- 1. Name of the medicinal product
- 2. Qualitative and quantitative composition
- 3. Pharmaceutical form
- 4. Clinical particulars
- 4.1 Therapeutic indications
- 4.2 Posology and method of administration
- 4.3 Contraindications
- 4.4 Special warnings and precautions for use
- 4.5 Interaction with other medicinal products and other forms of interaction
- 4.6 Pregnancy and lactation
- 4.7 Effects on ability to drive and use machines
- 4.8 Undesirable effects
- 4.9 Overdose
- 5. Pharmacological properties
- 5.1 Pharmacodynamic properties
- 5.2 Pharmacokinetic properties
- 5.3 Preclinical safety data
- 6. Pharmaceutical particulars
- 6.1 List of excipients
- 6.2 Incompatibilities
- 6.3 Shelf life
- 6.4 Special precautions for storage
- 6.5 Nature and contents of container
- 6.6 Special precautions for disposal and other handling
- 7. Marketing authorisation holder
- 8. Marketing authorisation number(s)
- 9. Date of first authorisation/renewal of the authorisation
- 10. Date of revision of the text
- 11 Legal category
|Desogestrel B.P.||150 micrograms|
|Ethinylestradiol Ph.Eur||30 micrograms|
4.2.1 How to take MarvelonTablets must be taken in the order directed on the package every day at about the same time with some liquid as needed. One tablet is to be taken daily for 21 consecutive days. Each subsequent pack is started after a 7-day tablet-free interval, during which time a withdrawal bleed usually occurs. This usually starts on day 2-3 after the last tablet and may not have finished before the next pack is started.
4.2.2 How to start Marvelon
No preceding hormonal contraceptive use [in the past month]It is preferable that tablet intake from the first pack is started on the first day of menstruation in which case no extra contraceptive precautions are necessary.If menstruation has already begun, (that is 2, 3, or 4 days previously), tablet taking should commence on day 5 of the menstrual period. In this case additional contraceptive precautions must be taken for the first 7 days of tablet taking.If menstruation began more than 5 days previously then the patient should be advised to wait until her next menstrual period before starting to take Marvelon.
Changing from a 21 day pill or another 22 day pill to Marvelon:All tablets in the old pack should be finished. The first Marvelon 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. Tablets should be taken as instructed in 'How to take Marvelon'. Additional contraceptive precautions are not required. The patient will not have a period until the end of the first Marvelon 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 Marvelon:Marvelon should be started after taking the last active tablet from the 'Every Day Pill' pack (i.e. after taking 21 or 22 tablets). The first Marvelon 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. One tablet is taken daily at the same time, without interruption for 21 days, followed by a 7 day tablet-free period. Each subsequent pack is started after the 7 day tablet-free period has elapsed. 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 Marvelon 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 Marvelon:The first Marvelon tablet should be taken on the first day of the period, even if the patient has already taken a mini pill on that day. One tablet is taken daily at the same time, without interruption for 21 days, followed by a 7 day tablet-free period. Each subsequent pack is started after the 7 day tablet-free period has elapsed. Additional contraceptive precautions are not then 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 Marvelon 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 seven days.
Changing from a progestogen-only injection, implant or from a progestogen- releasing intrauterine system [IUS]The woman may switch any day from an implant (or the IUS on the day of its removal, from an injectable when the next injection would be due). Additional contraceptive precautions must be taken for the first seven days.
Post-Partum AdministrationFollowing childbirth oral contraceptive administration to non-breast feeding mothers should be started 21 days post-partum in which case no additional contraceptive precautions are required. If intercourse has taken place post-partum, oral contraceptive use should be delayed until the first day of the menstrual period.If post-partum administration of Marvelon begins more than 21 days after delivery then additional contraceptive precautions are required for the first 7 days.N.B. 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).After miscarriage or abortion administration should start immediately in which case no additional contraceptive precautions are required.
Additional contraceptive precautionsWhen 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 e.g. changes in temperature and cervical mucus.
How to skip a periodTo skip a period, a new pack of Marvelon 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 breakthrough bleeding but contraceptive protection will not be diminished provided there are no tablet omissions. The next pack of Marvelon is started after the usual 7 tablet-free days, regardless of whether the period has completely finished or not.
4.2.3 Management of missed tablets
Advice in case of missed pillsThe reliability of Marvelon may be reduced if tablets are forgotten:If the forgotten tablet is taken within 12 hours, no further precautions are necessary, further tablets should be taken at the usual time.If one or more tablets are forgotten for more than 12 hours, contraceptive protection will be reduced. The patient should take the last forgotten tablet, even if this means taking two tablets in one day, and then continue to take tablets at the normal time. Additional contraceptive precautions should be taken for the next seven days, and the patient should follow 'the 7-day rule'.
The 7-Day rule
If any one tablet is forgotten for more than 12 hours
If the patient has vomiting or diarrhoea for more than 12 hours
If the patient is taking any of the drugs listed under 'Interactions':The patient should continue to take her tablets as usual andAdditional contraceptive precautions must be taken for the next 7 daysBut - if these 7 days run beyond the end of the current pack, the next pack must be started as soon as the current one is finished, i.e. no gap should be left between packs. (This prevents an extended break in tablet taking which may increase the risk of the ovaries releasing an egg and thus reducing contraceptive protection). The patient will not have a period until the end of 2 packs but this is not harmful nor does it matter if she experiences some bleeding on tablet taking days.
Advice in case of Vomiting or severe diarrhoeaIn case of severe gastro-intestinal disturbance, absorption may not be complete and additional contraceptive measures should be taken. Unless diarrhoea is extremely severe, it does not affect steroidal absorption.If vomiting occurs within 3-4 hours after tablet taking, or in cases of severe or prolonged diarrhoea, the advice concerning missed tablets, as given in Section 4.2.3, is applicable. If the woman does not want to change her normal tablet-taking schedule, she has to take the extra tablet(s) needed from another pack.
4.4.1 Medical Examination/consultationAssessment 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 (section 4.4) 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.Women should be advised that oral contraceptives do not protect against HIV infections (AIDS) and other sexually transmissible infections. If there is risk of STI/HIV (including during pregnancy or postpartum), the correct and consistent use of condoms is recommended, either alone or with another contraceptive method.
4.4.2 WarningsIf any of the conditions/risk factors mentioned below is present, the benefits of COC use should be weighed against the possible risks for each individual woman and discussed with the woman before she decides to start using it. In the event of aggravation, exacerbation or first appearance of any of these conditions or risk factors, the woman should contact her physician. The physician should then decide on whether COC use should be discontinued.
Relative ContraindicationsDisorders of coagulation.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.Migraine or a history of this condition. Diabetes mellitus.Severe depression or a history of this condition.If the results of liver function tests become abnormal, use should be discontinued.
1. Circulatory Disorders Some epidemiological studies have suggested an association between the use of COCs and an increased risk of arterial and venous thrombotic and thromboembolic diseases such as myocardial infarction, stroke, deep venous thrombosis, and pulmonary embolism. These events occur rarely. An increased risk of venous thromboembolic disease (VTE) associated with the use of oral contraceptives is well established. The excess risk of VTE is highest during the first year a woman ever uses a combined oral contraceptive. It is smaller than the risk associated with pregnancy, which has been estimated at 60 cases per 100,000 pregnancies. Venous thromboembolism is fatal in 1-2% of cases. Some epidemiological studies have reported a greater risk of VTE for women using combined oral contraceptives containing desogestrel or gestodene (the so-called third generation pills) than for women using pills containing levonorgestrel (the so-called second generation pills). The spontaneous incidence of VTE in healthy non-pregnant women (not taking any oral contraceptive) is about 5 cases per 100,000 women per year. The incidence in users of second generation pills is about 15 cases per 100,000 women per year. The incidence in users of third generation pills is about 25 cases per 100,000 women per year of use: this excess incidence has not been satisfactorily explained by bias or confounding. The level of all these risks of VTE increases with age and is likely to be further increased in women with other known risk factors for VTE such as obesity. Thrombosis has very rarely been reported to occur in other veins or arteries, e.g. hepatic, mesenteric, renal, cerebral or retinal, in COC users. There is no consensus as to whether the occurrence of these events is associated with the use of COCs. The risk of venous thromboembolism VTE 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;- prolonged immobilization, major surgery, any surgery to the legs, or major trauma. In these situations it is advisable to discontinue use (in the case of elective surgery at least four weeks in advance) and not to resume until two weeks after complete remobilization;- obesity (body mass index over 30 kg/m2);- and possibly also with superficial thrombophlebitis and varicose veins. There is no consensus about the possible role of these conditions in the etiology of venous thrombosis. 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. It has not been studied how Marvelon modifies the risk of AMI. The risk of arterial thromboembolic complications increases with:- increasing age;- smoking (with heavier smoking and increasing age the risk further increases, especially in women over 35 years of age);- dyslipoproteinemia;- obesity (body mass index over 30 kg/m2);- hypertension;- migraine;- valvular heart disease;- atrial fibrillation;- a positive family history (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. The increased risk of thromboembolism in the puerperium must be considered. Other medical conditions which have been associated with adverse circulatory events include diabetes mellitus, systemic lupus erythematosus, haemolytic uraemic syndrome, chronic inflammatory bowel disease (Crohn's disease or ulcerative colitis) and sickle cell disease. An increase in frequency or severity of migraine during COC use (which may be prodromal of a cerebrovascular event) may be a reason for immediate discontinuation of the COC. Biochemical factors that may be indicative of hereditary or acquired predisposition for venous or arterial thrombosis include Activated Protein C (APC) resistance, hyper homocysteinaemia, antithrombin-III deficiency, protein C deficiency, protein S deficiency, antiphospholipid antibodies (anticardiolipin antibodies, lupus anticoagulant).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.Signs and symptoms of a thrombotic event may include:- unilateral leg pain and/ or swelling;- sudden severe pain in the chest, whether or not reaching to the left arm;- sudden breathlessness;- sudden onset of coughing- any unusual severe, prolonged headache, especially if it occurs for the first time or gets progressively worse, or is associated with any of the following symptoms:- sudden partial or complete loss of vision or diplopia- slurred speech or aphasia- vertigo- collapse with or without focal epilepsy- weakness or very marked numbness suddenly affecting one side or one part of the body- motor disturbances- 'acute' abdomen
2. Tumours 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 such as human papilloma virus (HPV). 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 combined oral contraceptives (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 ten 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). In rare cases, benign liver tumours, and even more rarely, malignant liver tumours have been reported in users of COCs. In isolated cases, these tumours have led to life-threatening intra-abdominal haemorrhages. A hepatic tumour should be considered in the differential diagnosis when upper abdominal pain, enlarged liver or signs of intra-abdominal haemorrhage occur in women taking COCs.
3. Other conditions Women with hypertriglyceridemia, or a family history thereof, may be at an increased risk of pancreatitis when using COCs. Although small increases in blood pressure have been reported in many women taking COCs, clinically relevant increases are rare. 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. Where considered appropriate, COC use may be resumed if normotensive values can be achieved with antihypertensive therapy. The following conditions have been reported to occur or deteriorate with both pregnancy and COC use: jaundice and/or pruritus related to cholestasis; gallstone formation; porphyria; systemic lupus erythematosus; herpes gestationis; otosclerosis-related hearing loss; hereditary angioedema. Although COCs may have an effect on peripheral insulin resistance and glucose tolerance, there is no evidence for a need to alter the therapeutic regimen in diabetics using COCs. However, diabetic women should be carefully observed while taking COCs. 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. Marvelon contains < 80 mg lactose per tablet. Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose- galactose malabsorption should not take medicine.
4.4.2 Reduced EfficacyThe efficacy of COCs may be reduced in the event of missed tablets (Section 4.2.3), gastrointestinal disturbances (Section 4.2.4) or concomitant medication (Section 4.5.1).
4.4.2 Reduced Cycle Control/ irregular bleedingWith all COCs, irregular bleeding (spotting or breakthrough bleeding) may occur, especially during the first months of use. Therefore, the evaluation of any irregular bleeding is only meaningful after an adaptation interval of about three cycles.If bleeding irregularities persist or occur after previously regular cycles, then non- hormonal causes should be considered and adequate diagnostic measures are indicated to exclude malignancy or pregnancy. These may include curettage.In some women withdrawal bleeding may not occur during the tablet-free interval. If the COC has been taken according to the directions described in Section 4.2, it is unlikely that the woman is pregnant. However, if the COC has not been taken according to these directions prior to the first missed withdrawal bleed or if two withdrawal bleeds are missed, pregnancy must be ruled out before COC use is continued.
4.5.1 InteractionsInteractions between oral contraceptives and other drugs may lead to breakthrough bleeding and/or contraceptive failure. The following interactions have been reported:Hepatic metabolism:Interactions can occur with drugs that induce microsomal enzymes, which can result in increased clearance of sex hormones (e.g., phenytoin, barbiturates, primidone, carbamazepine, rifampicin, and possibly also oxcarbazepine, topiramate, felbamate, ritonavir, griseofulvin and products containing St. John's wort).Interference with Enterohepatic Circulation:Some clinical reports suggest that enterohepatic circulation of estrogens may decrease when certain antibiotic agents are given, which may reduce ethinylestradiol concentrations (e.g., penicillins, tetracyclines).Women on treatment with any of these drugs should temporarily use a barrier method in addition to the COC or choose another method of contraception. With microsomal enzyme-inducing drugs, the barrier method should be used during the time of concomitant drug administration and for 28 days after their discontinuation. Women on treatment with antibiotics (except rifampicin and griseofulvin) should use the barrier method until 7 days after discontinuation. If the period during which the barrier method is used runs beyond the end of the tablets in the COC pack, the next COC pack should be started without the usual tablet-free interval.Oral contraceptives may interfere with the metabolism of other drugs. Accordingly, plasma and tissue concentrations may be increased (e.g., ciclosporin) or decreased (e.g., lamotrigine).Note: The prescribing information of concomitant medications should be consulted to identify potential interactions.
4.5.2 Laboratory TestsThe use of contraceptive steroids may influence the results of certain laboratory tests, including biochemical parameters of liver, thyroid, adrenal and renal function, plasma levels of (carrier) proteins, e.g. corticosteroid binding globulin and lipid/lipoprotein fractions, parameters of carbohydrate metabolism and parameters of coagulation and fibrinolysis. Changes generally remain within the normal laboratory range.
|WHO system organ class||Common (> 1/100)||Rare (< 1/1000)|
|Body as a whole general Disorders||Fluid retention||Hypersensitivity reaction Systemic lupus Erythematosus|
|Cardiovascular disorders (general)||Increase in blood pressure*||Hypertension*|
|Central Nervous System||Headache Migraine Changes in libido Depressive moods||Sydenham's chorea|
|Gastro-intestinal disorders||Nausea Vomiting||Pancreatitis Crohn's disease Ulcerative colitis|
|Hearing and vestibular disorders||Otosclerosis-related hearing loss|
|Liver and biliary system disorders||Cholelithiasis Cholestatic jaundice|
|Metabolic and nutritional disorders||Change in body weight||reduced glucose tolerance* Porphyria|
|Neoplasms||Breast cancer* Cervical cancer* Liver tumours (benign)* Liver tumours (malignant)*|
|Platelet, bleeding and clotting disorders||Venous thromboembolic disorders* Arterial thromboembolic disorders*|
|Reproductive disorders female||Irregular vaginal bleeding* Breast tenderness Breast pain Breast secretion Changes in vaginal secretion|
|Skin and appendages disorders||rash, erythema nodosum.||Chloasma* Herpes gestationis|
|Vision disorders||Contact lens intolerance|
ABSORPTIONOrally administered desogestrel is rapidly and completely absorbed and converted to etonogestrel. Following ingestion of a single dose, peak serum concentrations of about 2 ng/mL are reached within 1-2 hours. At steady-state, mean peak serum concentrations of 5 ng/mL have been observed. Bioavailability is 62 - 81 %.
DISTRIBUTIONEtonogestrel is bound to serum albumin and to sex hormone binding globulin (SHBG). Only 2 - 4 % of the total serum drug concentrations are present as free steroid, 40 - 70 % are specifically bound to SHBG. The ethinylestradiol-induced increase in SHBG influences the distribution over the serum proteins, causing an increase of the SHBG-bound fraction and a decrease of the albumin-bound fraction. The apparent volume of distribution of desogestrel is 1.5 l/kg.
METABOLISMEtonogestrel is completely metabolized by the known pathways of steroid metabolism, including cytochrome P450 3A4. The metabolic clearance rate from serum is about 2 ml/min/kg. No interaction was found with the co-administered ethinylestradiol.
ELIMINATIONEtonogestrel serum levels decrease in two phases. The terminal disposition phase is characterized by a half-life of approximately 30 hours. Desogestrel and its metabolites are excreted at a urinary to biliary ratio of about 6:4.
STEADY-STATE CONDITIONSEtonogestrel pharmacokinetics are influenced by SHBG levels, which are increased threefold by ethinylestradiol. Following daily ingestion, drug serum levels increase about two- to threefold, reaching steady state conditions during the second half of a treatment cycle.Ethinylestradiol
ABSORPTIONOrally administered ethinylestradiol is rapidly and completely absorbed. Following ingestion of a single dose, peak serum concentrations of about 80 pg/mL are reached within 1-2 hours. At steady-state, mean peak serum concentrations of 130 pg/mL have been observed. Absolute bioavailability as a result of presystemic conjugation and first-pass metabolism is approximately 60%.
DISTRIBUTIONEthinylestradiol is highly but non-specifically bound to serum albumin (approximately 98.5%) and induces an increase in the serum concentrations of SHBG. An apparent volume of distribution of about 5 l/kg was determined.
METABOLISMEthinylestradiol is subject to presystemic conjugation in both small bowel mucosa and the liver. Ethinylestradiol is primarily metabolized by aromatic hydroxylation but a wide variety of hydroxylated and methylated metabolites are formed, and these are present as free metabolites and as conjugates with glucuronides and sulfate. The metabolic clearance rate is about 5 ml/min/kg.
ELIMINATIONEthinylestradiol serum levels decrease in two phases, the terminal disposition phase is characterized by a half-life of approximately 24 hours. Unchanged drug is not excreted, ethinylestradiol metabolites are excreted at a urinary to biliary ratio of 4:6. The half-life of metabolite excretion is about 1 day.
STEADY-STATE CONDITIONSSteady state concentrations are reached after 3-4 days when serum drug levels are higher by 30 - 40% as compared to single dose.
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