Microgynon ED Fe Oral Contraceptive Tablets

Microgynon® ED Fe

 

NAME OF THE PRODUCT

Microgynon ED Fe

 

QUALITATIVE AND QUANTITATIVE COMPOSITION

21 hormone-containing beige coated tablets:
Each coated tablet contains 0.03 mg ethinylestradiol, 0.15 mg levonorgestrel
7 hormone-free brown coated tablets.
Excipient: lactose 30 mg
For a full list of excipients, see ‘Pharmaceutical Particulars’

 

PRESENTATION

Coated tablets for Oral administration

 

CLINICAL DATA

Indications

Oral contraception

 

Dosage and method of administration
Method of administration

Oral use

Dosage regimen
How to take Microgynon ED Fe
Combined oral contraceptives, when taken correctly, have a failure rate of approximately 1% per year. The failure rate may increase when pills are missed or taken incorrectly.

Tablets must be taken in the order directed on the package every day at about the same time with some liquid as needed. Tablet taking is continuous. One tablet is to be taken daily for 28 consecutive days. Each subsequent pack is started the day after the last tablet of the previous pack

How to start Microgynon ED Fe
Tablet-taking has to start on day 1 of the woman’s natural cycle (i.e. the first day of her menstrual bleeding).

Advice in case of gastro-intestinal disturbances
In case of severe gastro-intestinal disturbances, absorption may not be complete and additional contraceptive measures should be taken. If vomiting occurs within 3-4 hours after taking a beige hormone-containing coated tablet, the advice concerning missed tablets, is applicable.

Additional information on special populations

Children and adolescents
Microgynon ED Fe is only indicated after menarche.

Geriatric patients
Not applicable. Microgynon ED Fe is not indicated after menopause.

Patients with hepatic impairment
Microgynon ED Fe is contraindicated in women with severe hepatic diseases.

See also section ‘Contraindications’.

Patients with renal impairment
Microgynon ED Fe has not been specifically studied in renally impaired patients. Available data do not suggest a change in treatment in this patient population.

 

Contraindications

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 COC use, the product should be stopped immediately.

˃Presence or a history of venous or arterial thrombotic/thromboembolic events (e.g. deep venous thrombosis, pulmonary embolism, myocardial infarction) or of a cerebrovascular accident.

˃Presence or history of prodromi of a thrombosis (e.g. transient ischaemic attack, angina pectoris).

˃A high risk of venous or arterial thrombosis (see ‘Special warnings and precautions for use).

˃History of migraine with focal neurological symptoms.

˃Diabetes mellitus with vascular involvement.

˃Pancreatitis or a history thereof if associated with severe hypertriglyceridemia.

˃Severe hepatic disease as long as liver function values have not returned to normal.

˃Presence or history of liver tumors (benign or malignant).

˃Known or suspected sex-steroid influenced malignancies (e.g. of the genital organs or the breasts).

˃Undiagnosed vaginal bleeding.

˃Known or suspected pregnancy.

˃Hypersensitivity to the active substances or to any of the excipients.

 

Special warnings and precautions for use

Warnings

Circulatory Disorders

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, deep venous thrombosis, pulmonary embolism and of cerebrovascular accidents. These events occur rarely.

The risk of VTE is highest during the first year of use. This increased risk is present after initially starting a COC or restarting (following a 4 week or greater pill free interval) the same or a different COC. Data from a Large, prospective 3-armed cohort study suggest that this increased risk is mainly present during the first 3 months.

Overall the risk for venous thromboembolism (VTE) in users of low estrogen dose (< 50 µg ethinylestradiol) COCs is two to threefold higher than for non-users of COCs who are not pregnant and remains lower than the risk associated with pregnancy and delivery.
VTE may be life-threatening or may have a fatal outcome. (in 1 – 2 % of the
cases).

Venous thromboembolism (VTE), manifestation as deep venous thrombosis and/or pulmonary embolism, may occur during the use of all COCs. Extremely rarely, thrombosis has been reported to occur in other blood vessels, e.g. hepatic, mesenteric, renal, cerebral or retinal veins and arteries, in COC users. There is no consensus as to whether the occurrence of these events is associated with the use of COCs.

Symptoms of deep vernous thrombosis (DVT) can include: unilateral swelling of the leg or along a vein in the leg; pain or tenderness in the leg which may be felt only when standing or walking, increased warmth in the affected leg; red  or discoloured skin on the leg.

Symptoms of pulmonary embolism (PE) can include: sudden onset of unexplained shortness of breath or rapid breathing; sudden coughing which may bring up blood; sharp chest pain which may increase with deep breathing; sense of anxiety; severe light headache or dizziness; rapid or irregular heartbeat. Some of these symptoms (e.g. “shortness of breath”, “coughing”) are non-specific and might be misinterpreted as more common or less severe events (e.g. respiratory tract infections).

An arterial thromboembolic event can include cerebrovascular accident, vascular occlusion or myocardial infarction (MI). Symptoms of a cerebrovascular accident can include: sudden numbness or weakness of the face, arm or leg, especially on one side of the body; sudden confusion, trouble speaking or understanding; sudden trouble seeing in one or both eyes; sudden trouble walking, dizziness, loss of balance or coordination; sudden, severe or prolonged headache with no known cause; loss of consciousness or fainting with or without seizure. Other signs of vascular occlusion can include: sudden pain, swelling and slight blue discoloration of an extremity; acute abdomen.

Symptoms of MI can include: pain, discomfort, pressure, heaviness, sensation of squeezing or fullness in the chest, arm, or below the breastbone; discomfort radiating to the back, jaw, throat, arm, stomach; fullness, indigestion or choking feeling; sweating, nausea, vomiting or dizziness; extreme weakness, anxiety, or shortness of breath; rapid or irregular heartbeats.

Arterial thromboembolic events may be life-threatening or may have a fatal outcome.
The potential for an increased synergistic risk of thrombosis should be considered in women who possess a combination of risk factors or exhibit a greater severity of an individual risk factor. This increased risk may be greater than a simple cumulative risk of the factors. A COC should not be prescribed in case of a negative risk benefit assessment. (see ‘Contraindications’)

The risk of venous or arterial thrombotic/thromboembolic events or of a cerebrovascular accident increases with:

˃age

˃obesity (body mass index over 30 kg/m2)

˃a positive family history (i.e. venous or arterial thromboembolism ever in a sibling or parent at a relatively early age). If a hereditary predisposition is known or suspected the woman should be referred to a specialist for advice before deciding about any COC use.

˃prolonged immobilization, major surgery, any surgery to the legs, or major trauma. In these situations it is advisable to discontinue COC use (in the case of elective surgery at least four weeks in advance) and not to resume until two weeks after complete remobilization;

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

˃dyslipoproteinemia;

˃hypertension;

˃migraine;

˃valvular heart disease;

˃atrial fibrillation;

There is no consensus about the possible role of varicose veins and superficial thrombophlebitis in venous thromboembolism. The increased risk of thromboembolism in the puerperium must be considered (for information on pregnancy and lactation see section ‘Pregnancy and Lactation’).

Other medical conditions which have been associated with adverse circulatory events include diabetes mellitus, systemic lupus erythematosus, hemolytic uremic 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, hyperhomocysteinemia, antithrombin-III deficiency, protein C deficiency, protein S deficiency, antiphospholipid antibodies (antcardiolipin 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 low-dose COCs (<0.05 mg ethinylestradiol).

Tumors
The most important risk factor for cervical cancer is persistent HPV infection. Some epidemiological studies have indicated that long-term use of COCs may further contribute to this increased risk but there continues to be controversy about the extent to which this finding is attributable to confounding effects, e.g., cervical screening and sexual behaviour including use of barrier contraceptives.

A meta-analysis from 54 epidemiological studies reported that there is a slightly increased relative risk (RR = 1.24) of having breast cancer diagnosed in women who are currently using COCs. The excess risk gradually disappears during the course of the 10 years after cessation of COC use. Because breast cancer is rare in women under 40 years of 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. These studies do not provide evidence for causation. 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 breast cancers diagnosed in ever-users tend to be less advanced clinically than the cancers diagnosed in never- users.

In rare cases, benign liver tumors, and even more rarely, malignant liver tumors have been reported in users of COCs. In isolated cases, these tumors have led to life-threatening intra-abdominal hemorrhages. A liver tumor should be considered in the differential diagnosis when severe upper abdominal pain, liver enlargement or signs of intra-abdominal hemorrhage occur in women taking COCs. Malignancies may be life-threatening or may have a fatal outcome.

Other conditions
Women with hypertrigliceridemia,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, but the evidence of an association with COC use is inconclusive: jaundice and/or pruritus related to cholestasis; gallstone formation; porphyria; systemic lupus erythematosus: hemolytic uremic syndrome; Sydenham’s chorea; herpes gestationis; otosclerosis-related hearing loss.

In women with hereditary angioedema exogenous estrogens may induce or exacerbate symptoms of angioedema.

Acute-or chronic disturbances of liver function may necessitate the discontinuation of COC use until markers of liver function return to normal. Recurrence of cholestatic jaundice which occurred first during pregnancy or previous use of sex steroids necessitates the discontinuation of COCs.

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 low-dose COCs (containing <0.05 mg ethinylestradiol). However, diabetic women should be carefully observed while taking COCs.

Crohn’s disease and ulcerative colitis have been associated with COC use. Chloasma gravidarum. Women with a tendency to chloasma should avoid exposure to the sun or ultraviolet radiation whilst taking COCs.

 

Medical examination/consultation

Women should be advised that oral contraceptives do not protect against HIV infections (AIDS) and other sexually transmitted diseases.

Reduced efficacy
The efficacy of COCs may be reduced in the event of e.g. missed hormone- containing beige coated tablets, gastro-intestinal disturbances (section ‘Advice in case of gastro-intestinal disturbances’) during hormone- containing beige coated tablet taking or concomitant medication (section ‘Interaction with other medicinal products and other forms of interaction’).

Reduced cycle control
With all COCs, irregular bleeding (spotting or breakthrough bleeding) may occur, especially during the first months of use.

In some women withdrawal bleeding may not occur during the hormone- free brown coated tablet phase. If the COC has been taken according to the directions described in section ‘Dosage and method of administration’ 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.

 

Interaction with other medicinal products and other forms of interaction

Effects of other medicaments on Microgynon ED Fe
Interactions can occur with drugs that induce microsomal enzymes which can result in increased clearance of sex hormones and which may lead to breakthrough bleeding and/or contraceptive failure. 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. The barrier method should be used during the time of concomitant drug administration and for 28 days after their discontinuation.

If the period during which the barrier method is used runs beyond the end of the hormone-containing beige coated tablets in the COC pack, the hormone-free brown coated tablets should be omitted and the next COC pack be started.

Substances increasing the clearance of COCs (diminished efficacy of COCs by enzyme-induction), e.g.:

Phenytoin, barbiturates, primidone, carbamazepine, rifampicin, and possibly also oxcarbazepine, topiramate, felbamate, griseofulvin and products containing St. John’s wort).

Substances with variable effects on the clearance of COCs, e.g.:

When co-administered with COCs, many HIV/HCV protease inhibitors and non-nucleoside reverse transcriptase inhibitors can increase or decrease plasma concentrations of estrogen or progestin. These changes may be clinically relevant in some cases.

Effects of COCs on other medicaments

Oral contraceptives may affect the metabolism of certain other drugs. Accordingly, plasma and tissue concentrations may either increase (e.g. cyclosporin) or decrease (e.g. lamotrigine).

Other forms of interactions
Laboratory tests
The use of contraceptive steroids may influence the results of certain laboratory tests.

 

Pregnancy and Lactation

Pregnancy
Microgynon ED Fe is not indicated during pregnancy. If pregnancy occurs during treatment with Microgynon ED Fe, further intake must be stopped. However, extensive 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.

Lactation
Lactation may be influenced by 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.

 

Effects on ability to drive or use machines

No studies on the effects on the ability to drive and use machines have been performed. No effects on ability to drive and use machines have been observed in users of COCs.

 

Undesirable effects

Side effects that have been reported in users of COCs but for which the association has been neither confirmed nor refuted are:

System Organ Class Common (≥ 1/100) Uncommon (≥1/1000 and <1/100) Rare (<1/1000)
Eye disorders Contact lens intolerance
Gastrointestinal disorders Nausea Abdominal pain Vomiting Diarrhea
Immune system disorders Hypersensitivity
Investigations Weight increased Weight decreased
Metabolism and nutrition disorders Fluid retention
Nervous system disorders Headache Migraine
Psychiatric disorders Depressed mood Mood altered Libido decreased Libido increased
Reproductive system and breast disorders Breast pain, Breast tenderness Breast hypertrophy Vaginal discharge Breast discharge
Skin and subcutaneous tissue disorders Rash Urticaria Erythema nodosum Erythema multiforme

The following serious adverse events have been reported in women using COCs, which are discussed in section ‘Special warnings and precautions for
use’:

˃Venous thromboembolic disorders

˃Arterial thromboembolic disorders

˃Cerebrovascular accidents

˃Hypertension

˃Hypertriglyceridemia

˃Changes in glucose tolerance or effect on peripheral insulin resistance

˃Liver tumours (benign and malignant)

˃Liver functions disturbances

˃In women with hereditary angioedema exogenous estrogens may induce or exacerbate symptoms of angiodema

˃Occurrence or deterioration of conditions for which association with COC use is not conclusive: jaundice and/or pruritus related to chelestasis; gallstone formation; porphyria; systemic lupus erythematosus; hemolytic uremic syndrome; Sydenham’s chorea; herpes gestations; otosclerosis-related hearing loss; Crohn’s disease; ulcerative colitis; cervical cancer.

The frequency of diagnosis of breast cancer is very slightly increased among OC 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 ‘Contraindication’ and ‘Special warning and precautions for use’

 

Overdose

There have been no reports of serious deleterious effects from overdose. Symptoms that may occur in case of taking an overdose of hormone- containing beige coated tablets are: nausea, vomiting and, in young girls, slight vaginal bleeding. There are no antidotes and further treatment should be symptomatic.

 

PHARMACOLOGICAL PROPERTIES

Pharmacodynamic properties
Pharmacotherapeutic group (ATC): Progestogens and estrogens, fixed combinations
ATC Code: G03AA

The contraceptive effect of COCs 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
Levonorgestrel
Absorption
Orally administered levonorgestrel is rapidly and completely absorbed. Peak serum concentrations of about 3 – 4 ng/ml are reached at about 1 hour after single ingestion. Levonorgestrel is almost completely bioavailable after oral administration.

Distribution
Levonorgestrel is bound to serum albumin and to sex hormone binding globulin (SHBG). Only 1.3% of the total serum drug concentrations are present as free steroid, approximately 64% are specifically bound to SHBG and about 35% are non-specifically bound to albumin. The ethylestradiol-induced increase in SHBG influences the proportion of levonorgestrel bound to 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 levonorgestrel is about 184 l after single administration.

Metabolism
Levonorgestrel is completely metabolized by the known pathways of steroid metabolism. The clearance rate from serum is approximately 1.3 – 1.6 ml/min/kg.

Elimination
Levonorgestrel serum levels decrease in two phases. The terminal disposition phase is characterized by a half-life of approximately 20 – 23 hours. Levonorgestrel is not excreted in unchanged form. Its metabolites are excreted at a urinary to biliary ratio of about 1:1 The half- life of metabolite excretion is about 1 day.

Steady-state conditions
Following daily ingestion drug serum levels increase about three – to fourfold reaching steady-state conditions during the second half of a treatment cycle. Levonorgestrel pharmacokinetics are influenced by SHBG levels, which are increased about 1.7 fold after daily oral administration of Microgynon. This effect leads to a reduction of the clearance rate to about 0.7 ml/min/kg at steady-state.

Ethinylestradiol
Absorption
Orally administered ethinylestradiol is rapidly and completely absorbed. Peak serum concentrations of about 95 pg/mI are reached within 1- 2 hours. During absorption and first-liver passage, ethinylestradiol is metabolized extensively, resulting in a mean oral bioavailability of about 45% with a large interindividual variation of about 20- 65%.

Distribution
Ethinylestradiol is highly but non-specifically bound to serum albumin (approximately 98%), and induces an increase in the serum concentrations of SHBG. An apparent volume of distribution of about 2.8 – 8.6 l/kg was reported.

Metabolism
Ethinytestradiol 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 clearance rate was reported to be 2.3-7 ml/min/kg.

Elimination
Ethinylestradiol serum levels decrease in two disposition phases characterized by half-lives of about 1 hour and 10-20 hours, respectively. Unchanged drug is not excreted, ethinylestradiol metabolites are excreted at a urinary to biliary ratio of 4:6. The half-life of metabolite excretion 1 day.

Steady-state conditions
Ethmnylestradiol serum concentrations increase slightly after daily oral administration of Microgynon. The maximum concentrations are about 114 pg/ml at the end of a treatment cycle. According to the variable half- life of the terminal disposition phase from serum and the daily ingestion steady-state serum levels of ethinylestradiol will be reached after about one week.

 

Preclinical safety data

Preclinical data reveal no special risks for humans based on conventional studies of repeated dose toxicity, genotoxicity, carcinogenic potential and toxicity to reproduction. However, it should be borne in mind that sex steroids can promote the growth of certain hormone-dependent tissues and tumors.

 

PHARMACEUTICAL PARTICULARS

List of excipients

Ferrous fumerate

Lactose Monohydrate

Maize Starch

Povidone 25

Talc

Magnesium Stearate

Sucrose

Povidone 700 000

Macrogol 6000

Calcium Carbonate

Glycerol 85%

Titanium Dioxide

Ferric Oxide Pigment Yellow

Montanglycol Wax

 

Incompatibilities

None

 

Special precautions for storage

Do not store above 25°C

Keep out of reach of children

 

Nature and contents of container

PVC/Alu blister packs

Microgynon ED Fe: boxes of 3 x 28

 

Instructions for Use of Family Planning Pills

Wait for your next period to start.

When it does, you should take your first pill on the first day of bleeding, either with your breakfast or your evening meal.

 

Take hold of one of the packs. You will see that it has two different sides.
The pills lie in the transparent plastic part.

On the same side are printed arrows which show you the direction in which you should take the pills from the pack.

 

On the first day of your bleeding you must take the pill which lies under the arrow at the top left-hand corner.

Using a finger, press this pill downwards out of the pack.

 

Put the pill in your mouth and swallow it with some liquid.

From now on you take a pill at the same hour every day. Always remove the pills in the direction shown by the printed arrows. You must continue to take a pill every day until the pack is empty. Your monthly bleeding will usually occur while you are taking the last few pills in the pack.

 

No matter whether your bleeding has stopped or not, on the day after you have taken the last pill in the pack take a new pack and continue to swallow a pill every

day again starting with the pill under the arrow at the top left-hand corner.

 

If you have any questions or if, while you are taking the pills, you have any complaints such as feeling poorly, headaches, blurred vision, pains in the legs or chest, or if your bleeding is irregular or fails to occur, go to your doctor or the nearest family planning clinic at once.

 

Manufactured by

Bayer Pharma AG

13342 Berlin, Germany.

 

DATE OF REVISION

19.11.2013

 

CCDS Ver 12

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