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MARVELON® 150/30 tablets

SCHEDULING STATUS:
S3

PROPRIETARY NAME
(and dosage form):

MARVELON® 150/30 tablets

COMPOSITION
21 larger white tablets containing 0,15 mg desogestrel and 0,03 mg ethinylestradiol.
7 smaller white tablets that do not contain any active ingredients.
List of excipients: colloidal silicon dioxide, lactose, magnesium stearate, potato starch, povidone, stearic acid, dl-alpha-tocopherol. The daily amount of lactose (<80 mg) is such that women with intolerance to lactose are highly unlikely to experience a problem.

PHARMACOLOGICAL CLASSIFICATION
A/18.8/Ovulation controlling agents

PHARMACOLOGICAL ACTION
MARVELON 150/30 is an oestrogen/progestogen combination oral contraceptive that inhibits ovulation.

Pharmacodynamic properties
The contraceptive effect of Marvelon 150/30 is based on the interaction of various factors, the most important of which are seen as the inhibition of ovulation and the changes in the cervical secretion.
Pharmacokinetic properties
Desogestrel
Absorption
Orally administered desogestrel is rapidly and completely absorbed and converted to etonogestrel. Peak serum concentrations of approximately 2 ng/ml are reached at about 1.5 hours after single ingestion. Bioavailability is 62 –81%.
Distribution
Etonogestrel 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.
Metabolism
Etonogestrel is completely metabolised by the known pathways of steroid metabolism. The metabolic clearance rate from serum is about 2 mL/min/kg. No interaction was found with the co-administered ethinylestradiol.
Elimination
Etonogestrel serum levels decrease in two phases. The terminal disposition phase is characterised 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 conditions
Etonogestrel 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 the treatment cycle.
Ethinylestradiol
Absorption
Orally administered ethinylestradiol is rapidly and completely absorbed. Peak serum concentrations of about 80 pg/ml are reached within 1-2 hours.Absolute bioavailability as a result of presystemic conjugation and first-pass metabolism is approximately 60%.
Distribution
Ethinylestradiol 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.
Metabolism
Ethinylestradiol is subject to presystemic conjugation in both small bowel mucosa and the liver. Ethinylestradiol is primarily metabolised 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 sulphate. The metabolic clearance rate is about 5 mL/min/kg.
Elimination
Ethinylestradiol serum levels decrease in two phases, the terminal disposition phase is characterised 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 conditions
Steady state concentrations are reached after 3-4 days when serum drug levels are higher by 30 - 40% as compared to single dose.

INDICATIONS
Oral contraception.

CONTRA-INDICATIONS
Combined oral contraceptives (COCs) should not be used in the presence of any of the conditions listed below. Should any of the conditions appear for the first time during combined oral contraceptive use, the product should be stopped immediately.

-	Thrombosis (venous or arterial) present or in history (e.g. deep venous thrombosis, pulmonary embolism, myocardial infarction, cerebrovascular accident).
-	Presence or history of prodromal features of a thrombosis (e.g. transient ischaemic attack, angina pectoris).
-	The presence of a serious single or multiple risk factors for venous or arterial thrombosis (such as e.g. hypertension, a family history of thromboembolic events, prolonged immobilization –see further risk factors for thromboembolism under “Warnings –Circulatory Disorders”below).
-	Presence or history of hepatic disease as long as liver function values have not returned to normal.
-	Presence or history of liver tumours (benign or malignant). Known or suspected malignant conditions of the genital organs or the breasts, if sex steroid-influenced.
-	Undiagnosed vaginal bleeding.
-	Known or suspected pregnancy.
-	Diabetes mellitus with vascular involvement.
-	Hypersensitivity to any of the components of Marvelon 150/30.

WARNINGS
If any of the conditions/risk factors mentioned below is present, the benefits of combined oral contraceptive 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 case of aggravation, exacerbation or firstappearance of any of these conditions or risk factors, the woman should contact her physician. The physician should then decide on whether its use should be discontinued.
Circulatory Disorders
Epidemiological studies have suggested an association between the use of combined oral contraceptives and an increased risk of arterial and venous thrombotic and thromboembolic diseases such as myocardial infarction, stroke, deep venous thrombosis, and pulmonary embolism.
Venous thromboembolism (VTE), manifesting as deep venous thrombosis and/or pulmonary embolism, may occur during the use of combined oral contraceptives. Thrombosis has been reported to occur in other blood vessels, e.g. hepatic, mesenteric, renal or retinal veins and arteries, in combined oral contraceptive users. 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 risk of thromboembolism (venous and/or arterial) increases with:

-	Age
-	Smoking (with heavier smoking and increasing age the risk further increases, especially in women over 35 years of age);
-	A positive family history (i.e. venous or arterial thromboembolism ever in a sibling or parent at a relatively early age). If an hereditary predisposition is suspected, the woman should be referred to a specialist for advice before deciding about any combined oral contraceptive use;
-	Obesity (Body mass index over 30 kg/m²);
-	Dyslipoproteinaemia;
-	Hypertension;
-	Valvular heart disease;
-	Atrial fibrillation;
-	Prolonged immobilisation, major surgery, any surgery to the legs, or major trauma. In these situations it is advisable to discontinue combined oral contraceptive use (in the case of elective surgery at least four weeks in advance) and not to resume until two weeks after complete remobilization.

Other medical conditions that have been associated with thrombotic disorders include diabetes mellitus,systemic lupus erythematosus, haemolytic uraemic syndrome, chronic inflammatory bowel disease (Crohn’s disease or ulcerative colitis) and sickle cell disease.
The onset of or increase in frequency or severity of migraine during combined oral contraceptive use (which may be prodromal of a cerebrovascular event) is a reason for immediate discontinuation of the combined oral contraceptive.
Biochemical factors that may be indicative of hereditary or acquired predisposition of venous or arterial thrombosis include Activated Protein C (APC) resistance, hyperhomocysteinaemia, antithrombin-III deficiency, protein C deficiency, protein S deficiency, antiphospholipid antibodies (anticardiolipin antibodies, plus anticoagulants).
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 combined oral contraceptive use.
Tumours
An increased risk of cervical cancer in long-term users of combined oral contraceptives has been reported in epidemiological studies.
A meta-analysis from epidemiological studies reports that there is an increased relative risk of having breast cancer diagnosed in women who are currently using combined oral contraceptives.
Benign liver tumours and, more rarely, malignant liver tumours, have been reported in users of combined oral contraceptives. In isolated cases, these tumours have led to life-threatening intra-abdominal haemorrhages. A hepatic tumour should be considered in the differential diagnosis when severe upper abdominal pain, liver enlargement or signs of intra-abdominal haemorrhage occur in women taking combined oral contraceptives.
Other conditions

•	Women with hypertriglyceridaemia, or a family history thereof, may be at an increased risk of pancreatitis when using combined oral contraceptives.
•	Small increases in blood pressure have been reported in many women taking combined oral contraceptives, clinically relevant increases may occur. If a sustained clinically significant hypertension develops during the use of a combined oral contraceptive then it is prudent for the physician to withdraw the combined oral contraceptive and treat the hypertension. Where considered appropriate, combined oral contraceptive use may be resumed if normotensive values can be achieved with antihypertensive therapy.
•	The following conditions have been reported to occur or deteriorate with combined oral contraceptive use:
	·	jaundice and/or pruritus related to cholestasis;
	·	gallstone formation;
	·	porphyria;
	·	systemic lupus erythematosis;
	·	haemolytic uraemic syndrome;
	·	Sydenham’s chorea;
	·	herpes gestationis;
	·	otosclerosis-related hearing loss.
•	Acute or chronic disturbances of liver function may necessitate the discontinuation of combined oral contraceptive use until markers of liver function return to normal. Recurrence of cholestatic jaundice that occurred first during pregnancy or previous use of sex steroids necessitates the discontinuation of combined oral contraceptives.
•	Although combined oral contraceptives 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 combined oral contraceptives. However, diabetic women should be carefully observed while taking combined oral contraceptives.
•	Crohn’s disease and ulcerative colitis have been associated with combined oral contraceptive use.
•	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 combined oral contraceptives.
•	Respiratory: Asthma may deteriorate in women using combined oral contraceptives.

Interactions
Drug interactions that result in an increased clearance of sex hormones can lead to breakthrough bleeding and oral contraceptive failure. This has been established with hydantoins, barbiturates, primidone, carbamazepine and rifampicin; oxcarbamazepine, topiramate, felbamate and griseofulvin are also suspected. The mechanism of this interaction appears to be based on the hepatic enzyme-inducing properties of these drugs. Maximal enzyme induction is generally not seen for 2-3 weeks but may then be sustained for at least 4 weeks after the cessation of drug therapy.
Contraceptive failures have also been reported with antibiotics, such as ampicillins and tetracyclines. The mechanism of this effect has not been elucidated.
Women on short-term treatment with any of the above-mentioned classes of drugs or individual drugs should use a barrier method temporarily in addition to the combined oral contraceptive, i.e. during the time of concomitant drug administration and for 7 days after their discontinuation. For women on rifampicin a barrier method should be used in addition to the combined oral contraceptive during the time of rifampicin administration and for 28 days after its discontinuation. If concomitant drug administration runs beyond the end of the tablets in the current oral contraceptive (COC) pack, the placebo tablets must be discarded and the next COC pack should be started right away, with the active ‘Saturday’tablet in the green starting zone.
In women on long-term treatment with hepatic enzyme-inducing drugs, increased contraceptive steroid doses are recommended. If a high contraceptive dosage is not desirable or appears to be unsatisfactory or unreliable, e.g. in the case of irregular bleeding, another method of contraception should be advised.
Oral contraceptives may interfere with the metabolism of other drugs. Accordingly, plasma and tissue concentrations may be affected (e.g. benzodiazepines).
Pregnancy and lactation
Extensive epidemiological studies have revealed neither an increased risk of birth defects in children born to women who have used combined oral contraceptives (COCs) prior to pregnancy, nor a teratogenic effect when COCs were taken inadvertently during early pregnancy. See also “Contra-indications”. Feminisation of the male foetus may occur.
Lactation may be influenced by combined oral contraceptives (COCs) as they may reduce the quantity and change the composition of breast milk, therefore, the use of COCs should generally not be recommended until the nursing mother has completely weaned her child. Small amounts of the contraceptive steroids and/or their metabolites may be excreted with the milk, but there is no evidence that this adversely affects infant health.

DOSAGE AND DIRECTIONS FOR USE
Medical examination/Consultation
A complete medical history and physical examination should be taken prior to the initiation or reinstitution of combined oral contraceptive (COC) use, guided by the contraindications and warnings and should be repeated at least annually during the use of combined oral contraceptives. Periodic medical assessment is also of importance because contraindications (e.g. a transient ischaemic attack, etc.) or risk factors (e.g. a family history of venous or arterial thrombosis) may appear for the first time during the use of a COC. The frequency and nature of these assessments should be adapted to the individual woman but should generally include special reference to blood pressure, breasts, abdomen and pelvic organs, including cervical cytology, and relevant laboratory tests.
How to take Marvelon 150/30
Tablets 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 28 consecutive days. The first tablet should be taken from the blister in the green section of the calendar pack marked with the appropriate day of the week. Each subsequent pack is started the day after the last tablet of the current pack. During the placebo days a withdrawal bleed usually occurs. This usually starts on day 2-3 after the last active tablet and may not have finished before the next pack is started.
How to start Marvelon 150/30
Nopreceding hormonal contraceptive use [in the past month]
Tablet taking has to start on day 1 of the woman's natural cycle (i.e. the first day of her menstrual bleeding). Ifthe woman starts with an inactive tablet on day 1, she should beadvised to additionally use a barrier method for the first 14 days of tablet- taking.
Changing from another combined oral contraceptive (COC)
The woman should start with Marvelon 150/30 on the dayafter the last active tablet of her previous combined oral contraceptive.
Changing from a progestogen-only-method (minipill, injection, implant)
The woman may switch any day from the minipill (from an implant on the day of its removal, from an injectable when the next injection would be due), but should in all of these cases be advised to use a barrier method additionally for the first 14 days of tablet-taking.
Following first-trimester abortion
The woman may start immediately. She should be advised to additionally use a barrier method for the first 14 days of tablet-taking.
Following delivery or second-trimester abortion.
For breastfeeding women see “Side-effects and Special Precautions”.
Women should be advised to start at day 21 after delivery or second-trimester abortion. When starting later, the woman should be advised to use a barrier method additionally for the first 14 days of tablet-taking. However, if intercourse has already occurred, pregnancy should be excluded before the actual start of combined oral contraceptive use, or the woman has to wait for her first menstrual period.
Management of Missed Tablets
Note: The five small tablets immediately before the green starting zone and the first two (small) tablets in the green starting zone of the blister pack contain placebo tablets and can thus be disregarded if missed. However, they should be discarded to avoid unintentional prolonging of the placebo tablet phase. These rules for the management of missed tablets refer to missed 'active' tablets, i.e. the 21 large tablets starting with 'Saturday’in the green section.
If the user is less than 12 hours late in taking any tablet, contraceptive protection is not reduced. The woman should take the tablet as soon as she remembers and should take further tablets at the usual time.
If she is more than 12 hours late in taking any active tablet, contraceptive protection may be reduced. The management of missed tablets can be guided by the following two basic rules:

·	'active tablet'-taking must never be discontinued for longer than 7 days.
·	7 days of uninterrupted 'active tablet'-taking are required to attain adequate suppression of the hypothalamic-pituitary-ovarian-axis.

Accordingly the following advice can be given in daily practice:

·

The user should take the last missed tablet as soon as she remembers, even if this means taking two tablets at the same time. She then continues to take tablets at her usual time. In addition, a barrier method such as a condom should be used for the next 7 days. If these 7 days extend beyond the last 'Friday' -tablet in the pack, the user should take the tablets up to and including that Friday, discard the pack and start a new pack next day with the Saturday tablet in the green starting zone. The user is unlikely to have a withdrawal bleed until the placebo tablet interval of the second pack, but she may experience spotting or breakthrough bleeding on 'active tablet'-taking days.

·

If the user has missed any of the first 7 active tablets (counting from 'Saturday' in the green starting zone onwards) and intercourse took place in the preceding 7 days, the possibility of a pregnancy should be considered. The more tablets missed and the closer they are to the regular placebo tablet interval, the higher the risk of a pregnancy.

If the woman missed active tablets and subsequently has no withdrawal bleed in the first normal placebo tablet interval, the possibility of a pregnancy should be considered.
Advice in case of vomiting
If vomiting occurs within 3-4 hours after tablet taking, absorption may not be complete. In such an event, the advice concerning missed tablets, as given in the previous section, 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.
How to delay a period
To delay a period the woman should continue with another pack of Marvelon 150/30 without having a placebo tablet interval (i.e. she should stop the current pack after taking the last large tablet on Friday, and start the next day with the 'Saturday' tablet in the green starting zone of the new pack). The extension can be carried on for as long as wished until the end of the second pack. During the extension the woman may experience breakthrough bleeding or spotting. Regular intake of Marvelon 150/30 is then resumed after the usual 7-day placebo tablet interval.
Reduced cycle control
With all combined oral contraceptives, 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 combined oral contraceptive has been taken according to the directions described above, it is unlikely that the woman is pregnant. However, if the combined oral contraceptive 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 combined oral contraceptive use is continued.

SIDE-EFFECTS AND SPECIAL PRECAUTIONS       
Serious adverse effects: Please refer to “Warnings”.
Other adverse effects: The following adverse effects have been reported in users of combined oral contraceptives. The association has been neither confirmed nor refuted: breast tenderness, pain, secretion; headache; migraine; changes in libido; depressive moods, contact lens intolerance; nausea, vomiting; changes in vaginal secretion; various skin disorders; fluid retention; changed body mass; hypersensitivity reaction.
Precautions
Women should be advised that oral contraceptives do not protect against HIV infections (AIDS) and other sexually transmissible diseases.
Reduced efficacy: The efficacy of combined oral contraceptives may be reduced in the event of missed tablets, vomiting, or concomitant medication.
Laboratory tests
The 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 metabolites and parameters of coagulation and fibrinolysis. Changes generally remain within the normal laboratory range.
Effects on ability to drive and use machines
No observed effects.

KNOWN SYMPTOMS OF OVERDOSAGE AND PARTICULARS OF ITS TREATMENT
There have been no reports of serious deleterious effects from overdose. Symptoms that may occur in this case are: nausea, vomiting and possible slight vaginal bleeding in young girls. There are no antidotes and further treatment should be symptomatic.

IDENTIFICATION
MARVELON 150/30 consists of two types of tablets distinguished by mark and size. The 21 larger white tablets contain the active ingredients and are round and biconvex. They have bevelled edges, coded ORGANON and a star on one side and the tablet code TR above 5 on the reverse. The 7 smaller white tablets are round and flat with bevelled edges coded KH above 2 on one side and a square on the reverse.

PRESENTATION
Push-through strips contain 21 active white tablets and 7 smaller white placebo tablets, the latter being circled in red on the strip foil.

STORAGE INSTRUCTIONS
Store below 30°C. Protect from light and moisture. Keep out of reach of children.

REGISTRATION NUMBER
Q/18.8/324

NAME AND BUSINESS ADDRESS OF THE HOLDER OF THE CERTIFICATE OF REGISTRATION
Donmed Pharmaceuticals (Pty) Ltd
Cambridge Place
cnr Kirkby & Oxford Roads
Bedfordview 2007

DATE OF PUBLICATION OF THE PACKAGE INSERT
11 June 2003

Under license of NV Organon, The Netherlands

Updated on this site: March 2004
Source: Pharmaceutical Industry

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