Each OVRAL 21 package contains:

21 white, round, biconvex, 6 mm diameter tablets each containing ethinylestradiol 50 micrograms and norgestrel 500 micrograms.

The hormonal components of OVRAL 21 inhibit ovulation by suppressing gonadotropin release. Secondary mechanisms which may contribute to the effectiveness of OVRAL 21 as a contraceptive include changes in the cervical mucus (which increase the difficulty of sperm penetration) and changes in the endometrium (which reduce the likelihood of implantation).

In addition to providing protection against pregnancy, oral contraceptives have been reported to be associated with the following beneficial effects: a reduction in the risk of endometrial carcinoma; a reduction in iron-deficiency anaemia, a reduction in the risk of ovarian cysts, a possible reduction in the incidence of ovarian carcinoma and a reduction in the incidence of benign breast lesions. Some protection is afforded in cystic breast disease and in the case of fibroadenomas, after long-term use.

Ethinylestradiol and norgestrel are rapidly and almost completely absorbed from the gastrointestinal tract. Ethinylestradiol is subject to considerable first-pass metabolism with a mean bioavailability of 40-45%. Norgestrel does not undergo first-pass metabolism and is therefore completely bioavailable.

Norgestrel is extensively plasma protein bound both to sex hormone binding globulin (SHBG) and albumin. Ethinyl-estradiol, however, is bound in plasma only to albumin and enhances the binding capacity of SHBG. Following oral administration, peak plasma levels of each medicine occur within 1 to 4 hours.

The elimination half-life for ethinylestradiol is approximately 25 hours. It is primarily metabolised by aromatic hydroxylation but a wide variety of hydroxylated and methylated metabolites are formed, and these are present both free and as conjugates with glucuronide and sulphate. Conjugated ethinylestradiol is excreted in bile and subject to enterohepatic recirculation. About 40% of the medicine is excreted in the urine and 60% is eliminated in the faeces.

The elimination half-life for norgestrel is approximately 24 hours. The medicine is primarily metabolised by reduction of the A ring followed by glucuronidation. About 60% of norgestrel is excreted in the urine and 40% is eliminated in the faeces.

OVRAL 21 is indicated for:

Prevention of pregnancy.

Treatment of primary dysmenorrhoea where contraception is required as a concurrent purpose.

Dosage And Administration

For Contraceptive And Non-Contraceptive Indications

To achieve maximum contraceptive effectiveness, OVRAL 21 must be taken as directed and at daily intervals not exceeding 24 hours. Patients should be instructed to take the tablets at the same time every day, preferably after the evening meal or at bedtime.

During the first cycle of administration, the patient is instructed to take one OVRAL 21 tablet daily for 21 consecutive days, beginning on Day 5 of her menstrual cycle. (The first day of bleeding is Day 1). The tablets are then discontinued for the next 7 days. Withdrawal bleeding should usually occur within 3 days after the last tablet is taken. The next and all subsequent courses will begin on the eighth day after discontinuance, even if withdrawal bleeding has not occurred or is still in progress. Each 21-day course of OVRAL 21 is thus begun on the same day of the week and follows the same schedule (21 days on, 7 days off) as the first course.

If the patient has a history of irregular or short (less than 24 days) menstrual cycles, the first cycle of OVRAL 21 should begin on Day 1 so that early ovulation will be reliably prevented. Subsequent cycles of OVRAL 21 will follow the usual schedule described above.

OVRAL 21 is effective from the first day of therapy if the tablets are begun as described. If the tablets are started after Day 5 or postpartum, a mechanical, i.e. barrier method of contraception should be used until 14 consecutive daily tablets have been taken. It must be considered that ovulation and conception may have occurred before the tablets were started in these situations.

The patient who is changing from another oral contraceptive product will begin OVRAL 21 on the day she would usually start a new package of the other product. During the first OVRAL 21 cycle, a mechanical, i.e. barrier method of contraception should be used until 14 consecutive daily tablets have been taken.

If transient spotting or breakthrough bleeding occurs, the patient is instructed to continue the regimen since such bleeding is usually without significance. If the bleeding is persistent or prolonged, the patient is advised to consult her physician.

In the nonlactating mother, OVRAL 21 may be begun immediately after delivery or at the first postpartum examination, whether or not menstruation has resumed.

The patient should be instructed that if one active tablet is missed and there is a delay of more than 12 hours after the normal time of taking it, it should be taken as soon as possible, with the next tablet being taken at the usual time, even if it means taking two tablets on the same day. If two consecutive active tablets are missed, they should both be taken as soon as remembered. The next tablet should be taken at its usual time.

Each time the patient misses one or two consecutive active tablets, an additional method of contraception such as a condom or no intercourse should be used for the next fourteen days, irrespective of bleeding. If three consecutive tablets are missed, OVRAL 21 should be discontinued and the remainder of the package discarded. A new package should be started immediately after the last tablet was taken. An additional method of contraception such as condom or no intercourse should be used until fourteen consecutive daily tablets have been taken.

If withdrawal bleeding does not occur and OVRAL 21 has been taken according to directions, it is unlikely that the patient has conceived. She should be instructed to begin a second course of OVRAL 21 on the usual day. If bleeding does not occur at the end of this second cycle, OVRAL 21 should not be taken until diagnostic procedures to exclude the possibility of pregnancy have been performed.

If the patient has not adhered to the prescribed regimen (missed one or more tablets or started taking them on a day later than recommended), the probability of pregnancy should be considered at the time of the first missed period before OVRAL is resumed.

OVRAL 21 should not be used in women with any of the following conditions:

Thrombophlebitis, thromboembolic disorders or cerebrovascular accident.

A history of deep-vein thrombophlebitis or thromboembolic disorders.

Cerebral-vascular or coronary-artery disease.

Known or suspected carcinoma of the breast.

Known or suspected estrogen-dependent neoplasia.

Undiagnosed abnormal genital bleeding.

Known or suspected pregnancy.

Benign or malignant liver tumour which developed during the use of estrogen-containing products.

Liver disease or a past history of cholestatic jaundice, pruritus of pregnancy or herpes gestationis.

Disturbance of lipometabolism.

Hemiplegic migraine.

Warnings And Precautions

Concurrent use of antibiotics or anticonvulsants may reduce the effective concentrations of the steroids and hence impair the contraceptive effect (see INTERACTIONS ).

Diarrhoea or vomiting can jeopardise the contraceptive effect by affecting absorption.

A thorough history and physical examination should be performed before prescribing oral contraceptives with special attention given to blood pressure, breasts, abdomen, and pelvic organs. As a general rule, oral contraceptives should not be prescribed for longer than one year without another physical examination being performed.

Under the influence of estrogen-containing oral contraceptives, pre-existing uterine leiomyomata may increase in size.

Oral contraceptives may cause depression. Patients with a history of depression should be carefully observed and the medicine discontinued if depression recurs to a serious degree.

These agents may cause some degree of fluid retention. Women with cardiac or renal dysfunction, convulsive disorders, migraine, or asthma require careful observation since these conditions may be exacerbated by the fluid retention which may occur in users of oral contraceptives.

Cholestatic jaundice has been reported in users of oral contraceptives. If this occurs, the medicine should be discontinued. Patients with a history of jaundice during pregnancy should be carefully observed whilst taking oral contraceptives.

Steroid hormones may be poorly metabolised in patients with impaired liver function and should be administered with caution to such patients.

Users of oral contraceptives may have disturbances in normal tryptophan metabolism which may result in a relative pyridoxine deficiency. The clinical significance of this is yet to be determined.

Serum folate levels may be depressed by oral contraceptive use. Women who become pregnant shortly after discontinuing these medicines may have a greater chance of developing folate deficiency and its complications.

Laboratory Tests - Papanicolaou smears should be performed before prescribing these medicines and periodically during their administration. Baseline and periodic blood glucose determinations should be performed in patients predisposed to diabetes mellitus.

Cigarette smoking increases the risk of serious cardiovascular side effects from the use of oral contraceptives. The risk increases with age and with heavy smoking (15 or more cigarettes per day) and is quite marked in women over 35 years of age. Women who use oral contraceptives should be strongly advised not to smoke.

An increased risk of thromboembolic and thrombotic disease associated with the use of oral contraceptives is well established. This risk is increased with age. The physician should be alert to the earliest manifestations of those disorders (e.g. thrombophlebitis, pulmonary embolism, cerebrovascular insufficiency, cerebral haemorrhage, cerebral thrombosis, coronary occlusion, retinal thrombosis, mesenteric thrombosis). Should any of these occur or be suspected, the medicine should be discontinued immediately.

A four- to six-fold increased risk of thromboembolic complications following surgery has been reported in users of oral contraceptives. Oral contraceptives should be discontinued at least 4 weeks before surgery associated with an increased risk of thromboembolism or prolonged immobilisation.

Myocardial Infarction And Coronary Artery Disease

An increased risk of myocardial infarction associated with the use of oral contraceptives has been reported. Studies found that the greater the number of underlying risk factors for coronary-artery disease (age, cigarette smoking, hypertension, hyper-cholesterolaemia, obesity, diabetes, history of pre-eclamptic toxaemia) the higher the risk of developing myocardial infarction, regardless of whether or not the patient used an oral contraceptive. Oral contraceptives, however, were found to be a clear additional risk factor.

Discontinue oral contraceptives and institute appropriate diagnostic and therapeutic measures if there is unexplained, gradual or sudden, partial or complete loss of vision, proptosis or diplopia; papilloedema; or any evidence of retinal vascular lesions or optic neuritis.

Long-term continuous administration of either natural or synthetic estrogen in certain animal species increases the frequency of carcinoma of the breast, cervix, vagina, and liver. At present, there is no confirmed evidence from human studies which would indicate that an increased risk of cancer is associated with oral contraceptives. Close clinical surveillance is nevertheless essential in all women taking these medicines. In all cases of undiagnosed, persistent, or recurrent abnormal vaginal bleeding, appropriate diagnostic measures should be taken to eliminate the possibility of malignancy. Women with a strong family history of breast cancer or who have breast nodules, fibrocystic disease, or abnormal mammograms should be monitored with particular care.

Benign hepatic adenomas have been found to be associated with the use of oral contraceptives. Although benign, hepatic adenomas may rupture and cause death through intra-abdominal haemorrhage. This has been reported in short- and long-term users of oral contraceptives. Such lesions may present as an abdominal mass or with the signs and symptoms of an acute abdomen and should be considered if the patient has abdominal pain and tenderness or evidence of intra-abdominal bleeding. A few cases of hepatocellular carcinoma have been reported in women taking oral contraceptives. This condition is exceedingly rare; the relationship between oral contraceptives and this disease has not been conclusively determined.

An increase in blood pressure has been reported in patients receiving oral contraceptives. In some women, hypertension may occur within a few months of beginning use. In the first year of use, the prevalence of women with hypertension is low but the incidence increases with increasing exposure. Age is also strongly correlated with the development of hypertension in oral contraceptive users. Women who previously have had hypertension during pregnancy may be more likely to develop an elevation of blood pressure when given oral contraceptives. If blood pressure rises markedly, the medicine should be discontinued. Hypertension that develops as a result of taking oral contraceptives usually returns to normal after discontinuing the medicine.

Studies report an increased risk of surgically confirmed gallbladder disease in users of estrogens and oral contraceptives.

The onset or exacerbation of migraine or development of headache of a new pattern which is recurrent, persistent, or severe requires discontinuation of the medicine and evaluation of the cause.

A decrease in glucose tolerance has been observed in a significant percentage of patients on oral contraceptives. For this reason, prediabetic and diabetic patients should be carefully observed whilst receiving the medicine. An increase in triglycerides and total phospholipids has been observed in patients receiving oral contraceptives.

Pregnancy Category B3. Foetal abnormalities, including heart defects and limb defects, have been reported in offspring of women who have taken oral contraceptives in early pregnancy. Pregnancy should be ruled out before an oral contraceptive regimen is begun and should be considered in women who have missed two consecutive menstrual periods. The possibility of pregnancy should be considered at the first missed period if the patient has not adhered to the prescribed regimen. Further oral contraceptive use should be withheld until pregnancy has been ruled out.

Oral contraceptives have not been shown to have any deleterious effects on the foetus or to increase the incidence of miscarriage in women who discontinue their use prior to conception. However, in women who discontinue oral contraceptives with the intent of becoming pregnant, a nonhormonal method of contraception is recommended for three months before attempting to conceive.

Female sex hormones have been used during pregnancy in an attempt to treat threatened or habitual abortion. There is considerable evidence that estrogens are ineffective for these indications, and there is no evidence from well-controlled studies that progestogens are effective for these uses.

The administration of progestogen-only or estrogen-progestogen combinations to induce withdrawal bleeding should not be used as a test for pregnancy.

Estrogen-containing oral contraceptives given in the postpartum period may interfere with lactation. There may be a decrease in the quantity and quality of the breast milk. Furthermore, a small fraction of the hormonal components of such oral contraceptives has been identified in the milk of mothers receiving them. The effects, if any, on the breast-fed infant have not been determined. If feasible, the use of estrogen-containing oral contraceptives should be deferred until the infant has been weaned.

Breakthrough bleeding, spotting and amenorrhoea are frequent reasons for patients discontinuing oral contraceptives. Organic disease should be excluded when breakthrough bleeding appears for the first time in women who have been previously well controlled and in all cases of irregular vaginal bleeding. In undiagnosed persistent or recurrent abnormal bleeding from the vagina, appropriate diagnostic measures are indicated to rule out pregnancy or malignancy. If pathology has been excluded, continuation of OVRAL 21 or a change to another formulation may solve the problem. Changing to a regimen with a higher estrogen content, whilst potentially useful in minimising menstrual irregularity, should be done only if necessary, since this may increase the risk of thromboembolic disease.

Women with a history of oligomenorrhoea or secondary amenorrhoea or young women without regular cycles may have a tendency to remain anovulatory or to become amenorrhoeic after discontinuation of oral contraceptives. Women with these pre-existing problems should be advised of this possibility and encouraged to use other methods of contraception. Post-use anovulation, possibly prolonged, may also occur in women without previous irregularities.

Ectopic as well as intrauterine pregnancy may occur in contraceptive failures.

The most serious adverse reactions associated with the use of oral contraceptives are indicated under WARNINGS AND PRECAUTIONS. The following have also been reported and are believed to be medicine-related:

Nausea and/or vomiting are usually the most common adverse reactions.

The following reactions, as a general rule, are seen much less frequently or only occasionally:

Gastrointestinal disturbances such as bloating and abdominal cramps

Change in menstrual flow

Dysmenorrhoea

Chloasma or melasma which may be persistent

Breast changes including tenderness, enlargement, and secretion

Increase or decrease in weight

Cervical erosion and changes in cervical secretion

Rash (allergic)

Vaginal candidiasis

Change in corneal curvature (steepening)

Intolerance to contact lenses

Breakthrough bleeding

Amenorrhoea during and after treatment

Anovulation post treatment

Cholestatic jaundice

Pruritus

Photosensitivity

Migraine

Drowsiness

The following adverse reactions have also been reported in users of oral contraceptives.

Premenstrual-like syndrome

Hirsutism

Cataracts

Loss of scalp hair

Changes in libido

Erythema multiforme

Chorea

Erythema nodosum

Changes in appetite

Haemorrhagic eruption

Cystitis-like syndrome

Vaginitis

Headache

Porphyria

Nervousness

Haemolytic uraemic syndrome

Dizziness

Estrogen-containing preparations affect the following blood components and endocrine- and liver-function tests:

Increased prothrombin and Factors II, V, VII, VIII, IX, X and XII; decreased antithrombin 3; increased noradrenaline-induced platelet aggregability.

Increased thyroid-binding globulin (TBG) leading to increased circulating total-thyroid hormone, as measured by protein-bound iodine (PBI), T4 by column, or T4 by radioimmunoassay. Free T3 resin uptake is decreased, reflecting the elevated TBG; free T4 concentration is unaltered.

Decreased pregnanediol excretion.

Reduced response to metyrapone test.

Increased sulphobromophthalein retention.

The results of these tests should not be regarded as reliable until oral contraceptive use has been discontinued for 1-2 months. Abnormal tests should then be repeated.

Oral contraceptives may produce false positive results when neutrophil alkaline phosphatase activity is evaluated for the early diagnosis of pregnancy.

The glucose tolerance test is usually impaired. Fasting blood glucose levels may also be raised.

Lipid metabolism may be affected with changed serum levels of HDL cholesterol, triglycerides and phospholipids being observed.

Serum albumin levels are usually decreased (along with the associated calcium levels).

Analytical interference is observed with the Zimmerman test for urinary 17-keto and 17-ketogenic steroids.

Abnormal results in the following tests may indicate impairment of organ function: Liver-increase in serum transaminases, alkaline phosphatase, gamma glutamyl transpeptidase, bilirubin and binding proteins.

Reduced contraceptive efficacy and increased incidence of breakthrough bleeding have been associated with the concomitant use of oral contraceptives and rifampicin. A similar association has been reported with the use of ampicillin, penicillin V, tetracycline, neomycin, chloramphenicol, sulphonamides, nitrofurantoin, barbiturates, phenylbutazones, meprobamate, phenacetin- and pyrazolone-containing analgesics, chlorpromazine, dihydroergotamine and chlordiazepoxide.

Breakthrough bleeding has been reported in patients taking oral contraceptives and St. John's wort (hypericum perforatum). St. John's wort may induce hepatic microsomal enzymes which theoretically may result in reduced efficacy of oral contraceptives. If oral contraceptives and St. John's wort are used concomitantly, a non-hormonal back-up method of birth control is recommended.

Oral contraceptives have been reported to antagonise the effectiveness of antihypertensive agents, anticonvulsants, oral anticoagulants, and hypoglycaemic agents. Patients should be carefully monitored for a decreased response to these medicines.

Oral contraceptives may alter the effectiveness of other medicines such as theophylline, phenothiazines, corticosteroids, beta-adrenergic antagonists, tricyclic antidepressants, caffeine and cyclosporin, by either potentiating/enhancing their pharmacological effect or by decreasing their clearance.

Oral contraceptives may interfere with the oxidative metabolism of diazepam and chlordiazepoxide, resulting in plasma accumulation of the parent compound. Patients receiving these benzodiazepines on a long-term basis should be monitored for increased sedative effects.

The effects of other benzodiazepines on oral contraceptive metabolism have not been determined.

Serious ill effects have not been reported following acute ingestion of large doses of oral contraceptives by young children. Overdosage may cause nausea; withdrawal bleeding may occur in females.

Store below 25°C.

Prescription Medicine.

Three month pack containing 3 blisters.

Ethinylestradiol is a white to creamy white, odourless, crystalline powder. It is insoluble in water and soluble in alcohol, chloroform, ether, vegetable oils, and aqueous solutions of alkali hydroxides. Chemically, ethinylestradiol is 19-nor-17a-pregna-1,3,5(10)-trien-20-yne-3,17-diol and has the following structure:

Norgestrel is a white, or nearly white, practically odourless, crystalline powder that is insoluble in water, sparingly soluble in alcohol and soluble in chloroform and acetone. Chemically, norgestrel is ( + )-13-ethyl-17-hydroxy-18,19-dinor-17a-pregn-4-en-20-yn-3-one and has the following structure: