Lizinna 250 Microgram/35 Microgram Tablets
SUMMARY OF PRODUCT CHARACTERISTICS
1 NAME OF THE MEDICINAL PRODUCT
Lizinna 250 microgram /35 microgram Tablets
2 QUALITATIVE AND QUANTITATIVE COMPOSITION
Lizinna are tablets for oral administration.
Each tablet contains norgestimate 250 microgram and ethinylestradiol 35 microgram. Excipient(s) of known effect:
Each uncoated tablet contains 89.357 mg of Lactose.
For the full list of excipients, see section 6.1.
3 PHARMACEUTICAL FORM
Tablet
Round, blue, uncoated, 6.4 mm uncoated flat beveled edge tablets with ‘146’ debossed on one side and the other side plain.
4 CLINICAL PARTICULARS
4.1 Therapeutic indications
Oral contraception
The decision to prescribe Lizinna should take into consideration the individual woman’s current risk factors, particularly those for venous thromboembolism (VTE), and how the risk of VTE with Lizinna compares with other CHCs (see sections 4.3 and 4.4).
4.2 Posology and method of administration
For oral administration.
Posology
Paediatric population
Lizinna is contraindicated in girls that have not reached pubertal age - before menarche (see section 4.3).
Adults
One tablet is taken daily at the same time (preferably in the evening) without interruption for 21 days, followed by a break of 7 tablet-free days. Each subsequent pack is started after the 7 tablet-free days have elapsed. Additional contraceptive precautions are not then required. During the tablet-free period, bleeding can be expected, usually beginning 2 to 4 days after the last tablet.
Elderly
Use of this product is not indicated in post-menopausal women.
Method of administration
Starting treatment
Tablet intake is started on day 1 of the woman's natural cycle (i.e. the first day of her menstrual bleeding).
Switching from another contraceptive
Changing from a combined hormonal contraceptive (combined oral contraceptive (COC), vaginal ring or transdermal patch)
The woman should start with Lizinna 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 Lizinna preferably on the day of removal, but at the latest when the next application would have been due.
Changing from a progestogen-only-method (progestogen-only pill, injection, implant) or from a progestogen-releasing intrauterine system (IUS)
The woman may switch any day from the progestogen-only pill (from an implant or the IUS 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 additionally use a barrier method for the first 7 days of tablet-taking.
Post-partum administration
Following a vaginal delivery, oral contraceptive administration to non-breastfeeding mothers can be started 21 days post-partum provided the patient is fully ambulant and there are no puerperal complications. No additional contraceptive precautions are required. If post-partum administration begins more than 21 days after delivery, additional contraceptive precautions are required for the first 7 days of pill-taking.
If intercourse has taken place post-partum, oral contraceptive use should be delayed until the first day of the first menstrual period.
For information on breast-feeding mothers, see sections 4.3, 4.4 and 4.6.
Use after Abortion or Miscarriage
Following first-trimester abortion
The woman may start immediately. When doing so, she need not take additional contraceptive measures.
Following delivery or second-trimester abortion
Women should be advised to start at day 21 to 28 after delivery or second-trimester abortion. When starting later, the woman should be advised to additionally use a barrier method for the first 7 days. However, if intercourse has already occurred, pregnancy should be excluded before the actual start of COC use or the woman has to wait for her first menstrual period.
For breastfeeding women see section 4.6.
To skip a period
To skip a period, a new pack of Lizinna 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 Lizinna is started after the usual 7 tablet-free days, regardless of whether the period has completely finished or not.
Reduced reliability
When Lizinna is taken according to the directions for use, the occurrence of pregnancy is highly unlikely. However, the reliability of oral contraceptives may be reduced under the following circumstances:
Management of missed tablets
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 tablet, contraceptive protection may be reduced. The management of missed tablets can be guided by the following two basic rules:
1. tablet-taking must never be discontinued for longer than 4 days
2. 7 days of uninterrupted tablet-taking are required to attain adequate suppression of the hypothalamic-pituitary-ovarian-axis.
Accordingly the following advice can be given in daily practice:
• Day 1-7
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 intercourse took place in the preceding 7 days, the possibility of a pregnancy should be considered. The more tablets are missed and the closer they are to the regular tablet-free interval, the higher the risk of a pregnancy.
• Day 8-14
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. Provided that the woman has taken her tablets correctly in the 7 days preceding the first missed tablet, there is no need to use extra contraceptive precautions. However, if she has missed more than 1 tablet, the woman should be advised to use extra precautions for 7 days.
• Day 15-21
The risk of reduced reliability is imminent because of the forthcoming 7 day tablet-free interval. However, by adjusting the tablet-intake schedule, reduced contraceptive protection can still be prevented. By adhering to either of the following two options, there is therefore no need to use extra contraceptive precautions, provided that in the 7 days preceding the first missed tablet the woman has taken all tablets correctly. If this is not the case, she should follow the first of these two options and use extra precautions for the next 7 days as well.
1. 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. The next blister pack must be started as soon as the current blister pack is finished, i.e., no gap should be left between packs. The user is unlikely to have a withdrawal bleed until the end of the blister, but she may experience spotting or breakthrough bleeding on tablet-taking days.
2. The woman may also be advised to discontinue tablet-taking from the current blister pack. She should then have a tablet-free interval of up to 7 days, including the days she missed tablets and subsequently continue with the next blister pack.
If the woman missed tablets and subsequently has no withdrawal bleed in the first normal tablet-free interval, the possibility of a pregnancy should be considered.
In case of severe gastro-intestinal disturbances (e.g., vomiting or diarrhoea), absorption may not be complete and additional contraceptive measures should be taken. If vomiting occurs within 3-4 hours after tablet-taking, a new (replacement) tablet should be taken as soon as possible. The new tablet should be taken within 12 hours of the usual time of tablet-taking if possible. If more than 12 hours elapse, the advice concerning missed tablets, as given in section 4.2 “Management of missed tablets”, is applicable. If the woman does not want to change her normal tablet-taking schedule, she has to take the extra tablet(s) from another blister pack.
4.3 Contraindications
• Hypersensitivity to the active substance(s) or to any of the excipients listed in section 6.1
• Presence or risk of venous thromboembolism (VTE)
o Venous thromboembolism - current VTE (on anticoagulants) or history of (e.g. deep venous thrombosis [DVT] or pulmonary embolism [PE])
o 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
o Major surgery with prolonged immobilisation (see section 4.4)
o 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)
o Arterial thromboembolism - current arterial thromboembolism, history of arterial thromboembolism (e.g. myocardial infarction) or prodromal condition (e.g. angina pectoris)
o Cerebrovascular disease - current stroke, history of stroke or prodromal condition (e.g. transient ischaemic attack, TIA)
o Known hereditary or acquired predisposition for arterial thromboembolism, such as hyperhomocysteinaemia and antiphospholipid-antibodies (anticardiolipin-antibodies, lupus anticoagulant).
o History of migraine with focal neurological symptoms.
o 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
• Breast-feeding mothers less than 6 weeks post-partum.
• The presence of serious or multiple risk factor(s) for the occurrence of arterial thrombosis: moderate to severe hypertension (Persistent blood pressure values of >160 mm Hg systolic or >95 mm Hg diastolic)
• Hereditary dyslipoproteinaemia
• Hereditary or acquired predisposition for venous or arterial thrombosis, such as activated protein C (APC-) resistance, antithrombin-III deficiency, protein C deficiency, protein S deficiency, hyperhomocysteinaemia, and antiphospholipid antibodies (anticardiolipin antibodies, lupus anticoagulant)
• Carcinoma of the endometrium or other known or suspected oestrogen-dependent neoplasia
• Undiagnosed abnormal genital bleeding
• Major surgery with prolonged immobilisation.
• Complicated valvular and congenital heart disease (e.g. with pulmonary hypertension, atrial fibrillation, history of subacute bacterial endocarditis)
• Migraine with focal aura.
• Diabetes with nephropathy/retinopathy/neuropathy or other vascular involvement or > 20 years' duration.
• Smoking 15 or more cigarettes per day in patients aged 35 years or more.
• Acute or chronic liver disease, including hepatitis (viral or non-viral) or severe cirrhosis, or a history of these conditions until at least 3 months after abnormal liver function tests have returned to normal; hepatic adenomas or carcinomas.
• Known or suspected carcinoma of the breast.
• Pancreatitis or a history thereof if associated with severe hypertriglyceridemia
• Lizinna is contraindicated in girls that have not reached pubertal age - before menarche.
Should any of these conditions occur for the first time during use of Lizinna, the
tablets should be discontinued immediately.
4.4 Special warnings and precautions for use
If any of the conditions or risk factors mentioned below is present, the suitability of Lizinna should be discussed with the woman.
In the event of aggravation, 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 Lizinna 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. Products that contain levonorgestrel, norgestimate (including Lizinna) or norethisterone are associated with the lowest risk of VTE. The decision to use Lizinna should be taken after a discussion with the woman to ensure she understands the risk of VTE with Lizinna, 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).
It is estimated that out of 10,000 women who use a CHC that contains levonorgestrel, about 61 will develop a VTE in a year.
Current evidence suggests that the risk of VTE with use of norgestimate-containing CHCs is similar to the risk with levonorgestrel-containing CHCs.
This number of VTEs per year is fewer than the number expected in women during pregnancy or in the postpartum period.
VTE may be fatal in 1-2% of cases.
1 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
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 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).
Lizinna 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).
Table: 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 surgery, any surgery to the legs or pelvis, neurosurgery, or major trauma Note: temporary immobilisation including air travel >4 hours can also be a risk factor for VTE, particularly in women with other risk factors |
In these situations it is advisable to discontinue use of the patch/pill/ring (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 Lizinna has not been discontinued in advance. |
|
Positive family history (venous thromboembolism ever in a sibling or parent especially at a relatively early age e.g. 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 (e.g. 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). Lizinna 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).
Table: 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 relatively early age e.g. below 50). |
If a hereditary predisposition is suspected, the woman should be referred to a specialist for advice before deciding about any CHC use |
|
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.
Medical examination/consultation
Prior to the initiation or reinstitution of Lizinna 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 Lizinna 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.
Tumours
An increased risk of cervical cancer in long-term users of COCs (> 5 years) has been reported in some epidemiological studies, but there continues to be controversy about the extent to which this finding is attributable to the compounding effects of sexual behaviour and other factors such as human papilloma virus (HPV).
A meta-analysis of 54 epidemiological studies reported that there is a slightly increased 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 breast cancers diagnosed in ever-users tend to be less advanced clinically than the cancers diagnosed in never-users. 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.
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. Therefore 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 using COCs.
With the use of the higher-dosed COCs (50 pg ethinylestradiol) the risk of endometrial and ovarian cancer is reduced. Whether this also applies to lower-dosed COCs remains to be confirmed.
Other conditions
Contraceptive efficacy may be reduced in women weighing equal or greater than 90 kg.
Women with hypertriglyceridaemia, or a family history thereof, may be at an increased risk of pancreatitis when using combination hormonal contraceptives.
Although small increases of blood pressure have been reported in many women using hormonal contraceptives, clinically relevant increases are rare. Only in these rare cases an immediate discontinuation of COC use is justified. If, during the use of a combination hormonal contraceptive in pre-existing hypertension, constantly elevated blood pressure values or a significant increase in blood pressure do not respond adequately to antihypertensive treatment, the combination hormonal contraceptive must be withdrawn. Combination hormonal 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 both pregnancy and COC use, but the evidence of an association with COC use is inconclusive: Jaundice and/or pruritus related to cholestasis; gallstones; porphyria; systemic lupus erythaematosus; haemolytic ureamic 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 combination hormonal contraceptives until markers of liver function return to normal. Recurrence of cholestatic-related pruritus, which occurred during a previous pregnancy or previous use of sex steroids, necessitates the discontinuation of combination hormonal contraceptives.
Although combined hormonal 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 low-dose COCs (containing < 0.05 mg ethinylestradiol).. However, diabetic women should be carefully observed, particularly in the early stage of COCs use.
Worsening of endogenous depression, of epilepsy, of Crohn’s disease and of ulcerative colitis has been reported during COC use.
Chloasma may occasionally occur, especially in users with a history of chloasma gravidarum. Users with a tendency to chloasma should avoid exposure to the sun or ultraviolet radiation while using COCs. Chloasma is often not fully reversible.
Medical examination/consultation
Prior to the initiation or reinstitution of Norgestimate/Ethinylestradiol a complete medical history (including family history) should be taken and pregnancy should be ruled out. Blood pressure should be measured and a physical examination should be performed guided by the contraindications (see section 4.3) and warnings (see section 4.4). The woman should also be instructed to carefully read the package leaflet and to adhere to the advice given.
The frequency and nature of subsequent examinations should be based on established guidelines and be adapted to the individual woman on the basis of clinical impression.
Women should be advised that hormonal 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 active tablets (see section 4.2), gastro-intestinal disturbances during active tablet taking (see section 4.2) or concomitant medication (see section 4.5).
Reduced cycle control
With all combination hormonal contraceptives, irregular blood loss (spotting or breakthrough bleeding) can occur, especially during the initial months of usage. For this reason, a medical opinion on irregular blood loss will only be useful after an adjustment period of approximately three cycles. If breakthrough bleeding persists, or breakthrough bleeding occurs after previously regular cycles, while the COC has been used according the recommended regimen, a cause other than COCs should be considered. Non-hormonal causes should be considered and, if necessary, adequate diagnostic measures taken to rule out organic disease or pregnancy. This may include curettage.
In some women withdrawal bleeding may not occur during this pill free period. 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 COCs use is continued.
Some users may experience amenorrhoea or oligomenorrhoea after discontinuing hormonal contraception, especially when such a condition was pre-existent.
Herbal preparations containing St John’s Wort (Hypericum perforatum) should not be used while taking Norgestimate/Ethinylestradiol (see section 4.5)
Excipients
The tablets contain lactose. Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicine.
4.5 Interaction with other medicinal products and other forms of interaction
Potential Reduction in Contraceptive Effectiveness Associated With CoAdministration of Other Drugs:
Hepatic enzyme inducers
Drugs or herbal products that induce enzymes, especially CYP3A4, may decrease the plasma concentrations of contraceptive hormones, and may decrease their effectiveness and/or increase breakthrough bleeding. Examples include:
• barbiturates
• bosentan
• carbamazepine
• felbamate
• hydantoins
• primidone
• griseofulvin
• some HIV protease inhibitors (e.g. ritonavir)
• modafinil
• some non-nucleoside reverse transcriptase inhibitors (e.g. nevirapine)
• oxcarbazepine
• phenytoin
• rifampicin and rifabutin
• St. John's Wort
• topiramate
Antibacterial drugs that are not enzyme inducers
There have been reports of pregnancy while taking hormonal contraceptives and antibiotics, but clinical pharmacokinetic studies have not shown consistent effects of antibiotics (eg ampicillin and tetracyclines) on plasma concentrations of synthetic steroids.
Drugs that affect absorption
Drugs that increase gastrointestinal motility, e.g. metoclopramide, may reduce hormone absorption.
Treatment with activated charcoal will compromise absorption of steroid hormones.
Management
For women on long-term treatment with drugs and herbal products that interact with hormonal contraception, another reliable, non-hormonal method of contraception is recommended.
Women on short-term treatment with drugs and herbal products that interact with hormonal contraception and may decrease plasma levels of contraceptive hormones could have their contraceptive effectiveness reduced. They should be advised to use a barrier contraceptive method (e.g. condoms, diaphragm) in addition to Lizinna as follows:
• Women using liver enzyme-inducing drugs should temporarily use a barrier contraceptive method in addition to Lizinna during the time of concomitant medicinal product administration and for 28 days after their discontinuation.
• In the case of modafinil, use of a barrier contraceptive method should continue for 56 days after discontinuation.
If discontinuation of the concomitant medicinal product occurs in week three or runs beyond the end of the tablets in the strip, the next strip should be started without a break.
Changes in Plasma Levels of Co-Administered Drugs that may be of Clinical Significance:
Combination hormonal contraceptives may also affect the pharmacokinetics of some other drugs if used concomitantly.
Drugs whose plasma levels may be increased (due to CYP inhibition). Examples include:
• ciclosporin
• prednisolone
• theophylline
Drugs whose plasma levels may be decreased (due to induction of glucuronidation). Examples include:
• lamotrigine
Management
Physicians are advised to consult the labelling of concurrently-used drugs to obtain further information about interactions with hormonal contraceptives and the possible need to adjust dosages.
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 metabolism and parameters of coagulation and fibrinolysis. Changes generally remain within the normal laboratory range.
4.6 Fertility, pregnancy and lactation
Pregnancy
Not indicated during pregnancy. Confirm suspected pregnancy before discontinuing treatment.
The increased risk of VTE during the postpartum period should be considered when re-starting Lizinna (see section 4.2 and 4.4).
Breastfeeding
Contraceptive steroids and/or their metabolites may be excreted in breast milk.
The use of COCs is contraindicated for breast-feeding mothers less than 6 weeks post-partum (see section 4.3) and should be used with clinical judgement for breastfeeding mothers between 6 weeks and 6 months post-partum (see section 4.4).
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).
Fertility
Norgestimate, alone and in combination with ethinyl estradiol, is an effective antiovulatory agent. After discontinuing oral contraceptive therapy, the patient should delay pregnancy until at least one normal spontaneous cycle has occurred in order to date the pregnancy. An alternative contraceptive method should be used during this time.
Norgestimate and Ethinyl Estradiol combination resulted in a dose-related suppression of fertility, decreased implantation efficiency and litter size and an increased fetal resorption in the female rats at all dose levels. It is moderately potent in the standard in vivo progestational assay which measures endometrial proliferation in rabbits, and it effectively blocks ovulation in rats, hamsters and rabbits.
4.7 Effects on ability to drive and use machines
Not applicable.
4.8 Undesirable effects
Certain adverse drug reactions (ADRs) that have been associated with oral contraceptive use may require immediate medical attention and/or cessation of oral contraceptive use. These ADRs include: myocardial infarction, deep venous thrombosis, pulmonary embolism, cerebrovascular accidents, retinal vein thrombosis, new onset of migraine -type headache, breast cancer, hepatic tumours adenomas, high blood pressure, angioedema, urticaria and hypersensitivity.
Alternative non-hormonal methods of contraception should be used, while appropriate diagnostic and therapeutic measures are undertaken.
Based on pooled safety data from 5 clinical trials, the most commonly reported C_ 10%) ADR was headache (27.9%). The most commonly reported (_ 10%) ADR identified during post-marketing experience was diarrhoea (11.8%).
The most common ADRs (_ 10%) reported in the first treatment cycle in clinical
trials were: dysmenorrhoea (40.4%); nausea (29.1%); metrorrhagia (26.3%); gastrointestinal disorder [reported as nausea or vomiting] (24.6%) and abnormal withdrawal bleeding (16.9%). The incidence of these ADRs was highest in cycle 1 and decreased over time with the exception dysmenorrhoea. The highest incidence of vomiting occurred in cycle 12 (11.8%).
The 5 clinical trials (2 randomised active-controlled trials and 3 uncontrolled open-label trials), which were used to evaluate the safety of Norgestimate / Ethinylestradiol, included 1,891 healthy women of child bearing potential. In 3 trials, subjects were followed for up to 24 cycles and in the other 2 trials for up to 12 cycles. An additional uncontrolled study (n=8,331) reported ADRs by treatment cycle for up to 24 cycles. As the frequency of ADRs vary according to the cycle of treatment, the highest cycle incidence has been used to assign the ADR to a frequency category.
The table below displays all ADRs that have been reported with the use of Norgestimate / Ethinylestradiol in clinical trials or from post marketing experiences with norgestimate and ethinyl estradiol tablets.
The displayed frequency categories use the following convention: Very common (>1/10); common (>1/100 to <1/10); uncommon (>1/1,000 to <1/100); rare (>1/10,000 to <1/1,000); very rare (<1/10,000); and not known (cannot be estimated from the available data).
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.
|
Infections and Infestations | |
|
Common |
Urinary tract infection, vaginal infection |
|
Neoplasms benign, malignant and unspecified (including cysts and polyps) | |
|
Uncommon |
Cervical dysplasia |
|
Rare |
Breast cyst |
|
Frequency not known |
Hepatic adenomas , breast cancer, benign breast neoplasm, focal nodular hyperplasia, fibroadenoma of breast |
|
Immune System Disorders | |
|
Common |
Hypersensitivity |
|
Metabolism and nutrition disorders | |
|
Common |
Fluid retention |
|
Uncommon |
Increase and decrease in appetite, weight fluctuation |
|
Rare |
Appetite disorder |
|
Frequency not known |
Dyslipidaemia |
|
Psychiatric disorders | |
|
Common |
Mood altered, depression, nervousness, insomnia |
|
Uncommon |
Anxiety, libido disorder |
|
Rare |
Loss of libido |
|
Nervous system disorders | |
|
Very common |
Headache |
|
Common |
Migraine, dizziness |
|
Uncommon |
Syncope, paraesthesia |
|
Frequency not known |
Cerebrovascular accident, convulsion |
|
Eye disorders | |
|
Uncommon |
Visual impairment, dry eye |
|
Frequency not known |
Intolerance to contact lenses, retinal vascular thrombosis* |
|
Ear and Labyrinth Disorders | |
|
Rare |
Vertigo |
|
Cardiac disorders | |
|
Uncommon |
Palpitations |
|
Rare |
Tachycardia |
|
Frequency not known |
Myocardial infarction |
|
Vascular disorders | |
|
Uncommon |
Thrombosis, hypertension, hot flush |
|
Rare |
VTE or ATE |
|
Respiratory, Thoracic and Mediastinal Disorders | |
|
Uncommon |
Dyspnoea |
|
Gastrointestinal disorders | |
|
Very common |
Gastrointestinal disorder vomiting, diarrhoea, nausea |
|
Common |
Gastrointestinal pain, abdominal pain, abdominal distension, constipation, flatulence |
|
Rare |
Pancreatitis |
|
Hepato-biliary disorders | |
|
Rare |
Hepatitis |
|
Skin and subcutaneous tissue disorders | |
|
Common |
Acne, rash |
|
Uncommon |
Alopecia, hirsutism, urticaria, pruritus, erythema, skin discolouration |
|
Rare |
Hyperhidrosis, photosensitivity reaction |
|
Frequency not known |
Angioedema, erythema nodosum, night sweats |
|
Musculoskeletal and Connective Tissue Disorders | |
|
Common |
Muscle spasms, pain in extremity, back pain |
|
Uncommon |
Myalgia |
|
Reproductive system and breast disorders | |
|
Very common |
Dysmenorrhoea, metrorrhagia, abnormal withdrawal bleeding |
|
Common |
Amenorrhoea, genital discharge, breast pain |
|
Uncommon |
Breast discharge, breast enlargement, ovarian cyst, vulvovaginal dryness |
|
Rare |
Vaginal discharge |
|
Frequency not known |
Suppressed lactation |
|
General disorders and administration site conditions | |
|
Common |
Chest pain, oedema, asthenic conditions |
|
Investigations | |
|
Common |
Weight increased |
|
Uncommon |
Weight decreased |
* Not seen in clinical trials therefore frequency cannot be estimated. See section 4.4 for frequency based on standard reporting rates for similar combined hormonal contraceptives.
4.9 Overdose
There have been no reports of serious ill-health from overdosage. Symptoms that may occur are nausea, vomiting and vaginal bleeding. There are no antidotes and further treatment should be symptomatic.
5 PHARMACOLOGICAL PROPERTIES
5.1 Pharmacodynamic properties
Pharmacotherapeutic Group: Hormonal Contraceptives for Systemic Use; Progestogens and estrogens, fixed combinations
ATC Code: G03AA11
Norgestimate / Ethinylestradiol acts through the mechanism of gonadotrophin suppression by the oestrogenic and progestational actions of ethinylestradiol and norgestimate. The primary mechanism of action is inhibition of ovulation, but alterations to the cervical mucus, the fallopian tube motility and to the endometrium may also contribute to the efficacy of the product.
5.2 Pharmacokinetic properties
Absorption: Norgestimate and ethinyl estradiol are rapidly absorbed following oral administration. Following single or multiple (three cycles) administration of Norgestimate / Ethinylestradiol, serum concentrations of norgestimate remain below the quantitation limit of the assay (0.1 ng/mL) metabolites of norgestimate, norelgestromin and norgestrel, are found in measurable concentrations in circulation, reaching maximal serum levels approximately 1.5 hours post-dose. Increase in Cmax and AUC for norelgestromin are proportional to dose after administration of 0.180 to 0.250 mg of norgestimate. Ethinyl estradiol serum concentrations are measurable within 0.5 hours of dosing, reaching peak levels approximately 1.2 hours post-dose.
Distribution: Norelgestromin and norgestrel are highly bound (>97%) to serum proteins. Norelgestromin is bound to albumin but not to SHBG, while norgestrel is bound primarily to SHBG and to a much lesser extent to albumin. Ethinyl estradiol is extensively bound to serum albumin.
Studies have shown that the lack of binding of norelgestromin to SHBG is unique when compared to other progestogens in oral contraceptives and plays a key role in enhancing its biological activity. In contrast, norgestrel formed from norgestimate is largely bound to SHBG, which limits its biological activity.
Metabolism: Norgestimate is rapidly metabolised by first-pass (intestinal and/or hepatic) mechanisms to norelgestromin (peak serum concentrations observed within 2 hours) and norgestrel, both of which are pharmacologically active progestogens. Ethinyl estradiol is metabolised to various hydroxylated metabolites and their glucuronide and sulphate conjugates.
Elimination: Both norelgestromin and norgestrel, and ethinyl estradiol are subsequently metabolised and their metabolites are eliminated by renal and faecal pathways. Elimination half-life values at steady-state were 10 to 15 hours for ethinyl estradiol, 24.9 hours for norelgestromin and 45 hours for norgestrel. Following administration of 14C-norgestimate, 47% of the administered radioactivity was eliminated in the urine and 37% in the faeces.
Steady-State Pharmacokinetics: Following administration of 0.250 mg norgestimate /0.035 mg ethinyl estradiol, the mean AUC 0-24h at steady-state, based on non-SHBG bound serum levels, was 18.1 h ng/mL for norelgestromin and 3.64 h ng/mL for norgestrel. The AUC for norgestrel following administration of 0.250 mg norgestimate /0.035 mg ethinyl estradiol corresponds to the exposure after a
levonorgestrel dose of approximately 30 micrograms in combination with ethinyl estradiol.
5.3 Preclinical safety data
Non-clinical studies reveal no special hazard for humans additional to those already mentioned in other sections of the SmPC. Among others, these studies have included single and repeated dose toxicity, genotoxicity, carcinogenicity and reproductive toxicity studies conducted with the combination of norgestimate with ethinylestradiol.
6 PHARMACEUTICAL PARTICULARS
6.1 List of excipients
Lactose, Anhydrous
Lactose, Monohydrate
Povidone K-25
dl-a-tocopherol
Microcrystalline cellulose
Croscarmellose sodium
Starch, Pregelatinised (starch 1500)
Magnesium Stearate
Indigo carmine aluminium lake (E 132)
6.2 Incompatibilities
Not applicable.
6.3 Shelf life
2 years
6.4 Special precautions for storage
Store in the original package to protect from light.
6.5 Nature and contents of container
PVC/PVdC- Aluminium blister strips of 21 tablets. Each blister is packed in a trilaminated pouch.
Packs containing 21, 63, 126 tablets
Not all pack sizes may be marketed.
6.6 Special precautions for disposal
Not applicable.
7 MARKETING AUTHORISATION HOLDER
MORNINGSIDE HEALTHCARE LIMITED 115 NARBOROUGH ROAD LEICESTER LE30PA
UNITED KINGDOM
8 MARKETING AUTHORISATION NUMBER(S)
PL 20117/0220
9 DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION
07/11/2012
10 DATE OF REVISION OF THE TEXT
21/07/2014