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

Posology

How to take Gracial
The tablets should be taken at about the same time every day, with a little liquid if needed, following the order shown on the blister strip. One tablet is taken daily for 22 consecutive days, starting with the blue tablets for 7 days and then the white tablets for 15 days. Successive blisters are started immediately after a 6-day tablet-free period, during which withdrawal bleeding usually occurs. The bleeding usually starts on the 2nd or 3rd day after taking the last tablet and may not have finished before starting the next blister.

Paediatric population
The safety and efficacy of Gracial in adolescents under 18 years of age have not yet been established. No data are available.

Method of administration

How to start taking Gracial
No previous administration of hormonal contraceptives (in the previous month)

The tablets should be started on day 1 of the woman’s natural cycle (i.e. the first day of menstrual bleeding). Starting on day 2-5 is also possible, but during the first cycle an additional barrier method is recommended for the first 7 days of taking the tablet.

When switching from another combined hormonal contraceptive (combined contraceptive pill, vaginal ring, or transdermal patch)
Ideally, the woman should start Gracial on the day after the last active tablet (the last tablet containing the active substances) of the previous combined hormonal contraceptive, or at the very latest on the day after the rest period or after the last inactive tablet of the previous combined hormonal contraceptive. If using a vaginal ring or transdermal patch, the woman should start using Gracial preferably on the same day as removal of the patch or ring, or at the very latest on the day when the next patch was due to be applied or the ring inserted.

If the woman has been using a contraceptive method continuously and correctly, and if she is reasonably confident that she is not pregnant, she could change from her previous combined hormonal contraceptive any day of the cycle.

The rest period of the previous contraceptive method should never be extended beyond the recommended duration.

Not all contraceptive methods (vaginal ring or transdermal patch) may be marketed in all EU countries.

Changing from a progestogen-only (pill, injection, implant) method or from a progestogen-releasing intrauterine system (IUS)
The woman may switch from the progesterone-only pill to Gracial any day (or on the day of extraction in the case of an implant or IUS, or on day when the next injection is due), but in all cases she should be advised to use an additional barrier method for the first 7 days of taking the tablet.

Following a first trimester miscarriage
Gracial may be started immediately. In this case, no additional contraceptive measures are necessary.

Following delivery or a second-trimester miscarriage
For women who are breast-feeding, see section 4.6.
Women should be advised to start on day 21 to 28 after giving birth or after a second-trimester miscarriage. If starting after this, the woman should be advised to use an additional barrier method for the first 7 days of taking the tablet. However, if she has already had sexual intercourse, pregnancy should be ruled out before starting the combined hormonal contraceptive, or wait for her first menstrual period.

The increased risk of VTE during the postpartum period should be considered when restarting Gracial (see section 4.4.1).

Recommendations to follow in the case of forgotten tablets
If the delay in taking the tablet is less than 12 hours, the contraceptive protection is not reduced. The user should take the forgotten tablet as soon as she remembers and then continue to take the other tablets at the usual time.

If the delay in taking the tablet is over 12 hours, the contraceptive protection may be reduced. The recommendations to ensure contraceptive protection in this case should be governed by the following two basic rules:

1. Never stop taking the tablets for more than 6 days.
2. The tablets must be taken for 7 days in a row to attain adequate suppression of the hypothalamic-pituitary-ovarian axis.

Accordingly, in daily practice, the following recommendations should be followed depending on the week:
• Week 1
The user should take the last forgotten tablet as soon as she remembers, even if this means taking two tablets at the same time, and then continue to take the rest of the tablets at the usual time. A barrier method (a condom) should also be used for the next 7 days. If intercourse took place in the 7 days before the forgotten tablet, the possibility of pregnancy should be considered. The more tablets that are missed and the closer they are to the tablet-free period, the higher the risk of pregnancy.
• Week 2
The user should take the last forgotten tablet as soon as she remembers, even if this means taking two tablets at the same time, and then continue to take the tablets at the usual time. Provided that the woman has taken her tablets correctly in the 7 days preceding the first forgotten tablet, there is no need to use additional contraceptive precautions. However, if this is not the case, or if she missed more than 1 tablet, the woman should be advised to use extra precautions for 7 days.
• Week 3
The risk of reduced reliability is high because of the proximity of the tablet-free period. However, if the tablet administration schedule is altered, reduced contraceptive protection can still be avoided by following either of the two options shown below. Also, it should be borne in mind that provided the user has correctly taken all the tablets in the 7 days prior to the first forgotten tablet, it is not necessary to take additional contraceptive measures. If this is not the case, the user should be advised to follow option one and to use additional contraceptive precautions for the first 7 days after the forgotten tablet.

1. The user should take the last missed pill as soon as she remembers, even if this means taking two tablets at the same time, and then continue to take the rest of the tablets at the usual time. Also, the next blister should be started as soon as the current blister is finished, i.e., with no rest period. In this case, the user is unlikely to have a withdrawal bleed until the end of the second blister, but she may experience spotting or breakthrough bleeding during this time.
2. The user may also be advised to stop taking the tablets in the current blister, and to allow a maximum rest period of 6 days, including the days the tablets were forgotten. Then, to continue with the next blister.

Whenever the user has forgotten to take some active tablets, and has no withdrawal bleed during the first rest period, the possibility of a pregnancy should be considered.

Recommendations in the case of gastrointestinal disturbances
In cases of severe gastrointestinal disturbance, absorption may be incomplete and additional contraceptive measures should be taken.
If severe diarrhoea and/or vomiting occurs within 3 to 4 hours of taking the tablet, the recommendations in section 4.2 should be followed. If the woman does not want to change her normal dose schedule, she could take the extra tablets needed from another pack.

How to delay a period or change day of period
Delaying or changing the day of the period is not an indication for the product. However, if in exceptional cases a period needs to be delayed, the woman should continue taking the white tablets from another Gracial blister without any rest period. This prolongation may be continued for a maximum of 15 days, until the end of the second blister. During this prolongation period, there may some breakthrough bleeding or spotting. Then, after the usual 6-day tablet-free period, Gracial is taken as usual.

If a woman wants to change her current dosing schedule to have her period another day of the week, she should be advised to shorten the next tablet-free interval by as many days as she likes. The shorter this interval, the higher the likelihood that there will be no withdrawal bleeding but that there will be breakthrough bleeding and spotting during the second blister (just like when delaying a period).

CHCs should not be used in the following conditions. Treatment should be stopped immediately if any of the conditions appear for the first time when taking CHC. -Presence or risk of venous thromboembolism (VTE) o Venous thromboembolism: current (on anticoagulants) or a history of VTE (e.g. deep venous thrombosis [DVT] or pulmonary embolism [PE]). o Known hereditary or acquired predisposition for VTE, such as activated protein C-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 VTE due to the presence of multiple risk factors (see section 4.4). - Presence or risk of arterial thromboembolism (ATE) o Arterial thromboembolism: current or a history of ATE (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 ATE, such as hyperhomocysteinaemia and antiphospholipid-antibodies (anticardiolipin-antibodies, lupus anticoagulant). o History of migraine with focal neurological symptoms. o A high risk of ATE 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 of pancreatitis associated with severe hypertriglyceridaemia. - Presence or history of severe liver disease, when liver function values have not returned to normal. - Presence or history of liver tumours (benign or malignant). - Confirmed or suspected sex steroid hormone-dependent malignancies (e.g. genital organs or breasts). - Endometrial hyperplasia. - Undiagnosed vaginal bleeding. - Confirmed or suspected pregnancy. - Hypersensitivity to the active substances or to any of the excipients listed in section 6.1. Concomitant use with the medicinal products containing ombitasvir/paritaprevir/ritonavir and dasabuvir, medicinal products containing glecaprevir/pibresntasvir or sofosbuvir/velpatasvir/voxilaprevir (see section 4.5)

Warnings
If any of the conditions or risk factors mentioned below is present, the suitability of combined hormonal contraceptive (CHC) use 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 CHC use should be discontinued.

Throughout this section the general term combined hormonal contraceptive (CHC) is used when data exist for oral and non-oral contraceptives. The term combined oral contraceptive (COC) is used when data exist only for oral contraceptives.

 

Circulation disorders

Risk of venous thromboembolism (VTE)

•  The use of any combined hormonal contraceptive (CHC) increases the risk of VTE compared with no use. Products that contain levonorgestrel, norgestimate or norethisterone are associated with the lowest risk of VTE. It is not yet known how the risk with Gracial compares with these lower risk products. The decision to use any product other than one known to have the lowest VTE risk should be taken only after a discussion with the woman to ensure she understands the risk of VTE with Gracial, 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 restarted after a break in use of 4 weeks or more.
•  In women who do not use a CHC and are not pregnant about 2 out of 10,000 will develop a VTE over the period of one year. However, in any individual woman the risk may be far higher, depending on her underlying risk factors (see below).
• It is estimated¹ that out of 10,000 women who use a CHC containing desogestrel between 9 and 12 will develop a VTE in one year, compared with 6² in women who use a levonorgestrel-containing CHC.
•  In both cases, the number of VTEs per year is lower than the number expected in women during pregnancy or in the postpartum period.
•  VTE may be fatal in 1-2% of cases.

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

Extremely rarely, thrombosis has been reported to occur in other blood vessels (e.g. hepatic, mesenteric, renal or retinal veins and arteries) in CHC users.

Risk factors for VTE
The risk for venous thromboembolic complications in CHC users may increase substantially in women with additional risk factors, particularly if there are multiple risk factors (see table).

Gracial is contraindicated if a woman has various risk factors that would 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 risk/benefit balance is considered negative, a CHC should not be prescribed (see section 4.3).

Table: Risk factors for VTE

Risk factors	Comment
Obesity (body mass index [BMI] over 30 kg/m²)	The risk increases substantially as the BMI rises.   Particularly important to consider if other risk factors are also present.
Prolonged immobilisation, major surgery, any surgery to the legs or pelvis, neurosurgery, or major trauma           Note: Temporary immobilisation including air travel >4 hours can also be a risk factor for VTE, particularly in women with other risk factors	In these situations, it is advisable to discontinue use of the patch/pill/ring (in the case of elective surgery at least four weeks in advance) and not to resume until two weeks after complete remobilisation. See also section 4.3 `Contraindications`.   Antithrombotic treatment should be considered if Gracial has not been discontinued in advance.
Positive family history (venous thromboembolism in a sibling or parent especially at a relatively early age e.g. under 50 years)	If a hereditary predisposition is suspected, the woman should be referred to a specialist for advice before reaching any decision 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 over 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 postpartum period, must be considered (for information on “Pregnancy and lactation” see section 4.6).

Symptoms of VTE (deep vein thrombosis and pulmonary embolism)

In the event of symptoms, the woman should be advised to seek urgent medical attention and to inform the healthcare professional that she is taking a CHC.

Symptoms of deep vein thrombosis (DVT) can include:
- Unilateral swelling of the leg and/or foot or along a vein in the leg.
- Pain or tenderness in the leg which may be felt only when standing or walking.
- Increased warmth in the affected leg; red or discoloured skin on the leg.

Symptoms of pulmonary embolism (PE) can include:
- Sudden onset of unexplained shortness of breath or rapid breathing.
- Sudden coughing which may be associated with haemoptysis.
- Sharp chest pain.
- Severe light headedness or dizziness.
- Rapid or irregular heartbeat.

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

Other signs of vascular occlusion can include: sudden pain, swelling and slight blue discolouration 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 shown an association between the use of CHCs and an increased risk of arterial and venous thrombotic and thromboembolic diseases such as myocardial infarction, stroke, deep venous thrombosis, and pulmonary embolism. These events occur rarely.

Risk factors for ATE
The risk of arterial thromboembolic complications or of a cerebrovascular accident in CHC users increases in women with risk factors (see table). Gracial is contraindicated if a woman has one serious or several risk factors for ATE that would put 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 risk/benefit balance is considered negative, a CHC should not be prescribed (see section 4.3).

Table: Risk factors for ATE

Symptoms of ATE

In the event of symptoms, the woman 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 may include:
- Sudden weakness or numbness of the face, arm or leg, especially on one side of the body.
- Sudden trouble walking, dizziness, loss of balance or coordination.
- Sudden confusion, difficulty speaking or understanding.
- Sudden trouble seeing in one or both eyes.
- Sudden, severe or prolonged headache with no known cause.
- Loss of consciousness or fainting with or without seizure.

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

Symptoms of myocardial infarction (MI) may include:
- Pain, discomfort, pressure, heaviness, sensation of squeezing or fullness in the chest, arm, or below the sternum.
- Discomfort radiating to the back, jaw, throat, arm or stomach.
- Feeling of fullness, indigestion or choking.
- Sweating, nausea, vomiting or dizziness.
- Extreme weakness, anxiety, or shortness of breath.
- Accelerated or irregular heartbeat.

Tumours

•  Epidemiological studies indicate that the long-term use of combined oral contraceptives is a risk factor for developing cervical cancer in women infected with the human papillomavirus (HPV). However, it is still unclear the degree to which this result is attributable to the effect produced by confounding factors (such as differences in the number of sexual partners or the use of barrier contraceptives).
•  A meta-analysis of 54 epidemiological studies reported that there is a slight increase in the relative risk (RR = 1.24) of presenting with diagnosed breast cancer in women taking oral contraceptives compared to those who have never taken them. This additional risk gradually disappears over the 10 years after stopping treatment. Breast cancer is rare among women under 40 years, so the increase in the number of diagnosed breast cancers among current or recent users of oral contraceptives is small in relation to the overall risk of breast cancer. The increased risk of diagnosing breast cancer may be due to early detection of cancer in patients treated with oral contraceptives (because they are subject to regular clinical monitoring), the biological effects of oral contraceptives or the combination of both factors. Breast cancers diagnosed in oral contraceptive users tend to be less clinically advanced than cancers diagnosed in women who have never used them.
•  Benign liver tumours have been observed in rare cases, and malignant liver tumours even more rarely, in users of combined hormonal contraceptives. In isolated cases, these tumours have caused life-threatening intra-abdominal haemorrhage. If severe epigastric pain, liver enlargement or signs of intra-abdominal haemorrhage occur, the differential diagnosis should consider the possibility of a liver tumour.

Hepatitis C
• During clinical trials with the HCV combination drug regimen ombitasvir/paritaprevir/ritonavir with or without dasbuvir, ALT elevations greater than 5 times the upper limit of normal (ULN) were significantly more frequent in women using ethinylestradoil-containg medications such as CHCs. Gracial must be discontinued prior to starting therapy with the combination drug regimen ombitasvir/paritaprevir/ritonavir with or without dasbuvir (see section 4.3 and 4.4). Gracial can be restarted approximately 2 weeks following completion of treatment with the combination drug regimen.

Other conditions

•  In women with hypertriglyceridaemia or a family history of hypertriglyceridemia, there may be an increased risk of pancreatitis when using combined hormonal contraceptives.
•  Many users have had slight increases in blood pressure during the use of combined hormonal contraceptives, but these increases have rarely had a significant clinical impact. No relationship has been established between the use of combined hormonal contraceptives and increased blood pressure. However, if sustained clinical relevant hypertension occurs during the administration of a combined hormonal contraceptive, the doctor should, as a precaution, recommend suspending the contraceptive and treating the hypertension. When appropriate, the combined hormonal contraceptive can then be restarted if normal blood pressure values have been reached with the antihypertensive treatment.
•  The following processes may appear or worsen during the course of pregnancy and during the use of combined hormonal contraceptives: jaundice and/or pruritus due to cholestasis; formation of gallstones; porphyria; systemic lupus erythematosus; haemolytic uraemic syndrome; Sydenham's chorea; gestational herpes; hearing loss due to otosclerosis, (hereditary) angioedema.
• Acute or chronic alterations of liver function would require discontinuation of the combined hormonal contraceptive until liver function markers have returned to normal levels. The reappearance of cholestatic jaundice that occurred for the first time during a pregnancy or coinciding with the previous use of sex hormones would require discontinuation of the combined hormonal contraceptive.
• Combined hormonal contraceptives can alter peripheral insulin resistance and glucose tolerance. However, there is no evidence to suggest that it would be necessary to modify treatment regimens in diabetic patients. However, these women require strict medical supervision when using combined hormonal contraceptives.
• The development of Crohn's disease and ulcerative colitis has been associated with the use of combined hormonal contraceptives.
• Occasionally, during the use of combined hormonal contraceptives, chloasma may occur, especially in women with a personal history of chloasma gravidarum. Women with a tendency to develop chloasma should avoid exposure to the sun or ultraviolet radiation while using combined hormonal contraceptives.

When advising women on the choice of contraceptive methods, all the above information should be taken into account.

Medical examination/consultation
Prior to the initiation or reinstitution of Gracial, a complete medical history (including family history) should be taken and pregnancy must be ruled out. Blood pressure should be measured and a physical examination should be performed, guided by the contraindications (see section 4.3) and warnings (see section 4.4). It is important to draw the woman’s attention to the information on venous and arterial thrombosis, including the risk of Gracial 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 each woman.

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

Reduced efficacy
The efficacy of CHCs may be reduced if, for example, the user forgets to take a tablet (see section 4.2), if she suffers gastrointestinal disturbances (see section 4.2) or is using concomitant medications (see section 4.5).

Herbal preparations containing St. John's wort (Hypericum perforatum) should not be co-administered with Gracial as this could reduce plasma Gracial concentrations with the risk of an unwanted pregnancy or breakthrough bleeding (see section 4.5).

Irregularities in cycle control
During the use of all CHCs, some bleeding may occur between periods (spotting or breakthrough bleeding), especially during the first months of use. Therefore, any irregular bleeding should only be evaluated after an adaptation interval of about three cycles.

If bleeding irregularities persist or occur after previously regular cycles, then non-hormonal causes should be considered and adequate diagnostic measures carried out to rule out any malignant process or pregnancy (this could include diagnostic dilation and curettage).

In some women, withdrawal bleeding may not occur during the tablet-free period. If the CHC has been taken according to the directions described in section 4.2, it is unlikely that the user is pregnant. However, if the CHC has not been taken according to these directions before the first missed withdrawal bleed or if two withdrawal bleeds are missed, pregnancy should be ruled out before continuing to use the CHC.

Laboratory tests
The use of contraceptive steroids can affect the results of some laboratory tests, including biochemical parameters of liver, thyroid, adrenal and renal function, plasma levels of protein (transporters) such as corticosteroid-binding globulin and lipid/lipoprotein fractions, carbohydrate metabolism parameters and coagulation and fibrinolysis parameters. In general, these changes remain within the normal laboratory range.

Important information about the excipients
This medicine contains lactose. Patients with hereditary problems of galactose intolerance, the Lapp lactase deficiency (insufficiency observed in certain populations of Laponia) or glucose-galactose malabsorption should not take this medicine.

 

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

Effects of other medicinal products on Gracial
Interactions can occur with products that induce microsomal enzymes, which could increase the clearance of the sex hormones and lead to breakthrough bleeding and/or contraceptive failure.

Measures to take
Enzyme induction may be observed within a few days of treatment. Maximal enzyme induction generally occurs within 2-3 weeks. Following discontinuation of the pharmacological treatment, enzyme induction may persist for about 4 weeks.

Short-term treatment
Women taking enzyme-inducing medications should temporarily use a barrier method or other contraceptive method in addition to the combined oral contraceptive (COC). The barrier method should be used for the entire duration of the concomitant administration and for 28 days after discontinuation. If the pharmacological treatment continues after finishing the current COC pack, the next COC pack should be started straight away without leaving the usual tablet-free period.

Long-term treatment
In women undergoing long-term treatment with active ingredients that induce hepatic enzymes, another reliable (not hormonal) contraceptive method is recommended.

The following interactions have been described in the medical literature.

Substances that increase the clearance of COCs (reduce the efficacy of COCs through enzyme induction): e.g. barbiturates, bosentan, carbamazepine, hydantoins (phenytoin), primidone, rifampin, rifabutin and HIV medications such as ritonavir, nevirapine and efavirenz and possibly also felbamate, griseofulvin, oxcarbazepine, modafinil, topiramate, and products containing the medicinal plant 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 and/or combinations with Hepatitis C virus (HCV) medicinal products (e.g., boceprevir, telaprevir) 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 for concomitant medications for HIV and HCV should be consulted to identify potential interactions and any related recommendations. When in doubt, women taking protease inhibitors or non-nucleoside reverse transcriptase inhibitors should use an additional barrier contraceptive method.

Concomitant administration of strong inhibitors of CYP3A4 (such as ketoconazole, itraconazole, clarithromycin) or moderate inhibitors (such as fluconazole, diltiazem, erythromycin) may increase serum concentrations of estrogen or progestogens, including etonogestrel, the active metabolite of desogestrel.

Effects of Gracial on other medications
Oral contraceptives can affect the metabolism of other medicinal products. The concentrations in plasma and tissues can be increased (e.g. cyclosporine) or decreased (e.g. lamotrigine).

Pharmacodynamic interactions
During clinical trials with patients treated for hepatitis C virus infections (HCV) with medicinal products containing ombitasvir / paritaprevir / ritonavir and dasabuvir with or without ribavirin, transaminase (ALT) elevations higher than 5 times the upper limit of normal (ULN) occurred significantly more frequently in women using ethinylestradiolcontaining medications such as combined hormonal contraceptives (CHCs). Additionally, also in patients treated with glecaprevir/pibrentasvir or sofosbuvir/velpatasvir/voxilaprevir, ALT
elevations were observed in women using ethinylestradiol-containing medications such as CHCs (see section 4.3).Therefore, women who take Gracial should switch to an alternative contraceptive method (e.g. progestogen-only or non-hormonal methods) before starting treatment with this combination. Gracial can be used 2 weeks after finishing treatment with this combination.

Laboratory tests
The use of contraceptive steroids can affect the results of some laboratory tests, such as the biochemical parameters of liver, thyroid, adrenal and renal function, plasma levels of proteins (transporters) such as corticosteroid-binding globulin and lipid/lipoprotein fractions, carbohydrate metabolism parameters and coagulation and fibrinolysis parameters. In general, the changes remain within normal limits.

Pregnancy
Gracial is not indicated during pregnancy. If a women becomes pregnant while taking Gracial, therapy should be stopped. However, in the numerous epidemiological studies on combined hormonal contraceptives, there were no findings that would suggest an increased risk of birth defects in children born to women who used CHCs prior to the pregnancy. Furthermore, there was no evidence to suggest a teratogenic effect when CHCs were taken inadvertently during the first few days of pregnancy.

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

Lactation
Lactation may be affected by CHCs as they may reduce the quantity and change the composition of breast milk. Generally, the use of CHCs should not be recommended until the nursing mother has completely weaned her child. Small amounts of the contraceptive steroids and/or their metabolites may be excreted with the milk but there is no evidence that this adversely affects the infant's health.

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

Description of selected adverse reactions
An increased risk of arterial and venous thrombotic and thrombo-embolic events, including myocardial infarction, stroke, transient ischaemic attacks, venous thrombosis and pulmonary embolism has been observed in women using CHCs, which are discussed in more detail in section 4.4.

Other adverse reactions have been reported in women using CHCs, which are discussed in more detail in section 4.4.

As with all combined hormonal contraceptives, women can experience changes in their bleeding patterns, especially during the first months of use. This could include irregular bleeding (absence, decreased, more frequent or continuous bleeding) or changes in the intensity of bleeding (increase or decrease) or duration.

Possibly related undesirable effects that have been reported in clinical trials or observational studies with Gracial or CHC users in general are listed in the table below1:

All the adverse reactions are listed by system organ class and frequency: common (≥1/100), uncommon (≥1/1,000 and < /100) and rare (<1/1,000).

System Organ Class	Common	Uncommon	Rare
Immune system disorders			Hypersensitivity
Metabolism and nutrition disorders		Fluid retention
Psychiatric disorders	Mood alterations, including depression	Libido decreased	Libido increased
Nervous system disorders	Headache	Migraine
Eye disorders			Contact lens intolerance
Vascular disorders			Venous thromboembolism2, arterial thromboembolism2
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	Altered menstrual flow, breast secretion
Investigations	Weight increase		Weight loss

¹ The most appropriate MedDRA term was used to describe the adverse reaction. Synonyms or related conditions are not listed, but should also be taken into account.

² Incidence in observational cohort studies of ≥ 1/10000 to < 1/1000 women-years.

Interactions
Breakthrough bleeding and/or contraceptive failure can occur as a result of interactions of other medications (enzyme inducers) with oral contraceptives (see section 4.5).

Please report adverse drug events to:

-  Saudi Arabia:

- The National Pharmacovigilance Centre (NPC): - 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.

 

There are no reports of serious adverse effects following overdose. Symptoms that may occur in this case are: nausea, vomiting. Some slight vaginal bleeding could occur in young girls. There are no antidotes and further treatment should be symptomatic.

Pharmacotherapeutic group: sex hormones and modulators of the genital system, hormonal contraceptives for systemic use, progestogens and estrogens, sequential preparations, ATC code: G03AB05.

Gracial is a biphasic combined oral contraceptive containing desogestrel (DSG) as the progestagenic component. The combined biphasic concept of Gracial means that the quantity of progestogen is low and increases gradually while maintaining a low oestrogen dose. In this way, the cycle is better controlled compared to a monophasic oral contraceptive while maintaining high contraceptive efficacy.

The contraceptive effect of combined hormonal contraceptives is based on the interplay of several factors of which the most important are ovulation inhibition and changes in cervical secretions. In addition to protecting against pregnancy, combined hormonal contraceptives produce other non-contraceptive beneficial effects which, even bearing in mind the possible undesirable effects (see sections 4.4 and 4.8), may be useful when deciding which fertility control method to use. When using combined hormonal contraceptives, cycles are more regular and menstruation is usually not as painful or as heavy. The latter may result in a lower incidence of iron deficiencies in women. Furthermore, it has been shown that high-dose combined hormonal contraceptives (ethinylestradiol 0.05 mg) reduce the incidence of fibrocystic breast tumours, ovarian cysts, pelvic inflammatory disease and ectopic pregnancies. It has not yet been confirmed whether these findings can be applied to low-dose combined hormonal contraceptives.

Paediatric population
There are no clinical data available on the safety and efficacy in adolescents under 18 years of age.

Desogestrel

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

Distribution
Etonogestrel is bound to serum albumin and to sex hormone-binding globulin (SHBG). Only 2 to 4% of the total serum concentrations are present as free steroid, and 40 to 70% are specifically bound to SHBG. Distribution in plasma proteins depends on the ethinylestradiol-induced increase in SHBG concentrations, which increases the SHBG-bound fraction and decreases the albumin-bound fraction. The apparent volume of distribution of desogestrel is 1.5 l/kg.

Biotransformation
Etonogestrel is completely metabolised by the known steroid metabolic pathways. The serum metabolic clearance rate is about 2 ml/min/kg. No interaction was found when co-administered with ethinylestradiol.

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

Pharmacokinetic/pharmacodynamic relationship
Etonogestrel pharmacokinetics are influenced by SHBG levels, which are increased threefold by ethinylestradiol. Following daily administration, drug serum levels increase about 2- to 3-fold, reaching steady state in the second half of the treatment cycle.

Ethinylestradiol

Absorption
Orally administered ethinylestradiol is rapidly and completely absorbed. Peak serum concentrations are reached within 1 to 2 hours. Absolute bioavailability as a result of presynaptic conjugation 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 SHBG concentrations. An apparent volume of distribution of about 5 l/kg was determined.

Biotransformation
Ethinylestradiol undergoes presynaptic conjugation in both the small intestine mucosa and the liver. Ethinylestradiol is primarily metabolised by aromatic hydroxylation with the formation of a wide variety of hydroxylated and methylated metabolites, which are present as free metabolites and as glucronide and sulphate conjugates. The metabolic clearance rate is about 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. The unchanged drug is not excreted. Ethinylestradiol metabolites are excreted via the urine and bile at a ratio of 4:6, with a half-life of about 1 day.

Pharmacokinetic/pharmacodynamic relationship
Steady state concentrations are reached after 3 to 4 days when serum drug levels are 30 to 40% higher compared to single dose administration.

Non-clinical data reveal no special hazard for humans when CHCs are used as recommended. This is based on conventional studies of repeated dose toxicity, genotoxicity, carcinogenic potential and toxicity to reproduction. However, it must be borne in mind that sex steroids can stimulate the growth of certain hormone-dependent tissues and tumours.

Blue tablets:
Colloidal anhydrous silica
All-rac-alpha-tocopherol
Indigotine (E132)
Lactose monohydrate
Potato starch
Povidone
Stearic acid

White tablets:
Colloidal anhydrous silica
All-rac-alpha-tocopherol
Lactose monohydrate
Potato starch
Povidone
Stearic acid

Not applicable.

3 years

Do not store above 30ºC.
Store in the original package.

Blisters with 7 blue tablets and 15 white tablets. The blister is made of aluminium/PVC and consists of an aluminium foil with a heat-seal coating and a PVC film. Each blister is packed in a sealed laminated aluminium sachet. The sachets are packed in a cardboard box together with the package leaflet (1 or 3 sachets per box).

Store correctly. Keep out of the reach of children.

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