Erlibelle

Erlibelle 30micrograms/150micrograms film-coated tablets.

Each film-coated tablet contains:

0.03 mg ethinylestradiol and 0.15 mg levonorgestrel

Excipient with known effect:

Each tablet contains 84.32 mg of lactose monohydrate.

Film-coated tablets.

Yellow, round tablet, with a diameter of 6 mm and thickness less than 4 mm approximately

Contraception

Route of administration: oral use

Posology

Tablets must be taken at approximately the same time each day, with some liquid if 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 usually occurs.

The bleeding usually starts within 2 to 3 days after the last tablet and may not end before the next pack is started.

Method of administration

- No preceding hormonal contraceptive use [in the past month]:

Tablet-taking is started on day 1 of the women's natural cycle (the first day of menstrual bleeding). When starting later, an additional non hormonal contraceptive method (barrier method) should be used during the first 7 days of tablet-taking If intercourse has already taken place, pregnancy must be ruled out before starting the use of Erlibelle, or the woman must wait until her first menstrual period.

Missed tablets

If one tablet is missed, but remembered and taken within 12 hours of the usual time, then contraceptive protection is not reduced. The subsequent tablets should be taken at the usual time.

If the usual tablet-taking time is missed by more than 12 hours, full contraceptive protection is no longer assured. The following two basic rules apply when a tablet is missed:

1. Tablet-taking must never be discontinued for longer than 7 days.

2. Tablets must be taken regularly for a minimum of 7 days in order to effectively suppress the hypothalamic-pituitary-ovarian axis.

Therefore, the following procedures should be followed in the event that tablets are missed:

- Week 1

The last tablet missed should be taken as soon as possible, even if this means taking 2 tablets in one day. The remaining tablets are then taken at the usual time. In addition, a non hormonal contraceptive method such as a condom should be used for the next 7 days. If intercourse took place in the 7 days before missing the tablet, the possibility of a pregnancy should be considered. The more tablets missed and the closer they are to the usual tablet-free interval, the higher the risk of pregnancy.

- Week 2

The last tablet missed should be taken as soon as possible, even if this means taking 2 tablets at the same time. The remaining tablets are then taken at the usual time. Provided that the user has taken the tablets correctly in the 7 days prior to the first missed tablet, it is not necessary to use additional contraceptive measures. However, if this is not the case or she has missed more than one tablet, the user should be advised to take additional contraceptive precautions for the next 7 days.

- Week 3

The risk of reduced reliability is imminent because of the forthcoming tablet-free interval. However, by adjusting the tablet-taking schedule, reduced contraceptive protection can still be prevented. Therefore, by adhering to one of the following two options, there is no need to take additional contraceptive precautions, provided that in the 7 days prior to the first missed tablet the user has taken all the tablets correctly. If this is not the case, the user should be advised to follow the first of these two options and take additional precautions for the next 7 days:

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 the tablets at the usual time. The next pack must be started as soon as the current pack is finished, i.e. without a break between packs. The user is unlikely to have withdrawal bleeding until the end of the second pack but she may experience spotting or breakthrough bleeding on tablet-taking days.

2. It is also possible to stop taking tablets from the current pack. The woman must then have a tablet-free break of 7 days, including the days she missed tablets, and then continue with the next pack.

If the user misses several tablets and subsequently has no withdrawal bleeding in the first normal tablet-free interval, the possibility of pregnancy should be considered.

Advice in case of gastrointestinal disorders

In case of severe gastrointestinal disorders (vomiting or diarrhoea), absorption of the active ingredients may not be complete and additional contraceptive measures should be taken.

If vomiting or severe diarrhoea occurs within 3 to 4 hours after taking a tablet, a new 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 woman should apply the advice given for missed tablets. If the woman does not want to change her normal tablet schedule, she has to take the extra tablets from another pack.

Changing the starting day of a withdrawal bleeding or delaying the withdrawal bleeding

To delay the withdrawal bleeding, the user should go directly to the next blister pack without a tablet-free interval. The withdrawal bleeding can be delayed as long as wished, but not later than till the end of the second pack. During this time, the woman may experience breakthrough bleeding or spotting. After the subsequent usual 7-day tablet-free interval, Erlibelle tablets should be continued as usual.

To change the starting day of her periods to another day of the week, the user can be advised to shorten the next tablet-free interval by as many days as she likes. The shorter the interval, the higher the risk that she does not have withdrawal bleeding and will experience breakthrough bleeding and spotting during the next pack (just as when delaying a period).

Combined oral contraceptives (COC) should not be used in the presence of any of the conditions listed below. If any of these conditions appear for the first time during COC use, treatment should be stopped immediately.

- venous thrombosis present or in history (deep venous thrombosis, pulmonary embolism),

- arterial thrombosis present or in history (e.g. myocardial infarction) or prodromal conditions (e.g. transient ischaemic attack, angina pectoris),

- cerebrovascular accident present or in history,

- The presence of a severe or multiple risk factor(s) for venous or arterial thrombosis may also constitute a contraindication :

- hereditary or acquired predisposition for venous or arterial thrombosis, such as APC-resistance, antithrombin-III-deficiency, protein C deficiency, protein S deficiency, hyperhomocysteinemia and antiphospholipid-antibodies (anticardiolipin-antibodies, lupus anticoagulant).

- presence or history of severe hepatic disease, as long as liver function values have not returned to normal,

- presence or history of liver tumours (benign or malignant),

- known or suspected sex-steroid influenced malignancies (e.g. of the genital organs or the breasts),

- undiagnosed vaginal bleeding,

- history of migraine with focal neurological symptoms,

- hypersensitivity to the active substances levonorgestrel or ethinylestradiol or to any of the excipients listed in section 6.1.

Warnings

If any of the conditions/risk factors mentioned below are present, the benefits of COC use should be weighed against the possible risks for each individual woman and discussed with her before she decides to start using the product. In the event of aggravation, exacerbation or first appearance of any of these conditions or risk factors, the user should contact her doctor as soon as possible. The doctor should decide whether Erlibelle use should be discontinued.

Circulatory Disorders

The use of any combined oral contraceptive (COC) carries an increased risk of venous thromboembolism (VTE) compared with no use.).

Other medical conditions that have been associated with adverse circulatory events include: diabetes mellitus, systemic lupus erythematosus, haemolytic uraemic syndrome, chronic inflammatory bowel disease (Crohn's disease or ulcerative colitis) and sickle cell disease.

An increase in migraine frequency or severity during COC use (which may be signs of a cerebrovascular accident) may be grounds for immediate discontinuation of the COC.

Tumours

Some epidemiological studies have reported an increased risk of cervical cancer in long-term COC users but there continues to be controversy about the extent to which this finding is attributable to the influence of confounding factors such as sexual behaviour and human papilloma virus (HPV).

A meta-analysis of 54 epidemiological studies showed that there is a slightly increased relative risk (RR=1.24) of having breast cancer diagnosed in women who are currently using combined oral contraceptive. This 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 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 clinically advanced than those diagnosed in never users.

In rare cases, benign, and even more rarely, malignant liver tumours have been reported in COC users. In isolated cases, these tumours have led to life-threatening intra-abdominal bleeding. The possibility of a liver tumour should be considered in the differential diagnosis of women taking COCs who report sever upper abdominal pain, liver enlargement or signs of intra-abdominal bleeding.

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 observed 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 during 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 uraemic syndrome, Sydenham's chorea, herpes gestationis and otosclerosis-related hearing loss.

In women with hereditary angioedema, exogenous estrogens can trigger or exacerbate angioedema symptoms.

Acute or chronic liver function disorders require discontinuation of COC use until liver function markers return to normal. Recurrence of cholestatic jaundice and/or cholestasis-related pruritus that first occurred during pregnancy or during previous sex hormone use requires 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 monitored, 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 particularly occur, especially in women with a history of chloasma gravidarum. If there is a tendency to chloasma, sunlight and ultraviolet radiation should be avoided when using combined oral contraceptive.

Medical examination/consultation

Prior to the initiation or reinstitution of Erlibelle 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 and warnings. 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 informed that oral contraceptives do not protect against HIV infection (AIDS) and other sexually transmitted diseases.

Reduced efficacy

The contraceptive efficacy of Erlibelle combined oral contraceptive may be reduced

- if tablets are missed ,

- in the event of gastrointestinal disorders,

- if certain other drugs are being taken concomitantly.

Reduced cycle control

When using any COC, irregular bleeding (spotting or breakthrough bleeding) may occur, especially during the first months of use. However, if the COC has not been taken according to these instructions prior to the first missed withdrawal bleed, or if two withdrawal bleeds are missed, pregnancy must be ruled out before continuing with COC use.

Warnings about excipients

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

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

Interactions

Interactions between oral contraceptives and other medicinal products may impair the contraceptive efficacy and/or lead to breakthrough bleeding and/or contraceptive failure.

Hepatic metabolism:

Interactions can occur with drugs that induce hepatic enzymes which can result in increased clearance of sex hormones (e.g. phenytoin, barbiturates, primidone, carbamazepine, rifampicin, bosentan and HIV-medication (e.g. ritonavir, nevirapine) and possibly also oxcarbazepine, topiramate, felbamate, griseofulvin and products containing the herbal remedy St. John's Wort (hypericum perforatum)). Maximal enzyme induction is generally seen in about 10 days but may then be sustained for at least 4 weeks after the cessation of drug therapy.

Management

Women on short-term treatment with any of the above-mentioned classes of medicinal products or individual active substances (hepatic enzyme-inducing medicine) besides rifampicin should temporarily use a barrier method in addition to the COC, i.e. during the time of concomitant medicinal product administration and for 7 days after their discontinuation.

For women on rifampicin a barrier method should be used in addition to the COC during the time of rifampicin administration and for 28 days after its discontinuation.

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

Influence of Erlibelle on other medicinal products

Oral contraceptives may affect the metabolism of certain other active substances. Accordingly, plasma and tissue concentrations may either increase (e.g. ciclosporin) or decrease (e.g. 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 blood coagulation and fibrinolysis. The changes generally remain within the normal laboratory range.

Pregnancy

Erlibelle is not indicated in pregnancy.

If the woman becomes pregnant while using Erlibelle tablets, further intake must be stopped immediately. However, most epidemiological studies have revealed neither an increased risk for birth defects in children born to women who used COCs before pregnancy, nor any teratogenic effects at unintentional intake of contraceptive pills in early pregnancy.

Breastfeeding

Breastfeeding may be influenced by contraceptive pills as they may reduce the amount of breast milk and change its composition. Therefore, the use of combined oral contraceptives should generally not be recommended until the nursing mother has weaned her child off breast milk. Small amounts of contraceptive steroids and/or their metabolites may be excreted in breast milk. These amounts may affect the child.

Erlibelle has no or negligible influence on the ability to drive and use machines.

The following undesirable effects have been observed with use of combined oral contraceptives containing ethinylestradiol/levonorgestrel:

:

- Venous thromboembolic disorders

- Arterial thromboembolic disorders

- Hypertension

- Liver tumours

- Crohn's disease, ulcerative colitis, epilepsy, uterine myoma, porphyria, systemic lupus erythematosus, herpes gestationis, Sydenham's chorea, haemolytic uremic syndrome, cholestatic jaundice;

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

The frequency of diagnosis of breast cancer is slightly increased among OC users.4 Special warnings and precautions for use.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorization of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via Yellow Card Scheme, Website: www.mhra.gov.uk/yellowcard

No serious adverse reactions due to overdose have been reported. Symptoms of overdose of a combined oral contraceptive may include: nausea, vomiting; in adolescents, slight vaginal bleeding may occur. There is no specific antidote. Treatment should be symptomatic.

Pharmacotherapeutic group (ATC): progestogen and estrogens, fixed combinations

ATC Code: G03AA07

Overall Pearl Index (method failure + patient failure): 0.59 (upper tow-sided 95% confidence limit: 0.85).

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

Ethinylestradiol

Absorption

Orally administered ethinylestradiol is absorbed rapidly and completely.

Peak serum concentrations of about 100 pg/ml are reached within 1-1.5 hours after taking 30 microgram ethinylestradiol. During absorption and first-pass hepatic metabolism ethinylestradiol is metabolized extensively, resulting in a mean oral bioavailability of about 40-60% (interindividual variation about).

Distribution

Ethinylestradiol is highly (approximately 98%) but nonspecifically bound to serum albumin, and induces an increase in the serum concentrations of sex hormone binding globulin (SHBG).The absolute volume of distribution of ethinylestradiol is 5 L/kg.

Biotransformation

Ethinylestradiol is subject to pre-systemic conjugation in both small bowel mucosa and the liver. Ethinylestradiol is primarily metabolised by aromatic hydroxylation, forming various hydroxylated and methylated metabolites that are present as free metabolites or as glucuronide or sulfate conjugates in serum. The metabolic clearance rate from serum is 5 ml/min/kg.

Elimination

Ethinylestradiol levels in serum decrease in two phases characterized by half-lives of about 1-2 hours and about 20 hours, respectively. Ethinylestradiol is not excreted in unchanged form. Its metabolites are excreted at a urinary to biliary ratio of 4:6. The elimination half-life is about 1 day.

Steady-State conditions

Ethinylestradiol concentration in serum increases about 40% after continuous use of tablets containing 150 microgram levonorgestrel and 30 microgram ethinylestradiol. Due to the variable half-life of the terminal phase in serum clearance and the daily administration, steady-state conditions are reached after approximately 5 daily administrations

Levonorgestrel

Absorption

Orally administered levonorgestrel is absorbed rapidly and completely. Peak serum levonorgestrel levels of about 3 ng/ml are reached around 1 hour after taking 150 microgram levonorgestrel. The bioavailability of levonorgestrel after oral administration is nearly 100%.

Distribution

Levonorgestrel is bound to serum albumin and sex hormone binding globulin (SHBG). Only 1.5% of the total serum drug concentrations are present as free steroid, approximately 65% are specifically bound to SHBG and approximately 35% are non-specifically bound to albumin. The ethinylestradiol-induced increase in the SHBG concentration influences the relative distribution of levonorgestrel into different protein fractions. Induction of the binding protein causes an increase in the SHBG-bound fraction and a decrease in the albumin-bound fraction.

Biotransformation

Levonorgestrel is completely metabolised by the typical pathways of steroid metabolism. The plasma clearance rate is approximately 1.5 ml/min/kg.

Elimination

Serum levonorgestrel levels decrease in two phases. The terminal phase is characterized by a half-life of approximately 1 hour and about 20hours, respectively. Levonorgestrel is metabolised before being excreted. Its metabolites are at a urinary to biliary (feces) ratio of about 1:1. The elimination half-life of the metabolites is about 1 day.

Steady-state condition

During the continuous use of Erlibelle tablets, serum levonorgestrel levels increase about fourfold reaching steady-state conditions during the second half of the treatment cycle. The pharmacokinetic of levonorgestrel is influenced by SHBG levels in serum, which increase by 1.7-fold after daily ingestion of a combined oral contraception containing estradiol. This effect leads to a reduction of the clearance rate to about 0.7 ml/min/kg at steady state.

Preclinical data for ethinylestradiol and levonorgestrel from conventional studies of general toxicity, genotoxicity, carcinogenic potential and toxicity to reproduction have not revealed other effects than those which can be explained bases on the known hormone profile of ethinylestradiol and levonorgestrel. However, it should be remembered that sex steroids can promote the growth of certain hormone-dependent tissues and tumours.

Tablet core:

Lactose monohydrate

Povidone K30

Crospovidone Type A

Magnesium stearate

Coating:

Polyvinyl alcohol, partial hydrolized

Titanium dioxide (E171)

Macrogol 3350

Talc (E553b)

Iron oxide yellow (E172)

Not applicable.

2 years

Do not store above 30°C.

Blisters of aluminium push-thru foil and PVC/PVDC film. The blister packs may come with a blister holder.

It is available in boxes of 1, 3, 6 and 13 packs (blisters), each one containing 21 tablets.

Not all pack sizes may be marketed.

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

Actavis Group PTC ehf.

Reykjavíkurvegi 76-78

220 Hafnarfjörður

Iceland

PL 30306/0434

11/09/2013

24/12/2015