Adverse reactions : תופעות לוואי

6 ADVERSE REACTIONS
The following serious adverse reactions with the use of COCs are discussed elsewhere in the labeling:
• Serious cardiovascular events and stroke [see Boxed Warning and Warnings and Precautions (5.1)]
• Vascular events [see Warnings and Precautions (5.1)]
• Liver disease [see Warnings and Precautions (5.4)] 6.1 Clinical Trials Experience
Because clinical trials are conducted under widely varying conditions, the adverse reaction rates observed cannot be directly compared to rates in other clinical trials and may not reflect the rates observed in practice.
Contraception and Folate Supplementation Clinical Trials
The data provided reflect the experience with the use of Yasmin (3 mg DRSP/0.03 mg EE) in the adequate and well- controlled studies for contraception (N=2,837) and folate supplementation (N=172). For contraception, the US pivotal clinical study (N=326) for the oral contraception indication for Yasmin was a multicenter, open-label trial in healthy women aged 18 -35 who were treated with Yasmin for up to 13 cycles. The second contraceptive pivotal study (N=442) was a multicenter, randomized, open-label comparative European study of Yasmin vs. 0.150 mg desogestrel/0.03 mg EE conducted in healthy women aged 17-40 who were treated for up to 26 cycles. The primary efficacy study using Yasmin Plus for folate supplementation was a randomized, single-center European trial in 172 healthy, female subjects aged 18-40 years comparing the pharmacodynamic effects of Yasmin + 0.451 mg levomefolate calcium to Yasmin co-administered with folic acid during 24 weeks of treatment followed by 20 weeks of open-label Yasmin.
The adverse reactions seen across the 2 indications overlapped and are reported using the frequencies from the pooled dataset. The most common adverse reactions (≥ 2% of users) were: premenstrual syndrome (12.4%), headache/migraine (10.3%), breast pain/tenderness/discomfort (8.1%), nausea/vomiting (4.4%), mood changes (depression, depressed mood, irritability, mood swings, mood altered and affect lability (2.3%), and abdominal pain/discomfort/tenderness (2.2%).
Adverse Reactions (≥ 1%) Leading to Study Discontinuation
Contraception Clinical Trials
Of 2,837 women, 6.7% discontinued from the clinical trials due to an adverse reaction; the most frequent adverse reaction leading to discontinuation was headache/migraine (1.5%).
Folate Clinical Trial
There were no subjects who discontinued due to an adverse reaction.
Serious Adverse Reactions:
Contraception Clinical Trials: depression, pulmonary embolism, toxic skin eruption, and uterine leiomyoma.
Folate Supplementation Clinical Trial: none reported in the clinical trial 6.2 Postmarketing Experience
Five studies that compared breast cancer risk between ever-users (current or past use) of COCs and never-users of COCs reported no association between ever use of COCs and breast cancer risk, with effect estimates ranging from 0.90 - 1.12 (Figure 3).
Three studies compared breast cancer risk between current or recent COC users (<6 months since last use) and never users of COCs (Figure 3). One of these studies reported no association between breast cancer risk and COC use. The other two studies found an increased relative risk of 1.19 - 1.33 with current or recent use. Both of these studies found an increased risk of breast cancer with current use of longer duration, with relative risks ranging from 1.03 with less than one year of COC use to approximately 1.4 with more than 8-10 years of COC use.



Figure 3: Relative Studies of Risk of Breast Cancer with Combined Oral Contraceptives 


RR = relative risk; OR = odds ratio; HR = hazard ratio. “ever COC” are females with current or past COC use; “never COC use” are females that never used COCs.


The following adverse reactions have been identified during post-approval use of Yasmin. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.
Adverse reactions, including fatalities, are grouped into System Organ Classes and ordered by frequency.
Vascular disorders: Venous and arterial thromboembolic events (including pulmonary emboli, deep vein thrombosis, intracardiac thrombosis, intracranial venous sinus thrombosis, sagittal sinus thrombosis, retinal vein occlusion, myocardial infarction and stroke), hypertension

Hepatobiliary disorders: Gallbladder disease

Immune system disorders: Hypersensitivity
Metabolism and nutrition disorders: Hyperkalemia

Skin and subcutaneous tissue disorders: Chloasma

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 https://sideeffects.health.gov.il