DADIVA 0.120 MG / 0.015 MG PER 24 HOURS VAGINAL DELIVERY SYSTEM - summary of medicine characteristics

1 NAME OF THE MEDICINAL PRODUCT

Dadiva 0.120 mg/0.015 mg per 24 hours, vaginal delivery system

2 QUALITATIVE AND QUANTITATIVE COMPOSITION

Dadiva contains 11.7 mg etonogestrel and 2.7 mg ethinylestradiol. The ring releases etonogestrel and ethinylestradiol at an average amount of 0.120 mg and 0.015 mg respectively per 24 hours, over a period of 3 weeks.

For the full list of excipients, see section 6.1.

3 PHARMACEUTICAL FORM

Vaginal delivery system.

Dadiva is flexible, transparent, and colourless to almost colourless ring, with an outer diameter of 54 mm and a cross-sectional diameter of 4 mm.

4 CLINICAL PARTICULARS

4.1 Therapeutic indications

Contraception.

Dadiva is intended for women of fertile age. The safety and efficacy have been established in women aged 18 to 40 years.

The decision to prescribe Dadiva should take into consideration the individual woman's current risk factors, particularly those for venous thromboembolism (VTE), and how the risk of VTE with Dadiva compares with other combined hormonal contraceptives (CHCs) (see sections 4.3 and 4.4).

4.2 Posology and method of administration

Posology

To achieve contraceptive effectiveness, Dadiva must be used as directed (see How to use Dadiva' and How to start Dadiva').

Paediatric population

The safety and efficacy of Dadiva in adolescents under the age of 18 have not been established.

Method of administration

HOW TO USE Dadiva

The woman herself can insert Dadiva in the vagina. The physician should advise the woman how to insert and remove Dadiva. For insertion the woman should choose a position that is most comfortable for her, e.g. standing with one leg up, squatting, or lying down. Dadiva should be compressed and inserted into the vagina until it feels comfortable. The exact position of Dadiva in the vagina is not critical for the contraceptive effect of the ring (see Figures 1–4).

Once Dadiva has been inserted (see ‚How to start Dadiva‘) it is left in the vagina continuously for 3 weeks. Advise women to regularly check for the presence of Dadiva in the vagina (for example, before and after intercourse). If Dadiva is accidentally expelled, the woman should follow the instructions given in section 4.2, ' What to do if the ring is temporarily outside the vagina' (for more information, see also section 4.4, ' Expulsion'). Dadiva must be removed after 3 weeks of use on the same day of the week as the ring was inserted. After a ring-free interval of one week a new ring is inserted (e.g. when Dadiva is inserted on a Wednesday at about 22.00 h the ring should be removed again on the Wednesday 3 weeks later at about 22.00 h. The following Wednesday a new ring should be inserted). Dadiva 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). The used ring should be placed in the sachet (keep out of the reach of children and pets) and discarded as described in section 6.6. The withdrawal bleed usually starts 2–3 days after removal of Dadiva and may not have finished completely before the next ring insertion is due.

Use with other female vaginal barrier methods

Dadiva 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 Dadiva.

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

Womb

Vagina

HOW TO START Dadiva

No hormonal contraceptive use in the preceding cycle

Dadiva has to be inserted on the first day of the woman's natural cycle (i.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 Dadiva use.

Figure 4A

Figure 4B

Figure 4C

Figure 5

Dadiva can be removed by hooking the index finger under the ring or by grasping the ring between the index and the middle finger and pulling it out

Changing from a combined hormonal contraceptive

The woman should insert Dadiva 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 Dadiva use.

Following first-trimester abortion

The woman may start immediately. When doing so, she needs not to take additional contraceptive measures. If an immediate application 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.

Following delivery or second-trimester abortion

For breast-feeding women, see section 4.6.

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 Dadiva use. However, if intercourse has already occurred, pregnancy should be excluded or the woman has to wait for her first menstrual period, before starting Dadiva 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 male 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

Dadiva 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 Dadiva has been out of the vagina for less than 3 hours contraceptive efficacy is not reduced. The woman should reinsert the ring as soon as possible, but at the latest within 3 hours.

If Dadiva has been out of the vagina, or is suspected to have been out of the vagina for more than 3 hours during the 1st or 2nd week of use, contraceptive efficacy may be reduced. The woman should reinsert the ring as soon as she remembers. A barrier method such as a male condom should be used until Dadiva has been in the vagina continuously for 7 days. The longer the time Dadiva has been out of the vagina and the closer this is to the ring-free interval, the higher the risk of a pregnancy.

If Dadiva has been out of the vagina, or is suspected to have been out of the vagina for more than 3 hours during the 3rd week of the three-week use period, contraceptive efficacy may be reduced. The woman should discard that ring, and one of the following two options should be chosen:

1. Insert a new ring immediately.

Note: Inserting a new ring will start the next three-week use period. The woman may not experience a withdrawal bleed from her previous cycle. However breakthrough spotting or bleeding may occur.

2. Have a withdrawal bleeding and insert a new ring no later than 7 days (7×24 hours) from the time the previous ring was removed or expelled.

Note: This option should only be chosen if the ring was used continuously for the preceding 7 days.

If Dadiva was out of the vagina for an unknown amount of time, the possibility of pregnancy should be considered. A pregnancy test should be performed prior to inserting a new ring.

What to do in case of lengthened ring-use

Although this is not the recommended regimen, as long as Dadiva has been used for maximally 4 weeks, contraceptive efficacy is still adequate. The woman may maintain her one-week ring-free interval and subsequently insert a new ring. If Dadiva has been left in place for more than 4 weeks, contraceptive efficacy may be reduced and pregnancy should be ruled out before inserting a new Dadiva.

If the woman has not adhered to the recommended regimen and subsequently has no withdrawal bleed in the following ring-free interval, pregnancy should be ruled out before inserting a new Dadiva.

HOW TO SHIFT PERIODS OR HOW TO DELAY A PERIOD

If in exceptional cases a period needs to be delayed, the woman may insert a new ring without having a ring-free interval. The next ring can be used for up to 3 weeks again. The woman may experience bleeding or spotting. Regular use of Dadiva is then resumed after the usual one week ring-free interval.

To shift her period to another day of the week than the woman is used to with her current scheme, she can be advised to shorten her forthcoming ring-free interval by as many days as she likes. The shorter the ring-free interval, the higher the risk that she does not have a withdrawal bleed and will experience breakthrough bleeding and spotting during the use of the next ring.

4.3 Contraindications

CHCs should not be used in the following conditions. Should any of the conditions appear for the first time during the use of Dadiva it should be removed immediately.

Presence or risk of venous thromboembolism (VTE)

o Venous thromboembolism – current VTE (on anticoagulants) or history of (e.g. deep venous thrombosis [DVT] or pulmonary embolism [PE]).

o 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.

o Major surgery with prolonged immobilisation (see section 4.4).

o A high risk of venous thromboembolism due to the presence of multiple risk factors (see section 4.4).

Presence or risk of arterial thromboembolism (ATE)

o Arterial thromboembolism – current arterial thromboembolism, history of arterial thromboembolism (e.g. myocardial infarction) or prodromal condition (e.g. angina pectoris).

o Cerebrovascular disease – current stroke, history of stroke or prodromal condition (e.g. transient ischaemic attack, TIA).

o Known hereditary or acquired predisposition for arterial thromboembolism, such as hyperhomocyste­inaemia and antiphospholipid-antibodies (anticardiolipin-antibodies, lupus anticoagulant).

o History of migraine with focal neurological symptoms.

o A high risk of arterial thromboembolism due to multiple risk factors (see section 4.4) 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.

Hypersensitivity to the active substances or to any of the excipients listed in section 6.1.

Dadivag is contraindicated for concomitant use with the medicinal products containing ombitasvir/pa­ritaprevir/ri­tonavir and dasabuvir (see sections 4.4 and 4.5).

4.4 Special warnings and precautions for use

WARNINGS

If any of the conditions or risk factors mentioned below is present, the suitability of Dadiva 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 Dadiva 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 Dadiva 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 Dadiva, 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 restarted 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. Inconsistent results on the risk of VTE with Dadiva compared with CHCs that contain levonorgestrel have been found (with relative risk estimates ranging from no increase, RR=0.96, to an almost 2-fold increase, RR=1.90). This corresponds to between about 6 and 12 VTEs in a year out of 10,000 women who use Dadiva.

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.

Number of VTE events per 10,000 women in one year

Extremely rarely, thrombosis has been reported to occur in CHC users in other blood vessels, e.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).

Dadiva is contraindicated if a woman has multiple risk factors that put her at high risk of venous thrombosis (see section 4.3). 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. If the balance of benefits and risks is considered to be negative, a CHC should not be prescribed (see section 4.3).

Table: Risk factors for VTE

1 Mid-point range of 5–7 per 10,000 WY, based on a relative risk for CHCs containing levonorgestrel versus non-use of approximately 2.3 to 3.6

There is no consensus about the possible role of varicose veins and superficial thrombophlebitis in the onset or progression of venous thrombosis.

The increased risk of thromboembolism in pregnancy, and particularly the 6-week period of the puerperium, must be considered (for information on “Pregnancy and lactation” see section 4.6).

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.

Some of these symptoms (e.g. “shortness of breath”, “coughing”) are non-specific and might be misinterpreted as more common or less severe events (e.g. respiratory tract infections).

Other signs of vascular occlusion can include: sudden pain, swelling and slight blue discoloration of an extremity.

If the occlusion occurs in the eye symptoms can range from painless blurring of vision which can progress to loss of vision. Sometimes loss of vision can occur almost immediately.

Risk of arterial thromboembolism (ATE)

Epidemiological studies have associated the use of CHCs with an increased risk for arterial thromboembolism (myocardial infarction) or for cerebrovascular accident (e.g. transient ischaemic attack, stroke). Arterial thromboembolic events may be fatal.

Risk factors for ATE

The risk of arterial thromboembolic complications or of a cerebrovascular accident in CHC users increases in women with risk factors (see table). Dadiva is contraindicated if a woman has one serious or multiple risk factors for ATE that puts her at high risk of arterial thrombosis (see section 4.3). 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 should be considered. If the balance of benefits and risks is considered to be negative a CHC should not be prescribed (see section 4.3).

Table: Risk factors for ATE

Symptoms of ATE

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 a cerebrovascular accident can include:

– sudden numbness or weakness of the face, arm or leg, especially on one side of the body;

– sudden trouble walking, dizziness, loss of balance or coordination;

– sudden confusion, trouble speaking or understanding;

– sudden trouble seeing in one or both eyes;

– sudden, severe or prolonged headache with no known cause;

– loss of consciousness or fainting with or without seizure.

Temporary symptoms suggest the event is a transient ischaemic attack (TIA).

Symptoms of a myocardial infarction (MI) can include:

– pain, discomfort, pressure, heaviness, sensation of squeezing or fullness in the chest, arm, or below the breastbone;

– discomfort radiating to the back, jaw, throat, arm, stomach;

– feeling of being full, having indigestion or choking;

– sweating, nausea, vomiting or dizziness;

– extreme weakness, anxiety, or shortness of breath;

– rapid or irregular heartbeats.

In case of suspected or confirmed VTE or ATE, CHC use should be discontinued. Adequate contraception should be initiated because of the teratogenicity of anti-coagulant therapy (coumarins).

2. Tumours

Epidemiological studies indicate that the long-term use of oral contraceptives displays a risk factor for the development of cervical cancer in women infected with human papillomavirus (HPV). However, there is still uncertainty about the extent to which this finding is influenced by confounding effects (e.g. differences in number of sexual partners or in use of barrier contraceptives). No epidemiological data on the risk of cervical cancer in users of Dadiva are available (see ‚Medical examination/con­sultation‘).

A meta-analysis from 54 epidemiological studies reported that there is a slightly increased relative risk (RR = 1.24) of having breast cancer diagnosed in women who are currently using COCs. The excess risk gradually disappears during the course of the 10 years after cessation of COC use. Because breast cancer is rare in women under 40 years of age, the excess number of breast cancer diagnoses in current and recent COC users is small in relation to the overall risk of breast cancer. The breast cancers diagnosed in ever-users tend to be less advanced clinically than the cancers diagnosed in never-users. The observed pattern of increased risk may be due to an earlier diagnosis of breast cancer in COC users, the biological effects of COCs or a combination of both.

In rare cases, benign liver tumours, and even more rarely, malignant liver tumours have been reported in users of COCs. In isolated cases, these tumours have led to life-threatening intra-abdominal haemorrhages. Therefore, a hepatic tumour should be considered in the differential diagnosis when severe upper abdominal pain, liver enlargement or signs of intraabdominal haemorrhage occur in women using Dadiva.

3. ALT elevations

During clinical trials with patients treated for hepatitis C virus infections (HCV) with the medicinal products containing ombitasvir/pa­ritaprevir/ri­tonavir and dasabuvir with or without ribavirin, transaminase (ALT) elevations higher than 5 times the upper limit of normal (ULN) occurred significantly more frequent in women using ethinylestradiol-containing medications such as combined hormonal contraceptives (CHCs). Additionally, also in patients treated with glecaprevir/pi­brentasvir, ALT elevations were observed in women using ethinylestradiol-containing medications such as CHCs (see sections 4.3 and 4.5).

4. Other conditions

Women with hypertriglyce­ridemia, or a family history thereof, may be at an increased risk of pancreatitis when using hormonal contraceptives.

Although small increases in blood pressure have been reported in many women using hormonal contraceptives, clinically relevant increases are rare. A definitive relationship between hormonal contraceptive use and clinical hypertension has not been established. However, if a sustained clinically significant hypertension develops during the use of Dadiva then it is prudent for the physician to suspend the use of the ring and treat the hypertension. Where considered appropriate, Dadiva use may be resumed if normotensive values can be achieved with antihypertensive therapy.

The following conditions have been reported to occur or deteriorate with both pregnancy and during the use of hormonal contraceptives, but the evidence of an association with its use is inconclusive: jaundice and / or pruritus related to cholestasis; gallstone formation; porphyria; systemic lupus erythematosus; hemolytic uraemic syndrome; Sydenham's chorea; herpes gestationis; otosclerosis-related hearing loss.

Exogenous ostrogens may induce or exacerbate symptoms of hereditary and acquired angioedema.

Acute or chronic disturbances of liver function may necessitate the discontinuation of the use of Dadiva until markers of liver function return to normal. Recurrence of cholestatic jaundice and/ or pruritus related to cholestasis, which occurred first during pregnancy or previous use of sex steroids necessitates the discontinuation of the ring.

Although oestrogens and progestagens may have an effect on peripheral insulin resistance and glucose tolerance, there is no evidence for a need to alter the therapeutic regimen in diabetics using hormonal contraception. However, diabetic women should be carefully monitored while using Dadiva especially in the first months of use.

New onset or deterioration of Crohn's disease and ulcerative colitis has been reported to occur with the use of hormonal contraceptives, but the evidence of an association with its use is inconclusive.

Chloasma may occasionally occur, especially in women with a history of chloasma gravidarum. Women with a tendency to chloasma should avoid exposure to the sun or ultraviolet radiation whilst using Dadiva.

If a woman has any of the following conditions she may not be able to insert Dadiva correctly or may in fact lose the ring: prolapse of the uterine cervix, cystocele and/or rectocele, severe or chronic constipation.

Very rarely it has been reported that Dadiva is inadvertently inserted in the urethra and possibly ending up in the bladder. Therefore, incorrect positioning should be considered in the differential diagnosis in case of symptoms of cystitis.

During the use of Dadiva, women may occasionally experience vaginitis. There are no indications that the efficacy of Dadiva is affected by the treatment of vaginitis, or that the use of Dadiva affects the treatment of vaginitis (see section 4.5).

Very rarely it has been reported that the ring adhered to vaginal tissue, necessitating removal by a healthcare provider. In some cases when the tissue had grown over the ring, removal was achieved by cutting the ring without incising the overlying vaginal tissue.

Depressed mood and depression are well-known undesirable effects of hormonal contraceptive use (see section 4.8). Depression can be serious and is a well-known risk factor for suicidal behaviour and suicide. Women should be advised to contact their physician in case of mood changes and depressive symptoms, including shortly after initiating the treatment.

MEDICAL EXAMINATION/CON­SULTATION

Prior to the initiation or reinstitution of Dadiva use a complete medical history (including family history) should be taken and pregnancy must be ruled out. Blood pressure should be measured and a physical examination should be performed, guided by the contraindications (see section 4.3) and warnings (see section 4.4). It is important to draw a woman's attention to the information on venous and arterial thrombosis, including the risk of Dadiva compared with other CHCs, the symptoms of VTE and ATE, the known risk factors and what to do in the event of a suspected thrombosis.

The woman should also be instructed to carefully read the user leaflet and to adhere to the advice given. The frequency and nature of examinations should be based upon established practice guidelines and be adapted to the individual woman.

Women should be advised that hormonal contraceptives do not protect against HIV infections (AIDS) and other sexually transmitted diseases.

REDUCED EFFICACY

The efficacy of Dadiva may be reduced in the event of non-compliance (section 4.2), or when concomitant medications that decrease the plasma concentration of ethinylestradiol and/or etonogestrel are used (section 4.5).

REDUCED CYCLE CONTROL

Irregular bleeding (spotting or breakthrough bleeding) may occur during the use of Dadiva. If bleeding irregularities occur after previously regular cycles while Dadiva has been used according to the recommended regimen, then non-hormonal causes should be considered, and adequate diagnostic measures are indicated to exclude malignancy or pregnancy. These may include curettage.

In some women a withdrawal bleed may not occur during the ring-free interval. If Dadiva has been used according to the instructions described in section 4.2, it is unlikely that the woman is pregnant. However, if Dadiva has not been used according to these instructions prior to the first missed withdrawal bleed or if two withdrawal bleeds are missed, pregnancy must be ruled out before use of Dadiva is continued.

MALE EXPOSURE TO ETHINYLESTRADIOL AND ETONOGESTREL

The extent and possible pharmacological role of exposure of male sexual partners to ethinylestradiol and etonogestrel through absorption through the penis have not been examined.

BROKEN RINGS

On very rare occasions Dadiva has been reported to get disconnected during use (see section 4.5). Vaginal injury associated with ring breakage has been reported. The woman is advised to remove the broken ring and reinsert a new ring as soon as possible and use a barrier method such as a male condom in addition for the next 7 days. The possibility of a pregnancy should be considered and the woman should contact her physician.

EXPULSION

Dadiva has been reported to get expelled, for example if the ring has not been inserted properly, while removing a tampon, during sexual intercourse, or in case of severe or chronic constipation. Prolonged expulsion may lead to contraceptive failure and/or breakthrough bleeding. Therefore, to ensure efficacy the woman should be advised to regularly verify the presence of Dadiva (for example, before and after intercourse).

If Dadiva is accidentally expelled and is left outside of the vagina for less than 3 hours contraceptive efficacy is not reduced. The woman should rinse the ring with cool to lukewarm (not hot) water and reinsert it as soon as possible, but at the latest within 3 hours.

If Dadiva has been out of the vagina, or is suspected to have been out of the vagina for more than 3 hours contraceptive efficacy may be reduced. In that case, the applicable advice given in section 4.2 ‚What to do if the ring was temporarily outside the vagina‘ should be followed.

4.5 Interaction with other medicinal products and other forms of interaction

INTERACTIONS WITH OTHER MEDICINAL PRODUCTS

Note: The prescribing information of concomitant medications should be consulted to identify potential interactions.

Effects of other medicinal products on Dadiva

Interactions can occur with drugs or herbal products that induce microsomal enzymes which can result in increased clearance of sex hormones and which may lead to breakthrough bleeding and/or contraceptive failure.

Management

Enzyme induction can already be observed after a few days of treatment. Maximum enzyme induction is generally seen within a few weeks. After the cessation of drug therapy, enzyme induction may be sustained for about 4 weeks.

Short-term treatment

Women on treatment with enzyme-inducing drugs or herbal products should temporarily use a barrier method or another method of contraception in addition to Dadiva.

Note: Dadiva should not be used with a diaphragm, cervical cap, or female condom. The barrier method must be used during the whole time of the concomitant drug therapy and for 28 days after its discontinuation. If concomitant drug administration runs beyond the 3 weeks of a ring-cycle, the next ring should be inserted immediately, without having the usual ringfree interval.

Long-term treatment

In women on long-term treatment with hepatic enzyme-inducing active substances, another reliable, non-hormonal method of contraception is recommended.

The following interactions have been reported in the literature.

Substances increasing the clearance of combined hormonal contraceptives

Interactions can occur with medicinal or herbal products that induce microsomal enzymes, specifically cytochrome P450 enzymes (CYP), which can result in increased clearance reducing plasma concentrations of sex hormones and may decrease the effectiveness of combined hormonal contraceptives, including Dadiva. These products include phenytoin, phenobarbital, primidone, bosentan, carbamazepine, rifampicin, and possibly also oxcarbazepine, topiramate, felbamate, griseofulvin, some HIV protease inhibitors (e.g. ritonavir) and non-nucleoside reverse transcriptase inhibitors (e.g. efavirenz), and products containing the herbal remedy St. John's wort.

Substances with variable effects on the clearance of combined hormonal contraceptives

When co-administered with hormonal contraceptives, many combinations of HIV protease inhibitors (e.g. nelfinavir) and non-nucleoside reverse transcriptase inhibitors (e.g. nevirapine), and/or combinations with Hepatitis C virus (HCV) medicinal products (e.g. boceprevir, telaprevir), can increase or decrease plasma concentrations of progestagens, including etonogestrel, or estrogen. The net effect of these changes may be clinically relevant in some cases.

Substances decreasing the clearance of combined hormonal contraceptives

The clinical relevance of potential interactions with enzyme inhibitors remains unknown. Concomitant administration of strong (e.g. ketoconazole, itraconazole, clarithromycin) or moderate (e.g. fluconazole, diltiazem, erythromycin) CYP3A4 inhibitors may increase the serum concentrations of estrogens or progestogens, including etonogestrel.

There have been reports of ring breakage during concomitant use of intravaginal preparations, including antimycotic, antibiotic and lubricant products (see section 4.4, ‚Broken Rings‘). Based on pharmacokinetic data, vaginally administered antimycotics and spermicides are unlikely to affect the contraceptive efficacy and safety of Dadiva.

Hormonal contraceptives may interfere with the metabolism of other drugs. Accordingly, plasma and tissue concentrations may either increase (e.g. ciclosporin) or decrease (e.g. lamotrigine).

Pharmacodynamic interactions

Concomitant use with the medicinal products containing ombitasvir/pa­ritaprevir/ri­tonavir and dasabuvir, with or without ribavirin may increase the risk of ALT elevations (see sections 4.3 and 4.4).

Therefore, Dadiva-users must switch to an alternative method of contraception (e.g., progestagen-only contraception or non-hormonal methods) prior to starting therapy with this combination drug regimen. Dadiva can be restarted 2 weeks following completion of treatment with this combination drug regimen.

LABORATORY TESTS

The use of contraceptive steroids may influence the results of certain laboratory tests, including biochemical parameters of liver, thyroid, adrenal and renal function, plasma levels of carrier proteins, (e.g. corticosteroid binding globulin and sex hormone binding globulin), lipid / lipoprotein fractions, parameters of carbohydrate metabolism and parameters of coagulation and fibrinolysis. Changes generally remain within the normal laboratory range.

INTERACTION WITH TAMPONS

Pharmacokinetic data show that the use of tampons has no effect on the systemic absorption of the hormones released by Dadiva. On rare occasions Dadiva might be expelled while removing a tampon (see advice for What to do if the ring was temporarily outside the vagina').

4.6 Fertility, pregnancy and lactation

Fertility

Dadiva is indicated for the prevention of pregnancy. If the woman wants to stop using Dadiva because she wants to get pregnant, she is advised to wait until she has a natural period before trying to conceive as this will help her calculate when the baby is due.

Pregnancy

Dadiva is not indicated during pregnancy. If pregnancy occurs with Dadiva in situ, the ring should be removed. Extensive epidemiological studies have revealed neither an increased risk of birth defects in children born to women who used COCs prior to pregnancy, nor a teratogenic effect when COCs were used inadvertently during early pregnancy.

A clinical study in a small number of women showed that despite the intravaginal administration, intrauterine concentrations of contraceptive steroids with Dadiva are similar to the levels observed in COC users (see section 5.2). Clinical experience of the outcomes of pregnancies exposed to Dadiva has not been reported.

The increased risk of VTE during the postpartum period should be considered when restarting Dadiva (see sections 4.2 and 4.4).

Breastfeeding

Lactation may be influenced by oestrogens, as they may reduce the quantity and change the composition of breast milk. Therefore, the use of Dadiva should generally not be recommended until the nursing mother has completely weaned her child. Small amounts of the contraceptive steroids and / or their metabolites may be excreted with the milk but there is no evidence that this adversely affects the infant's health.

4.7 Effects on ability to drive and use machines

Dadiva has no or negligible influence on the ability to drive and use machines.

4.8 Undesirable effects

The most frequently reported undesirable effects in the clinical trials with Dadiva were headache and vaginal infections and vaginal discharge, each reported by 5–6% of the women.

Description of selected adverse reactions

An increased risk of arterial and venous thrombotic and thromboembolic events, including myocardial infarction, stroke, transient ischaemic attacks, venous thrombosis and pulmonary embolism has been observed in women using CHCs, which are discussed in more detail in section 4.4.

Also other undesirable effects have been reported in women using CHCs: these are discussed in more detail in section 4.4.

Adverse drug reactions that have been reported in clinical trials, observational studies, or during postmarketing use with Dadiva 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).

1) Listing of adverse events based on spontaneous reporting.

Hormone-dependent tumours (e.g. liver tumours, breast cancer) have been reported in association with CHC use. For further information see section 4.4.

On very rare occasions Dadiva has been reported to get disconnected during use (see sections 4.4 and 4.5).

Interactions

Breakthrough bleeding and/or contraceptive failure may result from interactions of other drugs (enzyme inducers) with hormonal contraceptives (see section 4.5).

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. Healthcare professionals are asked to report any suspected adverse reactions via

Yellow Card Scheme

Website: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.

4.9 Overdose

There have been no reports of serious deleterious effects from an overdose of hormonal contraceptives. Symptoms that may occur in this case are: nausea, vomiting and, in young girls, slight vaginal bleeding. There are no antidotes and further treatment should be symptomatic.

5 PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties

Pharmacotherapeutic group: Other gynecologicals, Intravaginal contraceptives, vaginal ring with progestagen and oestrogen, ATC code: G02BB01.

Mechanism of action

Dadiva contains etonogestrel and ethinylestradiol. Etonogestrel is a 19-nortestosterone-derived progestagen and binds with high affinity to progesterone receptors in the target organs. Ethinylestradiol is an oestrogen widely used in contraceptive products. The contraceptive effect of ring containing etonogestrel/et­hinylestradiol is based on various mechanisms, the most important of which is the inhibition of ovulation.

Clinical efficacy and safety

Clinical studies were performed worldwide (US, EU, and Brazil) in women between the ages of18 and 40 years. The contraceptive efficacy appeared to be at least comparable with that known for combined oral contraceptives. The following table shows the Pearl Indices (number of pregnancies per 100 woman years of use) found in the clinical studies with ring containing etonogestrel/et­hinylestradiol.

With the use of higher-dosed COCs (0.05 mg ethinylestradiol) the risk of endometrial and ovarian cancer is reduced. Whether this also applies to a lower-dosed contraceptive like ring containing etonogestrel/et­hinylestradiol remains to be determined.

BLEEDING PATTERN

A large comparative study with 150/30 ^g levonorgestrel/et­hinylestradiol OC (n=512 vs n=518) evaluating vaginal bleeding characteristics over 13 cycles showed low incidences of breakthrough spotting or bleeding for ring containing etonogestrel/et­hinylestradiol (2.06.4%). Furthermore, vaginal bleeding was exclusively restricted to the ring-free interval for most subjects (58.8–72.8 %).

EFFECTS ON BONE MINERAL DENSITY

The effects of ring containing etonogestrel/et­hinylestradiol (n=76) on bone mineral density (BMD) were studied in comparison to a non-hormonal intrauterine device (IUD) (n=31) in women over a period of two years. No adverse effects on bone mass have been observed.

Paediatric population

The safety and efficacy of ring containing etonogestrel/et­hinylestradiol in adolescents under the age of 18 have not been studied.

5.2 Pharmacokinetic properties

Etonogestrel

Absorption

Etonogestrel released by ring containing etonogestrel/et­hinylestradiol is rapidly absorbed by the vaginal mucosa. Maximum serum concentrations of etonogestrel of approximately 1,700 pg/mL are reached at about 1 week after insertion. Serum concentrations show small fluctuations and slowly decrease to approximately 1,600 pg/mL after 1 week, 1,500 pg/mL after 2 weeks and 1,400 pg/mL after 3 weeks of use. Absolute bioavailability is approximately 100%, which is higher than after oral administration. Cervical and intrauterine etonogestrel levels were measured in a small number of women using ring containing etonogestrel/et­hinylestradiol or an oral contraceptive containing 0.150 mg desogestrel and 0.020 mg ethinylestradiol. The observed levels were comparable.

Distribution

Etonogestrel is bound to serum albumin and to sex hormone binding globulin (SHBG). The apparent volume of distribution of etonogestrel is 2.3 L/kg.

Biotransformation

Etonogestrel is metabolized by the known pathways of steroid metabolism. The apparent clearance from serum is about 3.5 L/h. No direct interaction was found with the co-administered ethinylestradiol.

Elimination

Etonogestrel serum levels decrease in two phases. The terminal elimination phase is characterized by a half-life of approximately 29 hours. Etonogestrel and its metabolites are excreted at a urinary to biliary ratio of about 1.7:1. The half-life of metabolite excretion is about 6 days.

Ethinylestradiol

Absorption

Ethinylestradiol released by ring containing etonogestrel/et­hinylestradiol is rapidly absorbed by the vaginal mucosa. Maximum serum concentrations of about 35 pg/mL are reached 3 days after insertion and decrease to 19 pg/mL after 1 week, 18 pg/mL after 2 weeks and 18 pg/mL after 3 weeks of use. The monthly systemic ethinylestradiol exposure (AUCO-o) with ring containing etonogestrel/et­hinylestradiol is 10.9 ng.h/mL. Absolute bioavailability is approximately 56%, which is comparable with oral administration of ethinylestradiol. Cervical and intrauterine ethinylestradiol levels were measured in a small number of women using ring containing etonogestrel/et­hinylestradiol or an oral contraceptive containing 0.150 mg desogestrel and 0.020 mg ethinylestradiol. The observed levels were comparable.

Distribution

Ethinylestradiol is highly but non-specifically bound to serum albumin. An apparent volume of distribution of about 15 L/kg was determined.

Biotransformation

Ethinylestradiol is primarily metabolized by aromatic hydroxylation but a wide variety of hydroxylated and methylated metabolites are formed. These are present as free metabolites and as sulphate and glucuronides conjugates. The apparent clearance is about 35 L/h.

Elimination

Ethinylestradiol serum levels decrease in two phases. The terminal elimination phase is characterized by a large individual variation in half-life, resulting in a median half-life of approximately 34 hours.

Unchanged ethinylestradiol is not excreted; ethinylestradiol metabolites are excreted at a urinary to biliary ratio of 1.3:1. The half-life of metabolite excretion is about 1.5 days.

Special populations

Paediatric population

The pharmacokinetics of ring containing etonogestrel/et­hinylestradiol in healthy postmenarcheal female adolescents under the age of 18 have not been studied.

Effect of renal impairment

No studies were performed to evaluate the effect of renal disease on the pharmacokinetics of ring containing etonogestrel/et­hinylestradiol.

Effect of hepatic impairment

No studies were conducted to evaluate the effect of hepatic disease on the pharmacokinetics of ring containing etonogestrel/et­hinylestradiol ring containing etonogestrel/et­hinylestradiol. However, steroid hormones may be poorly metabolized in women with impaired liver function.

Ethnic groups

No formal studies were performed to assess pharmacokinetics in ethnic groups.

5.3 Preclinical safety data

Non-clinical data with ethinylestradiol and etonogestrel reveal no special hazard for humans based on conventional studies of safety pharmacology, repeated dose toxicity, genotoxicity, carcinogenic potential, and toxicity to reproduction, other than those already known for humans.

Environmental Risk Assessment (ERA)

Environmental risk assessment studies have shown that 17a-ethinylestradiol and etonogestrel may pose a risk to surface water organisms (see section 6.6).

6 PHARMACEUTICAL PARTICULARS

6.1 List of excipients

Ethylene vinylacetate copolymer, 28% vinylacetate;

ethylene vinylacetate copolymer, 9% vinylacetate;

magnesium stearate.

6.2 Incompatibilities

Not applicable.

6.3 Shelf life

24 months.

6.4 Special precautions for storage

This medicinal product does not require any special temperature storage conditions.

Store in the original package in order to protect from light.

6.5 Nature and contents of container

Sachet containing one Dadiva The sachet is made of aluminum foil with an inner layer of low-density polyethylene and an outer layer of polyethylene terephthalate (PET). Depending on the country, it is reclosable or non-reclosable. The sachet is packed in a printed cardboard box together with the package leaflet. Each box contains 1, 3 or 6 rings.

Not all pack sizes may be marketed.

6.6 Special precautions for disposal

See section 4.2.

Dadiva should be inserted prior to the expiry date. After removal, Dadiva should be replaced in the sachet and disposed of with the normal household waste in a manner that avoids accidental contact with others. This medicinal product may pose a risk to the environment (see section 5.3). Dadiva should not be flushed down the toilet. Any unused (expired) rings should be disposed of in accordance with local requirements.