Oral contraception.

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

Posology

Intake of the tablets is started on the first day of menstruation and 1 tablet is taken daily without interruption for 21 days preferably always at the same time. This is followed by a break of 7 tablet- free days during which withdrawal bleeding occurs. The subsequent pack of 21 tablets should be started on the 8^th day after the 7 tablet-free days have elapsed (4 weeks after intake of the first tablet on the same day of the week) even if bleeding still has not stopped. This dosage schedule should be continued until contraceptive precautions are necessary. If the physician’s instructions are followed contraceptive protection also covers the tablet-free period.

How to start taking Regulon

No preceeding hormonal contraceptive use (in the past month)

The first Regulon tablet should be started on the first day of menstruation, in which case no additional contraceptive precautions are required.

Intake of the tablets can be started also on day 2 to 5 of menstruation, but in this case additional contraceptive precautions must be taken for the first 7 days of tablet taking during the first cycle.

If menstruation began more than 5 days previously, the patient should be advised to wait until her next menstrual period before starting to take Regulon.

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

The woman should start with Regulon preferably on the day after the last active tablet (the last tablet containing the active substance) of her previous combined oral contraceptive (COC), but at the latest on the day following the usual tablet-free or placebo tablet interval of her previous COC. In case a vaginal ring or a transdermal patch has been used, the woman should start using Regulon preferably on the day of removal, but at the latest when the next application would have been due. If the woman used the previous contraceptive method consequently and correctly and it is proven that she is not pregnant, she can cange on any day of the cycle. The recommended hormone-free interval of the previous method can never be exceeded.

Changing from a progestogen-only-method (minipill, injection, implant) or from a progestogen- releasing intrauterine system (IUS)

The woman may switch any day from the minipill [POP] (from an implant or the IUS on the day of its removal, from an injectable when the next injection would be due) but should in all of these cases be advised to additionally use a barrier method for the first 7 days of tablet-taking.

After abortion in the 1^st trimester

After miscarriage or abortion administration of the tablets can be started immediately. In this case no additional contraceptive precautions are required.

After delivery, or abortion in the 2^nd trimester

Oral contraceptive administration to non-breast feeding mothers should be started on day 21-28 after delivery, or abortion in the 2^nd trimester. In this case no additional contraceptive precautions are necessary.

If administration of Regulon tablets begins later, additional contraceptive precautions should be taken for the first 7 days.

If intercourse has already taken place post-partum, tablet intake should be delayed until the first menstrual period.

Remarks: Breast-feeding mothers should be advised not to take combined oral contraceptives since this may reduce the amount of breast-milk. See section 4.6.

Management of missed tablets

If the tablet intake is forgotten for less than 12 hours, contraceptive protection is not reduced. The woman should take the forgotten tablet as soon as she remembers, and the remaining tablets are taken as usual.

If the tablet intake is forgotten for more than 12 hours, contraceptive protection may be reduced. The following two basic rules should be considered in case of forgotten tablets:

1.              Continuous tablet intake must not be interrupted for longer than a period of 7 days.

2.              Seven days of uninterrupted tablet intake are required to achieve sufficient suppression of the hypothalamus-pituitary-ovarian-axis.

Thus, the following advice may be given for daily practice:

Week 1

The user should take the last forgotten tablet as soon as she remembers, even if this means that she has to take 2 tablets at the same time. Then, she continues taking the tablets at the usual time of the day.

She should concurrently use a barrier method, e.g. a condom, for the next 7 days. If intercourse has taken place during the preceding 7 days, the possibility of pregnancy should be considered. The more tablets are forgotten and the closer they are to the regular tablet-free period, the higher the risk of pregnancy is.

Week 2

The user should take the last forgotten tablet as soon as she remembers, even if this means that she has to take 2 tablets at the same time. Then, she continues taking the tablets at the usual time of the day.

Provided that the tablets have been taken in a correct manner during the 7 days preceding the forgotten tablet, it is not necessary to take further contraceptive measures. However, if this is not the case, or if more than 1 tablet has been forgotten, the woman should be advised to use another contraceptive method for 7 days.

Week 3

The risk of reduced contraceptive protection is imminent due to the next tablet-free period. However, this risk may be prevented by adjusting tablet intake. Thus, it is not necessary to take further contraceptive measures if one of the two alternatives below is followed, provided that all tablets have been taken in a correct manner during the 7 days preceding the forgotten tablet. If this is not the case, the woman should be advised to follow the first of the two alternatives and concurrently use another contraceptive method for the next 7 days.

1. The user should take the last forgotten tablet as soon as she remembers even if it means that she has to take 2 tablets at the same time. Then she continues taking the tablets at the usual time of the day. She will begin taking the next pack immediately after taking the last tablet in the present pack, i.e. there is no break between the packs. It is not very likely that the user will have her menstrual bleeding until the end of the second pack, but she may experience spotting or break-through bleeding on the days she is takingtablets.

2. The woman may also be advised to stop taking tablets from the present pack. In that case she should keep a tablet-free period of up to 7 days, including those days when she forgot tablets, and then continue with the next pack.

In case the woman has forgotten tablets and then does not have her menstrual bleeding in the first normal tablet-free period, the possibility of pregnancy should be considered.

Advice on gastro-intestinal disturbances

In case of severe gastro-intestinal disturbance, absorption may not be complete and additional contraceptive measures should be taken.

If vomiting occurs within 3-4 hours after tablet-taking, the advice concerning missed tablets, as given in Section 4. is applicable. If the woman does not want to change her normal tablet-taking schedule, she has to take the extra tablet(s) needed from another pack.

How to shift periods or how to delay a period

Delaying a period is not an indication for the product. However, if in exceptional cases a period needs to be delayed, the woman should continue with another pack of Regulon 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 Regulon is then resumed after the usual 7-day tablet-free interval.

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

Paediatric population

The safety and efficacy of desogestrel in adolescents below 18 years have not yet been established. No data are available.

Method of administration For oral administration.

 

Combined hormonal contraceptives (CHCs) should not be used in the following conditions. Should such a condition occur for the first time while taking CHCs, the use of oral contraceptives should immediately be discontinued. - Presence or risk of venous thromboembolism (VTE) o Venous thromboembolism – current VTE (on anticoagulants) or history of (e.g. deep venous thrombosis [DVT] or pulmonary embolism[PE]). o Known hereditary or acquired predisposition for venous thromboembolism, such as APC- resistance, (including Factor V Leiden), antithrombin-III-deficiency, protein C deficiency, protein S deficiency. o Major surgery with prolonged immobilisation (see section 4.4). o A high risk of venous thromboembolism due to the presence of multiple risk factors (see section 4.4). - Presence or risk of arterial thromboembolism(ATE) o Arterial thromboembolism – current arterial thromboembolism, history of arterial thromboembolism (e.g. myocardial infarction) or prodromal condition (e.g. angina pectoris). o Cerebrovascular disease – current stroke, history of stroke or prodromal condition (e.g. transient ischaemic attack, TIA). o Known hereditary or acquired predisposition for arterial thromboembolism, such as hyperhomocysteinaemia and 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. - Pancreatitis or a history thereof if associated with severe hypertriglyceridaemia. - Presence or history of severe hepatic disease as long as liver function values have not returned to normal. - Presence or a history of liver tumours (benign ormalignant). - Proven or suspected sex steroid-influenced malignancies (e.g. of the genital organs or the breasts). - Endometrial hyperplasia. - Undiagnosed vaginal bleeding. - Hypersensitivity to the active substances or to any of the excipients listed in section 6.1.

Warnings

If any of the conditions or risk factors mentioned below is present, the suitability of Regulon 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 Regulon should be discontinued.

1.  Circulatory disorders

Risk of venous thromboembolism (VTE)

The use of any combined hormonal contraceptive (CHC) increases the risk of venous thromboembolism (VTE) compared with no use. Products that contain levonorgestrel, norgestimate or norethisterone are associated with the lowest risk of VTE. Other products such as Regulon may have up to twice this level of risk. The decision to use any product other than one with the lowest VTE risk should be taken only after a discussion with the woman to ensure she understands the risk of VTE with Regulon, 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 ormore.

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

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

In both cases, the number of VTEs per year is fewer than the number expected during pregnancy or in the postpartum period.

VTE may be fatal in 1-2% of 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 venous thromboembolism (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).

Regulon 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 venous thromboembolism (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	In these situations it is advisable to discontinue use of

1 These incidences were estimated from the totality of the epidemiological study data, using relative risks for the different products compared with levonorgestrel-containing CHCs.

2 Mid-point of range of 5-7 per 10,000 WY, based on a relative risk for CHCs containing levonorgestrel versus non-use of approximately 2.3 to 3.6.

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.	the pill (in the case of elective surgery at least four weeks in advance) and not resume until two weeks after complete remobilisation. Another method of contraception should be used to avoid unintentional pregnancy. Antithrombotic treatment should be considered if Regulon 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 venous thromboembolism (VTE)

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 theleg;

- 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 rapidbreathing;

- sudden coughing which may be associated withhaemoptysis;

- 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 arterial thromboembolism (ATE)

The risk of arterial thromboembolic complications or of a cerebrovascular accident in CHC users increases in women with risk factors (see table). Regulon 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 arterial thromboembolism (ATE)

Risk factor	Comment
Increasing age.	Particularly above 35 years.
Smoking.	Women should be advised not to smoke if they wish to use a CHC. Women over 35 who continue to smoke should be strongly advised to use a different method of contraception.
Hypertension.
Obesity (body mass index over 30 kg/m2).	Risk increases substantially as BMI increases. Particularly important in women with additional risk. factors.
Positive family history (arterial thromboembolism ever in a sibling or parent especially at relatively early age e.g. below 50).	If a hereditary predisposition is suspected, the woman should be referred to a specialist for advice before deciding about any CHC use.
Migraine.	An increase in frequency or severity of migraine during CHC use (which may be prodromal of a cerebrovascular event) may be a reason for immediate discontinuation.
Other medical conditions associated with adverse vascular events.	Diabetes mellitus, hyperhomocysteinaemia, valvular heart disease and atrial fibrillation, dyslipoproteinaemia and systemic lupus erythematosus.

 Symptoms of arterial thromboembolism (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 orunderstanding;

-   sudden trouble seeing in one or both eyes;

-   sudden, severe or prolonged headache with no knowncause;

-   loss of consciousness or fainting with or withoutseizure.

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.

2.              Tumours

Epidemiological studies indicate that the long-term use of oral contraceptives displays a risk factor for the development of cervical cancer in women infected with human papillomavirus (HPV). However, there is still uncertainty about the extent to which this finding is influenced by confounding effects (e.g. differences in number of sexual partners or in use of barrier contraceptives).

According to the meta-analysis from 54 international studies the relative risk of breast cancer is slightly increased (RR=1.24) in women currently taking combined oral contraceptives.

The excess risk gradually disappears during the course of the 10 years after cessation of CHC use. Breast cancer occurs rarely among women under the age of 40 years, the excess number of breast cancer diagnoses in current and recent CHC users is small in relation to the overall risk of breast cancer. These studies do not provide evidence for causation. The reason of the observed increased risk may be due to an earlier diagnosis of breast cancer in combined oral contraceptive users, the biological effects of combined oral contraceptives 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.

Rarely benign and more rarely malign hepatic tumours have been reported in users of combined oral contraceptives. 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 combined oral contraceptives.

3.              Other conditions

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

Although small increases in blood pressure have been reported in many women taking COCs, clinically relevant increases are rare. A relationship between COC use and clinical hypertension has not been established. However, if a sustained clinically significant hypertension develops during the use of a COC then it is prudent for the physician to withdraw the COC and treat the hypertension.

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; gallstone formation; porphyria; systemic lupus erythematosus; haemolytic uraemic syndrome; Sydenham’s chorea; herpes gestationis; otosclerosisrelated hearing loss; (hereditary) angioedema.

Acute or chronic disturbances of liver function may necessitate the discontinuation of CHC use until markers of liver function return to normal. Recurrence of cholestatic jaundice which occurred first during pregnancy or previous use of sex steroids necessitates the discontinuation of COCs.

Although CHCs 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 CHCs. However, diabetic women should be carefully observed while taking COCs.

Crohn’s disease and ulcerative colitis have been associated with CHC 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.

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

When counselling the choice of contraceptive method(s), all the above information should be taken into account.

Medical examination/consultation

Prior to the initiation or reinstitution of Regulon a complete medical history (including family history) should be taken and pregnancy must be ruled out. Blood pressure should be measured and a physical examination should be performed, guided by the contra-indications (see section 4.3) and warnings (see section 4.4). It is important to draw a woman’s attention to the information on venous and arterial thrombosis, including the risk of Regulon compared with other CHCs, the symptoms of VTE and ATE, the known risk factors and what to do in the event of a suspected thrombosis.

The woman should also be instructed to carefully read the user leaflet and to adhere to the advice given. The frequency and nature of examinations should be based on established practice guidelines and be adapted to the individual woman.

Women should be advised that hormonal contraceptives do not protect against HIV infections (AIDS) and other sexually transmitted diseases.

Reduced contraceptive efficacy

The efficacy of CHCs may be reduced in the event of e.g., missed tablets (see section 4.2), gastro- intestinal disturbances (see section 4.2) or concomitant medication (see section 4.5).

Herbal preparations containing St. John's wort (Hypericum perforatum) should not be used while taking Regulon due to the risk of decreased plasma concentrations and reduced clinical effects of Regulon (see section 4.5).

Controlling of the menstrual cycle

With all CHCs, irregular bleeding (spotting or break-through bleeding) may occur, especially during the first months of use. Therefore, the evaluation of any irregular bleeding is only meaningful after an adaptation interval of about three cycles.

If bleeding irregularities persist or occur after previously regular cycles, then non-hormonal causes should be considered and malignancy or pregnancy should be excluded. These may include curettage.

In some women withdrawal bleeding may not occur during the tablet-free interval. If the CHC has been taken according to the directions described in section 4.2, it is unlikely that the woman is pregnant. However, if the CHC 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 CHC use is continued.

 

Drug interactions

Drug interactions resulting in an increased clearance of sexual hormones may lead to break-through bleeding and contraceptive failure. This has been established with hydantoins, barbiturates, primidone, bosentan, carbamazepine, rifampicin and rifabutin; oxcarbazepine, modafinil, topiramate, felbamate, griseofulvine, ritonavir and products containing St. John’s wort (Hypericum perforatum) are also suspected. Also HIV protease inhibitors with an inducing potential (e.g. ritonavir and nelfinavir) and non-nucleoside reverse transcriptase inhibitors (e.g. nevirapine and efavirenz), may affect hepatic metabolism. Maximal enzyme induction is generally not seen until 2-3 weeks after start of treatment, but may then persist for at least 4 weeks after discontinuation of treatment.

Women on treatment with antibiotics (except rifampicin and griseofulvin, which also act as microsomal enzyme-inducing drugs) should use the barrier method until 7 days after discontinuation. If the period during which the barrier method is used runs beyond the end of the tablets in the COC pack, the next contraceptive pill pack should be started without the usual tablet-free interval.

Women on short term treatment with some of the above mentioned groups of drugs should temporarily use a mechanical method concomitantly with the contraceptive pills, i.e. in the period of other concomitant drug intake and for 7 days after cessation of this drug. Women taking microsomal enzyme-inducing drugs (e.g. rifampicin) should use a barrier method concomitantly with intake of contraceptive pills for the period in which she is treated with rifampicin and for 28 days after cessation of the drug. In case of women receiving long-term therapy with enzyme-inducers other contraceptive method should be considered.

Oral contraceptives may affect the metabolism of other drugs. Accordingly, plasma and tissue concentrations may either increase (e.g. cyclosporin) 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, serum 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.

 

Pregnancy

Regulon is not indicated in pregnancy.

Before the administration of Regulon pregnancy should be excluded. If pregnancy occurs during medication with Regulon, treatment should be withdrawn immediately.

As revealed by epidemiological studies, malformation in new-borns of women who had used oral contraception prior to pregnancy was not higher, and no teratogenic effects could be detected if the pregnant woman had used the pill during the early period of pregnancy.

The increased risk of VTE during the postpartum period should be considered when re-starting Regulon (see sections 4.2 and 4.4).

Breast-feeding

Oral contraceptives may reduce the production of breast-milk and alter its composition, furthermore, they are secreted in human milk (but there is no evidence that this adversely affects infant health), therefore, their use is not recommended in breast-feeding mothers.

Small amounts of the steroids and/or their metabolites may be excreted with the milk but there is no evidence that this adversely affects infant health.

No effects on ability to drive and use machines have been observed.

Description of selected adverse reactions

An increased risk of arterial and venous thrombotic and thromboembolic events, including myocardial infarction, stroke, transient ischaemic attacks, venous thrombosis and pulmonary embolism has been observed in women using combined oral contraceptives, which are discussed in more detail in section 4.4.

Other undesirable effects have been reported in women using combined oral contraceptives. These include hypertension, hormone dependent tumours (e.g. liver tumours, breast tumours); chloasma which are discussed in more detail in section 4.4.

As with all CHCs, changes in menstrual bleeding patterns may occur, especially during the first months of use. These may include changes in bleeding frequency (absent, less, more frequent or continuous), intensity (reduced or increased) or duration.

Possibly related undesirable effects that have been reported in users of CHC containing

150 micrograms of desogestrel and 30 micrograms of ethinylestradiol (such as Regulon) or CHC users in general are listed in the table below³. All ADRs are listed by system organ class and frequency: very common (≥1/10), common (≥1/100 to <1/10), uncommon (≥1/1,000 to <1/100) and rare (≥1/10,000 to <1/1,000).

System organ class	Common	Uncommon	Rare
Immune system disorders			Hypersensitivity
Metabolism and nutrition disorders		Fluid retention
Psychiatric disorders	Depression Mood changes	Libido decreased	Libido increased
Nervous system disorders	Headache	Migraine
Eye disorders			Contact lens intolerance
Vascular disorders			Venous thromboembolism (VTE) or arterial thromboembolism (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 enlargement	Vaginal discharge Breast discharge
General disorders and administration site conditions	Weight increased		Weight decreased

³The most appropriate MedDRA term to describe a certain adverse reaction is listed. Synonyms or related conditions are not listed, but should be taken into account as well.

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.

To report any side effect(s):

• Saudi Arabia:
  • The National Pharmacovigilance Centre (NPC)
    • Fax: +966-11-205-7662
    • SFDA Call Center: 19999
    • E-mail: npc.drug@sfda.gov.sa
    • Website: https://ade.sfda.gov.sa 
• Other GCC States:
  Please contact the relevant competent authority.

No serious ill-effects have been reported after the intake of a considerable dose of the oral contraceptive. Symptoms that may occur in this case are: nausea, vomiting and, in young girls, slight vaginal bleeding. Therefore, it is unnecessary to treat overdosage. However, if overdosage is discovered within two or three hours or a great number of tablets has been taken, gastric lavage can be used. There is no antidote available, symptomatic treatment should be applied.

Pharmacotherapeutic group: hormonal contraceptives for systemic use, progestogens and estrogens

ATC code: G03A A09

The contraceptive effect of combined oral contraceptives 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. As well as protection against pregnancy, combined oral contraceptives have several positive properties which, next to the negative properties (see section 4.4 and 4.8), can be useful in deciding on the method of birth control. The cycle is more regular and the menstruation is often less painful and bleeding is lighter. The latter may result in a decrease in the occurrence of iron deficiency. Apart from this, with the higher-dosed combined oral contraceptives (50μg ethinylestradiol), there is evidence of a reduced risk of fibrocystic tumours of the breasts, ovarian cysts, pelvic inflammatory disease, ectopic pregnancy and endometrial and ovarian cancer. Whether this also applies to lower-dosed combined oral contraceptives remains to be confirmed.

Paediatric population

No clinical data on efficacy and safety are available in adolescents below 18 years.

Desogestrel

Absorption

Orally administered desogestrel is rapidly and completely absorbed and converted to etonogestrel. Peak serum concentrations are reached at about 1.5 hours. Bioavailability is 62-81 %.

Distribution

Etonogestrel is bound to serum albumin and to sex hormone binding globulin (SHBG). Only 2-4% of the total serum drug concentrations are present as free steroid, 40-70% are specifically bound to SHBG. The ethinylestradiol-induced increase in SHBG influences the distribution over the serum proteins, causing an increase of the SHBG-bound fraction and a decrease of the albumin-bound fraction. The distribution volume is 5 l/kg.

Biotransformation

Etonogestrel is metabolised completely via the known pathways of steroid metabolism. The metabolic clearance rate from serum is approximately 2 ml/min/kg. No interaction occurs when etonogestrel is taken together with ethinylestradiol.

Elimination

Etonogestrel serum levels decrease in two phases. The terminal disposition phase is characterised by a half-life of approximately 30 hours. Desogestrel and its metabolites are extracted at a urinary to biliary ratio of about 6:4.

Steady-state

Pharmacokinetics of etonogestrel is influenced by the levels of SHBG in serum, which increase to triple values with ethinylestradiol. Upon daily intake, steady state conditions are reached by the second half of the cycle, when the serum level of etonogestrel is elevated by two- to three-fold.

Ethinylestradiol 

Absorption

Orally administered ethinylestradiol is rapidly and completely absorbed. Peak serum concentrations are reached within 1-2 hours. Absolute bioavailability as a result of presynaptic coagulation and first pass metabolism is approximately 60%.

Distribution

Ethinylestradiol is highly but non-specifically bound to serum albumin (approximately 98.5%) and induces an increase in the serum concentrations of SHBG. Its distribution volume is 5 l/kg.

Biotransformation

Ethinylestradiol undergoes pre-systemic conjugation both in the mucosa of the small intestine, and in the liver. Ethinylestradiol is primarily metabolised by aromatic hydroxylation, but many different hydroxylated and methylated metabolites are formed and found as free metabolites and as glucuronide and sulphate conjugates. The metabolic clearance rate is approximately 5 ml/min/kg.

Elimination

Ethinylestradiol serum levels decrease in two disposition phases, the terminal disposition phase is characterised by a half-life of approximately 24 hours. Unchanged drug is not excreted; ethinylestradiol metabolites are excreted at urinary to biliary ratio of 4:6. The half-life of metabolite excretion is about 1 day.

Steady-state

Steady-state conditions are obtained after 3 to 4 days, when the serum level of the medicine is approximately 30 to 40% higher than after the administration of a single dose.

Conventional studies of pharmacological safety, repeated dose toxicity, genotoxicity, carcinogenic potential and toxicity to reproduction proved that there are no special risks in humans with combined oral contraceptives when used as appropriate.

However, it must be borne in mind that sex steroids can promote the growth of certain hormone- dependent tissues and tumours.

All-rac-a-tocopherol, magnesium stearate, colloidal anhydrous silica, stearic acid, povidone, potato starch, lactose monohydrate, propylene glycol, macrogol 6000, hypromellose.

Not applicable.

3 years

Store between +15 °C and +30°C.

Regulon film-coated tablets are packaged in hard PVC/PVDC Aluminium blister pack. The blisters are packed in folded carton box along with an “etui” storing bag and the patient information leaflet.

Pack sizes:

3x21film-coated tablets

6x21film-coated tablets

13x21 film-coated tablets

No special requirements.