Diosmin

Exposure related observations in humans: other data

Administrative data

Endpoint:

exposure-related observations in humans: other data

Type of information:

experimental study

Adequacy of study:

supporting study

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

study well documented, meets generally accepted scientific principles, acceptable for assessment

Data source

Reference

Reference Type:

publication

Title:

Unnamed

Year:

1997

Report date:

1997

Materials and methods

Type of study / information:

Human data: Open study on hospital outpatients. The aim of the study was to assess the safety, efficacy and acceptability of a micronized flavonoid formulation in the treatment of internal hemorrhoids of pregnancy.

Endpoint addressed:

repeated dose toxicity: oral

developmental toxicity / teratogenicity

Test guideline

Qualifier:

no guideline followed

Principles of method if other than guideline:

- Principle of test: An open study was performed on hospital outpatients. 50 women with acute hemorrhoids were treated with micronized diosmin 90% and hesperidin 10% for a median of 12 weeks (8 weeks before delivery and 4 weeks after delivery).
- Parameters analysed / observed: The outcome measures were symptoms and signs of hemorrhoids; adverse effects and acceptability of treatment.

GLP compliance:

no

Test material

Test material information

Constituent 1

Reference substance name:

Diosmin

EC Number:

208-289-7

EC Name:

Diosmin

Cas Number:

520-27-4

Molecular formula:

C28H32O15

IUPAC Name:

diosmin

Constituent 2

Reference substance name:

Hesperidin

EC Number:

208-288-1

EC Name:

Hesperidin

Cas Number:

520-26-3

IUPAC Name:

5-hydroxy-2-(3-hydroxy-4-methoxyphenyl)-4-oxo-3,4-dihydro-2H-chromen-7-yl 6-O-(6-deoxy-alpha-L-mannopyranosyl)-beta-D-glucopyranoside

Test material form:

solid

Specific details on test material used for the study:

SOURCE OF TEST MATERIAL
- Source: Serdia Pharmaceuticals (India) Ltd.
- Purity: 90% micronized diosmin in flavonoid therapy, each tablet containing 450 mg diosmin and 50 mg hesperidin (10%).

Method

Ethical approval:

confirmed and informed consent free of coercion received

Details on study design:

The treatment was divided into 3 phases:
1. to assess acute response, a loading dose was given for 7 days: 6 tablets for 4 days and 4 tablets per day for 3 days, in a divided dose after lunch and dinner.
2. to assess relapse in the antenatal period, a maintenance dose was given up to delivery day and 30 days thereafter: 2 tablets per day in a divided dose.
3. to assess relapse in the post-natal period: 2 tablets per day in a divided dose.

Exposure assessment:

estimated

Details on exposure:

TYPE OF EXPOSURE: oral administration.

EXPOSURE LEVELS: in the first phase, 675 mg of diosmin per day for 4 days, and then 1800 mg of diosmin for 3 days; 900 mg of diosmin per day thereafter.

EXPOSURE PERIOD: 12 weeks

DESCRIPTION / DELINEATION OF EXPOSURE GROUPS / CATEGORIES: Patients with amenorrhea of more than 28 weeks, with a history of acute hemorrhoids; age above 18 years; and visibly distended or displaced anal cushion on proctoscopy, in association with at least one symptom of bleeding, pain, anal exudation, or anal discomfort of not more than 7 days duration; and without inflammatory and infectious disease of the digestive tract, or colorectal cancer; previous laser treatment or use of phlebotonic drug for hemorrhoids 1 week prior to inclusion; use of steroidal or non-steroidal anti-inflammatory drugs, analgesics, topical anti-hemorrhoidal treatment, anticoagulants, and antiplatelet agents; or need for a surgical procedure for hemorrhoids, were eligible for the study. See table 1 in 'any other information on materials and methods'.

OBSERVATIONS: At the start of the study, a detailed history of hemorrhoids was obtained, and a clinical, proctoscopic, and abdominal ultrasonographic examination was performed. Venous blood was drawn for hematologic and biochemical tests.
On the 8th, 30th and 60th day of the antenatal period, and on the 1st and 30th day after delivery, the reassessment of the patients included a history of acute hemorrhoids, a clinical and proctoscopic examination and monitoring of side effects by asking open ended questions to identify any problems that had occurred since the previous visit. Severity of acute symptoms was self-assessed by patients on a scale (0, absent; 1, mild; 2, moderate; and 3, severe), and the traditional classification (lst-4th degree) was used to grade the internal hemorrhoids. Ultrasonography was repeated on the 30th and 60th assessment day of the antenatal period. The infant was examined on the 1st and 30th day after delivery, and maternal venous blood collected for biochemical tests at the end of the study.

Statistics:
Change in categorical data was tested by the Chi-squared test, and continuous variables by the Wilcoxon signed rank test, Mann-Whitney test, and the standard error of difference in means. Significance was defined as a two-tailed P-value of less than 0.05.

Results and discussion

Results:

- Side effects, nausea and diarrhea, not leading to withdrawal occurred in five patients (four in the loading treatment phase and one in the maintenance phase).
- Hemodynamic and biochemical variables showed no significant change with treatment during pregnancy and were normal at the end of the study.
- Effect of treatment on the fetus, placenta, and infant: No ultrasonographic fetal abnormality was detected during the study. One intrauterine death occurred but it was not treatment-related. At delivery, gross placental insufficiency was detected in six (13.6%) patients. The median maturity of the infant at birth was 39 weeks, and weight 2.9 kg (95% confidence interval, range 2.7-3.1). At the end of post-partum treatment, 38 (97.4%) infants were breast fed or supplemented artificially, and the median weight gain was 1 kg (95% confidence interval, range 0.6-1.2, P < 0.001).

Any other information on results incl. tables

Table 2. Response of maternal hemodynamic, clinical, and biochemical characteristics.

Characteristic	Antenatal treatment			Post-natal Day 30
	Day 7	Day 30	Day 60
Mean ± SD	N = 50	N = 47	N = 24	N = 41
-         Pulse rate (bpm)	81.5 ± 7.5	81.8 ± 9.0	80.8 ± 6.6	81.1 ± 6.0
-         Blood pressure (mmHg)
o   Systolic	112.4 ± 10.9	112 ± 10.4	112.6 ± 10.2	110.9 ± 6.4
o   Diastolic	73.2 ± 8.0	74.0 ± 7.8	73.0 ± 7.2	72.1 ± 5.6
-         Weight (kg)	57.3 ± 12.2	-	-	52.8 ± 9.5
-         SGOT (IU/L)	34.5 ± 34.5	-	-	36.2 ± 49.5
-         SGPT (IU/L)	33.4 ± 34.2	-	-	25.2 ± 8.6
-         S. bilirubin (mg%)	1.0 ± 2.6	-	-	0.6 ± 0.2
-         S. creatinine (mg%)	1.1 ± 3.1	-	-	0.7 ± 0.4
Number (%) with
-         Urine protein	5 (10)	-	-	1 (2.4)
-         Urine sugar	1 (2)	-	-	1 (2.4)

Table 3. Response of fetal, placental and infant characteristics to treatment. 

Characteristic
Fetal development	N = 44
Number (%) with
-         Normal antenatal ultrasound scan during treatment.	44 (100)
-         Congenital malformations*	1 (2.3)
-         Intrauterine death**	1 (2.3)
Placental	N = 44
Number (%) with
-         Gross placental insufficiency	6 (13.6)
-         Normal amniotic fluid	29 (66.9)
Infant	N = 39 ***
Median (95% CL)
-         Maturity (weeks)	39 (39-40)
-         Birth weight (kg)	2.9 (2.7-3.1)
-         Weight at 30^thpost-partum day (kg)	3.9 (3.5-4.1)
Number (%)
-         Breast fed	21 (53.9)
-         Artificial feeding	1 (2.3)
-         Mixed feeding	17 (43.6)

*Single umbilical artery. **True knot in cord and cord around the neck. ***One infant died due to a fall on the 27^thpost-partum day and could not be assessed at the end of the study.

Applicant's summary and conclusion

Conclusions:

The treatment with the test item was well accepted and did not affect pregnancy, fetal development, birth weight, infant growth and feeding.

Executive summary:

An open study on hospital outpatients was performed to assess the safety, efficacy and acceptability of a micronized flavonoid formulation (90% diosmin) in the treatment of internal hemorrhoids of pregnancy. 50 pregnant women with acute hemorrhoids were given the test item orally for a median of 12 weeks (8 weeks before delivery and 4 weeks after delivery) and observed for adverse effects and acceptability of treatment. The treatment was divided into 3 phases: a 7 day loading phase, in which the patients were given 6 tablets for 4 days (ca. 675 mg diosmin per day) and 4 tablets per day for 3 days (ca. 1800 mg diosmin per day), in a divided dose after lunch and dinner; an antenatal phase, and a post-natal phase, in both of which the patients were given 2 tablets per day (ca. 900 mg diosmin per day) in a divided dose after lunch and dinner. Under the conditions of the study, no adverse effects were observed on pregnancy, fetal development, birth weight, infant growth or feeding.