JASMINE 0,03 mg/3 mg Cpr pell Plq/63

Film-coated tablet (pale yellow, round, with convex faces, marked with the letters "DO" within a regular hexagon on one of the faces).
Box of 3 blister packs of 21.

For a film-coated tablet:

Drospirenone: 3,00 mg
Ethinylestradiol: 0,03 mg

Excipient with known effect: lactose 46 mg (as lactose monohydrate 48,17 mg).

Excipients:

Oral contraception.

The decision to prescribe JASMINE must take into account the patient's risk factors, in particular her venous thromboembolism (VTE) risk factors, as well as the VTE risk associated with JASMINE in comparison with other CHCs (Combined Hormonal Contraceptives) (see sections Contraindications and Warnings and precautions).

Method of administration

Oral use.

Dosage

Directions for use of JASMINE:

The tablets must be taken every day, at about the same time, possibly with a little liquid, following the order indicated on the blister pack.

Take one tablet every day for 21 consecutive days.

Start the next pack after a break of 7 days during which a withdrawal bleed usually occurs. This usually begins 2 or 3 days after the last tablet. It is possible that this withdrawal bleed may not have finished when starting the next pack.

Initiation of treatment with JASMINE:

• No previous hormonal contraception (in the previous month):
  Tablet taking must start on day 1^er of the cycle, i.e. the first day of menstruation.
• Switching from another estrogen-progestogen contraceptive method (combined oral contraceptive/COC, vaginal ring or transdermal patch):
  Start JASMINE treatment preferably on the day following the intake of the last active tablet (last tablet containing the active substances) of the previous COC, or at the latest on the day following the usual tablet-free interval, or the day after the last placebo tablet of the previous COC. In case of switching from a vaginal ring or transdermal patch, take the 1^er JASMINE tablet preferably on the day of removal, or at the latest on the day planned for the new insertion.
• Switching from a progestogen-only contraceptive (progestogen-only pill, injectable form, implant), or from an intrauterine system (IUS) containing a progestogen:
  In a woman, the switch may be made:
  • at any time in the cycle if it is a progestogen-only pill,
  • on the day of removal if it is an implant or IUS,
  • or on the day scheduled for the next injection if it is an injectable form.
  
  In all cases, women will be advised to use an additional mechanical contraceptive method during the first 7 days of taking JASMINE.
• After a termination of pregnancy during the first trimester:
  It is possible to start contraception immediately in these women. It is not necessary to use an additional contraceptive method.
• After delivery or termination of pregnancy during the second trimester:
  Women will be advised to start contraception only after 21 to 28 days. If this contraception is started later, they will be advised to use an additional mechanical contraceptive method during the first 7 days of treatment. However, if sexual intercourse has already taken place, it should be ensured that the woman is not pregnant before starting to take the oral combined contraceptive or wait for the first menstrual period.

In case of breastfeeding, see section Fertility, pregnancy and breastfeeding.

Management in case of one or more missed tablets:

A delay of less than 12 hours in taking one tablet does not alter contraceptive efficacy. Women will be advised to take the missed tablet immediately as soon as the omission is noticed; the following tablets are taken at the usual time.

If the delay is of more than 12 hours, contraceptive efficacy may be reduced. In case of forgotten tablets, the following two rules must be known, as they are necessary for choosing the course of action:

1. The interval between 2 packs must never exceed 7 days;
2. Seven days of uninterrupted treatment are necessary in order to achieve adequate inhibition of the hypothalamic-pituitary-ovarian axis.

Accordingly, the following advice may be given in daily practice.

• Week 1:

Women should be asked to take the last missed tablet as soon as the omission is noticed, even if this means taking two tablets at the same time.

The following tablets should be taken at the usual time. However, complementary mechanical contraception (condoms, for example) is necessary during the following 7 days. If sexual intercourse has taken place during the 7 days preceding the missed tablet, there is a risk of pregnancy.

The risk of pregnancy is all the higher the greater the number of missed tablets or the closer the date of the omission is to the start of the pack.

• Week 2:

Women should be advised to take the last missed tablet as soon as the omission is noticed, even if this means taking two tablets at the same time.

The following tablets should be taken at the usual time.

If the tablets have been taken correctly during the 7 days preceding the first missed tablet, no complementary contraceptive measures are necessary. However, in case of several missed tablets, women should be advised to take additional precautions for 7 days.

• Week 3:

The risk of reduced contraceptive activity is at its maximum due to the proximity of the 7-day break. However, it is possible to prevent the reduction of the contraceptive effect by adjusting the tablet-taking arrangements as follows:

• • If the woman has taken all tablets correctly during the 7 days preceding the omission of a tablet, no additional contraceptive measures are necessary. It is possible to follow one of the 2 intake schemes described below.
  • Otherwise, women should be advised to follow the first intake scheme and to use an additional contraceptive method during the following 7 days.

Diagram 1:

Women will be advised to take the last missed tablet as soon as the omission is noticed, even if two tablets must be taken at the same time. Subsequent tablets will then be taken at the usual time. The next pack should be started immediately after the end of the previous one, i.e., without a break between the two packs. A withdrawal bleed is unlikely before the end of the second pack, but spotting (drops or spots of blood) or metrorrhagia may be observed during the period of tablet taking.

Scheme 2:

A break in taking the tablets of the current blister pack may alternatively be advised to women in this situation. In this case, a break of no more than 7 days, including the number of days on which tablets were forgotten, must be observed before starting the next blister pack.

In a woman who has forgotten to take one (or more) tablet(s), the absence of withdrawal bleeding between the two packs should prompt investigation for a possible pregnancy.

Action to take in case of gastrointestinal disorders:

In case of severe gastrointestinal disorders (for example vomiting or diarrhoea), absorption of a tablet may not be complete; additional contraceptive measures must therefore be taken.

• If vomiting occurs within 3-4 hours of taking a tablet, a new replacement tablet must be taken as soon as possible. The new tablet should, if possible, be taken within 12 hours of the usual time of intake.
• If more than 12 hours have elapsed, the same instructions as those given for missed tablets must apply (see section Dosage and administration "Management of missed one or more tablets").

If the woman does not wish to change her normal tablet-taking schedule, she must take the additional tablet(s) from another pack.

How to delay menstruation?

The onset of menstruation can be delayed by starting a new pack of JASMINE without observing a break interval. Menstruation may be delayed until the end of the second pack if necessary. During this period, breakthrough bleeding or spotting may occur. JASMINE may then be resumed normally after the usual break interval of 7 days.

It is possible to shift the onset of menstruation to another day of the week by shortening the duration of the tablet-free interval by the required number of days.

As with delaying menstruation, the shorter the interval between two blister packs, the greater the risk of no withdrawal bleeding and of breakthrough bleeding or spotting when taking the tablets of the next blister pack.

Additional information concerning special populations:

Paediatric population

JASMINE is indicated only after the onset of the first menstruation. Epidemiological data collected on more than 2 000 adolescent girls aged under 18 years showed no differences in tolerability and efficacy in this young population compared with women aged over 18 years.

Elderly patients

JASMINE is not indicated after menopause.

Patients with hepatic impairment

JASMINE is contraindicated in women with severe hepatic disease (see also sections Contraindications and Pharmacokinetics).

Patients with renal impairment

JASMINE is contraindicated in women with severe renal failure or acute renal failure (see also sections Contraindications and Pharmacokinetics).

Combined hormonal contraceptives (CHCs) must not be used in the following situations.

If any of these conditions occur for the first time while taking a CHC, stop treatment immediately:

• Presence or risk of venous thromboembolism (VTE):
  • Venous thromboembolism – presence of VTE (patient being treated with anticoagulants) or history of VTE (e.g. deep vein thrombosis [DVT] or pulmonary embolism [PE]);
  • Known inherited or acquired predisposition to venous thromboembolism, such as activated protein C (APC) resistance (including factor V Leiden mutation), antithrombin III deficiency, protein C deficiency, protein S deficiency;
  • Major surgery with prolonged immobilisation (see section Warnings and precautions) ;
  • High risk of venous thromboembolism due to the presence of multiple risk factors (see section Warnings and precautions).
• Presence or risk of arterial thromboembolism (ATE):
  • Arterial thromboembolism – presence or history of arterial thromboembolism (e.g. myocardial infarction [MI]) or prodromal conditions (e.g. angina pectoris);
  • Cerebrovascular disease – presence or history of stroke or prodromal conditions (e.g. transient ischaemic attack [TIA]);
  • Known inherited or acquired predisposition to arterial thromboembolism, such as hyperhomocysteinaemia or the presence of antiphospholipid antibodies (anticardiolipin antibodies, lupus anticoagulant);
  • History of migraine with focal neurological signs;
  • High risk of arterial thromboembolism due to the presence of multiple risk factors (see section Warnings and precautions) or a severe risk factor such as:
    • diabetes with vascular symptoms,
    • severe hypertension,
    • severe dyslipoproteinaemia;
• Severe hepatic disease or history of severe hepatic disease, where liver function tests have not returned to normal;
• Severe or acute renal failure;
• Active or previous hepatic tumour (benign or malignant);
• Known or suspected hormone-dependent malignant tumour (example: genital organs or breasts);
• Vaginal bleeding of unknown origin;
• Hypersensitivity to the active substance(s) or to any of the excipients listed in section Composition.

Concomitant use of JASMINE with medicinal products containing ombitasvir/paritaprevir/ritonavir and dasabuvir or with medicinal products containing glecaprevir/pibrentasvir or sofosbuvir/velpatasvir/voxilaprevir is contraindicated (see section Interactions).

Special warnings

If the patient has any of the disorders or any of the risk factors mentioned below, the appropriateness of treatment with JASMINE should be discussed with her.

In the event of worsening or onset of any of these disorders or risk factors, the need to discontinue use of JASMINE should be discussed between the physician and the patient.

In the event of onset or suspicion of VTE or ATE, oral contraception must be discontinued. Due to the teratogenic potential of anticoagulant treatment with coumarin derivatives, another appropriate contraceptive method must be instituted.

Circulatory disorders:

Risk of venous thromboembolism (VTE)

The risk of VTE is increased in women who use a combined hormonal contraceptive (CHC) compared with women who do not use one. CHCs containing levonorgestrel, norgestimate or norethisterone are associated with the lowest risk of VTE. The risk of VTE associated with other CHCs, such as JASMINE, may be up to twice as high. The decision to use any CHC other than those associated with the lowest risk of VTE should be taken only after consultation with the patient to ensure she understands the risk of VTE associated with JASMINE, the influence of her current risk factors on this risk, and the fact that the risk of VTE is highest during the first year of use. Some data also indicate an increased risk when restarting a CHC after an interruption of 4 weeks or more.

Among women who do not use CHCs and are not pregnant, approximately 2 out of 10 000 will develop a VTE over a period of one year. However, for an individual woman, the risk may be considerably higher, depending on the risk factors she has (see below).

It is estimated¹ that out of 10 000 women who use a CHC containing drospirenone, 9 to 12 will develop a VTE over a one-year period; this number is to be compared with approximately 6² in women who use a CHC containing levonorgestrel.

In both cases, the number of VTEs per year is lower than that expected during pregnancy or in the postpartum period.

VTE may be fatal in 1 to 2 % of cases.

Number of VTE cases per 10 000 women over a one-year period

Very rarely, cases of thrombosis have been reported in CHC users in other blood vessels, e.g. hepatic, mesenteric, renal, or retinal veins and arteries.

¹ These incidences were estimated from all the data from epidemiological studies, based on the relative risks associated with the different CHCs compared with levonorgestrel-containing CHCs.

² central point of the range of 5-7 for 10 000 woman-years based on a relative risk, for levonorgestrel-containing CHCs compared with non-use of a CHC, of approximately 2,3 to 3,6.

Risk factors for VTE:

The risk of venous thrombo-embolic complications in users of CHC may be considerably increased if other risk factors are present, in particular if these are multiple (see the table below).

JASMINE is contraindicated in women with multiple risk factors that expose them to a high risk of venous thrombosis (see section Contraindications). When a woman has more than one risk factor, the increase in risk may be greater than the sum of the risks associated with each individual factor - in this case, the overall risk of VTE should be taken into account. If the benefit/risk balance is judged to be unfavourable, the CHC must not be prescribed (see section Contraindications).

Table: VTE risk factors

Risk factor	Comment
Obesity (body mass index greater than 30 kg/m2)	The increase in BMI considerably increases the risk. This is particularly important to consider if other risk factors are present.
Prolonged immobilisation, major surgical intervention, any surgical intervention on the legs or pelvis, neurosurgery or major trauma	In these situations, it is advised to discontinue use of the pill (at least four weeks in advance in the case of planned surgery) and to resume the CHC only two weeks or more after complete remobilisation. Another method of contraception must be used in order to avoid an unwanted pregnancy. Anti-thrombotic treatment should be considered if JASMINE has not been discontinued in advance.
Note: temporary immobilisation, including air travel > 4 hours, may also be a risk factor for VTE, particularly in women with other risk factors
Family history (venous thromboembolism in a sibling or parent, especially at a relatively young age, i.e. before 50 years)	In case of suspected hereditary predisposition, the woman should be referred to a specialist for advice before any decision regarding the use of CHC
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
Age	In particular above 35 years

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

The increased risk of thromboembolism during pregnancy, and in particular during the 6 weeks of the postpartum period, must be taken into account (for information on "Fertility, pregnancy and breast-feeding", see section Fertility, pregnancy and breastfeeding).

Symptoms of VTE (deep vein thrombosis and pulmonary embolism):

Women should be informed that if these symptoms occur, they should seek urgent medical attention and tell the doctor that they are using a CHC.

Symptoms of deep venous thrombosis (DVT) may include:

• unilateral swelling of one leg and/or foot or along a vein of the leg;
• pain or tenderness in one leg, which may only be felt when standing or walking;
• warmth, redness or change in skin colour of the affected leg.

Symptoms of pulmonary embolism (PE) may include:

• sudden and unexplained onset of shortness of breath or rapid breathing;
• sudden cough, which may be associated with haemoptysis;
• acute chest pain;
• severe dizziness or light-headedness;
• rapid or irregular heartbeat.

Some of these symptoms (e.g. "shortness of breath", "cough") are not specific and may be wrongly interpreted as signs of more frequent or less severe events (e.g. respiratory infections).

Other signs of vascular occlusion may include: sudden pain, swelling and slight blue discolouration of a limb.

If the occlusion occurs in the eye, symptoms may begin as painless blurred vision that may progress to loss of vision. In some cases, loss of vision may occur almost immediately.

Risk of arterial thromboembolism (ATE)

Epidemiological studies have shown an association between the use of CHC and an increased risk of arterial thromboembolism (myocardial infarction) or 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 cerebrovascular accident in CHC users increases with the presence of risk factors (see table). JASMINE is contraindicated in women with a severe risk factor or multiple risk factors for ATE that expose them to a high risk of arterial thrombosis (see section Contraindications). When a woman has more than one risk factor, the increase in risk may be greater than the sum of the risks associated with each factor taken individually - in this case, the overall risk must be taken into account. If the benefit/risk balance is judged to be unfavourable, CHC should not be prescribed (see section Contraindications).

Table: Risk factors for ATE

Risk factor	Comment
Age	In particular above 35 years
Smoking	Women should be advised not to smoke if they wish to use a CHC. Women over 35 years of age who continue to smoke should be strongly advised to use a different method of contraception.
Arterial hypertension
Obesity (body mass index greater than 30 kg/m2)	The increase in BMI considerably increases the risk. This is particularly important to consider in women with other risk factors.
Family history (arterial thromboembolism occurring in a sibling or parent, particularly at a relatively young age, i.e. before 50 years)	In case of suspected hereditary predisposition, the woman should be referred to a specialist for advice before any decision regarding the use of CHC.
Migraine	Increased frequency or severity of migraines during use of a CHC (which may be the prodrome of a cerebrovascular event) may constitute a reason for immediate discontinuation of the CHC.
Other medical conditions associated with adverse vascular events	Diabetes, hyperhomocysteinaemia, heart valve disease and atrial fibrillation, dyslipoproteinaemia and systemic lupus erythematosus

Symptoms of ATE:

Women should be informed that if these symptoms occur, they should seek urgent medical attention and tell the doctor that they are using a CHC.

Symptoms of a cerebrovascular accident may include:

• sudden onset of numbness or weakness of the face, arm or leg, especially on one side of the body;
• sudden onset of difficulty walking, dizziness, loss of balance or coordination;
• sudden onset of confusion, difficulty speaking or understanding;
• sudden onset of difficulty 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 that this is a transient ischaemic attack (TIA).

Symptoms of myocardial infarction (MI) may include:

• pain, discomfort, pressure, heaviness, sensation of tightness or congestion in the chest, the arm or under the sternum;
• sensation of discomfort radiating to the back, jaw, throat, arm, stomach;
• sensation of congestion, indigestion or suffocation;
• sweating, nausea, vomiting or dizziness;
• extreme weakness, anxiety or shortness of breath;
• rapid or irregular heartbeat.

Cancers:

Some epidemiological studies suggest that oral contraceptives may be associated with an increased risk of cervical cancer in long-term COC users (> 5 years). However, it has not been established whether these pathologies are due to other factors such as sexual behaviour and the papillomavirus human (HPV).

A meta-analysis of 54 epidemiological studies concluded that there is a slight increase in relative risk (RR = 1,24) of breast cancer in women using oral contraception. This increased risk gradually disappears over the 10 years following discontinuation of oral contraception.

As breast cancer is rare in women under 40 years of age, the higher number of cancers diagnosed in regular or new users of oral contraception remains low compared with the overall risk of breast cancer.

These studies do not establish a causal relationship. It is possible that, in oral contraceptive users, this increased risk is due to earlier diagnosis of breast cancer, to the biological effects of this contraception, or to a combination of both.

Breast cancers diagnosed in users tend to be clinically less advanced compared with those diagnosed in women who have never used it.

In rare cases, benign liver tumours, and in even rarer cases, malignant liver tumours have been reported in oral contraceptive users.

In isolated cases, these tumours have led to intra-abdominal haemorrhage threatening the vital prognosis. In women taking oral contraceptives, the occurrence of upper abdominal pain, enlargement of the liver or signs of intra-abdominal haemorrhage should prompt consideration of a liver tumour.

The use of more highly dosed oral contraceptives (50 μg of ethinylestradiol) reduces the risk of endometrial and ovarian cancer. This needs to be confirmed with lower-dose oral contraceptives.

Other pathologies:

JASMINE contains a progestogen that is an aldosterone antagonist with potassium-sparing properties. In most cases, no increase in serum potassium is expected. However, in one clinical study, a moderate, non-significant increase in serum potassium was observed in patients with mild to moderate renal impairment when drospirenone was taken concomitantly with potassium-sparing medicinal products. Therefore, it is recommended to check serum potassium during the first cycle of treatment in patients with renal impairment whose serum potassium is in the upper limit of normal before treatment, particularly in case of concomitant use of potassium-sparing medicinal products (see also section Interactions).

In women with hypertriglyceridaemia or with a family history of hypertriglyceridaemia, an increased risk of pancreatitis may occur when using oral contraception.

A moderate increase in blood pressure has been observed in many women taking oral contraception: rarely clinically significant. Immediate discontinuation of oral contraception is justified only in these rare cases.

Persistently high blood pressure readings, or failure to control blood pressure with antihypertensive treatment in a hypertensive woman taking oral contraception, should lead to its discontinuation. Oral contraception may possibly be resumed once blood pressure has been normalised with antihypertensive treatment.

The onset or worsening of the following pathologies has been observed during pregnancy or in women taking oral contraceptives, although a causal role of estrogen-progestogen combinations has not been established: jaundice and/or pruritus due to cholestasis, cholelithiasis, porphyria, systemic lupus erythematosus, haemolytic uraemic syndrome, Sydenham's chorea, herpes gestationis, hearing impairment due to otosclerosis.

Exogenous oestrogens may induce or exacerbate symptoms of hereditary or acquired angioedema.

The occurrence of acute or chronic liver abnormalities may require discontinuation of oral contraceptives until liver parameters return to normal.

Recurrence of cholestatic jaundice and/or pruritus associated with cholestasis that occurred during a previous pregnancy or prior use of steroid hormones should lead to discontinuation of oral contraceptives.

Oral contraceptives may have an effect on peripheral insulin resistance and glucose tolerance; however, it is not mandatory to modify treatment in diabetic patients using low-dose oral contraception (containing less than 0,05 mg of ethinylestradiol). Diabetic women should nevertheless be closely monitored, particularly when starting oral contraception.

Cases of worsening of epilepsy, Crohn's disease and ulcerative colitis have been observed with oral contraceptives.

Depressive mood and depression are well-known undesirable effects associated with the use of hormonal contraceptives (see section Adverse effects). Depression can be severe and is a well-known risk factor for suicidal behaviour and suicide. Women should be advised to contact their physician in the event of mood changes and depressive symptoms, including shortly after treatment initiation.

Chloasma may occur, particularly in women with a history of gravid chloasma. Women with a predisposition to chloasma while on oral contraceptives should avoid exposure to the sun or ultraviolet rays.

This medicine contains 46 mg of lactose per tablet. This should be taken into account in patients with rare hereditary disorders such as galactose intolerance, Lapp lactase deficiency or glucose-galactose malabsorption syndrome, or in case of a lactose-free diet.

Medical consultation/examination:

Before initiating or resuming treatment with JASMINE, a complete medical history (including family history) should be taken and pregnancy must be excluded. Blood pressure should be measured and a physical examination should be carried out, bearing in mind the contraindications (see section Contraindications) and warnings (see section Warnings and precautions). It is important to draw patients' attention to information regarding venous and arterial thrombosis, including the risk associated with JASMINE compared with that associated with other CHCs, the symptoms of VTE and ATE, known risk factors and the action to take in case of suspected thrombosis.

Patients should also be advised to read the leaflet carefully and follow the advice provided. The frequency and nature of examinations should be defined on the basis of current recommendations and adapted to each patient.

Patients must be informed that hormonal contraceptives do not protect against infection with HIV (AIDS) or other sexually transmitted diseases.

Reduced efficacy:

The efficacy of a COC may be reduced in case of missed tablets (see section Dosage and administration), gastrointestinal disorders (see section Dosage and administration) or concomitant use of certain medicinal products (see section Interactions).

Cycle disorders:

Irregular bleeding (spotting or breakthrough bleeding) may occur with oral contraceptives, particularly during the first months. This irregular bleeding will be considered significant if it persists after approximately 3 cycles.

If irregular bleeding persists or occurs after previously regular cycles, non-hormonal causes should be investigated; appropriate diagnostic measures should be taken to exclude malignancy or pregnancy. These measures may include curettage.

In some women, withdrawal bleeding may not occur during the pill-free interval. If the oral contraceptive has been taken as described in section Dosage and administration, it is unlikely that the woman is pregnant. However, if the oral contraceptive was not taken correctly before the first missed withdrawal bleed, or if two consecutive withdrawal bleeds do not occur, pregnancy should be ruled out before continuing the contraceptive.

NB: information on the prescribing of concomitant medicines should be consulted to identify any potential interactions.

Effects of other medicines on JASMINE

Interactions may occur with medicines that induce microsomal enzymes, which can lead to increased clearance of sex hormones, potentially causing breakthrough bleeding and/or contraceptive failure.

Management

Enzyme induction may be observed after only a few days of treatment. Maximal enzyme induction is generally observed within the first weeks. After discontinuation of treatment, enzyme induction may persist for approximately 4 weeks.

Short-term treatment

Women treated with enzyme-inducing medicines should temporarily use a mechanical or other contraceptive method in addition to the COC. The mechanical contraceptive method should be used throughout the duration of the concomitant treatment and for 28 days after discontinuation. If the concomitant treatment extends beyond the end of the COC pack, the next pack should be started immediately after the previous one, without observing the usual pill-free interval.

Long-term treatment

In women on long-term treatment with a medicine that has an enzyme-inducing effect on the liver, another reliable, non-hormonal contraceptive method is recommended.

The following interactions have been reported in the literature.

Substances increasing the clearance of COCs (COC efficacy reduced by enzyme induction), for example :

Barbiturates, bosentan, carbamazepine, phenytoin, primidone, rifampicin, anti-HIV medicines: ritonavir, nevirapine and efavirenz, and also potentially: felbamate, griseofulvin, oxcarbazepine, topiramate, and products containing St John's wort (Hypericum perforatum), a medicinal plant.

Substances with variable effects on COC clearance:

Co-administered with COCs, many combinations of HIV protease inhibitors and non-nucleoside reverse transcriptase inhibitors, including combinations with HCV inhibitors, may increase or decrease plasma concentrations of estrogens or progestins. The net effect of these changes may be clinically significant in some cases.

Therefore, the prescribing information for HIV/HCV medicines should be consulted to identify potential interactions and associated recommendations. If in doubt, women treated with a protease inhibitor or a non-nucleoside reverse transcriptase inhibitor should use an additional mechanical contraceptive method.

Substances decreasing COC clearance (enzyme inhibitors):

The clinical relevance of potential interactions with enzyme inhibitors remains unknown.

Concomitant administration of potent CYP3A4 inhibitors may increase plasma concentrations of estrogen, progestogen, or both.

In a multiple-dose study with a combination of drospirenone (3 mg/day)/ethinylestradiol (0,02 mg/day), co-administration of ketoconazole, a potent CYP3A4 inhibitor, for 10 days increased the AUC(0-24 h) of drospirenone by 2,7-fold and of ethinylestradiol by 1,4-fold.

It has been shown that daily doses of 60 to 120 mg of etoricoxib taken concomitantly with a combined hormonal contraceptive containing 0.035 mg of ethinylestradiol increased plasma ethinylestradiol concentrations by 1,4 to 1,6-fold, respectively.

Effects of JASMINE on other medicinal products

COCs may alter the metabolism of certain other active substances. Plasma and tissue concentrations may therefore be either increased (e.g. ciclosporin) or decreased (e.g. lamotrigine).

In female volunteers, interaction studies in vivo performed with omeprazole, simvastatin and midazolam as markers showed that a clinically significant interaction of drospirenone at doses of 3 mg with the metabolism of other medicinal products involving cytochrome P450 is unlikely.

Clinical data suggest that ethinylestradiol inhibits the clearance of CYP1A2 substrates, thereby leading to a small (e.g. theophylline) or moderate (e.g. tizanidine) increase in their plasma concentrations.

Pharmacodynamic interactions

In clinical trials conducted in patients treated for hepatitis C virus (HCV) infection and receiving medicines containing ombitasvir/paritaprevir/ritonavir and dasabuvir, with or without ribavirin, transaminase (ALT) elevations greater than 5 times the upper limit of normal (ULN) were observed, significantly more frequently in women using medicines containing ethinylestradiol, such as combined hormonal contraceptives (CHCs). In addition, in patients treated with glecaprevir/pibrentasvir or sofosbuvir/velpatasvir/voxilaprevir, ALT elevations were observed in women using medicines containing ethinylestradiol such as CHCs (see section Contraindications).

Therefore, JASMINE users should switch to an alternative contraceptive method (e.g. progestogen-only contraception or non-hormonal methods) before starting treatment with these medicinal product combinations. JASMINE may be restarted 2 weeks after the end of treatment with these medicinal product combinations.

In patients with normal renal function, the combination of drospirenone with an ACE inhibitor or an NSAID has not shown a significant effect on serum potassium. Nevertheless, the use of JASMINE in combination with aldosterone antagonists or potassium-sparing diuretics has not been studied. In this case, serum potassium measurement during the first treatment cycle is recommended (see also section Warnings and precautions).

Other forms of interactions

Laboratory examinations:

The use of hormonal contraceptives may alter the results of certain laboratory tests such as liver, thyroid, adrenal and renal function tests, plasma levels of (carrier) proteins such as corticosteroid-binding globulin (CBG), lipid/lipoprotein fractions, carbohydrate metabolism parameters, and coagulation and fibrinolysis parameters. Changes generally remain within the normal range. Due to its weak anti-mineralocorticoid activity, drospirenone increases plasma renin activity and aldosterone levels.

Pregnancy

JASMINE is not indicated during pregnancy.

If pregnancy is diagnosed during treatment with JASMINE, its use should be stopped immediately.

Numerous epidemiological studies have not revealed an increased risk of congenital anomalies in children born to women who used oral contraceptives before pregnancy. No teratogenic effect has been observed if a contraceptive was taken inadvertently during pregnancy.

Animal studies have shown the presence of adverse effects during pregnancy and lactation (see section Preclinical safety). Based on these animal data, an adverse effect due to the hormonal activity of the active substances cannot be excluded. However, based on experience with the use of oral contraceptives during pregnancy, such an adverse effect has not been observed in humans.

The available data on the use of JASMINE during pregnancy are too limited to draw conclusions regarding possible adverse effects of JASMINE on pregnancy or on the health of the foetus or newborn. No epidemiological data allow a conclusion to be drawn at this time.

The increased risk of VTE in the postpartum period must be taken into account when resuming JASMINE (see sections Dosage and administration and Warnings and precautions).

Breast-feeding

As hormonal contraceptives may influence the quantity and quality of breast milk, they are generally not recommended until breastfeeding has ended. The use of oral contraceptives may be accompanied by excretion of small amounts of these contraceptives and/or their metabolites in milk, which may have an effect on the child.

No studies on the effects on the ability to drive vehicles and use machines have been performed.

No effect on the ability to drive or use machines has been observed in users of oral contraceptives.

With regard to serious adverse reactions in users of COCs, see also the section Warnings and precautions.

The following adverse reactions have been reported during use of JASMINE:

System Organ Classes (MedDRA)	Frequency of adverse effects
	Common ≥ 1/100 to < 1/10	Uncommon ≥ 1/1 000 to < 1/100,	Rare ≥ 1/10 000 to < 1/1 000	Frequency not known
Immune system disorders			Hypersensitivity Asthma	Worsening of symptoms of hereditary or acquired angioedema
Psychiatric disorders	Depressed mood	Increased libido Decreased libido
Nervous system disorders	Headache
Ear and labyrinth disorders			Hypoacusis
Vascular disorders	Migraine	Hypertension Hypotension	Venous thromboembolism (VTE) Arterial thromboembolism (ATE)
Gastrointestinal disorders	Nausea	Vomiting Diarrhoea
Skin and subcutaneous tissue disorders		Acne Eczema Pruritus Alopecia	Erythema nodosum Erythema multiforme
Disorders of the reproductive system and breast	Menstrual disorders Intercurrent bleeding Breast pain Breast tenderness Vaginal discharge Vulvovaginal candidiasis	Increase in breast volume Vaginal infection	Breast discharge
General disorders and administration site conditions		Fluid retention Weight increased Decrease in weight

Description of certain particular adverse effects

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; this is discussed in more detail in section Warnings and precautions.

The following serious adverse effects that have been reported in women using COCs are discussed in the section Warnings and precautions :

• venous thromboembolic events,
• arterial thromboembolic events,
• hypertension,
• liver tumours,
• onset or worsening of conditions whose association with COCs is not certain: Crohn's disease, haemorrhagic colitis, epilepsy, uterine fibroid, porphyria, disseminated lupus erythematosus, herpes gestationis, Sydenham's chorea, haemolytic uraemic syndrome, cholestatic jaundice,
• chloasma,
• chronic or acute disturbances of liver function that may require discontinuation of a COC until liver function tests normalise.

The frequency of breast cancer diagnosis is very slightly increased in COC users. As breast cancer is rare in women under 40 years, this increase is small compared with the overall risk of breast cancer. The causal relationship with COC use remains unknown. For more information, refer to the sections Contraindications and Warnings and precautions.

Interactions

Breakthrough bleeding and/or contraceptive failure may result from interactions between oral contraceptives and other medicinal products (enzyme inducers) (see section Interactions).

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 the national reporting system: National Agency for the Safety of Medicines and Health Products (ANSM) and the network of Regional Pharmacovigilance Centres - Website: https://signalement.social-sante.gouv.fr/.

No cases of overdose have been reported with JASMINE.

The general experience with combined oral contraceptives shows that the symptoms that may appear in such a case are: nausea, vomiting and withdrawal bleeding. Withdrawal bleeding may also occur in girls before menarche if they accidentally take the medicine. There is no antidote and treatment must be purely symptomatic.

Pharmacotherapeutic class: Progestogens and Oestrogens. Fixed Combinations, ATC code: G03AA12.

Pearl Index for method failure: 0,09 (upper limit of the two-sided 95% confidence interval: 0,32)

Overall Pearl Index (method failure + patient failure): 0,57 (upper limit of the two-sided 95% confidence interval: 0,90).

The contraceptive effect of JASMINE relies on the interaction of various factors, the most important being inhibition of ovulation and changes in the endometrium.

JASMINE is an oral contraceptive combining ethinylestradiol and a progestogen, drospirenone. At therapeutic doses, drospirenone also has anti-androgenic properties and slight anti-mineralocorticoid activity. It has no oestrogenic, glucocorticoid or anti-glucocorticoid activity. Drospirenone therefore has a pharmacological profile close to that of the natural hormone, progesterone.

Clinical studies indicate that the slight anti-mineralocorticoid activity of JASMINE results in a moderate anti-mineralocorticoid effect.

DROSPIRENONE

Absorption

When administered orally, drospirenone is absorbed rapidly and almost completely. After a single administration, the peak serum concentration of the active substance, approximately 38 ng/ml, is reached in about one to two hours. Bioavailability is between 76 and 85%. Concomitant food intake has no influence on the bioavailability of drospirenone.

Distribution

After oral administration, serum concentrations of drospirenone decline with a terminal half-life of 31 hours. Drospirenone binds to serum albumin, but not to SHBG (sex hormone binding globulin) nor to CBG (corticosteroid binding globulin). Only 3 to 5% of the total serum concentrations of the active substance are found as free steroid. The increase in SHBG induced by ethinylestradiol does not influence the binding of drospirenone to serum proteins. The mean apparent volume of distribution of drospirenone is 3,7 ± 1,2 l/kg.

Biotransformation

After oral administration, drospirenone undergoes extensive metabolism. The main plasma metabolites are drospirenone acid, formed by opening of the lactone ring, and the 3-sulfate of 4,5-dihydrodrospirenone, formed by reduction followed by sulfation. Drospirenone also undergoes oxidative metabolism catalysed by CYP3A4.

In vitro, drospirenone is capable of weakly to moderately inhibiting the CYP1A1, CYP2C9, CYP2C19 and CYP3A4 isoforms of cytochrome P450.

Elimination

The serum metabolic clearance of drospirenone is 1,5 ± 0,2 ml/min/kg. Drospirenone is excreted unchanged only in trace amounts. Drospirenone metabolites are excreted via faeces and urine in a ratio of 1,2 to 1,4. The half-life of urinary and faecal excretion of the metabolites is approximately 40 h.

Conditions at steady state

During a treatment cycle, at steady state, the maximum serum concentrations of drospirenone (approximately 70 ng/ml) are reached after 8 days of treatment. Serum drospirenone levels accumulate by a factor of approximately 3, depending on the ratio of the terminal half-life to the dosing interval.

Special populations

Effect on renal impairment :

At steady state, in women with mild renal impairment (creatinine clearance Clcr, 50-80 ml/min), serum concentrations of drospirenone are comparable to those of women with normal renal function.

In women with moderate renal impairment (Clcr, 30-50 ml/min), serum concentrations of drospirenone are on average 37 % higher than those observed in women with normal renal function.

Treatment with drospirenone is also well tolerated by women with mild to moderate renal impairment. No clinically significant effect of drospirenone treatment on serum potassium has been observed.

Effect on hepatic impairment :

In a single-dose study, oral clearance (Cl/F) was decreased by approximately 50 % in volunteers with moderate hepatic impairment compared with those with normal hepatic function. This decrease in drospirenone clearance did not result in any apparent difference in serum potassium. No increase in serum potassium concentrations above the upper limit of normal was observed in the presence of diabetes and concomitant treatment with spironolactone (two risk factors for hyperkalaemia). It can be concluded that drospirenone is well tolerated in patients with mild or moderate hepatic impairment (Child-Pugh B).

Ethnic groups :

No clinically significant difference in the pharmacokinetic parameters of drospirenone and ethinylestradiol has been observed between Japanese and Caucasian women.

ETHINYLESTRADIOL

Absorption

After oral administration, absorption of ethinylestradiol is rapid and complete. Ingestion of 30 μg results in a peak plasma concentration of 100 pg/ml after 1 to 2 hours. Ethinylestradiol undergoes a significant first-pass effect, which is highly variable from one subject to another. Absolute bioavailability is approximately 45 %.

Distribution

The apparent volume of distribution of ethinylestradiol is 5 l/kg and its binding to plasma proteins is approximately 98 %. Ethinylestradiol induces hepatic synthesis of SHBG and CBG. During treatment with 30 μg of ethinylestradiol, the SHBG concentration increases from 70 to approximately 350 nmol/l.

Ethinylestradiol passes into breast milk in small quantities (0,02 % of the administered dose).

Biotransformation

Ethinylestradiol undergoes significant intestinal and hepatic first-pass metabolism. Ethinylestradiol is mainly metabolised by aromatic hydroxylation and is converted into numerous hydroxylated and methylated metabolites. These are present as free metabolites and as glucuronide and sulphate conjugates. The plasma metabolic clearance of ethinylestradiol is approximately 5 ml/min/kg.

In vitro, ethinylestradiol is a reversible inhibitor of CYP2C19, CYP1A1 and CYP1A2, as well as a suicide inhibitor of CYP3A4/5, CYP2C8, and CYP2J2.

Elimination

Ethinylestradiol is not excreted significantly unchanged. Metabolites of ethinylestradiol are excreted with a renal to biliary excretion ratio of 4/6. The elimination half-life of the metabolites is approximately 1 day. The elimination half-life is 20 hours.

Conditions at steady state

Steady state is reached during the second part of a treatment cycle and ethinylestradiol accumulates in serum by a factor of approximately 1,4 to 2,1.

In animals, the effects of drospirenone and ethinylestradiol are limited to those associated with the known pharmacological action. In particular, in reproduction studies, embryo- and foetotoxic effects were considered species-specific. At exposures higher than those used in JASMINE, an effect on sexual differentiation was observed in rat foetuses but not in monkeys. Environmental risk assessment studies have shown that ethinylestradiol and drospirenone have the potential to present a risk to the aquatic environment (see section Disposal and handling).

3 years.

Store at a temperature not exceeding 30 °C.

Store in the original blister pack, protected from moisture.

This medicine may present a risk to the environment (see section Preclinical safety). Any unused medicinal product or waste material should be disposed of in accordance with local requirements.

List I

Marketing authorisation (AMM)

CIP 3400935605672 (Blister/63).

Not reimbursed by Social Security.