.7 ± 1.3	27.3 ± 5.6	37.0 ± 11.0	0.99/0.28
ODT/intranasal dose ratio after adjusting age	-	-	-	-/0.02

Table 2. The Comparison Between Patients With and Without Hyponatremia in the Early Phase

Na ≥ 135 mEq/L (n = 36)

Na < 135 mEq/L (n = 14)

Na < 130 mEq/L (n = 6)

P value

The left value of P value indicates the comparison between Na ≥ 135 mEq/L and Na < 135 mEq/L. The right value of P value indicates the comparison between Na ≥ 135 mEq/L and Na < 130 mEq/L. The model comparison of ODT/intranasal dose ratio after adjusting age between Na ≥ 135 mEq/L and Na < 135 mEq/L was not established. GH: growth hormone; TSH: thyroid-stimulating hormone; ACTH: adrenocorticotropic hormone; LH: luteinizing hormone; FSH: follicle-stimulating hormone; ODT: orally disintegrating tablet.

Age (years)

49.1 ± 3.1

56.6 ± 6.1

56.8 ± 9.7

0.23/0.37

Male/female

14/22

6/8

3/3

0.80/0.67

Anterior pituitary deficiency

28 (77.8%)

13 (92.9%)

5 (83.3%)

0.21/0.76

17 (47.2%)

10 (71.4%)

4 (66.7%)

0.12/0.38

TSH

23 (63.9%)

11 (78.6%)

5 (83.3%)

0.32/0.35

ACTH

22 (61.1%)

9 (64.3%)

4 (66.7%)

0.84/0.80

20 (55.6%)

12 (85.7%)

5 (83.3%)

0.04/0.20

FSH

16 (44.4%)

9 (64.3%)

3 (50.0%)

0.21/0.80

Intranasal desmopressin (µg)

6.34 ± 0.57

7.14 ± 1.13

5.21 ± 1.14

0.52/0.53

Desmopressin ODT (µg)

130.6 ± 10.0

169.3 ± 46.6

215.0 ± 108.6

0.99/0.72

ODT/intranasal dose ratio

20.7 ± 1.3

27.3 ± 5.6

37.0 ± 11.0

0.99/0.28

ODT/intranasal dose ratio after adjusting age

-/0.02

**Table 3.** Characteristics of the Patients With Serum Sodium Levels Below 130 mEq/L
No	Age (yrs)	Sex	Etiology	AP	Nasal device	Nasal dose (µg)	ODT dose (µg)	Dose ratio	Date	Duration (month)	Na (mEq/L)	Serum osmolality (mOsm/kg)
M: male; F: female; yrs: years old; AP: anterior pituitary dysfunction; G: GH; T: TSH; L: LH; FS: FSH; A: ACTH; D: drop; S: spray; ODT: orally disintegrating tablet; Dose ratio: the ratio of ODT to nasal desmopressin dose; Date: the date of switching to desmopressin ODT; Before: before October 2014; After: after November 2014; Duration: the duration to take desmopressin ODT; Na: the lowest serum sodium level; N/A: not available. GH: growth hormone; TSH: thyroid-stimulating hormone; ACTH: adrenocorticotropic hormone; LH: luteinizing hormone; FSH: follicle-stimulating hormone; ODT: orally disintegrating tablet.
1	85	F	Rathke cleft cyst	(-)	D	1.25	60	48	Before	1	129	259
2	50	M	Craniopharyngioma	G, T, L, FS	D	10	720	72	Before	26	126	264
3	81	M	Sarcoidosis	G, T, L, A	S	5	30	6	Before	8	124	258
4	30	F	Craniopharyngioma	G, T, L, A	S	5	300	60	Before	0	128	N/A
5	63	M	Craniopharyngioma	T, L, A	S	5	120	24	After	0	123	272
6	32	F	Craniopharyngioma	G, T, L, FS, A	D	5	60	12	After	1	127	N/A

Table 3. Characteristics of the Patients With Serum Sodium Levels Below 130 mEq/L

Age (yrs)

Sex

Etiology

Nasal device

Nasal dose (µg)

ODT dose (µg)

Dose ratio

Date

Duration (month)

Na (mEq/L)

Serum osmolality (mOsm/kg)

M: male; F: female; yrs: years old; AP: anterior pituitary dysfunction; G: GH; T: TSH; L: LH; FS: FSH; A: ACTH; D: drop; S: spray; ODT: orally disintegrating tablet; Dose ratio: the ratio of ODT to nasal desmopressin dose; Date: the date of switching to desmopressin ODT; Before: before October 2014; After: after November 2014; Duration: the duration to take desmopressin ODT; Na: the lowest serum sodium level; N/A: not available. GH: growth hormone; TSH: thyroid-stimulating hormone; ACTH: adrenocorticotropic hormone; LH: luteinizing hormone; FSH: follicle-stimulating hormone; ODT: orally disintegrating tablet.

Rathke cleft cyst

(-)

1.25

Before

129

259

Craniopharyngioma

G, T, L, FS

720

Before

126

264

Sarcoidosis

G, T, L, A

Before

124

258

Craniopharyngioma

G, T, L, A

300

Before

128

N/A

Craniopharyngioma

T, L, A

120

After

123

272

Craniopharyngioma

G, T, L, FS, A

After

127

N/A