Adverse reactions : תופעות לוואי

4.8   Undesirable effects

The following adverse reactions, associated with estrogen treatment may occur during estriol therapy or overdose: Nausea and vomiting, breast tenderness or pain in the breasts, vaginal bleeding or spotting during or on withdrawal of therapy, excessive production of cervical mucus, headache.

From Literature and safety surveillance monitoring, the following adverse reactions have been reported:

System organ class                           Adverse reactions*
General disorders and administration Application site irritation and pruritus site conditions                              Influenza-like illness
Reproductive system and breast               Breast discomfort and pain disorders
*MedDRA version9.1
These adverse reactions are usually transient, but may also be indicative of too high a dosage.

Breast cancer risk
• An up to 2-fold increased risk of having breast cancer diagnosed is reported in women taking combined estrogen-progestagen therapy for more than 5 years.
• Any increased risk in users of estrogen-only therapy is substantially lower than that seen in users of estrogen-progestagen combinations.
• The level of risk is dependent on the duration of use (see section 4.4).
• Results of the largest randomized placebo-controlled trial (WHI-study) and largest epidemiological study (MWS) are presented.


Million Women study– Estimated additional risk of breast cancer after 5 years’ use 
Age range       Additional cases per 1000         Risk ratio #        Additional cases (yrs)         never-users of HRT over                                per 1000 HRT a 5 year period*                                 users over 5 years
(95%CI)
Estrogen only HRT
50-65                   9-12                         1.2                  1-2 (0-3) Combined estrogen-progestagen
50-65                   9-12                         1.7                   6 (5-7) #Overall risk ratio. The risk ratio is not constant but will increase with increasing duration on use
* Taken from baseline incidence rates in developed countries.

US WHI studies - additional risk of breast cancer after 5 years’ use 
Age range     Incidence per 1000 women           Risk ratio &          Additional cases (yrs)       in placebo arm over 5 years          95%CI                per 1000 HRT users over 5 years
(95%CI)
CEE estrogen-only
50-79              21                          0.8 (0.7 – 1.0)         -4 (-6 – 0)* CEE+MPA estrogen & progestagen‡
50-79              14                            1.2 (1-1.5)            +4 (0 – 9) 
‡When the analysis was restricted to women who had not used HRT prior to the study there was no increased risk apparent during the first 5 years of treatment: after 5 years the risk was higher than in non-users. * WHI study in women with no uterus, which did not show an increase in risk of breast cancer

Ovarian cancer

Long-term use of estrogen-only and combined estrogen-progestagen HRT has been associated with a slightly increased risk of ovarian cancer. In the Million Women Study 5 years of HRT resulted in 1 extra case per 2500 users.

Risk of venous thromboembolism

HRT is associated with a 1.3-3-fold increased relative risk of developing venous thromboembolism (VTE), i.e. deep vein thrombosis or pulmonary embolism. The occurrence of such an event is more likely in the first year of using HT (see section 4.4). Results of the WHI studies are presented:


WHI Studies - Additional risk of VTE over 5 years’ use
Age range Incidence per 1000 women           Risk ratio &            Additional cases (yrs)      in placebo arm over 5 years        95%CI                 per 1000 HRT users
Oral estrogen-only
50-59                  7                     1.2 (0.6 – 2.4)         1 (-3 – 10) Oral combined estrogen-progestagen
50-59                  4                     2.3 (1.2 – 4.3)         5 (1 – 13) * Study in women with no uterus

Risk of coronary artery disease

The risk of coronary artery disease is slightly increased in users of combined estrogen- progestagen HRT over the age of 60 (see section 4.4).

Risk of ischaemic stroke

The use of estrogen-only and estrogen-progestagen therapy is associated with an up to 1.5 fold increased relative risk of ischaemic stroke. The risk of haemorrhagic stroke is not increased during use of HRT. This relative risk is not dependent on age or on duration of use, but as the baseline risk is strongly age-dependent, the overall risk of stroke in women who use HRT will increase with age, see section 4.4.

WHI studies combined - Additional risk of ischaemic stroke* over 5 years’ use Age            Incidence per 1000          Risk ratio        Additional cases range            women in placebo          and 95%CI           per 1000 HRT (years)           arm over 5 years                            users over 5 years 50-59                   8                 1.3 (1.1– 1.6)           3 (1-5) *no differentiation was made between ischaemic and haemorrhagic stroke.

Other adverse reactions have been reported in association with estrogen-only and estrogen/progestagen combined treatment:
• Estrogen-dependent neoplasms benign and malignant, e.g. endometrial cancer.
•     Gall bladder disease.
• Skin and subcutaneous disorders: chloasma, erythema multiforme, erythema nodosum, vascular purpura.
• Probable dementia over the age of 65 (see section 4.4).

Reporting of suspected adverse reactions
Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product.

Any suspected adverse events should be reported to the Ministry of Health according to the National Regulation by using an online form
(http://forms.gov.il/globaldata/getsequence/getsequence.aspx?formType=AdversEffect Medic@moh.gov.il).
Additionally, you can also report to www.perrigo-pharma.co.il