1. Name Of The Medicinal Product
Trinordiol
2. Qualitative And Quantitative Composition
Each light brown tablet contains 50 micrograms Levonorgestrel BP and 30 micrograms Ethinylestradiol Ph. Eur.
Each white tablet contains 75 micrograms Levonorgestrel BP and 40 micrograms Ethinylestradiol Ph. Eur.
Each ochre tablet contains 125 micrograms Levonorgestrel BP and 30 micrograms Ethinylestradiol Ph. Eur.
For excipients see 6.1.
3. Pharmaceutical Form
White or ochre or light brown lustrous sugar coated tablets.
4. Clinical Particulars
4.1 Therapeutic Indications
Oral contraception.
4.2 Posology And Method Of Administration
For oral administration
First treatment cycle:
1 tablet daily for 21 days, starting with the tablet marked number 1, on the first day of the menstrual cycle. Additional contraception (barriers and spermicide) is not required.
Subsequent cycles:
Each subsequent course is started when seven tablet—free days have followed the preceding course. A withdrawal bleed should occur during the 7 tablet—free days.
Changing from another 21 day combined oral contraceptive:
The first tablet of Trinordiol should be taken on the first day immediately after the end of the previous oral contraceptive course. Additional contraception is not required. A withdrawal bleed should not be expected until the end of the first pack of Trinordiol.
Changing from an Every Day (ED) 28 day combined oral contraceptive:
The first tablet of Trinordiol should be taken on the day immediately after the day on which the last active pill in the ED pack has been taken. The remaining tablets in the ED pack should be discarded. Additional contraception is not required. A withdrawal bleed should not be expected until the end of the first pack of Trinordiol.
Changing from a Progestogen—only—Pill (POP):
The first tablet of Trinordiol should be taken on the first day of menstruation even if the POP for that day has already been taken. The remaining tablets in the POP pack should be discarded. Additional contraception is not required.
Post—partum and post—abortum use:
After pregnancy combined oral contraception can be started in non—lactating women 21 days after a vaginal delivery, provided that the patient is fully ambulant and there are no puerperal complications.
If the pill is started later than 21 days after delivery, then alternative contraception (barriers and spermicides) should be used until oral contraception is started and for the first 7 days of pill—taking. If unprotected intercourse has taken place after 21 days post partum, then oral contraception should not be started until the first menstrual bleed after childbirth.
After a miscarriage or abortion oral contraception may be started immediately.
Elderly: Not applicable
Children: Not applicable
Special Circumstances Requiring Additional Contraception
Missed Pills:
If a tablet is delayed it should be taken as soon as possible and if it is taken within 12 hours of the correct time, additional contraception is not needed. Further tablets should then be taken at the usual time. If the delay exceeds 12 hours, the last missed pill should be taken when remembered, the earlier missed pills left in the pack and normal pill—taking resumed. If one or more tablets are omitted from the 21 days of pill—taking, additional contraception (barriers and spermicides) should be used for the next 7 days of pill—taking. In addition, if one or more pills are missed during the last 7 days of pill—taking, the subsequent pill—free interval should be disregarded and the next pack started the day after taking the last tablet from the previous pack. In this case, a withdrawal bleed should not be expected until the end of the second pack. If the patient does not have a withdrawal bleed at the end of the second pack she must return to her doctor to exclude the possibility of pregnancy.
Gastro—Intestinal Upset:
Vomiting or diarrhoea may reduce the efficacy by preventing full absorption. Additional contraception (barriers and spermicides) should be used during the stomach upset and for the 7 days following the upset. If these 7 days overrun the end of a pack, the next pack should be started without a break. In this case, a withdrawal bleed should not be expected until the end of the second pack. If the patient does not have a withdrawal bleed at the end of the second pack she must return to her doctor to exclude the possibility of pregnancy.
Mild laxatives do not impair contraceptive action.
Interaction with other drugs:
Some drugs may reduce the efficacy of oral contraceptives (refer to "4.5. Interaction with other medicaments and other forms of interaction.").It is therefore, advisable to use non-hormonal methods of contraception (barriers and spermicides) in addition to the oral contraceptive as long as an extremely high degree of protection is required during treatment with such drugs. The additional contraception should be used while the concurrent medication continues and for 7 days afterwards. If these extra precautions overrun the end of the pack, the next pack should be started without a break. In this case, a withdrawal bleed should not be expected until the end of the second pack. If the patient does not have a withdrawal bleed at the end of the second pack she must return to her doctor to exclude the possibility of pregnancy.
4.3 Contra—indications
1. Suspected pregnancy.
2. History of confirmed venous thromboembolism (VTE). Family history of idiopathic VTE. Other known risk factors for VTE.
3. Arterial thrombotic disorders and a history of these conditions, sickle—cell anaemia, disorders of lipid metabolism and other conditions in which, in individual cases, there is known or suspected to be a much increased risk of thrombosis.
4. Sickle—cell anaemia.
5. Acute or severe chronic liver diseases. Dubin—Johnson syndrome. Rotor syndrome. History, during pregnancy, of idiopathic jaundice or severe pruritus.
6. History of herpes gestationis.
7. Mammary or endometrial carcinoma, or a history of these conditions.
8. Abnormal vaginal bleeding of unknown cause.
9. Deterioration of otosclerosis during pregnancy.
4.4 Special Warnings And Precautions For Use
Warnings:
1. Some epidemiology studies have suggested an association between the use of combined oral contraceptives (COCs) and an increased risk of arterial and venous thrombotic and thromboembolic diseases such as myocardial infarction, stroke, deep venous thrombosis and pulmonary embolism. These events occur rarely. Full recovery from such disorders does not always occur and it should be realised that in a few cases they are fatal.
An increased risk of venous thromboembolic disease (VTE) associated with the use of oral contraceptives is well established but is smaller than that associated with pregnancy, which has been estimated at 60 cases per 100,000 pregnancies. Some epidemiological studies have reported a greater risk of VTE for women using combined oral contraceptives containing desogestrel or gestodene (the so-called third generation pills) than for women using pills containing levonorgestrel (the so-called second generation pills).
The spontaneous incidence of VTE in healthy non-pregnant women (not taking any oral contraceptive) is about 5 cases per 100,000 women per year. The incidence in users of the second generation pills is about 15 per 100,000 women per year of use. The incidence in users of third generation pills is about 25 cases per 100,000 women per year of use: this excess incidence has not been satisfactorily explained by bias or confounding. The level of all of these risks of VTE increases with age and is likely to be further increased in women with other known risk factors for VTE.
Risk factors for venous and arterial thrombosis include smoking (especially over the age of 35 years); obesity (body mass index over 30kg/m2); cardiovascular diseases (such as hypertension, valvular heart disease, atrial fibrillation and dyslipoproteinaemia); systemic lupus erythematosus; diabetes; migraine; a positive family history (ie venous or arterial thromboembolism ever in a sibling or parent at a relatively early age); prolonged immobilisation, major surgery, surgery to the legs and major trauma.
There is no consensus about the possible role of varicose veins and superficial thrombophlebitis in venous thromboembolism
The suitability of a combined oral contraceptive should be judged according to the severity of such conditions in the individual case, and should be discussed with the patient before she decides to take it.
2. The risk of arterial thrombosis associated with combined oral contraceptives increases with age, and this risk is aggravated by cigarette smoking. The use of combined oral contraceptives by women in the older age group, especially those who are cigarette smokers, should therefore be discouraged and alternative methods used.
3. The possibility cannot be ruled out that certain chronic diseases may occasionally deteriorate during the use of combined oral contraceptives. (See 'Precautions').
4. Malignant liver tumours have been reported on rare occasions in long—term users of oral contraceptives. Benign hepatic tumours have also been associated with oral contraceptive usage. A hepatic tumour should be considered in the differential diagnosis when upper abdominal pain, enlarged liver or signs of intra—abdominal haemorrhage occur.
5. Numerous epidemiological studies have been reported on the risks of ovarian, endometrial, cervical and breast cancer in women using combined oral contraceptives. The evidence is clear that combined oral contraceptives offer substantial protection against both ovarian and endometrial cancer.
An increased risk of cervical cancer in long term users of combined oral contraceptives has been reported in some studies, but there continues to be controversy about the extent to which this is attributable to the confounding effects of sexual behaviour and other factors.
A meta-analysis from 54 epidemiological studies reported that there is a slightly increased relative risk (RR = 1.24) of having breast cancer diagnosed in women who are currently using combined oral contraceptives (COCs). The observed pattern of increased risk may be due to an earlier diagnosis of breast cancer in COC users, the biological effects of COCs or a combination of both. The additional breast cancers diagnosed in current users of COCs or in women who have used COCs in the last ten years are more likely to be localised to the breast than those in women who never used COCs.
Breast cancer is rare among women under 40 years of age whether or not they take COCs. Whilst this background risk increases with 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 (see bar chart).
The most important risk factor for breast cancer in COC users is the age women discontinue the COC; the older the age at stopping, the more breast cancers are diagnosed. Duration of use is less important and the excess risk gradually disappears during the course of the 10 years after stopping COC use such that by 10 years there appears to be no excess.
The possible increase in risk of breast cancer should be discussed with the user and weighed against the benefits of COCs taking into account the evidence that they offer substantial protection against the risk of developing certain other cancers (e.g. ovarian and endometrial cancer).
Reasons for stopping oral contraception immediately:
1. Occurrence of migraine in patients who have never previously suffered from it. Exacerbation of pre—existing migraine. Any unusually frequent or unusually severe headaches.
2. Any kind of acute disturbance of vision.
3. Suspicion of thrombosis or infarctionincluding symptoms such as unusual pains in or swelling of the legs, stabbing pains on breathing, persistent cough or coughing blood, pain or tightness in the chest.
4. Six weeks before elective operations or treatment of varicose veins by sclerotherapy and during immobilisation, e.g. after accidents, etc.
5. Significant rise in blood—pressure.
6. Jaundice.
7. Clear exacerbation of conditions known to be capable of deteriorating during oral contraception or pregnancy.
8. Pregnancy is a reason for stopping immediately because it has been suggested by some investigations that oral contraceptives taken in early pregnancy may slightly increase the risk of foetal malformations. Other investigations have failed to support these findings. The possibility therefore cannot be excluded, but it is certain that if a risk exists at all, it is very small.
If oral contraception is stopped for any reason and pregnancy is not desired, it is recommended that alternative non-hormonal methods of contraception (such as barriers or spermicides) are used to ensure contraceptive protection is maintained.
4.3 Contraindications
1. Assessment of women prior to starting oral contraceptives (and at regular intervals thereafter) should include a personal and family medical history of each woman. Physical examination should be guided by this and by the contraindications (section 4.3) and warnings (section 4.4) for this product. The frequency and nature of these assessments should be based upon relevant guidelines and should be adapted to the individual woman, but should include measurement of blood pressure and, if judged appropriate by the clinician, breast, abdominal and pelvic examination including cervical cytology.
2. Before starting treatment, pregnancy must be excluded.
3. The following conditions require careful observation during medication: a history of severe depressive states, varicose veins, diabetes, hypertension, epilepsy, otosclerosis, multiple sclerosis, porphyria, tetany, disturbed liver function, gall—stones, cardiovascular diseases, renal diseases, chloasma, uterine fibroids, asthma, the wearing of contact lenses, or any disease that is prone to worsen during pregnancy. The first appearance or deterioration of any of these conditions may indicate that the oral contraceptive should be stopped.
4. The risk of the deterioration of chloasma, which is often not fully reversible, is reduced by the avoidance of excessive exposure to sunlight.
Menstrual changes:
1 Reduction of menstrual flow: This is not abnormal and it is to be expected in some patients.
2 Missed menstruation: Occasionally withdrawal bleeding may not occur at all. If the tablets have been taken correctly, pregnancy is very unlikely but should be ruled out before a new course of tablets is started.
Intermenstrual bleeding:
Very light "spotting" or heavier "break through bleeding" may occur during tablet-taking, especially in the first few cycles. It appears to be generally of no significance, except where it indicates errors of tablet-taking, or where the possibility of interaction with other drugs exists. However, if irregular bleeding is persistent an organic cause should be considered.
4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction
Some drugs accelerate the metabolism of oral contraceptives when taken concurrently and these include barbiturates, phenytoin, phenylbutazone and rifampicin. Other drugs suspected of having the capacity to reduce the efficacy of oral contraceptives include ampicillin and other antibiotics. It is therefore, advisable to use non-hormonal methods of contraception (barriers and spermicides). Please refer to "4.2 Posology and Method of Administration, Interaction with other drugs.".
The response to metyrapone is less pronounced than in untreated women and is thus similar to that during pregnancy.
ACTH function test remains unchanged. The reduction in corticosteroid excretion and elevation of plasma corticosteroids are due to increased cortisol-binding capacity of the plasma proteins.
Serum protein-bound iodine levels should not be used for evaluation of thyroid function as levels may rise due to increased thyroid hormone binding capacity of plasma proteins.
Erythrocyte sedimentation may be accelerated in the absence of any disease due to a change in the proportion of plasma protein fractions. Increases in plasma copper, iron and alkaline phosphatase have been recorded.
The herbal remedy St John's Wort (Hypericum perforatum) should not be taken concomitantly with this medicine as it could potentially lead to a loss of contraceptive effect.
4.6 Pregnancy And Lactation
Pregnancy is a reason for stopping administration immediately because it has been suggested by some investigations that oral contraceptives taken in early pregnancy may slightly increase the risk of foetal malformations. Other investigations have failed to support these findings. The possibility, therefore, can not be excluded, but it is certain that if a risk exists at all, it is very small. After pregnancy combined oral contraception can be started in non-lactating women 21 days after a vaginal delivery, provided that the patient is fully ambulant and there are no puerperal complications. Please refer to "4.2 Posology and Method of Administration, Post-partum and Post-abortum use".
Administration of oestrogens to lactating women may decrease the quantity or quality of the milk.
4.7 Effects On Ability To Drive And Use Machines
None known.
4.8 Undesirable Effects
See "4.4 Special Warnings and Special Precautions for Use".
Occasional side-effects may include nausea, vomiting, headaches, breast tenderness, irregular bleeding or missed bleeds, changed body weight or libido, depressive moods, chloasma and altered serum lipid profile.
4.9 Overdose
There have been no reports of serious ill-effects from overdosage, even when a considerable number of tablets have been taken by a small child. In general, it is therefore unnecessary to treat overdosage. However, if overdosage is discovered within two or three hours and is so large that treatment seems desirable, gastric lavage can be safely used.
There are no specific antidotes and further treatment should be symptomatic.
5. Pharmacological Properties
5.1 Pharmacodynamic Properties
Ethinylestradiol is a synthetic oestrogen which has actions and uses similar to those of oestradiol, but is more potent.
Norgestrel is a progestational agent with actions similar to those of progesterone.It is much more potent as an inhibitor of ovulation than norethisterone and has androgenic activity.
5.2 Pharmacokinetic Properties
Ethinylestradiol is absorbed by the gastro-intestinal tract. It is only slowly metabolised and excreted in the urine.
Norgestrel is absorbed from the gastro-intestinal tract. Metabolites are excreted in the urine and faeces as glucuronide and sulphate conjugates.
5.3 Preclinical Safety Data
No pre-clinical safety data other than those described elsewhere in this document are considered relevant to the prescriber.
6. Pharmaceutical Particulars
6.1 List Of Excipients
Lactose
Maize starch
Povidone (E1201)
Magnesium stearate (E572)
Sucrose
Polyethylene glycol 6000
Calcium carbonate (E170)
Talc (E553b)
Glycerol (E442)
Titanium dioxide (E171)
Wax E
Iron oxide pigment (E172) red brown (light brown tablets)
Iron oxide pigment (E172) yellow (light brown and ochre tablets)
6.2 Incompatibilities
None known.
6.3 Shelf Life
5 years
6.4 Special Precautions For Storage
Store at or below room temperature
6.5 Nature And Contents Of Container
Primary container: Polyvinylchloride (PVC) / aluminium foil blister pack.
Secondary container: Cardboard carton.
Presentation: Memo pack containing 21 tablets -
6 light brown tablets: 50 micrograms Levonorgestrel / 30 micrograms Ethinylestradiol
5 white tablets: 75 micrograms Levonorgestrel / 40 micrograms Ethinylestradiol
10 ochre tablets: 125 micrograms Levonorgestrel / 30 micrograms Ethinylestradiol
6.6 Special Precautions For Disposal And Other Handling
Not applicable.
7. Marketing Authorisation Holder
John Wyeth and Brother Limited
Trading as Wyeth Laboratories
Huntercombe Lane South
Taplow
Maidenhead
Berkshire SL6 0PH
UK
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