Rosemar 150/30 Coated Tablets

SUMMARY OF PRODUCT CHARACTERISTICS

1 NAME OF THE MEDICINAL PRODUCT

2 QUALITATIVE AND QUANTITATIVE COMPOSITION

Each coated tablet contains Levonorgestrel 150 micrograms and Ethinylestradiol 30 micrograms.

Also contains 58.170 mg of lactose monohydrate and 12.030 mg of Sucrose For a full list of excipients, see section 6.1

3 PHARMACEUTICAL FORM

Coated tablet

White, circular, biconvex, coated tablets.

4 CLINICAL PARTICULARS

4.1 Therapeutic indications

Oral contraception.

4.2 Posology and method of administration Posology

One tablet is to be taken daily for 21 consecutive days, Each subsequent pack is started after a 7day 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.

Paediatric population

There is no relevant use of Rosemar in the paediatric population.

Method of administration

• No preceding hormonal contraceptive use (in the past month), tablet-taking is started 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 in that case an additional barrier method is recommended for the first 7 days of the first cycle

• • Changing from another combined hormonal contraceptive (COC, vaginal ring, transdermal patch) The use of Rosemar is preferably started on the day after the last active tablet of the previous COC (or after removal of the ring or patch), but

at the latest on the day following the usual tablet-free (ring-free, patch-free) break or the last placebo tablet of the previous hormonal contraceptive.

• Changing from a progestogen-only method (oral pill, injection, implant) or intrauterine system (IUS) The woman can switch to Rosemar any day from the minipill (from an implant or the IUS on the day of its removal, from an injectable when the next injection would be due) but should in all of these cases be advised to use an additional barrier method for the first 7 days of tablet-taking.

• Following first-trimester abortion The use of the tablets can start immediately. In such a case, no other contraceptive measures are needed.

• Following delivery or second-trimester abortion For breast-feeding, see Section 4.6 Pregnancy and Lactation. The use of the tablets is started 21 to 28 days after delivery or second-trimester abortion. When starting later, an additional barrier method must be used for the first 7 days of tablet-taking. If the woman has already had sexual intercourse, pregnancy must be excluded before the actual start of COC use or the woman has to wait for her next menstrual period.

Missed tablets

Rosemar contains a very low dose of both hormones, and, as a consequence, the contraceptive efficacy margin is small, if a pill is missed. If the woman is less than 12 hours late in taking any tablet, contraceptive protection is not reduced. The woman should take the tablet as soon as she remembers and take the next tablets at the usual time. If she is more than 12 hours late in taking any tablet, contraceptive protection may be reduced. The following two basic rules apply in cases where tablets have been missed:

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

2. Adequate suppression of the hypothalamic-pituitary-ovarian axis requires 7 days of uninterrupted tablet-taking.

Accordingly, the following advice can be given for daily practice:

Week 1

The woman should take the last missed tablet as soon as she remembers, even if this means taking two tablets at the same time. She then continues to take the next tablets at her usual time. In addition, a barrier method such as a condom should be used for the next 7 days. If the woman has had sexual intercourse in the 7 days before missing the tablet, the possibility of a pregnancy must be considered. The more tablets have been missed and the closer they are to the regular tablet-free break, the higher the risk of pregnancy.

Week 2

The woman should take the last missed tablet as soon as she remembers, even if this means taking two tablets at the same time. She then continues to take the next tablets at her usual time. Provided that the woman has taken her tablets correctly in the 7 days preceding the first missed tablet, there is no need to use extra contraceptive precautions. If she has not taken the tablets correctly or has missed more than one tablet, she should be advised to use extra contraceptive precautions for the next 7 days.

Week 3

The risk of reduced contraceptive reliability is imminent because of the forthcoming tablet-free break of 7 days. However, reduced contraceptive protection can still be prevented by adjusting the dosage. By adhering to the following advice, there is no need to use extra contraceptive precautions, provided that all the tablets have been taken correctly in the 7 days preceding the first missed tablet. If this is not the case, the woman should follow the first of these two options and use extra contraceptive precautions for the next 7 days as well.

1. The woman should take the last missed tablet as soon as she remembers, even if this means taking two tablets at the same time. She then continues to take the next tablets at her usual time. The next pack is started as soon as the current pack is finished, i.e. there is no tablet-free break. There will probably be no withdrawal bleed until the end of the second pack, but the woman 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 woman misses several tablets and has no withdrawal bleed during the first normal tablet-free break, the possibility of a pregnancy must be considered.

Advice in case of gastrointestinal disturbances

In case of severe gastrointestinal symptoms, 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, 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.

How to change the starting day of a period or to delay a period

To delay a period the woman should start a new pack immediately after finishing the current pack without any break. Periods can be delayed as long as wished, but no later than till the end of the second pack. During this time the woman may experience breakthrough bleeding or spotting. Regular intake of Rosemar is then resumed after the usual 7-day tablet-free break.

If the woman wants to change the starting day or her periods to another day of the week, she can be advised to shorten her next tablet-free break by as many days as she likes. The shorter the break, the higher the risk that there will be no withdrawal bleed and that the woman will experience breakthrough bleeding and spotting during the second pack (just as when delaying a period).

4.3 Contraindications

Combined oral contraceptives (COCs) should not be used in the presence of any of the conditions listed below. Should any of the conditions appear for the first time during COC use, the product 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. angina pectoris and transient ischaemic attack).

• Cerebrovascular accident present or in history

• The presence of a severe or multiple risk factor(s) for arterial thrombosis:

• Diabetes mellitus with vascular symptoms

• Severe hypertension

• Severe dyslipoproteinemia

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

• History of migraine with focal neurological symptoms

• Pancreatitis or history of such a condition, if associated with severe hypertriglyceridemia

• 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).

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

• Undiagnosed vaginal bleeding

• Amenorrhoea of unknown cause

• Hypersensitivity to any of the active substances or to any of the excipients listed in section 6.1

4.4 Special warnings and precautions for use

Warnings: If any of the conditions/risk factors mentioned below is present, the benefits of COC use should be weighed against the possible risks for each individual woman and discussed with the woman before she decides to start using it. In the event of aggravation, exacerbation or first appearance of any of these conditions or risk factors, the woman should contact her physician. The physician should then decide on whether COC use should be discontinued.

Vascular disorders

Epidemiological studies have shown that the incidence of VTE in users of oral contraceptives with low oestrogen content (<50 pg ethinylestradiol) ranges from about 20 to 40 cases per 100,000 women-years, but this risk estimate varies according to the progestogen. This compares with 5 to 10 cases per 100,000 women-years for non-users. The use of any combined oral contraceptive carries an increased risk of venous thromboembolism (VTE) compared with no use.

The excess risk of VTE is highest during the first year a woman ever uses a combined oral contraceptive. This increased risk is less than the risk of VTE associated with pregnancy, which is estimated as 60 cases per 100,000 pregnancies. VTE is fatal in 12% of cases.

The overall absolute risk (incidence) of VTE for levonorgestrel containing combined oral contraceptives with 30 ^g ethinylestradiol is approximately 20 cases per 100,000 women-years of use.

Epidemiological studies have also associated the use of combined COCs with an increased risk for myocardial infarction, transient ischaemic attack and for stroke.

Extremely rarely, thrombosis has been reported to occur in other blood vessels, e.g. hepatic, mesenteric, renal or retinal veins and arteries, in contraceptive pill users. There is no consensus as to whether the occurrence of these events is associated with the use of hormonal contraceptives.

Symptoms of venous or arterial thrombotic /thromboembolic events or of a cerebrovascular accident can include:

• unusual unilateral leg pain and/ or swelling

• sudden severe pain in the chest, whether or not it radiates to the left arm

• sudden breathlessness

• sudden onset of coughing

• any unusual, severe, prolonged headache

• first occurrence or worsening of migraine

• sudden partial or complete loss of vision

• diplopia

• slurred speech or aphasia

• vertigo

• collapse with or without focal seizure

• weakness or very marked numbness suddenly affecting one side or one part of the body

• motor disturbances

• ‘acute’ abdomen.

Occurrence of one or more of these symptoms may be a reason for immediate discontinuation of Rosemar.

The risk for venous thromboembolic complications in COCs users increases with:

• increasing age

• a positive family history (venous thromboembolism ever in a sibling or parent at relatively early age). If a hereditary predisposition is suspected, the woman should be referred to a specialist for advice before deciding about any COC use.

• prolonged immobilisation, major surgery, any surgery to the legs, or major trauma. In these situations it is advisable to discontinue the pill (in the case of elective surgery at least four weeks in advance) and not resume until two weeks after complete remobilisation. Antithrombotic treatment should be considered if the pills have not been discontinued in advance.

• obesity (body mass index over 30 kg/m²).

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

The risk of arterial thrombo-embolic complications or of a cerebrovascular accident in COC users increases with:

• increasing age

• smoking (women over 35 years should be strongly advised not to smoke if they wish to use an COC)

• dyslipoproteinemia

• hypertension

• migraine, especially migraine with focal neurological symptoms

• valvular heart disease

• atrial fibrillation

The presence of one serious risk factor or multiple risk factors for venous or arterial disease, respectively, can also constitute a contra-indication. The possibility of anticoagulant therapy should also be taken into account. COC users should be specifically pointed out to contact their physician in case of possible symptoms of thrombosis. In case of suspected or confirmed thrombosis, COC use should be discontinued. Adequate alternative contraception should be initiated because of the teratogenicity of anticoagulant therapy (coumarins).

The increased risk of thromboembolism in the puerperium must be considered (see Section 4.6 Pregnancy and Lactation).

Other medical conditions which have been associated with adverse vascular events include diabetes mellitus, systemic lupus erythematosus, haemolytic uremic syndrome and chronic inflammatory bowel disease (Crohn's disease or ulcerative colitis).

An increase in frequency or severity of migraine during COC use (which may be prodromal of a cerebrovascular event) may be a reason for immediate discontinuation of the COC.

• Tumours

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 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 COCs. This excess risk gradually disappears during the course of 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 everusers tend to be less advanced clinically than the cancers diagnosed in never-users.

In rare cases, benign liver tumours, and even more rarely, malignant liver tumours have been reported in users of COCs. In isolated cases, these tumours have led to life-threatening intra-abdominal haemorrhages. A hepatic tumour should be considered in the differential diagnosis when severe upper abdominal pain, liver enlargement or signs of intra-abdominal haemorrhage occur in women taking COCs.

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. A systematic relationship between COC use and clinical hypertension has not been established. 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 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, hemolytic uremic syndrome, Sydenham's chorea, herpes gestationis, otosclerosis-related hearing loss depressive mood.

In women with hereditary angioedema exogenous estrogens may induce or exacerbate symptoms of angioedema. Acute or chronic disturbances of liver function may necessitate discontinuation of COC use until the liver function values return to normal. Recurrence of cholestatic jaundice jaundice and/or cholestasis-related pruritus which previously occurred during pregnancy or previous use of sex steroids necessitates 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. 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 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 Rosemar 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 Contraindications) and warnings (see section 4.4 Special Warnings and special precautions for use). 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 transmissible diseases.

Reduced efficacy

The efficacy of COCs may be reduced, in the event of missed tablets vomiting or diarrhoea 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. In users of Rosemar, any bleeding (spotting and/or break-through bleeding) was reported by more than 50% during the first 6 months of use.

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.

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

Patients with rare hereditary problems of fructose intolerance, glucose-galactose malabsorption or sucrase-isomaltase insufficiency should not take this medicine.

Paediatric population

There is no relevant use of Rosemar in the paediatric population.

4.5 Interaction with other medicinal products and other forms of interaction

• Interactions

Effects of other medicinal products on Rosemar

Interactions can occur with drugs that induce microsomal enzymes which can result in increased

clearance of sex hormones and which may lead to breakthrough bleeding and/or contraceptive failure.

Reduced absorption: Drugs that increase gastrointestinal motility, e.g. Metoclopramid, may reduce hormone absorption.

Management

Enzyme induction can already be observed after a few days of treatment. Maximal enzyme induction is generally seen within a few weeks. After the cessation of drug therapy enzyme induction may be sustained for about 4 weeks.

Short-term treatment

Women on treatment with enzyme inducing drugs should temporarily use a barrier method or another method of contraception in addition to the COC. The barrier method must be used during the whole time of the concomitant drug therapy and for 28 days after its discontinuation.

If the drug therapy runs beyond the end of the tablets in the COC pack, the next COC pack should be started right after the previous one without the usual tablet-free interval.

Long-term treatment

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

The following interactions have been reported in the literature.

Substances increasing the clearance of COCs (diminished efficacy of COCs by enzyme-induction),e.g.: Barbiturates, bosentan, carbamazepine, phenytoin, primidone, rifampicin, and HIV medication ritonavir, nevirapine and efavirenz and possibly also felbamate, griseofulvin, oxcarbazepine, topiramate and products containing the herbal remedy St. John's Wort (hypericum perforatum).

Substances with variable effects on the clearance of COCs, When co-administered with COCs, many combinations of HIV protease inhibitors and non-nucleoside reverse transcriptase inhibitors, including combinations with HCV inhibitors can increase or decrease plasma concentrations of estrogen or progestins. The net effect of these changes may be clinically relevant in some cases.

Therefore, the prescribing information of concomitant HIV/HCV medications should be consulted to identify potential interactions and any related recommendations. In case of any doubt, an additional barrier contraceptive method should be used by women on protease inhibitor or non-nucleoside reverse transcriptase inhibitor therapy.

Effects of Rosemar 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. Cyclosporine) or decrease (e.g. Lamotrigine).

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

• Laboratory tests

The use of contraceptive steroids may influence the results of certain laboratory tests, including biochemical parameters of liver, thyroid, adrenal and renal function, plasma levels of (carrier) proteins (e.g. corticosteroid binding globulin and lipid/lipoprotein fractions), parameters of carbohydrate metabolism, and parameters of blood coagulation and fibrinolysis. The changes generally remain within the normal laboratory range.

Paediatric population

There is no relevant use of Rosemar in the paediatric population.

4.6 Fertility, pregnancy and lactation

Pregnancy

Rosemar is not indicated in pregnancy.

If the woman becomes pregnant while using Rosemar, further intake must be stopped immediately.

However, most epidemiological studies have revealed neither an increased risk of birth defects in children born to women taking contraceptive pills before pregnancy, nor any teratogenic effects at unintentional intake of contraceptive pills in early pregnancy.

Breast-feeding

Lactation may be influenced by contraceptive pills since they may reduce the amount of breast milk and change its composition. Thus, 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 the contraceptive steroids and/or their metabolites may be excreted in breast milk. These amounts may affect the infant.

4.7 Effects on ability to drive and use machines

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

4.8 Undesirable effects

The most commonly adverse drug reaction in COC users is headache (17 - 24 % of women). Other adverse effects that have been reported in users of combined hormonal contraceptives including Rosemar are:

Organ system	Common (>1/100)	Uncommon (>1/1000 and <1/100)	Rare (< 1/1000),
Eye disorders			contact lens intolerance
Gastrointestinal disorders	nausea, abdominal pain	vomiting, diarrhoea
Immune system disorders			hypersensitivity
Investigations	weight increased		weight decreased
Metabolism and nutrition disorders		fluid retention
Nervous system disorders	headache	migraine
Psychiatric disorders	depressed mood, mood altered	libido decreased	libido increased
Reproductive system and breast disorders	breast tenderness, breast pain	breast enlargement	breast discharge, vaginal discharge
Skin and subcutaneous tissue disorders	rash	urticaria	erythema nodosum, erythema multiforme

*The most appropriate MedDRA term (version 7.0) to describe a certain adverse reaction is listed. Synonyms or related conditions are not listed, but should be taken into account as well.

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

- Venous thromboembolic disorders;

- Arterial thromboembolic disorders;

- Hypertension;

- Liver tumours;

- Occurrence or deterioration of conditions for which association with COC use is not conclusive: Crohn’s disease, ulcerative colitis, epilepsy, migraine, endometriosis, uterine myoma, porphyria, systemic lupus erythematosus, herpes gestationis, Sydenham's chorea, haemolytic uremic syndrome, cholestatic jaundice;

The frequency of diagnosis of breast cancer is very 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 warning and precautions for use.

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

Interactions

Breakthrough bleeding and/or contraceptive failure may result from interactions of other drugs (enzyme inducers) with oral contraceptives (see section 4.5).

Paediatric population

There is no relevant use of Rosemar in the paediatric population.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the national reporting system listed in www.mhra.go.uk/yellowcard

4.9 Overdose

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

Paediatric population

There is no relevant use of Rosemar in the paediatric population.

5 PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties

Pharmacotherapeutic group: Progestogen and estrogens, fixed combinations, ATC Code: G03AA07

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

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 absorbed rapidly and completely. Peak serum concentrations of about 2.3 ng/ml are reached about 1.3 hours after taking a Rosemar. The bioavailability is nearly 100%.

Distribution

Levonorgestrel is bound to serum albumin and 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 approximately 35% are nonspecifically 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. The apparent volume of distribution of levonorgestrel is 129 l after a single dose.

Biotransformation

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

Elimination

Levonorgestrel levels in serum decrease in two phases. The terminal 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 (feces) ratio of about 1:1. The half-life of metabolite excretion is about 1 day.

Steady state

During the continuous use of Rosemar, serum levonorgestrel levels increase about threefold reaching steady-state conditions during the second half of the treatment cycle. Levonorgestrel pharmacokinetics are influenced by the SHBG levels in serum, which are increased 1.5-1.6-fold during the use of estradiol. Therefore, the clearance rate from serum and the volume of distribution are slightly reduced at steady state (0.7 ml/min/kg and about 100 l).

• Ethinylestradiol

Absorption Orally administered ethinylestradiol is absorbed rapidly and completely. Peak serum concentrations of about 50 pg/ml are reached within 1-2 hours after taking a Rosemar. During absorption and first-pass hepatic metabolism ethinylestradiol is metabolized extensively, resulting in a mean oral bioavailability of about 45% (inter individual variation about 20-65%).

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

Biotransformation Ethinylestradiol is subject to presystemic conjugation in both small bowel mucosa and the liver. Ethinylestradiol is primarily metabolized 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 2.3-7 ml/min/kg.

Elimination Ethinylestradiol levels in serum decrease in two phases characterized by half-lives of about 1 hour and 10-20 hours, respectively.

Ethinylestradiol is not excreted in unchanged form. Its metabolites are excreted at a urinary to biliary ratio of 4:6, and the half-life is about 1 day.

Steady state Ethinylestradiol concentration in serum increases about twofold after continuous use of Rosemar. Due to the variable half-life of the terminal phase in serum clearance and the daily administration, steady-state conditions are reached within about a week.

5.3 Preclinical safety data

Non-clinical data reveal no special hazard for humans based on conventional studies of safety pharmacology, repeated dose toxicity, genotoxicity, carcinogenic potential, toxicity to reproduction.

However, it should 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 Maize Starch Talc (E No: E553b)

Povidone K-25 (E No: E1201)

Magnesium Stearate (E No: E470b)

Coating:

Sucrose

Talc (E No: E553b)

Calcium carbonate (E No: E170)

Povidone K-90 (E No: E1201) Glycerol (E No: E422) Macrogol 6000 (E No: E1521) Titanium dioxide (E No: E171) Carnauba Wax (E No: E903)

6.2 Incompatibilities

Not applicable

6.3 Shelf life

3 years

6.4 Special precautions for storage

Store below 25 °C

6.5 Nature and contents of container

Tablets are packed in PVC/PVDC/Aluminium blisters

Presentation:

Pack sizes: 21 coated tablets (1 blister of 21)

63 coated tablets (3 blisters of 21)

126 coated tablets (6 blisters of 21)

273 coated tablets (13 blisters of 21)

6.6 Special precautions for disposal

Keep out of sight and reach of children

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

7 MARKETING AUTHORISATION HOLDER

Famy Care Europe Ltd.

One Wood Street London, EC2V 7WS United Kingdom

8 MARKETING AUTHORISATION NUMBER(S)

PL 32821/0056

9 DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

16/12/2013

10 DATE OF REVISION OF THE TEXT

20/10/2016