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Title : Role of micronised Diosmin in DUB & puberty

menorrhagia
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 Role of
MICRONISED DIOSMIN
in
Dysfunctional Uterine Bleeding &
Puberty Menorrhagia

Brought to You by
 Talking Points

Introduction of Venous Disease

Abnormal Uterine Bleeding (AUB)
Dysfunctional uterine bleeding
Puberty Menorrhagia (Anovulatory menorrhagia)
What is Micronized Diosmin?
Role of Diosmin in AUB (DUB, Puberty menorrhagia,
etc.)
Diosmin – Safety Data
Clinical Efficacy Data of Diosmin in DUB
Conclusion
 Introduction of Venous Disease

► Manifestations of venous disease are routinely seen in

daily practice.
► Some key manifestations are Venous congestion -
Dysfunctional Uterine Bleeding (DUB), Chronic Venous
Insufficiency, and Haemorrhoids
► DUB, CVI and Haemorrhoids are quite prevalent in
India
► This presentation focuses on therapeutic approach to
venous disease particularly with respect to Micronised
Diosmin.
 Abnormal Uterine Bleeding (AUB)

AUB is menstrual bleeding that is abnormal in volume,

pattern and/or timing with or without identifiable factors
Blood loss > 80ml/month and/or for > 7 days
Reasons:
Organic causes (PALM)
DUB : No organic cause found (COEIN)
Disturbed local hemostasis (AUB-Coagulopathy)
Estrogen – progesterone imbalance (AUB-Ovulatory)
Altered prostaglandin synthesis (AUB-Endometrial)
Endocrine abnormality (AUB-Iatrogenic)
 PALM-COEIN Classification of AUB

FIGO Menstrual Disorders Group (FMDG) Stratified into 9

basic categories acc. to the acronym
FIGO Working Group on Menstrual Disorders. Int J Gynaecol Obstet. 2011
Apr;113(1):3-13
 Prevalence-Abnormal Uterine Bleeding (AUB)
Very common gynecological problem:1
15% OPD visits
25% of gynecological surgeries
Incidence of AUB:2
20-30% women in reproductive age
AUB in 46% of all hysterectomies in U.K. – Nearly half of the
hysterectomies performed on women complained of DUB

Almost a quarter of population in developing countries comprises girls below

20 years.3
In India:
40% population are below 15 years age
Menstrual disorder affects about 75% adolescent females (Pubertal
Menorrhagia)
1. Goodman AA. Clin Cornerstone 2000;3(1):25-35
2. The VALUE national hysterectomy study, BJOG. 2002 Mar;109(3):302-12
3. Krishna et al. Adolescent and paediatric gynaecological problems. In:Obstetrics & Gynaecology for
 Dysfunctional Uterine Bleeding

► DUB is a poorly understood, common gynaecological condition,

defined as excessively heavy, prolonged or frequent bleeding of
uterine origin, not due to pregnancy, pelvic or generalized medical
disease.
► It is a diagnosis by exclusion.
► Most common menstrual disorder.
► Often the 1 st clinical diagnosis for any excessive menstrual bleeding
► DUB is classified into
- Anovulatory DUB – 20% of cases. Seen in adolescents (Pubertal
menorrhagia) and perimenopausal women.
- Ovulatory DUB – 80% of cases. Seen in mid-reproductive years.
Pathophysiology : Hormone Theory

ANOVULATORY

MENARCHE (ADOLESCENT)
Defect in the feedback response to estrogen;
delay in the maturity of hypothalamic
control.

PERIMENOPAUSAL

Dynamics of estrogen are disturbed leading

to fluctuation in plasma levels. Defect in
hypothalamo-pituitary & intra-ovarian mechanisms.

OVULATORY

MID-REPRODUCTIVE YEARS
Plasma LH, FSH, estrogen and progesterone
levels & secretory endometrium are
indistinguishable from natural menstruation.
Local function abnormality exists.
 Prostaglandin theory
► Endometrial PG release is greatly influenced by
circulating steroid levels
PGE2, PGI2 Vasodilatation
PGF2α Vasoconstriction
► Smith and his colleagues (1982) have demonstrated
that persistent proliferative endometrium (Anovulatory
DUB) lacks endogenous stores of PG precursor,
arachidonic acid
Deficiency of PGs such as PGF 2α

Excessive blood loss & painless bleeding periods

Cont…

► Smith et al. 1981 have demonstrated that

endometria from women with unexplained
menorrhagia (Ovulatory DUB) produced more
PGE2 than PGF 2α
PGF2α / PGE 2 ratio

Excessive blood loss

► Also, PGI2 having potent vasodilator and anti-
aggregatory properties is increased in women
with ovulatory DUB
 Mechanisms of Bleeding

APART FROM HORMONAL and PGs IMBALANCE

► Disturbance in capillary permeability is a consequence of
imbalance in hormone effect in luteal phase. (Meyer 1992)
► Lymphatic drainage is underdeveloped in human endometrium.
Increased bleeding causes accumulation of debris and tissue
products which lymphatic drainage is unable to cope. (JAMA 1947 )

“ Local functional abnormality exists within the uterus or some unidentified

circulating substance exacerbates menstrual bleeding ” (Shearman, 1985)
 Symptoms & complications of DUB

Symptoms of DUB
● Changes in Menstrual cycle
● Breast tenderness
● Cyclic changes in the basal body temperature with ovulation
(not in anovulatory DUB)
● Sometimes dysmenorrhoea
● Hot flashes
● Mood swings
● Fatigue due too much blood loss
► Complications of DUB*
● Infertility
● Anaemia *Amir et el, emedicine, 2010
 Diagnosis of DUB
DUB is a diagnosis of exclusion.
After taking detailed menstrual as well as medical history of
the patient a thorough physical examination should be
performed to rule out mechanical causes (IUCD insertion etc.).
Depending on the results of history and physical examination
various tests are performed to evaluate the presence of other
causes.
The various tests performed are:
1. Hormone levels:
• Rule out endocrine causes such as PCOD, Hypo/
Hperthyroidism, etc.
• Progesterone levels to determine type of DUB
2. Wet Mounts: Rule out infections such as PID, Endometritis, etc.
3. Urine Pregnancy: To exclude pregnancy related abnormal
bleeding
4. Pap Test, endometrial sampling and transvaginal
Amir et el,sampling:
emedicine, 2010
 Management of DUB
Individualized according to the severity, pattern and duration
of bleeding, age and fertility desire of the patient.
► Mild Cases: * Reassurance
* Iron and vitamin supplementation
* Maintenance of Menstrual calendar and Basal
body
temperature chart to give an idea of the
ovulatory status
* Periodic re-evaluation
Medical:
Non hormonal
Hormonal

Surgical:
Minimally invasive
Radical
 MEDICAL MANAGEMENT

NON-HORMONAL HORMONAL
• PG synth inhibitors Progestogens
• Antifibrinolytics Oral (Norethisterone)
- Tranexamic acid Injectable: DMPA
LNG-IUS: Mirena
• Ethamsylate
Estrogen+progesterone OCP
• Diosmin
Danazol
• Ormeloxifene
GnRH analogues
• Mifepristone Testosterone
 Medical Management Options of DUB
Primary Management Options:

Diosmin

Norethisterone from days 5 to 26, or injected

long- acting progestogens

LNG-IUS provided >12 months use anticipated

Tranexamic acid or NSAIDs or

Combined oral contraceptives (COCP)

Estrogen therapy for acute & recurrent cases

NSAIDs &/or Tranexamic acid till beneficial

When any of primary drug fails, try another before surgery

Hysterectomy has its own place in AUB M/T.

Treatment on the basis of Endometrial
Thickness
Bleeding > 8 days

Endometrial Thickness

< 6 mm 6-11 mm > 11 mm

COCs Estradiol + Megesterol

Progesterone (after Bx)

Bleedin COCs Estradiol + Megesterol

g Progesterone
Score
Baseline 46 41 54
AfterMuneyyirci-Delale
T/ 8 9 3
O et al. Int J Womens Health. 2010 Sep 1;2:297-302.
 Hysterectomy in DUB
To
ADVANTAGES:
One time procedure
Total amenorrhoea do…
DISADVANTAGES:
Mortality 1 : 6 per 10,000
Morbidity2 :42.8 per 100
OR
LONG TERM EFFECTS:
Premature ovarian failure
Not
to
CV disease
Psychosexual dysfunction
1. Wingo et al. Am J Obstet Gynecol. 1985 Aug 1;152(7 Pt 1):803-8
 SAVE THE UTERUS

Is Hysterectomy the Radical Mastectomy of

Gynaecology??

“Both hysterectomy for HMB & radical mastectomy for

breast cancer steeped in history of surgery & have recently
been challenged as being too radical” thus women should be
empowered to choose from options available and hence
medical intervention should be encouraged.

Munro MG. Clin Obstet Gynecol. 2007 Jun;50(2):324-53.

 Puberty Menorrhagia

► Puberty menorrhagia is defined as excessive bleeding of

>80ml for >7days, between menarche & 19 yrs of age.1,2
► Due to immature hypothalamic pituitary-ovarian (HPO)
axis. It is an anovulatory cycle.
► The complete maturation of the axis may take up to two
years.1
► Without ovulation oestrogen effect is unopposed by
endogenous progesterone resulting in endometrial
proliferation, with eventual excessive menstrual bleeding.
1. Rao et al. Medical intervention in puberty menorrhagia. Bombay Hospital Journal 2004;46(2)
2. Gillani et al. Puberty Menorrhagia: causes and management. J. Med. Sci. 2012;20(1):15-18
 Puberty menorrhagia - Etiology & Management
Principles
Etiology: Factors determining Treatment objective: Assessment: Assess the
Major the choice of treatment severity
✔ Immature ✔ Early control of ✔ Hb %,
hypothalamo- ✔ Age excessive bleeding✔ Hematocrit
pituitary axis ✔ Parity ✔ Normalizing ✔ Menstrual history (last
✔ Excess/ ✔ Histopathologicalchan cyclical rhythms menstrual period,
unopposed ges in Endometrium ✔ Prevention of frequency, duration, flow,
oestrogen ✔ Need for recurrence pain)
✔ Absent contraception
progesterone in ✔ Availability of Categorized as
anovulatory cycles treatment option ✔ Mild (Hb >10g%)
Minor ✔ Moderate (Hb = 8 to
✔ Coagulation 10g%)
disorders ✔ Severe (Hb < 5g%)
✔ Blood dyscrasias
✔ Hypothyroidism
 Puberty Menorrhagia-Management
Mild pubertal Moderate pubertal Severe pubertal menorrhagia
menorrhagia menorrhagia ✔ Admission of the patient
✔ Reassurance ✔ High dose progestogen ✔ Blood Transfusion
✔ Maintenance of st
Norethisterone acetate 1 Rule out
menstrual calendar, 48hrs 5 -10 mg tds ✔ Hypothyroidism
pictorial bleeding ✔ Next 2 weeks 5 -10mg bd ✔ Thyroid profile
assessment chart & ✔ Next 1 week 5-10mg od ✔ Bleeding diathesis
assessment of ✔ Then stop norethisterone & ✔ FBC, platelet count, bleeding time, PTT,vwf antigen
menstrual blood loss continue with Venusmin To Achieve Haemostasis
✔ Venusmin (900 mg (900 mg in divided doses) ✔ High dose progestogen: Norethisterone acetate 1 st
in divided doses) Progestogen 48hrs 5 -10mg tds
✔ Iron & Vitamin Cyclical/Luteal Phase ✔ Next 2 weeks 5-10mg bd
Supplementation ✔ Administer Norethisterone ✔ Next 1week 5-10mg od & then stop the drug
✔ Periodic revaluation acetate for 3-6 months 10 ✔ Maintain Venusmin administration
✔ No Specific mg/day for 10 days/month To Regularise Menstrual Cycles
treatment required with continued venusmin ✔ Cyclical progestogen for 6 months or longer along
✔ Normal menstrual ✔ Re-evaluation after stopping with administration of venusmin
pattern occurs the drug ✔ Re-evaluation upto 12 months or longer if necessary
spontaneously Other drugs
within 1 or 2 years ✔ Venusmin (900 mg in divided doses)
✔ OCP-20-30 microgram tabs
✔ Tranexemic acid 500-1000 mg 8 hourly
✔ Mefenemic acid 500 mg tds for 6 days
✔ GnRH-leuprolide -3.75 mg im monthly for 6 months
Last resort
✔ Dilatation and curettage (D&C)
✔ Rule out Tuberculous Endometritis
 Hormonal drugs used in Puberty Menorrhagia
Therapy MOA Side Effects Contraindications Disadvantage
Combined Oral Suppresses Oestrogen related ✔ Smoker ≥ 15 cigtt./D, with age > 35 yrs✔ Requires
Contraceptive ovulation: ✔ Nausea ✔ BP ≥ 100/160 daily
Pills pituitary effect ✔ Breast tenderness ✔ Pregnancy administrati
✔ Reduces ✔ Breast cancer ✔ Ischemic heart disease on
GnRH ✔ Venous thrombosis✔ Hx of cerebrovascular accident
pulsations ✔ Fluid retention ✔ Comp. valvular heart disease (pul. ✔ Multiple
✔ Reduces ✔ Metaststis of HPT, atrial fibrilation, SABE) side effects
pituitary breast tumour ≥10 ✔ Migraine C focal neurological
response to yrs symptoms
GnRH Progestin related ✔ Unknown etiology of vaginal bleeding
Estrogen ✔ Mood depression ✔ Diabetes with retinopathy/
Effect: ⇓ FSH ✔ Androgenic effects nephropathy/ neuropathy
secretion ✔ Severe liver cirrhosis
Progestin ✔ Liver tumour ( adenoma or hepatoma)
Effect: ⇓ LH ✔ Breast cancer
secretion ✔ Impaired liver function
✔ Hx of thromboembolic disorder
Progestin Only, ✔ No estrogen ✔ More intra- Absolute Contraindications ✔ Must be
“Minipill” component menstural spotting ✔ Pregnancy taken at
✔ Norethindro✔ Causes ✔ Weight gain & ✔ Breast cancer same time
ne cervical depression in some Relative Contraindications each day
✔ Desogestrel mucus to patients ✔ Active viral hepatitis within 3 hrs
thicken ✔ Slow Return to ✔ Liver tumours
✔ Endometrium fertility NB:Progesterone IUD is restricted in
involutes ✔ Decrease in bone teens as it increases tendency towards
mass multiple sexual partners. Inherent risk of
 Non Hormonal drugs used in Puberty Menorrhagia
Therapy Mechanism of action Side Effects Contraindications
NSAIDS ✔ Inhibits Cyclo-oxygenase ✔ GIT Symptoms✔ Hypersensitivity
✔ Mefenamic acid 500mg pathway, imparing the ✔ Bleeding
TDS production of vasodialator Time is ✔ Bleeding
✔ Flurbiprofen 100mg TDS PGE2 , PGI 2 . increased, disorders
✔ Inhibits binding of PGE 2 to ✔ Pruritus, ✔ Compromised
✔ Naproxen 500mg BD its specific receptor in ✔ Rashes, Renal function
Indomethacin 25mg QID uterine Myometrium. ✔ Edema, ✔ Active
taken during menstruation✔ Improve platelet aggregation,✔ Abnormal Ulceration
degranulation & Renal function ✔ Chronic
vasoconstriction tests, inflammation of
✔ Increased Liver GIT
Enzymes
ANTI-FIBRINOLYTICS ✔ Prevents Plasminogen ✔ GI symptoms ✔ Renal failure
✔ Tranexamic acid 1-1.5g activation & Fibrinolysis & ✔ Thrombotic
3-4 times/day for 3-4 days Dissolution of Clot events
✔ ETHAMSYLATE 500mg ✔ Inhibits capillary fragility ✔ Comparatively ✔ Less efficacious
QID From 5 th day prior to less side effects
start of menses to 10
days after
✔ Venusmin (900 mg in✔ Inhibit capillary fragility ✔ Rarely nausea,✔ Used for more
divided doses) ✔ Inhibit PGE 2 production vomiting & than 40 years
✔ Improves lymphatic drainage diarrhoea with good
 What is Micronised Diosmin?
► Diosmin is a naturally occurring flavonoid glycoside that
is derived from the flavonoid hesperidin.
► Introduced as a therapeutic agent in 1969.
► Venusmin (Superior Standardized Bioflavonoid) is
Micronized Purified Flavonoid Fraction (MPFF) containing
100% pure Natural micronized synthesized Diosmin
……Free from impurities
► Has been widely used for more than 40 years worldwide
with good efficacy and safety profile.
► Considered as vascular-protecting agent with multimodal
action, used to treat dysfunctional uterine bleeding,
chronic venous insufficiency, hemorrhoids, lymphedema
and varicose veins.
 Micronisation

Reduction of particle size < 10 microns

Increases effective surface area

Higher dissolution rates

Increases Bioavailability

Greater Efficacy
 Diosmin-Pharmacokinetics
► Diosmin is rapidly biotransformed by intestinal flora to its aglycone
form, diosmetin.
► Diosmetin is absorbed and rapidly distributed throughout the body
with a plasma half-life of 8 -12 hours.
► Significant plasma level is achieved in one hour and peak plasma
level in 2-9 hour with high affinity for walls of veins.
► Diosmetin is degraded to phenolic acids or their glycine-conjugated
derivatives and eliminated through the urine.
► Diosmin or diosmetin not absorbed, is eliminated in the feces.
Int J Clin Pharmacol Ther Toxicol. 1992 Jan;30(1):29-33.
 Mechanism of Action of Diosmin
Phlebotonic Action (Venoconstrictive Action)
DIOSMI
N

Inhibits
Catechol-o-methyl
transferase
enzyme

Increases level
of
Noradrenaline

Reinstates normal
contractility
of venous wall

Normalise Disperses Platelet Aggregates Improves Oxygenati

s
 Mechanism of Action of Diosmin
Effect on Capillaries
DIOSMI
N

Inhibits Inflammatory
Reduces Potentiate action of
Mediators
intracapillary pressure Vitamin C
Histamine, PGE 2, TxA 2

Reduces Improves Increases capillary

capillary fragility capillary permeability, resistance
reduces risk of
viscosity

RESTORES FUNCTION OF CAPILLARIES

 Mechanism of Action of Diosmin

► Added Attributes
- analgesic action
- improvement of red blood cell rheology
- profibrinolytic action
- inhibition of lysosomal enzymes
- anti- free radical properties
- protection of fibrous proteins (collagen)
- anti-mutagenic properties
 Role of Diosmin in DUB

► Hormonal treatment does play an important role in Mx of

DUB but has limitations –
- Long drawn treatment, sometimes upto 6 months.
- Frequent clinical monitoring required.
- Poor acceptability due to side effects.
► An adjunctive is required to hormonal therapy for
correction of basic abnormalities seen in DUB i.e.
- Increased capillary fragility
- Increased PGE2 production
- Impaired lymphatic drainage
 Preference of Diosmin in DUB
Preferred therapy
- Adolescent DUB: The cause of bleeding is anovulation due to delay in
maturation of hypothalamic control. Hormones may further suppress
GnRH, FSH, LH causing persistent anovulation and DUB.
- Ovulatory DUB – Diosmin is T/t of choice in DUB patients in mid
reproductive yrs desiring conception as diosmin doesn’t interefere with
normal hormonal changes, & don’t affect pregnancy, fetal development,
birth weight, infant growth & feeding.1
- Perimenopausal DUB: In these women, anovulatory cycles & unopposed
effects of estrogen increase risk of Endometrial Hyperplasia and
Adenocarcinoma
- Primary Hormonal Failure: Patients unresponsive to hormone therapy may
respond non hormonal therapy by decreasing capillary fragility, inhibiting
PGE 2 production & improve lymphatic drainage.
- High Risk Patients: Patients > 40 yrs with history of CVD / Diabetes /
Hypertension.
1. Buckshee et al. Micronized flavonoid therapy in internal haemorrhoids of pregnancy. Int J Gyae & Obstet 1997. 145-51
 Preference of Diosmin in DUB

► Often where there are concerns about prescribing

hormones, Diosmin is the preferred choice for the
management of both ovulatory and anovulatory
DUB.

► Diosmin may be prescribed along with hormones,

for correction of basic abnormalities seen in DUB i.e.
- Increased capillary fragility
- Increased PGE2 production
- Impaired lymphatic drainage

Dosage: 900 mg in divided doses daily until normalisation of

menstrual cycle
 Diosmin – Clinical Efficacy Data in DUB
Referen Study Design Results
ces
Int J Outpatients with history of untreated In 70 % of the patients
Gynaecol Menorrhagia over 3 previous cycles were total amount of bleeding
Obstet. prescribed Diosmin 5 days prior to the decreased by 50%,
2005 expected onset of menstruation and upto duration of bleeding
the end of bleeding for 3 consecutive cycles. decreased by 33% & 50%,
improvement in
Mukherjee GG, Gajaraj AJ, Mathias J, Marya D. Treatment of associated
abnormal uterine bleeding with micronized flavonoids.
Int J Gynaecol Obstet. 2005 May;89(2):156-7. dysmenorrhea in about
75% of cases
Guerrero 18 patients with hypermenorrhea and 16 Out of all the 34 patients
Moreira patients with menometrorrhagias were treated, 28 i.e., 82% of
A, 1983 recruited in the study. Hypermenorrhagic patients have got their
patients received 600 mg of diosmin / day in cycle normalized.
2 intakes starting from the 15th day of the
menstrual cycle until the end of the
menstruation itself. Where as patients
suffering from menometrorrhagias were
administered a dose of 900mg a day in 2
divided intakes until normalization of the
 Diosmin – Safety Data

► Extensive studies have found Diosmin to be essentially

nontoxic.
► Diosmin given to 50 pregnant women in a research
study, without apparent harm to mothers or babies.
► Diosmin is considered to have no mutagenic activity,
embryo toxicity nor any significant effect on
reproductive system.
► Transplacental migration and passage into breast milk
is minimal.
Angiology. 1994, Int J Gynaecol Obstet. 1997
 Diosmin – Safety Data

► Animal studies have shown the absence of acute,

subacute, or chronic toxicity after repeated oral dosing
for 13 and 26 weeks using 35 times the recommended
daily dose.
► Diosmin significantly increased Diclofenac Cmax and t1/2
with concomitant reduction in CL/f. Diosmin might have
inhibited microsomal CYP2C9 mediated oxidation of
diclofenac. Thus, diclofenac dose needs to be reduced.

Drug Metabol Drug Interact. 2007;22(2-3):165-74

 Conclusion of Diosmin

► Micronised Disomin has well established effect in DUB

- in relieving signs & symptoms of disease
- treating underlying pathology
- effective and safe for long term therapy
- minimal drug interactions
- safe in pregnancy in 2 nd and 3 rd trimester
► 1st line treatment alone or in conjunction to other
procedures and surgery.
MICRONISED DIOSMIN
provides a unique multimodal
action
that allows healthy venous tone in
Phlebology
Proctology
Gynaecology
Thank You

100% Pure Micronised Diosmin……Free from Impurities