DESOGESTREL AND ETHINYL ESTRADIOL TABLET

NAME OF THE MEDICINAL PRODUCT

Desogestrel + Ethinylestradiol Tablets USP 0.15 mg/0.02 mg

Desogestrel + Ethinylestradiol Tablets USP 0.15 mg/0.03 mg

QUALITATIVE AND QUANTITATIVE COMPOSITION
Each tablet contains 0.15 milligrams desogestrel (= 150 micrograms) 0.02 milligrams ethinylestradiol (= 20 micrograms)

Each tablet contains 0.15 milligrams desogestrel (= 150 micrograms) 0.03 milligrams ethinylestradiol (= 30 micrograms)

Contains 68,55 mg lactose (as lactose monohydrate).
Contains 68,54 mg lactose (as lactose monohydrate).

PHARMACEUTICAL FORM
Tablet. White, biconvex round tablets.

CLINICAL PARTICULARS

Therapeutic indications
Oral contraception

Posology and method of administration

How to take Desogestrel + Ethinylestradiol The tablets should be taken in the order of succession stated on the package every day at about the same time of the day. One tablet is taken daily for 21 consecutive days. Each subsequent pack is started after a 7-day tablet-free interval; during this tablet-free interval a menstruation- like withdrawal bleeding occurs. This bleeding usually begins on the 2nd or 3rd day after ingestion of the last tablet and it may not have ceased, before the next pack is started. The safety and efficacy of desogestrel in adolescents below 18 years has not yet been established. No data are available.

How to start Desogestrel + Ethinylestradiol No preceding intake of hormonal contraceptives (within the last month) The tablet intake should be started on day 1 of the normal menstrual cycle (i.e. on the first day on which the woman has a menstrual bleeding). Tablet intake is also allowed to start on day 2-5, but during the first cycle concurrent use of a barrier method for the first 7 days of tablet intake is advisable.

Changing from another combined hormonal contraceptive (combined oral contraceptive (COC), combined contraceptive vaginal ring or transdermal patch)
The woman should start taking Desogestrel + Ethinylestradiol Generis preferably on the day after the last active tablet (the last tablet containing the active substance) of her previous COC, but at the latest on the day following the usual tablet-free interval or following the last placebo tablet of her previous COC.
In case a vaginal ring or a transdermal patch has been used, the woman should start using Desogestrel + Ethinylestradiol Generis preferably on the day of removal, but at the latest when the next application would have been due.

Changing from progestogen only products (progetogen-only-pills, injection, implant) or from a progestogen-releasing intrauterine system (IUS)
The woman can change from progestogen-only pills on any day (changing from implant or IUS on the day of its removal; changing from injection when the next injection should have been given) but should in all of these cases be advised to additionally use a barrier method for the first 7 days of tablet-taking.

After abortion in the 1st trimester
Tablet intake should start immediately. In this case no further contraceptive measures are necessary.
After delivery or abortion in the 2nd trimester
The woman should be advised to start the pill on day 21-28 after delivery or abortion in the 2nd trimester. She should be advised to use a barrier method concurrently during the first 7 days of tablet intake if she starts the pill later. In case she has already had intercourse, pregnancy should be excluded before she starts tablet intake, or she should wait for her first menstrual bleeding.

Forgotten tablets
If the tablet intake is forgotten for less than 12 hours, contraceptive protection is not reduced. The woman should take the forgotten tablet as soon as she remembers, and the remaining tablets are taken as usual.

If the tablet intake is forgotten for more than 12 hours, contraceptive protection may be reduced.
The following two basic rules should be considered in case of forgotten tablets:
1. Continuous tablet intake must not be interrupted for longer than a period of 7 days.
2. 7 days of uninterrupted tablet intake are required to achieve sufficient suppression of the hypothalamus-pituitary-ovarian-axis.

Thus, the following advice may be given for daily practice:

Week 1
The user should take the last forgotten tablet as soon as she remembers, even if this means that she has to take 2 tablets at the same time. Then, she continues taking the tablets at the usual time of the day. She should concurrently use a barrier method, e.g. a condom, for the next 7 days. If intercourse has taken place during the preceding 7 days, the possibility of pregnancy should be considered. The more tablets are forgotten and the closer they are to the regular tablet-free period, the higher the risk of pregnancy is.

Week2
The user should take the last forgotten tablet as soon as she remembers, even if this means that she has to take 2 tablets at the same time. Then, she continues taking the tablets at the usual time of the day. Provided that the tablets have been taken in a correct manner during the 7 days preceding the forgotten tablet, it is not necessary to take further contraceptive measures. However, if this is not the case, or if more than 1 tablet has been forgotten, the woman should be advised to use another contraceptive method for 7 days.

Week3
The risk of reduced contraceptive protection is imminent due to the next tablet-free period. However, this risk may be prevented by adjusting tablet intake. Thus, it is not necessary to take further contraceptive measures if one of the two alternatives below is followed, provided that all tablets have been taken in a correct manner during the 7 days preceding the forgotten tablet. If this is not the case, the woman should be advised to follow the first of the two alternatives and concurrently use another contraceptive method for the next 7 days.

1 The user should take the last forgotten tablet as soon as she remembers even if it means that she has to take 2 tablets at the same time. Then she continues taking the tablets at the usual time of the day. She will begin taking the next pack immediately after taking the last tablet in the present pack, i.e. there is no break between the packs. It is not very likely that the user will have her menstrual bleeding until the end of the second pack, but she may experience spotting or breakthrough bleeding on the days she is taking tablets. 2. The woman may also be advised to stop taking tablets from the present pack. In that case she should keep a tablet-free period of up to 7 days, including those days when she forgot tablets, and then continue with the next pack. In case the woman has forgotten tablets and then does not have her menstrual bleeding in the first normal tablet-free period, the possibility of pregnancy should be considered

Precautions in case of vomiting or severe diarrhoea
If vomiting or severe diarrhoea occur within 3-4 hours after tablet intake, the tablet may not be absorbed completely. If the woman does not want to change her usual tablet intake, she has to take the necessary extra tablet(s) from another pack.

How to postpone a withdrawal bleed
To delay a period the woman should continue with another blister pack of Desogestrel + Ethinylestradiol without a tablet-free interval. The extension can be carried on for as long as wished until the end of the second pack. During the extension the woman may experience breakthrough-bleeding or spotting. Regular intake of Desogestrel + Ethinylestradiol  is then resumed after the usual 7-day tablet-free interval
To shift her periods to another day of the week than the woman is used to with her current scheme, she can be advised to shorten her forthcoming tablet-free interval by as many days as she likes. The shorter the interval, the higher the risk that she does not have a withdrawal bleed and will experience breakthrough-bleeding and spotting during the subsequent pack (just as when delaying a period).

CONTRAINDICATION
COCs should not be used under any of the following conditions. Should such a condition occur for the first time while taking COCs, the use of COCs should be discontinued immediately.
– Venous thrombosis present or in history (deep venous thrombosis, pulmonary embolism).
– Arterial thrombosis present or in history (e.g. cerebro-vascular accident, myocardial infarction) or prodromal conditions (e.g. angina pectoris and transient ischaemic attack).
– Cerebrovascular accident present or in history
– The presence of a severe or multiple risk factor(s) for arterial thrombosis:
– diabetes mellitus with vascular symptoms – severe hypertension
– severe dyslipoproteinemia
– 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).
– Pancreatitis or a history thereof if associated with severe hypertriglyceridemia – 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 malignan cies (e.g. of the genital organs or the breasts)
– Undiagnosed vaginal bleeding. – History of migraine with focal neurological symptoms
– Hypersensitivity to the active substances or to any of the excipients of Desogestrel + Ethinylestradiol

SPECIAL PRECAUTIONS & WARNINGS

Warnings
 If one of the conditions or risk factors mentioned below is present, the advantages of taking COCs should be weighed against the possible risks in each individual case and discussed with the woman, before she decides whether to take COCs. In case of worsening or if any of these risk factors occurs, the woman should contact her physician. The physician should then decide whether the use of COCs should be discontinued.
1. Circulatory disorders
Epidemiological studies have shown that the incidence of VTE in users of oral contraceptives with low oestrogen content ranges from about 20 to 40 cases per 100,000 woman-years, but this risk estimate varies according to the progestogen. This compares with 5 to 10 cases per 100,000 woman-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 ever uses a combined oral contraceptive. The incidence of VTE associated with pregnancy is estimated as 60 cases per 100,000 pregnancies. VTE is fatal in 1-2% of cases.
Epidemiological studies have also associated the use of COCs with an increased risk for arterial (myocardial infarction, transient ischaemic attack) thromboembolism.

For brands containing 30m g of ethinylestradiol combined with desogestrel or gestodene compared to those less than 50 mg of ethinylestradiol and levonorgestrel, the overall relative risk of VTE has been estimated to range between 1.5 and 2.0. The incidence of VTE for g of ethinylestradiol is approximately 20 casesmlevonorgestrel containing COCs with less than 50  per 100,000 women-years of use. For Desogestrel + Ethinylestradiol Generis the incidence is approximately 30-40 cases per 100,000 women-years of use, i.e. additional 10-20 cases per 100,000 women-years of use.
The impact of the relative risk on the number of additional cases would be the greatest in women during the first year they ever use a COC when the risk for VTE with all COCs is highest.

For COCs containing desogestrel or gestodene with 20 m  g of ethinylestradiol.mdata do not suggest a lower VTE risk than for those containing 30 mg of ethinylestradiol

Extremely rarely, thrombosis has been reported to occur in other blood vessels, e.g. hepatic, mesenteric, renal, cerebral or 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 pain in the chest, whether or not it radiates to the left arm
– sudden breathlessness
– sudden onset of coughing
– any unusual, severe, prolonged headache
– sudden partial or complete loss of vision
– diplopia
– slurred speech or aphasia
– vertigo
– collapse with or without focal seizure
– weakness or very marked numbness suddenly affecting one side or one part of the body
– motor disturbances
– ,acute’ abdomen.

COC-users should be specifically pointed out to contact their physician in case of possible symptoms of thrombosis. In case of suspected thrombosis, COC use should be discontinued.

The risk for venous thromboembolic complications in COCs users increases with: – increasing age
– a positive family history (venous 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.
– prolonged immobilisation, major surgery, any surgery to the legs, or major trauma. In these situations it is advisable to discontinue the pill (in the case of elective surgery at least four weeks in advance) and not resume until two weeks after complete remobilisation. Antithrombotic treatment should be considered.
– obesity (body mass index over 30 kg/m2). – there is no consensus about the possible role of varicose veins and superficial thrombophlebitis in the onset or progression of venous thrombosis

The risk of arterial thrombo-embolic complications or of a cerebrovascular accident in COC users increases with:
– increasing age
– smoking (women over 35 years should be strongly advised not to smoke if they wish to use an COC)
– dyslipoproteinemia
– hypertension
– migraine
– 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
– valvular heart disease
– atrial fibrillation

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.

The increased risk of thromboembolism during the postpartum period must be taken into consideration

Other medical conditions which have been linked to circulatory disorders include diabetes mellitus, systemic lupus erythematosus, haemolytic uraemic syndrome, chronic inflammatory intestinal disease (Crohn’s disease or ulcerative colitis) and sickle-cell anaemia.
An increase in frequency or severity of migraine during use of COCs (which may be prodromal of a cerebrovascular condition) must lead to consideration of immediate discontinuation of COCs.

  1. Tumours
    In some epidemiological studies an increased risk of uterine cervix cancer in long-term users of COCs has been reported, but it has still not been sufficiently clarified to which extent this finding may be influenced by effects of sexual behaviour and other factors like human papillomatous virus (HPV).
    A meta-analysis from 54 epidemiological studies has shown that women using COCs have a slightly increased relative risk (RR = 1.24) to be diagnosed with breast cancer. This increased risk gradually declines for 10 years after cessation of COCs. Since breast cancer is a rare condition in women below 40 years of age, the increase in the number of diagnosed cases of breast cancer in present and former users of COCs is low compared to the risk of breast cancer in their entire lifetime. These studies do not put forward evidence of a causal relationship. The observed pattern of an increased risk may be due to an earlier diagnosing of breast cancer in users of COCs, the biological effects of COCs or a combination of both. The diagnosed cases of breast cancer in users of COCs have a tendency to be less clinically advanced compared to the diagnosed cases of breast cancer in never-users.
    ‘ Benign liver tumours have been reported in rare cases, and even more rarely malignant liver tumours in users of COCs. These tumours have in a few cases led to life-threatening intraabdominal bleedings. A liver tumour should be taken into consideration as a differential diagnose when severe pain occurs in upper abdomen, in case of hepatomegaly or at signs of intraabdominal bleeding in women taking COCs. The size of fibromyomas of uterus can change after administration of oral contraceptive COCs.
  2. Other conditions
    Women with hypertriglyceridaemia or hereditary disposition for this condition may have an increased risk of pancreatitis when taking COCs.
    Although small increases in blood pressure have been reported in many women taking COCs, clinically relevant increases are rare. Only in these rare cases an immediate discontinuation of COC use is justified. A systematic relationship between COC use and clinical hypertension has not been established. If, during the use of a COC in preexisting 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, contraceptive pill use may be resumed if normotensive values can be achieved with antihypertensive therapy.
    It has been reported that the following conditions may arise or have been aggravated both during pregnancy and use of COCs, but the evidence of a relationship with use of COCs is inconclusive:
    Jaundice and/or itching in connection with cholestasis; formation of gallstones; porphyria; systemic lupus erythematosus; haemolytic uraemic syndrome; Sydenham’s chorea; herpes gestationis; hearing loss due to otosclerosis.
    Acute or chronic disturbances of liver function may necessitate discontinuation of COCs until liver function parameters have been normalised. Recurrent cholestatic jaundice and/or cholestasisrelated pruritus which previously occurred during pregnancy or during previous use of sexual hormones, requires discontinuation of COCs.
    Even though COCs may have an influence on peripheral insulin resistance and glucose tolerance there is no indication that it is necessary to change the therapeutic regime in diabetics using COCs. However, diabetics should be followed closely during use of COCs.
    Worsening of endogenous depression, of epilepsy, of Crohn’s disease and of ulcerative colitis has been reported during COC use.
    Chloasma may occasionally occur, in particular in women with a medical history of chloasma during pregnancy. Women with a tendency to chloasma should avoid exposure to sunlight or ultra-violet radiation while taking COCs.
    Desogestrel + Ethinylestradiol Generis contains lactose. Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicinal product.

Reduced cycle control
In connection with intake of all COCs irregular bleeding (spotting and break-through bleeding) may occur, during the first months in particular. It is therefore only relevant to evaluate the occurrence of irregular bleeding after a period of adaptation of approx. 3 cycles.
If the bleeding irregularities persist or occur after previous regular cycles non-hormonal causes should be considered and adequate, diagnostic precautions should be taken to exclude malignancy or pregnancy. These may include curettage.
Some women do not have a menstrual bleeding during the tablet-free period. If the COCs have been taken according to the instructions described in section 4.2, it is unlikely that the woman is pregnant. If, however, the COCs have not been taken according to the instructions prior to the first missing menstrual bleeding, or in case two menstrual bleedings are missing, pregnancy should be excluded before continuation of intake of the COCs

Interaction with other medicinal products and other forms of interaction

Influence of other medical products on Desogestrel + Ethinylestradiol
 Drug interactions resulting in an increased clearance of sexual hormones may involve breakthrough bleeding and contraceptive failure. This has been established with hydantoins, barbiturates, primidone, carbamazepine and rifampicine; oxcarbazepine, topiramate, felbamate, griseofulvine and nevirapine are also suspected. The mechanism of this interaction seems to be based on the liver enzyme inducing properties of these drugs. Maximal enzyme induction is generally not seen until 2-3 weeks after start of treatment, but may then persist for at least 4 weeks after discontinuation of treatment.

Contraceptive failure has also been reported with antibiotics like ampicillin and tetracyclines.
This mechanism of action has not been elucidated.
Women on short term treatment (up to one week) with some of the above mentioned groups of drugs or individual drugs should temporarily use a barrier method concomitantly with the COCs, i.e. in the period of other concomitant drug intake and for 7 days after cessation of this drug. Women taking rifampicine should use a barrier method concomitantly with intake of COCs for the period in which she is treated with rifampicine and for 28 days after cessation of rifampicine. In case other concomitant drug intake exceeds the number of tablets in the COCs pack, she should start the next pack of pills without keeping the usual tablet-free period.

There is a risk of galactorrhea due to an increased sensitivity of mammary tissue to prolactin caused by flunarizine. Troleandomycin may increase the risk for intrahepatic cholestasis during co-administration with COCs.

It is recommended by experts to increase the contraceptive steroid dosage for women who are on long-term treatment with liver enzyme inducing drugs. If a high contraceptive dosage is not advisable or this high dosage turns out to be insufficient or unsafe, e.g. in case of irregular bleeding, another contraceptive method should be advised.

The herbal preparation St.John’s wort (Hypericum perforatum) should not be taken concomitantly with this medicine as this could potentially lead to a loss of contraceptive effect. Break-through bleeding and unintended pregnancies have been reported. This is due to induction of drug metabolising enzymes by St.John’s wort. The inducing effect may persist for at least 2 weeks after cessation of treatment with St.John’s wort.

Concomitant administration of ritonavir with a fixed COC resulted in a reduction of the ethinyl oestradiol mean AUC by 41 %, increased doses of COCs containing ethinyl oestradiol, or alternate methods of contraception should be considered.

 Influence of Desogestrel + Ethinylestradiol 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. cyclosporin) or decrease (e.g. lamotrigine).
Laboratory analyses
The use of contraceptive steroids may have an influence on the results of certain laboratory analyses, including biochemical parameters for liver, thyroidea, adrenal and kidney function; the plasma levels of (transport)-proteins, e.g. corticosteroid-binding globulin and lipid/lipoprotein fractions; parameters for carbohydrate metabolism and parameters for coagulation and fibrinolysis. Changes usually remain within the normal laboratory reference values.

Fertility, pregnancy and lactation

Desogestrel + Ethinylestradiol is not indicated in pregnancy.
If pregnancy occurs, the treatment with Desogestrel + Ethinylestradiol Generis should be discontinued immediately. However, extensive epidemiological studies have neither showed an increased risk of birth defects in children born to women taking COCs before pregnancy, nor any teratogenic effect at unintentional intake of COCs in early pregnancy,

Lactation may be influenced by COCs since they may reduce the amount and change the composition of breast milk, thus, the use of COCs should generally not be recommended until the nursing mother has weaned the child completely. Small amounts of contraceptive steroids and/or their metabolites may be excreted with the milk during COC use. These amounts may affect the child

Effects on ability to drive and use machines
Desogestrel + Ethinylestradiol  has no influence on the ability to drive and use machines

UNDESIRABLE EFFECTS
The following serious adverse events were reported in women using COCs and are discussed in:
– Venous thromboembolic conditions;
– Arterial thromboembolic conditions;
– Hypertension;
– Liver tumours;
– Occurence or deterioriation of conditions for which an association with COC use has not been established: Crohn’s disease, ulcerative colitis, epilepsy, migraine, endometriosis, uterine myoma, porphyria, generalised lupus erythematosus, gestational herpes, Sydenham’s chorea, haemolytic uraemic syndrome, cholestatic icterus;
– Chloasma

Overdose
There have been no reports of serious, harmful effects after overdose. The symptoms which may occur in connection with overdose are: nausea, vomiting and, in young girls, a small vaginal bleeding. There is no antidote, and further treatment should be symptomatic.

 Pharmacological properties

Pharmacodynamic properties

Pharmacotherapeutic group: Progestogens and estrogens, fixed combinations ATC code: G03AA09 The contraceptive action of COCs is based on interaction of different factors, out of which the most important is the inhibition of ovulation and changes in the cervical secretion. Besides protection against pregnancy, COCs have several positive properties which, next to the negative properties (see Warnings, Undesirable effects), can be useful in deciding on the method of birth control. The cycle is more regular and the menstruation is often less painful and bleeding is lighter. The latter may result in a decrease in the occurrence of iron deficiency. In the largest multicenter trial (n=23 258 cycles), the uncorrected Pearl Index is estimated at 0.1 (95% confidence interval 0.0-0.3). Furthermore, 4.5% of the women reported absence of withdrawal bleeding and 9.2% reported occurrence of irregular bleeding after 6 treatment cycles.

Desogestrel + Ethinylestradiol  is a COC with ethinylestradiol and the progestogen desogestrel.
Ethinylestradiol is a well known synthetic estrogen.
Desogestrel is a synthetic progestogen. After oral administration it has a strong ovulationinhibiting activity.
With the use of higher dosed COCS (50 microgram ethinylestradiol) ovarian cancer is reduced.
Whether this also applies to lower-dosed COCs remains to be confirmed.

Paediatric population
No clinical data on efficacy and safety are available in adolescents below 18 years.

Pharmacokinetic properties

Desogestrel

Absorption
After oral administration of Desogestrel + Ethinylestradiol , desogestrel is rapidly absorbed and converted into 3-keto- desogestrel. Peak plasma levels are reached after 1.5 hours. The absolute bioavailability of 3-keto-desogestrel is 62-81 %.

Distribution
3-keto-desogestrel is 95.5-99% bound to the plasma proteins, mainly albumin and SHBG. The ethinyl-oestradiol-induced increase in SHBG influences both the amount of bindings and distribution of 3-keto-desogestrel in the plasma proteins. As a consequence the concentration of 3- keto-desogestrel rises slowly during treatment until steady state is reached within 3-13 days.

Metabolism
The phase-I metabolism of desogestrel includes cytochrom P-450 catalysed hydroxylation and subsequent dehydrogenation at C3. The active metabolite of 3-keto-desogestrel is further reduced, the degradation products are conjugated to sulphate and glucuronides. Animal studies indicate that the enterohepatic circulation has no relevance for the gestagenic activity of desogestrel.

Elimination
3-keto-desogestrel is eliminated with a mean half-life of approx. 31 hours (24-38 hours), plasma clearance varies from 5.0-9.5 l/hour. Desogestrel and its metabolites are eliminated via the urine and in the faeces, either as free steroids or conjugates. Ratio for elimination in urine or faeces is 1.5: 1.

Steady-State Conditions
In steady-state conditions the serum level of 3-keto-desogestrel is elevated by two- to threefold.

Ethinylestradiol

Absporption
Ethinyl oestradiol is rapidly absorbed and peak plasma levels are reached after 1.5 hours. As a consequence of presystemic conjugation and first-pass metabolism the absolute bioavailability is 60%. The area under the curve and Cmax may be expected to rise slightly over time.

Distribution
Ethinyl oestradiol is 98.8% bound to the plasma proteins, almost exclusively to albumin.

Metabolism
PT/H/0278/01-02/DC Ethinyl oestradiol undergoes presystemic conjugation both in the mucosa of the small intestine and in the liver. Hydrolysis of the direct conjugates of ethinyl oestradiol with the aid of the intestinal flora gives ethinyl oestradiol, which can be re-absorbed, and an enterohepatic circulation is hereby set up. The primary pathway of ethinyl oestradiol metabolism is cytochrom P-450- mediated hydroxylation in which the primary metabolites are 2-OH-EE and 2-methoxy-EE. 2-OH-EE is further metabolised to chemically reactive metabolites.

Elimination
Ethinyl oestradiol disappears from plasma with a half-life of approx. 29 hours (26-33 hours), plasma clearance varies from 10-30 1/hour. The conjugates of ethinyl oestradiol and its metabolites are excreted via urine and faeces (ratio 1:1).

Steady-state conditions
Steady-state conditions are obtained after 3 to 4 days, when the serum drug level is approx. 30 to 40% higher than after the administration of a single dose.

Preclinical safety data

Toxicological studies have not revealed other effects than those, which can be explained, based on the hormone profile of Desogestrel + Ethinylestradiol

Pharmaceutical particulars

List of excipients
Potato starch;
Stearic acid;
All-rac-alpha-tocopherol (E 307);
Lactose monohydrate;
Povidone.

 Incompatibilities

Not applicable.

 Shelf life

Desogestrel + Ethinylestradiol 0.15 mg/0.02 mg tablets: 30 months
Desogestrel + Ethinylestradiol  0.15 mg/0.03 mg tablets: 3 years

Special precautions for storage
This medicinal product does not require any special storage conditions.

Nature and contents of container

PVC-Aluminium blisters of 21 tablets blister strip available in packs containing 1×21, 3×21 and 6×21 tablets.
Not all pack sizes may be marketed.

 Special precautions for disposal and other handling

No special 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
Desogestrel and ethinyl estradiol  0.15mg/0.03mg tablets
Desogestrel and ethinyl estradiol  0.15mg/0.02mg tablets

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. See section 4.

What is in this leaflet

  1. What Desogestrel/ EE is and what is it used for
    2. What do you need to know Before you take Desogestrel/ EE
    3. How to take Desogestrel/ EE
    4. Possible side effects
    5. How to store Desogestrel/ EE
    6. Contents of the pack and other information

 

1.What  Desogestrel/ EE is and what is it used for

Ethinyl estradiol and desogestrel is a combination birth control pill containing female hormones that prevent ovulation (the release of an egg from an ovary). This medicine also causes changes in your cervical mucus and uterine lining, making it harder for sperm to reach the uterus and harder for a fertilized egg to attach to the uterus.
Ethinyl estradiol and desogestrel is used to prevent pregnancy. There are many brands of this medicine available. Not all brands are listed on this leaflet.
Ethinyl estradiol and desogestrel may also be used for purposes not listed in this medication guide.

  1. What do you need to know Before you take Cyproterone Acetate/Ethinylestradiol

Before you take Desogestrel/ EE
This medication can cause birth defects. Do not use if you are pregnant. Tell your doctor right away if you become pregnant, or if you miss two menstrual periods in a row. If you have recently had a baby, wait at least 4 weeks before taking birth control pills.

You should not take birth control pills if you have:

  • untreated or uncontrolled high blood pressure;
  • heart disease (coronary artery disease, uncontrolled heart valve disorder, history of heart attack, stroke, or blood clot);
  • a blood-clotting disorder or circulation problems;
  • problems with your eyes, kidneys or circulation caused by diabetes;
  • a history of hormone-related cancer such as breast or uterine cancer;
  • unusual vaginal bleeding that has not been checked by a doctor;
  • liver disease or liver cancer;
  • severe migraine headaches (with aura, numbness, weakness, or vision changes), especially if you are older than 35;
  • a history of jaundice caused by pregnancy or birth control pills; or
  • if you smoke and are over 35 years old.

To make sure you can safely take birth control pills, tell your doctor if you have any of these other conditions:

The hormones in birth control pills can pass into breast milk and may harm a nursing baby. This medication may also slow breast milk production. Do not use if you are breast feeding a baby.


SPECIAL PRECAUTIONS & WARNINGS

Warnings
 If one of the conditions or risk factors mentioned below is present, the advantages of taking COCs should be weighed against the possible risks in each individual case and discussed with the woman, before she decides whether to take COCs. In case of worsening or if any of these risk factors occurs, the woman should contact her physician. The physician should then decide whether the use of COCs should be discontinued.

1. Circulatory disorders
Epidemiological studies have shown that the incidence of VTE in users of oral contraceptives with low oestrogen content ranges from about 20 to 40 cases per 100,000 woman-years, but this risk estimate varies according to the progestogen. This compares with 5 to 10 cases per 100,000 woman-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 ever uses a combined oral contraceptive. The incidence of VTE associated with pregnancy is estimated as 60 cases per 100,000 pregnancies. VTE is fatal in 1-2% of cases.
Epidemiological studies have also associated the use of COCs with an increased risk for arterial (myocardial infarction, transient ischaemic attack) thromboembolism.

For brands containing 30m g of ethinylestradiol combined with desogestrel or gestodene compared to those less than 50 mg of ethinylestradiol and levonorgestrel, the overall relative risk of VTE has been estimated to range between 1.5 and 2.0. The incidence of VTE for g of ethinylestradiol is approximately 20 casesmlevonorgestrel containing COCs with less than 50  per 100,000 women-years of use. For Desogestrel + Ethinylestradiol Generis the incidence is approximately 30-40 cases per 100,000 women-years of use, i.e. additional 10-20 cases per 100,000 women-years of use.
The impact of the relative risk on the number of additional cases would be the greatest in women during the first year they ever use a COC when the risk for VTE with all COCs is highest.

For COCs containing desogestrel or gestodene with 20 m  g of ethinylestradiol.mdata do not suggest a lower VTE risk than for those containing 30 mg of ethinylestradiol

Extremely rarely, thrombosis has been reported to occur in other blood vessels, e.g. hepatic, mesenteric, renal, cerebral or 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 pain in the chest, whether or not it radiates to the left arm
– sudden breathlessness
– sudden onset of coughing
– any unusual, severe, prolonged headache
– sudden partial or complete loss of vision
– diplopia
– slurred speech or aphasia
– vertigo
– collapse with or without focal seizure
– weakness or very marked numbness suddenly affecting one side or one part of the body
– motor disturbances
– ,acute’ abdomen.

COC-users should be specifically pointed out to contact their physician in case of possible symptoms of thrombosis. In case of suspected thrombosis, COC use should be discontinued.

The risk for venous thromboembolic complications in COCs users increases with: – increasing age
– a positive family history (venous 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.
– prolonged immobilisation, major surgery, any surgery to the legs, or major trauma. In these situations it is advisable to discontinue the pill (in the case of elective surgery at least four weeks in advance) and not resume until two weeks after complete remobilisation. Antithrombotic treatment should be considered.
– obesity (body mass index over 30 kg/m2). – there is no consensus about the possible role of varicose veins and superficial thrombophlebitis in the onset or progression of venous thrombosis

The risk of arterial thrombo-embolic complications or of a cerebrovascular accident in COC users increases with:
– increasing age
– smoking (women over 35 years should be strongly advised not to smoke if they wish to use an COC)
– dyslipoproteinemia
– hypertension
– migraine
– 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
– valvular heart disease
– atrial fibrillation

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.

The increased risk of thromboembolism during the postpartum period must be taken into consideration

Other medical conditions which have been linked to circulatory disorders include diabetes mellitus, systemic lupus erythematosus, haemolytic uraemic syndrome, chronic inflammatory intestinal disease (Crohn’s disease or ulcerative colitis) and sickle-cell anaemia.
An increase in frequency or severity of migraine during use of COCs (which may be prodromal of a cerebrovascular condition) must lead to consideration of immediate discontinuation of COCs.

  1. Tumours
    In some epidemiological studies an increased risk of uterine cervix cancer in long-term users of COCs has been reported, but it has still not been sufficiently clarified to which extent this finding may be influenced by effects of sexual behaviour and other factors like human papillomatous virus (HPV).
    A meta-analysis from 54 epidemiological studies has shown that women using COCs have a slightly increased relative risk (RR = 1.24) to be diagnosed with breast cancer. This increased risk gradually declines for 10 years after cessation of COCs. Since breast cancer is a rare condition in women below 40 years of age, the increase in the number of diagnosed cases of breast cancer in present and former users of COCs is low compared to the risk of breast cancer in their entire lifetime. These studies do not put forward evidence of a causal relationship. The observed pattern of an increased risk may be due to an earlier diagnosing of breast cancer in users of COCs, the biological effects of COCs or a combination of both. The diagnosed cases of breast cancer in users of COCs have a tendency to be less clinically advanced compared to the diagnosed cases of breast cancer in never-users.
    ‘ Benign liver tumours have been reported in rare cases, and even more rarely malignant liver tumours in users of COCs. These tumours have in a few cases led to life-threatening intraabdominal bleedings. A liver tumour should be taken into consideration as a differential diagnose when severe pain occurs in upper abdomen, in case of hepatomegaly or at signs of intraabdominal bleeding in women taking COCs. The size of fibromyomas of uterus can change after administration of oral contraceptive COCs.
  2. Other conditions
    Women with hypertriglyceridaemia or hereditary disposition for this condition may have an increased risk of pancreatitis when taking COCs.
    Although small increases in blood pressure have been reported in many women taking COCs, clinically relevant increases are rare. Only in these rare cases an immediate discontinuation of COC use is justified. A systematic relationship between COC use and clinical hypertension has not been established. If, during the use of a COC in preexisting 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, contraceptive pill use may be resumed if normotensive values can be achieved with antihypertensive therapy.
    It has been reported that the following conditions may arise or have been aggravated both during pregnancy and use of COCs, but the evidence of a relationship with use of COCs is inconclusive:
    Jaundice and/or itching in connection with cholestasis; formation of gallstones; porphyria; systemic lupus erythematosus; haemolytic uraemic syndrome; Sydenham’s chorea; herpes gestationis; hearing loss due to otosclerosis.
    Acute or chronic disturbances of liver function may necessitate discontinuation of COCs until liver function parameters have been normalised. Recurrent cholestatic jaundice and/or cholestasisrelated pruritus which previously occurred during pregnancy or during previous use of sexual hormones, requires discontinuation of COCs.
    Even though COCs may have an influence on peripheral insulin resistance and glucose tolerance there is no indication that it is necessary to change the therapeutic regime in diabetics using COCs. However, diabetics should be followed closely during use of COCs.
    Worsening of endogenous depression, of epilepsy, of Crohn’s disease and of ulcerative colitis has been reported during COC use.
    Chloasma may occasionally occur, in particular in women with a medical history of chloasma during pregnancy. Women with a tendency to chloasma should avoid exposure to sunlight or ultra-violet radiation while taking COCs.
    Desogestrel + Ethinylestradiol Generis contains lactose. Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicinal product.

Reduced cycle control
In connection with intake of all COCs irregular bleeding (spotting and break-through bleeding) may occur, during the first months in particular. It is therefore only relevant to evaluate the occurrence of irregular bleeding after a period of adaptation of approx. 3 cycles.
If the bleeding irregularities persist or occur after previous regular cycles non-hormonal causes should be considered and adequate, diagnostic precautions should be taken to exclude malignancy or pregnancy. These may include curettage.
Some women do not have a menstrual bleeding during the tablet-free period. If the COCs have been taken according to the instructions described in section 4.2, it is unlikely that the woman is pregnant. If, however, the COCs have not been taken according to the instructions prior to the first missing menstrual bleeding, or in case two menstrual bleedings are missing, pregnancy should be excluded before continuation of intake of the COCs

 Interaction with other medicinal products and other forms of interaction

Influence of other medical products on Desogestrel + Ethinylestradiol
 Drug interactions resulting in an increased clearance of sexual hormones may involve breakthrough bleeding and contraceptive failure. This has been established with hydantoins, barbiturates, primidone, carbamazepine and rifampicine; oxcarbazepine, topiramate, felbamate, griseofulvine and nevirapine are also suspected. The mechanism of this interaction seems to be based on the liver enzyme inducing properties of these drugs. Maximal enzyme induction is generally not seen until 2-3 weeks after start of treatment, but may then persist for at least 4 weeks after discontinuation of treatment.

Contraceptive failure has also been reported with antibiotics like ampicillin and tetracyclines.
This mechanism of action has not been elucidated.
Women on short term treatment (up to one week) with some of the above mentioned groups of drugs or individual drugs should temporarily use a barrier method concomitantly with the COCs, i.e. in the period of other concomitant drug intake and for 7 days after cessation of this drug. Women taking rifampicine should use a barrier method concomitantly with intake of COCs for the period in which she is treated with rifampicine and for 28 days after cessation of rifampicine. In case other concomitant drug intake exceeds the number of tablets in the COCs pack, she should start the next pack of pills without keeping the usual tablet-free period.

There is a risk of galactorrhea due to an increased sensitivity of mammary tissue to prolactin caused by flunarizine. Troleandomycin may increase the risk for intrahepatic cholestasis during co-administration with COCs.

It is recommended by experts to increase the contraceptive steroid dosage for women who are on long-term treatment with liver enzyme inducing drugs. If a high contraceptive dosage is not advisable or this high dosage turns out to be insufficient or unsafe, e.g. in case of irregular bleeding, another contraceptive method should be advised.

The herbal preparation St.John’s wort (Hypericum perforatum) should not be taken concomitantly with this medicine as this could potentially lead to a loss of contraceptive effect. Break-through bleeding and unintended pregnancies have been reported. This is due to induction of drug metabolising enzymes by St.John’s wort. The inducing effect may persist for at least 2 weeks after cessation of treatment with St.John’s wort.

Concomitant administration of ritonavir with a fixed COC resulted in a reduction of the ethinyl oestradiol mean AUC by 41 %, increased doses of COCs containing ethinyl oestradiol, or alternate methods of contraception should be considered.

Influence of Desogestrel + Ethinylestradiol 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. cyclosporin) or decrease (e.g. lamotrigine).
Laboratory analyses
The use of contraceptive steroids may have an influence on the results of certain laboratory analyses, including biochemical parameters for liver, thyroidea, adrenal and kidney function; the plasma levels of (transport)-proteins, e.g. corticosteroid-binding globulin and lipid/lipoprotein fractions; parameters for carbohydrate metabolism and parameters for coagulation and fibrinolysis. Changes usually remain within the normal laboratory reference values.

 Fertility, pregnancy and lactation

Desogestrel + Ethinylestradiol is not indicated in pregnancy.
If pregnancy occurs, the treatment with Desogestrel + Ethinylestradiol Generis should be discontinued immediately. However, extensive epidemiological studies have neither showed an increased risk of birth defects in children born to women taking COCs before pregnancy, nor any teratogenic effect at unintentional intake of COCs in early pregnancy,

Lactation may be influenced by COCs since they may reduce the amount and change the composition of breast milk, thus, the use of COCs should generally not be recommended until the nursing mother has weaned the child completely. Small amounts of contraceptive steroids and/or their metabolites may be excreted with the milk during COC use. These amounts may affect the child

 Effects on ability to drive and use machines
Desogestrel + Ethinylestradiol  has no influence on the ability to drive and use machines

 

  1. How to take Desogestrel/ EE40mg

The tablets should be taken in the order of succession stated on the package every day at about the same time of the day. One tablet is taken daily for 21 consecutive days. Each subsequent pack is started after a 7-day tablet-free interval; during this tablet-free interval a menstruation- like withdrawal bleeding occurs. This bleeding usually begins on the 2nd or 3rd day after ingestion of the last tablet and it may not have ceased, before the next pack is started. The safety and efficacy of desogestrel in adolescents below 18 years has not yet been established. No data are available.

How to start Desogestrel + Ethinylestradiol No preceding intake of hormonal contraceptives (within the last month) The tablet intake should be started on day 1 of the normal menstrual cycle (i.e. on the first day on which the woman has a menstrual bleeding). Tablet intake is also allowed to start on day 2-5, but during the first cycle concurrent use of a barrier method for the first 7 days of tablet intake is advisable.

Changing from another combined hormonal contraceptive (combined oral contraceptive (COC), combined contraceptive vaginal ring or transdermal patch)
The woman should start taking Desogestrel + Ethinylestradiol Generis preferably on the day after the last active tablet (the last tablet containing the active substance) of her previous COC, but at the latest on the day following the usual tablet-free interval or following the last placebo tablet of her previous COC.
In case a vaginal ring or a transdermal patch has been used, the woman should start using Desogestrel + Ethinylestradiol Generis preferably on the day of removal, but at the latest when the next application would have been due.

Changing from progestogen only products (progetogen-only-pills, injection, implant) or from a progestogen-releasing intrauterine system (IUS)
The woman can change from progestogen-only pills on any day (changing from implant or IUS on the day of its removal; changing from injection when the next injection should have been given) but should in all of these cases be advised to additionally use a barrier method for the first 7 days of tablet-taking.

After abortion in the 1st trimester
Tablet intake should start immediately. In this case no further contraceptive measures are necessary.
After delivery or abortion in the 2nd trimester
The woman should be advised to start the pill on day 21-28 after delivery or abortion in the 2nd trimester. She should be advised to use a barrier method concurrently during the first 7 days of tablet intake if she starts the pill later. In case she has already had intercourse, pregnancy should be excluded before she starts tablet intake, or she should wait for her first menstrual bleeding.

Forgotten tablets
If the tablet intake is forgotten for less than 12 hours, contraceptive protection is not reduced. The woman should take the forgotten tablet as soon as she remembers, and the remaining tablets are taken as usual.

If the tablet intake is forgotten for more than 12 hours, contraceptive protection may be reduced.
The following two basic rules should be considered in case of forgotten tablets:
1. Continuous tablet intake must not be interrupted for longer than a period of 7 days.
2. 7 days of uninterrupted tablet intake are required to achieve sufficient suppression of the hypothalamus-pituitary-ovarian-axis.

Thus, the following advice may be given for daily practice:

Week 1
The user should take the last forgotten tablet as soon as she remembers, even if this means that she has to take 2 tablets at the same time. Then, she continues taking the tablets at the usual time of the day. She should concurrently use a barrier method, e.g. a condom, for the next 7 days. If intercourse has taken place during the preceding 7 days, the possibility of pregnancy should be considered. The more tablets are forgotten and the closer they are to the regular tablet-free period, the higher the risk of pregnancy is.

Week2
The user should take the last forgotten tablet as soon as she remembers, even if this means that she has to take 2 tablets at the same time. Then, she continues taking the tablets at the usual time of the day. Provided that the tablets have been taken in a correct manner during the 7 days preceding the forgotten tablet, it is not necessary to take further contraceptive measures. However, if this is not the case, or if more than 1 tablet has been forgotten, the woman should be advised to use another contraceptive method for 7 days.

Week3
The risk of reduced contraceptive protection is imminent due to the next tablet-free period. However, this risk may be prevented by adjusting tablet intake. Thus, it is not necessary to take further contraceptive measures if one of the two alternatives below is followed, provided that all tablets have been taken in a correct manner during the 7 days preceding the forgotten tablet. If this is not the case, the woman should be advised to follow the first of the two alternatives and concurrently use another contraceptive method for the next 7 days.

1 The user should take the last forgotten tablet as soon as she remembers even if it means that she has to take 2 tablets at the same time. Then she continues taking the tablets at the usual time of the day. She will begin taking the next pack immediately after taking the last tablet in the present pack, i.e. there is no break between the packs. It is not very likely that the user will have her menstrual bleeding until the end of the second pack, but she may experience spotting or breakthrough bleeding on the days she is taking tablets. 2. The woman may also be advised to stop taking tablets from the present pack. In that case she should keep a tablet-free period of up to 7 days, including those days when she forgot tablets, and then continue with the next pack. In case the woman has forgotten tablets and then does not have her menstrual bleeding in the first normal tablet-free period, the possibility of pregnancy should be considered

Precautions in case of vomiting or severe diarrhoea
If vomiting or severe diarrhoea occur within 3-4 hours after tablet intake, the tablet may not be absorbed completely. If the woman does not want to change her usual tablet intake, she has to take the necessary extra tablet(s) from another pack.

How to postpone a withdrawal bleed
To delay a period the woman should continue with another blister pack of Desogestrel + Ethinylestradiol without a tablet-free interval. The extension can be carried on for as long as wished until the end of the second pack. During the extension the woman may experience breakthrough-bleeding or spotting. Regular intake of Desogestrel + Ethinylestradiol  is then resumed after the usual 7-day tablet-free interval
To shift her periods to another day of the week than the woman is used to with her current scheme, she can be advised to shorten her forthcoming tablet-free interval by as many days as she likes. The shorter the interval, the higher the risk that she does not have a withdrawal bleed and will experience breakthrough-bleeding and spotting during the subsequent pack (just as when delaying a period).

  1. Possible side effects

Get emergency medical help if you have any of these signs of an allergic reaction: hives; difficult breathing; swelling of your face, lips, tongue, or throat.

Stop using birth control pills and call your doctor at once if you have a serious side effect such as:

  • sudden numbness or weakness, especially on one side of the body;
  • sudden and severe headache, confusion, problems with vision, speech, or balance;
  • chest pain or heavy feeling, pain spreading to the arm or shoulder, nausea, sweating, general ill feeling;
  • sudden cough, wheezing, rapid breathing, coughing up blood;
  • pain, swelling, warmth, or redness in one or both legs;
  • a change in the pattern or severity of migraine headaches;
  • nausea, upper stomach pain, itching, loss of appetitedark urine, clay-colored stools, jaundice(yellowing of the skin or eyes);
  • swelling in your hands, ankles, or feet;
  • breast lump; or
  • symptoms of depression (sleep problems, weakness, tired feeling, mood changes).

Less serious side effects may include:

  • mild nausea (especially when you first start taking this medicine), vomiting, bloating, stomach cramps;
  • breast tenderness or swelling, nipple discharge;
  • freckles or darkening of facial skin, increased hair growth, loss of scalp hair;
  • changes in weight or appetite;
  • problems with contact lenses;
  • vaginal itching or discharge; or
  • changes in your menstrual periods, decreased sex drive.

This is not a complete list of side effects and others may occur. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

  1. How to store Desogestrel/ EE

Keep this medicine out of the sight and reach of children.
Do not use this medicine after the expiry date which is stated on the carton/strip after EXP. The expiry date refers to the last day of that month.
Keep the blister strips in the outer carton in order to protect from light. Do not store above 25degrees.
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.

  1. Contents of the pack and other information


What  Desogestrel/ EEcontain

The active substances are Desogestrel and ethinylestradiol. Each coated tablet contains Desogestrel 2 mg and ethinylestradiol 30 micrograms/20 micrograms
The tablet also contains: Potato starch;
Stearic acid;
All-rac-alpha-tocopherol (E 307);
Lactose monohydrate;
Povidone.

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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