Smilla 125 Micrograms/30 Micrograms Coated Tablets
SUMMARY OF PRODUCT CHARACTERISTICS
1 NAME OF THE MEDICINAL PRODUCT
Smilla 125 micrograms/30 micrograms coated tablets
2 QUALITATIVE AND QUANTITATIVE COMPOSITION
Each tablet contains 125 micrograms levonorgestrel and 30 micrograms ethinylestradiol.
Excipients with known effect:
Each tablet contains 31.35 mg of lactose (as lactose monohydrate) and 22.01 mg of sucrose.
For the full list of excipients, see section 6.1
3 PHARMACEUTICAL FORM
Coated tablet
Light brownish yellow, biconvex, round, coated tablets. Diameter is approximately 5.7 mm.
4 CLINICAL PARTICULARS
4.1 Therapeutic indications
Oral contraception.
The decision to prescribe Smilla should take into consideration the individual woman’s current risk factors, particularly those for venous thromboembolism (VTE), and how the risk of VTE with Smilla compares with other combined hormonal contraceptives (CHCs) (see sections 4.3 and 4.4).
4.2
Posology and method of administration
Method of administration
Oral use.
Posology
Tablets must be taken orally in the order directed on the blister package at about the same time every day, with some liquid if necessary. One tablet is to be taken daily for 21 consecutive days. Each subsequent blister pack is started after a 7- day tablet free interval, during which time a withdrawal bleed usually occurs. The withdrawal bleed usually starts on the 2nd or 3rd day after the last tablet has been taken and may still persist when the next blister pack is started.
How to start taking Smilla
No preceding use of hormonal contraceptives [in the past month]
Tablet-taking is started on day 1 of the woman’s natural cycle (= the first day of her menstrual bleeding). Starting on days 2-5 is also possible, but the concomitant use of a barrier method is recommended for the first 7 days of the first cycle
Changing from another combined hormonal contraceptive ( combined oral contraceptive (COC) vaginal ring, transdermal patch)
The woman should start with Smilla preferably on the day after the last active tablet (the last tablet containing the active substances) of her previous COC, but at the latest on the day following the usual tablet-free or placebo tablet interval of her previous COC. In case a vaginal ring or transdermal patch has been used, the woman should start using Smilla preferably on the day of removal, but at the latest when the next application would have been due.
Change from a progestogen-only preparation (progestogen-only pill, injection, implant) or from an intrauterine system (IUS)
If the progestogen-only pill has been taken previously, the change can be made on any day (the change from an implant or an IUS may take place on the day of removal, and from an injectable when the next injection would be due). However, in all cases, during the first 7 days of tablet intake, additional contraceptive measures are necessary.
Following first-trimester abortion
The woman may start taking the tablets immediately. In this case, it is not necessary to take further contraceptive precautions.
Following delivery or second-trimester abortion For breast-feeding - see section 4.6.
Taking the tablets should be started 21 to 28 days after delivery by women who are not breast-feeding or after second-trimester abortion, respectively, as in this postpartal phase there is an increased risk for thromboembolic disorders. When starting later, the woman must use a concomitant barrier method for the first 7 days of tablet-taking. If the woman has already had sexual intercourse, pregnancy must be excluded before she starts the tablets or she should wait for her next menstrual period.
Management of forgotten tablet intake
Smilla contains a very low dose of both hormones and therefore, the range of contraceptive efficacy is very narrow when a tablet has been forgotten.
If the time of intake is less than 12 hours late, contraceptive effect is not reduced. The woman should make up the tablet as soon as possible and take the next tablets at the usual time.
If the time of intake is more than 12 hours late, contraceptive effect may be reduced. The following two basic rules apply when tablets have been missed:
1. Taking the tablets must never be discontinued for longer than 7 days.
2. Adequate suppression of the hypothalamic-pituitary-ovarian axis requires 7 days of uninterrupted tablet-taking.
Accordingly, the following advice can be given for daily practice:
Week 1
The intake of the last missed tablet should be made up as soon as possible, even if this means that the woman is taking two tablets at the same time. She then continues to take the next tablets at her usual time. In addition, she should use a barrier method such as a condom for the next 7 days. If the woman has had sexual intercourse in the previous 7 days, the possibility of a pregnancy must be considered. The more tablets have been missed and the closer the forgotten intake is to the regular tablet-free break, the higher is the risk of pregnancy.
Week 2
The intake of the last missed tablet should be made up as soon as possible, even if this means that the woman is taking two tablets at the same time. She then continues to take the next tablets at her usual time. Provided that the woman has taken her tablets correctly in the 7 days preceding the first missed tablet, there is no need to use additional precautions. If this is not the case or if more than one tablet has been missed, the woman should be advised to use an additional barrier method (such as a condom) for 7 days.
Week 3
The risk of contraceptive failure is imminent because of the ensuing tablet-free interval. However, reduced contraceptive protection can still be prevented by adjusting the intake. By adhering to one of the following alternatives, there is no need to use extra precautions, provided that all the tablets have been taken correctly in the 7 days preceding the missed tablet. If this is not the case, the woman should follow the first of these two options. Additionally a concomitant barrier method (such as a condom) should be used for the next 7 days.
1. The intake of the last missed tablet should be made up as soon as possible, even if this means that the woman is taking two tablets at the same time. She then continues to take the next tablets at her usual time. Taking the tablets from the next blister pack is started as soon as the current blister pack is finished, i.e. there is no tablet-free interval between the blister packs. There will probably be no withdrawal bleed until the end of the second blister pack, but the woman may experience spotting or breakthrough bleeding on tablet-taking days.
2. The woman can also stop taking tablets from the current blister pack immediately. In this case she should have a tablet-free break of up to 7 days, including the days the intake of the tablets was missed, and then continue with the next blister pack.
If the woman missed several tablets and has no withdrawal bleed during the first normal tablet-free break, the possibility of a pregnancy must be considered.
Advice in case of gastro-intestinal disturbances
In case of severe gastro-intestinal symptoms (e.g., vomiting or diarrhoea), absorption of the active ingredients may not be complete and additional contraceptive measures should be taken.
If vomiting or severe diarrhoea occurs within 3 to 4 hours after taking a tablet, the woman should apply the advice concerning missed tablets. If the woman does not want to change her normal tablet intake, she has to take the necessary extra tablet(s) from another blister pack.
Postponement of the date of the period and change of the weekday of the start of the period
To delay a withdrawal bleed the woman should start a new blister pack of Smilla immediately after taking the last tablet from the current pack without any tablet-free break. The prolonged intake can be continued as long as desired, till all tablets from the second pack have been used. During this prolonged intake breakthrough bleeding or spotting may occur. The regular intake of Smilla tablets is then resumed after the usual 7-day tablet-free break.
To change the day of the week the withdrawal bleed begins during the current tablet intake, she can shorten her next tablet-free break by as many days as she likes. The shorter the break, the higher the risk that there will be no withdrawal bleed and that breakthrough bleeding and spotting will appear during the intake from the second blister pack (just as when delaying a period). The tablet-free break must in no case be prolonged.
4.3 Contraindications
Combined hormonal contraceptives (CHCs) must not be taken in the presence of any of the conditions listed below. Should any of the conditions appear for the first time during the use of combined hormonal contraceptives, the product should be stopped immediately.
Presence or risk of venous thromboembolism (VTE)
- Venous thromboembolism - current VTE (on anticoagulants) or history of (e.g. deep venous thrombosis [DVT] or pulmonary embolism [PE])
- Known hereditary or acquired predisposition for venous thromboembolism, such as APC-resistance, (including Factor V Leiden), antithrombin-III-deficiency, protein C deficiency, protein S deficiency
- Major surgery with prolonged immobilisation (see section 4.4)
- A high risk of venous thromboembolism due to the presence of multiple risk factors (see section 4.4)
Presence or risk of arterial thromboembolism (ATE)
- Arterial thromboembolism - current arterial thromboembolism, history of arterial thromboembolism (e.g. myocardial infarction) or prodromal condition (e.g. angina pectoris)
- Cerebrovascular disease - current stroke, history of stroke or prodromal condition (e.g. transient ischaemic attack, TIA)
- Known hereditary or acquired predisposition for arterial thromboembolism, such as hyperhomocysteinaemia and antiphospholipid-antibodies (anticardiolipin-antibodies, lupus anticoagulant).
- History of migraine with focal neurological symptoms.
- A high risk of arterial thromboembolism due to multiple risk factors (see section 4.4) or to the presence of one serious risk factor such as:
- diabetes mellitus with vascular symptoms
- severe hypertension
- severe dyslipoproteinaemia
- Pancreatitis or pancreatitis in the medical history, when accompanied by severe hypertriglyceridemia,
- Known or suspected sex-steroid influenced malignancies (e. g. of the breasts or the genital organs),
- Severe hepatic disease, current or previous, as long as liver function values have not returned to normal,
- Presence or history of benign or malignant liver tumours,
- Undiagnosed vaginal bleeding,
- Amenorrhea of unknown cause,
- Hypersensitivity to the active substances (levonorgestrel, ethinylestradiol) or to any of the excipients listed in section 6.1
4.4 Special warnings and precautions for use
Warnings
If any of the conditions or risk factors mentioned below is present, the suitability of Smilla should be discussed with the woman.
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 doctor to determine whether the use of Smilla should be discontinued.
Risk of venous thromboembolism (VTE)
The use of any combined hormonal contraceptive (CHC) increases the risk of venous thromboembolism (VTE) compared with no use.
The decision to use Smilla should be taken only after a discussion with the woman to ensure she understands:
- the risk of VTE with Smilla
- how her current risk factors influence this risk
- and that her VTE risk is highest in the first ever year of use.
There is also some evidence that the risk is increased when a CHC is re-started after a break in use of 4 weeks or more.
In women who do not use a CHC and are not pregnant about 2 out of 10,000 will develop a VTE over the period of one year. However, in any individual woman the risk may be far higher, depending on her underlying risk factors (see below).
Out of 10,000 women who use a levonorgestrel-containing CHC containing about 61 will develop a VTE in one year.
The number of VTEs per year with low dose CHCs is fewer than the number expected in women during pregnancy or in the postpartum period.
VTE may be fatal in 1-2 % of the cases.
Number of VTE events per 10,000 women in one year
Extremely rarely, thrombosis has been reported to occur in CHC users in other blood vessels, e.g. hepatic, mesenteric, renal, cerebral or retinal veins and arteries.
Risk factors for VTE
The risk for venous thromboembolic complications in CHC users may increase substantially in a woman with additional risk factors, particularly if there are multiple risk factors (see table).
Smilla is contraindicated if a woman has multiple risk factors that put her at high risk of venous thrombosis (see section 4.3). If a woman has more than one risk factor, it is possible that the increase in risk is greater than the sum of the individual factors - in this case her total risk of VTE should be considered. If the balance of benefits and risks is considered to be negative a CHC should not be prescribed (see section 4.3).
Risk factors for VTE
|
Risk factor |
Comment |
|
Obesity (body mass index over 30 kg/m2) |
Risk increases substantially as BMI rises. Particularly important to consider if other risk factors also present. |
|
Prolonged immobilisation, major |
In these situations it is advisable to |
|
surgery, any surgery to the legs or pelvis, neurosurgery, or major trauma |
discontinue use of the tablet (in the case of elective surgery at least four weeks in advance) and not resume until two weeks after complete remobilisation. Another method of contraception should be used to avoid unintentional pregnancy. Antithrombotic treatment should be considered if Smilla has not been discontinued in advance. |
|
Note: temporary immobilisation including air travel > 4 hours can also be a risk factor for VTE, particularly in women with other risk factors | |
|
Positive family history (venous thromboembolism ever in a sibling or parent especially at a relatively early age eg. before 50). |
If a hereditary predisposition is suspected, the woman should be referred to a specialist for advice before deciding about any CHC use |
|
Other medical conditions associated with VTE |
Cancer, systemic lupus erythematosus, haemolytic uraemic syndrome, chronic inflammatory bowel disease (Crohn’s disease or ulcerative colitis) and sickle cell disease |
|
Increasing age |
Particularly above 35 years |
There is no consensus about the possible role of varicose veins and superficial thrombophlebitis in the onset or progression of venous thrombosis.
The increased risk of thromboembolism in pregnancy, and particularly the 6 week period of the puerperium, must be considered (for information on “Pregnancy and lactation” see section 4.6).
Symptoms of VTE (deep vein thrombosis and pulmonary embolism)
In the event of symptoms women should be advised to seek urgent medical attention and to inform the healthcare professional that she is taking a CHC.
Symptoms of deep vein thrombosis (DVT) can include:
- unilateral swelling of the leg and/or foot 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 be associated with haemoptysis;
sharp chest pain;
severe light headedness 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).
Other signs of vascular occlusion can include: sudden pain, swelling and slight blue discoloration of an extremity.
If the occlusion occurs in the eye symptoms can range from painless blurring of vision which can progress to loss of vision. Sometimes loss of vision can occur almost immediately.
Risk of arterial thromboembolism (ATE)
Epidemiological studies have associated the use of CHCs with an increased risk for arterial thromboembolism (myocardial infarction) or for cerebrovascular accident (eg transient ischaemic attack, stroke). Arterial thromboembolic events may be fatal.
Risk factors for ATE
The risk of arterial thromboembolic complications or of a cerebrovascular accident in CHC users increases in women with risk factors (see table). Smilla is contraindicated if a woman has one serious or multiple risk factors for ATE that puts her at high risk of arterial thrombosis (see section 4.3). If a woman has more than one risk factor, it is possible that the increase in risk is greater than the sum of the individual factors - in this case her total risk should be considered. If the balance of benefits and risks is considered to be negative a CHC should not be prescribed (see section 4.3).
Risk factors for ATE
|
Risk factor |
Comment |
|
Increasing age |
Particularly above 35 years |
|
Smoking |
Women should be advised not to smoke if they wish to use a CHC. Women over 35 who continue to smoke should be strongly advised to use a different method of contraception. |
|
Hypertension | |
|
Obesity (body mass index over 30 kg/m2) |
Risk increases substantially as BMI increases. Particularly important in women with additional risk factors |
|
Positive family history (arterial thromboembolism ever in a sibling or parent especially at |
If a hereditary predisposition is suspected, the woman should be referred to a specialist for advice before deciding about any CHC use |
|
relatively early age eg. below 50). | |
|
Migraine |
An increase in frequency or severity of migraine during CHC use (which may be prodromal of a cerebrovascular event) may be a reason for immediate discontinuation |
|
Other medical conditions associated with adverse vascular events |
Diabetes mellitus, hyperhomocysteinaemia, valvular heart disease and atrial fibrillation, dyslipoproteinaemia and systemic lupus erythematosus. |
Symptoms of ATE
In the event of symptoms women should be advised to seek urgent medical attention and to inform the healthcare professional that she is taking a CHC.
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 trouble walking, dizziness, loss of balance or coordination;
- sudden confusion, trouble speaking or understanding;
- sudden trouble seeing in one or both eyes;
- sudden, severe or prolonged headache with no known cause;
- loss of consciousness or fainting with or without seizure.
Temporary symptoms suggest the event is a transient ischaemic attack (TIA).
Symptoms of myocardial infarction (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;
- feeling of being full, having indigestion or choking;
- sweating, nausea, vomiting or dizziness;
- extreme weakness, anxiety, or shortness of breath;
- rapid or irregular heartbeats.
Tumours
An increased risk of cervical cancer in long-term users of CHCs has been reported in some epidemiological studies, but there continues to be controversy about the extent to which this finding is attributable to the confounding effects of sexual behaviour and other factors such as human papilloma virus (HPV).
A meta-analysis of 54 epidemiological studies showed that there is a slightly increased relative risk (RR = 1.24) of having breast cancer diagnosed in women who are currently using CHCs. The excess risk gradually disappears during the course of the 10 years after cessation of CHC use. Because breast cancer is rare in women
under 40 years of age, the excess number of breast cancer diagnoses in current and recent CHC 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 CHC users, the biological effects of CHCs or a combination of both. The tumours diagnosed in ever-users tend to be less advanced clinically than the tumours diagnosed in never-users.
In rare cases, benign liver tumours, and even more rarely, malignant liver tumours have been reported in users of CHCs. In isolated cases, these tumours have led to life-threatening intraabdominal 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 CHCs.
Other diseases
Women with hypertriglyceridaemia, or a positive family history of hypertriglyceridaemia, may be at an increased risk of pancreatitis when using CHCs.
Although small increases in blood pressure have been reported in many women taking CHCs, clinically relevant increases are rare. In these rare cases, an immediate discontinuation of CHC is justified. Up to now, there is no evidence of a systematic connection between CHC use and clinical hypertension. If persistent clinical hypertension or a significant increase in blood pressure occurs in users with preexisting hypertension during the use of a CHC and an antihypertensive treatment is not effective, the intake must be stopped. Where considered appropriate, CHC use may be resumed if normotensive values can be achieved with antihypertensive therapy.
The following conditions have been reported to occur or worsen during both pregnancy and CHC use, but the evidence of an association with CHC use is inconclusive: cholestatic icterus and/or pruritus, cholelihtiasis, porphyria, systemic lupus erythematosus, haemolytic uremic syndrome, Sydenham's chorea, herpes gestationis, otosclerosis-related hearing loss, depressive disorders.
In woman with a hereditary angioedema, exogenously administered estrogens may cause or aggravate symptoms of angioedema.
Acute or chronic disturbances of liver function may necessitate the discontinuation of CHC use until the liver function values return to normal. Recurrence of cholestatic icterus and/or cholestasis-related pruritus which occurred during a previous pregnancy or previous use of sex steroids necessitates the discontinuation of CHCs.
Although CHCs 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 CHCs (< 50 micrograms ethinylestradiol). However, diabetic women should be carefully monitored, particularly in the early stage of CHC use.
Aggravation of major depression, epilepsy, Crohn’s disease and ulcerative colitis have been reported during CHC use.
Chloasma may occasionally occur during CHC use, 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 CHCs.
Medical examination/consultation
Prior to the initiation or reinstitution of Smilla a complete medical history (including family history) should be taken and pregnancy must be ruled out. Blood pressure should be measured and a physical examination should be performed, guided by the contra-indications (see section 4.3) and warnings (see section 4.4). It is important to draw a woman’s attention to the information on venous and arterial thrombosis, including the risk of Smilla compared with other CHCs, the symptoms of VTE and ATE, the known risk factors and what to do in the event of a suspected thrombosis. The woman should also be instructed to carefully read the user leaflet and to adhere to the advice given. The frequency and nature of examinations should be based on established practice guidelines and be adapted to the individual woman.
Women should be advised that hormonal contraceptives do not protect against HIV infections (AIDS) and other sexually transmitted diseases.
Reduced efficacy
The efficacy of CHCs may be reduced, in the event of missed tablets vomiting or diarrhoea (see section 4.2) or concomitant medication (see section 4.5).
Irregular bleeding
With all CHCs, 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. Irregular bleeding (spotting or breakthrough bleedings) were reported in more than 50% of the users of contraceptives containing ethinylestradiol/levonorgestrel in the first six intake-cycles.
If bleeding irregularities persist or occur after previously regular cycles, then nonhormonal causes should be considered and adequate diagnostic measures are indicated to exclude malignancy or pregnancy. A curettage might be necessary.
Sometimes withdrawal bleeding may not occur during the tablet-free interval at all. If the tablets have been taken according to the directions described in section 4.2, it is unlikely that the woman is pregnant. However, if the tablets have 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 CHC use is continued.
This medicine contains lactose and sucrose.
Patients with rare hereditary problems of galactose intolerance, fructose intolerance, the Lapp lactase deficiency, glucose-galactose malabsorption or sucrase-isomaltase insufficiency should not take this medicine.
4.5 Interaction with other medicinal products and other forms of interaction
Note: The prescribing information of concomitant medications should be consulted to identify potential interactions.
Effects of other medicinal products on Smilla
Interactions may occur with drugs that induce microsomal enzymes. This may result in an increased clearance of sex hormones and may lead to breakthrough bleeding and/or contraceptive failure.
Management
Enzyme induction can already be observed after a few days of treatment. Maximal enzyme induction is generally seen within a few weeks. After the cessation of drug therapy enzyme induction may be sustained for about 4 weeks.
Short-term treatment
Women on treatment with one of these drugs should temporarily use a barrier method or another method of contraception in addition to the COC. The barrier method must be used during the whole time of the concomitant drug therapy and for up to 28 days after its discontinuation. If one of these drugs must be taken beyond the end of the blister pack of the COC, the next blister pack of the COC should be started right away without the usual intake-free interval.
Long-term treatment
In women on long-term treatment with enzyme-inducing active substances, another reliable, nonhormonal, method of contraception is recommended.
The following interactions have been reported in the literature.
Substances increasing the clearance of COCs (diminished efficacy of COCs by enzyme-induction), e.g.:
Barbiturates, bosentan, carbamazepine, phenytoin, primidone, rifampicin, and HIV medication ritonavir, nevirapine and efavirenz and possibly also felbamate, griseofulvin, oxcarbazepine, topiramate and products containing the herbal remedy St. John's Wort (hypericum perforatum).
Medicinal products increasing gastrointestinal motility may reduce the absorption of hormones, e.g.:
Metoclopramide.
Substances with variable effects on the clearance of COCs:
When co-administered with COCs many combinations of HIV protease inhibitors and non-nucleoside reverse transcriptase inhibitors, including combinations with HCV inhibitors can increase or decrease plasma concentrations of estrogen or progestins.
These changes may be clinically relevant in some cases.
Therefore, the prescribing information of concomitant HIV/HCV medications should be consulted to identify potential interactions and any related recommendations. In case of any doubt, an additional barrier contraceptive method should be used by women on protease inhibitor or non-nucleoside reverse transcriptase inhibitor therapy.
Substances decreasing the clearance of COCs (enzyme inhibitors):
The clinical relevance of potential interactions with enzyme inhibitors remains unknown.
Strong and moderate CYP3A4 inhibitors such as azole antimycotics (e.g. itraconazole, voriconazole, fluconazole), verapamil, macrolides (e.g. clarithromycin, erythromycin), diltiazem and grapefruit juice may increase plasma concentrations of estrogen or progestogen or both.
It has been shown for etoricoxib in doses of 60 to 120 mg/day that it increases plasma concentrations of ethinylestradiol 1.4 or 1.6 fold if COCs containing 35 micrograms of ethinylestradiol were taken concomitantly.
Effects of COCs on other medicinal products
COCs may affect the metabolism of certain other active substances. Accordingly, plasma and tissue concentrations may either increase (e.g. ciclosporin) or decrease (e.g. lamotrigine).
Troleandomycin may increase the risk of intrahepatic cholestasis during concomitant use of COCs.
In vitro, Ethinylestradiol is a reversible inhibitor of CYP2C19, CYP1A1 and CYP1A2 as well as a mechanism-based inhibitor of CYP3A4/5, CYP2C8 and CYP2J2. In clinical trials, the use of a hormonal contraceptive containing Ethinylestradiol did not lead to an increase or to only a slight increase of plasma concentrations of CYP3A4 substrates (e.g. midazolam), whereas the plasma concentrations of CYP1A2 substrates could be increased slightly (e.g. theophylline) or moderately (e.g. melatonin and tizanidin).
Laboratory tests
The use of steroidal contraceptives may influence the results of certain laboratory tests, among others the biochemical parameters of liver, thyroid, adrenal and renal function, as well as the plasma levels of (carrier) proteins (e.g. corticosteroid binding globulin and lipid/lipoprotein fractions), parameters of carbohydrate metabolism, and parameters of blood coagulation and fibrinolysis. However the changes generally remain within the normal laboratory range.
4.6 Fertility, pregnancy and lactation
Pregnancy
Smilla is not indicated in pregnancy.
If pregnancy occurs during the treatment with Smilla, further intake must be stopped immediately.
However, in most epidemiological studies neither an increased risk of birth defects in children born to mothers who used combined oral contraceptives prior to pregnancy, nor a teratogenic effect following unintentional intake of combined oral contraceptives during early pregnancy was observed.
The increased risk of VTE during the postpartum period should be considered when re-starting Smilla (see section 4.2 and 4.4).
Breast-feeding
Lactation may be influenced by CHCs since they may reduce the amount of breast milk and change its composition. Thus, the use of combined oral contraceptives should generally not be recommended until the nursing mother has weaned her child off breast milk. Small amounts of the contraceptive steroids and/or their metabolites may be excreted in breast milk. These amounts may affect the child.
4.7 Effects on ability to drive and use machines
Smilla has no or only negligible influence on the ability to drive and use machines.
4.8 Undesirable effects
The most common adverse drug reactions caused by oral contraceptives containing ethinlyestradiol/levonorgestrel are headache, spotting and breakthrough bleeding.
Further adverse drug reactions reported in users of CHCs containing ethinylestradiol/levonorgestrel, including Smilla:
|
System Organ Class |
Common |
Uncommon |
Rare |
|
(>1/100 to <1/10) |
(>1/1,000 to <1/100) |
(>1/10,000 to <1/1,000) | |
|
Immune system disorders |
hypersensitivity | ||
|
Metabolism and nutrition disorders |
fluid retention | ||
|
Psychiatric disorders |
depressive mood, mood changes |
libido decreased |
libido increased |
|
Nervous system disorders |
headache |
migraine | |
|
Eye disorders |
contact lens intolerance | ||
|
Vascular disorders |
venous thromboembolism (VTE), arterial thromboembolism (ATE) | ||
|
Gastrointestinal disorders |
nausea, abdominal pain |
vomiting, diarrhoea | |
|
Skin and subcutaneous tissue disorders |
rash, urticaria |
erythema nodosum, erythema multiforme | |
|
Reproductive system and breast disorders |
breast tenderness, breast pain |
breast enlargement |
breast discharge, vaginal discharge |
|
Investigations |
weight increased |
weight decreased |
Description of selected adverse reactions
An increased risk of arterial and venous thrombotic and thrombo-embolic events, including myocardial infarction, stroke, transient ischemic attacks, venous thrombosis and pulmonary embolism has been observed in women using CHCs, which are discussed in more detail in section 4.4.
The following serious adverse events have been reported in women using CHCs, see section 4.4.
- Venous thromboembolic disorders,
- Arterial thromboembolic disorders,
- Cervix carcinoma,
- Hypertension,
- Hypertrigylceridemia,
- Effects on peripheral insulin resistance and glucose tolerance,
- Liver tumours,
- Liver function disorders,
- Chloasma,
- Crohn’s disease, ulcerative colitis,
- Epilepsy,
- Migraine,
- Endometriosis, uterine myoma,
- Porphyria,
- Systemic lupus erythematosus,
- Herpes gestationis,
- Sydenham’s chorea,
- Haemolytic uremic syndrome,
- Cholestatic icterus,
- Otosclerosis.
The frequency of diagnosis of breast cancer is very slightly increased among CHC 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 CHC use is unknown. For further information, see sections 4.3 and 4.4.
In women with hereditary angioedema exogenous estrogens may induce or exacerbate symptoms of angioedema.
Reporting of suspected adverse reactions
Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the Yellow Card Scheme at: www.mhra.gov.uk/yellowcard.
4.9 Overdose
There have been no reports of serious adverse effects from overdose. Symptoms that may be caused by overdose are nausea, vomiting and, in young girls, slight vaginal bleeding. There is no antidote and the treatment is symptomatic.
5 PHARMACOLOGICAL PROPERTIES
5.1 Pharmacodynamic properties
Pharmacotherapeutic group: Progestogen and estrogens, fixed combinations, ATC Code: G03AA07
The contraceptive effects of CHCs are based on the interaction of various factors, of which the inhibition of ovulation and changes in the endometrium and the cervical mucosa are the most important.
Clinical studies were performed on 2,498 women between 18 and 40 years of age. The calculated Pearl Index was 0.69 (95%-confidence interval 0.30-1.36), based on 15026 cycles.
5.2 Pharmacokinetic properties
Levonorgestrel
Absorption
Orally administered levonorgestrel is absorbed rapidly and completely. Maximum levonorgestrel serum levels of about 2.3 ng/ml are reached within 1.3 h after oral administration. Bioavailability is nearly 100%.
Distribution
Levonorgestrel is to a large extent bound to albumin and SHBG (Sex Hormon Binding Globulin) in plasma. Only 1.1% of total serum levels of the active substance are present as a free steroid, about 65% are specifically bound to SHBG and about 35% are unspecifically bound to albumin. Ethniylestradiol-induced increase in SHBG levels has an influence on relative distribution of levonorgestrel in different protein fractions. Induction of the binding protein causes an increase of the fraction bound to SHBG and a decrease of the fraction bound to albumin. The apparent distribution volume of levonorgestrel is 129 l after one dose.
Biotransformation
Levornogestel is metabolised completely via well-known steroid metabolism pathways. The main metabolites in plasma are the unconjugated and conjugated forms of 3a, 5p-tetrahydrolevonorgestrel. Based on in vitro and in vivo studies, CYP3A4 is the main enzyme involved in the metabolism of levonorgestrel. The metabolic clearance rate from the serum is about 1.0 ml/min/kg.
Elimination
The serum level of levornogestrel decreases in two phases. The terminal phase is marked by a half-life of about 25 h.
Levonorgestrel is not excreted unchanged. A 1:1 ratio of urinary to bile excretion of the metabolites was found. Half-life of metabolite excretion is about 1 day.
Steady-State
During continuous administration of Smilla, levonorgestrel serum levels increase about threefold, reaching the steady-state in the second half of the administration cycle. Levonorgestrel pharmacokinetics are influenced by SHBG serum levels, which are 1.5 to 1.6-fold higher while using estradiol. For this reason, clearance rate from serum and distribution volume are slightly decreased in the steady-state (0.7 ml/min/kg, or about 100 l).
Ethinylestradiol
Absorption
Ethinylestradiol is rapidly and completely absorbed after oral administration, and peak serum concentrations (about 50 pg/l) are reached within 1-2 hours after oral administration. Following resorption and extensive first-pass metabolism the average oral bioavailability is about 45% (interindividual variety of about 20-65%).
Distribution
Ethinylestradiol is almost entirely (about 98%) but unspecifically bound to serum albumin, inducing an increase in SHBG serum levels. The apparent distribution volume of ethinylestradiol is 2.8-8.6 l/kg.
Biotransformation
Ethinylestradiol undergoes pre-systemic conjugation both in the small intestinal mucosa and in the liver. Ethinylestradiol is metabolised by aromatic hydroxylation primarily, resulting in various hydroxylated and methylated metabolites which are detectable in the serum as free metabolites or conjugated glucoronides or sulfates. Metabolic clearance rate from the serum is 2.3-7 ml/min/kg.
Elimination
Ethinylestradiol is eliminated from serum in two phases, with half-lives of about 1 h and 10-20 h, respectively.
Ethinylestradiol is not excreted unchanged. The excretion of metabolites takes place via urine and bile in a ratio of 4:6. The half-life is about 1 day.
Steady-State
During continuous administration of Smilla, ethinylestradiol serum levels double. Due to the daily administration and the variable half-life in the terminal phase of serum clearance, the steady-state is reached after approximately 1 week.
5.3 Preclinical safety data
Preclinical studies (on general toxicity, genotoxicity, carcinogenic potential and on reproductive toxicity) revealed no indication on additional effects other than those already explained by the known hormone profile of ethinylestradiol or levonorgestrel.
However, it should be considered that sex steroids can promote growth of certain hormone-dependent tissues and tumours.
6 PHARMACEUTICAL PARTICULARS
6.1 List of excipients
Tablet core:
Lactose monohydrate Maize Starch Talc (E553b)
Magnesium stearate (E470b)
Silica, colloidal anhydrous (E551)
Coating:
Sucrose Talc (E553b)
Calcium carbonate Titanium dioxide (E171)
Copovidone K-28 Iron oxide, yellow (E172)
Macrogol 6000
Silica, colloidal anhydrous (E551)
Povidone K-30 Carmellose sodium
6.2 Incompatibilities
Not applicable.
6.3 Shelf life
2 years
6.4 Special precautions for storage
Do not store above 25°C.
Store in the original package in order to protect from light.
6.5 Nature and contents of container
Transparent, hard PVC/PVDC//Aluminium blisters with package leaflet and etui storage bag.
Pack sizes: 1 x 21, 3 x 21, 6 x 21 and 13 x 21 coated tablets.
Not all pack sizes may be marketed.
6.6 Special precautions for disposal
No special requirements.
Any unused medicinal product or waste material should be disposed of in accordance with local requirements.
7 MARKETING AUTHORISATION HOLDER
Gedeon Richter Plc 1103 Budapest Gyomroi ut 19-21 Hungary
8 MARKETING AUTHORISATION NUMBER(S)
PL 04854/0131
9 DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION
13/10/2016
10 DATE OF REVISION OF THE TEXT
13/10/2016
Mid-point of range of 5-7 per 10,000 WY, based on a relative risk for CHCs containing levonorgestrel versus non-use of approximately 2.3 to 3.6.