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Millinette 30/75 microgram coated tablets

Last Updated on eMC 25-Jul-2012 View changes  | Consilient Health Ltd Contact details

1. Name of the medicinal product

Millinette 30/75 microgram coated tablets

2. Qualitative and quantitative composition

Each tablet contains 30 micrograms ethinylestradiol and 75 micrograms gestodene.

For a full list of excipients, see section 6.1.

3. Pharmaceutical form

Coated tablet.

Yellow, round, biconvex sugar-coated tablets, both sides are without imprinting.

4. Clinical particulars
4.1 Therapeutic indications

Oral contraception.

4.2 Posology and method of administration

How to take Millinette

The tablets should be taken in the order indicated on the package, every day at approximately the same time. One tablet per day should be taken for 21 days. Each subsequent pack should be started after a 7 day tablet-free interval during which time a withdrawal bleeding will occur. This bleeding usually starts on the 2nd or 3rd day after taking the last tablet, and may not stop until the next pack is started.

How to start taking Millinette

If no preceding hormonal contraceptive use in the past month

Taking of the tablets should begin on the first day of the woman's natural cycle (i.e. on the first day of the woman's menstrual bleeding). One may begin taking the pills on day 2-5, but in these cases it is recommended that a barrier method also be used for the first 7 days on which pills are taken during the first cycle.

When replacing another contraceptive pill of the combination type

The woman should start taking Millinette on the next day after taking the last active tablet in her previous package of contraceptive pills – but no later than the day after the usual tablet-free or placebo-tablet period of her previous contraceptive pill.

When changing from progestogen-only preparations (progestogen-only pills, injection, implant)

The woman may change from progestogen-only pills (POPs) on any day. The first tablet should be taken on the day after any tablet of the POP package. When changing from an implant, Millinette should be started on the day the implant is removed. When changing from injections, Millinette should be started when the next injection is due to be given. In all these cases the woman is advised to also use a barrier method for the first 7 days of taking the pills.

After an abortion in the first trimester

The woman may start taking the pills immediately. If she does so, no further contraceptive steps need be taken.

After delivery or abortion in the second trimester

For breastfeeding women - see section 4.6.

The woman should be advised to begin taking the tablets on day 21- 28 after delivery in non-lactating women or after abortion in the second trimester. If she starts later, she should be advised to also use a barrier method during the first 7 days of taking the pills. If she has already had intercourse, the possibility of pregnancy should be excluded before she begins taking the pills, or she should wait for her first menstruation.

Missed tablets

Missing a tablet for less than 12 hours does not diminish the contraceptive protection. The woman should take the tablet as soon as she remembers, and continue taking the rest of the tablets as usual.

Missing a tablet for more than 12 hours can diminish the contraceptive protection. The two following rules may be helpful in dealing with missed tablets.

1. Taking of the tablets should never be delayed by a period longer than 7 days.

2. It takes 7 days of uninterrupted ingestion of the tablets to achieve sufficient suppression of the hypothalamus-pituitary-ovarian axis.

Thus, the following advice can be given in daily practice:

Week 1

The user should take the last missed tablet as soon as she remembers, even if this means that she needs to take 2 tablets at the same time. From then on she should continue to take the tablets at the usual time. At the same time she should use a barrier method, i.e. a condom, for the next 7 days. If she had intercourse during the past 7 days, she should consider the possibility that she might be pregnant. The more tablets have been missed, and the closer this happened to the monthly tablet-free period, the higher the risk of pregnancy.

Week 2

The user should take the last missed tablet as soon as she remembers, even if this means that she needs to take 2 tablets at the same time. From then on she should continue to take the tablets at the usual time. If the tablets have been taken correctly for the 7 days prior to the missed tablet, it is not necessary to take any additional contraceptive precautions. If this is not the case, however, or if more than 1 tablet has been missed, the woman should be advised to use another birth control method for 7 days.

Week 3

The risk of reduced protection is imminent because of the approaching tablet-free period. The reduced contraceptive protection can be prevented, however, by adjusting the intake of the tablets. It is, therefore, not necessary to take any additional contraceptive precautions, provided that the tablets have been taken correctly for the 7 days prior to the missed tablet, if one follows one of the following choices. If this is not the case, the woman should be advised to follow the first of the two choices, and at the same time use another birth-control method for 7 days.

1. The user should take the last missed tablet as soon as she remembers even if this means that she needs to take 2 tablets at the same time. From then on she should continue to take the tablets at the usual time. She begins the next pack immediately after she took the last tablet from the current package; that means no pause between packages. The user will probably not get her menstruation before the end of the second package, but she may experience spotting or withdrawal bleeding on the days when she takes the tablets.

2. The woman can also be advised to stop taking tablets from the current package. In that case she should observe a tablet-free period for up to 7 days, including the days when she missed the tablets, and then continue with the next pack.

If the woman missed the tablets, and subsequently did not get her menstruation in the first normal tablet-free period, she should consider the possibility that she may be pregnant.

What to do in case of vomiting/diarrhoea

If vomiting occurs within 3-4 hours after tablet taking, absorption may not be complete. In this case the advice concerning missed tablets, described above should be followed. Diarrhoea may reduce the efficacy by preventing full absorption. If the woman does not want to change her usual tablet intake, she should take the required extra tablet(s) from another blister pack.

How to advance or delay menstruation

Only in exceptional cases menstruation can be delayed as described below.

To delay menstruation, the woman should continue with another pack of Millinette without observing the tablet-free period. Menstruation can be delayed as long as is desired up to the end of the second package, but no longer. While menstruation is being delayed the woman may experience withdrawal bleeding or spotting. Regular intake of Millinette should be resumed after the normal tablet-free period of 7 days.

To move menstruation to a weekday other than that on which the woman is used to having it under the current tablet schedule, she can be advised to shorten the next tablet-free period by as many days as she wishes. The shorter the pause, the higher the risk that she will not get her menstruation and will have withdrawal bleeding or spotting while she is taking the next pack (which is also true when menstruation is being delayed).

4.3 Contraindications

Combined oral contraceptives (COCs) must not be used in the presence of the conditions mentioned below. If such a condition should occur for the first time during use of COCs, the use must be discontinued immediately:

- Venous thromboembolism or medical history of venous thromboembolism (deep venous thrombosis, pulmonary embolism) with or without risk factors (see section 4.4)

- Arterial thromboembolism or medical history of arterial thromboembolism, in particular myocardial infarction, cerebrovascular disorder (see section 4.4)

- Considerable or multiple risk factors for venous or arterial thrombosis (see section 4.4)

- Previous prodromal symptoms of thrombosis (e.g. transient cerebral ischaemia, angina pectoris)

- Cardiovascular disorders, i.e. cardiac diseases, valvulopathy, arrhythmic disturbances

- Severe hypertension

- Diabetes, complicated with micro or macro angiopathy

- Ocular disorder of vascular origin

- Known or suspected malignant tumours in the breast

- Known or suspected malignant endometrial tumours or other oestrogen-dependent neoplastic disorders

- Serious or recent hepatic disorders, as long as liver function tests are not normalised

- Present or previous benign or malignant liver tumours

- Undiagnosed vaginal bleeding

- Migraine with focal neurological symptoms

- Pregnancy or suspected pregnancy (see section 4.6)

Hypersensitivity to the active substances or to any of the excipients

4.4 Special warnings and precautions for use

Assessment and examination prior to starting combined oral contraceptives

Before the start or resumption of treatment with combined oral contraceptives a complete personal and family medical history must be obtained and pregnancy should be ruled out. Blood pressure should be measured and a physical examination performed if clinically indicated, guided by the contraindications (see section 4.3) and warnings (see “Warnings” in this section). The woman should be instructed to carefully read the user leaflet and adhere to the advice given. The frequency and nature of further periodic checks should be based on established practice guidelines and adapted to the individual woman

Warnings

General

Women should be advised that COCs do not protect against HIV (AIDS) or other sexually transmitted infections (STI).

Cigarette smoking increases the risk of serious cardiovascular side effects from COC use. This risk increases with age and with the extent of smoking and is particularly marked in women over 35 years of age. All women who use COCs should be strongly advised not to smoke. Other methods of contraception should be considered for those women over 35 years old who smoke.

If any of the risk factors below is present in any individual woman, the benefits of combined oral contraception must be weighed against possible risks in each individual case and discussed with the woman before combined oral contraception is commenced. In the event of aggravation, exacerbation or first appearance of any of these conditions or risk factors the woman should be advised to contact her physician. The physician must then decide, whether the use of COCs should be discontinued.

Circulatory disorders

The use of any COC carries an increased risk of venous thromboembolism (VTE) 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 cases per 100,000 pregnancies. VTE is fatal in 1-2% of cases.

In several epidemiological studies it has been found that women using combined oral contraceptives with ethinylestradiol, mostly with a dose of 30 μg, and a progestin such as gestagen have an increased risk of VTE compared with those who using combined oral contraceptives containing less than 50 μg ethinylestradiol and the progestin levonorgestrel.

For combined oral contraceptives containing 30 μg of ethinylestradiol combined with desogestrel or gestodene compared with those containing less than 50 μg of ethinylestradiol and levonorgestrel, the overall relative risk of VTE has been estimated to range between 1.5 and 2.0. The incidence of VTE for levonorgestrel containing combined oral contraceptives with less than 50 μg of ethinylestradiol is approximately 20 cases per 100,000 women-years of use. For Millinette the incidence is approximately 30-40 cases per 100,000 women-years of use, i.e. additional 10-20 cases per 100,000 women-years of use. The impact of the relative risk on the number of additional cases would be the greatest in women during the first year they ever use a combined oral contraceptive when the risk for VTE with all combined oral contraceptives is highest.

Thrombosis in other blood vessels has very rarely been reported, i.e. hepatic, mesenteric, renal or retinal veins and arteries, in users of oral contraceptives. There is no consensus, whether the occurrence of these cases is related to use of COCs.

The risk for development of venous thromboembolism increases with:

− Increasing age.

− A positive family history (e.g. venous thromboembolism in siblings or parents at a relatively young age). In the case of suspected hereditary predisposition, the woman should be referred to a specialist before she decides to use oral contraception.

− Obesity (body mass index above 30 kg/m²).

− Prolonged immobilisation, major surgery, surgery on the legs or major trauma. In such cases, it is recommended that treatment with oral contraceptives be discontinued (in the case of elective surgery at least 4 weeks prior to the operation) and should not be resumed until 2 weeks after complete remobilisation.

− There is no consensus concerning the possible role of varicose veins and superficial thrombophlebitis in venous thromboembolism.

The use of COCs in general has been associated with an increased risk of acute myocardial infarction (AMI) or stroke, a risk that is strongly influenced by the presence of other risk factors (e.g. smoking, high blood pressure, and age) (see also below). These events occur rarely.

The risk of arterial thromboembolic events increases with:

− increasing age;

− smoking (with heavier smoking and increasing age the risk further increases, especially in women over 35 years of age);

− dyslipoproteinaemia;

− obesity (body mass index over 30 kg/m2);

− hypertension;

− valvular heart disease;

− atrial fibrillation;

− a 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.

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.

The increased risk of venous thromboembolism during the puerperal period should be taken into consideration.

Other medical conditions which have been related to circulatory disorders include diabetes mellitus, systemic lupus erythematosus, haemolytic uraemic syndrome, chronic inflammatory bowel disease (Crohn's disease or colitis ulcerosa) and sickle cell anaemia.

An increase in the frequency or severity of migraine (which may be prodromal for a cerebrovascular condition) during use of oral contraceptives must lead to consideration of immediate discontinuation of oral contraceptives.

Biochemical factors indicating hereditary or acquired predisposition for venous or arterial thrombosis, include activated protein C (APC) resistance, factor V Leiden mutation, hyperhomocysteinaemia, antithrombin III deficiency, protein C deficiency, protein S deficiency, antiphospholipid antibodies (anticardiolipin antibodies, lupus anticoagulant) and dyslipoproteinaemia.

When considering risk/benefit, the physician should take into account that adequate treatment of a condition may reduce the associated risk of thrombosis and that the risk associated with pregnancy is higher than that associated with COC use.

Tumours:

Cervical cancer

In some epidemiological studies an increased risk of cervical cancer has been reported in long term users of COCs, but it is still not clear to which extent this finding may be influenced by impacts of sexual behaviour and other factors, such as human papilloma virus (HPV).

Breast cancer

A meta-analysis from 54 epidemiological studies has shown that women using combined oral contraceptives have a slightly increased relative risk (RR=1.24) of having breast cancer diagnosed. This increased risk gradually declined over 10 years following cessation of COC use. Since breast cancer is a rare condition in women below 40 years of age, the increase in number of diagnosed cases of breast cancer in current and previous users of COCs is small compared to the risk of breast cancer during their entire life time.

These studies do not present evidence for a causal relationship. The observed pattern of an increased risk may be caused by an earlier diagnosing of breast cancer in COC users, the biological effects of COCs or a combination of both.

Liver tumours

Benign and malignant liver tumours have been reported in users of COCs. These tumours have, in isolated cases, lead to life threatening, intra-abdominal haemorrhage. A liver tumour must be taken into consideration as a differential diagnosis when severe pain occurs in the upper abdomen, if there is hepatomegaly, or if there are signs of intra-abdominal haemorrhage in women taking COCs.

Other conditions

Women with hypertriglyceridaemia, or a family history thereof, may be at increased risk of pancreatitis when taking COCs.

In the case of acute or chronic impairment of liver function the use of Millinette should be stopped until liver function tests have returned to normal. Steroid hormones may be poorly metabolised in patients with impaired liver function.

Hyperlipidaemic women should be closely monitored if they choose to use COCs.

Even though slight increases in blood pressure have been reported in many women taking COCs, clinically important increases in blood pressure are rare. If persistent clinical hypertension develops during COC use, intake should be discontinued and the hypertension treated. Use of COCs may be resumed, if appropriate, when normotensive values are reached with antihypertensive therapy.

It has been reported that the following conditions may occur, or worsen both during pregnancy and during use of COCs, but the evidence of a relationship is inconclusive: Jaundice and/or pruritus in connection with cholestasis; development of gallstones; porphyria; systemic lupus erythematosus; haemolytic uraemic syndrome; Sydenham's chorea; herpes gestationis; loss of hearing due to otosclerosis.

COCs may have an influence on the peripheral insulin resistance and glucose tolerance. Therefore, diabetics should be closely monitored during COC use.

Millinette contains lactose and sucrose. Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption or with rare hereditary problems of fructose intolerance should not take this medicinal product.

Crohn's disease and colitis ulcerosa have been associated with the use of combined oral contraceptives.

Chloasma may occur, in particular in women with a medical history of chloasma gravidarum. Women with a tendency to chloasma should avoid exposure to sunlight or ultraviolet radiation while taking COCs.

There have been case reports of retinal thrombosis with the use of COCs. COCs should be discontinued if there is unexplained partial or complete loss of vision; onset of proptosis or diplopia; papilloedema; or retinal vascular lesions.

Women who get severely depressed during the use of COCs should discontinue use and be advised to use an alternative contraceptive method while trying to determine if the symptoms are due to the COC preparation. Women who have previously suffered from episodes of major depression should be closely monitored and stop the use of the COC if the symptoms of depression relapse.

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

Reduced efficacy

The efficacy of oral contraceptives may be reduced in the case of missed tablets or vomiting (see section 4.2) or concomitant use of other medicinal product (see section 4.5).

Reduced cycle control

With all combined oral contraceptives, irregular bleeding (spotting or break through bleeding) may occur, especially during the first months. Hence, the evaluation of any irregular bleeding should be considered after a period of adaptation of approximately 3 cycles.

If bleeding irregularities persist COCs with a higher hormonal content may need to be considered. If bleeding irregularities occur after previously regular cycles, then non-hormonal causes should be considered, and adequate diagnostic measures are indicated to exclude malignancy or pregnancy.

Occasionally withdrawal bleeding during the tablet-free interval may not occur at all. If the tablets have been taken according to the instructions described in section 4.2, it is unlikely that the woman is pregnant. However, if the tablets have not been taken according to the instructions, before the first absent withdrawal bleeding, or if two withdrawal bleedings are overdue, pregnancy should be excluded before COC use is continued

4.5 Interaction with other medicinal products and other forms of interaction

Drug interaction resulting in elevated clearance of sex hormones may cause withdrawal bleeding and contraceptive failure. This has been established with hydantoins, barbiturates, primidone, carbamazepine and rifampicin; oxcarbazepine, topiramate, griseofulvin, felbamate and ritonavir are also suspected. The mechanism of this interaction seems to rest upon the liver enzyme-inducing properties of these medicinal products. Maximal enzyme induction is generally not visible before 2-3 weeks after the start of the treatment, but it may persist for at least 4 weeks after the end of treatment.

Contraceptive failure has also been reported with antibiotics, such as ampicillin and tetracyclins. The mechanism of this action has not been elucidated.

Women undergoing short-term treatment with any of the above mentioned groups, or individual medicinal products, should temporarily use a barrier method along with the contraceptive pills; that means during the time when both this medicinal product and the contraceptive pills are taken, as well as 7 days after the medicinal product is discontinued. Women treated with rifampicin should use a barrier method along with the contraceptive pills during the time when they are treated with rifampicin as well as for 28 days after they stop taking rifampicin. If the intake of another concomitant medicinal product stretches beyond the number of tablets in the contraceptive pill pack, the woman should start the next pack without observing the normal tablet-free period.

For long-term users of medicinal products that induce liver enzymes, use of other contraceptive measures should be advised.

Patients being treated with Millinette should not simultaneously use products/alternative medicinal products containing Hypericum perforatum (St. John's wort), as this can lead to loss of contraceptive effect. Withdrawal bleeding and undesired pregnancy have been reported.

Hypericum perforatum (St. John's wort) increases, by enzyme induction, the amount of enzymes that metabolise medicinal products. The effect of the enzyme induction may last for at least 1-2 weeks after the end of treatment with Hypericum.

COC effects on other drugs: oral contraceptives may interfere with the metabolism of other drugs. Accordingly, plasma and tissue concentrations may be affected (e.g. cyclosporine, lamotrigine).

Laboratory tests

The use of contraceptive steroids can influence the results of certain laboratory tests, including the biochemical parameters of liver, thyroid, adrenal, and kidney function; plasma levels of (transport) proteins, such as corticosteroid-binding globulin and lipid/lipoprotein fractions; the parameters of carbohydrate metabolism, and the parameter of coagulation and fibrinolysis. The changes usually remain within the normal test ranges.

4.6 Pregnancy and lactation

Millinette is not indicated during pregnancy. If pregnancy occurs during medication with Millinette, the preparation should be withdrawn immediately.

Data on pregnancies exposed to gestodene are too limited to permit conclusions concerning negative effects of gestodene on pregnancy, health of the foetus or neonate. Until now, no relevant epidemiological data are available.

Animal studies do not indicate direct or indirect harmful effects with respect to pregnancy, embryonal/foetal development, parturition or post-natal development (see section 5.3).

Most epidemiological studies have revealed neither an increased risk of birth defects in children born to women who used COCs prior to pregnancy, nor a teratogenic effect when COCs were taken inadvertently during early pregnancy. However, based on the hormonal action of the active substances, an adverse effect of the active substances on embryo-foetal development cannot be fully excluded.

Contraceptive steroids can influence breastfeeding, as they can lower the amount and change the composition of breast milk. The use of contraceptive steroids should, therefore, generally not be advised to a breastfeeding mother before her child is completely weaned. Small amounts of contraceptive steroids and/or their metabolites can be excreted in the milk, but there are no indications that this has a deleterious effect on the health of the infant.

Millinette should not be used during breastfeeding.

4.7 Effects on ability to drive and use machines

Millinette has no or negligible influence on the ability to drive and use machines.

4.8 Undesirable effects

The most commonly reported ADRs (≥1/10) are menstruation irregular, nausea, weight increased, breast tenderness and headache. They occur usually at the beginning of therapy and are transient.

System Organ class

Very common

≥1/10

Common

≥1/100 to <1/10

Uncommon and Rare

≥1/10000 to <1/1000

Very rare

< 1/10000

Not known

Neoplasm benign, malignant and unspecified

(including cysts and polyps)

  

Breast cancer

Hepatic adenoma

Hepatic neoplasm malignant

Cervix carcinoma

  

Immune system disorders

  

Anaphylactic/anaphylactoid reactions, including very rare cases of urticaria, angioedema, and severe reactions with respiratory and circulatory symptoms

Systemic lupus erythematosus

Exacerbation of systemic lupus erythematosus

 

Metabolism and nutrition disorders

 

Fluid retention

Hyperlipidaemia

Changes in appetite (increase or decrease)

Exacerbation of porphyria

 

Psychiatric disorders

 

Changes in libido

Mood changes, including depression

Nervousness

   

Nervous sytem disorders

Headache

Migraine

Dizziness

Chorea

Exacerbation of chorea

 

Eye disorders

 

Corneal disorder

Visual disturbance

Intolerance to contact lenses

Optic neuritis*

Retinal vascular thrombosis

 

Ear and labyrinth disorders

  

Otosclerosis

  

Vascular disorders

  

Hypertension

Venous thrombosis

Arterial thrombosis

Embolism

Aggravation of varicose veins

 

Gastrointestinal disorders

Nausea

Abdominal pain

Vomiting

Pancreatitis

Abdominal cramps

Bloating

Ischemic colitis

 

Hepatobiliary disorders

   

Gallbladder disease, including gallstones**

Hepatocellular injury (e.g. hepatitis, hepatic function abnormal)

Skin and subcutaneous tissue disorders

 

Acne

Chloasma (melasma), which may persist

hirsutism

Alopecia

Rash

Erythema nodosum

Erythema multiforme

 

Renal and urinary disorders

   

Hemolytic uremic syndrome

 

Reproductive system and breast disorders

Menstruation irregular

Breast tenderness

Amenorrhoea

Hypomenorrhoea

Breast enlargement, secretion

Dysmenorrhea

Change in menstrual flow

Change in cervical ectropion and secretion

   

General disorders and administration site conditions

 

Irritability

   

Investigations

Weight increased

Changes in weight (increase or decrease)

Smear vaginal abnormal

Changes in serum lipid levels, including hypertriglyceridemia

Decrease in serum folate levels***

  

The following serious adverse events have been reported in women using COCs, see sections 4.3 and 4.4.

• Venous thromboembolism, i.e. deep leg or pelvic venous thrombosis and pulmonary embolism.

• Arterial thromboembolic disorders

• Cervical cancer

• Liver tumours

• Skin and subcutaneous disorders: chloasma.

The frequency of diagnosis of breast cancer is very slightly increased among COC-users. As breast cancer is rare in women under 40 years of age the excess number is small in relation to the overall risk of breast cancer. Causation with COC use is unknown. For further information, see sections 4.3 and 4.4.

4.9 Overdose

No serious harmful effects have been reported with overdoses. Symptoms that can arise in connection with an overdose are: Nausea, vomiting, and vaginal bleeding. There is no antidote, and further treatment should be symptomatic.

5. Pharmacological properties
5.1 Pharmacodynamic properties

Pharmacotherapeutic group: hormonal contraceptives for systemic use

ATC code: G03 AA10

The contraceptive effect of contraceptive pills rests on the interaction of various factors, the most important of which are inhibition of ovulation and changes in cervical secretions. Besides protection from pregnancy, contraceptive pills have several positive qualities which, when considered against their negative points, are useful to know when one is making a decision about the prevention of pregnancy. The menstrual cycle becomes more regular, menstruation is often less painful, and bleeding is not as heavy. The latter can contribute to reducing the occurrence of iron deficiency. In addition to this, it has been demonstrated that high-dosage contraceptive pills (50 μg ethinylestradiol) lower the risk of fibrocystic tumours of the breast, ovarian cysts, adnexitis, ectopic pregnancy, as well as endometrial and ovarian cancer. It has not yet been confirmed whether this also applies to low-dosage contraceptive pills.

5.2 Pharmacokinetic properties

Gestodene

Absorption

Gestodene, when taken orally, is absorbed quickly and completely. Following a single dose the maximum serum concentration of 4 ng/ml is reached in approximately one hour. Bioavailability is approximately 99%.

Distribution

Gestodene is bound to serum albumin and to sex hormone binding globulin (SHBG). Only 1-2% of the total amount of gestodene in serum is found as free steroid, while 50-70% is specifically bound to SHBG. The ethinylestradiol-induced increase in SHBG influences the distribution of serum proteins, which causes an increase of the SHBG-bound fraction, and a decrease of the albumin-bound fraction. The apparent distribution volume of gestodene is 0.7 l/kg.

Metabolism

Gestodene is metabolised completely via the known pathways of steroid metabolism. The metabolic clearance rate from serum is 0.8 ml/min/kg. No interaction occurs when gestodene is taken together with ethinylestradiol.

Elimination

Serum level of gestodene is reduced at 2 rates. The last rate is characterised by a half-life of 12 – 15 hours. Gestodene is not excreted. Its metabolites are excreted in urine and in bile at a ratio of 6:4.

The half-life of metabolite excretion is approximately 1 day.

Steady-state

Pharmacokinetics of gestodene is influenced by the levels of SHBG in serum, which increase to triple values with ethinylestradiol. Upon daily intake, the level of gestodene in serum increases till approximately four times the single dose value, and reaches steady-state within the second half of the treatment cycle.

Ethinylestradiol

Absorption

Ethinylestradiol, taken orally, is absorbed quickly and completely. Maximal serum concentration of about 80 pg/ml is reached within 1-2 hours. Complete bioavailability, resulting from pre-systemic conjugation and first-pass metabolism, is approximately 60%.

Distribution

Ethinylestradiol is predominantly bound non-specifically to albumin (approx. 98.5), and causes increase in serum concentration of SHBG. The apparent distribution volume is found to be approximately 5 l/kg.

Metabolism

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

Elimination

Serum level of ethinylestradiol is reduced at 2 rates, the last one with a half-life of 24 hours. Ethinylestradiol is not excreted, but its metabolites are excreted in urine and in bile at a ratio of 4:6. The half-life of metabolite excretion is approximately 1 day.

Steady-state

Steady-state occurs after 3-4 days, and the serum levels of ethinylestradiol are 30-40% higher than at single dose.

5.3 Preclinical safety data

In order to assess the risk to humans, animal toxicity studies were performed with both ingredients, ethinylestradiol and gestodene, used either separately or in combination.

Systemic tolerance studies did not show any form of undesirable effect, which could indicate an unexpected risk to humans upon repeated intake.

Longer lasting toxicity studies with repeated administration to investigate the risk of tumorigenic activity did not indicate any special risk to humans. It should, however, be pointed out that sex hormones can advance the growth of certain hormone-dependent tissues and tumours.

Studies of toxicity to the embryo and teratogenicity with ethinylestradiol and assessment of the effects of the combination on the fertility of the parent animals, development of the foetus, lactation, and reproductive ability revealed no risk of undesirable effects for humans with the recommended use of the preparation.

In vitro and in vivo studies do not indicate a risk of mutagenicity.

6. Pharmaceutical particulars
6.1 List of excipients

Tablet core:

Sodium calcium edetate

Magnesium stearate

Silica colloidal anhydrous

Povidone K-30

Maize starch

Lactose monohydrate

Tablet coat:

Quinoline yellow (E 104)

Povidone K-90

Titanium dioxide (E 171)

Macrogol 6000

Talc

Calcium carbonate (E170)

Sucrose

6.2 Incompatibilities

Not applicable.

6.3 Shelf life

3 years.

6.4 Special precautions for storage

Store below 25°C. Store in the original package in order to protect from light and moisture.

6.5 Nature and contents of container

Blister: PVC/PVDC/aluminium.

Blister: PVC/PVDC/aluminium in PETP/aluminium/PE bag.

Pack sizes: 1 x 21 tablets; 3 x 21 tablets, 6 x 21 tablets, 13 x 21 tablets.

Not all pack sizes may be marketed.

6.6 Special precautions for disposal and other handling

No special requirements.

7. Marketing authorisation holder

Medimpex S.A.

1-3 rue Caumartin

75009 Paris

France

8. Marketing authorisation number(s)

PL 17550/0043

9. Date of first authorisation/renewal of the authorisation

31.03.2009 / 28.05.2009

10. Date of revision of the text

25.02.2011

Company contact details

Consilient Health Ltd

Company image
Address

No. 1 Church Road, Richmond upon Thames, Surrey, TW9 2QE, UK

Fax

+44(0)20 3751 1889

Telephone

+44(0) 20 3751 1888

Medical Information e-mail

Before you contact this company: often several companies will market medicines with the same active ingredient. Please check that this is the correct company before contacting them. Why?

Active ingredients

ethinylestradiol, gestodene

Legal categories

POM - Prescription Only Medicine

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