1. Name Of The Medicinal Product
Cilest
2. Qualitative And Quantitative Composition
Cilest are tablets for oral administration.
Each tablet contains norgestimate 0.25 mg and ethinylestradiol PhEur 0.035 mg.
3. Pharmaceutical Form
Tablets (small, round, dark blue, engraved 'C 250' on both faces).
4. Clinical Particulars
4.1 Therapeutic Indications
Contraception and the recognised indications for such oestrogen/progestogen combinations.
4.2 Posology And Method Of Administration
For oral administration.
4.2.1 Adults
How to take Cilest
One tablet is taken daily at the same time (preferably in the evening) without interruption for 21 days, followed by a break of 7 tablet-free days. Each subsequent pack is started after the 7 tablet-free days have elapsed. Additional contraceptive precautions are not then required. During the tablet-free period, bleeding can be expected, usually beginning 2 to 4 days after the last tablet.
Starting treatment
It is preferable that tablet intake from the first pack is started up to and including day 5 of menstruation in which case no extra contraceptive precautions are necessary.
Cilest can be started at any other time, if pregnancy can reasonably be excluded. In this case additional contraceptive precautions must be taken for the first 7 days of tablet taking
Switching from another contraceptive
Hormonal methods: Cilest can be started immediately if the patient has been using the current hormonal method consistently and correctly, or if pregnancy can reasonably be excluded. There is no need to wait for the next menstruation. Additional contraceptive precautions are not required.
Non-hormonal methods: If Cilest is started after the first 5 days of menstruation, additional contraceptive precautions are required for the next 7 days.
Post-partum administration
Following a vaginal delivery, oral contraceptive administration to non-breast-feeding mothers can be started 21 days post-partum provided the patient is fully ambulant and there are no puerperal complications. No additional contraceptive precautions are required. If post-partum administration begins more than 21 days after delivery, additional contraceptive precautions are required for the first 7 days of pill-taking.
If intercourse has taken place post-partum, oral contraceptive use should be delayed until the first day of the first menstrual period.
For information on breast-feeding mothers, see sections 4.3, 4.4 and 4.6.
Use after Abortion or Miscarriage
After an abortion or miscarriage that occurs prior to 24 weeks gestation, oral contraceptives can be started immediately. An additional method of contraception is not needed.
After an induced or spontaneous abortion that occurs at or after 24 weeks gestation, hormonal contraceptives may be started either on Day 21 post-abortion or on the first day of the first spontaneous menstruation, whichever comes first. No additional contraceptive precautions are required.
To skip a period
To skip a period, a new pack of Cilest should be started on the day after finishing the current pack (the patient skips the tablet-free days). Tablet-taking should be continued in the usual way.
During the use of the second pack she may experience slight spotting or break-through bleeding but contraceptive protection will not be diminished provided there are no tablet omissions.
The next pack of Cilest is started after the usual 7 tablet-free days, regardless of whether the period has completely finished or not.
Reduced reliability
When Cilest is taken according to the directions for use, the occurrence of pregnancy is highly unlikely. However, the reliability of oral contraceptives may be reduced under the following circumstances:
(i) Missed tablets
If the patient forgets to take one tablet or if a new strip is started one day late, she should take it as soon as she remembers and take the next one at the normal time. This may mean that two tablets are taken in one day. No additional contraceptive precautions are required. If more than one tablet is missed or if a new strip is started more than one day late, she should take the last missed tablet as soon as she remembers but leave the other missed tablets in the strip. She should continue to take the rest of the strip as usual but must use extra precautions (eg condom, diaphragm, plus spermicide) for the next 7 days.
If the tablets are missed:
• In week 1
If unprotected sex has taken place, the use of emergency contraception should be considered. The usual 7-day break can be left before starting the next strip.
• In week 2
The usual 7-day break can be left before starting the next strip.
• In week 3
When the strip is finished the next strip should be started the next day without a break. If withdrawal bleeding does not occur at the end of the second strip, a pregnancy test should be performed.
(ii) Vomiting or diarrhoea
If a patient vomits within two hours of taking a tablet she should take another tablet from a spare strip.
If severe vomiting or diarrhoea continues for more than one day, she should follow the procedure for missed tablets (and continue taking the tablets if she can).
4.2.2. Elderly:
Use of this product is not indicated in post-menopausal women.
4.2.3. Children:
Use of this product before menarche is not indicated
4.3 Contraindications
− Breast-feeding mothers less than 6 weeks post-partum
− Venous thrombo-embolism (VTE) requiring concurrent anticoagulant therapy, personal history of confirmed VTE or known thrombogenic mutations.
− Major surgery with prolonged immobilisation.
− Moderate to severe hypertension (systolic
− Complicated valvular and congenital heart disease (e.g. with pulmonary hypertension, artrial fibrillation, history of subacute bacterial endocarditis)
− Migraine with focal aura.
− Diabetes with nephropathy/retinopathy/neuropathy or other vascular involvement or > 20 years' duration.
− Smoking 15 or more cigarettes per day in patients aged 35 years or more.
− Acute or chronic liver disease, including hepatitis (viral or non-viral) or severe cirrhosis, or a history of these conditions until at least 3 months after abnormal liver function tests have returned to normal; hepatic adenomas or carcinomas;.
− Known or suspected carcinoma of the breast.
− Raynaud's disease, with Systemic Lupus Erythematosus (SLE) if lupus anticoagulant is present.
− Hypersensitivity to norgestimate or ethinylestradiol or to any of the excipients.
Should any of these conditions occur for the first time during use of Cilest, the tablets should be discontinued immediately.
4.4 Special Warnings And Precautions For Use
Assessment of women prior to starting oral contraceptives (and at regular intervals thereafter) should include a personal and family medical history of each woman. Physical examination should be guided by this and by the contraindications (Section 4.3) and warnings for this product. The frequency and nature of these assessments should be based upon relevant guidelines and should be adapted to the individual woman, but should include measurement of blood pressure and, if judged appropriate by the clinician, breast, abdominal and pelvic examination including cervical cytology.
Exclude likelihood of pregnancy before starting treatment.
Undiagnosed vaginal bleeding should be investigated further.
Oral contraceptives DO NOT protect against HIV infections (AIDS) or any other sexually transmitted disease.
Conditions requiring supervision:
The theoretical or proven risks usually outweigh the advantages of using Combined Oral Contraceptives (COCs) in the conditions listed below. Consequently the decision to prescribe the COC must be made with specialist clinical judgement and in consultation with the individual patient. If any of these conditions appears for the first time, or is aggravated, whilst the patient is taking Cilest, consideration should be given to discontinuing its use.
− Non-breast-feeding mothers less than 21 days post-partum.
− Breast-feeding mothers 6 weeks to 6 months post-partum.
− Increased risk of venous thrombo-embolic disorders (See “Circulatory disorders” below).
− Presence of multiple risk factors for arterial disease (See “Circulatory disorders” below).
− Adequately controlled hypertension (persistently elevated baseline systolic values 140-159 mm Hg or diastolic values 90-94 mm Hg)
− Obesity (BMI 2)
− Past history (
− History of cholestasis (related to COCs), current or medically treated gall bladder disease, porphyria.
− History of breast cancer, 5 years disease-free.
− Diabetes mellitus with mild nephropathy, neuropathy or retinopathy.
Circulatory disorders
Venous Thrombo-Embolism (VTE)
The use of any Combined Oral Contraceptives (COCs) carries an increased risk for venous thrombo-embolism (VTE), including deep venous thrombosis and pulmonary embolism, compared with no use. The excess risk of VTE is highest during the first year a woman ever uses a COC. This increased risk is less than the risk of VTE associated with pregnancy, which is estimated as 60 per 100,000 pregnancies. VTE is fatal in 1-2% of cases.
It is not known how Cilest influences the risk of VTE compared with other COCs.
However, epidemiological studies have shown that the incidence of VTE in users of oral contraceptives with low oestrogen content (<50 μg ethinyl estradiol) ranges from about 20-40 cases per 100,000 women years, but this risk estimate varies according to the progestogen. This compares with 5-10 cases per 100,000 women years for non-users.
The risk of venous thrombo-embolism increases with
− Increasing age
− Family history (VTE in first degree relative less than 45 years of age)
− Obesity (BMI 2)
− Prolonged immobilisation, major surgery, any surgery to the legs, major trauma. Hormonal contraception should be discontinued 4-6 weeks before elective surgery and not recommenced until two weeks after complete remobilisation. In case of emergency surgery, thrombotic prophylaxis is usually indicated e.g. with subcutaneous heparin.
There is no consensus about the role of varicose veins in VTE.
Symptoms of venous thrombotic or thrombo-embolic events can include:
• unusual unilateral leg pain and/or redness and swelling, typically of the calf
• sudden breathlessness or onset of coughing
• sudden partial or complete loss of vision.
Arterial thrombo-embolism
Epidemiological studies have also associated the use of COCs with an increased risk for arterial thrombo-embolism (e.g. myocardial infarction, transient ischaemic attack or stroke). This increased risk is likely to be extremely small in women who do not smoke and who do not have other risk factors of arterial thrombo-embolic complications (see below).
The risk of arterial thrombo-embolic complications increases with:
− Increasing age
− Smoking. The risk increases with age and with heavy smoking and is more marked in women over 35 years of age. Women who use oral contraceptives should be strongly advised not to smoke.
− Obesity (BMI 2)
− Hyperlipidaemia
− Hypertension or a history of hypertension
− Valvular heart disease
− Atrial fibrillation
− Family history of arterial thrombo-embolic complications
− Diabetes mellitus
− Sickle cell haemoglobinopathy.
Symptoms of an arterial or cerebrovascular event can include:
• sudden severe pain in the chest, whether or not it radiates to the left arm
• any unusual, severe, prolonged headache, especially if it occurs for the first time or gets progressively worse
• diplopia or sudden partial or complete loss of vision
• slurred speech or aphasia
• weakness or very marked numbness suddenly affecting one side or one part of the body
• collapse with or without focal seizure, motor disturbances, vertigo.
Hepatic adenomas
Malignant hepatic tumours have been reported on rare occasions in long-term users of oral contraceptives. Benign hepatic tumours have also been associated with oral contraceptive usage. A hepatic tumour should be considered in the differential diagnosis when upper abdominal pain, enlarged liver or signs of intra-abdominal haemorrhage occur. In isolated cases, life-threatening intra-abdominal haemorrhage may occur.
Breast cancer
A meta-analysis from 54 epidemiological studies reported that there is a slightly increased relative risk (RR = 1.24) of having breast cancer diagnosed in women who are currently using COCs. The observed pattern of increased risk may be due to an earlier diagnosis of breast cancer in COC users, the biological effects of COCs or a combination of both. The additional breast cancers diagnosed in current users of COCs or in women who have used COCs in the last 10 years are more likely to be localised to the breast than those in women who never used COCs.
Breast cancer is rare among women under 40 years of age whether or not they take COCs. Whilst this background risk increases with 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 (see bar chart).
The most important risk factor for breast cancer in COC users is the age women discontinue the COC; the older the age at stopping, the more breast cancers are diagnosed. Duration of use is less important and the excess risk gradually disappears during the course of the 10 years after stopping COC use such that by 10 years there appears to be no excess.
The possible increase in risk of breast cancer should be discussed with the user and weighed against the benefits of COCs taking into account the evidence that they offer substantial protection against the risk of developing certain other cancers (e.g. ovarian and endometrial cancer).
Cervical cancer
The most important risk factor for cervical cancer is persistent Human Papilloma Virus (HPV) infection. Some epidemiological studies have indicated that long-term use of COCs may further contribute to this increased risk but there continues to be controversy about the extent to which this finding is attributable to confounding effects, e.g. cervical screening and sexual behaviour including use of barrier contraceptives.
There is some theoretical concern that COCs enhance progression of Cervical Intraepithelial Neoplasia (CIN) to invasive disease. For women with diagnosed cervical cancer, COCs may be used whilst awaiting treatment.
Other tumours
Numerous epidemiological studies have been reported on the risk of ovarian and endometrial cancer in women using COCs. The evidence is clear that COCs offer substantial protection against both ovarian and endometrial cancer.
Bleeding irregularities
Breakthrough bleeding, spotting and/or absence of withdrawal flow may be encountered in patients on oral contraceptives, especially during the first three months of use.
If bleeding irregularities persist beyond three cycles or occur after previously regular cycles, non-hormonal causes should be considered and adequate diagnostic measures are indicated to exclude malignancy or pregnancy.
Some woman may experience post-pill amenorrhoea or oligomenorrhoea, especially when such a condition was pre-existing.
Laboratory tests
In the literature, at least a hundred different laboratory test parameters have been reported to be possibly influenced by oral contraceptive use, predominantly by the oestrogenic component. Among these are: biochemical parameters of the liver, thyroid, adrenal and renal function, plasma levels of (carrier) proteins and lipid/lipoprotein fractions and parameters of coagulation and fibrinolysis.
Other conditions
In the following conditions the benefit of oral contraception generally outweighs the theoretical or known risk. However, they may need to be considered before prescribing to individual patients:
• Known hyperlipidaemias. A small proportion of women will have persistent hypertriglyceridemia while on the pill. Changes in serum triglycerides and lipoprotein levels have been reported in oral contraceptive users. However, routine screening of women with hypertriglyceridaemia is not considered appropriate.
• Diabetes without vascular involvement (although all patients with diabetes are at increased risk of arterial disease).
• Decreased glucose tolerance. The oestrogen component of Cilest may cause a decrease in glucose tolerance, while the progestogens may increase insulin secretion and create insulin resistance. Because of these demonstrated effects, pre-diabetic and diabetic women in particular should be carefully monitored while taking oral contraceptives.
• Asymptomatic gall bladder disease or cholecystectomy.
• Benign liver tumours (focal nodular hyperplasia). There is limited, direct evidence that hormonal contraceptive use does not influence either progression or regression of liver lesions among women with focal nodular hyperplasia.
• Migraine without focal aura . The onset or exacerbation of migraine or development of headache with a new pattern which is recurrent, persistent or severe requires discontinuation of oral contraceptives and evaluation of the cause.
If any of the following conditions developed or worsened during a prior pregnancy or during previous COC use, they may occur while taking Cilest:
• elevated blood pressure
• cholestasis
• herpes gestationis
• otosclerosis
• SLE
• severe headaches.
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 whilst taking this preparation. Chloasma is often not fully reversible.
Additional contraceptive precautions
When additional contraceptive precautions are required, the patient should be advised either not to have sex, or to use a cap plus spermicide or for her partner to use a condom. Rhythm methods should not be advised as the pill disrupts the usual cyclical changes associated with the natural menstrual cycle, eg changes in temperature and cervical mucus.
Excipients
The tablets contain lactose. Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicine.
4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction
Potential Reduction in Contraceptive Effectiveness Associated With Co-Administration of Other Drugs:
Hepatic enzyme inducers
Drugs or herbal products that induce enzymes, especially CYP3A4, may decrease the plasma concentrations of contraceptive hormones, and may decrease their effectiveness and/or increase breakthrough bleeding.
Examples include:
• barbiturates
• bosentan
• carbamazepine
• felbamate
• hydantoins
• primidone
• griseofulvin
• some HIV protease inhibitors (e.g. ritonavir)
• modafinil
• some non-nucleoside reverse transcriptase inhibitors (e.g. nevirapine)
• oxcarbazepine
• phenytoin
• rifampicin and rifabutin
• St. John's Wort
• topiramate
Antibacterial drugs that are not enzyme inducers
There have been reports of pregnancy while taking hormonal contraceptives and antibiotics, but clinical pharmacokinetic studies have not shown consistent effects of antibiotics (eg ampicillin and tetracyclines) on plasma concentrations of synthetic steroids.
Drugs that affect absorption
Drugs that increase gastrointestinal motility, e.g. metoclopramide, may reduce hormone absorption.
Treatment with activated charcoal will compromise absorption of steroid hormones.
Management
For women on long-term treatment with drugs and herbal products that interact with hormonal contraception, another reliable, non-hormonal method of contraception is recommended.
Women on short-term treatment with drugs and herbal products that interact with hormonal contraception and may decrease plasma levels of contraceptive hormones could have their contraceptive effectiveness reduced. They should be advised to use a barrier contraceptive method (e.g. condoms, diaphragm) in addition to Cilest as follows:
• Women using liver enzyme-inducing drugs should temporarily use a barrier contraceptive method in addition to Cilest during the time of concomitant medicinal product administration and for 28 days after their discontinuation.
• In the case of modafinil, use of a barrier contraceptive method should continue for 56 days after discontinuation.
If discontinuation of the concomitant medicinal product occurs in week three or runs beyond the end of the tablets in the strip, the next strip should be started without a break.
Changes in Plasma Levels of Co-Administered Drugs that may be of Clinical Significance:
Combination hormonal contraceptives may also affect the pharmacokinetics of some other drugs if used concomitantly.
Drugs whose plasma levels may be increased (due to CYP inhibition)
Examples include:
• ciclosporin
• prednisolone
• theophylline
Drugs whose plasma levels may be decreased (due to induction of glucuronidation)
Examples include:
• lamotrigine
Management
Physicians are advised to consult the labelling of concurrently-used drugs to obtain further information about interactions with hormonal contraceptives and the possible need to adjust dosages.
4.6 Pregnancy And Lactation
4.6.1. Use during pregnancy
Not indicated during pregnancy. Confirm suspected pregnancy before discontinuing treatment.
The majority of recent studies do not indicate a teratogenic effect, particularly in so far as cardiac anomalies and limb reduction defects are concerned, when taken inadvertently during early pregnancy.
4.6.2. Use during lactation
Contraceptive steroids and/or their metabolites may be excreted in breast milk.
The use of COCs is contraindicated for breast-feeding mothers less than 6 weeks post-partum (see section 4.3) and should be used with clinical judgement for breast-feeding mothers between 6 weeks and 6 months post-partum (see section 4.4).
Mothers who are breast-feeding should be advised not to use the combined pill since this may reduce the amount of breast-milk, but may be advised instead to use a progestogen-only pill (POP).
4.7 Effects On Ability To Drive And Use Machines
Not applicable.
4.8 Undesirable Effects
Certain adverse drug reactions (ADRs) that have been associated with oral contraceptive use may require immediate medical attention and/or cessation of oral contraceptive use. These ADRs include: myocardial infarction, deep venous thrombosis, pulmonary embolism, cerebrovascular accidents, retinal vein thrombosis, new onset of migraine -type headache , breast cancer, hepatic tumours adenomas, high blood pressure, angioedema, urticaria and hypersensitivity.
Alternative non-hormonal methods of contraception should be used, while appropriate diagnostic and therapeutic measures are undertaken.
Based on pooled safety data from 5 clinical trials, the most commonly reported (
The most common ADRs (
The 5 clinical trials (2 randomised active-controlled trials and 3 uncontrolled open-label trials), which were used to evaluate the safety of Cilest, included 1,891 healthy women of child bearing potential. In 3 trials, subjects were followed for up to 24 cycles and in the other 2 trials for up to 12 cycles. An additional uncontrolled study (n=8,331) reported ADRs by treatment cycle for up to 24 cycles. As the frequency of ADRs vary according to the cycle of treatment, the highest cycle incidence has been used to assign the ADR to a frequency category.
The table below displays all ADRs that have been reported with the use of Cilest in clinical trials or from post marketing experiences with norgestimate and ethinyl estradiol tablets.
The displayed frequency categories use the following convention: Very common (>1/10); common (>1/100 to <1/10); uncommon (>1/1,000 to <1/100); rare (>1/10,000 to <1/1,000); very rare (<1/10,000); and not known (cannot be estimated from the available data).
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* Not seen in clinical trials therefore frequency cannot be estimated. See section 4.4 for frequency based on standard reporting rates for similar combined hormonal contraceptives.
4.9 Overdose
There have been no reports of serious ill-health from overdosage.. Symptoms that may occur are nausea, vomiting and vaginal bleeding There are no antidotes and further treatment should be symptomatic.
5. Pharmacological Properties
5.1 Pharmacodynamic Properties
Pharmacotherapeutic Group: Hormonal Contraceptives for Systemic Use; Progestogens and estrogens, fixed combinations
ATC Code: G03AA11
Cilest acts through the mechanism of gonadotrophin suppression by the oestrogenic and progestational actions of ethinylestradiol and norgestimate. The primary mechanism of action is inhibition of ovulation, but alterations to the cervical mucus, the fallopian tube motility and to the endometrium may also contribute to the efficacy of the product.
5.2 Pharmacokinetic Properties
Absorption: Norgestimate and ethinyl estradiol are rapidly absorbed following oral administration. Following single or multiple (three cycles) administration of Cilest, serum concentrations of norgestimate remain below the quantitation limit of the assay (0.1 ng/mL) metabolites of norgestimate, norelgestromin and norgestrel, are found in measurable concentrations in circulation, reaching maximal serum levels approximately 1.5 hours post-dose. Increase in Cmax and AUC for norelgestromin are proportional to dose after administration of 0.180 to 0.250 mg of norgestimate. Ethinyl estradiol serum concentrations are measurable within 0.5 hours of dosing, reaching peak levels approximately 1.2 hours post-dose.
Distribution: Norelgestromin and norgestrel are highly bound (>97%) to serum proteins. Norelgestromin is bound to albumin but not to SHBG, while norgestrel is bound primarily to SHBG and to a much lesser extent to albumin. Ethinyl estradiol is extensively bound to serum albumin.
Studies have shown that the lack of binding of norelgestromin to SHBG is unique when compared to other progestogens in oral contraceptives and plays a key role in enhancing its biological activity. In contrast, norgestrel formed from norgestimate is largely bound to SHBG, which limits its biological activity.
Metabolism: Norgestimate is rapidly metabolised by first-pass (intestinal and/or hepatic) mechanisms to norelgestromin (peak serum concentrations observed within 2 hours) and norgestrel, both of which are pharmacologically active progestogens. Ethinyl estradiol is metabolised to various hydroxylated metabolites and their glucuronide and sulfate conjugates.
Elimination: Both norelgestromin and norgestrel, and ethinyl estradiol are subsequently metabolised and their metabolites are eliminated by renal and faecal pathways. Elimination half-life values at steady-state were 10 to 15 hours for ethinyl estradiol, 24.9 hours for norelgestromin and 45 hours for norgestrel. Following administration of 14C-norgestimate, 47% of the administered radioactivity was eliminated in the urine and 37% in the faeces.
Steady-State Pharmacokinetics: Following administration of 0.250 mg norgestimate /0.035 mg ethinyl estradiol, the mean AUC 0-24h at steady-state, based on non-SHBG bound serum levels, was 18.1 h ng/mL for norelgestromin and 3.64 h ng/mL for norgestrel. The AUC for norgestrel following administration of 0.250 mg norgestimate /0.035 mg ethinyl estradiol, corresponds to the exposure after a levonorgestrel dose of approximately 30 micrograms in combination with ethinyl estradiol.
5.3 Preclinical Safety Data
The toxicology of norgestimate and ethinylestradiol has been extensively investigated in animal studies and through long term clinical experience with widespread use in contraceptives.
6. Pharmaceutical Particulars
6.1 List Of Excipients
Lactose (anhydrous)
Magnesium Stearate
Pregelatinised Starch
F.D. & C. Blue No. 2 Lake
Methanol (does not appear in final product)
6.2 Incompatibilities
Not applicable.
6.3 Shelf Life
Three years.
6.4 Special Precautions For Storage
Store at room temperature (below 25°C). Protect from light.
6.5 Nature And Contents Of Container
Cartons containing 1 (Starter Pack), 3 and 6 PVC/foil blister strips of 21 tablets each.
6.6 Special Precautions For Disposal And Other Handling
Not applicable.
7. Marketing Authorisation Holder
Janssen-Cilag Limited
50 -100 Holmers Farm Way
High Wycombe
Buckinghamshire
HP12 4EG
UK
8. Marketing Authorisation Number(S)
PL 00242/0209
9. Date Of First Authorisation/Renewal Of The Authorisation
1 July 1995 / 7 January 2009
10. Date Of Revision Of The Text
28 June 2011
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