WYETH

Levonorgestrel 30 microgram tablets are white, round, bi-convex with 6 mm diameter.

The primary mechanism through which MICROVAL prevents conception is not known, but progestogen-only contraceptives are known to alter the cervical mucus, exert a progestational effect on the endometrium, interfering with implantation,and in some patients, suppress ovulation.

Levonorgestrel is rapidly and completely absorbed after oral administration; peak plasma levels occur within 1 to 2 hours after a single dose in most subjects. Levonorgestrel is extensively plasma protein bound to both sex hormone binding globulin (high affinity, low capacity) and albumin (low affinity, high capacity).

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

MICROVAL is indicated for prevention of pregnancy in women who elect to use oral contraceptives as a method of contraception, particularly when the administration of estrogen is contraindicated.

To achieve maximum contraceptive effectiveness, MICROVAL must be taken exactly as directed and at 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.

The patient begins the drug on Day 1 of her menstrual cycle, i.e. the first day of bleeding taking the tablet marked with the appropriate day. One tablet is taken every day at the same time, without interruption, as long as contraception is desired.

Tablets should be taken on this continuous daily regimen whether or not bleeding occurs. A mechanical method of contraception should be used until the first 14 tablets have been taken.

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

If prolonged bleeding occurs, the patient should be advised to consult her physician.

The risk of pregnancy increases with each tablet missed. If the patient misses one tablet she should be instructed to take it as soon as she remembers and to also take her next tablet at the regular time. If she misses two tablets, she should take one of the missed tablets as soon as she remembers, as well as taking her regular tablet for that day at the proper time. In either case, she should use a mechanical method of contraception until 14 consecutive tablets have been taken.

If she missed one or two tablets and does not have a period within 45 days of her last period, she should discontinue MICROVAL and depend upon a mechanical method of contraception until the possibility of pregnancy has been excluded.

If more than two tablets have been missed, MICROVAL should be discontinued immediately and a mechanical method of contraception should be used until a period has appeared or the possibility of pregnancy has been excluded.

Alternatively, if the patient has taken the tablets correctly and her period does not appear within 60 days from the last period, a mechanical method of contraception should be substituted until an appropriate diagnostic procedure is performed to exclude the possibility of pregnancy.

Oral contraceptives 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 or genital organs.

Known or suspected hormone-dependent neoplasia.

Undiagnosed abnormal genital bleeding.

Known or suspected pregnancy.

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

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

Disturbance of lipometabolism.

Hemiplegic migraine.

Concurrent use of antibiotics or anticonvulsants may reduce the effective concentration of the steroid 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 such contraceptives pre-existing uterine fibroids may increase in size.

Oral contraceptives may cause depression. Patients with a history of depression should be carefully observed and the oral contraceptive 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 oral contraceptive should be discontinued. Patients with a history of jaundice during pregnancy should be carefully observed while 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.

MICROVAL should be used with caution in women with a previous history of ectopic pregnancy.

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

Patients with conditions such as diabetes, hypertension, migraine and cardiac dysfunction, ovarian cysts or a malabsorption syndrome require careful observation whilst on progestogen contraceptives.

Laboratory Tests - Papanicolaou smears should be performed before prescribing these oral contraceptives 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 oral contraceptive 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.

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, hypercholesterolaemia, 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.

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 oral contraceptives.

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 using 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 oral contraceptive should be discontinued. Hypertension that develops as a result of taking oral contraceptives usually returns to normal after discontinuing the oral contraceptive.

Studies report an increased risk of surgically confirmed gallbladder disease in users of 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 oral contraceptive 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, pre-diabetic and diabetic patients should be carefully observed whilst receiving the oral contraceptive. An increase in triglycerides and total phospholipids has been observed in patients receiving oral contraceptives.

Ectopic as well as intrauterine pregnancy may occur in contraceptive failures. However, in progestogen-only oral contraceptive failures, the ratio of ectopic to intrauterine pregnancies is higher than in women who are not receiving oral contraceptives, since progestogen-only oral contraceptives are more effective in preventing intrauterine than ectopic pregnancies.

Pregnancy Category 3B. 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 no evidence from well-controlled studies that progestogens are effective for these uses.

The administration of progestogens to induce withdrawal bleeding should not be used as a test for pregnancy.

Progestogen-only oral contraceptives given in the postpartum period do not appear to interfere with lactation. A small fraction of levonorgestrel has been detected in the milk of mothers receiving MICROVAL. Although no adverse effects on the infant have been reported, the long-term consequences have not been determined. If the physician decides to prescribe a progestogen-only oral contraceptive to a nursing woman, the growth and development of the infant must be closely monitored.

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, time or a change to another formulation may solve the problem. Changing from a progestogen-only oral contraceptive to an estrogen-progestogen oral contraceptive, whilst potentially useful in minimising menstrual irregularity, should be done only if necessary, since this may increase the risk of thromboembolic disease.

An alteration in menstrual patterns is likely to occur in women using progestogen-only oral contraceptives. The amount and duration of flow, cycle length, breakthrough bleeding, spotting and amenorrhoea will probably be quite variable. Bleeding irregularities occur more frequently with the use of progestogen-only oral contraceptives than with estrogen-progestogen oral contraceptives.

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 another method of contraception. Post-use anovulation, possibly prolonged, may also occur in women without previous irregularities.

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

Nausea and/or vomiting

Chloasma

Minor weight changes

Breast changes (tenderness, enlargement, and secretion)

Change in menstrual flow

Change in libido

Temporary slight intermenstrual bleeding

Depressive moods

The following have been reported in users of other oral contraceptives and should be considered a potential side effect of MICROVAL.

Gastrointestinal disturbances such as bloating and abdominal cramps

Dysmenorrhoea

Changes in cervical erosion and cervical secretions

Rash (allergic)

Vaginal candidiasis

Change in corneal curvature (steepening)

Intolerance to contact lenses

Amenorrhoea during and after treatment

Anovulation post treatment

Migraine

Photosensitivity

Drowsiness

Cholestatic jaundice

Pruritus

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

Premenstrual-like syndrome

Hirsutism

Cataracts

Loss of scalp hair

Chorea

Erythema multiforme

Changes in appetite

Erythema nodosum

Cystitis-like syndrome

Haemorrhagic eruption

Headache

Vaginitis

Nervousness

Porphyria

Dizziness

Haemolytic uraemic syndrome

Effects On Laboratory Tests

Progestogen contraceptives may cause alterations in certain laboratory estimation. A drug free period of two months may be required before some of these parameters return to normal.

With the following tests abnormal results may reflect a biological interference with the test analyte and not an impairment of organ function.

Increase in serum amino acid levels.

Decrease in pregnanediol excretion.

With the following tests abnormal results may indicate impairment of organ function:

Liver - increase in bilirubin, binding proteins, alkaline phosphatase and gamma glutamyl transpeptidase.

Interactions

Most interactions documented apply to combination products but this does not conclusively rule out progestogen-only formulations.

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.

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

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

Combination 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 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. The small amount of active substance in each tablet would support the idea of relative safety. Overdosage may cause nausea; withdrawal bleeding may occur in females.

Store in a cool, dry place.

Prescription medicine.

Three month pack containing 3 blisters. Each blister contains 28 white tablets containing 30 microgram levonorgestrel.

Levonorgestrel is white, crystalline powder that is very slightly soluble in water, slightly soluble in alcohol and acetone, and soluble in chloroform. Chemically, levonorgestrel is (-)-13ß-ethyl-17ß-hydroxy-18,19-dinor-17a-pregna-4-en-20-yn-3-one and has the following structure: