Levonorgestrel 0.15mg and Ethinyl Estradiol 0.03mg Tablets USP Taj Pharma

Name of the medicinal product

Levonorgestrel 0.25mg and Ethinyl Estradiol 0.05mg Tablets USP Taj Pharma
Levonorgestrel 0.125mg and Ethinyl Estradiol 0.03mg Tablets USP Taj Pharma
Levonorgestrel 0.09mg and Ethinyl Estradiol 0.02mg Tablets USP Taj Pharma
Levonorgestrel 0.15mg and Ethinyl Estradiol 0.03mg Tablets USP Taj Pharma

Qualitative and quantitative composition

A) Each uncoated tablet contains:
Levonorgestrel 0.25mg
and Ethinyl estradiol USP 0.05mg
Excipients q.s

B) Each uncoated tablet contains:
Levonorgestrel 0.125mg
and Ethinyl estradiol USP 0.03mg
Excipients q.s

C) Each uncoated tablet contains:
Levonorgestrel 0.15mg
and Ethinyl estradiol USP 0.03mg
Excipients q.s

D) Each uncoated tablet contains:
Levonorgestrel 0.09mg
and Ethinyl estradiol USP 0.02mg
Excipients q.s

For full list of excipients, see section 6.1

Pharmaceutical form

Tablets

Clinical particulars

4.1 Therapeutic indications

Oral contraception and the recognised gynaecological indications for such oestrogen-progestogen combinations.

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

4.2 Posology and method of administration

Tablets must be taken orally in the order directed on the blister package at about the same time every day, with some liquid if necessary.

First treatment cycle: 1 tablet daily for 28 days, starting on the first day of the menstrual cycle. 21 (small) active tablets are taken followed by 7 (larger) placebo tablets. Contraceptive protection begins immediately.

Subsequent cycles: Tablet-taking is continuous, which means that the next pack of Levonorgestrel and Ethinyl Estradiol follows immediately without a break. A withdrawal bleed usually occurs when the placebo tablets are being taken.

Changing from 21-day combined oral contraceptives: The first tablet of Levonorgestrel and Ethinyl Estradiol should be taken on the first day immediately after the end of the previous oral contraceptive course. Additional contraceptive precautions are not required.

Changing from a combined Every Day pill (28 -day pill): Levonorgestrel and Ethinyl Estradiol should be started after taking the last active tablet from the previous Every Day pill pack. The first Levonorgestrel and Ethinyl Estradiol tablet is taken the next day. Additional contraceptive precautions are not then required.

Changing from a progestogen-only pill (POP):

The first tablet of Levonorgestrel and Ethinyl Estradiol should be taken on the first day of bleeding, even if a POP has already been taken on that day. Additional contraceptive precautions are not then required. The remaining progestogen-only pills should be discarded.

Post-partum and post-abortum use: After pregnancy, oral contraception can be started 21 days after a vaginal delivery, provided that the patient is fully ambulant and there are no puerperal complications. Additional contraceptive precautions will be required for the first 7 days of tablet taking to ensure adequate contraceptive cover if early ovulation has occurred. Since the first post-partum ovulation may precede the first bleeding, another method of contraception should be used in the interval between childbirth and the first course of tablets. After a first-trimester abortion, oral contraception may be started immediately in which case no additional contraceptive precautions are required.

Special circumstances requiring additional contraception

Incorrect administration: Errors in taking the 7 placebo tablets (i.e. the larger white tablets in the last row) can be ignored.

A single delayed active (small) tablet should be taken as soon as possible, and if this can be done within 12 hours of the correct time, contraceptive protection is maintained.

With longer delays in taking active tablets, additional contraception is needed. Only the most recently delayed tablet should be taken, earlier missed tablets being omitted, and additional non-hormonal methods of contraception (except the rhythm or temperature methods) should be used for the next 7 days, while the next 7 active (small) tablets are being taken. Therefore, if the 7 days additional contraception extend beyond the last active (small) tablet, the user should finish taking all the active tablets, discard the placebo tablets and start a new pack of Levonorgestrel and Ethinyl Estradiol the next day with an appropriate active (small) tablet. Thus, active tablet follows active tablet with no 7 day break. In this situation, a withdrawal bleed should not be expected until the end of the second pack. Some breakthrough bleeding may occur on tablet taking days but this is not clinically significant. If the patient does not have a withdrawal bleed following the end of the second pack, the possibility of pregnancy must be ruled out before starting the next pack.

Gastro-intestinal upset: Vomiting or diarrhoea may reduce the efficacy of oral contraceptives by preventing full absorption. If vomiting or diarrhoea occurs within 4 hours of tablet-taking from the current pack should be continued. Additional non-hormonal methods of contraception (except the rhythm or temperature methods) should be used during the gastro-intestinal upset and for 7 days following the upset. If these 7 days extend beyond the last active (small) tablet the user should finish taking all the active tablets, discard the placebo tablets and start a new pack of Levonorgestrel and Ethinyl Estradiol the next day with an appropriate active (small) tablet. In this situation, a withdrawal bleed should not be expected until the end of the second pack. If the patient does not have a withdrawal bleed at the end of the second pack, the possibility of pregnancy must be ruled out before starting the next pack. Other methods of contraception should be considered if the gastro-intestinal disorder is likely to be prolonged.

Children: Not applicable

Elderly: Not applicable

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 anti-phospholipid 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, e.g. active viral hepatitis and severe cirrhosis, as long as liver function values have not returned to normal.
Presence or history of liver tumours (benign or malignant).
Current or history of breast cancer.
Hypersensitivity to the active substance(s) or to any of the excipients.

Relevant UK clinical guidance should also be consulted.

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

4.4 Special warnings and precautions for use

Warnings

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

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, such as Levonorgestrel and Ethinyl Estradiol, norgestimate or norethisterone are associated with the lowest risk of VTE. The decision to use Levonorgestrel and Ethinyl Estradiol should be taken after a discussion with the woman to ensure she understands the risk of VTE with Levonorgestrel and Ethinyl Estradiol, 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 estimated that out of 10,000 women who use a CHC that contains levonorgestrel, about 6¹ will develop a VTE in a year.

This number of VTEs per year is fewer than the number expected in women during pregnancy or in the postpartum period.

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

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

Extremely rarely, thrombosis has been reported to occur in CHC users in other blood vessels, e.g. hepatic, mesenteric, renal, cerebral 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).

Levonorgestrel and Ethinyl Estradiol 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 Levonorgestrel and Ethinyl Estradiol 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:

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

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

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

Symptoms of pulmonary embolism (PE) can include:

– sudden onset of unexplained shortness of breath or rapid breathing;

– sudden coughing which may be associated with haemoptysis;

– sharp chest pain;

– severe light headedness or dizziness;

– rapid or irregular heartbeat.

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

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

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

Risk of arterial thromboembolism (ATE)

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

Risk factors for ATE

The risk of arterial thromboembolic complications or of a cerebrovascular accident in CHC users increases in women with risk factors (see table). Levonorgestrel and Ethinyl Estradiol 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:

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

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

– sudden confusion, trouble speaking or understanding;

– sudden trouble seeing in one or both eyes;

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

– loss of consciousness or fainting with or without seizure.

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

Symptoms of myocardial infarction (MI) can include:

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

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

– feeling of being full, having indigestion or choking;

– sweating, nausea, vomiting or dizziness;

– extreme weakness, anxiety, or shortness of breath;

– rapid or irregular heartbeats.

Medical Examination/Consultation

Prior to the initiation or reinstitution of Levonorgestrel and Ethinyl Estradiol 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 Levonorgestrel and Ethinyl Estradiol 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.

Undiagnosed vaginal bleeding that is suspicious for underlying conditions should be investigated.

Conditions which require strict medical supervision

The decision to prescribe the COC must be made using clinical judgement and in consultation with the woman. Exacerbation or first appearance of any of these conditions or risk factors may indicate that use of the oral contraceptive should be discontinued. The woman should contact her physician, who should then decide on whether COC use should be discontinued:

Diabetes mellitus with mild vascular disease or mild nephropathy, retinopathy or neuropathy
Hypertension that is adequately controlled, i.e. systolic >140 to159 mm Hg or diastolic > 90 to 94 mm Hg (see also Section 4.4 ‘Reasons for stopping oral contraception immediately’)
porphyria
obesity
migraine
cardiovascular diseases

Reasons for stopping oral contraception immediately:

When stopping oral contraception non-hormonal contraception should be used to ensure contraceptive protection is maintained.

Occurrence for the first time, or exacerbation, of migrainous headaches or unusually frequent or unusually severe headaches
Sudden disturbances of vision, of hearing or other perceptual disorders
First signs of thrombosis or blood clots (e.g. unusual pains in or swelling of the leg(s), stabbing pains on breathing or coughing for no apparent reason). Feeling of pain and tightness in the chest
Six weeks before an elective major operation (e.g. abdominal, orthopaedic), any surgery to the legs, medical treatment for varicose veins or prolonged immobilisation, e.g. after accidents or surgery. Do not restart until 2 weeks after full ambulation. In case of emergency surgery, thrombotic prophylaxis is usually indicated e.g. subcutaneous heparin
Onset of jaundice, hepatitis, itching of the whole body
Significant rise in blood pressure
Severe upper abdominal pain or liver enlargement
Clear exacerbation of conditions known to be capable of deteriorating during oral contraception or pregnancy (see section 4.4 ‘Conditions which deteriorate in pregnancy or during previous COC use’ under ‘Other conditions’)

Tumours

Numerous epidemiological studies have been reported on the risks of ovarian, endometrial, cervical and breast cancer in women using combined oral contraceptives. The evidence is clear that high dose combined oral contraceptives offer substantial protection against both ovarian and endometrial cancer. However, it is not clear whether low dose COCs confer protective effects to the same level.

Breast cancer

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 combined oral contraceptives (COCs). 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 additional breast cancers diagnosed in current users of COCs or in women who have used COCs in the last ten years are more likely to be localised to the breast than those in women who never used COCs.

Breast cancer is rare among women under 40 years of age whether or not they take COCs. Whilst this background risk increases with 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 (see bar chart).

The most important risk factor for breast cancer in COC users is the age women discontinue the COC; the older the age at stopping, the more breast cancers are diagnosed. Duration of use is less important and the excess risk gradually disappears during the course of the 10 years after stopping COC use such that by 10 years there appears to be no excess.

The possible increase in risk of breast cancer should be discussed with the user and weighed against the benefits of COCs taking into account the evidence that they offer substantial protection against the risk of developing certain other cancers (e.g. ovarian and endometrial cancer).

Cervical Cancer

The most important risk factor for cervical cancer is persistent HPV infection. Some epidemiological studies have indicated that long-term use of COCs may further contribute to this increased risk but there continues to be controversy about the extent to which this finding is attributable to confounding effects, e.g., cervical screening and sexual behaviour including use of barrier contraceptives.

Liver Cancer

In rare cases benign and, in even rarer cases, malignant liver tumours leading in isolated cases to life-threatening intra-abdominal haemorrhage have been observed after the use of hormonal substances such as those contained in Levonorgestrel and Ethinyl Estradiol. If severe upper abdominal complaints, liver enlargement or signs of intra-abdominal haemorrhage occur, the possibility of a liver tumour should be included in the differential diagnosis.

Other conditions

The possibility cannot be ruled out that certain chronic diseases may occasionally deteriorate during the use of combined oral contraceptives.

Known hyperlipidaemias

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

Women with hyperlipidaemias are at an increased risk of arterial disease (see section 4.4 ‘Risk of arterial thromboembolism (ATE)’). However routine screening of women on COCs is not appropriate.

Blood pressure

Hypertension is a risk factor for stroke and myocardial infarction (see section 4.4 ‘Risk of arterial thromboembolism (ATE)’). Although small increases in blood pressure have been reported in many women taking COCs, clinically relevant increases are rare. However, if sustained hypertension develops during the use of a COC, antihypertensive treatment should normally be instigated at a level of 160/100 mm Hg in uncomplicated patients or at 140/90 mm Hg in those with target organ damage, established cardiovascular disease, diabetes or with increased cardiovascular risk factors. Decisions about the continued use of the COC should be made at lower BP levels, and alternative contraception may be advised.

Conditions which deteriorate in pregnancy or during previous COC use

The following conditions have been reported to occur or deteriorate with both pregnancy and COC use. Consideration should be given to stopping Levonorgestrel and Ethinyl Estradiol if any of the following occur during use:

• jaundice and/or pruritus related to cholestasis

• COCs may increase the risk of gallstone formation and may worsen existing disease.

• systemic lupus erythematosus

• herpes gestationis

• otosclerosis-related hearing loss

• sickle cell anaemia

• renal dysfunction

• hereditary angioedema

• any other condition an individual woman has experienced worsening of during pregnancy or previous use of COCs.

Disturbances of liver function

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 occurred during pregnancy or previous use of sex steroids necessitates the discontinuation of COCs.

Diabetes (without vascular involvement)

Insulin-dependent diabetics without vascular disease can use COCs. However it should be remembered that all diabetics are at an increased risk of arterial disease and this should be considered when prescribing COCs. Diabetics with existing vascular disease are contraindicated from using COCs (see section 4.3 Contraindications).

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.

Psychiatric disorders

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

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.

Menstrual Changes

Reduction of menstrual flow: This is not abnormal and it is to be expected in some patients. Indeed, it may be beneficial where heavy periods were previously experienced.

Missed menstruation: Occasionally, withdrawal bleeding may not occur at all. If the tablets have been taken correctly, pregnancy is very unlikely. If withdrawal bleeding fails to occur at the end of a second pack, the possibility of pregnancy must be ruled out before resuming with the next pack.

Intermenstrual bleeding: 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. This may include curettage.

Some women may experience amenorrhoea or oligomenorrhoea after discontinuation of oral contraceptives, especially when these conditions existed prior to use. Women should be informed of this possibility.

Lactose and Sucrose Intolerance

Each tablet of this medicinal product contains 32.97 mg lactose and 19.371 mg sucrose per tablet. Each placebo tablet contains 48.25 mg lactose and 33.98 mg sucrose per tablet. Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency, fructose intolerance or glucose-galactose malabsorption or sucrase-isomaltase should not take this medicine.

Reduced efficacy

The efficacy of COCs may be reduced, in the event of missed tablets, vomiting or diarhhoea, or concomitant medication.

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) (see sections 4.3 and 4.5).

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.

Interactions

Enzyme inducers

Interactions can occur with drugs that induce microsomal enzymes (especially cytochrome P450 3A4) which can result in increased clearance of sex hormones and which may lead to breakthrough bleeding and/or contraceptive failure.

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.

Women on short term treatment with any of these drugs should temporarily use a barrier method in addition to the COC or choose another method of contraception. The barrier method should be used during the time of concomitant drug administration and for 28 days after their discontinuation. If the period during which the barrier methods used runs beyond the last active (small) tablet, the user should finish taking all the active tablets, discard the placebo (large) tablets and start a new pack of Levonorgestrel and Ethinyl Estradiol the next day with an appropriate active (small) tablet. In this situation, a withdrawal bleed should not be expected until the end of the second pack. If the patient does not have a withdrawal bleed during the tablet free interval following the end of the second pack, the possibility of pregnancy must be ruled out before resuming with the next pack.

For women receiving long-term therapy with enzyme inducers, another method of contraception should be used.

The following have been shown to have clinically important interactions with COCs:

Anticonvulsants: barbiturates (including phenobarbitone), primidone, phenytoin, carbamazepine, oxcarbazepine, topiramate.

Antibiotics/antifungals: griseofulvin, rifampacin.

Herbal remedies: St John’s wort (Hypericum perforatum)

Antiretroviral agents: ritonavir, nelfinavir, nevirapine.

Note: There are other antiretroviral agents that may increase plasma concentration of sex hormones.

Substances decreasing the clearance of COCs (enzyme inhibitors)

Strong and moderate CYP3A4 inhibitors such as azole antifungals (e.g. itraconazole, voriconazole, fluconazole), and macrolides (e.g. erythromycin) can increase plasma concentrations of the oestrogen or the progestin or both.

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 on other drugs

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

Pharmacodynamic interactions

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

Therefore, Levonorgestrel and Ethinyl Estradiol-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. Levonorgestrel and Ethinyl Estradiol can be restarted 2 weeks following completion of treatment with this combination drug regimen.

Laboratory tests

The use of oral contraceptives 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. Laboratory staff should therefore be informed about oral contraceptive use when laboratory tests are requested.

4.6 Pregnancy and lactation

Levonorgestrel and Ethinyl Estradiol is not indicated during pregnancy. If pregnancy occurs during treatment with Levonorgestrel and Ethinyl Estradiol, further intake must be stopped. However, 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 early pregnancy.

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

The use of Levonorgestrel and Ethinyl Estradiol during lactation may lead to a reduction in the volume of milk produced and to a change in its composition. Minute amounts of the active substances are excreted with the milk. These amounts may affect the child particularly in the first 6 weeks post-partum. Mothers who are breast-feeding may be advised instead to use another method of contraception.

4.7 Effects on ability to drive and use machines

Ethinylestradiol / levonorgestrel has no effects or negligible influence on the ability to drive and use machines.

4.8 Undesirable effects

Summary of the safety profile

The most commonly reported adverse reactions with Levonorgestrel and Ethinyl Estradiol are nausea, abdominal pain, increased weight, headache, depressed mood, altered mood, breast pain, breast tenderness. They occur in ≥1% of users.

Serious adverse reactions are arterial and venous thromboembolism.

The following adverse events have been reported during use of ethinylestradiol / levonorgestrel:

System Organ Class	Adverse events reported in clinical trials			Adverse events reported post marketing
System Organ Class	Common (≥ 1/100)	Uncommon (≥ 1/1000, <1/100)	Rare (< 1/1000)
Eye disorders			contact lens intolerance
Gastrointestinal disorders	nausea, abdominal pain	vomiting, diarrhea		Crohn’s disease, ulcerative colitis
Immune system disorders			hypersensitivity	exacerbation of hereditary angioedema
Investigations	weight increased		weight decreased
Metabolism and nutrition disorders		fluid retention		Hypertriglyceridemia
Nervous system disorders	headache	migraine		exacerbation of chorea
Vascular system disorders			Venous thromboembolism (VTE), Arterial thromboembolism (ATE)
Hepatobiliary disorders				liver function disturbances
Psychiatric disorders	depressed mood, mood altered	libido decreased	libido increased
Reproductive system and breast disorders	breast pain, breast tenderness	breast hypertrophy	vaginal discharge, breast discharge	reduced menstrual flow, spotting, breakthrough bleeding and missed withdrawal bleeding, post pill amenorrhoea
Skin and subcutaneous tissue disorders		rash, urticaria	erythema nodosum, erythema multiforme	chloasma

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.

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

Venous thromboembolic disorders
Arterial thromboembolic disorders
Strokes (e.g. transient ischemic attack, ischemic stroke, haemorrhagic stroke)
Hypertension
Liver tumours (benign and malignant)

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 ‘Contraindications’ and 4.4 ‘Special warnings and precautions for use’.

Conditions reported to deteriorate with pregnancy or previous COC use

Jaundice and/or pruritus related to cholestasis; gallstone formation; systemic lupus erythematosus; herpes gestationis; otosclerosis-related hearing loss; sickle cell anaemia; renal dysfunction; hereditary angioedema; porphyria; cervical cancer.

Changes in glucose tolerance or effect on peripheral insulin resistance have been reported in women using COCs (see section 4.4).

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 have been no reports of serious effects from overdose. Overdosage may cause nausea, vomiting and, in females, withdrawal bleeding. Withdrawal bleeding may even occur in girls before their menarche, if they accidentally take the medicinal product.

There are no specific antidotes and treatment should be symptomatic.

Pharmacological properties

5.1 Pharmacodynamic properties

Levonorgestrel and Ethinyl Estradiol is an oestrogen-progestogen combination which acts by inhibiting ovulation by suppression of the mid-cycle surge of luteinizing hormone, the inspissation of cervical mucus so as to constitute a barrier to sperm, and the rendering of the endometrium unreceptive to implantation.

5.2 Pharmacokinetic properties

Levonorgestrel

Levonorgestrel is absorbed quickly and completely. Maximum active substance levels of approx. 3 ng/ml were reached in serum just one hour after ingestion of Levonorgestrel and Ethinyl Estradiol. The serum concentrations subsequently fell in 2 phases with half-lives of around 0.5 hours and 20 hours. The metabolic clearance rate from plasma is approx. 1.5 ml/min/kg.

Levonorgestrel is eliminated not in unchanged form, but in the form of metabolites with a half-life of around one day and in almost equal proportions via the kidney and bile. Levonorgestrel is extensively metabolised. The major metabolites in plasma are the unconjugated and conjugated forms of 3α, 5β-tetrahydrolevonorgestrel. Based on in vitro and in vivo studies, CYP3A4 is the main enzyme involved in the metabolism of levonorgestrel.

Levonorgestrel is bound to serum albumin and SHBG. Only around 1.5% of the respective total concentration is present in unbound form, while approx. 65% is bound to SHBG. The relative proportions (free, albumin-bound, SHBG-bound) depend on the concentration of SHBG. After induction of the binding protein, the portion bound to SHBG increases, while the free portion and that bound to albumin decreases.

After daily repeated ingestion, levonorgestrel accumulates by about the factor 2. A steady state is reached during the second half of the treatment cycle. The pharmacokinetics of levonorgestrel are dependent on the concentration of SHBG in plasma. Under treatment with Levonorgestrel and Ethinyl Estradiol, an increase in the serum levels of SHBG effect a concomitant increase in the specific binding capacity and therefore also an increase in levonorgestrel serum levels.

The levonorgestrel serum levels do not change any further after 1 – 3 cycles of use owing to the fact that SHBG induction is concluded. Compared to a single administration, 3 – 4 fold higher levonorgestrel serum levels are reached in the steady state.

The absolute bioavailability of levonorgestrel amounts to almost 100%.

Approx. 0.1% of the maternal dose can be passed on to a baby with the breast milk.

Ethinylestradiol

Orally administered ethinylestradiol is absorbed quickly and completely. Ingestion of Levonorgestrel and Ethinyl Estradiol leads to maximum plasma levels of approx. 100 pg/ml after 1 – 2 hours. The substance concentration then falls in 2 phases for which half-lives of around 1 – 2 hours and about 20 hours have been determined. For technical reasons, these data can only be calculated at higher dosages.

An imaginary distribution volume of around 5 l/kg and a metabolic clearance rate from plasma of approx. 5 ml/min/kg have been determined for ethinylestradiol. Ethinylestradiol is bound non-specifically to serum albumin to the extent of 98%.

Ethinylestradiol is metabolised even during its absorption phase and during its first liver transit, leading to reduced and individually varying oral bioavailability. Ethinylestradiol is eliminated not in unchanged form, but in the form of metabolites with a half-life of around one day. The excretion ratio is 40 (urine) : 60 (bile).

Because of the half-life of the terminal elimination phase from plasma, a steady state characterised by a 30 – 40% higher plasma substance level becomes established after approx. 5 – 6 daily administrations.

The absolute bioavailability of ethinylestradiol is subject to considerable interindividual variations. After oral ingestion, it amounts to around 40 – 60% of the dose.

In women with fully established lactation, around 0.02% of the maternal dose can be passed on to the baby with the breast milk.

Other drugs can have a negative or positive effect on the systemic availability of ethinylestradiol. No interaction with vitamin C takes place. On continuous use, ethinylestradiol induces the hepatic synthesis of CBG and SHBG, the extent of SHBG induction being dependent on the type and dose of the simultaneously administered progestogen.

5.3 Preclinical safety data

There is no preclinical safety data which could be of relevance to the prescriber and which are not already included in other relevant sections of the SPC.

Pharmaceutical particulars

6.1 List of excipients

Active tablets	Placebo tablets
lactose	lactose
maize starch	maize starch
povidone	povidone
magnesium stearate	magnesium stearate
sucrose	sucrose
polyethylene glycol 6000	polyethylene glycol 6000
calcium carbonate	calcium carbonate
talc
montan glycol wax
titanium dioxide
ferric oxide pigment yellow
glycerin

6.2 Incompatibilities

None known.

6.3 Shelf life

5 years.

6.4 Special precautions for storage

Not applicable.

6.5 Nature and contents of container

Deep drawn strips made of polyvinyl chloride film with counter-sealing foil made of aluminium with heat sealable coating.

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

Levonorgestrel 0.25mg and Ethinyl Estradiol 0.05mg Taj Pharma

Package booklet: Information for the user

Levonorgestrel and Ethinylestradiol

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 2.3 ‘Blood clots’).
The Pill may reduce your risk of cancer of the ovary and womb if used in the long term.
The Pill will not protect you against sexually transmitted diseases.
This medicine can increase your risk of problems such as blood clots and breast cancer.
Some women should not take the Pill because of current medical problems or illnesses. Please read this booklet to make sure Levonorgestrel and Ethinyl Estradiol is right for you.
To prevent pregnancy it is important to take Levonorgestrel and Ethinyl Estradiol as instructed and start each pack on time. Please make sure that you understand what to do if you miss a pill or if you think you are pregnant.

Read all of this booklet carefully before you start taking this medicine.

Keep this booklet. You may need to read it again.
If you have any questions or need more advice, ask your doctor, family planning nurse or pharmacist.
This medicine has been prescribed for you. Do not pass it on to others. It may harm them.
If any of the side effects get severe, or if you notice any not listed in this booklet, please tell your doctor, family planning nurse or pharmacist.

In this booklet:

1. What Levonorgestrel and Ethinyl Estradiol does
2. What you need to know before you use Levonorgestrel and Ethinyl Estradiol
3. Taking Levonorgestrel and Ethinyl Estradiol
3.3 A missed pill
4. Possible side effects
5. How to store Levonorgestrel and Ethinyl Estradiol
6. What is in Levonorgestrel and Ethinyl Estradiol and who makes it

What Levonorgestrel and Ethinyl Estradiol does

Levonorgestrel and Ethinyl Estradiol is a combined oral contraceptive pill (‘the Pill’). You take it to stop you getting pregnant.

This contraceptive contains two types of female sex hormones, oestrogen and progestogen. These hormones stop you getting pregnant by working in three ways: by preventing an egg being released from your ovaries; by making the fluid (mucus) in your cervix thicker, which makes it more difficult for sperm to enter the womb; and by preventing the lining of your womb thickening enough for an egg to grow in it.

Levonorgestrel and Ethinyl Estradiol is taken every day without a break. You take an ‘active pill’ each day for 21 days, followed by an ‘inactive pill’ each day for 7 days.

The benefits of taking the Pill include:

it is one of the most reliable reversible methods of contraception if used correctly
it doesn’t interrupt sex
it usually makes your periods regular, lighter and less painful
it may help with pre-menstrual symptoms.

Levonorgestrel and Ethinyl Estradiol will not protect you against sexually transmitted infections, such as Chlamydia or HIV. Only condoms can help to do this.

Levonorgestrel and Ethinyl Estradiol needs to be taken as directed to prevent pregnancy.

What you need to know before you use Levonorgestrel and Ethinyl Estradiol

General notes

Before you start using Levonorgestrel and Ethinyl Estradiol 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 2.3 ‘Blood clots’.

It’s important that you understand the benefits and risks of taking the Pill before you start taking it, or when deciding whether to carry on taking it. Although the Pill is suitable for most healthy women it isn’t suitable for everyone.

Tell your doctor if you have any of the illnesses or risk factors mentioned in this booklet.

Before you start taking the Pill

Your doctor will ask about you and your family’s medical problems, check your blood pressure and exclude the likelihood of you being pregnant. You may also need other checks, such as a breast examination, but only if these examinations are necessary for you, or if you have any special concerns.

While you’re on the Pill

You will need regular check-ups with your doctor or family planning nurse, usually when you need another prescription of the Pill.
You should go for regular cervical smear tests.
Check your breasts and nipples every month for changes – tell your doctor if you can see or feel anything odd, such as lumps or dimpling of the skin.
If you need a blood test tell your doctor that you are taking the Pill, because the Pill can affect the results of some tests.
If you’re going to have an operation, make sure your doctor knows about it. You may need to stop taking the Pill about 4–6 weeks before the operation. This is to reduce the risk of a blood clot (see section 2.3). Your doctor will tell you when you can start taking the Pill again.

2.1 When you should not use Levonorgestrel and Ethinyl Estradiol

You should not use Levonorgestrel and Ethinyl Estradiol 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 Levonorgestrel and Ethinyl Estradiol:

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 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 breast cancer
If you have ever had a severe liver disease, and you have been told by your doctor that your liver function test results are not yet back to normal
If you have ever had liver tumours
If you are allergic (hypersensitive) to any of the ingredients in Levonorgestrel and Ethinyl Estradiol.

Do not use Levonorgestrel and Ethinyl Estradiol if you have hepatitis C and are taking the medicinal products containing ombitasvir/paritaprevir/ritonavir and dasabuvir (see also in section “Taking other medicines”).

Tell your doctor or family planning nurse if you have any medical problems or illnesses.

2.2 When to take special care with Levonorgestrel and Ethinyl Estradiol

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”.

Some of the conditions listed below can be made worse by taking the Pill. Or they may mean it is less suitable for you. You may still be able to take Levonorgestrel and Ethinyl Estradiol but you need to take special care and have check-ups more often.

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

If the condition develops, or gets worse while you are using Levonorgestrel and Ethinyl Estradiol, you should also tell your doctor.

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 inflammation of the pancreas (pancreatitis)
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 2.3 ‘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 Levonorgestrel and Ethinyl Estradiol
If you have an inflammation in the veins under the skin (superficial thrombophlebitis)
If you have varicose veins
If you have diabetes
If you or your close family have ever had problems with your heart, or circulation such as high blood pressure
If you or your close family have ever had problems with blood clotting
If you have the inherited disease called porphyria
If you are overweight (obese)
If you have migraines
If you have any illness that worsened during pregnancy or previous use of the Pill (see section 4.2)

2.3 Blood clots

Using a combined hormonal contraceptive such as Levonorgestrel and Ethinyl Estradiol 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 (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 having a harmful blood clot due to Levonorgestrel and Ethinyl Estradiol is small.

HOW TO RECOGNISE A BLOOD CLOT

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