Drospirenone and ethinyl acetate film coated tablet USP 3mg/0.03mg Taj Pharma

1. Name of the medicinal product
a) Drospirenone and ethinyl acetate  film coated tablet USP 3mg/0.03mg Taj Pharma
b) Drospirenone and ethinyl acetate  film coated tablet USP 3mg/0.02mg Taj Pharma

2. Qualitative and quantitative composition
a) Each film coated tablet contains:
Drospirenone USP 3mg
Ethinyl acetate (as betadex clathrate) 0.03mg
Excipients        q.s.

b) Each film coated tablet contains:
Drospirenone USP 3mg
Ethinyl acetate (as betadex clathrate) 0.02mg
Excipients     q.s.

3. Pharmaceutical form

Film-coated tablets
The active tablets are light pink, round with convex faces.
The placebo tablets are white, round with convex faces.

4. Clinical particulars

4.1 Therapeutic indications
Oral contraception.

The decision to prescribe Drospirenone/ EE should take into consideration the individual woman’s current risk factors, particularly those for venous thromboembolism (VTE), and how the risk of VTE with Drospirenone/ EE compares with other Combined Hormonal Contraceptives (CHCs)

4.2 Posology and method of administration
Method of administration: oral use
Posology

How to take DROSPIRENONE/ EE
The tablets must be taken every day at about the same time, if necessary with a little liquid, in the order shown on the blister pack. 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 pack. Withdrawal bleeding usually starts on day 2-3 after starting the placebo tablets (last row) and may not have finished before the next pack is started.

How to start DROSPIRENONE/ EE
• 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 Drospirenone/ EE preferably on the day after the last active tablet (the last tablet containing the active substances) of her previous COC, but at the latest on the day following the usual tablet-free or placebo tablet interval of her previous COC. In case a vaginal ring or transdermal patch has been used the woman should start using Drospirenone/ EE preferably on the day of removal, but at the latest when the next application would have been due.
• 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 7 days of tablet-taking.

• Following first-trimester abortion
  The woman may start immediately. When doing so, she need not take additional contraceptive measures.
• Following delivery or second-trimester abortion
  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 7 days. 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.

For breastfeeding women see section 4.6.

Management of missed tablets
Placebo tablets from the last (4^th) row of the blister can be disregarded. However, they should be discarded to avoid unintentionally prolonging the placebo tablet phase. The following advice only refers to missed active tablets:

If the user is less than 24 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 24 hours late in taking any tablet, contraceptive protection may be reduced. The management of missed tablets can be guided by the following two basic rules:

1. the recommended hormone-free tablet interval is 4 days, tablet-taking must never be discontinued for longer than 7 days
2. 7 days of uninterrupted tablet-taking are required to attain adequate suppression of the hypothalamic-pituitary-ovarian-axis.

Accordingly the following advice can be given in daily practice:

• Day 1-7
  The user 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. In addition, a barrier method such as a condom should be used for the next 7 days. If intercourse took place in the preceding 7 days, the possibility of a pregnancy should be considered. The more tablets are missed and the closer they are to the placebo tablet phase, the higher the risk of a pregnancy.
• Day 8-14
  The user 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. Provided that the woman has taken her tablets correctly in the 7 days preceding the first missed tablet, there is no need to use extra contraceptive precautions. However, if she has missed more than 1 tablet, the woman should be advised to use extra precautions for 7 days.
• Day 15-24
  The risk of reduced reliability is imminent because of the forthcoming placebo tablet phase. However, by adjusting the tablet-intake schedule, reduced contraceptive protection can still be prevented. By adhering to either of the following two options, there is therefore no need to use extra contraceptive precautions, provided that in the 7 days preceding the first missed tablet the woman has taken all tablets correctly. If this is not the case, she should follow the first of these two options and use extra precautions for the next 7 days as well.

1. The user 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 until the active tablets are used up. The 4 placebo tablets from the last row must be discarded. The next blister pack must be started right away. The user is unlikely to have a withdrawal bleed until the end of the active tablets section of the second pack, but she may experience spotting or breakthrough bleeding on tablet-taking days.
2. . The woman may also be advised to discontinue active tablet-taking from the current blister pack. She should then take placebo tablets from the last row for up to 4 days, including the days she missed tablets, and subsequently continue with the next blister pack.

If the woman missed tablets and subsequently has no withdrawal bleed in the placebo tablet phase, 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, a new (replacement) tablet should be taken as soon as possible. The new tablet should be taken within 24 hours of the usual time of tablet-taking if possible.. If the woman does not want to change her normal tablet-taking schedule, she has to take the extra tablet(s) from another blister pack.

How to postpone a withdrawal bleed
To delay a period the woman should continue with another blister pack of Drospirenone/ EE without taking the placebo tablets from her current pack. The extension can be carried on for as long as wished until the end of the active tablets in the second pack. During the extension the woman may experience breakthrough-bleeding or spotting. Regular intake of Drospirenone/ EE is then resumed after the placebo tablet phase.

To shift her periods to another day of the week than the woman is used to with her current scheme, she can be advised to shorten her forthcoming placebo tablet phase by as many days as she likes. The shorter the interval, the higher the risk that she does not have a withdrawal bleed and will experience breakthrough-bleeding and spotting during the subsequent pack (just as when delaying a period).

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)
• Venous thromboembolism – current VTE (on anticoagulants) or history of (e.g. deep venous thrombosis [DVT] or pulmonary embolism [PE])
•Known hereditary or acquired predisposition for venous thromboembolism, such as APC resistance, (including Factor V Leiden), antithrombin-III-deficiency, protein C deficiency, protein S deficiency
• Major surgery with prolonged immobilisation
• A high risk of venous thromboembolism due to the presence of multiple risk factors
• Presence or risk of arterial thromboembolism (ATE)
• Arterial thromboembolism – current arterial thromboembolism, history of arterial thromboembolism (e.g. myocardial infarction) or prodromal condition (e.g. angina pectoris)
• Cerebrovascular disease – current stroke, history of stroke or prodromal condition (e.g. transient ischaemic attack, TIA)
• Known hereditary or acquired predisposition for arterial thromboembolism, such as hyperhomocysteinaemia and antiphospholipid-antibodies (anticardiolipin-antibodies, lupus anticoagulant)
• History of migraine with focal neurological symptoms
• A high risk of arterial thromboembolism due to multiple risk factors or to the presence of one serious risk factor such as:

• Presence or history of severe hepatic disease as long as liver function values have not returned to normal
  • Severe renal insufficiency or acute renal failure
  • 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.

The drug  is contraindicated for concomitant use with the medicinal products containing ombitasvir/paritaprevir/ritonavir and dasabuvir

4.4 Special warnings and precautions for use
Warnings
If any of the conditions or risk factors mentioned below is present, the suitability of Drospirenone/ EE 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 DROSPIRENONE/ EE 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).

• Circulatory Disorders

Risk of venous thromboembolism (VTE)
The use of any combined hormonal contraceptive (CHC) increases the risk of venous thromboembolism (VTE) compared with no use. Products that contain levonorgestrel, norgestimate or norethisterone are associated with the lowest risk of VTE. Other products such as DROSPIRENONE/ EE may have up to twice this level of risk. The decision to use any product other than one with the lowest VTE risk should be taken only after a discussion with the woman to ensure she understands the risk of VTE with Drospirenone/ EE, how her current risk factors influence this risk, and that her VTE risk is highest in the first ever year of use. There is also some evidence that the risk is increased when a CHC is re-started after a break in use of 4 weeks or more.

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

It is estimated¹ that out of 10,000 women who use a CHC containing drospirenone between 9 and 12 women will develop a VTE in one year; this compares with about 6² in women who use a levonorgestrel-containing CHC.

In both cases, the number of VTEs per year is fewer than the number expected 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).

Drospirenone/ EE is contraindicated if a woman has multiple risk factors that put her at high risk of venous thrombosis. 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

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

TABLE: Risk factors for VTE
The increased risk of thromboembolism in pregnancy, and particularly the 6 week period of the puerperium, must be considered 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 discolouration 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.

TABLE: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). Drospirenone/ EE is contraindicated if a woman has one serious or multiple risk factors for ATE that puts her at high risk of arterial thrombosis. 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

Risk factors for ATE

Symptoms of ATE
In the event of symptoms women should be advised to seek urgent medical attention and to inform the healthcare professional that she is taking a CHC.
Symptoms of a cerebrovascular accident can include:
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 haemorrhages. A hepatic tumour should be considered in the differential diagnosis when severe upper abdominal pain, liver enlargement or signs of intra-abdominal haemorrhage occur in women taking COCs.

With the use of the higher-dosed COCs (50 µg ethinylestradiol) the risk of endometrial and ovarian cancer is reduced. Whether this also applies to lower-dosed COCs remains to be confirmed.

• Other conditions

The progestin component in DROSPIRENONE/ EE is an aldosterone antagonist with potassium sparing properties. In most cases, no increase of potassium levels is to be expected. In a clinical study, however in some patients with mild or moderate renal impairment and concomitant use of potassium-sparing medicinal products serum potassium levels slightly, but not significantly, increased during drospirenone intake. Therefore, it is recommended to check serum potassium during the first treatment cycle in patients presenting with renal insufficiency and a pretreatment serum potassium in the upper reference range, and particularly during concomitant use of potassium sparing medicinal products. See also.

Women with hypertriglyceridemia, 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. Only in these rare cases an immediate discontinuation of COC use is justified. If, during the use of a COC in pre-existing hypertension, constantly elevated blood pressure values or a significant increase in blood pressure do not respond adequately to antihypertensive treatment, the COC must be withdrawn. 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; gallstones; porphyria; systemic lupus erythematosus; haemolytic 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 and/or cholestasis-related pruritus which previously occurred during pregnancy or during 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, 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.

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.

Each light pink tablet of this medicinal product contains 46 mg lactose per tablet, each white tablet contains 22 mg. 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.

ALT elevations

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

Medical examination/consultation
Prior to the initiation or reinstitution of DROSPIRENONE/ EE 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 DROSPIRENONE/ EE 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 in the event of e.g. missed active tablets gastro-intestinal disturbances during active tablet taking or concomitant medication.

Reduced 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 three cycles.

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.

In some women withdrawal bleeding may not occur during the placebo tablet phase. If the COC has been taken according to the directions described in section 4.2, it is unlikely that the woman is pregnant. However, if the COC has not been taken according to these directions prior to the first missed withdrawal bleed or if two withdrawal bleeds are missed, pregnancy must be ruled out before COC use is continued.
¹ These incidences were estimated from the totality of the epidemiological study data, using relative risks for the different products compared with levonorgestrel-containing CHCs.
² 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.
• Effects of other medicinal products on Drospirenone/ EE
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.
The following interactions have been reported in the literature.
Substances increasing the clearance of COCs (diminished efficacy of COCs by enzyme-induction), e.g.:
Barbiturates, bosentan, 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).

Substances with variable effects on the clearance of COCs:
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)
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.
In a multiple dose study with a drospirenone (3 mg/day) / ethinylestradiol (0.02 mg/day) combination, co-administration of the strong CYP3A4 inhibitor ketoconazole for 10 days increased the AUC(0-24h) of drospirenone and ethinylestradiol 2.7-fold and 1.4-fold respectively.
Etoricoxib doses of 60 to 120 mg/day have been shown to increase plasma concentrations of ethinylestradiol 1.4 to 1.6-fold, respectively when taken concomitantly with a combined hormonal contraceptive containing 0.035 mg ethinylestradiol.

• Effects of Drospirenone/ EE on other medicinal products
  COCs may affect the metabolism of certain other active substances. Accordingly, plasma and tissue concentrations may either increase (e.g. ciclosporin) or decrease (e.g. lamotrigine).
  Based on in vivo interaction studies in female volunteers using omeprazole, simvastatin or midazolam as marker substrate,a interaction of drospirenone at doses of 3 mg with the cytochrome P450 mediated metabolism of other active substances is unlikely.
  Clinical data suggests that ethinylestradiol is inhibiting the clearance of CYP1A2 substrates leading to a weak (e.g. theophylline) or moderate (e.g. tizanidine) increase in their plasma concentration.
• Pharmacodynamic interactions
  Concomitant use with the medicinal products containing ombitasvir/paritaprevir/ritonavir and dasabuvir, with or without ribavirin may increase the risk of ALT elevations
  Therefore, Drospirenone/ EE-users must switch to an alternative method of contraception (e.g., progestagen-only contraception or non-hormonal methods) prior to starting therapy with this combination drug regimen. Drospirenone/ EE can be restarted 2 weeks following completion of treatment with this combination drug regimen.
  In patients without renal insufficiency, the concomitant use of drospirenone and ACE-inhibitors or NSAIDs did not show a significant effect on serum potassium. Nevertheless, concomitant use of Drospirenone/ EE with aldosterone antagonists or potassium-sparing diuretics has not been studied. In this case, serum potassium should be tested during the first treatment cycle.
• 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. Drospirenone causes an increase in plasma renin activity and plasma aldosterone induced by its mild antimineralocorticoid activity.

4.6 Fertility, pregnancy and lactation
Pregnancy
Drospirenone/ EE is not indicated during pregnancy.
If pregnancy occurs during use of with Drospirenone/ EE, the preparation should be withdrawn immediately. Extensive epidemiological studies have revealed neither an increased risk of birth defects in children born to women who used COCs prior to pregnancy, nor a teratogenic effect when COCs were taken inadvertently during pregnancy.
Animal studies have shown undesirable effects during pregnancy and lactation. Based on these animal data, undesirable effects due to hormonal action of the active compounds cannot be excluded. However, general experience with COCs during pregnancy did not provide evidence for an actual adverse effect in humans.
The available data regarding the use of Drospirenone/ EE during pregnancy are too limited to permit conclusions concerning negative effects of Drospirenone/ EE on pregnancy, health of the foetus or neonate. To date, no relevant epidemiological data are available.
The increased risk of VTE during the postpartum period should be considered when re-starting Drospirenone/ EE

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 breast-feeding mother has completely weaned her child. Small amounts of the contraceptive steroids and/or their metabolites may be excretewith the milk during COC use. These amounts may affect the child.

Fertility
Drospirenone/ EE is indicated for the prevention of pregnancy. For information on return to fertility

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
The following adverse drug reactions have been reported during use of Drospirenone/ EE:

The table below reports adverse reactions by MedDRA system organ classes (MedDRA SOCs). The frequencies are based on clinical trial data. The most appropriate MedDRA term is used to describe a certain reaction and its synonyms and related conditions.

Adverse drug reactions which have been associated with the use of Drospirenone/ EE as oral contraceptive or in the treatment of moderate acne vulgaris according to the MedDRA system organ classes and MedDRA terms

* bleeding irregularities usually subside during continued treatment

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,.
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:

– Venous thromboembolic disorders;
– Arterial thromboembolic disorders;
– Hypertension;
– Liver tumours;
– Occurrence or deterioration of conditions for which association with COC use is not conclusive: Crohn’s disease, ulcerative colitis, epilepsy, uterine myoma, porphyria, systemic lupus erythematosus, herpes gestationis, Sydenham’s chorea, haemolytic uremic syndrome, cholestatic jaundice;
– Chloasma;
– Acute or chronic disturbances of liver function may necessitate the discontinuation of COC use until markers of liver function return to normal.

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

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,

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

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.

4.9 Overdose
There has not yet been any experience of overdose with Drospirenone/ EE. On the basis of general experience with combined oral contraceptives, symptoms that may possibly occur in case of taking an overdose of active tablets are nausea, vomiting and withdrawal bleeding. Withdrawal bleeding may even occur in girls before their menarche, if they accidentally take the medicinal product. There are no antidotes and further treatment should be symptomatic.

5. Pharmacological properties

5.1 Pharmacodynamic properties
Pharmacotherapeutic group (ATC): Progestogens and estrogens, fixed combinations
ATC Code: G03AA12
Pearl Index for method failure: 0.41 (upper two-sided 95 % confidence limit: 0.85)
Overall Pearl Index (method failure + patient failure): 0.80 (upper two-sided 95% confidence limit: 1.30)
The contraceptive effect of Drospirenone/ EE is based on the interaction of various factors, the most important of which are seen as the inhibition of ovulation and the changes in the endometrium.
In a 3-cycle ovulation inhibition study comparing drospirenone 3 mg / ethinylestradiol 0.020 mg in a 24-day-regimen and a 21-day-regimen, the 24-day-regimen was associated with greater suppression of follicular development. After intentionally introduced dosing errors during the third cycle of treatment, a greater proportion of women in the 21-day-regimen showed ovarian activity including escape ovulations compared to the women taking the 24-day-regimen. Ovarian activity returned to pre-treatment levels during the post-treatment cycle in 91.8% of the women who took the 24-day regimen.

Drospirenone/ EE is a combined oral contraceptive with ethinylestradiol and the progestogen drospirenone. In a therapeutic dosage, drospirenone also possesses antiandrogenic and mild antimineralocorticoid properties. It has no estrogenic, glucocorticoid and antiglucocorticoid activity. This gives drospirenone a pharmacological profile closely resembling the natural hormone progesterone.
There are indications from clinical studies that the mild antimineralocorticoid properties of Drospirenone/ EE result in a mild antimineralocorticoid effect.
Two multicenter, double blind, randomized, placebo controlled studies were performed to evaluate the efficacy and safety of Drospirenone/ EE in women with moderate acne vulgaris.
After six months of treatment, in comparison with placebo,Drospirenone/ EE showed a statistically significantly greater reduction of 15.6 % (49.3% versus 33.7%) in inflammatory lesions, 18.5% (40.6% versus 22.1%) in non-inflammatory lesions, and 16.5% (44.6% versus 28.1%) in total lesion counts. In addition, a higher percentage of subjects 11.8% (18.6% versus 6.8%) showed a ‘clear’ or ‘almost clear’ rating on the Investigator’s Static Global Assessment (ISGA) scale.

5.2 Pharmacokinetic properties

• Drospirenone

Absorption
Orally administered drospirenone is rapidly and almost completely absorbed. Maximum concentrations of the active substance in serum of about 38 ng/ml are reached at about 1-2 h after single ingestion. Bioavailability is between 76 and 85 %. Concomitant ingestion of food has no influence on the bioavailability of drospirenone.

Distribution
After oral administration, serum drospirenone levels decrease with a terminal half-life of 31 h. Drospirenone is bound to serum albumin and does not bind to sex hormone binding globulin (SHBG) or corticoid binding globulin (CBG). Only 3 – 5 % of the total serum concentrations of the active substance are present as free steroid. The ethinylestradiol-induced increase in SHBG does not influence the serum protein binding of drospirenone. The mean apparent volume of distribution of drospirenone is 3.7 ± 1.2 l/kg.

Biotransformation
Drospirenone is extensively metabolized after oral administration. The major metabolites in plasma are the acid form of drospirenone, generated by opening of the lactone ring, and the 4,5-dihydro-drospirenone-3-sulfate, formed by reduction and subsequent sulfatation. . Drospirenone is also subject to oxidative metabolism catalyzed by CYP3A4.

Elimination
The metabolic clearance rate of drospirenone in serum is 1.5 ± 0.2 ml/min/kg. Drospirenone is excreted only in trace amounts in unchanged form. The metabolites of drospirenone are excreted with the faeces and urine at an excretion ratio of about 1.2 to 1.4. The half-life of metabolite excretion with the urine and faeces is about 40h.

Steady-State Conditions
During a treatment cycle, maximum steady-state concentrations of drospirenone in serum of about 70 ng/ml are reached after about 8 days of treatment. Serum drospirenone levels accumulated by a factor of about 3 as a consequence of the ratio of terminal half-life and dosing interval.

Special Populations

Effect of renal impairment
Steady-state serum drospirenone levels in women with mild renal impairment (creatinine clearance CLcr, 50-80 mL/min) were comparable to those of women with normal renal function. The serum drospirenone levels were on average 37 % higher in women with moderate renal impairment (CLcr, 30 – 50 mL/min) compared to those in women with normal renal function. Drospirenone treatment was also well tolerated by women with mild and moderate renal impairment. Drospirenone treatment did not show any clinically significant effect on serum potassium concentration.

Effect of hepatic impairment
In a single dose study, oral clearance (CL/F) was decreased approximately 50 % in volunteers with moderate hepatic impairment as compared to those with normal liver function. The observed decline in drospirenone clearance in volunteers with moderate hepatic impairment did not translate into any apparent difference in terms of serum potassium concentrations. Even in the presence of diabetes and concomitant treatment with spironolactone (two factors that can predispose a patient to hyperkalemia) an increase in serum potassium concentrations above the upper limit of the normal range was not observed. It can be concluded that drospirenone is well tolerated in patients with mild or moderate hepatic impairment (Child-Pugh B).

Ethnic groups
No clinically relevant differences in the pharmacokinetics of drospirenone or ethinylestradiol between Japanese and Caucasian women have been observed.

• Ethinylestradiol

Absorption
Orally administered ethinylestradiol is absorbed rapidly and completely. Peak serum concentrations of about 33 pg/ml are reached within 1 – 2 hours after single oral administration. Absolute bioavailability as a result of presystemic conjugation and first-pass metabolism is approximately 60 %. Concomitant intake of food reduced the bioavailability of ethinylestradiol in about 25 % of the investigated subjects while no change was observed in the others.

Distribution
Serum ethinylestradiol levels decrease in two phases, the terminal disposition phase is characterized by a half-life of approximately 24 hours. Ethinylestradiol is highly but non-specifically bound to serum albumin (approximately 98.5 %), and induces an increase in the serum concentrations of SHBG and corticoid binding globulin (CBG). An apparent volume of distribution of about 5 l/kg was determined.

Biotransformation
Ethinylestradiol is subject to significant gut and hepatic first-pass metabolism . Ethinylestradiol is primarily metabolized by aromatic hydroxylation but a wide variety of hydroxylated and methylated metabolites are formed, and these are present as free metabolites and as conjugates with glucuronides and sulfate. The metabolic clearance rate of ethinylestradiol is about 5 ml/min/kg.
In vitro ethinylestradiol is a reversible inhibitor of CYP2C19, CYP1A1 and CYP1A2 as well as a mechanism based inhibitor of CYP3A4/5, CYP2C8 and CYP2J2.

Elimination
Ethinylestradiol is not excreted in unchanged form to any significant extent. The metabolites of ethinylestradiol are excreted at a urinary to biliary ratio of 4:6. The half-life of metabolite excretion is about 1 day.

Steady-state conditions
Steady-state conditions are reached during the second half of a treatment cycle and serum levels of ethinylestradiol accumulate by a factor of about 2.0 to 2.3.

5.3 Preclinical safety data
In laboratory animals, the effects of drospirenone and ethinylestradiol were confined to those associated with the recognised pharmacological action. In particular, reproduction toxicity studies revealed embryotoxic and fetotoxic effects in animals which are considered as species specific. At exposures exceeding those in users of DROSPIRENONE/ EE, effects on sexual differentiation were observed in rat foetuses but not in monkeys. Environmental risk assessment studies have shown that ethinylestradiol and drospirenone have the potential of posing a risk to the aquatic environment.

6. Pharmaceutical particulars

6.1 List of excipients

6.2 Incompatibilities
Not applicable.

6.3 Shelf life
5 years.

6.4 Special precautions for storage
This medical product does not require any special storage conditions.

6.5 Nature and contents of container
Transparent PVC/Aluminium blister in a folding box.
Pack sizes:
28 tablets
3 x 28 tablets
6 x 28 tablets

Each blister contains 24 light pink active film-coated tablets and 4 white placebo film-coated tablets.
Not all pack sizes may be marketed.

6.6 Special precautions for disposal and other handling
This medicinal product may pose a risk to the environment . Any unused medicinal 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

Drospirenone and ethinyl acetate  film coated tablet USP 3mg/0.03mg Taj Pharma

Package leaflet: Information for the patient

a) Drospirenone and ethinyl acetate  film coated tablet USP 3mg/0.03mg Taj Pharma
b) Drospirenone and ethinyl acetate  film coated tablet USP 3mg/0.02mg Taj Pharma

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, even if their signs of illness are the same as yours.
– If you get any side effects, talk to your doctor or pharmacist. This includes any possible side effects not listed in this leaflet.

What is in this leaflet
1. What Drospirenone and ethinyl acetate Tablets are and what they are used for
2. What you need to know before you take Drospirenone and ethinyl acetate Tablets
3. How to take Drospirenone and ethinyl acetate Tablets
4. Possible side effects
5. How to store Drospirenone and ethinyl acetate Tablets
6. Contents of the pack and other information

1. WHAT DROSPIRENONE AND ETHINYL ACETATE TABLETS ARE AND WHAT THEY ARE USED FOR
Drospirenone and ethinyl acetate is a contraceptive pill and is used to prevent pregnancy.
Each light yellow tablet contains a small amount of two different female hormones, namely drospirenone and ethinylestradiol.
Contraceptive pills that contain two hormones are called “combination” pills.

2. WHAT YOU NEED TO KNOW BEFORE YOU TAKE DROSPIRENONE AND ETHINYL ACETATE TABLETS
Before you start using Drospirenone and ethinyl acetate, you should read the information on blood clots in. It is particularly important to read the symptoms of a blood clot
Before you can begin taking Drospirenone and ethinyl acetate, 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 booklet, several situations are described where you should stop using Drospirenone and ethinyl acetate, or where the reliability of Drospirenone and ethinyl acetate 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 Drospirenone and ethinyl acetate alters the monthly changes of body temperature and cervical mucus.

DROSPIRENONE AND ETHINYL ACETATE, like other hormonal contraceptives, does not protect against HIV infection (AIDS) or any other sexually transmitted disease.
When you should not use Drospirenone and ethinyl acetate
You should not use Drospirenone and ethinyl acetate 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 use DROSPIRENONE AND ETHINYL ACETATE
–if you have (or have ever had) a blood clot in a blood vessel of your leg (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 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 your kidneys are not working well (renal failure)
• if you have (or have ever had) had a tumour in the liver
• if you have (or have ever had) or if you are suspected of having breast cancer or cancer of the genital organs
• if you have any unexplained bleeding from the vagina
• if you are allergic to ethinylestradiol or drospirenone, or any of the other ingredients of this medicine.This may cause itching, rash or swelling.

Do not use Drospirenone and ethinyl acetate if you have hepatitis C and are taking the medicinal products containing ombitasvir/paritaprevir/ritonavir and dasabuvir.

Additional information on special populations
Use in children
Drospirenone and ethinyl acetate is not intended for use in females whose periods have not yet started.
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
Talk to your doctor before taking Drospirenone and ethinyl acetate. In some situations you need to take special care while using Drospirenone and ethinyl acetate or any other combination pill, and your doctor may need to examine you regularly. If the condition develops, or gets worse while you are using Drospirenone and ethinyl acetate, 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 the gallbladder
• if you have diabetes
• if you have depression
• if you have Crohn’s disease or ulcerative colitis (chronic inflammatory bowel disease);
• 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 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 Drospirenone and ethinyl acetate;
• If you have an inflammation in the veins under the skin (superficial thrombophlebitis);
• If you have varicose veins;
• if you have epilepsy (see page 9 “Other medicines and Drospirenone and ethinyl acetate;
• if you have systemic lupus erythematosus (SLE – a disease affecting your natural defence system);
• if you have a disease that first appeared during pregnancy or earlier use of sex hormones (for example, hearing loss, a blood disease called porphyria, yellowing of the skin or eyes (jaundice), itching of the whole body (pruritis), skin rash with blisters during pregnancy (gestational herpes), a nerve disease causing sudden movements of the body (Sydenham’s chorea))
• if you have ever had a discolouration of the skin especially on the face or neck known as “pregnancy patches” (chloasma). If so, avoid direct sunlight or ultraviolet light.
• if you have hereditary angioedema, products containing oestrogens may cause or worsen the symptoms. You should see 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.

BLOOD CLOTS
Using a combined hormonal contraceptive such as Drospirenone and ethinyl acetate increases your risk of developing a blood clot compared with not using one. In rare cases a blood clot can block vessels and cause serious problems.
Blood clots can develop in veins 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 DROSPIRENONE AND ETHINYL ACETATE 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
ensation 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, oshortness 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?
welling 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 Drospirenone and ethinyl acetate 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 DROSPIRENONE AND ETHINYL ACETATE 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.
Out of 10,000 women who are using a combined hormonal contraceptive that contains drospirenone such as Drospirenone and ethinyl acetate, between about 9 and 12 women will develop a blood clot in a year.

The risk of having a blood clot will vary according to your personal medical history Women who are not using a combined hormonal pill and are not pregnant
Risk of developing a blood clot in a year – About 2 out of 10,000 women
Women using a combined hormonal contraceptive pill containing levonorgestrel, norethisterone or norgestimate
Risk of developing a blood clot in a year – About 5-7 out of 10,000 women
Women using Drospirenone and ethinyl acetate
Risk of developing a blood clot in a year – About 9-12 out of 10,000 women

Factors that increase your risk of a blood clot in a vein
The risk of a blood clot with Drospirenone and ethinyl acetate is small but some conditions will increase the risk. Your risk is higher:if you are very overweight (body mass index or BMI over 30kg/m²);
if one of your immediate family has had a blood clot in the leg, lung or other organ at a young age (eg. 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 Drospirenone and ethinyl acetate may need to be stopped several weeks before surgery or while you are less mobile. If you need to stop Drospirenone and ethinyl acetate 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 Drospirenone and ethinyl acetate needs to be stopped.
If any of the above conditions change while you are using Drospirenone and ethinyl acetate, 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 Drospirenone and ethinyl acetate is very small but can increase:
with increasing age (beyond about 35 years);
if you smoke. When using a combined hormonal contraceptive like Drospirenone and ethinyl acetate, 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 Drospirenone and ethinyl acetate, 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.
Drospirenone and ethinyl acetate and cancer
Breast cancer has been observed slightly more often in women using combination pills, but it is not known whether this is caused by the treatment. For example it may be that more tumours are detected in women on combination 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 pill users. Contact your doctor if you have unusually severe abdominal pain.
Bleeding between periods
During the first few months that you are taking Drospirenone and ethinyl acetate, you may have unexpected bleeding (bleeding outside the seven pill-free days). If this bleeding occurs for more than a few months, or if it begins after some months, contact your doctor as they must find out if anything is wrong.
What to do if no bleeding occurs during the seven pill-free days
If you have taken all the tablets correctly, have not had 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 succession, you may be pregnant. Contact your doctor immediately. Only start the next strip if you are sure that you are not pregnant.
Other medicines and Drospirenone and ethinyl acetate
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) that you take Drospirenone and ethinyl acetate. They can tell you if you need to take additional contraceptive precautions (for example condoms) and if so, for how long, or, whether the use of another medicine you need must be changed.

Some medicines

• can have an influence on the blood levels of Drospirenone and ethinyl acetate
• 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)
• 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 (griseofulvin, ketoconazole)
• arthritis, arthrosis (etoricoxib)
• high blood pressure in the blood vessels in the lungs (bosentan)
• the herbal remedy St. John’s wort

Drospirenone and ethinyl acetate may influence the effect of other medicines, e.g.

• medicines containing ciclosporin
• the anti-epileptic lamotrigine (this could lead to an increased frequency of seizures)
• theophylline (used to treat breathing problems)
• tizanidine (used to treat muscle pain and/or muscle cramps).

Do not use Drospirenone and ethinyl acetate if you have hepatitis C and are taking the medicinal products containing ombitasvir/paritaprevir/ritonavir and dasabuvir as this may cause increases in liver function blood test results (increase in ALT liver enzyme). Your doctor will prescribe another type of contraceptive prior to start of the treatment with these medicinal products. Drospirenone and ethinyl acetate can be restarted approximately 2 weeks after completion of this treatment. See section “Do not use Drospirenone and ethinyl acetate”.
Ask your doctor or pharmacist for advice before taking any medicine.

Drospirenone and ethinyl acetate with food and drink
Drospirenone and ethinyl acetate may be taken with or without food, if necessary with a small amount of water.

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

Pregnancy
If you are pregnant, you must not take Drospirenone and ethinyl acetate. If you become pregnant while taking Drospirenone and ethinyl acetate you must stop taking it immediately and contact your doctor. If you want to become pregnant, you can stop taking Drospirenone and ethinyl acetate at any time (see also page 14 “If you stop taking Drospirenone and ethinyl acetate”).
Ask your doctor or pharmacist for advice before taking any medicine.

Breast-feeding
Use of Drospirenone and ethinyl acetate is generally not advisable when a woman is 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.

Driving and using machines
There is no information suggesting that use of Drospirenone and ethinyl acetate affects driving or the use of machines.
Drospirenone and ethinyl acetate contains lactose
If you cannot tolerate certain sugars, contact your doctor before you take Drospirenone and ethinyl acetate.

3. HOW TO TAKE DROSPIRENONE AND ETHINYL ACETATE TABLETS
Take Drospirenone and ethinyl acetate every day for 21 days Drospirenone and ethinyl acetate comes in strips of 21 pills, each marked with a day of the week.

• Take your pill at the same time every day.
• Start by taking a pill marked with the correct day of the week.
• Follow the direction of the arrows on the strip. Take one pill each day, until you have finished all 21 pills.
• Swallow each pill whole, with water if necessary. Do not chew the pill.

Then have seven pill-free days
After you have taken all 21 pills in the strip, you have seven days when you take no pills. So, if you take the last pill of one pack on a Friday, you will take the first pill of your next pack on the Saturday of the following week.
Within a few days of taking the last pill from the strip, you should have a withdrawal bleed like a period. This bleed may not have finished when it is time to start your next strip of pills.
You don’t need to use extra contraception during these seven pill-free days – as long as you have taken your pills correctly and start the next strip of pills on time.

Then start your next strip
Start taking your next strip of Drospirenone and ethinyl acetate after the seven pill-free days – even if you are still bleeding. Always start the new strip on time.

During the seven pill-free days, when you take no tablets, bleeding should begin (so-called withdrawal bleeding). This usually starts on the 2^nd or 3^rd day after the last tablet of Drospirenone and ethinyl acetate. Start the following strip after the last day of the seven pill-free days, whether your bleeding has stopped or not.

When can you start with the first strip?

• If you have not used a contraceptive with hormones in the previous month
  Begin with Drospirenone and ethinyl acetate on the first day of your cycle (that is, the first day of your period). If you start Drospirenone and ethinyl acetate on the first day of your period you are immediately protected against pregnancy. You may also begin on day 2-5 of the cycle, but then you must use extra protective measures (for example, a condom) for the first 7 days.
• Changing from a combination hormonal contraceptive, or combination contraceptive vaginal ring or patch
  You can start Drospirenone and ethinyl acetate preferably on the day after the last active tablet (the last tablet containing the active substances) of your previous pill, but at the latest on the day after the tablet-free days of your previous pill finish (or after the last inactive tablet of your previous pill). When changing from a combination contraceptive vaginal ring or patch, follow the advice of your doctor.
• Changing from a progestogen-only-method (progestogen-only pill, injection, implant or a progestogen-releasing intrauterine system IUS)
  You may switch any day from the progestogen-only pill (from an implant or an IUS on the day of its removal, from an injectable when the next injection would be due) but in all of these cases use extra protective measures (for example, a condom) for the first 7 days of taking Drospirenone and ethinyl acetate.
• After a miscarriage or abortion
  If you have had a miscarriage or abortion during the first three months of pregnancy, your doctor may tell you to start taking Drospirenone and ethinyl acetate straight away. This means that you will have contraceptive protection with your first pill.
• After having a baby
  You can start taking Drospirenone and ethinyl acetate between 21 and 28 days after having a baby. If you start later than day 28, use a so-called barrier method (for example, a condom) during the first seven days of taking Drospirenone and ethinyl acetate.
  If, after having a baby, you have had sex before starting Drospirenone and ethinyl acetate (again), you must first be sure that you are not pregnant or wait until your next period.
• If you are breast-feeding and want to start Drospirenone and ethinyl acetate after having a baby
  Read the section on “Breast-feeding”.

Ask your doctor what to do if you are not sure when to start.
If you take more Drospirenone and ethinyl acetate than you should
There are no reports of serious harmful
results of taking too many Drospirenone and ethinyl acetate tablets.
If you take several tablets at once then you may feel sick or vomit or you may bleed from the vagina.
Even girls who have not yet started to menstruate but have accidentally taken this medicine may experience such bleeding.
If you have taken too many Drospirenone and ethinyl acetate tablets, or you discover that a child has taken some, ask your doctor or pharmacist for advice
If you forget to take Drospirenone and ethinyl acetate

• If you are less than 12 hours late taking a tablet, the protection against pregnancy is not reduced. Take the tablet as soon as you remember and then take the following tablets again at the usual time.
• If you are more than 12 hours late taking a tablet, the protection against pregnancy may be reduced. The greater the number of tablets you have forgotten, the greater is the risk of becoming pregnant.

The risk of incomplete protection against pregnancy is greatest if you forget a tablet at the beginning or at the end of the strip. Therefore, you should keep to the following rules (see also the diagram on page 14):

• More than one tablet forgotten in this strip
  Contact your doctor.
• One tablet forgotten between days 1 – 7

Take the forgotten tablet as soon as you remember, even if that means that you have to take two tablets at the same time. Continue taking the tablets at the usual time and use extra precautions for the next 7 days, for example, a condom. If you have had sex in the week before forgetting the tablet you may be pregnant. In that case, contact your doctor.

• One tablet forgotten between days 8 – 14

Take the forgotten tablet as soon as you remember, even if that means that you have to take two tablets at the same time. Continue taking the tablets at the usual time. The protection against pregnancy is not reduced, and you do not need to take extra precautions. If you forget more than one tablet use an additional barrier method such as a condom for 7 days.

• One tablet forgotten between days 15 – 21
• You can choose between two possibilities:
  Take the forgotten tablet as soon as you remember, even if that means that you have to take two tablets at the same time. Continue taking the tablets at the usual time. Instead of having seven pill-free days start the next strip as soon as you have taken the last tablet.
  Most likely, you will have a period at the end of the second strip – but you may also have light or menstruation-like bleeding during the second strip.
  2. You can also stop the tablets and go directly to the tablet-free period (record the day on which you forgot your tablet). If you want to start a new strip on the day you always start, make the tablet-free period less than 7 days.

If you follow one of these two recommendations, you will remain protected against pregnancy.

• If you have forgotten any of the tablets in a strip, and you do not have a bleeding during the first tablet-free period, you may be pregnant. Contact your doctor before you start the next strip.

What to do in the case of vomiting or severe diarrhoea

If you vomit within 3-4 hours of taking a tablet or you have severe diarrhoea, there is a risk that the active substances in the pill will not be fully taken up by your body. The situation is almost the same as forgetting a tablet. After vomiting or diarrhoea, take another tablet from a reserve strip as soon as possible. If possible take it within 12 hours of when you normally take your pill. If that is not possible or 12 hours have passed, you should follow the advice given under “If you forget to take Drospirenone and ethinyl acetate” on page 12.

Delaying your period: what you need to know

Although it is not recommended, you can delay your period by skipping the seven pill-free days and going straight to a new strip of Drospirenone and ethinyl acetate and finishing it. You may experience light or menstruation-like bleeding while using this second strip. After the usual pill-free period of 7 days start your next strip.

It is advisable to consult your doctor for advice before deciding to delay your menstrual period.

Changing the first day of your period: what you need to know

If you take the tablets according to the instructions, then your period will begin during the seven pill-free days. If you have to change this day, make the pill-free period shorter – (but never longer – 7 days is the maximum!). For example, if you start the seven pill-free days on a Friday, and you want to change this to a Tuesday (3 days earlier) start a new strip 3 days earlier than usual. If you make the pill-free period very short (for example 3 days or less) you may not have any bleeding during this time. You may then experience light or menstruation-like bleeding.

If you are not sure what to do, consult your doctor.
If you stop taking Drospirenone and ethinyl acetate
You can stop taking Drospirenone and ethinyl acetate whenever you want. 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 Drospirenone and ethinyl acetate and wait for a menstrual period before trying 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 medicine, ask a doctor or pharmacist.

4. POSSIBLE SIDE EFFECTS
Like all medicines, this medicine 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 Drospirenone and ethinyl acetate, 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 “What you need to know before you take Drospirenone and ethinyl acetate”.

The following is a list of the side effects that have been linked with the use of Drospirenone and ethinyl acetate:

Serious side effects: – see your doctor straight away

Signs of a severe allergic reaction to Drospirenone and ethinyl acetate:

• swelling of the face, lips, mouth, tongue or throat

Signs of breast cancer include:

• dimpling of the skin
• changes in the nipple
• any lumps you can see or feel.

Signs of cancer of the cervix include:

• vaginal discharge that smells and/or contains blood
• unusual vaginal bleeding
• pelvic pain
• painful sex

Signs of severe liver problems include:

• severe pain in your upper abdomen
• yellow skin or eyes (jaundice)
• inflammation of the liver (hepatitis)
• your whole body starts itching
• If you think you may have any of these, see a doctor straight away. You may need to stop taking Drospirenone and ethinyl acetate

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

• depressive mood
• headache, migraine
• nausea
• breast pain, breast tenderness, menstrual disorders, bleeding between periods, thick whitish vaginal discharge, vaginal yeast infection

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

• breast enlargement
• altered interest in sex
• high blood pressure, low blood pressure
• vomiting, diarrhoea
• acne, severe itching, skin rash, hair loss (alopecia)
• vaginal infection
• fluid retention
• body weight changes

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

• hearing impairment
• asthma
• breast secretion
• allergic reactions (hypersensitivity)
• the skin conditions erythema nodosum (characterized by painful reddish skin nodules) or erythema multiforme (characterized by rash with target-shaped reddening or sores).
• 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

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 DROSPIRENONE AND ETHINYL ACETATE TABLETS
Keep this medicine out of the sight and reach of children.
Do not store above 25 °C. Store in the original package.
Do not use this medicine after the expiry date which is stated on the packaging after “Do not use after:” or “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. Further Information

What Drospirenone and ethinyl acetate Soluble Tablets contain
The active substance is Drospirenone and ethinyl acetate.
a) Each film coated tablet contains:
Drospirenone USP     3mg
Ethinyl acetate (as betadex clathrate)  0.03mg
Excipients        q.s.

b) Each film coated tablet contains:
Drospirenone USP         3mg
Ethinyl acetate (as betadex clathrate)  0.02mg
Excipients       q.s.

Other ingredients in the active tablets are lactose monohydrate, maize starch, pregelatinised maize starch, povidone K25, magnesium stearate (E470b), hypromellose (E464), macrogol 6000, talc (E553b), titanium dioxide (E171) and iron oxide yellow (E172).

What Drospirenone and ethinyl acetate Tablets look like and contents of the pack
White, oval, flat tablets with bevelled edges. One side is smooth and the other side has a dividing score line. Each amber glass bottle contains 8 tablets with a tamper evident, child-resistant screw cap which contain silica gel desiccant.

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