MERCILON 28

Desogestrel plus ethinyloestradiol

Presentation

Each pack MERCILON 28 consists of:

• 21 large (6mm diameter), white, round biconvex tablets coded TR/4 on one side and ORGANON and a star on the other side, and containing desogestrel (a progestagen) 0.15mg, ethinyloestradiol (an oestrogen) 0.02mg.
• 7 small (4.5mm diameter), white, round, flat tablets with bevelled edges, coded KH/2 on one side and a square on the other side, and containing no active ingredients.

Uses

ACTIONS

MERCILON 28 is a combined oral contraceptive preparation for continuous administration containing as active substances the oestrogen ethinyloestradiol and the progestagen desogestrel. Clinical studies have revealed that the oral contraceptive preparations containing ethinyloestradiol and desogestrel lack undesirable metabolic effects. These effects are thought to result from the androgenic activity of some progestagens in oral contraceptives. Because of this, MERCILON 28 may have a favourable effect on androgen-related skin disorders such as acne and hirsutism.

When taken according to the recommended dosage scheme MERCILON 28 suppresses the hypophyseal gonadal function and thereby ovulation. In addition, it induces a regular uterine bleeding which, with respect to amount of flow and duration, resembles a normal menstrual bleeding. Usually this bleeding starts two or three days after the intake of the last active tablet and is painless. In clinical trials, MERCILON 28 showed a very low pregnancy rate, a good cycle control, a low incidence of side-effects and, as a result, a low drop-out rate.

PHARMACOKINETICS

Ethinyloestradiol

Absorption: Ethinyloestradiol (EE) is rapidly and completely absorbed from the intestine with an absorption half-life of 0.2-0.4 hours. After oral administration of 50 mcg EE, the plasma peak time was approximately 1-2 hours, whereas plasma peak height amounted to 0.12 ± 0.03 mcg/l and the area under curve to 1048 ± 247 pg/ml/h. With EE, a great inter- and intra-population variability of plasma levels has been reported. As a result of gut wall metabolism during absorption and the effect of first-pass metabolism, the absolute bioavailability of EE after single-dose administration is approx. 45%. The absolute bioavailability of EE calculated on the basis of repeated measurements after administration of DSG (desogestrel)/EE 150/30 mcg/d for 21 days is 74 ± 25%. The reason for this figure being higher than the average figure of 45% mentioned above, probably has to do with the fact that the former figure is based on single-dose administration and single measurements. A possible explanation for the higher absolute bioavailability of EE upon repeated measurements could be an influence on hepatic enzyme systems.

Distribution: After absorption there is a rapid distribution of EE over the body, with a volume of distribution of 3.8 l/kg, whereas the distribution half-life amounts to 0.5-2.5 hrs. Plasma protein binding with EE and its metabolites is almost completely (± 95%), mainly to albumin.

Metabolism: EE is subject to a significant degree of presystemic conjugation in both the small bowel mucosa (the major metabolite being EE-3-sulphate) and the liver. EE escaping gut wall conjugation undergoes hepatic conjugation and phase I metabolism (oxidation, reduction or hydrolysis).

Sulphate and glucuronide conjugates of both EE (direct conjugates) and phase I metabolites, which are excreted in bile, can undergo hydrolysis by gut flora. Hydrolysis of the direct conjugates yields EE which can be reabsorbed, thus producing an enterohepatic circulation.

Whether the enterohepatic circulation of EE contributes significantly to plasma concentration and hence to therapeutic effect in most women is not known. The metabolic pathways of EE are of two general types, hydroxylation, being the principal route, and in addition, although to a very minor extent, modification of the ethinylgroup. The principal hydroxylated metabolites of EE are, in order of importance respectively, the catechol oestrogen 2-hydroxy(OH)-EE and the catechol 2-methoxy-EE, whereas in addition small amounts of both 6alpha-OH-EE and 16B-OH-EE have been identified. 2-OH-EE is further metabolised to chemically reactive metabolites, probably o-quinone/o-semi-quinones, which can bind irreversibly to protein.

Elimination: EE disappears from the plasma in an elimination phase with a half-life of 13-27 hours. The excretion of conjugates of EE and its metabolites is via the urine and with the faeces (ratio 1:1.5).

Reports on the time after which steady state conditions are reached reflect great differences: 3-4 days (no specific preparation mentioned); 7 days triphasic LNG (levonorgestrel)/EE; 10-13 days (DSG/EE 150/30 mcg/d).

Desogestrel

Absorption: After oral administration, desogestrel (DSG) is rapidly and almost completely absorbed (most probably from the duodenum), with an absorption half-life of 0.2 hours (range 0.1-0.4 h). During phase I metabolism DSG is almost completely converted in the body, mainly into the pharmacologically active metabolite 3-ketodesogestrel (3K-DSG). After oral administration of 150 mcg DSG + 30 mcg EE the plasma peak time of 3K-DSG was 1.8 ± 0.8 h whereas peak height amounted to 6.4 ± 3.7 mcg/l. The mean serum level of 3K-DSG 12 hours after dosing was 1.4 ± 0.5 mcg/l and the mean area under curve was 45.5 ± 24.4 mcg/h/l. There was, however, a great inter-individual variability of the plasma levels, a well-known phenomenon with progestagens.

Abovementioned parameters point to a high first pass metabolism of DSG and indicate that the relative bioavailability of the agent is comparable to that of 3K-DSG. The absolute bioavailability of 3K-DSG after single dose administration is about 76 ± 23% and during steady-state conditions 81 ± 27%.

Distribution: The distribution half-life of 3K-DSG in women is ± 1.4 hours (range 1.1-1.8 hrs). Plasma protein binding of 3K-DSG and its metabolites in clinical and experimental studies is almost complete (98%), mainly to albumin.

Metabolism: Studies in female volunteers with radioactive-labelled desogestrel show that the compound is completely metabolized. Phase I metabolism (biotransformation), which is rapid, includes hydroxylation of the C3-atom, whereby 3-alpha and 3-beta hydroxy-DSG are formed, which are subsequently dehydrogenized into 3K-DSG. There is no indication for the biotransformation of the 11-methylene-group. Hydroxylation and dehydrogenation are normal metabolic processes in the liver. The rapid biotransformation indicates that this process does not constitute a burden to the liver. The active metabolite 3K-DSG is further reduced to 3-alpha-OH-5-alpha-H-DSG via 3K-5-alpha-H-DSG.

Subsequently, these degradation products are partly converted into polar metabolites by conjugation into sulphates and glucuronides. Enterohepatic circulation is not of importance for the progestagenic activity of desogestrel, since only some inactive metabolites undergo this pathway.

Elimination: 3K-DSG disappears from the plasma in an elimination phase with a half-life of 21 hrs (range 16-29 hrs). The excretion of DSG and its metabolites is via the urine and with the faeces, the ratio being 1.5:1. As a result of the pharmacokinetic properties of desogestrel, steady-state conditions (no further increase in plasma concentration) are reached within 10 days of daily administration. Based on both steady state and excretion data, it can be assumed that there is no accumulation of the drug in the body.

Indications

• Oral contraception.
• Dosage And Administration

The first tablet of the first pack is taken on the first day of menstruation. This also applies when changing over from another brand of oral contraceptive. One tablet is taken daily at the same time, without interruption for 28 days. If the first day of menstruation falls on a Thursday or Friday additional contraceptive precautions are necessary until 7 of the (larger) hormone tablets have been taken on consecutive days. Subsequent packs should be started one after the other, without tablet-free interval.

After delivery administration can be started on the first day of the first spontaneous menstruation. If it is necessary to start earlier, e.g. immediately after delivery, additional contraceptive precautions are necessary until 7 of the (larger) hormone tablets have been taken on consecutive days. If the first day of menstruation falls on a Thursday or Friday additional contraceptive precautions are necessary until 7 of the (larger) hormone tablets have been taken on consecutive days.

After a miscarriage or abortion administration should start immediately. In this way no additional contraceptive precautions are required. If the first day of tablet intake falls on a Thursday or Friday additional contraceptive precautions are necessary until 7 of the (larger) hormone tablets have been taken on consecutive days.

N.B. Additional information on directions for use, changing from another oral contraceptive, missed tablets, delay of menstruation, etc. is given in the package leaflet.

Contra-Indications

• Pregnancy.
• Cardiovascular or cerebrovascular disorders, e.g. thrombophlebitis, thrombo-embolic processes or a history of these conditions.
• Hereditary or acquired predisposition for venous or arterial thrombosis (e.g. APC-resistance, hyperhomocysteinaemia, antithrombin-III deficiency, protein C deficiency, protein S deficiency, antiphospholipid antibodies (anticardiolipin antibodies, lupus anticoagulant)).
• Prodromal conditions for arterial disease (e.g. angina pectoris, transient ischaemic attack and 'classic' migraine with aura), valvular heart disease.
• Severe hypertension (blood pressure of diastolic > 100mm Hg and/or systolic ³ 160mm Hg on repeated testing).
• Diabetes mellitus with vascular involvement.
• The presence of more than one of the risk factors for venous or arterial disease, respectively, mentioned under Warnings and Precautions.
• Severe liver disease or a history of this condition if the results of liver function tests have failed to return to normal; cholestatic jaundice; a history of jaundice of pregnancy or jaundice due to the use of steroids; Rotor syndrome and Dubin-Johnson syndrome.
• Known or suspected carcinoma of the breast or genital organs or suspect oestrogen-dependent neoplasia.
• Endometrial hyperplasia.
• Undiagnosed vaginal bleeding.
• Porphyria.
• Hyperlipoproteinaemia, especially in the presence of other risk factors predisposing to cardiovascular disorders.
• A history during pregnancy or previous use of steroids of severe pruritus or herpes gestationis.
• Classical migraine.
• Otosclerosis with deterioration in previous pregnancies.

Warnings And Precautions

If any signs of thrombo-embolic processes occur, treatment should be discontinued immediately.

The risk of venous thromboembolism increases with age, and further with:

• a positive family history (if venous thromboembolism ever occurred in a sibling or parent at a relatively early age, the presence of a hereditary factor should be excluded);
• obesity (body mass index over 30kg/m2);
• the presence or a history of haemolytic uraemic syndrome (the condition may have occurred first or worsened during previous pregnancy or previous use of sex steroids);
• systemic lupus erythematosus (also in the absence of antiphospholipid antibodies);

In patients using oestrogen-containing preparations, the risk of deep-vein thrombosis may be temporarily increased when undergoing major surgery or prolonged immobilisation. Oral contraceptive therapy should be discontinued at least four weeks prior to elective surgery because of the danger of thrombosis.

If there is sudden, partial or complete loss of vision, or if there is sudden onset of proptosis, diplopia or migraine, medication should be discontinued and examination made. If examination reveals papilloedema or retinal lesions, medication should be withdrawn.

In the presence of severe varicose veins, the benefits of oestrogen-containing preparations must be weighed against the possible risks.

Four recently published studies have suggested a higher risk of venous thromboembolism with combined OCs containing desogestrel or gestodene than with those containing levonorgestrel. The absolute risk of venous thromboembolism appears to be approximately 2 per 10,000 woman years for the OCs containing desogestrel or gestodene and 1 in 10,000 woman years for those containing levonorgestrel. For comparison, the risk associated with pregnancy is 6 cases per 10,000 pregnant woman years. The figures in the four studies point to a lower risk with the OCs containing levonorgestrel than revealed in earlier studies rather than an additional risk with OCs containing desogestrel or gestodene. Bias and confounding factors may partially explain the difference in risk.

The recent studies indicate a possibly lower risk of myocardial infarction with OCs containing desogestrel or gestodene than with OCs containing levonorgestrel, but definite data are not available as yet.

Other epidemiological studies (involving mainly users of older high dose OCs) have suggested a very weak association with the occurrence of coronary and cerebrovascular accidents. In addition, extremely rarely, in users of these OCs thrombosis has been reported to occur in other blood vessels, e.g. hepatic, mesenteric, renal or retinal veins and arteries. There is no consensus as to whether the occurrence of these events is associated with the use of OCs.

The risk of occlusive arterial disease increases with age, and further with:

• smoking (women over 35 years are advised not to smoke if they wish to use an OC)
• dyslipoproteinaemia;
• obesity (body mass index over 30kg/m2);
• diabetes mellitus;
• hypertension (diastolic blood pressure of 95-100mm Hg);
• a positive family history (if an arterial disease ever occurred in a sibling or parent at a relatively low age, the presence of a hereditary factor should be excluded);
• the presence or a history of haemolytic uraemic syndrome;
• chronic inflammatory bowel disease (such as Crohn's disease or ulcerative colitis);
• systemic lupus erythematosus (also in the absence of antiphospholipid antibodies);

All the above considerations should be taken into account when making a benefit/risk assessment of the use of these OCs, in particular in the presence of other risk factors for the occurrence of venous or arterial thrombosis.

Since the safety of oral contraceptives in pregnancy has not been established it is recommended that for any patient who has missed two consecutive periods pregnancy should be ruled out before continuing therapy. If the patient has not adhered to the prescribed schedule the possibility of pregnancy should be considered at the time of the first missed period.

Treatment should be discontinued if liver function tests become abnormal.

Hepatic cell adenomas have been reported very rarely in women using oral contraceptives. The adenoma may present itself as an abdominal mass and/or with the signs and symptoms of an acute abdomen. A bleeding hepatic cell adenoma should be considered if the patient has abdominal pain or signs of intra-abdominal bleeding.

Oestrogen/progestagen-containing oral contraceptives may affect the quality and reduce the quantity of milk produced. A small proportion of the active substances may be excreted in the milk.

Before prescribing oral contraceptives physical examination is desirable including especially breasts, pelvis and liver.

Chloasma is occasionally seen during the use of oestrogen and/or progestagen-containing preparations, especially in women with a history of chloasma gravidarum. Women with a tendency to chloasma should avoid exposure to the sun while taking this preparation.

Patients with a history of depression should be carefully observed during the use of oestrogen-containing oral contraceptives as depression may occasionally occur. If this is accompanied by a disturbance of tryptophan metabolism, administration of vitamin B6 might be of therapeutic value. The medicine should be discontinued if serious depression recurs.

Organic disease should be excluded when breakthrough bleeding appears for the first time in women who have been previously well controlled and in all cases of irregular vaginal bleeding.

During prolonged treatment with oestrogen and/or progestagen-containing preparations periodic medical examination is advisable.

Patients with the following conditions should be monitored:

• latent or overt cardiac failure, renal dysfunction, hypertension, epilepsy, diabetes, or migraine (or a history of these conditions), since aggravation or recurrence may occasionally be induced.
• oestrogen-sensitive gynaecological disorders, e.g. uterine fibromyomata which may increase in size, and endometriosis which may become aggravated during oestrogen treatment.

Oral contraceptives may cause alterations in certain laboratory estimations. A medicine-free period of two months may be required before some of these parameters return to normal.

With the following tests abnormal results may reflect a biological interference with the test analyte and not an impairment of organ function.

The glucose tolerance test is usually impaired. Fasting blood glucose levels may also be raised.

Although free thyroxine levels are unaffected, an increase in thyroid binding globulin means that other estimations of thyroid function may be erroneous.

Lipid metabolism may be affected with changed serum levels of HDL cholesterol, triglycerides and phospholipids being observed.

Urinary pregnanediol levels may be decreased.

Serum albumin levels are usually decreased (along with the associated calcium levels).

Analytical interference is observed with the Zimmerman test for urinary 17-keto and 17-ketogenic steroids.

With the following tests abnormal results may indicate impairment of organ function:

• Liver - increase in serum transaminases, alkaline phosphatase, gamma glutamyl transpeptidase, bilirubin and binding proteins.
• Clotting factors - increase in factors II, V, VII, IX, X, XII and especially VII; decrease of AT III.

Reduced Reliability

When this product is taken according to the directions for use the occurrence of pregnancy is highly unlikely. However, the reliability of oral contraceptives may be reduced when:

• the tablets have not been taken in accordance with the directions for use e.g. one or more tablets have been missed.
• gastro-intestinal disturbances with diarrhoea and/or vomiting have occurred within 4 hours of tablet-intake.
• other medicines (see paragraph Interactions ) are used concomitantly.

If withdrawal bleeding fails to occur and none of the abovementioned events has taken place, pregnancy is highly unlikely and oral contraceptive use can be continued. If however any of these events has occurred, tablet intake should be discontinued and pregnancy excluded before oral contraceptive use can be resumed.

Adverse Effects

The following adverse reactions have been associated with oestrogen and/or progestagen therapy:

• Genito-urinary tract - intermenstrual bleeding, cervical erosion and changes in cervical secretion, amenorrhoea during and after treatment, changes in menstrual flow, anovulation post treatment, increase in size of uterine fibromyomata, aggravation of endometriosis, certain vaginal infections e.g. candidiasis.
• Breast - tenderness, pain, enlargement, secretion.
• Gastro-intestinal tract - nausea, vomiting, cholelithiasis, cholestatic jaundice, abdominal cramps.
• Cardiovascular system - thrombosis, rise of blood pressure, haemorrhagic eruption.
• Skin - chloasma, erythema nodosum, rash, pruritis, photosensitivity, alopecia, erythema multiforme, hirsutism.
• Eyes - discomfort of the cornea if contact lenses are used.
• CNS - headache, migraine, mood changes, dizziness, drowsiness.
• Various - fluid retention, reduced glucose tolerance, change in body weight, changes in appetite.

Interactions

Irregular bleedings and reduced reliability may occur when oral contraceptives are used concomitantly with medicines such as anticonvulsants, barbiturates, antibiotics (e.g. tetracyclines, rifampicin, etc.), activated charcoal and certain laxatives.

Oral contraceptives may diminish glucose tolerance and increase the need for insulin or other antidiabetic medicines.

Overdosage

The toxicity of both desogestrel and ethinyloestradiol is very low. Therefore with MERCILON 28 toxic symptoms are not expected to occur when, e.g. by young children, several tablets are taken simultaneously. Symptoms that possibly may occur in this case are: nausea, vomiting and in young girls slight vaginal bleeding.

A specific treatment is probably not required, if necessary supportive treatment can be given.

Pharmaceutical Precautions

Nil.

Package Quantities

Each strip contains 21 active tablets and 7 inactive tablets (placebos). Cartons containing 3 strips are available.

   Inhouse Pharmacy