Estradiol Valerate/Dienogest Tablets Taj Pharma

1.Name of the medicinal product

Estradiol Valerate and Dienogest, Tablets Taj Pharma

2.Qualitative and quantitative composition

Each wallet (28 film-coated tablets) contains in the following order:

2 dark yellow tablets
Each containing
Estradiol valerate 3mg
Excipients q.s.

5 medium red tablets
Each containing
Estradiol valerate                                          2mg
Dienogest                                                       2mg
Excipients                                                       q.s.

17 light yellow tablets
Each containing
Estradiol valerate                                          2mg
Dienogest                                                      3mg
Excipients                                                      q.s.

2 dark red tablets
Each containing
Estradiol valerate 1mg
Excipients q.s.

2 white tablets do not contain active substances

Excipient with known effect: lactose (not more than 50 mg per tablet)

For the full list of excipients, see section 6.1.

3.Pharmaceutical form

Film-coated tablet (tablet).

Dark yellow film-coated tablet, round with biconvex faces.

Medium red film-coated tablet, round with biconvex faces.

Light yellow film-coated tablet, round with biconvex faces.

Dark red film-coated tablet, round with biconvex faces.

White film-coated tablet, round with biconvex faces.

4.Clinical particulars

4.1 Therapeutic indications

Oral contraception.

Treatment of heavy menstrual bleeding in women without organic pathology who desire oral contraception.

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

4.2 Posology and method of administration

Method of administration

Oral use

Posology

How to take Estradiol Valerate and Dienogest

Tablets must be taken in the order directed on the package every day at about the same time with some liquid as needed. Tablet taking is continuous. One tablet is to be taken daily for 28 consecutive days. Each subsequent pack is started the day after the last tablet of the previous wallet. Withdrawal bleeding usually starts during the intake of the last tablets of a wallet and may not have finished before the next wallet is started. In some women, the bleeding starts after the first tablets of the new wallet are taken.

How to start Estradiol Valerate and Dienogest

No preceding hormonal contraceptive use (in the past month)

Tablet-taking has to start on day 1 of the woman’s natural cycle (i.e. the first day of her menstrual bleeding).

Changing from a combined hormonal contraceptive (combined oral contraceptive /COC), vaginal ring, or transdermal patch

The woman should start with Estradiol Valerate and Dienogest on the day after the last active tablet (the last tablet containing the active substances) of her previous COC. In case a vaginal ring or transdermal patch has been used, the woman should start using Estradiol Valerate and Dienogest on the day of removal.

Changing from a progestogen-only method (progestogen-only pill, injection, implant) or from a progestogen-releasing intrauterine system (IUS)

The woman may switch any day from the progestogen-only pill (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 be advised to additionally use a barrier method for the first 9 days of tablet-taking.

Following first-trimester abortion

The woman may start immediately. When doing so, she needs not take additional contraceptive measures.

Following delivery or second-trimester abortion

For breastfeeding women see section 4.6.

Women should be advised to start at day 21 to 28 after delivery or second-trimester abortion. When starting later, the woman should be advised to additionally use a barrier method for the first 9 days of tablet-taking. However, if intercourse has already occurred, pregnancy should be excluded before the actual start of COC use or the woman has to wait for her first menstrual period.

Management of missed tablets

Missed (white) placebo tablets can be disregarded. However, they should be discarded to avoid unintentionally prolonging the interval between active-tablet taking.

The following advice only refers to missed active tablets:

If the woman is less than 12 hours late in taking any tablet, contraceptive protection is not reduced. The woman should take the tablet as soon as she remembers and should take further tablets at the usual time.

If she is more than 12 hours late in taking any tablet, contraceptive protection may be reduced. The woman should take the last missed tablet as soon as she remembers, even if this means taking two tablets at the same time. She then continues to take tablets at her usual time.

Depending on the day of the cycle on which the tablet has been missed (see chart below for details), back-up contraceptive measures (e.g. a barrier method such as a condom) have to be used according to the following principles:

DAY	Color Content of estradiol valerate (EV)/dienogest (DNG)	*Principles to follow if missing one* tablet for more than 12 hours:**
1 – 2	Dark yellow tablets (3.0 mg EV)	– Take missed tablet immediately and the following tablet as usual (even if this means taking two tablets on the same day) – Continue with tablet-taking in the normal way – Use back-up contraception for the next 9 days
3 – 7	Medium red tablets (2.0 mg EV + 2.0 mg DNG)
8 – 17	Light yellow tablets (2.0 mg EV + 3.0 mg DNG)
18 – 24	Light yellow tablets (2.0 mg EV + 3.0 mg DNG)	– Discard current wallet, and start immediately with the first pill of a new wallet – Continue with tablet-taking in the normal way – Back-up contraception for the next 9 days
25 – 26	Dark red tablets (1.0 mg EV)	– Take missed tablet immediately and the following tablet as usual (even if this means taking two tablets on the same day) – No back-up contraception necessary
27-28	White tablets (Placebos)	– Discard missed tablet and continue tablet-taking in the normal way – No back-up contraception necessary

Not more than two tablets are to be taken on a given day.

If a woman has forgotten to start a new wallet, or if she has missed one or more tablets during days 3 -9 of the wallet, she may already be pregnant (provided she has had intercourse in the 7 days before the oversight). The more tablets (of those with the two combined active ingredients on days 3 – 24) that are missed and the closer they are to the placebo tablet phase, the higher the risk of a pregnancy.

If the woman missed tablets and subsequently has no withdrawal bleed at the end of the wallet /beginning of new wallet, the possibility of a pregnancy should be considered.

Advice in case of gastro-intestinal disturbances

In case of severe gastro-intestinal disturbances (e.g., vomiting or diarrhoea), absorption may not be complete and additional contraceptive measures should be taken.

If vomiting occurs within 3-4 hours after active tablet-taking, the next tablet should be taken as soon as possible. This tablet should be taken within 12 hours of the usual time of tablet-taking, if possible. If more than 12 hours elapse, the advice concerning missed tablets, as given in section 4.2 “Management of missed tablets”, is applicable. If the woman does not want to change her normal tablet-taking schedule, she has to take the corresponding tablet(s) needed from another pack.

Additional information on special populations

Children and adolescents

No data available for use in adolescents below 18 years.

Geriatric patients

Estradiol Valerate and Dienogest is not indicated after menopause.

Patients with hepatic impairment

Estradiol Valerate and Dienogest is contraindicated in women with severe hepatic diseases. See also section 4.3.

Patients with renal impairment

Estradiol Valerate and Dienogest has not been specifically studied in renally impaired patients.

4.3 Contraindications

Combined hormonal contraceptives (CHCs) should not be used in the following conditions. Should any of the conditions appear for the first time during CHC use, the product should be stopped 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

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 sex-steroid influenced malignancies (e.g. of the genital organs or the breasts).
Undiagnosed vaginal bleeding.
Hypersensitivity to the active substances or to any of the excipients listed in section 6.1.

4.4 Special warnings and precautions for use

Warnings

If any of the conditions or risk factors mentioned below is present, the suitability of Estradiol Valerate and Dienogest 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 Estradiol Valerate and Dienogest should be discontinued.

In case of suspected or confirmed VTE or ATE, CHC use should be discontinued. In case anticoagulant therapy is started, adequate alternative contraception should be initiated because of the teratogenicity of anticoagulant therapy (coumarins).

The following warnings and precautions are mainly derived from clinical and epidemiological data of ethinyl estradiol containing COCs.

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. Limited data suggests that Estradiol Valerate and Dienogest may have a risk of VTE in the same range. The decision to use any other product (such as Estradiol Valerate and Dienogest) than one known to have the lowest VTE risk should be taken only after a discussion with the woman to ensure she understands the risk of VTE with CHCs, how her current risk factors influence this risk, and that her VTE risk is highest in the first ever year of use. There is also some evidence that the risk is increased when a CHC is re-started after a break in use of 4 weeks or more.

In women who do not use a CHC and are not pregnant about 2 out of 10,000 will develop a VTE over the period of one year. However, in any individual woman the risk may be far higher, depending on her underlying risk factors (see below).

Epidemiological studies in women who use low dose (<50 µg ethinylestradiol) combined hormonal contraceptives have found that out of 10,000 women between about 6 and 12 will develop a VTE in one year

It is estimated that out of 10,000 women who use a levonorgestrel-containing CHC about 6¹ will develop a VTE in one year.

Limited epidemiological evidence suggests that the risk of VTE with the use of Estradiol Valerate and Dienogest may be in the same range as the risk with other CHCs, including CHCs containing levonorgestrel.

The number of VTEs per year with low dose CHCs is fewer than the number expected in women during pregnancy or in the postpartum period.

VTE may be fatal in 1-2% of the cases.

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).

Estradiol Valerate and Dienogest 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

Risk factor	Comment
Obesity (body mass index over 30 kg/m²)	Risk increases substantially as BMI rises. Particularly important to consider if other risk factors also present.
Prolonged immobilisation, major surgery, any surgery to the legs or pelvis, neurosurgery, or major trauma Note: temporary immobilisation including air travel >4 hours can also be a risk factor for VTE, particularly in women with other risk factors	In these situations it is advisable to discontinue use of the pill (in the case of elective surgery at least four weeks in advance) and not resume until two weeks after complete remobilisation. Another method of contraception should be used to avoid unintentional pregnancy. Antithrombotic treatment should be considered if Estradiol Valerate and Dienogest has not been discontinued in advance.
Positive family history (venous thromboembolism ever in a sibling or parent especially at a relatively early age e.g. before 50).	If a hereditary predisposition is suspected, the woman should be referred to a specialist for advice before deciding about any CHC use
Other medical conditions associated with VTE	Cancer, systemic lupus erythematosus, haemolytic uraemic syndrome, chronic inflammatory bowel disease (Crohn’s disease or ulcerative colitis) and sickle cell disease
Increasing age	Particularly above 35 years

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

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:

o unilateral swelling of the leg and/or foot or along a vein in the leg

o pain or tenderness in the leg which may be felt only when standing or walking

o increased warmth in the affected leg; red or discoloured skin on the leg.

Symptoms of pulmonary embolism (PE) can include:

o sudden onset of unexplained shortness of breath or rapid breathing

o sudden coughing which may be associated with haemoptysis

o sharp chest pain

o severe light headedness or dizziness

o 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). Estradiol Valerate and Dienogest 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

Risk factor	Comment
Increasing age	Particularly above 35 years
Smoking	Women should be advised not to smoke if they wish to use a CHC. Women over 35 who continue to smoke should be strongly advised to use a different method of contraception.
Hypertension
Obesity (body mass index over 30 kg/m²)	Risk increases substantially as BMI increases. Particularly important in women with additional risk factors
Positive family history (arterial thromboembolism ever in a sibling or parent especially at relatively early age e.g. below 50).	If a hereditary predisposition is suspected, the woman should be referred to a specialist for advice before deciding about any CHC use
Migraine	An increase in frequency or severity of migraine during CHC use (which may be prodromal of a cerebrovascular event) may be a reason for immediate discontinuation
Other medical conditions associated with adverse vascular events	Diabetes mellitus, hyperhomocysteinaemia, valvular heart disease and atrial fibrillation, dyslipoproteinaemia and systemic lupus erythematosus.

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:

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

o sudden trouble walking, dizziness, loss of balance or coordination

o sudden confusion, trouble speaking or understanding

o sudden trouble seeing in one or both eyes

o sudden, severe or prolonged headache with no known cause

o loss of consciousness or fainting with or without seizure.

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

Symptoms of myocardial infarction (MI) can include:

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

o discomfort radiating to the back, jaw, throat, arm, stomach

o feeling of being full, having indigestion or choking

o sweating, nausea, vomiting or dizziness

o extreme weakness, anxiety, or shortness of breath

o rapid or irregular heartbeats.

Tumours

An increased risk of cervical cancer in long-term users of COCs (> 5 years) has been reported in some epidemiological studies, but there continues to be controversy about the extent to which this finding is attributable to the confounding effects of sexual behaviour and other factors such as human papilloma virus (HPV).

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. These studies do not provide evidence for causation. 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. The breast cancers diagnosed in ever-users tend to be less advanced clinically than the cancers diagnosed in never-users.

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 hemorrhages. A hepatic tumour should be considered in the differential diagnosis when severe upper abdominal pain, liver enlargement or signs of intra-abdominal hemorrhage occur in women taking COCs.

Other conditions

Women with hypertriglyceridaemia, or a family history thereof, may be at an increased risk of pancreatitis when using COCs.

Although small increases in blood pressure have been reported in many women taking COCs, clinically relevant increases are rare. However, if a sustained clinically significant hypertension develops during the use of a COC then it is prudent for the physician to withdraw the COC and treat the hypertension. Where considered appropriate, COC 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 COC use, but the evidence of an association with COC use is inconclusive: jaundice and/or pruritus related to cholestasis; gallstone formation; porphyria; systemic lupus erythematosus; hemolytic uremic syndrome; Sydenham’s chorea; herpes gestationis; otosclerosis-related hearing loss.

In women with hereditary angioedema exogenous estrogens may induce or exacerbate symptoms of angioedema.

Acute or chronic disturbances of liver function may necessitate the discontinuation of COC use until markers of liver function return to normal. Recurrence of cholestatic jaundice which occurred first during pregnancy or previous use of sex steroids necessitates the discontinuation of COCs.

Although COCs 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 low-dose COCs (containing <0.05 mg ethinylestradiol). However, diabetic women should be carefully observed while taking COCs, particularly in the early stage of COC use.

Worsening of endogenous depression, of epilepsy, of Crohn’s disease and of ulcerative colitis has been reported during COC use.

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.

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 taking COCs.

Estrogens may cause fluid retention, and therefore patients with cardiac or renal dysfunction should be carefully observed. Patients with terminal renal insufficiency should be closely observed, since the level of circulating estrogens may be increased after administration of Estradiol Valerate and Dienogest.

This medicinal product contains not more than 50 mg lactose per tablet. Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption who are on a lactose-free diet should take this amount into consideration.

Medical examination/consultation

Prior to the initiation or reinstitution of Estradiol Valerate and Dienogest 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 contra-indications (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 Estradiol Valerate and Dienogest 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 on 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 COCs may be reduced for example in the following events: missed active tablets (section 4.2), gastro-intestinal disturbances (section 4.2) during active tablet taking or concomitant medication (section 4.5).

Cycle control

With all COCs, irregular bleeding (spotting or breakthrough bleeding) may occur, especially during the first months of use. Therefore, the evaluation of any irregular bleeding is only meaningful after an adaptation interval of about 3 cycles.

Based on patient diaries from a comparative clinical trial, the percentage of women per cycle experiencing intracyclic bleeding was 10 – 18 % for women using Estradiol Valerate and Dienogest.

Users of Estradiol Valerate and Dienogest may experience amenorrhea although not being pregnant. Based on patient diaries, amenorrhea occurs in approximately 15% of cycles.

If Estradiol Valerate and Dienogest has been taken according to the directions described in Section 4.2, it is unlikely that the woman is pregnant. If Estradiol Valerate and Dienogest has not been taken according to these directions prior to the first missed withdrawal bleed or if the withdrawal bleeding is missed in two consecutive cycles, pregnancy must be ruled out before Estradiol Valerate and Dienogest use is continued.

If bleeding irregularities persist or occur after previously regular cycles, then non-hormonal causes should be considered and adequate diagnostic measures are indicated to exclude malignancy or pregnancy. These may include curettage.

¹ Mid-point of 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

4.5 Interaction with other medicinal products and other forms of interaction

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

Interaction studies have only been performed in adults.

The following interactions have been reported in the literature for COCs in general or were studied in clinical trials with Estradiol Valerate and Dienogest.

Effects of other medicinal products on Estradiol Valerate and Dienogest

Interactions can occur with drugs 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. Maximal 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 should temporarily use a barrier method or another method of contraception in addition to the COC. The barrier method must be used during the whole time of the concomitant drug therapy and for 28 days after its discontinuation. If the drug therapy runs beyond the end of the active tablets in the COC pack, the placebo tablets must be discarded and the next COC pack should be started right away.

Long-term treatment

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

Substances increasing the clearance of COCs (diminished efficacy of COCs by enzyme-induction), e.g.:

Barbiturates, carbamazepine, phenytoin, primidone, rifampicin, and HIV medication ritonavir, nevirapine and efavirenz and possibly also felbamate, griseofulvin, oxcarbazepine, topiramate and products containing the herbal remedy St. John’s Wort (hypericum perforatum).

In a clinical study the strong cytochrome P450 (CYP 3A4) inducer rifampicin led to significant decreases in steady state concentrations and systemic exposures of dienogest and estradiol. The AUC (0-24h) of dienogest and estradiol at steady state, were decreased by 83% and 44%, respectively.

Substances with variable effects on the clearance of COC:

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

Therefore, the prescribing information of concomitant HIV/HCV medications should be consulted to identify potential interactions and any related recommendations. In case of any doubt, an additional barrier contraceptive method should be used by women on protease inhibitor or non-nucleoside reverse transcriptase inhibitor therapy.

Substances decreasing the clearance of COCs (enzyme inhibitors):

Dienogest is a substrate of CYP3A4.

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

Concomitant administration of strong CYP3A4 inhibitors can increase plasma concentrations of the estrogen or the progestin or both.

Coadministration with the strong CYP3A4 enzyme inhibitor ketoconazole resulted in a 2.9-fold and 1.6-fold increase of AUC (0-24h) at steady state for dienogest and estradiol, respectively. Concomitant administration of the moderate inhibitor erythromycin increased the AUC (0-24h) of dienogest and estradiol at steady state by 1.6-fold and 1.3-fold, respectively.

Effects of Estradiol Valerate and Dienogest on other medicinal products

Oral contraceptives may affect the metabolism of certain other active substances. Accordingly, plasma and tissue concentrations may either increase (e.g. cyclosporin) or decrease (e.g. lamotrigine).

Pharmacokinetics of nifedipine were not affected by concomitant administration of 2 mg dienogest + 0.03 mg ethinyl estradiol thus confirming results of in vitro studies indicating that inhibition of CYP enzymes by Estradiol Valerate and Dienogest is unlikely at the therapeutic dose.

Other forms of interactions

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 lipid/lipoprotein fractions, parameters of carbohydrate metabolism and parameters of coagulation and fibrinolysis. Changes generally remain within the normal laboratory range.

4.6 Fertility, pregnancy and lactation

Pregnancy

Estradiol Valerate and Dienogest should not be used during pregnancy.

If pregnancy occurs during use of Estradiol Valerate and Dienogest, further intake must be stopped. However, extensive epidemiological studies with ethinylestradiol containing COCs 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 taken inadvertently during pregnancy. Animal studies do not indicate a risk for reproductive toxicity (see section 5.3).

The increased risk of VTE during the postpartum period should be considered when re-starting Estradiol Valerate and Dienogest (see section 4.2 and 4.4).

Breastfeeding

Lactation may be influenced by COCs as they may reduce the quantity and change the composition of breast milk. Therefore, the use of COCs 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. These amounts may affect the child.

Fertility

Estradiol Valerate and Dienogest is indicated for the prevention of pregnancy. For information on return to fertility, see section 5.1.

4.7 Effects on ability to drive and use machines

No studies on the effects on the ability to drive and use machines have been performed. No effects on ability to drive and use machines have been observed in users of COCs.

4.8 Undesirable effects

Summary of the safety profile

The most commonly reported adverse reactions with Estradiol Valerate and Dienogest when used as an oral contraceptive or in the treatment of heavy menstrual bleeding in women without organic pathology who desire oral contraception are acne, breast discomfort, headache, intracyclic bleeding, nausea and weight increased.

Serious adverse reactions are arterial and venous thromboembolism, which are discussed in section 4.4.

Tabulated list of adverse reactions

The table below reports adverse reactions (ARs) by MedDRA system organ classes (MedDRA SOCs). The most appropriate MedDRA term (version 12.0) to describe a certain adverse reaction is listed. Synonyms or related conditions are not listed, but should be taken into account as well. The frequencies are based on clinical trial data. The adverse reactions were recorded in 5 phase III clinical studies (N=2,266 women at risk for pregnancy, N=264 women suffering from dysfunctional uterine bleeding without organic pathology who desire oral contraception) and considered at least possibly causally related to Estradiol Valerate and Dienogest use. All ADRs listed in the category ‘rare’ occurred in 1 to 2 volunteers resulting in < 0.1%.

N= 2,530women (100.0%)

System Organ Class	Common (≥ 1/100 to <1/10)	Uncommon (≥ 1/1,000 to <1/100)	Rare (≥ 1/10,000 to < 1/1,000)
Infections and infestations		Fungal infection Vulvovaginal mycotic infection¹ Vaginal infection	Candidiasis Oral herpes Pelvic inflammatory disease Presumed ocular histoplasmosis syndrome Tinea versicolor Urinary tract infection Vaginitis bacterial
Metabolism and nutrition disorders		Increased appetite	Fluid retention Hypertriglyceridaemia
Psychiatric disorders		Depression/depressed mood Emotional disorder² Insomnia Libido decreased³ Mental disorder Mood change⁴	Aggression Anxiety Dysphoria Libido increased Nervousness Nightmare Restlessness Sleep disorder Stress
Nervous system disorders	Headache⁵	Dizziness Migraine⁶	Disturbance in attention Paraesthesia Vertigo
Eye disorders			Contact lens intolerance Dry eye Eye swelling
Cardiac disorders			Myocardial infarction Palpitations
Vascular disorders		Hot flush Hypertension	Bleeding varicose vein Venous thromboembolism (VTE) Arterial thromboembolism (ATE) Hypotension Phlebitis superficialis Vein pain
Gastrointestinal disorders	Abdominal pain⁷ Nausea	Diarrhoea Vomiting	Constipation Dry mouth Dyspepsia Gastrooesophageal reflux disease
Hepatobiliary disorders		Liver enzymes increased⁸	Focal nodular hyperplasia of the liver Cholecystitis chronic
Skin and subcutaneous tissue disorders	Acne⁹	Alopecia Hyperhidrosis Pruritus¹⁰ Rash¹¹	Allergic skin reaction¹² Chloasma Dermatitis Hirsutism Hypertrichosis Neurodermatitis Pigmentation disorder Seborrhoea Skin disorder¹³
Musculoskeletal and connective tissue disorders		Muscle spasms	Back pain Pain in jaw Sensation of heaviness
Renal and urinary disorders			Urinary tract pain
Reproductive system and breast disorders	Amenorrhea Breast discomfort¹⁴ Dysmenorrhoea Intracyclic bleeding (Metrorrhagia)¹⁵	Breast enlargement¹⁶ Breast mass Cervical dysplasia Dysfunctional uterine bleeding Dyspareunia Fibrocystic breast disease Menorrhagia Menstrual disorder Ovarian cyst Pelvic pain Premenstrual syndrome Uterine leiomyoma Uterine spasm Uterine/ vaginal bleeding incl. spotting¹⁷ Vaginal discharge Vulvovaginal dryness	Abnormal withdrawal bleeding Benign breast neoplasm Breast cancer in situ Breast cyst Breast discharge Cervical polyp Cervix erythema Coital bleeding Galactorrhea Genital discharge Hypomenorrhoea Menstruation delayed Ovarian cyst ruptured Vaginal odour Vulvovaginal burning sensation Vulvovaginal discomfort
Blood and lymphatic system disorders			Lymphadenopathy
Respiratory, thoracic and mediastinal disorders			Asthma Dyspnoea Epistaxis
General disorders and administration site conditions		Fatigue Irritability Oedema¹⁸	Chest pain Malaise Pyrexia
Investigations	Weight increased	Weight decreased Blood pressure changes¹⁹	Smear cervix abnormal

¹ including vulvovaginal candidiasis and fungus cervical specimen identified

² including crying and affect lability

³ including loss of libido

⁴ including mood altered and mood swings

⁵ including tension headache and sinus headache

⁶ including migraine with aura and migraine without aura

⁷ including abdominal distension, abdominal pain upper and abdominal pain lower

⁸ including alanine aminotransferase increased, aspartate aminotransferase increased and gamma- glutamyltransferase increased

⁹ including acne pustular

¹⁰ including pruritus generalized and rash pruritic

¹¹ including rash macular

¹² including dermatitis allergic and urticaria

¹³ including skin tightness

¹⁴ including breast pain, breast tenderness, nipple disorder and nipple pain

¹⁵ including menstruation irregular

¹⁶ including breast swelling

¹⁷ including vaginal hemorrhage, genital hemorrhage and uterine hemorrhage

¹⁸ including oedema peripheral

¹⁹ including blood pressure increased and blood pressure decreased

Description of selected adverse reactions

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

Occurrence of amenorrhea and intracyclic bleeding based on patient diaries is summarized in section 4.4 Cycle control.

The following serious adverse events have been reported in women using COCs, which are discussed in section 4.4 Special warning and precautions for use:

Tumours

– The frequency of diagnosis of breast cancer is very slightly increased among COC users. As breast cancer is rare in women under 40 years of age the excess number is small in relation to the overall risk of breast cancer. Causation with COC use is unknown. For further information, see sections 4.3 and 4.4;

– Liver tumours;

Other conditions

– Erythema nodosum, Erythema multiforme;

– Breast discharge;

– Hypertension;

– Occurrence or deterioration of conditions for which association with COC use is not conclusive: Crohn’s disease, ulcerative colitis, epilepsy, migraine, uterine myoma, porphyria, systemic lupus erythematosus, herpes gestationis, Sydenham’s chorea, haemolytic uremic syndrome, cholestatic jaundice;

– In women with hereditary angioedema exogenous estrogens may induce or exacerbate symptoms of angioedema;

– Acute or chronic disturbances of liver function may necessitate the discontinuation of COC use until markers of liver function return to normal.

– Chloasma;

– Hypersensitivity (including symptoms such as rash, urticaria);

Interactions

Breakthrough bleeding and/or contraceptive failure may result from interactions of other drugs (enzyme inducers) with oral 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;

United Kingdom

Yellow Card Scheme

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

Malta

ADR Reporting

Website: www.medicinesauthority.gov.mt/adrportal

4.9 Overdose

There have been no reports of serious deleterious effects from overdose. Symptoms that may occur in case of taking an overdose of active tablets 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: progestogens and estrogens, sequential preparations

In clinical trials performed with Estradiol Valerate and Dienogest in the European Union and in the USA/Canada the following Pearl indices were calculated:

Pearl Index (18-50 years of age)

Method failure: 0.42 (upper limit 95% CI 0.77)

User + method failure: 0.79 (upper limit 95% CI 1.23)

Pearl Index (18-35 years of age)

Method failure: 0.51 (upper limit 95% CI 0.97)

User + method failure: 1.01 (upper limit 95% CI 1.59)

The contraceptive effect of COCs is based on the interaction of various factors, the most important of which are seen as the inhibition of ovulation, changes in the cervical secretion, and changes in the endometrium.

In a 3-cycle ovulation inhibition study, treatment with Estradiol Valerate and Dienogest led to suppression of follicular development in the majority of women. Ovarian activity returned to pre-treatment levels during the post-treatment cycle.

Estradiol Valerate and Dienogest is dosed using an estrogen step-down and a progestin step-up regimen that can be used to treat heavy menstrual bleeding in the absence of an organic pathology, symptoms sometimes referred to as dysfunctional uterine bleeding (DUB).

Two multicenter, double blind randomised studies of similar design were performed to evaluate the efficacy and safety of Estradiol Valerate and Dienogest in women with symptoms of DUB who desired oral contraception. In total, 269 women were randomised on Estradiol Valerate and Dienogest and 152 patients on placebo.

After 6 months of treatment, the median menstrual blood loss (MBL) was decreased by 88% from 142 mL to 17 mL in the Estradiol Valerate and Dienogest group compared to 24% from 154 mL to 117 mL in the placebo group.

After 6 months of treatment, the proportion of women who were completely cured from any DUB symptom was 29% in the Estradiol Valerate and Dienogest group compared to 2% in the placebo group.

The estrogen in Estradiol Valerate and Dienogest is estradiol valerate, an ester of the natural human 17ß-estradiol (1 mg estradiol valerate corresponds to 0.76 mg 17 ß-estradiol). This estrogen differs from the estrogens ethinylestradiol or its prodrug mestranol used in other COCs by the lack of an ethinyl group in 17alpha position.

Dienogest is a nortestosterone derivative with no androgenic but rather an antiandrogenic activity of approximately one third of that of cyproterone acetate. Dienogest binds to the progesterone receptor of the human uterus with only 10% of the relative affinity of progesterone. Despite its low affinity to the progesterone receptor, dienogest has a strong progestogenic effect in vivo. Dienogest has no significant androgenic, mineralocorticoid or glucocorticoid activity in vivo.

Endometrial histology was investigated in a subgroup of women (n=218) in one clinical study after 20 cycles of treatment. There were no abnormal results.

5.2 Pharmacokinetic properties

Dienogest

Absorption

Orally administered dienogest is rapidly and almost completely absorbed. Maximal serum concentrations of 90.5ng/ml are reached at about 1 hour after oral administration of the Estradiol Valerate and Dienogest tablet containing 2 mg estradiol valerate + 3 mg dienogest. Bioavailability is about 91 %. The pharmacokinetics of dienogest is dose-proportional within the dose range of 1 – 8 mg.

Concomitant food intake has no clinically relevant effect on the rate and extent of dienogest absorption.

Distribution

A relatively high fraction of 10% of circulating dienogest is present in the free form, with approx. 90% being bound non-specifically to albumin. Dienogest does not bind to the specific transport proteins SHBG and CBG. The volume of distribution at steady state (V_d,ss) of dienogest is 46 l after the intravenous administration of 85 µg ³H-dienogest.

Biotransformation

Dienogest is nearly completely metabolized by the known pathways of steroid metabolism (hydroxylation, conjugation), mainly by CYP3A4. The pharmacologically inactive metabolites are excreted rapidly resulting in dienogest as the major fraction in plasma accounting for approximately 50% of circulating dienogest derived compounds. The total clearance following the intravenous administration of ³H-dienogest was calculated as 5.1 l/h.

Elimination

The plasma half-life of dienogest is approximately 11 hours. Dienogest is extensively metabolized and only 1% of drug is excreted unchanged. The ratio of urinary to fecal excretion is about 3:1 after oral administration of 0.1 mg/kg. Following oral administration, 42% of the dose is eliminated within the first 24 h and 63% within 6 days by renal excretion. A combined 86% of the dose is excreted by urine and feces after 6 days.

Steady-State Conditions

Pharmacokinetics of dienogest are not influenced by SHBG levels. Steady state is reached after 3 days of the same dosage of 3 mg dienogest in combination with 2 mg estradiol valerate. Trough, maximum and average dienogest serum concentrations at steady state are 11.8 ng/ml, 82.9 ng/ml and 33.7 ng/ml, respectively. The mean accumulation ratio for AUC (0-24h) was determined to be 1.24.

Estradiol valerate

Absorption

After oral administration estradiol valerate is completely absorbed. Cleavage to estradiol and valeric acid takes place during absorption by the intestinal mucosa or in the course of the first liver passage. This gives rise to estradiol and its metabolites estrone and estriol. Maximal serum estradiol concentrations of 70.6 pg/ml are reached between 1.5 and 12 hours after single ingestion of the tablet containing 3 mg estradiol valerate on Day 1.

Biotransformation

The valeric acid undergoes very fast metabolism. After oral administration approximately 3% of the dose is directly bioavailable as estradiol. Estradiol undergoes an extensive first-pass effect and a considerable part of the dose administered is already metabolized in the gastrointestinal mucosa. Together with the presystemic metabolism in the liver, about 95 % of the orally administered dose becomes metabolized before entering the systemic circulation. The main metabolites are estrone, estrone sulfate and estrone glucuronide.

Distribution

In serum 38 % of estradiol is bound to SHBG, 60 % to albumin and 2-3 % circulate in free form. Estradiol can slightly induce the serum concentrations of SHBG in a dose-dependent manner. On day 21 of the treatment cycle, SHBG was approximately 148% of the baseline, it decreased to about 141% of the baseline by day 28 (end of placebo phase). An apparent volume of distribution of approximately 1.2 l/kg was determined after iv. administration.

Elimination

The plasma half-life of circulating estradiol is about 90 min. After oral administration, however, the situation differs. Because of the large circulating pool of estrogen sulfates and glucuronides, as well as enterohepatic recirculation, the terminal half-life of estradiol after oral administration represents a composite parameter which is dependent on all of these processes and is in the range of about 13-20 h.

Estradiol and its metabolites are mainly excreted in urine, with about 10% being excreted in the stool.

Steady-state conditions

Pharmacokinetics of estradiol are influenced by SHBG levels. In young women, the measured estradiol plasma levels are a composite of the endogenous estradiol and the estradiol generated from Estradiol Valerate and Dienogest. During the treatment phase of 2 mg estradiol valerate + 3 mg dienogest, maximum and average estradiol serum concentrations at steady state are 66.0 pg/ml and 51.6 pg/ml, respectively. Throughout the 28 day cycle, stable minimum estradiol concentrations were maintained and ranged from 28.7 pg/ml to 64.7 pg/ml.

Special Populations

Pharmacokinetics of Estradiol Valerate and Dienogest was not investigated in patients with impaired renal or liver function.

5.3 Preclinical safety data

Preclinical data reveal no special risks for humans based on conventional studies of repeated dose toxicity, genotoxicity, and toxicity to reproduction. A carcinogenicity study with dienogest in mice and a more limited study in rats showed no increase in tumours, however, it is well known that due to their hormonal action, sex steroids can promote the growth of certain hormone-dependent tissues and tumours.

6.Pharmaceutical particulars

6.1 List of excipients

Active film-coated tablets	Placebo (inactive) film-coated tablet
Tablet core:
Lactose monohydrate Maize starch Pregelatinized maize starch Povidone K25 Magnesium stearate	Lactose monohydrate Maize starch Povidone K25 Magnesium stearate
Tablet coating:
Hypromellose type 2910 Macrogol 6000 Talc Titanium dioxide Iron oxide red and/or Iron oxide yellow	Hypromellose type 2910 Talc Titanium dioxide

6.2 Incompatibilities

Not applicable

6.3 Shelf life

5 years

6.4 Special precautions for storage

This medicinal product does not require any special storage conditions.

6.5 Nature and contents of container

Transparent PVC/Aluminium blister in a cardboard wallet

Presentation

Pack sizes:

1 x 28 film-coated tablets

3 x 28 film-coated tablets

6 x 28 film-coated tablets

Each wallet (28 film-coated tablets) contains in the following order: 2 dark yellow tablets and 5 medium red tablets and 17 light yellow tablets and 2 dark red tablets and 2 white tablets

Not all pack sizes may be marketed.

6.6 Special precautions for disposal and other handling

Any unused product or waste material should be disposed of in accordance with local requirements.

7. Manufactured in India by:

TAJ PHARMACEUTICALS LTD.
Mumbai, India
Unit No. 214.Old Bake House,
Maharashtra chambers of Commerce Lane,
Fort, Mumbai – 400001
at:Gujarat, INDIA.
Customer Service and Product Inquiries:
1-800-TRY-FIRST (1-800-222-434 & 1-800-222-825)
Monday through Saturday 9:00 a.m. to 7:00 p.m. EST
E-mail: tajgroup@tajpharma.com

Estradiol Valerate/Dienogest Tablets Taj Pharma

PATIENT INFORMATION LEAFLET

Due to regulatory changes, the content of the following Patient Information Leaflet may vary from the one found in your medicine pack. Please compare the ‘Leaflet prepared/revised date’ towards the end of the leaflet to establish if there have been any changes.

If you have any doubts or queries about your medication, please contact your doctor or pharmacist.

Read all of this leaflet carefully before you start taking this medicine because it contains important information for you.

Keep this leaflet. You may need to read it again.
If you have any further questions, ask your doctor or pharmacist.
This medicine has been prescribed for you only. Do not pass it on to others. It may harm them.
If you get any side effects, talk to your doctor or pharmacist. This includes any possible side effects not listed in this leaflet. See section 4.

Important things to know about combined hormonal contraceptives (CHCs):

They are one of the most reliable reversible methods of contraception if used correctly
They slightly increase the risk of having a blood clot in the veins and arteries, especially in the first year or when restarting a combined hormonal contraceptive following a break of 4 or more weeks
Please be alert and see your doctor if you think you may have symptoms of a blood clot (see section 2 “Blood clots”)

What is in this leaflet:

1. What Estradiol Valerate and Dienogest is and what it is used for
2.What you need to know before you take Estradiol Valerate and Dienogest
When not to take Estradiol Valerate and Dienogest
Warnings and precautions
Blood clots
Estradiol Valerate and Dienogest and cancer
Bleeding between periods
What to do if no bleeding occurs on day 26 or the following day(s)
Other medicines and Estradiol Valerate and Dienogest
Estradiol Valerate and Dienogest with food and drink
Laboratory tests
Pregnancy and breast-feeding
Driving and using machines
Estradiol Valerate and Dienogest contains lactose
3. How to take Estradiol Valerate and Dienogest
Preparation of the wallet
When can you start with the first wallet?
If you take more Estradiol Valerate and Dienogest than you should
If you forget to take Estradiol Valerate and Dienogest
Use in children
What to do if you vomit or have severe diarrhoea
If you stop taking Estradiol Valerate and Dienogest
4. Possible side effects
5. How to store Estradiol Valerate and Dienogest
6. Contents of the pack and other information

1. What Estradiol Valerate and Dienogest is and what it is used for

Estradiol Valerate and Dienogest is a contraceptive pill and is used to prevent pregnancy.
Estradiol Valerate and Dienogest is used for the treatment of heavy menstrual bleeding (not caused by any disease of the womb) in women who wish to use oral contraception.
- Each coloured active tablet contains a small amount of female hormones, either estradiol valerate, or estradiol valerate combined with dienogest.
- The 2 white tablets. contain no active substances and are called inactive tablets

Contraceptive pills that contain two hormones are called “combined pills”.

2. What you need to know before you take Estradiol Valerate and Dienogest

General notes

Before you start using Estradiol Valerate and Dienogest you should read the information on blood clots in section 2. It is particularly important to read the symptoms of a blood clot – see Section 2 “Blood clots”.

Before you can begin taking Estradiol Valerate and Dienogest, your doctor will ask you some questions about your personal health history and that of your close relatives. The doctor will also measure your blood pressure and, depending upon your personal situation, may also carry out some other tests.

In this leaflet, several situations are described where you should stop using Estradiol Valerate and Dienogest, or where the reliability of Estradiol Valerate and Dienogest may be decreased. In such situations you should either not have sex or you should take extra non-hormonal contraceptive precautions, e.g. use a condom or another barrier method. Do not use rhythm or temperature methods. These methods can be unreliable because Estradiol Valerate and Dienogest alters the monthly changes of body temperature and cervical mucus.

Estradiol Valerate and Dienogest, like other hormonal contraceptives, does not protect against HIV infection (AIDS) or any other sexually transmitted disease

When not to take Estradiol Valerate and Dienogest

You should not use Estradiol Valerate and Dienogest if you have any of the conditions listed below. If you do have any of the conditions listed below, you must tell your doctor. Your doctor will discuss with you what other form of birth control would be more appropriate.

Do not take Estradiol Valerate and Dienogest:

if you have (or have ever had) a blood clot in a blood vessel of your legs (deep vein thrombosis, DVT), your lungs (pulmonary embolus, PE) or other organs;
if you know you have a disorder affecting your blood clotting – for instance, protein C deficiency, protein S deficiency, antithrombin-III deficiency, Factor V Leiden or antiphospholipid antibodies;
if you need an operation or if you are off your feet for a long time (see section ‘Blood clots’)
if you have ever had a heart attack or a stroke;
if you have (or have ever had) angina pectoris (a condition that causes severe chest pain and may be a first sign of a heart attack) or transient ischaemic attack (TIA – temporary stroke symptoms);
if you have any of the following diseases that may increase your risk of a clot in the arteries:
- severe diabetes with blood vessel damage
- very high blood pressure
- a very high level of fat in the blood (cholesterol or triglycerides)
- a condition known as hyperhomocysteinaemia
if you have (or have ever had) a type of migraine called ‘migraine with aura’;
if you have (or have ever had) liver disease and your liver function is still not normal
if you have (or have ever had) a tumour of the liver
if you have (or have ever had) cancer or suspected cancer of the breast or genital organs
if you have any unexplained bleeding from the vagina
if you are allergic (hypersensitive) to estradiol valerate or dienogest, or any of the other ingredients of this medicine (listed in section 6). This may cause itching, rash or swelling

Warnings and precautions

When should you contact your doctor?

Seek urgent medical attention

if you notice possible signs of a blood clot that may mean you are suffering from a blood clot in the leg (i.e. deep vein thrombosis), a blood clot in the lung (i.e. pulmonary embolism), a heart attack or a stroke (see ‘Blood clots’ section below).

For a description of the symptoms of these serious side effects please go to “How to recognise a blood clot”.

Tell your doctor if any of the following conditions apply to you.

In some situations you need to take special care while taking Estradiol Valerate and Dienogest or any other combined pill, and your doctor may need to examine you regularly. If the condition develops, or gets worse while you are using Estradiol Valerate and Dienogest, you should also tell your doctor.

if a close relative has or has ever had breast cancer
if you have a disease of the liver or gall bladder
if you have jaundice
if you have diabetes
if you have depression
if you have Crohn’s disease or ulcerative colitis (chronic inflammatory bowel disease);
if you have systemic lupus erythematosus (SLE – a disease affecting your natural defence system);
if you have haemolytic uraemic syndrome (HUS – a disorder of blood clotting causing failure of the kidneys);
if you have sickle cell anaemia (an inherited disease of the red blood cells);
if you have elevated levels of fat in the blood (hypertriglyceridaemia) or a positive family history for this condition. Hypertriglyceridaemia has been associated with an increased risk of developing pancreatitis (inflammation of the pancreas);
if you need an operation, or you are off your feet for a long time (see in section 2 ‘Blood clots’).
if you have just given birth you are at an increased risk of blood clots. You should ask your doctor how soon after delivery you can start taking Estradiol Valerate and Dienogest.
if you have an inflammation in the veins under the skin (superficial thrombophlebitis).
if you have varicose veins.
if you have epilepsy (see “Other medicines and Estradiol Valerate and Dienogest”)
if you have a disease that first appeared during pregnancy or earlier use of sex hormones, for example, hearing loss, porphyria (a disease of the blood), gestational herpes (skin rash with blisters during pregnancy), Sydenham’s chorea (a nerve disease causing sudden movements of the body)
if you have (or have ever had) golden brown pigment patches so-called “pregnancy patches” especially on the face (Chloasma). If this is the case, avoid direct exposure to sunlight or ultraviolet light
if you have hereditary angioedema. Consult your doctor immediately if you experience symptoms of angioedema such as swollen face, tongue and/or throat and/or difficulty swallowing or hives, together with difficulty breathing. Products containing oestrogens may induce or worsen symptoms of angioedema
if you have cardiac or renal insufficiency

Talk to your doctor before taking Estradiol Valerate and Dienogest.

Additional information on special populations

Use in children

Estradiol Valerate and Dienogest is not intended for use in females whose periods have not yet started.

BLOOD CLOTS

Using a combined hormonal contraceptive such as Estradiol Valerate and Dienogest increases your risk of developing a blood clot compared with not using one. In rare cases a blood clot can block blood vessels and cause serious problems.

Blood clots can develop

in veins (referred to as a ‘venous thrombosis’, ‘venous thromboembolism’ or VTE)
in the arteries (referred to as an ‘arterial thrombosis’, ‘arterial thromboembolism’ or ATE).

Recovery from blood clots is not always complete. Rarely, there may be serious lasting effects or, very rarely, they may be fatal.

It is important to remember that the overall risk of a harmful blood clot due to Estradiol Valerate and Dienogest is small.

HOW TO RECOGNISE A BLOOD CLOT

Seek urgent medical attention if you notice any of the following signs or symptoms.

Are you experiencing any of these signs?

swelling of one leg or along a vein in the leg or foot especially when accompanied by:
- pain or tenderness in the leg which may be felt only when standing or walking
- increased warmth in the affected leg

change in colour of the skin on the leg e.g. turning pale, red or blue