INDICATIONS     CONTRA-INDICATIONS     DOSAGE     SIDE-EFFECTS     PREGNANCY     OVERDOSE     IDENTIFICATION     PATIENT INFORMATION

Logo MINULETTE® tablets

SCHEDULING STATUS:
S3

PROPRIETARY NAME
(and dosage form):

MINULETTE® tablets

COMPOSITION:
The 21 white active tablets contain:
Gestodene 75 µg
Ethinyl oestradiol 30 µg
The 7 red tablets are inactive.

PHARMACOLOGICAL CLASSIFICATION:
Category A, 18.8 Ovulation controlling agents.

PHARMACOLOGICAL ACTION:
The hormonal components of MINULETTE inhibit ovulation by suppressing gonadotropin release. Secondary mechanisms include changes in the cervical mucous (which increase the difficulty of sperm penetration) and changes in the endometrium (which reduce the likelihood of implantation). The pharmacological and biochemical profile of gestodene is very similar to that of progesterone. Due to the high binding affinity and biological activity of gestodene, there is an effective inhibition of ovulation at an exceptionally low dose.

Pharmacokinetics:
Ethinyl oestradiol and gestodene are rapidly and almost completely absorbed from the gastro-intestinal tract. Peak plasma levels of each medicine are reached within 1 - 2 hours. Post maximum concentration curves show two phases with half lives of 1 and 15 hours in the case of gestodene, and 1 - 3 and approximately 24 hours in the case of ethinyl oestradiol.
After oral administration, gestodene, unlike ethinyl oestradiol is not subject to first-pass metabolism. Following oral administration, gestodene is completely bioavailable, ethinyl oestradiol about 40%.
Gestodene is extensively plasma protein bound to sex hormone binding globulin (SHBG). Ethinyl oestradiol is bound in plasma to albumin and enhances the binding capacity of SHBG.
The elimination half-life for ethinyl oestradiol is approximately 25 hours. It is primarily metabolized 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 ethinyl oestradiol is excreted in bile and is 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 gestodene is approximately 16 - 18 hours after multiple oral doses. The medicine is primarily metabolized by reduction of the A ring, followed by glucuronidation. About 50% of gestodene is excreted in the urine and 33% is eliminated in the faeces.

INDICATIONS:
MINULETTE is indicated for fertility control in women.

CONTRA-INDICATIONS:
Oral contraceptives are contra-indicated in patients with recurrent cholestatic jaundice, or markedly impaired liver function, hormone-dependent neoplasms, thrombophlebitis, or thromboembolic disorders, or a history thereof, severe migraine, cerebrovascular insufficiency, coronary-artery disease, and undiagnosed abnormal vaginal bleeding. Medication should be discontinued immediately if migraine becomes focal or there is a loss of vision, or if there is an onset of unexplained chest pain.
Known or suspected carcinoma of the breast.
Known or suspected oestrogen-dependent neoplasia.
Benign or malignant liver tumour which developed during the use of oral contraceptives or other oestrogen containing products, or a history thereof.
Combined oral contraceptives should be avoided in known or suspected pregnancy.
Severe disturbances of liver function; a history of idiopathic jaundice of pregnancy or severe pruritis of pregnancy; Dubin-Johnson syndrome; Rotor syndrome.
Disturbances of lipometabolism.
A history of herpes of pregnancy.
Severe diabetes with vascular changes.
Otosclerosis with deterioration during pregnancies.
Relative contra-indications include a history of diabetes mellitus, epilepsy, asthma, hypertension, depression, porphyria, or states in which fluid retention occur.
Reasons for Immediate Discontinuation of MINULETTE tablets:
The occurrence for the first time of migrainous headaches or the more frequent occurrence of unusually severe headaches.
Acute disturbances of vision, hearing or other perceptual disorders.
First symptoms of thrombophlebitis or thromboembolism.
Development of jaundice (cholestasis), anicteric hepatitis or generalized pruritis.
Increase in epileptic seizures.
Significant rise in blood pressure.
Known or suspected pregnancy.
WARNINGS:
CIGARETTE SMOKING:
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 ADVISED NOT TO SMOKE.

Thromboembolic Disorders:
The physician should be alert to the earliest manifestations of thromboembolic disorders (e.g., thrombophlebitis, pulmonary embolism, cerebrovascular insufficiency, cerebral haemorrhage, cerebral thrombosis, coronary occlusion, retinal thrombosis, mesenteric thrombosis). If feasible, oral contraceptives should be discontinued at least 6 weeks before surgery associated with an increased risk of thromboembolism or prolonged immobilization. The use should not, however, be interrupted before emergency operations.

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 (cigarette smoking, hypertension, hypercholesterolaemia, obesity, diabetes, history of pre-eclamptic toxaemia) the higher the risk of developing myocardial infarction.

Risk of Carcinoma:
At present, there is no confirmed evidence from human studies which would indicate that an increased risk of cancer is associated with oral contraceptives. Endometrial, breast and liver tumours have been associated with the use of oral contraceptives.

Hepatic Tumours:
Hepatic tumours have been found to be associated with the use of oral contraceptives.

A hepatic tumour should nevertheless be included in the differential diagnostic considerations when severe abdominal complaints, enlargement of the liver or signs of acute intra-abdominal haemorrhage occur in a woman taking oral contraceptives.

Elevated Blood Pressure:
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.

Carbohydrate and Lipid Metabolic Effects:
A decrease in glucose tolerance (excessive glucose and plasma insulin reaction, particularly on oral glucose loading) has been observed in a significant percentage of patients on oral contraceptives. The changes are generally reversible after discontinuation of medication. Since the influence on carbohydrate metabolism is unpredictable, prediabetic and diabetic patients should be closely supervised while receiving the medicine. The requirement for insulin or oral antidiabetics can either increase or decrease. Ovulation inhibitors are contraindicated in severe diabetes which has already lead to vascular changes.
In general, the urine should be checked for glucose before the prescription of and at six-month intervals during the use of ovulation inhibitors.
In the case of combined progestogen-oestrogen preparations the influence exerted by the particular preparation on important values of lipometabolism depends both on the absolute dose of the individual substances and on their ratio to each other.
It is, however, advisable not to prescribe oral ovulation inhibitors for patients with congenital or acquired disturbances of lipometabolism.

Use During or Immediately Preceding Pregnancy:
A possible association between the administration of female sex hormones in early pregnancy and the occurrence of foetal malformations has been the subject of discussion over the years.

Use During Lactation:
Oestrogen-containing oral contraceptives given in the post partum 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 has been identified in the milk of mothers receiving them.

Bleeding Irregularities:
Intermenstrual bleeding is more likely to occur during the first few cycles of use. Breakthrough bleeding, spotting and amenorrhoea are frequent reasons for patients discontinuing oral contraceptives. In breakthrough bleeding, as in all cases of irregular bleeding from the vagina nonfunctional causes should be borne in mind. 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 MINULETTE or a change to another formulation may solve the problem. Changing to a regimen with a higher oestrogen content may be useful in minimizing menstrual irregularity.
In rare instances, amenorrhoea of protracted duration may occur after discontinuation of oral contraceptives. It has been observed more often in patients with a history of oligomenorrhoea or secondary amenorrhoea.

DOSAGE AND DIRECTIONS FOR USE:
1. For Contraception:
  To achieve maximum contraceptive effectiveness, MINULETTE must be taken 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. On the first day of the menstrual cycle, i.e. the first day of bleeding, the patient will take the first tablet marked with the appropriate day of the week from those in the red area of the package. Thereafter, one tablet is taken daily following the arrows on the package, until all 28 tablets have been taken. Withdrawal bleeding should usually occur within 2 to 4 days after the last active tablet is taken. During this first cycle, a mechanical method of contraception should be supplemented until 14 tablets have been taken. If the tablets are begun after Day 5, it must be considered that ovulation and conception may have occurred before the tablets were started.
  The next and all subsequent courses of MINULETTE will begin on the day after the last package was completed, even if withdrawal bleeding has not occurred or is still in progress. Each course of MINULETTE is thus begun on the same day of the week as the first course, with a tablet from the red area of the package.
  The patient who is changing from another oral contraceptive product will begin MINULETTE on day 1 of the next menstrual period. If more than seven days elapse before MINULETTE is begun, pregnancy must first be excluded. During the first MINULETTE 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.
  MINULETTE can be prescribed postpartum or postabortum as soon as the first normal menstrual period following a normal biphasic cycle occurs. If a further pregnancy is contra-indicated for medical reasons, medication with MINULETTE must be initiated by the 12th (but not the 7th) day postpartum, or immediately postabortum or by the 5th day postabortum at the latest.
OMITTED TABLETS:
  The patient should be instructed to take a missed active tablet as soon as it is remembered. If two consecutive active tablets are missed, they should both be taken as soon as remembered. In either case, the next tablet should be taken at its usual time. Each time the patient misses one or two consecutive active tablets, a mechanical method of contraception should be supplemented until 14 consecutive daily tablets have been taken, or until the package is finished if less than 14 tablets remain. If the patient misses one or more inert tablets she is still protected against pregnancy, provided she begins the active tablets on the proper day. If three consecutive active tablets are missed, MINULETTE should be discontinued and the remainder of the package discarded. A new package should be started on the eighth day after the last tablet was taken. A mechanical method of contraception should be used until 14 consecutive daily tablets have been taken. If withdrawal bleeding does not occur and MINULETTE has been taken according to directions, it is unlikely that the patient has conceived. She should be instructed to begin a second course of MINULETTE on the usual day. If bleeding does not occur at the end of this second cycle, MINULETTE 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 active 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 MINULETTE is resumed.
  Mild laxatives do not impair the effectiveness of MINULETTE. If however, vomiting or diarrhoea occur during or shortly after the intake of MINULETTE, contraceptive reliability may be jeopardized. Tablet-taking should not be interrupted to avoid premature withdrawal bleeding. A nonhormonal method of contraception (with the exception of the calendar or morning temperature methods) should be employed in the cycle concerned. If the circumstances reducing the effectiveness of MINULETTE is protracted, other methods of contraception should be considered.
SIDE-EFFECTS AND SPECIAL PRECAUTIONS:
The most serious adverse reactions associated with the use of oral contraceptives are indicated under “Warnings”and “Precautions”. The following side-effects were reported in clinical trials of MINULETTE: 
  Vomiting Nervousness 
  Spotting Depressive moods 
  Breakthrough bleeding Change in libido 
  Dysmenorrhoea Varicose complaints 
  Breast tension Oedema 
The following side-effects have been reported less frequently: 
Chloasma Galactorrhoea 
  Gastritis Mastopathy 
  Abdominal complaints Paraesthesia 
  Alopecia Insomnia 
  Vaginal discharge Flush 
  Aggressive behaviour Tiredness 
  Increased appetite 
  Androgenic symptoms 
  Amenorrhoea, hypomenorrhoea, 
  and metrorrhagia 
The following have been reported in users of oral contraceptives and should be considered potential side-effects of MINULETTE : 
    Change in cervical erosion or cervical secretion; 
    Intolerance to contact lenses. 
The following adverse reactions have been reported in users of oral contraceptives, but the association has been neither confirmed nor refuted: 
  Chorea Porphyria
  Hirsutism 
The incidence of diseases of the circulatory system in women using combined oral contraceptives is significantly greater than those of controls, and the mortality is slightly increased. Coronary thrombosis, cerebrovascular accidents and venous thrombosis, are more likely to occur in women aged 35 years or over, particularly if they have used the contraceptive for longer than five years, if they smoke, if they are obese or if they are hypertensive. Additional risk factors are diabetes, hypercholesterolaemia and familial hyperlipoproteinaemia. 
  However, the risk of mortality due to oral contraceptives in women under 35 who are in the high risk group is in general far less than the risk of mortality due to pregnancy. 
Hypertension may occur in association with the use of oral contraceptives. Regular blood pressure checks, including a pretreatment level, are advisable. 
Prolonged amenorrhoea following the use of oral contraceptives may occur. The incidence is in the order of 1 % of users. Caution should be advised where oligomenorrhoea or amenorrhoea have occurred in the past. 
Mood changes, mass gain, skin pigmentation, vaginal candidiasis, gall bladder disease, gastro-intestinal irritation and fluid retention may occur. 
Case reports have been published of benign hepatic tumours in women on oral contraceptives for a prolonged time, but a causal relationship has not been established. The preparation should be discontinued it persistent upper abdominal pain develops. 
Interactions with other medicines and efficacy: 
  Oral contraceptive failure may occur with concomitant antibiotic therapy. For maximal protection, additional non-hormonal contraception should be recommended for the duration of antibiotic: therapy and for seven days afterwards. Those on long term antibiotic therapy need only take extra precautions for the first two weeks of antibiotic therapy. 
  Spotting and breakthrough bleeding are possible signs of diminished contraceptive effectiveness. 
  Induction of the microsomal liver enzyme system may occur and thus accelerate the oxidative degeneration of, among other things, sex hormones. Of particular clinical relevance are potent enzyme inducers such as barbiturates, hydantoins, phenylbutazone, and rifampicin, since both cycle disturbances (increased rate of intermenstrual bleeding and amenorrhoea) and individual pregnancies have been recorded under their concurrent use. 
  Reports have also been made of reduced substance levels under the simultaneous use of certain antibiotics (e.g., ampicillin). 
  An interaction should be considered in particular when intermenstrual bleeding suddenly occurs under oral ovulation inhibitors. An additional, non-hormonal method of contraception (with the exception of the rhythm and temperature methods) is recommended, if the greatest possible protection against pregnancy must be ensured in such cases. An alternative method of contraception should be considered if enzyme-inducing preparations must be administered for a protracted period of time. The efficacy of the contraceptive pill may be decreased when it is administered concomitantly with other medicines such as anti-epileptic agents, rifampicin, phenylbutazone and ampicillin. Patients should be carefully monitored for a decreased response to these drugs. 
  Combination oral contraceptives have been reported to antagonize the effectiveness of oral anticoagulants, antihypertensive agents, anticonvulsants, and hypoglycaemic agents. 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. 
  Oestrogen therapy may decrease the antidepressant response to tricyclic antidepressants and increase their incidence of toxic side-effects. 
  Oestrogens may enhance the effects of glucocorticoids. 
Effects on laboratory tests: 
  Oestrogen-containing preparations can effect many laboratory tests. Some examples are: 
  a. Increased prothrombin and Factors VII, VIII, IX and X; decreased anti-thrombin 3; increased norepinephrine induced platelet aggregability; 
  b. Increased thyroid-binding globulin (TBG) leading to increased circulating total-thyroid hormone, as measured by protein-bound iodine (PBI), T4 by radio immunoassay. Free T3 resin uptake is decreased, reflecting the elevated TBG; free T4 concentration is unaltered. 
  c. Reduced response to metyrapone test. 
  The results of these tests should not be regarded as reliable until oral contraceptive use has been discontinued for 1 to 2 months. Abnormal tests should then be repeated. 
  Oral contraceptives may produce false positive results when neutrophil alkaline phosphate activity is evaluated for the early diagnosis of pregnancy. 
Surgery is more likely to be associated with an increased incidence of thrombotic side-effects. Adequate precaution should be taken. 
PRECAUTIONS:
A thorough history and physical examination should be performed before prescribing oral contraceptives and periodically during their administration. Special attention should be given to blood pressure, breasts, abdomen and pelvic organs.
Oral contraceptives may cause depressive moods. Patients with a history of mental depression should be carefully observed and the drug discontinued if depression recurs to a serious degree.
These agents may cause a degree of fluid retention. Women with cardiac or renal dysfunction, or asthma, require careful observation since these conditions may be exacerbated by the fluid retention, which may occur in oral contraceptive users.
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 drugs may have a greater chance of developing folate deficiency and its complications.
Laboratory tests:
  Papanicolaou smears should be performed before prescribing these drugs and periodically during their administration. Baseline and periodic blood glucose determinations should be performed in patients predisposed to diabetes mellitus. UNDER NO CIRCUMSTANCES SHOULD THE ORAL CONTRACEPTIVE TABLETS BE STOPPED WITHOUT HAVING ADOPTED A SATISFACTORY ALTERNATIVE METHOD OF CONTRACEPTION.
KNOWN SYMPTOMS OF OVERDOSAGE AND PARTICULARS OF ITS TREATMENT:
Overdosage may cause nausea. Withdrawal bleeding may occur in females. Treatment is supportive and symptomatic.

IDENTIFICATION:
The MINULETTE package contains 28 tablets (21 white and 7 red).

PRESENTATION:
Each course of MINULETTE comprises of 21 white and 7 red tablets packed in a blister type package.

STORAGE DIRECTIONS:
Store in a cool (below 25 °C), dry place.
Keep out of reach of children.

REGISTRATION NUMBER:
W/18.8/11

NAME AND BUSINESS ADDRESS OF APPLICANT:
AKROMED PRODUCTS
Electron Avenue
ISANDO 1600
Trademark and product, under
licence from
WYETH-AYERST LABORATORIES, U.S.A.

DATE OF PUBLICATION OF THIS PACKAGE INSERT:
15 September 1989
        24580 GH901
        Davbar Dbn.

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