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Janssen-Cilag Ltd

50 - 100 Holmers Farm Way, High Wycombe, Bucks, HP12 4EG, UK
Telephone: +44 1494 567 567
Fax: +44 1494 567 568
Medical Information Direct Line: +353 1 800 709 122
Medical Information e-mail: medinfo@janssen-cilag.co.uk
Customer Care direct line: +353 1 620 2300
Medical Information Facsimile: +44 (0) 1494 567 445
Summary of Product Characteristics last updated on medicines.ie: 2/14/2018
SPC Cilest 250/35 microgram tablets

When a pharmaceutical company changes an SPC or PIL, a new version is published on medicines.ie. For each version, we show the dates it was published on medicines.ie and the reasons for change.

Updated on 2/14/2018 and displayed until Current
Reasons for adding or updating:
  • Change to section 4.4 - Special warnings and precautions for use
  • Change to section 4.5 - Interaction with other medicinal products and other forms of interaction
  • Change to section 10 - Date of revision of the text
  • Correction of spelling/typing errors
Date of revision of text on the SPC:   12-Feb-2018
Legal Category:   Product subject to medical prescription which may be renewed (B)

Free-text change information supplied by the pharmaceutical company



4.4       Special warnings and precautions for use

Hepatic adenomas

In rare cases benign and, in even rarer cases, malignant liver tumours leading in isolated cases to life-threatening intra-abdominal haemorrhage have been observed after the use of hormonal substances such as those contained in Cilest. Case-control studies have indicated that the risk of these tumours may increase in association with the duration of use of oral contraceptives. If severe upper abdominal complaints, liver enlargement or signs of intra-abdominal haemorrhage occur, the possibility of a liver tumour should be included in the differential diagnosis.

Other warnings

·         An increase in blood pressure has been reported in women taking oral contraceptives. Clinically relevant increases are rare. A relationship between CHC 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. Oral contraceptive therapy should be discontinued if significant persistent elevation of blood pressure (³ 160 mm Hg systolic or ³ 100 mm Hg diastolic) occurs and cannot be adequately controlled. In general, women who develop hypertension during hormonal contraceptive therapy should be switched to a non-hormonal contraceptive. If other contraceptive methods are not suitable and where considered appropriate, COC use may be resumed if normotensive values can be achieved with antihypertensive therapy., hormonal contraceptive therapy may continue, combined with antihypertensive therapy. Regular monitoring of BPblood pressure throughout hormonal contraceptive therapy is recommended. Elevated blood pressure usually returns to normal after discontinuation of oral contraceptives. Women with hypertension should have their condition under control before oral contraceptive therapy can be started.

4.5       Interaction with other medicinal products and other forms of interaction

Laboratory tests

The use of oral contraceptives may influence the results of certain laboratory tests including biochemical parameters of liver, thyroid, adrenal, and renal function, plasma levels of carrier proteins and lipid/lipoprotein fractions, parameters of carbohydrate metabolism and parameters of coagulation and fibrinolysis.

·           Increased prothrombin and factors II, VII, VIII, IX, X, XII and XIII; decreased antithrombin 3; increased norepinephrine-induced platelet aggregability.

·           Increased thyroid binding globulin (TBG) leading to increased circulating total thyroid hormone, as measured by protein-bound iodine (PBI), T4 by column or by radioimmunoassay. Free T3 resin uptake is decreased, reflecting the elevated TBG, free T4 concentration is unaltered.

·           Other binding proteins may be elevated in serum.

·           Sex hormone-binding globulins are increased and result in elevated levels of total circulating sex steroids; however, free or biologically active levels either decrease or remain unchanged

·           High-density lipoprotein (HDL-C) and total cholesterol (Total-C) may be increased, low-density lipoprotein (LDL-C) may be increased or decreased, while LDL-C/HDL-C ratio may be decreased and triglycerides may be unchanged. These effects are related to the doses of oestrogen and progestin, and to progestin type.

·           Glucose tolerance may be decreased.

Updated on 11/16/2017 and displayed until 2/14/2018
Reasons for adding or updating:
  • Change to section 4.3 - Contraindications
  • Change to section 4.4 - Special warnings and precautions for use
  • Change to section 4.5 - Interaction with other medicinal products and other forms of interaction
  • Change to section 4.8 - Undesirable effects
  • Change to section 10 - Date of revision of the text
Date of revision of text on the SPC:   15-Nov-2017
Legal Category:   Product subject to medical prescription which may be renewed (B)

Free-text change information supplied by the pharmaceutical company



4.3       Contraindications

Cilest is contraindicated for concomitant use with the medicinal products containing ombitasvir/paritaprevir/ritonavir and dasabuvir, (see sections 4.4 and section 4.5).

 

4.4       Special warnings and precautions for use

               

ALT elevations

During clinical trials with patients treated for hepatitis C virus infections (HCV) with the 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 frequent in women using ethinylestradiol-containing medications such as combined hormonal contraceptives (CHCs) (see sections 4.3 and 4.5).

 

4.5       Interaction with other medicinal products and other forms of interaction

Pharmacodynamic interactions

Concomitant use with the medicinal products containing ombitasvir/paritaprevir/ritonavir and dasabuvir, with or without ribavirin may increase the risk of ALT elevations (see sections 4.3 and 4.4).  Therefore, Cilest users must switch to an alternative method of contraception (e.g., progestagen-only contraception or non-hormonal methods) prior to starting therapy with this combination drug regimen. Cilest can be restarted 2 weeks following completion of treatment with this combination drug regimen.

 

4.8       Undesirable effects

Table A

Venous thrombosis* added as adverse event with frequency not known under ‘Vascular disorders’

* The bundled terms for venous thrombosis include Budd Chiari Syndrome and hepatic vein thrombosis.

 

Updated on 8/11/2016 and displayed until 11/16/2017
Reasons for adding or updating:
  • Change to section 4.5 - Interaction with other medicinal products and other forms of interaction
Date of revision of text on the SPC:   10-Aug-2016
Legal Category:   Product subject to medical prescription which may be renewed (B)

Free-text change information supplied by the pharmaceutical company

Section 4.5 - addition of separate management section and deletion of Antibiotics
Updated on 9/7/2015 and displayed until 8/11/2016
Reasons for adding or updating:
  • Change to section 2 - Qualitative and quantitative composition
  • Change to section 3 - Pharmaceutical form
  • Change to section 6.1 - List of excipients
  • Change to section 6.3 - Shelf life
  • Change to section 10 - Date of revision of the text
Date of revision of text on the SPC:   05-Feb-2015
Legal Category:   Product subject to medical prescription which may be renewed (B)

Free-text change information supplied by the pharmaceutical company



 NEW FORMULATION

3. PHARMACEUTICAL FORM

Film-coated tablet

Blue, round, biconvex coated tablet imprinted “0 250” on one side and “35” on the other side.


Section 6,1 List of Excipients
 
~revised excipient list

Section 6.3 Shelf Life

New shelf life 24 months (previously 12 months)

 

  

Updated on 10/16/2014 and displayed until 9/7/2015
Reasons for adding or updating:
  • Change to section 4.5 - Interaction with other medicinal products and other forms of interaction
  • Change to Section 4.8 – Undesirable effects - how to report a side effect
  • Change to section 10 - Date of revision of the text
Date of revision of text on the SPC:   15-Oct-2014
Legal Category:   Product subject to medical prescription which may be renewed (B)

Free-text change information supplied by the pharmaceutical company

section 4.5 addition in bold text:

some HCV protease inhibitors (e.g.boceprevir, telaprevir)

Physicians are advised to consult the labelling of concurrently-used drugs to obtain further information about interactions with hormonal contraceptives or the potential for enzyme alterations and the possible need to adjust dosages, advice regarding extra precautions and how long they must be used for.

Section 4.8

address and website updated to HPRA

Updated on 5/27/2014 and displayed until 10/16/2014
Reasons for adding or updating:
  • Change to section 4.1 - Therapeutic indications
  • Change to section 4.3 - Contraindications
  • Change to section 4.4 - Special warnings and precautions for use
  • Change to section 4.6 - Pregnancy and lactation
  • Change to Section 4.8 – Undesirable effects - how to report a side effect
  • Change to section 10 - Date of revision of the text
Date of revision of text on the SPC:   20-May-2014
Legal Category:   Product subject to medical prescription which may be renewed (B)

Free-text change information supplied by the pharmaceutical company

 The Ciest SPC has been updated with DVT information agreed after the conclusion Article 31 referral for Combined oral contraceptives and risks regarding deep veinthrombosis and bloosd clots
Updated on 7/19/2013 and displayed until 5/27/2014
Reasons for adding or updating:
  • Change to section 6.3 - Shelf life
  • Change to section 10 - Date of revision of the text
Date of revision of text on the SPC:   16-Jul-2013
Legal Category:   Product subject to medical prescription which may be renewed (B)

Free-text change information supplied by the pharmaceutical company


Section 6.3

           3 years  12 months
Updated on 7/16/2013 and displayed until 7/19/2013
Reasons for adding or updating:
  • Change to section 4.5 - Interaction with other medicinal products and other forms of interaction
  • Change to section 10 - Date of revision of the text
Date of revision of text on the SPC:   11-Jul-2013
Legal Category:   Product subject to medical prescription which may be renewed (B)

Free-text change information supplied by the pharmaceutical company



section 4.5,

Addition of

eslicarbazepine acetate, aprepitant and fosaprepitant,  some (combinations of) HIV protease inhibitors (e.g. nelfinavir, ritonavir, ritonavir-boosted protease inhibitors), some non-nucleoside reverse transcriptase inhibitors (e.g. nevirapine)

fosphenytoin, primidone, and rifabutin, rufinamide, some HIV protease inhibitors (e.g. atazanavir, indinavir)

some non-nucleoside reverse transcriptase inhibitors (e.g. etravirine). Selegiline, tizanidine

Updated on 8/16/2012 and displayed until 7/16/2013
Reasons for adding or updating:
  • Change to section 4.5 - Interaction with other medicinal products and other forms of interaction
  • Change to section 4.8 - Undesirable effects
  • Change to section 10 - Date of revision of the text
Date of revision of text on the SPC:   09-Aug-2012
Legal Category:   Product subject to medical prescription which may be renewed (B)

Free-text change information supplied by the pharmaceutical company

Change to section 4.5 Addition of colesevalam and etoricoxib interactions 
Change to section 4.8 Loss of libido deleted from System Organ Class SOC ‘Psychiatric  disorders’Arterial Thromboembolism , moved from SOC ‘Nervous System Disorders’ to ‘Vascular Disorders’
Change to section 10
09 August 2012
Updated on 5/5/2011 and displayed until 8/16/2012
Reasons for adding or updating:
  • Change to section 4.8 - Undesirable effects
Date of revision of text on the SPC:   21-Apr-2011
Legal Category:   Product subject to medical prescription which may be renewed (B)

Free-text change information supplied by the pharmaceutical company

The introduction has been updated

Adverse event table updated.

.
Updated on 11/23/2010 and displayed until 5/5/2011
Reasons for adding or updating:
  • Change to section 2 - Qualitative and quantitative composition
  • Change to section 9 - Date of renewal of authorisation
  • Change to section 10 - Date of revision of the text
Date of revision of text on the SPC:   29-Oct-2010
Legal Category:   Product subject to medical prescription which may be renewed (B)

Free-text change information supplied by the pharmaceutical company

Change to section 2 - Addition of: Excipients: Contains Lactose Anhydrous 89.007mg
Change to section 9 - Renewal date; 23 August 2010
Change to section 10 - Approval: 19 October 2010
Updated on 6/8/2010 and displayed until 11/23/2010
Reasons for adding or updating:
  • Change to section 4.4 - Special warnings and precautions for use
  • Change to section 4.6 - Pregnancy and lactation
  • Change to section 4.7 - Effects on ability to drive and use machines
  • Change to section 4.8 - Undesirable effects
  • Change to section 4.9 - Overdose
  • Change to section 10 - Date of revision of the text
  • Change to section 4.2 - Posology and method of administration
  • Change to section 4.3 - Contraindications
Date of revision of text on the SPC:   28-May-2010
Legal Category:   Product subject to medical prescription which may not be renewed (A)

Free-text change information supplied by the pharmaceutical company



Change to section 4.2 - Posology and method of administration

For oral administration.

Adults:

When used perfectly, without missing any pills, the chance of becoming pregnant is less than 1% (i.e. <1 pregnancy per 100 women in their first year of use). Typical failure rates are actually 5% in the first year. The chance of becoming pregnant increases with each missed pill during a menstrual cycle.

Before starting Cilest, a thorough general medical and gynaecological examination (including the breasts and a cytological smear of the cervix) if appropriate should be carried out and the family medical history carefully noted. Disturbances of menstruation, such as oligomenorrhea and amenorrhea should be investigated prior to prescription. Disturbances of the clotting mechanisms should be ruled out if any members of the family have suffered from thrombo-embolic diseases (eg deep vein thrombosis, stroke, myocardial infarction) at a young age.

Pregnancy must be excluded ideally by a pregnancy test.

The woman should be instructed to carefully read the user leaflet and to adhere to the advice given.

As a precaution, thorough medical examinations should be conducted at approximately six month intervals during use of the tablets.

Children:

Safety and efficacy of Cilest Tablets have only been established in women of reproductive age.

Elderly:

Not indicated in post menopausal women.

-          First cycle

Tablet-taking from the first pack of Cilest is started on the 1st day of the menstrual cycle, ie the first day of menstrual bleeding. If menstruation has already begun, Cilest may be commenced up to day 5 of the menstrual period, provided additional contraceptive precautions are taken for the first 7 days of tablet taking.

One tablet is to be taken at around the same time of day on each of 21 consecutive days followed by a tablet-free interval of 7 days, during which a withdrawal bleeding occurs.

-          Subsequent cycles

Tablet-taking from the next pack of Cilest is continued after the 7-day interval, beginning on the same day of the week as the first pack.

Changing from another oral contraceptive

-          Changing from a 21 day pill to Cilest:

All tablets in the old pack should be finished. The first Cilest tablet is taken the next day i.e. no gap is left between taking tablets nor does the patient need to wait for her period to begin. Additional contraceptive precautions are not required. The patient will not have a period until the end of the first Cilest pack, but this is not harmful, nor does it matter if she experiences some bleeding on tablet-taking days.

-          Changing from a combined every day pill (28 day tablets) to Cilest:

Cilest should be started after taking the last active tablet from the 'Every day Pill' pack (ie after taking 21 tablets). The first Cilest tablet is taken the next day, ie no gap is left between taking tablets nor does the patient need to wait for her period to begin. Additional contraceptive precautions are not required. Remaining tablets from the every day (ED) pack should be discarded.

The patient will not have a period until the end of the first Cilest pack, but this is not harmful, nor does it matter if she experiences some bleeding on tablet-taking days.

-          Changing from a progestogen-only pill (POP or mini pill) to Cilest:

The first Cilest tablet should be taken on the first day of the period, even if the patient has already taken a mini pill on that day. Additional contraceptive precautions are not required. All the remaining progestogen-only pills in the mini pill pack should be discarded.

If the patient is taking a mini pill, then she may not always have a period, especially when she is breast-feeding. The first Cilest tablet should be taken on the day after stopping the mini pill. All remaining pills in the mini pill packet must be discarded. Additional contraceptive precautions must be taken for the first 7 days.

Physicians are advised to refer to prescribing information for recommendations regarding switching from another form of hormonal contraception (e.g. transdermal contraceptive system, injectables etc.).

-          Irregular tablet-taking

If the patient 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 should take further tablets at the usual time.

If she is more than 12 hours late in taking any tablet, contraceptive protection may be reduced. The management of missed tablets can be guided by the following two basic rules:

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

2.  7 days of uninterrupted tablet-taking are required to attain adequate suppression of the hypothalamic-pituitary-ovarian-axis.

Accordingly the following advice can be given in daily practice:

• Week 1

The patient 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 tablets at her usual time. In addition, a barrier method such as a condom should be used for the next 7 days. If intercourse took place in the preceding 7 days, the possibility of a pregnancy should be considered. The more tablets are missed and the closer they are to the regular tablet-free interval, the higher the risk of a pregnancy.

• Week 2

The patient 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 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. 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 imminent because of the forthcoming tablet-free interval. However, by adjusting the tablet-intake schedule, reduced contraceptive protection can still be prevented. By adhering to either of the following two options, there is therefore no need to use extra contraceptive precautions, provided that in the 7 days preceding the first missed tablet the woman has taken all tablets correctly. If this is not the case, the woman should be advised to follow the first of these two options and to use extra precautions for the next 7 days as well.

1.         The patient 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 tablets at her usual time. The next pack must be started as soon as the current pack is finished, i.e. no gap should be left between packs. The patient is unlikely to have a withdrawal bleed until the end of the second pack, but she may experience spotting or breakthrough bleeding on tablet-taking days.

2.         The woman may also be advised to discontinue tablet-taking from the current pack. She should then have a tablet-free interval of up to 7 days, including the days she missed tablets, and subsequently continue with the next pack.

If the woman missed tablets and subsequently has no withdrawal bleed in the first normal tablet-free interval, the possibility of a pregnancy should be considered.

-          Postpartum

Women who choose not to breast-feed their newborn infant may start a new Cilest treatment on the first day of the first spontaneous menstruation or 3 weeks after delivery, whichever comes first.

-          Postmiscarriage

Following a miscarriage at, or before, 20 weeks gestation, oral contraception can be started immediately (day 2 but no later than 5) for immediate cover. Ovulation may occur within 10 days of miscarriage.

NB: When oral contraceptives are administered in the immediate postpartum/ postmiscarriage period, the increased risk of thrombo-embolic disease must be considered.

-   Delaying of menstruation

-          When all the tablets of the strip have been taken, a new strip can be started and tablets taken for the number of days needed. Subsequently, no tablets are taken for 7 days, followed by starting a new strip of 21 tablets with a new start day.Absence of withdrawal bleeding

If, in exceptional cases, withdrawal bleeding fails to occur, pregnancy must be ruled out before the use of Cilest is continued.

-          Procedure in the event of irregular bleeding

Breakthrough bleeding and spotting are sometimes encountered, primarily during the first three months of use, and usually cease spontaneously. The woman, therefore, should continue to use Cilest even if irregular bleeding occurs. Should break-through bleeding persist or recur, appropriate diagnostic measures to exclude an organic cause are indicated, and may include curettage.

This also applies in the case of spotting which occurs at irregular intervals in several consecutive cycles or which occurs for the first time after long use of Cilest.

-          Gastro-intestinal upset

Vomiting or diarrhoea may reduce the efficacy of oral contraceptives by preventing full absorption. If vomiting occurs within 3 hours of taking the tablet, or if severe diarrhoea lasts for more than 24 hours, the effectiveness of the contraception may not be adequate, and an additional non-hormonal method of contraception should be used until 7 tablets have been taken for 7 days without interruption. If these 7 days overrun the end of a pack, the next pack should be started without a break. In this situation, a withdrawal bleed should not be expected until the end of the second pack.

If the patient does not have a withdrawal bleed during the tablet-free interval following the end of the second pack, the possibility of pregnancy must be ruled out before resuming with the next pack. Other methods of contraception should be considered if the gastro-intestinal disorder is likely to be prolonged (ie greater than 12 hours).

 

Change to section 4.3 - Contraindications

1.      Confirmed or suspected pregnancy

2.      Patients breast feeding infants.

3.      Acute or chronic liver disease with abnormal liver function, jaundice or persistent pruritus during a previous pregnancy, Dubin-Johnson syndrome, Rotor syndrome, porphyria.

4.      Active viral hepatitis

5.      Severe cirrhosis of the liver

6.      Existing or previous arterial or venous thrombotic or embolic processes or conditions which predispose to them, eg disorders of the clotting processes, coronary artery disease, cerebrovascular disease, valvular heart disease and atrial fibrillation. Severe or multiple risk factors for venous or arterial cardiovascular disease (such as older age, smoking, diabetes and hypertension).

7.      Sickle-cell anaemia.

8.      Current or previous known or suspected oestrogen-dependent neoplasia, eg previous or existing liver tumours, cancer of the breast or endometrium.

9.      Endometrial hyperplasia

10.  Severe diabetes mellitus with vascular changes (including retinopathy, nephropathy or neuropathy), or > 20 years’ duration.

11.  Disorders of lipid metabolism. (See 4.4 Precautions and Warnings).

12.  Pemphigoid gestationis.

13.  Manifestation or deterioration of otosclerosis during pregnancy.

14.  Undiagnosed vaginal bleeding.

15.  Hypersensitivity to any of the components of Cilest.

16.  Cholelithiasis.

17.  Cholestatic jaundice of pregnancy or jaundice with prior pill use

18.  Systemic lupus erythematosus or a history of this condition.

19.  Migraine with focal aura, or without focal aura in patients aged 35 years and over.

20.  Persistent blood pressure values of ³ 160 mm Hg systolic or ³ 100 mm Hg diastolic.

21.  Smoking more than 15 cigarettes per day in patients aged 35 years or more.

22.  Known thrombogenic mutations (e.g. Factor V Leiden; Prothrombin mutation; Protein S, Protein C, and Antithrombin deficiencies).

 

Change to section 4.4 - Special warnings and precautions for use

Reasons for immediate discontinuation of medication with Cilest.

1.      Suspected or confirmed symptoms or signs of thrombophlebitis or thrombo-embolic events (eg unusual pains in or swelling of the legs).

2.      Feeling of pain and tightness in the chest (stabbing pains on breathing or coughing for no apparent reason).

3.      Occurrence for the first time, or exacerbation of migrainous headaches or development of headache with a new pattern which is recurrent, persistent or severe. Evaluation of the cause is required.

4.      Sudden disturbances of vision or hearing.

5.      Six weeks before elective surgery and during prolonged immobilisation eg after accidents, surgery.

6.      Onset of jaundice, hepatitis, itching of the whole body.

7.      Recurrence of cholestatic jaundice which occurred first during pregnancy or previous use of sex steroids.

8.      Onset or worsening of epilepsy.

9.      Significant rise in blood pressure.

10.  Onset of severe depression.

11.  Severe upper abdominal pain or liver enlargement.

12.  Pregnancy.

Patients with the following conditions should only use the oral contraceptive pill after detailed discussion with their General Practitioner. Patients with these conditions require strict medical supervision during medication:

1.      Diabetes mellitus.

2.      Varicose veins.

3.      Otosclerosis.

4.      Multiple sclerosis.

5.      Epilepsy.

6.      Tetany.

7.      Sydenham’s chorea.

8.      Renal dysfunction.

9.      Family history of breast cancer or past history of breast nodules.

10.  Fibrocystic disease of the breast.

11.  Asthma.

12.  History of clinical depression.

13.  Systemic lupus erythematosus.

14.  Uterine myoma.

15.  Migraine.

16.  Endometriosis.

17.  Conditions implicated in an increased risk of developing venous thrombo‑embolic complications, eg severe varicose veins or prolonged immobilisation or major surgery. Disorders of coagulation. Presence of any risk factor for arterial disease, such as smoking, hyperlipidemia, hypertension (persistent blood pressure values ³ 140 mm Hg systolic or ³ 90 mm Hg diastolic) and obesity. With regards to smoking, the risk of cardiovascular complications increases with age and the number of cigarettes smoked.

18.  Other conditions associated with an increased risk of circulatory disease such as latent or overt cardiac failure, renal dysfunction or a history of these conditions.

19.  A history of cholelithiasis.

20.  Concurrent administration of rifampicin or any other product known to affect liver enzymes (see section 4.5).

Deterioration in any of the above conditions may indicate that use of the oral contraceptive should be discontinued.

Oral contraceptives DO NOT protect against HIV infections (AIDS) or any other sexually transmitted disease.

In case of undiagnosed, persistent or recurrent abnormal vaginal bleeding, appropriate measures should be conducted to rule out malignancy.

Circulatory disorders

The physician should be alert to the earliest manifestations of venous and arterial thrombo‑embolic disease, ie myocardial infarction, pulmonary embolism, thrombophlebitis, stroke or retinal thrombosis.

Symptoms of venous or arterial thrombosis can include: 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; 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.

Should any of these occur or be suspected, Cilest should be discontinued immediately. The presence of one serious risk factor or multiple risk factors for venous or arterial disease, respectively, may also contribute to a contraindication.

Biochemical factors that may be indicative of hereditary or acquired predisposition for venous or arterial thrombosis include Activated Protein C (APC) resistance, hyperhomocysteinemia, antithrombin-III deficiency, protein C deficiency, protein S deficiency, antiphospholipid antibodies (anticardiolipin antibodies, lupus anticoagulant).

The physician should bear in mind the possibility of vascular accidents occurring and that there may not be full recovery from such disorders and they may be fatal.

Venous Thrombo-Embolism (VTE)

The use of combined oral contraceptives carries an increased risk of venous thrombo-embolism (VTE) compared with no use. The excess risk of VTE is highest during the first year a woman ever uses a combined oral contraceptive. The approximate occurrence of VTE in users of oral contraceptives with low oestrogen content (<50 μg ethinyl estradiol) is about 20 cases per 100,000 women-years compared to 5 to 10 cases per 100,000 women-years for non-users. 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 1 to 2% of these cases.

It is not known how Cilest influences the risk of VTE compared with other oral contraceptives.

The risk of venous thromboembolism increases with:

·         increasing age;

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

·         obesity (body mass index over 30 kg/m2)

·         prolonged immobilisation, major surgery, any surgery to the legs, or major trauma. In these situations it is advisable to discontinue COC use (in the case of elective surgery at least four weeks in advance) and not to resume until two weeks after complete remobilisation.

·         and possibly also with superficial thrombophlebitis and varicose veins. However, there is no consensus about the possible role of these conditions in the etiology of venous thromboembolism.

Arterial thrombo-embolism

The relative risk of arterial thromboses (eg stroke, myocardial infarction) is increased by the presence of other predisposing factors such as:

a)      cigarette smoking (with heavier smoking and increasing age, the risk is further increased, especially in women over 35 years of age)

b)      dyslipoproteinaemia

c)      hypertension

d)      valvular heart disease

e)      atrial fibrillation

f)       obesity

g)      diabetes

h)      history of pre-eclamptic toxaemia

i)        increasing age

j)        positive family history (i.e. arterial thrombosis ever in a sibling or parent at a relatively early age). If a hereditary predisposition is suspected, the woman should be referred to a specialist for advice before deciding about any hormonal contraceptive use.

After the age of 35 years, the physician and patients should carefully reassess the risk/benefit ratio of using combined oral contraceptives as opposed to alternative methods of contraception.

 Tumours

Studies in animals have indicated that administration of very high doses of oestrogens and/or progestogens will induce neoplastic tumours in some animal species.

Numerous epidemiological studies have been reported on the risk of ovarian, endometrial, cervical and breast cancer in women using combined oral contraceptives. The evidence is clear that combined oral contraceptives offer substantial protection against both ovarian and endometrial cancer.

Breast cancer

While there are conflicting reports, most studies suggest that use of oral contraceptives is not associated with an overall increase in the risk of developing breast cancer. Some studies have reported an increased relative risk of developing breast cancer, particularly at a younger age. This increased relative risk has been reported to be related to duration of use.

A meta-analysis of 54 epidemiological studies reports that women who are currently using combined oral contraceptives or have used them in the past 10 years are at a slightly increased risk of having breast cancer diagnosed, although the additional cancers tend to be localized to the breast. The excess risk gradually disappears during the course of the 10 years after cessation of COC use. Because breast cancer is rare in women under 40 years of age, the excess number of breast cancer diagnoses in current and recent COC users is small in relation to the overall risk of breast cancer.

It is not possible to infer from the data whether the patterns of risk observed are due to an earlier diagnosis of breast cancer in ever-users, the biological effects of hormonal contraceptives, or a combination of both factors. This meta-analysis also suggests that the age at which women discontinue the use of combined oral contraceptives is an important risk factor for breast cancer; the older the age at stopping, the more breast cancers are diagnosed. Duration of use was considered less important.

The results of recent studies in human beings suggest that there is a small but statistically increased incidence of breast cancer in women who have been treated with oestrogens. The possible increase in risk of breast cancer should be discussed with women and weighed against the benefits of combined oral contraceptives.

All women, in particular those over 35 years, should have regular breast examinations while on the pill.

Cervical cancer

An increased risk of cervical cancer in long term users of combined oral contraceptives has been reported in some studies, but there continues to be controversy about the extent to which this is attributable to the confounding effects of sexual behaviour and other factors.

Hepatic adenomas

In rare cases benign and, in even rarer cases, malignant liver tumours leading in isolated cases to life-threatening intra-abdominal haemorrhage have been observed after the use of hormonal substances such as those contained in Cilest. If severe upper abdominal complaints, liver enlargement or signs of intra-abdominal haemorrhage occur, the possibility of a liver tumour should be included in the differential diagnosis.

Chloasma

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 while taking this preparation. Chloasma is often not fully reversible.

Reduced efficacy

The efficacy of COCs may be reduced in the event of missed tablets (section 4.2), vomiting (section 4.2) or concomitant medication (section 4.5).

Herbal preparations containing St John’s Wort (Hypericum perforatum) should not be used while taking Cilest due to the risk of decreased plasma concentrations and reduced clinical effects of Cilest (see Section 4.5 Interactions).

Other warnings

·         An increase in blood pressure has been reported in women taking oral contraceptives. Clinically relevant increases are rare. A relationship between COC use and clinical hypertension has not been established. Oral contraceptive therapy should be discontinued if significant persistent elevation of blood pressure (³ 160 mm Hg systolic or ³ 100 mm Hg diastolic) occurs and cannot be adequately controlled. In general, women who develop hypertension during hormonal contraceptive therapy should be switched to a non-hormonal contraceptive. If other contraceptive methods are not suitable, hormonal contraceptive therapy may continue, combined with antihypertensive therapy. Regular monitoring of BP throughout hormonal contraceptive therapy is recommended. Elevated blood pressure usually returns to normal after discontinuation of oral contraceptives.

·         At least three months should elapse after liver function tests have returned to normal following any hepatitis before administration of the oral contraceptive pill.

·         Some women may experience amenorrhoea or oligomenorrhoea after discontinuation of oral contraceptives, especially when these conditions existed prior to use. Women should be informed of this possibility.

·         Oral contraceptives may cause a decrease in glucose tolerance. This effect has been shown to be directly related to oestrogen dose. Additionally, progestogens may increase insulin secretion and create insulin resistance, this effect varies with different progestational agents. However, in the non-diabetic woman, oral contraceptives appear to have no effect on fasting blood glucose. Because of these demonstrated effects, pre-diabetic and diabetic women in particular should be carefully monitored while taking oral contraceptives.

·         A small proportion of women will have persistent hypertriglyceridemia while on the pill. Changes in serum triglycerides, cholesterol and lipoprotein levels have been reported in users of oral contraceptives. Women with hypertriglyceridaemia, or a family history thereof, may be at an increased risk of pancreatitis when using COCs.

·         Crohn’s disease and ulcerative colitis have been associated with COC use.

·         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; otosclerosis-related hear-loss.

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

 

Change to section 4.6 - Pregnancy and lactation

Pregnancy

Cilest is contraindicated during pregnancy.

If pregnancy occurs during medication with Cilest, the preparation should be withdrawn immediately.

Epidemiological studies indicate no increased risk of congenital anomalies in children born to women who used oral contraceptives prior to pregnancy. The majority of recent epidemiological studies also do not indicate a teratogenic effect, when taken inadvertently during early pregnancy.

Lactation

The use of Cilest during lactation may lead to a reduction in the volume of milk produced and to a change in its composition. Minute amounts of the active substances are excreted with the milk.

Cilest is contraindicated during breast-feeding. A decision must be made whether to discontinue breast-feeding or to discontinue/abstain from Cilest.

 

Change to section 4.7 - Effects on ability to drive and use machines

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

Change to section 4.8 - Undesirable effects

 

Change to section 4.9 - Overdose

Overdosage may cause nausea, vomiting and, in young girls, withdrawal bleeding. Serious ill effects have not been reported following large doses of oral contraceptives in children. There are no antidotes and treatment should be symptomatic.

 

Change to section 10 - Date of revision of the text

28 May 2010

Updated on 2/9/2010 and displayed until 6/8/2010
Reasons for adding or updating:
  • Change to section 4.3 - Contraindications
  • Change to section 4.4 - Special warnings and precautions for use
  • Change to section 4.5 - Interaction with other medicinal products and other forms of interaction
  • Change to section 10 - Date of revision of the text
Date of revision of text on the SPC:   29-Jan-2010
Legal Category:   Product subject to medical prescription which may be renewed (B)

Free-text change information supplied by the pharmaceutical company



4.3

Contraindications

Revised values for hypertension and revisions of the hypertension wording

4.4

Special Warnings and Special Precautions for Use

Revised values for hypertension and revisions of the hypertension wording

4.5

Interaction with other medicinal products and other forms of interaction

·          Addition of interaction with lamotrigine

 

·          This section has been reformatted.  Two sub-sections were added in this section, “Increase in Plasma Hormone Levels Associated with Co-Administered Drugs” and “Changes in Plasma Levels of Co-Administered Drugs”.

10.

DATE OF REVISION OF THE TEXT

29-01-2010

Updated on 1/26/2009 and displayed until 2/9/2010
Reasons for adding or updating:
  • Change to section 7 - Marketing authorisation holder
  • Change to section 10 - Date of revision of the text
Date of revision of text on the SPC:   01/2009
Legal Category:   prescription only

Free-text change information supplied by the pharmaceutical company

7.

MARKETING AUTHORISATION HOLDER

New MAH Address

10.

DATE OF REVISION OF THE TEXT

16th January 2009

Updated on 11/11/2008 and displayed until 1/26/2009
Reasons for adding or updating:
  • Change to section 4.8 - Undesirable effects
  • Change to section 10 - Date of revision of the text
Date of revision of text on the SPC:   10/2008
Legal Category:   prescription only

Free-text change information supplied by the pharmaceutical company

4.8

Undesirable effects

Skin and subcutaneous tissue: seborrhea, hypertrichosis, pemphigoid (herpes gestationis), melasma which may persist, hemorrhagic eruption, urticaria, angioedema.

Eyes: change in corneal curvature (steepening), intolerance to contact lenses, cataracts, neuro-ocular lesions

CNS: chorea, severe headache

Metabolic: reduced glucose-tolerance

Urinary: impaired renal function, hemolytic uremic syndrome

During postmarketing surveillance to date no other adverse drug reactions have been reported beyond those identified within this document.

10.

DATE OF REVISION OF THE TEXT

31 October 2008

Updated on 9/12/2008 and displayed until 11/11/2008
Reasons for adding or updating:
  • Change to section 4.5 - Interaction with other medicinal products and other forms of interaction
  • Change to section 10 - Date of revision of the text
Date of revision of text on the SPC:   09/2008
Legal Category:   prescription only

Free-text change information supplied by the pharmaceutical company

Change to section 4.5 - Addition of bosentan to interactions list
Change to section 10 - 03 September 2008
Updated on 3/29/2007 and displayed until 9/12/2008
Reasons for adding or updating:
  • Change to section 4.2 - Posology and method of administration
  • Change to section 4.3 - Contraindications
  • Change to section 4.4 - Special warnings and precautions for use
  • Change to section 4.5 - Interaction with other medicinal products and other forms of interaction
  • Change to section 4.6 - Pregnancy and lactation
  • Change to section 4.8 - Undesirable effects
  • Change to section 5 - Pharmacological properties
  • Change to section 5.2 - Pharmacokinetic properties
  • Change to section 5.3 - Preclinical safety data
  • Change to section 9 - Date of renewal of authorisation
  • Change to section 10 - Date of revision of the text
  • Change to separate SPCs covering individual presentations
Date of revision of text on the SPC:   03/2007
Legal Category:   prescription only

Free-text change information supplied by the pharmaceutical company

Change to section 4.2 – Posology and |Method of Administration

CCDS updates

Change to section 4.3 – Contra-indications

CCDS updates

Change to section 4.4 – Special Warnings and Precautions for Use

CCDS updates

Change to section 4.5 –Interaction with other medicinal products and other forms of interaction

CCDS updates

Change to section 4.6 – Pregnancy and Lactation

CCDS updates

Change to section 4.8 – Undesirable effects

CCDS updates

Change to section 5.1 - Pharmacodynamic properties

CCDS updates

Change to section 5.2 - Pharmacokinetic properties

CCDS updates

Change to section 5.3 - Preclinical Safety Data

CCDS updates

Change to section 9 – Date of Renewal of Authorisation

CCDS updates

Change to section 10 – Date of revision of text

Change to march 2007

Change of separate SPCs covering individual presentations

CCDS updates

Updated on 2/7/2007 and displayed until 3/29/2007
Reasons for adding or updating:
  • Change to section 1 - Name of medicinal product
  • Change to section 2 - Qualitative and quantitative composition
  • Change to section 3 - Pharmaceutical form
  • Change to section 6.4 - Special precautions for storage
  • Change to section 6.5 - Nature and contents of container
  • Change to section 6.6 - Special precautions for disposal and other handling
  • Change to section 10 - Date of revision of the text
  • Change to separate SPCs covering individual presentations
Date of revision of text on the SPC:   01/2007
Legal Category:   prescription only

Free-text change information supplied by the pharmaceutical company

Change to section 1 - Cilest 250/35 microgram tablets (from Cilest oral contraceptive tablets)
Change to section 2 - Addition of quantitative composition (250 micrograms norgestimate & 35 micrograms ethinylestradiol) and cross-reference to section 6.1 for excipients.
Change to section 3 - Addition of pharmaceutical form ‘tablet’.
Change to section 6.4 - Update to include statement: ‘Store blister in outer carton’
Change to section 6.5 - Addition of statement ‘not all pack sizes may be marketed’
Change to section 6.6 - Addition of standard statement ‘No special requirements’
Change to section 10 - Change to date of revision of the text to ‘January 2007’
 
Updated on 12/17/2004 and displayed until 2/7/2007
Reasons for adding or updating:
  • Change to section 4.3 - Contraindications
  • Change to section 4.4 - Special warnings and precautions for use
  • Change to section 4.8 - Undesirable effects
  • Change to section 10 - Date of revision of the text
Updated on 6/5/2003 and displayed until 12/17/2004
Reasons for adding or updating:
  • New SPC for medicines.ie

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Active Ingredients

 
   Ethinylestradiol
   Norgestimate