LEVONORGESTREL / ETHINYLESTRADIOL TABLET

NAME OF THE MEDICINAL PRODUCT

Levonorgestrel And Ethinylestradiol Tablet IP 0.15/0.03 mg,

Levonorgestrel And Ethinylestradiol Tablet IP 0.25/0.05 mg,

Levonorgestrel And Ethinylestradiol Tablet USP 0.15/0.03 mg,

Levonorgestrel And Ethinylestradiol Tablet USP 0.09/0.02mg,

Levonorgestrel And Ethinylestradiol Tablet USP 0.10/0.02mg

 

QUALITATIVE AND QUANTITATIVE COMPOSITION
Each film-coated tablet contains:
0.03 mg and 0.05mg ethinylestradiol/0.15 mg and 0.25mg  levonorgestrel

Excipient with known effect:
Each tablet contains 84.32 mg of lactose monohydrate.
For the full list of excipients,

PHARMACEUTICAL FORM
Film-coated tablets.
Yellow, round tablet, with a diameter of 6 mm and thickness less than 4 mm
approximately

CLINICAL PARTICULARS
Therapeutic indications
Contraception

Posology and method of administration
Route of administration: oral use

Posology
Tablets must be taken at approximately the same time each day, with some liquid if needed.
One tablet is to be taken daily for 21 consecutive days. Each subsequent pack is started after a 7- day tablet free interval, during which time a withdrawal bleed usually occurs.
The bleeding usually starts within 2 to 3 days after the last tablet and may not end before the next pack is started.

Method of administration
No preceding hormonal contraceptive use [in the past month]:
Tablet-taking is started on day 1 of the women’s natural cycle (the first day of menstrual bleeding). Starting on day 2-day 5 is allowed, but in that case an additional nonhormonal contraceptive method (barrier method) should be used during the first 7 days of treatment.
Changing from another combined hormonal contraceptive (combined oral contraceptive (COC), vaginal ring, transdermal patch): The use of Levonorgestrel/EE tablets is preferably started on the day after the last active tablet of the previous COC (or after removal of the ring or patch), but at the latest on the day following the usual tablet-free (ring-free, patch-free) break or the last placebo tablet of the previous hormonal contraceptive.
Changing from a progestogen-only method (oral contraceptive with only progesteron, injection, implant) or progestogen-releasing intrauterine system (IUS)
If the oral contraceptive with only progesterone was used previously, the change can take place on any day; the change from an implant or IUS must take place on the day of removal, and from an injectable contraceptive at the time when the next injection would be due. In each case, the use of an additional non hormonal contraceptive method (barrier method) is necessary during the first 7 days taking Levonorgestrel/EE.
Following first-trimester abortion
Levonorgestrel/EE may be started immediately. In this case, no additional contraceptive method is required.
Following childbirth or second-trimester abortion

The use of the tablets is started 21 to 28 days after delivery or second-trimester abortion. For breast-feeding,
Pregnancy and Lactation. When starting later, an additional non hormonal contraceptive method (barrier method) should be used during the first 7 days of tablet-taking If intercourse has already taken place, pregnancy must be ruled out before starting the use of Levonorgestrel/EE, or the woman must wait until her first menstrual period.

Missed tablets

If one tablet is missed, but remembered and taken within 12 hours of the usual time, then contraceptive protection is not reduced. The subsequent tablets should be taken at the usual time.
If the usual tablet-taking time is missed by more than 12 hours, full contraceptive protection is no longer assured. The following two basic rules apply when a tablet is missed:
Tablet-taking must never be discontinued for longer than 7 days.
Tablets must be taken regularly for a minimum of 7 days in order to effectively suppress the hypothalamic-pituitary-ovarian axis.
Therefore, the following procedures should be followed in the event that tablets are missed:

Week 1
The last tablet missed should be taken as soon as possible, even if this means taking 2 tablets in one day. The remaining tablets are then taken at the usual time. In addition, a non hormonal contraceptive method such as a condom should be used for the next 7 days. If intercourse took place in the 7 days before missing the tablet, the possibility of a pregnancy should be considered. The more tablets missed and the closer they are to the usual tablet-free interval, the higher the risk of pregnancy.

Week 2
The last tablet missed should be taken as soon as possible, even if this means taking 2 tablets at the same time. The remaining tablets are then taken at the usual time. Provided that the user has taken the tablets correctly in the 7 days prior to the first missed tablet, it is not necessary to use additional contraceptive measures. However, if this is not the case or she has missed more than one tablet, the user should be advised to take additional contraceptive precautions for the next 7 days.

Week 3
The risk of reduced reliability is imminent because of the forthcoming tablet-free interval. However, by adjusting the tablet-taking schedule, reduced contraceptive protection can still be prevented. Therefore, by adhering to one of the following two options, there is no need to take additional contraceptive precautions, provided that in the 7 days prior to the first missed tablet the user has taken all the tablets correctly. If this is not the case, the user should be advised to follow the first of these two options and take additional precautions for the next 7 days:
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 the tablets at the usual time. The next pack must be started as soon as the current pack is finished, i.e. without a break between packs. The user is unlikely to have withdrawal bleeding until the end of the second pack but she may experience spotting or breakthrough bleeding on tablet-taking days.
It is also possible to stop taking tablets from the current pack. The woman must then have a tablet-free break of 7 days, including the days she missed tablets, and then continue with the next pack.
If the user misses several tablets and subsequently has no withdrawal bleeding in the first normal tablet-free interval, the possibility of pregnancy should be considered.

Advice in case of gastrointestinal disorders
In case of severe gastrointestinal disorders (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, a new 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 woman should apply the advice given for missed tablets. If the woman does not want to change her normal tablet schedule, she has to take the extra tablets from another pack.

Changing the starting day of a withdrawal bleeding or delaying the withdrawal bleeding
To delay the withdrawal bleeding, the user should go directly to the next blister pack without a tablet-free interval. The withdrawal bleeding can be delayed as long as wished, but not later than till the end of the second pack. During this time, the woman may experience breakthrough bleeding or spotting. After the subsequent usual 7-day tablet-free interval, Levonorgestrel/EE tablets should be continued as usual.
To change the starting day of her periods to another day of the week, the user can be advised to shorten the next tablet-free interval by as many days as she likes. The shorter the interval, the higher the risk that she does not have withdrawal bleeding and will experience breakthrough bleeding and spotting during the next pack (just as when delaying a period).

CONTRAINDICATION
Combined oral contraceptives (COC) should not be used in the presence of any of the conditions listed below. If any of these conditions appear for the first time during COC use, treatment should be stopped immediately.

venous thrombosis present or in history (deep venous thrombosis, pulmonary embolism),
arterial thrombosis present or in history (e.g. myocardial infarction) or prodromal conditions (e.g. transient ischaemic attack, angina pectoris),
cerebrovascular accident present or in history,
The presence of a severe or multiple risk factor(s) for venous or arterial thrombosis may also constitute a contraindication

diabetes mellitus with vascular disease,

severe hypertension,

severe dyslipoproteinaemia

hereditary or acquired predisposition for venous or arterial thrombosis, such as APC-resistance, antithrombin-III-deficiency, protein C deficiency, protein S deficiency, hyperhomocysteinemia and antiphospholipid-antibodies (anticardiolipin-antibodies, lupus anticoagulant).
presence or history of severe hepatic disease, as long as liver function values have not returned to normal,
presence or history of liver tumours (benign or malignant),
known or suspected sex-steroid influenced malignancies (e.g. of the genital organs or the breasts),
undiagnosed vaginal bleeding,
history of migraine with focal neurological symptoms,
hypersensitivity to the active substances levonorgestrel or ethinylestradiol or to any of the excipients.

SPECIAL PRECAUTIONS & WARNINGS


Warnings

If any of the conditions/risk factors mentioned below are present, the benefits of COC use should be weighed against the possible risks for each individual woman and discussed with her before she decides to start using the product. In the event of aggravation, exacerbation or first appearance of any of these conditions or risk factors, the user should contact her doctor as soon as possible. The doctor should decide whether Levonorgestrel/EE use should be discontinued.
Circulatory Disorders
The use of any combined oral contraceptive (COC) carries an increased risk of venous thromboembolism (VTE) compared with no use. The excess risk of VTE is highest during the first year a woman initially starts using a COC or when she restarts COC use after a pill-free interval of at least a month.
Epidemiological studies have shown that the incidence of VTE in users of oral contraceptives with low oestrogen content (<50 µg ethinylestradiol) ranges from about 20 to 40 cases per 100,000 women-years, but this risk estimate varies according to the progestogen. This compares with 5 to 10 cases per 100,000 women-years for non-users. The use of any combined oral contraceptive carries an increased risk of venous thromboembolism (VTE) compared with no use. The excess risk of VTE is highest during the first year a woman uses a combined oral contraceptive. This increased risk is less than the risk of VTE associated with pregnancy, which is estimated as 60 cases per 100,000 pregnancies. VTE is fatal in 1-2% of cases.
The overall absolute risk (incidence) of VTE for levonorgestrel containing combined oral contraceptives with 30 µg ethinylestradiol is approximately 20 cases per 100,000 women-years of use. Epidemiological studies have also associated the use of combined COCs with an increased risk for myocardial infarction, transient ischaemic attack and for stroke.
Extremely rarely, thrombosis has been reported to occur in other blood vessels, e.g. hepatic, mesenteric, renal, retinal veins and arteries, in contraceptive pill users. There is no consensus as to whether the occurrence of these events is associated with the use of hormonal contraceptives.
Symptoms of venous or arterial thrombosis can include:
unusual unilateral leg pain and/or swelling;
sudden severe chest pain, which may or may not radiate to the left arm;
sudden dyspnoea;
sudden onset of coughing;
unusual, severe and prolonged headache;
sudden partial or complete loss of vision;
diplopia;
slurred speech or aphasia;
vertigo;
collapse with or without focal seizure;
weakness or very marked numbness suddenly affecting one side or one part of the body;
motor disturbances;
“acute” abdomen.
The risk for venous thromboembolic complications in combined oral contraceptive users increases with:
increasing age;
positive family history (venous thromboembolism in a sibling or parent at a relatively early age). If a hereditary predisposition is suspected, the woman should be referred to a specialist for advice before deciding whether to use any combined oral contraceptive;
obesity (body mass index over 30 kg/m2) ; prolonged immobilization, major surgery, any surgery to the legs or major trauma. In these situations it is advisable to discontinue combined oral contraceptive use (in the case of elective surgery, at least four weeks in advance) and not to resume until two weeks after completely remobilisation.
There is no consensus about the possible role of varicose veins and superficial thrombophlebitis in the onset or progression of venous thromboembolism.
The risk factors for arterial thromboembolic complications include:
increasing age
smoking (women over 35 years should be strongly advised not to smoke if they wish to use) a COC).
dyslipoproteinemia,
hypertension
migraine, especially migraine with focal neurological symptoms
valvular heart disease
atrial fibrillation
obesity (body mass index over 30 kg/m2),
a positive family history (arterial thromboembolism ever in a sibling or parent at relatively early age). If a hereditary predisposition is suspected, the woman should be referred to a specialist for advice before deciding about any COC use.
The presence of one serious risk factor or multiple risk factors for venous or arterial disease, respectively, can also constitute a contra-indication. The possibility of anticoagulant therapy should also be taken into account. COC users should be specifically pointed out to contact their physician in case of possible symptoms of thrombosis. In case of suspected or confirmed thrombosis, COC use should be discontinued. Adequate alternative contraception should be initiated because of the teratogenicity of anticoagulant therapy (coumarins).
The increased risk of thromboembolism in the puerperium must be considered.
Other medical conditions that have been associated with adverse circulatory events include: diabetes mellitus, systemic lupus erythematosus, haemolytic uraemic syndrome, chronic inflammatory bowel disease (Crohn’s disease or ulcerative colitis) and sickle cell disease.
An increase in migraine frequency or severity during COC use (which may be signs of a cerebrovascular accident) may be grounds for immediate discontinuation of the COC.

Tumours
Some epidemiological studies have reported an increased risk of cervical cancer in long-term COC users but there continues to be controversy about the extent to which this finding is attributable to the influence of confounding factors such as sexual behaviour and 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 combined oral contraceptive. This 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 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 clinically advanced than those diagnosed in never users.
In rare cases, benign, and even more rarely, malignant liver tumours have been reported in COC users. In isolated cases, these tumours have led to life-threatening intra-abdominal bleeding. The possibility of a liver tumour should be considered in the differential diagnosis of women taking COCs who report sever upper abdominal pain, liver enlargement or signs of intra-abdominal bleeding.

Other conditions
Women with hypertriglyceridemia, or a family history thereof, may be at an increased risk of pancreatitis when using COCs.

Although small increases in blood pressure have been observed in many women taking COCs, clinically relevant increases are rare. Only in these rare cases an immediate discontinuation of COC use is justified. If, during the use of a COC in pre-existing hypertension, constantly elevated blood pressure values or a significant increase in blood pressure do not respond adequately to antihypertensive treatment, the COC must be withdrawn. 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 during 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 erythematosus, haemolytic uraemic syndrome, Sydenham’s chorea, herpes gestationis and otosclerosis-related hearing loss.
In women with hereditary angioedema, exogenous estrogens can trigger or exacerbate angioedema symptoms.
Acute or chronic liver function disorders require discontinuation of COC use until liver function markers return to normal. Recurrence of cholestatic jaundice and/or cholestasis-related pruritus that first occurred during pregnancy or during previous sex hormone use requires 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 monitored, particularly in the early stage of COC use.
Worsening of endogenous depression, of epilepsy, of Crohn’s disease and of ulcerative colitis has been reported during COC use.
Chloasma may particularly occur, especially in women with a history of chloasma gravidarum. If there is a tendency to chloasma, sunlight and ultraviolet radiation should be avoided when using combined oral contraceptive.

Medical examination/consultation
Prior to the initiation or reinstitution of Levonorgestrel/EE 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 contraindications and warnings. 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 informed that oral contraceptives do not protect against HIV infection (AIDS) and other sexually transmitted diseases.


Reduced efficacy
The contraceptive efficacy of Levonorgestrel/EE combined oral contraceptive may be reduced if tablets are missed
in the event of gastrointestinal disorders
if certain other drugs are being taken concomitantls.


Reduced cycle control
When using any COC, irregular bleeding (spotting or breakthrough bleeding) may occur, especially during the first months of use. Therefore, the evaluation of any irregular bleeding is only meaningful after an adaptation interval of about three cycles.
If bleeding irregularities persist or occur after previously regular cycles, possible non-hormonal causes should be considered and adequate diagnostic measures are indicated to exclude malignancies or pregnancy. These may include curettage.

In some women, withdrawal bleeding may not occur during the tablet-free interval., it is unlikely that the woman is pregnant. However, if the COC has not been taken according to these instructions prior to the first missed withdrawal bleed, or if two withdrawal bleeds are missed, pregnancy must be ruled out before continuing with COC use.

Warnings about excipients
This medicinal product contains lactose. Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicinal product.

Interaction with other medicinal products and other forms of interaction
Note: The prescribing information of concomitant medications should be consulted to identify potential interactions.

Interactions
Interactions between oral contraceptives and other medicinal products may impair the contraceptive efficacy and/or lead to breakthrough bleeding and/or contraceptive failure.

Hepatic metabolism:
Interactions can occur with drugs that induce hepatic enzymes which can result in increased clearance of sex hormones (e.g. phenytoin, barbiturates, primidone, carbamazepine, rifampicinbosentan and HIV-medication (e.g. ritonavir, nevirapine) and possibly also oxcarbazepine, topiramate, felbamate, griseofulvin and products containing the herbal remedy St. John’s Wort (hypericum perforatum)). Maximal enzyme induction is generally seen in about 10 days but may then be sustained for at least 4 weeks after the cessation of drug therapy.

Management
Women on short-term treatment with any of the above-mentioned classes of medicinal products or individual active substances (hepatic enzyme-inducing medicine) besides rifampicin should temporarily use a barrier method in addition to the COC, i.e. during the time of concomitant medicinal product administration and for 7 days after their discontinuation.
For women on rifampicin a barrier method should be used in addition to the COC during the time of rifampicin administration and for 28 days after its discontinuation.
In women on long-term treatment with hepatic enzyme-inducing active substances, another reliable, non-hormonal, method of contraception is recommended.
Influence of Levonorgestrel/EE on other medicinal products
Oral contraceptives 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).

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 blood coagulation and fibrinolysis. The changes generally remain within the normal laboratory range.

Fertility, pregnancy and lactation

Pregnancy
Levonorgestrel/EE is not indicated in pregnancy.
If the woman becomes pregnant while using Levonorgestrel/EE tablets, further intake must be stopped immediately. However, most epidemiological studies have revealed neither an increased risk for birth defects in children born to women who used COCs before pregnancy, nor any teratogenic effects at unintentional intake of contraceptive pills in early pregnancy.

Breastfeeding
Breastfeeding may be influenced by contraceptive pills as they may reduce the amount of breast milk and change its composition. Therefore, 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 contraceptive steroids and/or their metabolites may be excreted in breast milk. These amounts may affect the child.


Effects on ability to drive and use machines
Levonorgestrel/EE has no or negligible influence on the ability to drive and use machines.

UNDESIRABLE EFFECTS
The following undesirable effects have been observed with use of combined oral contraceptives containing ethinylestradiol/levonorgestrel:
The following serious adverse events have been reported in women using COCs, Special warnings and precautions for use:
Venous thromboembolic disorders
Arterial thromboembolic disorders Hypertension
Liver tumours
Crohn’s disease, ulcerative colitis, epilepsy, uterine myoma, porphyria, systemic lupus erythematosus, herpes gestationis, Sydenham’s chorea, haemolytic uremic syndrome, cholestatic jaundice;
In women with hereditary angioedema exogenous estrogens may induce or exacerbate symptoms of angiodema.
The frequency of diagnosis of breast cancer is 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.

Reporting of suspected adverse reactions
Reporting suspected adverse reactions after authorization 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 Yellow Card Scheme, Website: www.mhra.gov.uk/yellowcard

Organ system Common

(≥ 1/100 to < 1/10)

Uncommon

(≥ 1/1,000 to <1/100)

Rare

(≥1/10,000 to < 1/1,000)

Immune system disorders Hypersensitivity
Metabolism and nutrition disorders Fluid retention
Psychiatric disorders Depressed mood

Mood altered

Libido decreased Libido increased
Nervous system disorders Headache Migraine
Eye disorders Contact lens intolerance
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

Overdose
No serious adverse reactions due to overdose have been reported. Symptoms of overdose of a combined oral contraceptive may include: nausea, vomiting; in adolescents, slight vaginal bleeding may occur. There is no specific antidote. Treatment should be symptomatic.

Pharmacological particulars


Pharmacodynamic properties
Pharmacotherapeutic group (ATC): progestogen and estrogens, fixed combinations
ATC Code: G03AA07
Overall Pearl Index (method failure + patient failure): 0.59 (upper tow-sided 95% confidence limit: 0.85).
The contraceptive effect of COCs is based on the interaction of various factors. The most important are the inhibition of ovulation and changes in the cervical mucus

Pharmacokinetic properties

Ethinylestradiol


Absorption
Orally administered ethinylestradiol is absorbed rapidly and completely.
Peak serum concentrations of about 100 pg/ml are reached within 1–1.5 hours after taking 30 microgram ethinylestradiol. During absorption and first-pass hepatic metabolism ethinylestradiol is metabolized extensively, resulting in a mean oral bioavailability of about 40-60% (interindividual variation about).

Distribution
Ethinylestradiol is highly (approximately 98%) but nonspecifically bound to serum albumin, and induces an increase in the serum concentrations of sex hormone binding globulin (SHBG).The absolute volume of distribution of ethinylestradiol is 5 L/kg.

Biotransformation
Ethinylestradiol is subject to pre-systemic conjugation in both small bowel mucosa and the liver. Ethinylestradiol is primarily metabolised by aromatic hydroxylation, forming various hydroxylated and methylated metabolites that are present as free metabolites or as glucuronide or sulfate conjugates in serum. The metabolic clearance rate from serum is 5 ml/min/kg.

Elimination
Ethinylestradiol levels in serum decrease in two phases characterized by half-lives of about 1-2 hours and about 20 hours, respectively. Ethinylestradiol is not excreted in unchanged form. Its metabolites are excreted at a urinary to biliary ratio of 4:6. The elimination half-life is about 1 day.


Steady-State conditions
Ethinylestradiol concentration in serum increases about 40% after continuous use of tablets containing 150 microgram levonorgestrel and 30 microgram ethinylestradiol. Due to the variable half-life of the terminal phase in serum clearance and the daily administration, steady-state conditions are reached after approximately 5 daily administrations


Levonorgestrel


Absorption
Orally administered levonorgestrel is absorbed rapidly and completely. Peak serum levonorgestrel levels of about 3 ng/ml are reached around 1 hour after taking 150 microgram levonorgestrel. The bioavailability of levonorgestrel after oral administration is nearly 100%.


Distribution
Levonorgestrel is bound to serum albumin and sex hormone binding globulin (SHBG). Only 1.5% of the total serum drug concentrations are present as free steroid, approximately 65% are specifically bound to SHBG and approximately 35% are non-specifically bound to albumin. The ethinylestradiol-induced increase in the SHBG concentration influences the relative distribution of levonorgestrel into different protein fractions. Induction of the binding protein causes an increase in the SHBG-bound fraction and a decrease in the albumin-bound fraction.

Biotransformation
Levonorgestrel is completely metabolised by the typical pathways of steroid metabolism. The plasma clearance rate is approximately 1.5 ml/min/kg.

Elimination
Serum levonorgestrel levels decrease in two phases. The terminal phase is characterized by a half-life of approximately 1 hour and about 20hours, respectively. Levonorgestrel is metabolised before being excreted. Its metabolites are at a urinary to biliary (feces) ratio of about 1:1. The elimination half-life of the metabolites is about 1 day.


Steady-state condition
During the continuous use of Levonorgestrel/EE tablets, serum levonorgestrel levels increase about fourfold reaching steady-state conditions during the second half of the treatment cycle. The pharmacokinetic of levonorgestrel is influenced by SHBG levels in serum, which increase by 1.7-fold after daily ingestion of a combined oral contraception containing estradiol. This effect leads to a reduction of the clearance rate to about 0.7 ml/min/kg at steady state.

Preclinical safety data
Preclinical data for ethinylestradiol and levonorgestrel from conventional studies of general toxicity, genotoxicity, carcinogenic potential and toxicity to reproduction have not revealed other effects than those which can be explained bases on the known hormone profile of ethinylestradiol and levonorgestrel. However, it should be remembered that sex steroids can promote the growth of certain hormone-dependent tissues and tumours.

Pharmaceutical particulars


List of excipients


Tablet core:
Lactose monohydrate
Povidone K30
Crospovidone Type A
Magnesium stearate


Coating:

Polyvinyl alcohol, partial hydrolyzed
Titanium dioxide (E171)
Macrogol 3350
Talc (E553b)
Iron oxide yellow (E172)

Incompatibilities
Not applicable.

 Shelf life

2 years

Special precautions for storage
Do not store above 30°C.

Nature and contents of container

Blisters of aluminium push-thru foil and PVC/PVDC film. The blister packs may come with a blister holder.
It is available in boxes of 1, 3, 6 and 13 packs (blisters), each one containing 21 tablets.
Not all pack sizes may be marketed.

Special precautions for disposal and other handling

Any unused medicinal product or waste material should be disposed of in accordance with local requirements.


MARKETING AUTHORISATION HOLDER

TAJ PHARMA CIS LTD.
Marksistsky lane 6, office 221, Moscow, 109147, Russia

MANUFACTURER:

Manufactured in India by:
TAJ PHARMACEUTICALS LTD,
220, Mahagujarat Ind. Estate,  Moraiya,

Tal. Sanand , Dist. Ahmedabad,

Gujarat, INDIA.

Package leaflet:

Information for the patient

Read all of this leaflet carefully before you start taking this medicine because it contains important information for you.
– Keep this leaflet. You may need to read it again.
 – If you have any further questions, ask your doctor or pharmacist.
– This medicine has been prescribed for you only. Do not pass it on to others. It may harm them, even if their signs of illness are the same as yours.
– If you get any side effects, talk to your doctor or pharmacist. This includes any possible side effects not listed in this leaflet.

What is in this leaflet

What is in this leaflet
1. What LEVONORGESTREL/EE Tablets are and what they are used for
2. What you need to know before you take LEVONORGESTREL/EE Tablets
3. How to take LEVONORGESTREL/EE Tablets
4. Possible side effects
5. How to store LEVONORGESTREL/ EE Tablets
6. Contents of the pack and other information

 WHAT LEVONORGESTREL/EE TABLETS ARE AND WHAT THEY ARE USED FOR

Levonorgestrel/EE is a contraceptive pill and it is used to prevent pregnancy.
Each tablet contains a small amount of two different female hormones, namely ethinylestradiol and levonorgestrel.
Contraceptive pills that contain two hormones are called “combination” pills.

WHAT YOU NEED TO KNOW BEFORE YOU TAKE LEVONORGESTREL/EE TABLETS

Before you can begin taking Levonorgestrel/EE, your doctor will ask you some questions about your personal health history and that of your close relatives. The doctor will also measure your blood pressure, and depending upon your personal situation, may also carry out some other tests.
In this leaflet, several situations are described where you should stop using Levonorgestrel/EE, or where the reliability of Levonorgestrel/EE may be decreased. In such situations you should either not have intercourse or you should take extra non-hormonal contraceptive precautions, for example use a condom or another barrier method. Do not use rhythm or temperature methods. These methods can be unreliable because Levonorgestrel/EE alters the monthly changes of the body temperature and of the cervical mucus.


Levonorgestrel/EE, like other hormonal contraceptives, does not protect you against HIV infection (AIDS) or any other sexually transmitted disease.

Do not take Levonorgestrel/EE


if you have (or have ever had) a blood clot in a blood vessel of the leg (thrombosis), lung (pulmonary embolism) or other organs
if you have (or have ever had) a heart attack or stroke;
if you have (or have ever had) a disease that can be an indicator of a heart attack (for example, angina pectoris, which causes severe pain in the chest) or of a stroke (for example, a passing slight stroke with no residual effects);
if you have a disease that may increase the risk of a clot in the arteries. This applies to the following diseases:
diabetes with damaged blood vessels;
very high blood pressure;
a very high level of fat in the blood (cholesterol or triglycerides);
if you have a disturbance of blood clotting (for example, protein C deficiency);
if you have (or have ever had) a liver disease and your liver function is still not normal;
if you have (or have ever had) a tumour in the liver;
if you have (or have ever had) or if you are suspected of having breast cancer or cancer of the genital organs;
if you have any unexplained bleeding from the vagina;
if you have (or have ever had) a certain form of migraine (with so-called focal neurological symptoms);
if you are allergic to ethinylestradiol, levonorgestrel or any of the other ingredients of this medicine. An allergic reaction may cause itching, rash or swelling

Warnings and precautions

In some situations you need to take special care while using Levonorgestrel/EE or any other combination pill, and it may be necessary that you are regularly checked by your doctor. If any of the following conditions applies to you, inform your doctor before starting to take Levonorgestrel/EE.
Also if any of the following conditions develops or worsens while you are using Levonorgestrel/EE, you must consult your doctor:
if a close relative has or has ever had breast cancer;
if you have a disease of the liver or the gallbladder;
if you have diabetes;
if you have depression;
if you have Crohn’s disease or inflammatory bowel disease (ulcerative colitis);
if you have a blood disease called HUS (haemolytic uraemic syndrome) which causes kidney damage);
if you have a blood disease called sickle cell anaemia;
if you have epilepsy (see section “Other medicines and Levonorgestrel/EE”);
if you have a disease of the immune system called SLE (systemic lupus erythematosus);
if you have a disease that first appeared during pregnancy or earlier use of sex hormones (for example hearing loss), a blood disease called porphyria, skin rash with blisters during pregnancy (gestational herpes), a nerve disease causing sudden movements of the body (Sydenham’s chorea);
if you have or have ever had chloasma (a discoloration of the skin especially of the face or neck known as “pregnancy patches”). If so, avoid direct exposure to sunlight or ultraviolet light
if you have hereditary angioedema, products containing estrogens may cause or worsen symptoms. Talk to your doctor immediately if you experience symptoms of angioedema, such as swollen face, tongue and/or throat and/or difficulty swallowing or hives together with difficulty breathing.
Talk to your doctor, pharmacist or nurse before taking Levonorgestrel/EE.

Levonorgestrel/EE and venous and arterial blood clots

The use of any combination pill, including Levonorgestrel/EE, increases a woman’s risk of developing a venous blood clot (venous thrombosis) compared with women who do not take any contraceptive pill. The excess risk is highest during the first year a woman initially starts using a combination pill or when she restarts use after a pill-free interval of at least a month.
The risk of venous blood clots in users of combination pills increases:
with increasing age;
if you are overweight;
if one of your close relatives ever had a blood clot in the leg, lung (pulmonary embolism), or other organ at a young age;
if you have to have surgery,
if you have had a serious accident or if you are immobilised for a long time. It is important to tell your doctor that you are using Levonorgestrel/EE as you may have to stop taking it. Your doctor will tell you when to start using it again. This is usually about two weeks after you are back on your feet.
Your chances of having a blood clot are increased by taking the pill.
Of 100,000 women who are not on the pill and not pregnant, about 5-10 may have a blood clot in a year.
Of 100,000 women taking a pill like Levonorgestrel/EE, 30-40 may have a blood clot in a year, the exact number is unknown.
Of 100,000 women who are pregnant, around 60 may have a blood clot in a year.
A blood clot in the veins may travel to the lungs and may block blood vessels (called a lung embolus). Formation of blood clots in the veins may be fatal in 1-2% of cases.
The level of risk may vary according to the type of pill you take. Discuss with your doctor the available options.
The use of the combination pill has been connected with an increase of the risk of an arterial blood clot (arterial thrombosis), for example, in the blood vessels of the heart (heart attack) or the brain (stroke).

The risk of arterial blood clot in users of combination pills increases:

if you smoke. You are strongly advised to stop smoking when you use Levonorgestrel/EE, especially if you are older than 35 years.
if the fat content of your blood is increased (cholesterol or triglycerides);
if you are overweight;
if one of your close relatives ever had a heart attack or stroke at a young age;
if you have high blood pressure;
if you suffer from migraine;
if you have a problem with your heart (valve disorder, a disturbance of the cardiac rhythm).

Stop taking Levonorgestrel/EE and contact your doctor immediately if you notice possible signs of a blood clot, such as:
severe pain and/or swelling in one of your legs;
sudden severe pain in the chest which may reach the left arm;
sudden breathlessness;

sudden cough without an obvious cause;
any unusual, severe or long-lasting headache or worsening of migraine;
partial or complete blindness or double vision;
difficulty in speaking or inability to speak;
giddiness or fainting;
weakness, strange feeling, or numbness in any part of the body.
severe pain in your stomach (acute abdomen).

Levonorgestrel/EE and cancer
Breast cancer has been observed slightly more often in women using combination pills, but it is not known whether this is caused by the treatment. For example, it may be that more tumours are detected in women using the pill because they see the doctor more often.
The occurrence of breast tumours becomes gradually less after stopping the combination hormonal contraceptives. It is important to regularly check with your doctor if you feel any lump.
Cervical cancer in long-term users has been reported, but it is not clear if it is contributed by sexual behaviour or other factors such as human papilloma virus (HPV).
In rare cases, benign liver tumours, and in even fewer cases malignant liver tumours have been reported in pill users. Contact your doctor if you have unusually severe abdominal pain.

Bleeding between periods
During the first few months that you are taking Levonorgestrel/EE, you may have unexpected bleeding (bleeding outside the gap week). If this bleeding occurs for more than a few months, or if it begins after some months, talk to your doctor, who will find out what is wrong.

What to do if no bleeding occurs during the gap week
If you have taken all the tablets correctly, have not had vomiting or severe diarrhoea and you have not taken any other medicines, it is highly unlikely that you are pregnant.
If the expected bleeding does not happen twice in a row, you may be pregnant. Contact your doctor immediately. Do not start the next strip until you are sure that you are not pregnant.

Other medicines and Levonorgestrel/EE
Always tell your doctor, who prescribes Levonorgestrel/EE, if you are using, have recently used or might use any other medicines, including herbal products. Also tell any other doctor or dentist who prescribes another medicine (or the pharmacist) that you take Levonorgestrel/EE. They can tell you if you need to take additional contraceptive precautions (for example condoms) and if so, for how long.
Some medicines can make Levonorgestrel/EE less effective in preventing pregnancy, or can cause unexpected bleeding. These include
medicines used for the treatment of:
epilepsy (for example primidone, phenytoin, barbiturates, carbamazepine, oxcarbazepine, topiramate and felbamate);
tuberculosis (for example rifampicin);
HIV infections (ritonavir, nevirapin) or other infections (griseofulvin);
high blood pressure in the blood vessels in the lungs (bosentan);
the herbal remedy St. John’s wort.
Levonorgestrel/EE may influence the effect of other medicines, for example:
medicines containing cyclosporine
the anti-epileptic lamotrigine (this could lead to an increased frequency of seizures).

Levonorgestrel/EE with food and drink
Levonorgestrel/EE may be taken with or without food, if necessary with a small amount of water.

Laboratory tests
If you need a blood test, tell your doctor or the laboratory staff that you are taking the pill, because hormone contraceptives can affect the results of some tests.

Pregnancy and breast-feeding
If you are pregnant or breast-feeding, think you may be pregnant or are planning to have a baby, ask your doctor or pharmacist for advice before taking this medicine.

Pregnancy
If you are pregnant, do not take Levonorgestrel/EE. If you become pregnant while taking Levonorgestrel/EE stop using the pill immediately and contact your doctor. If you want to become pregnant, you can stop taking the pill at any time (see also “If you want to stop taking Levonorgestrel/EE”).

Breast-feeding
Use of Levonorgestrel/EE is generally not advisable when a woman is breast-feeding. If you want to take the pill while you are breast-feeding, contact your doctor.

Driving and using machines
There is no information suggesting that the use of Levonorgestrel/EE affects driving or use of machines.

Levonorgestrel/EE contains lactose
This medicine contains lactose. If you cannot tolerate certain sugars, contact your doctor before you take Levonorgestrel/EE.

HOW TO TAKE LEVONORGESTREL/EE TABLETS

Always take this medicine exactly as your doctor has told you. Check with your doctor or pharmacist if you are not sure. Remember to take Levonorgestrel/EE as prescribed because missing tablets could reduce the effectiveness of the medicine.

How and when should Levonorgestrel/EE be used:
Each strip contains 21 tablets.
Take one Levonorgestrel/EE tablet every day, if necessary with a small amount of water. You should take the tablets every day around the same time.
Next to each tablet is printed the day of the week when it should be taken. Start by taking a tablet from the first row marked with the correct day of the week. If, for example, you start on a Wednesday, take a tablet with “WED” next to it. Follow the direction of the arrows on the strip until you have taken all 21 tablets. Then take no tablets for 7 days. In the course of these 7 tablet-free days (otherwise called a stop or gap week) bleeding should begin. This so-called “withdrawal bleeding” usually starts on the 2nd or 3rdday of the gap week.

On the 8th day after the last Levonorgestrel/EE tablet (that is, after the 7-day gap week), you should start with the following strip, whether your bleeding has stopped or not. This means that you should start every strip on the same day of the week and that the withdrawal bleed should occur on the same days each month.
If you use Levonorgestrel/EE in this manner, you are also protected against pregnancy during the 7 days when you are not taking tablets.

When can you start taking Levonorgestrel/EE

If you have not used any contraceptive with hormones in the previous month
Start taking Levonorgestrel/EE on the first day of the cycle
(that is, on the first day of your menstrual period). If you start Levonorgestrel/EE on the first day of your menstruation, you are immediately protected against pregnancy. You may also begin on days 2-5 of the cycle, but then you must use extra protective measures (for example, a condom) for the first 7 days.

If you are changing from a combination hormonal contraceptive, vaginal ring or a patch
You can start Levonorgestrel/EE preferably on the day after the last active tablet (the last tablet containing active substances) of your previous pill, but at the latest on the day after the tablet-free days of your previous pill). When changing from a combination contraceptive vaginal ring or patch, follow the advice of your doctor.

If you are changing from a progestogen-only-method (progestogen-only–pill, injection, implant or progestogen releasing intrauterine device – IUD)
You may switch any day from the progestogen-only pill (from an implant or an IUD on the day of its removal, from an injectable when the next injection would be due) but in all the cases use extra protective measures (for example, a condom) for the first 7 days of tablet-taking.

If you had a miscarriage
Follow the advice of your doctor.

After having a baby
You can start taking Levonorgestrel/EE between 21 and 28 days after having a baby. If you start later than day 28, use a barrier contraceptive method (for example, a condom) during the first seven days. If, after having a baby, you have had sex before starting to take Levonorgestrel/EE (again), be sure that you are not pregnant or wait until the next menstrual period before taking this medicine.

While breast-feeding
If you are breast-feeding and want to start taking Levonorgestrel/EE (again) after having a baby, read the section “Pregnancy and breast-feeding”.
Ask your doctor what to do if you are not sure when to start taking Levonorgestrel/EE.

If you take more Levonorgestrel/EE than you should
There are no reports of serious harmful results of taking too many Levonorgestrel/EE tablets.
If you take several tablets at once then you may have symptoms of nausea or vomiting. Young girls may have bleeding from the vagina.
If you have taken too many Levonorgestrel/EE tablets, or you discover that a child has taken some, ask your doctor or pharmacist for advice.

If you forget to take Levonorgestrel/EE
If you are less than 12 hours late taking a tablet, the protection from pregnancy is not reduced. Take the tablet as soon as you remember and then continue to take the following tablets at the usual time (even if this means taking two tablets the same day). In this case you do not need to use any additional method of contraception.
If you are more than 12 hours late taking a tablet, the protection from pregnancy may be reduced. The greater the number of tablets you have forgotten, the greater is the risk of becoming pregnant.
The risk of incomplete protection against pregnancy is greatest if you forget a tablet at the beginning or the end of the strip.

Follow the instructions below if you have forgotten to take a tablet:

If you forgot more than one tablet in this strip
Contact your doctor.

If you forgot one tablet in week 1
Take the forgotten tablet as soon as you remember, even if that means taking two tablets at the same time. Continue taking the tablets at the usual time and use extra
contraceptive
 barrier methods for the next 7 days, for example, a condom. If you have had sex in the week before forgetting the tablet, you may be pregnant. In that case, contact your doctor.

If you forgot one tablet in week 2
Take the forgotten tablet as soon as you remember, even if that means taking two tablets at the same time. Continue taking the tablets at the usual time. The contraceptive effect of the medicine is not reduced, and you do not need to take extra precautions.

If you forgot one tablet in week 3
You can choose between two options:
Take the forgotten tablet as soon as you remember, even if that means taking two tablets at the same time. Continue taking the tablets at the usual time. Instead of the tablet-free period, start the next strip.
Most likely, you will have a period at the end of the second strip but you may also have light or menstruation-like bleeding during the second strip.

You can also stop taking the tablets in the strip and immediately start the tablet-free period of 7 days (record the day on which you forgot your tablet). If you want to start a new strip on the day you always start, make the tablet-free period less than 7 days.
If you follow any of the above recommendations, you will remain protected against pregnancy.
If you have forgotten any of the tablets in a strip, and you do not have bleeding in the first tablet-free days, this may mean that you are pregnant. Contact your doctor before you start the next strip.

What to do if you vomit or have severe diarrhea
If you vomit within 3-4 hours after taking a tablet or you have severe diarrhoea, there is a risk that the active substances in the tablet are not fully absorbed in your body. The situation is almost the same as forgetting a tablet. After vomiting or having diarrhoea, take another tablet from a reserve strip as soon as possible. If possible take it within 12 hours of when you normally take your tablets. If this is not possible or 12 hours have passed, follow the advice given under “If you forget to take Levonorgestrel/EE”.

Delaying your period: what you need to know
Even though it is not recommended, you can delay your period by going straight to a new strip of Levonorgestrel/EE (and finishing it) instead of the tablet-free period. You may experience light or menstruation-like bleeding while taking the tablets from this second strip. After the usual tablet-free period of 7 days, start the next strip.

You might ask your doctor for advice before deciding to delay your menstrual period.

Changing the first day of your period: what you need to know
If you take the tablets according to the instructions, then your period will begin during the tablet-free week. If you want to change this day, reduce the number of tablet-free days (but never increase them – 7 is the maximum!). For example, if your tablet-free days normally begin on a Friday, and you want to change this to a Tuesday (3 days earlier) start a new strip 3 days earlier than usual. If you make the tablet-free interval very short (for example, 3 days or less) you may not have any bleeding during these days. You may then experience light or menstruation-like bleeding.

If you are not sure what to do, consult your doctor.

If you want to stop taking Levonorgestrel/EE
You can stop taking Levonorgestrel/EE whenever you want. If you do not want to become pregnant, ask your doctor for advice about other reliable methods of birth control. If you want to become pregnant, stop taking Levonorgestrel/EE and wait for a menstrual period before trying to become pregnant. You will be able to calculate the expected delivery date more easily.
If you have any further questions on the use of this medicine, ask your doctor or pharmacist.

 POSSIBLE SIDE EFFECTS

Like all medicines, this medicine can cause side effects, although not everybody gets them.
The following is a list of the side effects that have been linked with the use of Levonorgestrel/EE:


Common (may affect up to 1 in 10 people):
nausea
abdominal pain
increased weight
headache
depressed mood
altered mood
breast tenderness
breast pain

Uncommon (may affect up to 1 in 100 people):
vomiting
diarrhea
fluid retention
migraine
decreased libido
breast enlargement
rash
hives (urticaria)

Rare (may affect up to 1 in 1,000 people):
contact lens intolerance
hypersensitivity
decreased weight
increased libido
breast discharge
vaginal discharge
a type of skin inflammation resulting in reddish, painful, tender lumps (erythema nodosum)
a skin disorder that causes red, target-shaped or ”bulls-eye” patches or sores (erythema multiforme)

Oral contraceptive use has been associated with:
Increased risk of blood clots in arteries and veins and disorders caused by a blood clot that breaks loose, including heart attack, blood clot in a vein and blood clot in the lung.
Increased risk of changes in the surface of the neck of the uterus (intraepithelial neoplasia) and cancer of the neck of the uterus.
Increased risk of breast cancer diagnosis.

Reporting of side effects
If you get any side effects, talk to your doctor, pharmacist or nurse. This includes any possible side effects not listed in this leaflet. You can also report side effects directly via the Yellow Card Scheme, Website: www.mhra.gov.uk/yellowcard. By reporting side effects you can help provide more information on the safety of this medicine.

 HOW TO STORE LEVONORGESTREL/EE TABLETS

Keep this medicine out of the sight and reach of children.
Do not store above 30°C.
Do not use this medicine after the expiry date which is stated on the carton and strip after “EXP”. The expiry date refers to the last day of that month.
Do not throw away any medicines via wastewater or household waste.
Ask your pharmacist how to throw away medicines you no longer use. These measures will help protect the environment.

Further Information

What Levonorgestrel/EE contains
The active ingredients are ethinylestradiol and levonorgestrel. Each tablet contains 0.03mg and 0.05 of ethinylestradiol /0.15mg and 0.25 of levonorgestrel.
The other ingredients are:
Tablet core: lactose monohydrate, povidone K30, crospovidone type A and magnesium stearate.
Coating: polyvinyl alcohol, titanium dioxide (E171), macrogol 3350, talc (E553b) and iron oxide yellow (E172)

 

What Levonorgestrel/EE looks like and contents of the pack
Each strip of Levonorgestrel/EE contains 21 yellow film-coated tablets.
Levonorgestrel/EE tablets are film-coated tablets. The tablets are yellow, round, with a diameter of 6mm and thickness less than 4mm approximately.
Levonorgestrel/EE is available in packs of 3 strips, each strip with 21 tablets.

Manufactured by:
Taj Pharmaceuticals Limited
220, Mahagujarat Ind. Estate, Moraiya, Tal. Sanand, Dist. Ahmedabad, Gujarat, INDIA

Marketing Authorization Holder:
Regal sun co., Ltd.Myanmar

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