Estradiol Valerate/Dienogest Tablets Taj Pharma

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 (Vd,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

What are you possibly suffering from?

Deep vein thrombosis

Are you experiencing any of these signs?

  • sudden unexplained breathlessness or rapid breathing;
  • sudden cough without an obvious cause, which may bring up blood;
  • sharp chest pain which may increase with deep breathing;
  • severe light headedness or dizziness;
  • rapid or irregular heartbeat
  • severe pain in your stomach;

If you are unsure, talk to a doctor as some of these symptoms such as coughing or being short of breath may be mistaken for a milder condition such as a respiratory tract infection (e.g. a ‘common cold’).

What are you possibly suffering from?

Pulmonary embolism

Are you experiencing any of these signs?

Symptoms most commonly occur in one eye:

  • immediate loss of vision or painless blurring of vision which can progress to loss of vision

What are you possibly suffering from?

Retinal vein thrombosis (blood clot in the eye)

Are you experiencing any of these signs?

  • chest pain, discomfort, pressure, heaviness
  • sensation of squeezing or fullness in the chest, arm or below the breastbone;
  • fullness, indigestion or choking feeling;
  • upper body discomfort radiating to the back, jaw, throat, arm and stomach;
  • sweating, nausea, vomiting or dizziness;
  • extreme weakness, anxiety, or shortness of breath;
  • rapid or irregular heartbeats

What are you possibly suffering from?

Heart attack

Are you experiencing any of these signs?

  • sudden weakness or numbness of the face, arm or leg, especially on one side of the body;
  • sudden confusion, trouble speaking or understanding;
  • sudden trouble seeing in one or both eyes;
  • sudden trouble walking, dizziness, loss of balance or coordination;
  • sudden, severe or prolonged headache with no known cause;
  • loss of consciousness or fainting with or without seizure.

Sometimes the symptoms of stroke can be brief with an almost immediate and full recovery, but you should still seek urgent medical attention as you may be at risk of another stroke.

What are you possibly suffering from?

Stroke

Are you experiencing any of these signs?

  • swelling and slight blue discolouration of an extremity;
  • severe pain in your stomach (acute abdomen)

What are you possibly suffering from?

Blood clots blocking other blood vessels

BLOOD CLOTS IN A VEIN

What can happen if a blood clot forms in a vein?

  • The use of combined hormonal contraceptives has been connected with an increase in the risk of blood clots in the vein (venous thrombosis). However, these side effects are rare. Most frequently, they occur in the first year of use of a combined hormonal contraceptive.
  • If a blood clot forms in a vein in the leg or foot it can cause a deep vein thrombosis (DVT).
  • If a blood clot travels from the leg and lodges in the lung it can cause a pulmonary embolism.
  • Very rarely a clot may form in a vein in another organ such as the eye (retinal vein thrombosis).

When is the risk of developing a blood clot in a vein highest?

The risk of developing a blood clot in a vein is highest during the first year of taking a combined hormonal contraceptive for the first time. The risk may also be higher if you restart taking a combined hormonal contraceptive (the same product or a different product) after a break of 4 weeks or more.

After the first year, the risk gets smaller but is always slightly higher than if you were not using a combined hormonal contraceptive.

When you stop Estradiol Valerate and Dienogest your risk of a blood clot returns to normal within a few weeks.

What is the risk of developing a blood clot?

The risk depends on your natural risk of VTE and the type of combined hormonal contraceptive you are taking.

The overall risk of a blood clot in the leg or lung (DVT or PE) with Estradiol Valerate and Dienogest is small.

  • Out of 10,000 women who are not using any combined hormonal contraceptive and are not pregnant, about 2 will develop a blood clot in a year.
  • Out of 10,000 women who are using a combined hormonal contraceptive that contains levonorgestrel, norethisterone, or norgestimate about 5-7 will develop a blood clot in a year.
  • The risk of a blood clot with Estradiol Valerate and Dienogest is about the same as with other combined hormonal contraceptives including contraceptives containing levonorgestrel.
  • The risk of having a blood clot will vary according to your personal medical history (see “Factors that increase your risk of a blood clot” below)

Risk of developing a blood clot in a year

Women who are not using a combined hormonal pill and are not pregnant

About 2 out of 10,000 women

Risk of developing a blood clot in a year

Women using a combined hormonal contraceptive pill containing levonorgestrel, norethisterone or norgestimate

About 5-7 out of 10,000 women

Risk of developing a blood clot in a year

Women using Estradiol Valerate and Dienogest

Not yet known.

Factors that increase your risk of a blood clot in a vein

The risk of a blood clot with Estradiol Valerate and Dienogest is small but some conditions will increase the risk. Your risk is higher:

  • if you are very overweight (body mass index or BMI over 30 kg/m2);
  • if one of your immediate family has had a blood clot in the leg, lung or other organ at a young age (e.g. below the age of about 50). In this case you could have a hereditary blood clotting disorder;
  • if you need to have an operation, or if you are off your feet for a long time because of an injury or illness, or you have your leg in a cast. The use of Estradiol Valerate and Dienogest may need to be stopped several weeks before surgery or while you are less mobile. If you need to stop Estradiol Valerate and Dienogest ask your doctor when you can start using it again.
  • as you get older (particularly above about 35 years);
  • if you gave birth less than a few weeks ago.

The risk of developing a blood clot increases the more conditions you have.

Air travel (>4 hours) may temporarily increase your risk of a blood clot, particularly if you have some of the other factors listed.

It is important to tell your doctor if any of these conditions apply to you, even if you are unsure. Your doctor may decide that Estradiol Valerate and Dienogest needs to be stopped.

If any of the above conditions change while you are using Estradiol Valerate and Dienogest, for example a close family member experiences a thrombosis for no known reason; or you gain a lot of weight, tell your doctor.

BLOOD CLOTS IN AN ARTERY

What can happen if a blood clot forms in an artery?

Like a blood clot in a vein, a clot in an artery can cause serious problems. For example, it can cause a heart attack or a stroke.

Factors that increase your risk of a blood clot in an artery

It is important to note that the risk of a heart attack or stroke from using Estradiol Valerate and Dienogest is very small but can increase:

  • with increasing age (beyond about 35 years);
  • if you smoke. When using a combined hormonal contraceptive like Estradiol Valerate and Dienogest you are advised to stop smoking. If you are unable to stop smoking and are older than 35 your doctor may advise you to use a different type of contraceptive;
  • if you are overweight;
  • if you have high blood pressure;
  • if a member of your immediate family has had a heart attack or stroke at a young age (less than about 50). In this case you could also have a higher risk of having a heart attack or stroke;
  • if you, or someone in your immediate family, have a high level of fat in the blood (cholesterol or triglycerides);
  • if you get migraines, especially migraines with aura;
  • if you have a problem with your heart (valve disorder, disturbance of the rhythm called atrial fibrillation)
  • if you have diabetes.

If you have more than one of these conditions or if any of them are particularly severe the risk of developing a blood clot may be increased even more.

If any of the above conditions change while you are using Estradiol Valerate and Dienogest, for example you start smoking, a close family member experiences a thrombosis for no known reason; or you gain a lot of weight, tell your doctor.

Estradiol Valerate and Dienogest and cancer

Breast cancer has been observed slightly more often in women using combined pills, but it is not known whether this is caused by the treatment itself. For example, it may be that more tumours are detected in women on combined pills because they are examined by their doctor more often. The risk of breast tumours becomes gradually less after stopping the combination hormonal contraceptives. It is important to regularly check your breasts and you should contact your doctor if you feel any lump.

In rare cases, benign liver tumours, and in even fewer cases malignant liver tumours have been reported in contraceptive pill users. In isolated cases, these tumours have led to life-threatening internal bleeding. Contact your doctor if you have unusually severe abdominal pain.

Some studies suggest that long-term use of the pill increases a woman’s risk of developing cervical cancer. However, it is not clear to what extent sexual behaviour or other factors such as Human Papilloma Virus (HPV) increases this risk.

Psychiatric disorders

Some women using hormonal contraceptives including Estradiol Valerate and Dienogest have reported depression or depressed mood. Depression can be serious and may sometimes lead to suicidal thoughts. If you experience mood changes and depressive symptoms contact your doctor for further medical advice as soon as possible.

Bleeding between periods

During the first few months of taking Estradiol Valerate and Dienogest, you may have unexpected bleeding. Usually bleeding starts on day 26, the day you take the second dark red tablet, or the following day(s). The information provided by women in the diaries they kept during a clinical study of Estradiol Valerate and Dienogest shows that it is not unusual to experience unexpected bleeding in a given cycle (10-18 % of users). If unexpected bleeding occurs more than 3 months in a row, or if it begins after some months, your doctor will have to investigate the cause.

What to do if no bleeding occurs on day 26 or the following day(s)

The information provided by women in the diaries they kept during a clinical study of Estradiol Valerate and Dienogest shows that it is not unusual to miss your regular bleeding after day 26 (observed in about 15 % of cycles).

If you have taken all the tablets correctly, have not had any vomiting or severe diarrhoea and you have not taken any other medicines, it is highly unlikely that you are pregnant.

If the expected bleeding does not happen twice in a row or you have taken the tablets incorrectly, you may be pregnant. Contact your doctor immediately. Do not start the next wallet until you are sure that you are not pregnant.

Other medicines and Estradiol Valerate and Dienogest

Always tell your doctor which medicines or herbal products you are already using. Also tell any other doctor or dentist who prescribes another medicine (or the pharmacist from whom you got the medicine) that you take Estradiol Valerate and Dienogest. They can tell you if you need to take additional contraceptive precautions (for example condoms) and if so, for how long.

Some medicines

  • can have an influence on the blood levels of Estradiol Valerate and Dienogest
  • can make it less effective in preventing pregnancy
  • can cause unexpected bleeding.

These include:

  • medicines used for the treatment of:
    • epilepsy (e.g. primidone, phenytoin, barbiturates, carbamazepine, oxcarbazepine, topiramate, felbamate)
    • tuberculosis (e.g. rifampicin)
    • HIV and Hepatitis C Virus infections (so-called protease inhibitors and non-nucleoside reverse transcriptase inhibitors such as ritonavir, nevirapine, efavirenz)
    • fungal infections (e.g. griseofulvin, ketoconazole)
  • the herbal remedy St. John’s wort
  • Estradiol Valerate and Dienogest may influence the effect of other medicines, e.g.
    • medicines containing cyclosporin
    • the anti-epileptic lamotrigine (this could lead to an increased frequency of seizures).

Ask your doctor or pharmacist for advice before taking any medicine. Your doctor or pharmacist may advise on extra protective measures while you are taking other medication together with Estradiol Valerate and Dienogest.

Estradiol Valerate and Dienogest with food and drink

Estradiol Valerate and Dienogest may be taken with or without food, if necessary with a small amount of water.

Laboratory tests

If you need a blood test or other laboratory tests tell your doctor or the laboratory staff that you are taking the pill because oral contraceptives can affect the results of some tests.

Pregnancy and breast-feeding

Do not take Estradiol Valerate and Dienogest if you are pregnant. If you become pregnant while taking Estradiol Valerate and Dienogest, stop taking it immediately and contact your doctor. If you want to become pregnant, you can stop taking Estradiol Valerate and Dienogest at any time (see also “If you stop taking Estradiol Valerate and Dienogest”).

In general you should not take Estradiol Valerate and Dienogest while you are breast-feeding. If you want to take the pill while you are breast-feeding you should contact your doctor.

Ask your doctor or pharmacist for advice before taking any medicine when you are pregnant or breast-feeding.

Driving and using machines

There is nothing to suggest that the use of Estradiol Valerate and Dienogest affects driving or use of machines.

Estradiol Valerate and Dienogest contains lactose

If you have been told by your doctor that you have an intolerance to some sugars, contact your doctor before taking Estradiol Valerate and Dienogest.

3.How to take Estradiol Valerate and Dienogest

Each wallet contains 26 coloured active tablets and 2 white inactive-tablets.

Take one tablet of Estradiol Valerate and Dienogest every day, if necessary with a small amount of water. You may take the tablets with or without food, but you should take the tablets at around the same time every day.

Preparation of the wallet

To help you keep track, there are 7 weekday sticker strips marked with the 7 days of the week.

Choose the weekday sticker strip that starts with the day you begin taking the tablets. For example, if you start on a Wednesday, use the weekday sticker strip that starts with “WED”.

Stick the weekday sticker strip along the top of the Estradiol Valerate and Dienogest wallet where it reads “Place weekday sticker strip here”, so that the first day is above the tablet marked “1”.

There is now a day shown above every tablet and you can see whether you have taken a pill on a particular day. Follow the direction of the arrow on the wallet until all 28 tablets have been taken.

Usually, so-called withdrawal bleeding starts when you are taking the second dark red tablet or the white tablets and may not have finished before you start the next wallet. Some women still experience bleeding after taking the first tablets of the new wallet.

Start the following wallet without a gap, in other words the day after you have finished your current wallet, even if the bleeding has not stopped. This means that you should start your following wallet on the same day of the week as the current wallet and that the withdrawal bleed should occur on the same weekdays each month.

If you use Estradiol Valerate and Dienogest in this manner, you are protected against pregnancy even during the 2 days when you take inactive tablets.

When can you start with the first wallet?

  • If you have not used a contraceptive with hormones during the previous month.
    Start taking Estradiol Valerate and Dienogest on the first day of the cycle (that is, the first day of your period).
  • Changing from another combined hormonal contraceptive pill, or combined contraceptive vaginal ring or patch.
    Start Estradiol Valerate and Dienogest the day after taking the last active tablet (the last tablet containing the active substance) of your previous pill. When changing from a combined contraceptive vaginal ring or patch, start using Estradiol Valerate and Dienogest on the day of removal or, follow the advice of your doctor.
  • Changing from a progestogen-only-method (progestogen-only pill, injection, implant or a progestogen-releasing ‘IUS’, intrauterine system).
    You may switch from the progestogen-only pill any day (from an implant or the IUS on the day of its removal, from an injectable when the next injection would be due) but in all of these cases you must use extra protective measures (for example, a condom) during the first 9 days of Estradiol Valerate and Dienogest use.
  • After a miscarriage.
    Follow the advice of your doctor.
  • After having a baby.
    You can start Estradiol Valerate and Dienogest between 21 and 28 days after having a baby. If you start later than day 28, use a barrier method (for example, a condom) during the first 9 days of Estradiol Valerate and Dienogest use.
    If, after having a baby, you have had sex before re-starting Estradiol Valerate and Dienogest, be sure that you are not pregnant or wait until the next menstrual period.
    If you want to start Estradiol Valerate and Dienogest after having a baby and are breast-feeding, read the section on “Pregnancy and breast-feeding”.

Ask your doctor what to do if you are not sure when to start.

If you take more Estradiol Valerate and Dienogest than you should

There are no reports of serious harmful effects of taking too many Estradiol Valerate and Dienogest tablets.

If you take several active tablets at once, you may feel sick or throw up. Young girls may have bleeding from the vagina.

If you have taken too many Estradiol Valerate and Dienogest tablets, or you discover that a child has taken some, ask your doctor or pharmacist for advice.

If you forget to take Estradiol Valerate and Dienogest

Inactive tablets: If you miss a white tablet (2 tablets at the end of the wallet), you do not need to take it later because they do not contain any active substances. However, it is important that you discard the missed white tablet(s) to make sure that the number of days when you take tablets is not increased as this would increase the risk of pregnancy. Continue with the next tablet at the usual time.

Active tablets: Depending on the day of the cycle on which one active tablet has been missed, you may need to take additional contraceptive precautions, for example a barrier method such as a condom. Take the tablets according to the following principles. See also the ‘missed pill chart’ for details.

  • If you are less than 12 hours late when taking a tablet, the protection against pregnancy is not reduced. Take the tablet as soon as you remember and then continue taking the tablets again at the usual time.
  • If you are more than 12 hours late taking a tablet, the protection against pregnancy may be reduced. Depending on the day of the cycle on which one tablet has been missed, use additional contraceptive precautions e.g. a barrier method such as a condom. See also the ‘missed pill chart’ for details.
  • More than one tablet forgotten in this wallet
    Contact your doctor.

Do not take more than 2 active tablets on a given day.

If you have forgotten to start a new wallet, or if you have missed one or more tablets during days 3 – 9 of your wallet, there is a risk that you are already pregnant (if you had sex in the 7 days before forgetting the tablet). In that case, contact your doctor. The more tablets you have forgotten (especially those on days 3 – 24) and the closer they are to the inactive tablet phase, the greater the risk that the protection from pregnancy is reduced. See also the ‘missed pill chart’ for details.

If you have forgotten any of the active tablets in a wallet, and you have no bleeding at the end of a wallet, you may be pregnant. Contact your doctor before you start the next wallet.

Missed more than 1 coloured pill

Forgot to start a new wallet

Contact your doctor straight away

Only missed 1 pill (more than 12 hours late)

Day 1-9

Have had sex in the 7 days before forgetting?

YES

Contact your doctor straight away

Only missed 1 pill (more than 12 hours late)

Day 1-9

Have had sex in the 7 days before forgetting?

NO

  • Take the missed tablet and continue taking the tablets as usual (this may mean 2 tablets in one day).
  • Use barrier method (condom) for the next 9 days

Only missed 1 pill (more than 12 hours late)

Day 10-17

  • Take the missed tablet and continue taking the tablets as usual (this may mean 2 tablets in one day).
  • Use barrier method (condom) for the next 9 days

Only missed 1 pill (more than 12 hours late)

Day 18-24

  • Do not take the missed tablet
  • Start immediately with the next wallet
  • Use a barrier method (condom) for the next 9 days

Only missed 1 pill (more than 12 hours late)

Day 25-26

  • Take the missed tablet and continue taking the tablets as usual (this may mean 2 tablets in one day)
  • No additional contraception necessary

Only missed 1 pill (more than 12 hours late)

Day 27-28

  • Discard the missed tablets and continue taking the tablets as usual
  • No additional contraception necessary

Use in children

No data available in adolescents below 18 years.

What to do if you vomit or have severe diarrhoea

If you throw up within 3-4 hours of taking an active tablet or you have severe diarrhoea, there is a risk that the active substances in the pill are not fully absorbed by your body.

The situation is almost the same as forgetting a tablet. After throwing up or having diarrhoea, take the next tablet as soon as possible. If possible, take it within 12 hours of when you normally take your pill. If this is not possible or 12 hours have passed, you should follow the advice given under “If you forget to take Estradiol Valerate and Dienogest”. If you do not want to change your normal tablet-taking pattern take the corresponding tablet from another wallet.

If you stop taking Estradiol Valerate and Dienogest

You can stop taking Estradiol Valerate and Dienogest at any time. If you do not want to become pregnant, ask your doctor for advice about other reliable methods of birth control. If you want to become pregnant, stop taking Estradiol Valerate and Dienogest and wait for a menstrual period before starting to try to become pregnant. You will be able to calculate the expected delivery date more easily.

If you have any further questions on the use of this product, ask your doctor or pharmacist.

4. Possible side effects

Like all medicines, Estradiol Valerate and Dienogest can cause side effects, although not everybody gets them. If you get any side effect, particularly if severe and persistent, or have any change to your health that you think may be due to Estradiol Valerate and Dienogest, please talk to your doctor.

An increased risk of blood clots in your veins (venous thromboembolism (VTE)) or blood clots in your arteries (arterial thromboembolism (ATE)) is present for all women taking combined hormonal contraceptives. For more detailed information on the different risks from taking combined hormonal contraceptives please see section 2 “What you need to know before you take Estradiol Valerate and Dienogest”.

Serious side effects

Serious reactions associated with the use of the pill, as well as the related symptoms, are described in the following sections: “Blood clots” and “Estradiol Valerate and Dienogest and cancer“. Please read these sections carefully and consult your doctor at once where appropriate.

Other possible side effects

The following side effects have been linked with the use of Estradiol Valerate and Dienogest:

Common side effects (between 1 and 10 in every 100 users may be affected):

  • headache
  • abdominal pain, nausea
  • acne
  • no periods, breast discomfort, painful periods, irregular bleeding (heavy irregular bleeding)
  • weight gain

Uncommon side effects (between 1 and 10 in every 1,000 users may be affected):

  • fungal infections, fungal infection of the vulva and vagina, vaginal infection
  • increased appetite
  • depression, depressed mood, emotional disorder, problems sleeping, decreased interest in sex, mental disorder, mood swings
  • dizziness, migraine
  • hot flush, high blood pressure
  • diarrhoea, vomiting
  • increased liver enzymes
  • hair loss, excessive sweating (hyperhidrosis), itching, rash
  • muscle cramps
  • swollen breasts, lumps in the breast, abnormal cell growth on the neck of the womb (cervical dysplasia), dysfunctional genital bleeding, pain with intercourse, fibrocystic breast disease, heavy periods, menstrual disorders, ovarian cyst, pelvic pain, premenstrual syndrome, growth in the uterus, contractions of the uterus, uterine/vaginal bleeding incl. spotting, vaginal discharge, vulvovaginal dryness
  • fatigue, irritability, swelling of parts of your body, e.g. ankles (oedema)
  • weight loss, blood pressure changes.

Rare side effects (between 1 and 10 in every 10,000 users may be affected):

  • candida infection, oral herpes, pelvic inflammatory disease, a vessel disease of the eye resembling a fungal infection (presumed ocular histoplasmosis syndrome), a fungal infection of the skin (tinea versicolor), urinary tract infection, bacterial inflammation of the vagina
  • fluid retention, increase in certain blood fats (triglycerides)
  • aggression, anxiety, feelings of unhappiness, increased interest in sex, nervousness, night mare, restlessness, problems sleeping, stress
  • reduced attention, “pins and needles”, giddiness
  • contact lens intolerance, dry eye, eye swelling
  • heart attack (myocardial infarction), palpitations
  • bleeding in a varicose vein, low blood pressure, inflammation of superficial veins, painful veins
  • harmful blood clots in a vein or artery for example:
    • in a leg or foot (i.e. DVT)
    • in a lung (i.e. PE)
    • heart attack
    • stroke
    • mini-stroke or temporary stroke-like symptoms, known as a transient ischaemic attack (TIA)
    • blood clots in the liver, stomach/intestine, kidneys or eye.

The chance of having a blood clot may be higher if you have any other conditions that increase this risk (See section 2 for more information on the conditions that increase risk for blood clots and the symptoms of a blood clot).

  • constipation, dry mouth, indigestion, heartburn
  • liver nodules (focal nodular hyperplasia), chronic inflammation of gallbladder
  • allergic skin reactions, golden brown pigment patches (chloasma) and other pigmentation disorders, male pattern hair growth, excessive hair growth, skin conditions such as dermatitis and neurodermatitis, dandruff and oily skin (seborrhoea) and other skin disorders
  • back pain, pain in jaw, sensation of heaviness
  • urinary tract pain
  • abnormal withdrawal bleeding, benign breast nodules, breast cancer in early stage, breast cysts, breast discharge, polyp on the neck of the womb, reddening on the neck of the womb, bleeding during intercourse, spontaneous milk flow, genital discharge, lighter periods, delayed periods, rupture of an ovarian cyst, vaginal odour, burning sensation in the vulva and vagina, vulvovaginal discomfort
  • swollen lymph nodes
  • asthma, difficulty in breathing, nose bleeding
  • chest pain, tiredness and feeling generally unwell, fever
  • abnormal smear from the neck of the womb

Further information (taken from the diaries women kept during a Estradiol Valerate and Dienogest clinical trial) on the possible side effects “irregular bleeding (heavy irregular bleeding)” and “no periods” is given in the sections “Bleeding between periods” and “What to do if no bleeding occurs on day 26 or the following day(s)”.

Description of selected adverse reactions

Adverse reactions with very low frequency or with delayed onset of symptoms which are considered to be related to the group of combined oral contraceptives, and could also occur during use of Estradiol Valerate and Dienogest, are listed below (see also sections “When not to take Estradiol Valerate and Dienogest”, “Warnings and precautions”:

  • liver tumors (benign and malignant)
  • Erythema nodosum (tender red nodules under the skin), Erythema multiforme (skin rash with red spots or lesions)
  • hypersensitivity (including symptoms such as rash, urticaria)
  • in women with hereditary angioedema (characterized by sudden swelling of e.g. the eyes, mouth, throat etc.) estrogens in combined oral contraceptive pills may induce or worsen symptoms of angioedema

In case of disturbed liver function, it may be necessary to temporarily stop the use of combined oral contraceptive pills.

Reporting of side effects

If you get any side effects, talk to your doctor or pharmacist. This includes any possible side effects not listed in this leaflet. You can also report side effects directly (see details below). By reporting side effects you can help provide more information on the safety of this medicine.

5. How to store Estradiol Valerate and Dienogest

Keep this medicine out of the sight and reach of children.

This medicinal product does not require any special storage conditions.

Do not use this medicine after the expiry date which is stated on the wallet after EXP. The expiry date refers to the last day of that month.

Do not throw away any medicines via wastewater or household waste. Ask your pharmacist how to throw away medicines you no longer use. These measures will help protect the environment.

6.Contents of the pack and other information

What Estradiol Valerate and Dienogest contains

The active substances are estradiol valerate, or estradiol valerate combined with dienogest.

Each wallet (28 film-coated tablets) of Estradiol Valerate and Dienogest contains 26 active tablets in 4 different colours in rows 1, 2, 3 and 4, as well as 2 white inactive-tablets in row 4.

Composition of the coloured tablets containing one or two active substances:

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

Composition of the white inactive tablets:

These tablets do not contain any active substances.

Other ingredients in the coloured active tablets are:

Tablet core: lactose monohydrate, maize starch, pregelatinised maize starch, povidone K25, magnesium stearate

Tablet film-coating: hypromellose type 2910, macrogol 6000, talc, titanium dioxide (E171), iron oxide yellow and/or iron oxide red

Other ingredients in the white inactive tablets are:

Tablet core: lactose monohydrate, maize starch, povidone K25, magnesium stearate

Tablet film-coating: hypromellose type 2910, talc, titanium dioxide

What Estradiol Valerate and Dienogest looks like and content of the pack

Estradiol Valerate and Dienogest tablets are film-coated tablets; the core of the tablet is covered with a coating.

Each wallet (28 film-coated tablets) contains 2 dark yellow tablets in row 1, 5 medium red tablets in row 1, 17 light yellow tablets in rows 2, 3 and 4, 2 dark red tablets in row 4 as well as 2 white tablets in row 4.

The dark yellow active tablet is round with biconvex faces,.

The medium red active tablet is round with biconvex faces.

The light yellow active tablet is round with biconvex faces.

The dark red active tablet is round with biconvex faces.

The white inactive tablet is round with biconvex faces.

Estradiol Valerate and Dienogest is available in packs of 1, 3, or 6 wallets each containing 28 tablets.

Not all pack sizes may be marketed.

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

 

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Taj Generics (Taj Pharma) provides a wide range of products to the Indian market, including an extensive range of generics and specialty products; Our products cover a vast array of therapeutic categories, and we offer an extensive range of dosage forms and delivery systems including oral solids, controlled-release, steriles, injectables, topicals, liquids, transdermals, semi-solids and high-potency products. Our Generics portfolio offers over 1500 products in the major therapeutic areas of gastro-intestinal, cardiovascular, pain management, oncology, anti-infectives, paediatrics and dermatology.