SYRENIRING

Posology To achieve contraceptive effectiveness, SyreniRing must be used as directed (see “How to use SyreniRing” and “How to start SyreniRing”). Paediatric Population The safety and efficacy of SyreniRing in adolescents under the age of 18 have not been studied.

Method of administration HOW TO USE SYRENIRING The woman herself can insert SyreniRing in the vagina. The physician should advise the woman how to insert and remove SyreniRing. g. standing with one leg up, squatting, or lying down. SyreniRing should be compressed and inserted into the vagina until it feels comfortable.

The exact position of SyreniRing in the vagina is not critical for the contraceptive effect of the ring (see Figures 1-4). Once SyreniRing has been inserted (see “How to start SyreniRing”) it is left in the vagina continuously for 3 weeks.

Advise women to regularly check for the presence of SyreniRing in the vagina (for example, before and after intercourse). 4, “Expulsion”). SyreniRing must be removed after 3 weeks of use on the same day of the week as the ring was inserted.

g. 00 h. The following Wednesday a new ring should be inserted). SyreniRing can be removed by hooking the index finger under the ring or by grasping the ring between the index and middle finger and pulling it out (Figure 5). 6. The withdrawal bleed usually starts 2-3 days after removal of SyreniRing and may not have finished completely before the next ring insertion is due.

Use with other female vaginal barrier methods SyreniRing may interfere with the correct placement and position of certain female barrier methods, such as a diaphragm, cervical cap, or female condom. These contraceptive methods should not be used as back-up methods with SyreniRing.

Figure 1 Take SyreniRing out of the sachet Figure 2 Compress the ring Figure 3 Choose a position that is most comfortable for her Figure 4A Figure 4B Figure 4C Insert the ring into the vagina with one hand (Figure 4A), if necessary the labia may be spread with the other.

Push the ring into the vagina until the ring feels comfortable (Figure 4B). Leave the ring in place for 3 weeks (Figure 4C).

Figure 5:

SyreniRing can be removed by hooking the index finger under the ring or by grasping the ring between the index and middle finger and pulling it out. e. the first day of her menstrual bleeding). Starting on days 2-5 is allowed, but during the first cycle a barrier method is recommended in addition for the first 7 days of SyreniRing use.

Changing from a combined hormonal contraceptive:

The woman should insert SyreniRing at the latest on the day following the usual tablet-free, patch-free or placebo tablet interval of her previous combined hormonal contraceptive. If the woman has been using her previous method consistently and correctly and if it is reasonably certain that she is not pregnant she may also switch from her previous combined hormonal contraceptive on any day of the cycle.

The hormone-free interval of the previous method should never be extended beyond its recommended length. Changing from a progestagen-only method (minipill, implant, or injection), or from a progestagen-releasing intrauterine system [IUS].

The woman may switch on any day from the minipill (from an implant, or the IUS on the day of its removal, from an injectable when the next injection would be due) but should in all of these cases use an additional barrier method for the first 7 days of SyreniRing use.

Following first-trimester abortion:

The woman may start immediately. When doing so, she needs not to take additional contraceptive measures. If an immediate switch is considered undesirable, the woman should follow the advice given for “No hormonal contraceptive use in the preceding cycle”.

In the meantime, she should be advised to use an alternative contraceptive method. 6. Women should be advised to start during the fourth week after delivery or second- trimester abortion. When starting later, the woman should be advised to additionally use a barrier method for the first 7 days of SyreniRing use.

However, if intercourse has already occurred, pregnancy should be excluded or the woman has to wait for her first menstrual period, before starting SyreniRing use. DEVIATIONS FROM THE RECOMMENDED REGIMEN Contraceptive efficacy and cycle control may be compromised if the woman deviates from the recommended regimen.

To avoid loss of contraceptive efficacy in case of a deviation, the following advice can be given: • What to do in case of a lengthened ring-free interval The woman should insert a new ring as soon as she remembers. A barrier method such as a condom should be used in addition for the next 7 days.

If intercourse took place during the ring-free interval, the possibility of a pregnancy should be considered. The longer the ring-free interval, the higher the risk of a pregnancy. • What to do if the ring was temporarily outside the vagina SyreniRing should be left in the vagina for a continuous period of 3 weeks.

If the ring is accidentally expelled, it can be rinsed with cool to lukewarm (not hot) water and should be reinserted immediately. If SyreniRing has been out of […]

The most frequently reported undesirable effects in the clinical trials with Etonogestrel/Ethinylestradiol were headache and vaginal infections and vaginal discharge, each reported by 5-6% of the women. 4. 4. Adverse drug reactions that have been reported in clinical trials, observational studies, or during post-marketing use with ring containing Etonogestrel / Ethinylestradiol are listed in the Table below.

The most appropriate MedDRA term to describe a certain adverse event is listed. All adverse reactions are listed by system organ class and frequency; common (≥ 1/100 to < 1/10), uncommon (≥ 1/1,000 to < 1/100), rare (≥ 1/10,000 to < 1/1,000), and not known (cannot be estimated from the available data).

System Organ Class Common Uncommon Rare Not known1 Infections and infestations Vaginal infection Cervicitis, Cystitis, Urinary tract infection Immune system disorders Hypersensit ivity Reactions, including angioedema and anaphylaxis Exacerbatio n of symptoms of hereditary and acquired angioedema Metabolism and nutrition disorders Increased appetite Psychiatric disorders Depression, Libido decreased Affect lability, Mood altered, Mood swings Nervous system disorders Headache, Migraine Dizziness, Hypoaesthes ia Eye disorders Visual disturbance Vascular disorders Hot flush Venous thromboemb olism, Arterial thromboemb olism Gastrointestina l disorders Abdominal pain, Nausea Abdominal distension, Diarrhoea, Vomiting, Constipation Skin and subcutaneous tissue disorders Acne Alopecia, Eczema, Pruritus, Rash, Urticaria Exacerbation of symptoms of hereditary and acquired angioedema, Chloasma, Urticaria Musculoskelet al and connective tissue disorders Back pain, Muscle spasms, Pain in extremity Renal and urinary disorders Dysuria, Micturition urgency, Pollakiuria Reproductive system and breast disorders Breast tenderness, Genital pruritus female, Dysmenorrho ea, Pelvic Amenorrhoe a,Breast discomfort, Breast enlargement, Breast mass, Cervical Galactorrhoe a Penis disorders pain, Vaginal discharge polyp, Coital bleeding, Dyspareunia, Ectropion of cervix, Fibrocystic breast disease, Menorrhagia , Metrorrhagia , Pelvic discomfort, Premenstrual syndrome, Uterine spasm, Vaginal burning sensation, Vaginal odour, Vaginal pain, Vulvovagina l discomfort, Vulvovagina l dryness General disorders and administration site conditions Fatigue, Irritability, Malaise, Oedema, Sensation of foreign body Vaginal ring site tissue overgrowth Investigations Weight increased Blood pressure increased Injury, poisoning and procedural complications Vaginal ring discomfort, Vaginal ring expelled Vaginal ring complication , Vaginal injury associated with ring breakage 1 Listing of adverse events based on spontaneous reporting.

g. liver tumours, breast cancer) have been reported in association with CHC use. 4. 5). 5). 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.

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WARNINGS

If any of the conditions or risk factors mentioned below is present, the suitability of SyreniRing should be discussed with the woman. In the event of aggravation, or first appearance of any of these conditions or risk factors, the woman should be advised to contact her doctor to determine whether the use of SyreniRing should be discontinued.

1. Circulatory Disorders Risk of venous thromboembolism (VTE) • The use of any combined hormonal contraceptive (CHC) increases the risk of venous thromboembolism (VTE) compared with no use. Products that contain levonorgestrel, norgestimate or norethisterone are associated with the lowest risk of VTE.

Other products such as SyreniRing may have up to twice this level of risk. The decision to use any product other than one with the lowest VTE risk should be taken only after a discussion with the woman to ensure she understands the risk of VTE with SyreniRing, how her current risk factors influence this risk, and that her VTE risk is highest in the first ever year of use.

There is also some evidence that the risk is increased when a CHC is re-started after a break in use of 4 weeks or more. • In women who do not use a CHC and are not pregnant about 2 out of 10,000 will develop a VTE over the period of one year.

However, in any individual woman, the risk may be far higher, depending on her underlying risk factors (see below). • It is estimated that out of 10,000 women who use a low dose CHC that contains levonorgestrel, about 61 will develop a VTE in one year.

90). This corresponds to between about 6 and 12 VTEs in a year out of 10,000 women who use ring containing Etonogestrel / Ethinylestradiol. • In both cases, the number of VTEs per year is fewer than the number expected in women during pregnancy or in the postpartum period.

• VTE may be fatal in 1-2 % of cases. g. hepatic, mesenteric, renal, or retinal veins and arteries. Risk factors for VTE The risk for venous thromboembolic complications in CHC users may increase substantially in a woman with additional risk factors, particularly if there are multiple risk factors (see table).

3). If a woman has more than one risk factor, it is possible that the increase in risk is greater than the sum of the individual factors – in this case her total risk of VTE should be considered. 3).

Table:

Risk factors for VTE Risk factor Risk factor Comment CommentObesity (body mass index over 30 kg/m²) Risk increases substantially as BMI rises. Particularly important to consider if other risk factors also present. Prolonged immobilisation, major surgery, any surgery to the legs or pelvis, neurosurgery, or major trauma Note: temporary immobilisation including air travel >4 hours can also be a risk factor for VTE, particularly in women with other risk factors In these situations it is advisable to discontinue use of the patch/pill/ring (in the case of elective surgery at least four weeks in advance) and not resume until two weeks after complete remobilisation.

Another method of contraception should be used to avoid unintentional pregnancy. Antithrombotic treatment should be considered if SyreniRing has not been discontinued in advance. g. before 50). If a hereditary predisposition is suspected, the woman should be referred to a specialist for advice before deciding about any CHC use Other medical conditions associated with VTE Cancer, systemic lupus erythematosus, haemolytic uraemic syndrome, chronic inflammatory bowel disease (Crohn’s disease or ulcerative colitis) and sickle cell disease Increasing age Particularly above 35 years • There is no consensus about the possible role of varicose veins and superficial thrombophlebitis in the onset or progression of venous thrombosis.

6). Symptoms of VTE (deep vein thrombosis and pulmonary embolism) In the event of symptoms women should be advised to seek urgent medical attention and to inform the healthcare professional that she is taking a CHC. Symptoms of deep vein thrombosis (DVT) can include: • unilateral swelling of the leg and/or foot or along a vein in the leg; • pain or tenderness in the leg which may be felt only when standing or walking; • increased warmth in the affected leg; red or discoloured skin on the leg.

Symptoms of pulmonary embolism (PE) can include: • sudden onset of unexplained shortness of breath or rapid breathing; • sudden coughing which may be associated with haemoptysis; • sharp chest pain; • severe light headedness or dizziness; • rapid or irregular heartbeat.

g. g. respiratory tract infections). Other signs of vascular occlusion can include: sudden pain, swelling and slight blue discoloration of […]

CHCs should not be used in the following conditions. Should any of the conditions appear for the first time during the use of SyreniRing, it should be removed immediately. g. deep venous thrombosis [DVT] or pulmonary embolism [PE]). • Known hereditary or acquired predisposition for venous thromboembolism, such as APC-resistance (including Factor V Leiden), antithrombin-III-deficiency, protein C deficiency, protein S deficiency.

4). 4). g. g. angina pectoris). g. transient ischaemic attack, TIA). • Known hereditary or acquired predisposition for arterial thromboembolism, such as hyperhomocysteinaemia and antiphospholipid- antibodies (anticardiolipin-antibodies, lupus anticoagulant).

• History of migraine with focal neurological symptoms. 4) or to the presence of one serious risk factor such as: • Diabetes mellitus with vascular symptoms • Severe hypertension • Severe dyslipoproteinaemia. • Pancreatitis or a history thereof if associated with severe hypertriglyceridemia.

• Presence or history of severe hepatic disease as long as liver function values have not returned to normal. • Presence or history of liver tumours (benign or malignant). • Known or suspected malignant conditions of the genital organs or the breasts, if sex steroid-influenced.

• Undiagnosed vaginal bleeding. 1 of SyreniRing. 5).