SUMMARY OF PRODUCT CHARACTERISTICS

1 NAME OF THE MEDICINAL PRODUCT

Violite 100/20 micrograms film-coated tablets

2    QUALITATIVE AND QUANTITATIVE    COMPOSITION

Each film-coated tablet contains 100 micrograms levonorgestrel and 20 micrograms ethinylestradiol.

For the full list of excipients, see section 6.1.

Excipients with known effect:

Each film-coated tablet contains 66.94 mg of lactose

3    PHARMACEUTICAL FORM

Film coated tablets.

Pink, cylindrical, biconvex, film coated tablet of 6 mm    approximately.

4    CLINICAL PARTICULARS

4.1    Therapeutic indications

Oral contraception.

4.2    Posology and method of administration

How to take Violite

Tablets must be taken in the order directed on the package, every day, at about the same time, with some liquid as needed. One tablet is to be taken daily for 21 consecutive days. Each subsequent pack is started after a 7-day tablet-free interval, during which time a withdrawal bleed occurs. This usually starts on days 2-3 after the last tablet and may not have finished before the next pack is started.

How to start Violite

No preceding hormonal contraceptive use [in the past month]

Tablet-taking should start on day 1 of the woman’s natural cycle (i.e. the first day of her menstrual bleeding). Starting on days 2-5 is allowed, but during the first cycle a barrier method of birth control is recommended in addition for the first 7 days of tablet-taking.

Changing from another combined oral contraceptive (COC), vaginal ring, or transdermal patch)

The woman should start Violite preferably on the day after the last active tablet of her previous COC, but at the latest on the day following the usual tablet-free or inactive tablet interval of her previous COC. In case a vaginal ring or transdermal patch has been used, the woman should start using Violite preferably on the day of removal, but at the latest when the next application would have been due.

Changing from a progestin-only method (progestin-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). In all of these situations, the woman should be advised to additionally use a back-up 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

Since the immediate post-partum period is associated with an increased risk of thromboembolism, oral contraceptives should be started no earlier than day 28 after delivery or second-trimester abortion. The woman should be advised to additionally use a back-up method for the first 7 days of tablet-taking. However, if intercourse has already occurred, pregnancy should be excluded before the actual start of COC use, or the woman has to wait for her first menstrual period. (See sections 4.4 and 4.6.)

Management of missed tablets

Contraceptive reliability may be reduced if tablets are missed, and particularly if the missed tablets extend the tablet-free interval. If tablets were missed in the first week of the cycle and intercourse took place in the week before the tablets were missed, the possibility of a pregnancy should be considered.

•Provided that the user is less than 12 hours late in taking any tablet, she should take it as soon as she remembers, and further tablets should be taken at the usual time.

•If she is more than 12 hours late in taking any tablet, contraceptive protection may be reduced.

•The user should take the last missed tablet as soon as she remembers, even if this means taking two tablets in one day. She then continues to take tablets at her usual time. In addition, a back-up method, such as the condom, should be used for the next 7 days.

•If these 7 days run beyond the last tablet in the current pack, the next pack must be started as soon as the current pack is finished; no gap should be left between packs. This prevents an extended break in tablet-taking, which may increase the risk of escape ovulation. The user is unlikely to have a withdrawal bleed until the end of the second pack, but she may experience spotting or breakthrough-bleeding on tablettaking days.

•If the user does not have a withdrawal bleed at the end of the second pack, the possibility of pregnancy must be ruled out before resuming tablet-taking from the next pack.

In case of gastrointestinal upset

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 tablet-taking, a new (replacement) tablet should be taken as soon as possible. The new tablet should be taken within 12 hours of the usual time of tablet-taking if possible. If more than 12 hours elapse, the advice concerning missed tablets, as given in section 4.2 “management of missed tablets”, is applicable.

How to delay a period

To delay a period, the woman should continue with another pack of Violite without a tablet-free interval. The extension can be carried on for as long as wished until the end of the second pack. During the extension, the woman may experience breakthrough-bleeding or spotting.

Regular intake of Violite is then resumed after the usual 7-day, tablet-free interval.

Paediatric population

Safety and efficacy was evaluated in subjects aged 18 years and above.

Method of administration Oral use

4.3 Contraindications

Combined oral contraceptives (COCs) should not be used in women with any of the following conditions listed below.

Should any of the conditions appear for the first time during COC use the product must 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-In-deficiency, protein C deficiency, protein S deficiency

o Major surgery with prolonged immobilisation (see section 4.4) o A high risk of venous thromboembolism due to the presence of multiple risk factors (see section 4.4)

•    Presence or risk of arterial thromboembolism (ATE)

o Arterial thromboembolism - current arterial thromboembolism, history of arterial thromboembolism (e.g. myocardial infarction) or prodromal condition (e.g. angina pectoris)

o Cerebrovascular disease - current stroke, history of stroke or prodromal condition (e.g. transient ischaemic attack, TIA) o Known hereditary or acquired predisposition for arterial thromboembolism, such as hyperhomocysteinaemia and antiphospholipid-antibodies (anticardiolipin-antibodies, lupus anticoagulant).

o History of migraine with focal neurological symptoms. o A high risk of arterial thromboembolism due to multiple risk factors (see section 4.4) or to the presence of one serious risk factor such as:

•    diabetes mellitus with vascular symptoms

•    severe hypertension

•    severe dyslipoproteinaemia

•    Presence or history of severe hepatic disease, current or previous, as long as liver function values have not returned to normal.

•    Presence or history of liver tumours (benign or malignant)

•    History of migraine with focal neurological symptoms

•    Known or suspected pregnancy

•    Hypersensitivity to the active substances (levonorgestrel, ethinylestradiol) or to any of the excipients of Violite listed in section 6.1

4.4 Special warnings and precautions for use

Warnings

If any of the conditions or risk factors mentioned below is present, the suitability of Violite 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 Violite 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 (including Violite), norgestimate or norethisterone are associated with the lowest risk of VTE. The decision to use Violite should be taken after a discussion with the woman to ensure she understands the risk of VTE with Violite, 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 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).

Violite 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 patch/pill/ring (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 Violite 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). Violite 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	Diabetes mellitus,

conditions associated	hyperhomocysteinaemia, valvular heart
with adverse vascular	disease and atrial fibrillation,
events	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.

Tumours

The most important risk factor for cervical cancer is persistent HPV infection.

An increased risk of cervical cancer in long-term users of COCs 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 behavior 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 liver 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.

Other conditions

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 preexisting 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.

Medical examination/consultation

Prior to the initiation or reinstitution of Violite 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 contraindications (see section 4.3 Contraindications) and warnings (see section 4.4 Special Warnings and special precautions for use'). It is important to draw the woman’s attention to the information on venous and arterial thrombosis, including the risk of Violite compared with other CHC, 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 oral 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 tablets, vomiting or diarrhea or concomitant medication 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 nonhormonal 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 tablet-free interval. 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.

Violite contains lactose. Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicine.

4.5 Interaction with other medicinal products and other forms of interaction

Effects of other medications on Violite

Interactions between COCs and other drugs may impair the contraceptive efficacy and/or lead to breakthrough bleeding and/or contraceptive failure.

Reduced absorption:

Drugs that increase gastrointestinal motility, e.g. Metoclopramide, may reduce hormone absorption.

Enzyme induction (increase of hepatic metabolism):

Interactions can occur with drugs that induce hepatic microsomal enzymes, resulting in increased clearance of sex hormones (e.g. phenytoin, barbiturates, primidone, phenylbutazone, carbamazepine, oxycarbamazepine, rifampicin, rifabutin, modafinil and possibly also oxcarbazepine, topiramate, felbamate, griseofulvin, and products containing the herbal remedy St. John’s wort (Hypericumperforatum)). The inducing effect can persist for at least 2 weeks after cessation of treatment with St John’s Wort. If COC’s and St John’s Wort are used concomitantly, a non-hormonal backup method of birth control is recommended.

Also HIV protease (e.g. ritonavir) and non-nucleoside reverse transcriptase inhibitors (e.g. nevirapine), and combinations of them, have been reported to potentially increase hepatic metabolism.

Antibiotics (interference with enterohepatic circulation):

Some clinical reports suggest that enterohepatic circulation of estrogens may decrease when certain antibiotic agents (e.g. penicillins, tetracyclins) are given at the same time, which may reduce ethinylestradiol concentrations in serum (e.g. penicillins, tetracyclines).

Troleandomycin may increase the risk of intrahepatic cholestasis during coadministration with COCs.

Women on treatment with any of these drugs should temporarily use a barrier method or another method of contraception in addition to the COC. With liver enzyme inducing drugs, the barrier method must be used during the whole time of the concomitant drug therapy and for 28 days after its discontinuation. Women on treatment with antibiotics (except rifampicin and griseofulvin) should use a barrier method during the use of the antibiotics and until 7 days after their discontinuation. If the drug therapy runs beyond the end of the tablets in the COC pack, the next COC pack should be started right after the previous one without the usual tablet-free interval.

Effects of COCs on other medication

Oral contraceptives may interfere with the metabolism of certain other drugs. Increased plasma concentrations of cyclosporin have been reported with concomitant administration of OCs. COCs have been shown to induce metabolism of lamotrigine resulting in sub-therapeutic plasma concentrations of lamotrigine.

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.

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

4.6 Fertility, pregnancy and lactation

Fertility

There are no clinical safety data on the effects of Violite on fertility.

Pregnancy

Violite is not indicated during pregnancy.

If the woman becomes pregnant while using Violite 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 at unintentional intake of contraceptive pills in early pregnancy.

Breastfeeding

Lactation may be influenced by COCs, as they may reduce the amount and change the composition of breast milk, therefore, the use of COCs should generally not be recommended until the nursing mother has weaned her child off breast milk. Small amounts of contraceptive steroids and/or metabolites have been identified in the milk of nursing mothers.

These amounts may affect the child.

4.7 Effects on ability to drive and use machines

The impact of Violite on the ability to drive and use machines has not been systematically evaluated. Patients should exercise caution until they know that Violite does not affect these abilities.

4.8 Undesirable effects

For serious adverse effects when taking COCs, see section 4.4. Special warnings and precaution for use. For venous and arterial thromboemebolic events, lipid disorders, gallbladder diseases, breast cancer, hypertension, liver tumours, Crohn’s disease, ulcerative colitis, porphyria, systemic lupus erythematosus, herpes gestationis, Sydenham’s chorea, haemolytic uremic syndrome, cholestatic jaundice see also section 4.4.

The frequency of diagnosis of breast cancer is slightly increased among OC 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.

The most frequently (greater than 10%) reported adverse events during phase III studies and postmarketing surveillance in women using Violite are headache, including migraines, dysmenorrhoea, abdominal pain, nausea, and breakthrough bleeding/spotting.

Other adverse events have been reported in women taking Violite*:

System organ class	Frequency of adverse events
	Common	Uncommon	Rare (>1/10,000 to

	(>1/100 to <1/10)	(>1/1,000 to <1/100)	<1/1,000)
Immune system disorders			Hypersensitivity
Metabolism and nutrition disorders		Fluid retention
Psychiatric disorders	Depressed mood Mood altered	Libido decreased	Libido increased
Nervous system disorders	Headache Dizziness	Migraine
Eye disorders			Contact lens intolerance
Vascular disorders		Aggravation of varicose veins	VTE ATE
Gastrointestinal disorders	Nausea, Abdominal pain	Vomiting, Diarrhoea
Skin and subcutaneous tissue disorders		Rash, Urticaria	Erythema nodosum, Erythema multiforme
Reproductive system and breast disorders	Breast pain, Breast tenderness,	Breast Hypertrophy	Vaginal discharge, breast discharge
Investigations	Weight increased		Weight decreased

* The most appropriate MedDRA term (version 12.0) to describe a certain adverse reaction is listed. Synonyms or related conditions are not listed but should be taken into account as well.

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.

Reporting of side effects - United Kingdom

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 effect directly via the Yellow Card Scheme at: www.mhra.gov.uk/yellowcard. By reporting side effects, you can help provide more information on the safety of this medicine.

4.9 Overdose

There have been no reports of serious effects from overdose. Symptoms that may be caused by overdose are nausea, vomiting, drowsiness/fatigue, and slight vaginal bleeding in young girls. There are no antidotes and the treatment is symptomatic.

5 PHARMACOLOGICAL PROPERTIES

Pharmacodynamic properties

Pharmacotherapeutic group: Progestogens and estrogens, fixed combinations ATC code: G03AA07

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

Combined oral contraceptives, when taken correctly, have a failure rate of approximately 1% per year. The failure rate may increase when pills are missed or taken incorrectly.

The contraceptive effect of COCs is based on the interaction of various factors. The most important of these factors are the inhibition of ovulation and changes in the cervical mucus.

Clinical trials have been performed in 2498 women aged 18 to 40 years. The overall Pearl Index calculated from these trials was 0.69 (95% confidence interval 0.30 -1.36) based on 15,026 treatment cycles.

5.2 Pharmacokinetic properties

Levonorgestrel

Absorption

Orally administered levonorgestrel is rapidly and completely absorbed. Peak serum concentrations of 2.3 ng/ml are reached at about 1.3 hours after single ingestion. Levonorgestrel is almost completely bioavailable after oral administration.

Distribution

Levonorgestrel is bound to serum albumin and to sex hormone binding globulin (SHBG). Only 1.1% of the total serum drug concentrations are present as free steroid, approximately 65% are specifically bound to SHBG and about 34% are nonspecifically bound to albumin. The ethinylestradiol-induced increase in SHBG influences the proportion of levonorgestrel bound to the serum proteins, causing an increase of the SHBG-bound fraction and a decrease of the albumin-bound fraction. The apparent volume of distribution of levonorgestrel is 129l.

Metabolism

Levonorgestrel is completely metabolised by the known pathways of steroid metabolism. The clearance rate from serum is approximately 1.0 ml/min/kg.

Elimination

Levonorgestrel serum levels decrease in two phases. The terminal disposition phase is characterized by a half-life of approximately 25 hours. Levonorgestrel is not excreted in unchanged form. Its metabolites are excreted at a urinary to biliary ratio of about 1:1. The half-life of metabolite excretion is about 1 day.

Steady-state conditions

Following daily ingestion drug serum levels increase about threefold reaching steady-state conditions during the second half of a treatment cycle. Levonorgestrel pharmacokinetics are influenced by SHBG levels, which are increased 1.5 - 1.6 fold when co-administered with ethinylestradiol. At steady-state, clearance rate and volume of distribution are slightly reduced to 0.7 ml/min/kg and about 100 l, respectively.

Ethinylestradiol

Absorption

Orally administered ethinylestradiol is rapidly and completely absorbed. Peak serum concentrations of about 50 pg/ml are reached within 1 - 2 hours. During absorption and first-liver passage, ethinylestradiol is metabolised extensively, resulting in a mean oral bioavailability of about 45% with a large interindividual variation of about 2065%.

Distribution

Ethinylestradiol is highly but non-specifically bound to serum albumin (approximately 98%) and induces an increase in the serum concentrations of SHBG. An apparent volume of distribution of about 2.8 - 8.6 l/kg was reported.

Metabolism

Ethinylestradiol is subject to presystemic conjugation in both small bowel mucosa and the liver. Ethinylestradiol is primarily metabolised 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 sulphate. The metabolic clearance rate was reported to be 2.3 - 7 ml/min/kg.

Elimination

Ethinylestradiol serum levels decrease in two disposition phases characterized by half-lives of about 1 hour and 10 - 20 hours, respectively. Unchanged drug is not excreted; ethinylestradiol metabolites are excreted at a urinary to biliary ratio of 4:6. The half-life of metabolite excretion is about 1 day.

Steady-state conditions

Ethinylestradiol serum concentrations increase about two-fold after daily oral administration of levonorgestrel/ethinylestradiol. According to the variable half-life of the terminal disposition phase from serum and the daily ingestion, steady-state serum levels of ethinylestradiol will be reached after about one week.

5.3 Preclinical safety data

The toxicity profiles of ethinylestradiol and levonorgestrel alone and in combination are well known. Because of marked species differences, preclinical results possess a limited predictive value for the application of estrogens in humans.

In experimental animals, ethinylestradiol displayed an embryotoxic effect; malformation of the urogenital tract and feminisation of male fetuses were observed.

Levonorgestrel displayed an embryotoxic effect in animal experiments a virilising effect on female fetuses. Reproduction toxicology studies in rats, mice and rabbits provided no other evidence of teratogenicity.

Preclinical data based on conventional studies of repeated dose toxicity, genotoxicity and carcinogenic potential revealed no particular human risk beyond those discussed in other sections of the SmPC. However, it must be borne in mind that sex steroids can promote the growth of certain hormone-dependent tissues and tumours.

6    PHARMACEUTICAL PARTICULARS

6.1    List of excipients

Tablet core:

Lactose monohydrate,

Polacrilin potassium,

Microcrystalline cellulose,

Magnesium stearate.

Tablet coating:

Opadry II pink, consisting of:

Macrogol 3350,

Titanium dioxide (E171)

Polyvinyl alcohol,

Talc (E533b),

Iron oxide red (E172),

Iron oxide yellow (E172).

6.2    Incompatibilities

Not applicable.

6.3    Shelf life

2    years.

6.4    Special precautions for storage

Do not store above 25°C.

6.5    Nature and contents    of container

Violite is packed in PVC/PVDC/Aluminium blister packs of 21 tablets.

Each pack may contain either:

1 x 21 film-coated tablets or

3    x 21 film-coated tablets

Not all pack sizes may be marketed.

6.6 Special precautions for disposal

No special requirements.

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

7    MARKETING AUTHORISATION HOLDER

Consilient Health Limited 5th Floor, Beaux Lane House,

Mercer Street Lower,

Dublin 2,

Ireland

8    MARKETING AUTHORISATION NUMBER(S)

PL 24837/0080

9    DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

11/05/2016

10    DATE OF REVISION OF THE TEXT

11/05/2016

1

Mid-point of range of 5-7 per 10,000 WY, based on a relative risk for CHCs containing levonorgestrel versus

2

non-use of approximately 2.3 to 3.6