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MIRANOVA

SCHEDULING STATUS:
S3

PROPRIETARY NAME
(and dosage form):

MIRANOVA

Tablets

COMPOSITION
The 28-day pack (Every-Day pack) contains 21 hormonal tablets each with levonorgestrel 0,1 mg and ethinylestradiol 0,02 mg plus 7 inactive tablets.

PHARMACOLOGICAL CLASSIFICATION
A. 21.8.2 Progesterones with estrogens.

PHARMACOLOGICAL ACTION
Pharmacodynamics
The contraceptive effect of Miranova is based on the inhibition of ovulation and the changes in the cervical secretion.
Pharmacokinetics
•        Levonorgestrel
Absorption
Orally administered levonorgestrel is completely absorbed. Peak serum concentrations of 2,3 ng/mL are reached at about 1,3 hours after single ingestion. Levonorgestrel is almost completely bioavailable after oral administration.
Distribution
Levonorgestrel is bound to serum albumin and to sex hormone binding globulin (SHBG). Only 1,1% of the total serum drug concentrations are present as free steroid, approximately 65% are specifically bound to SHBG and about 34% are non-specifically bound to albumin. The ethinylestradiol-induced increase in SHBG influences the proportion of levonorgestrel bound to the serum proteins, causing an increase of the SHBG-bound fraction and a decrease of the albumin-bound fraction. The apparent volume of distribution of levonorgestrel is 129 L.
Metabolism
Levonorgestrel is completely metabolised by the known pathways of steroid metabolism. The clearance rate from serum is approximately 1,0 mL/min/kg.
Elimination
Levonorgestrel serum levels decrease in two phases. The terminal disposition phase is characterised by a half-life of approximately 25 hours.
Levonorgestrel is not excreted in unchanged form. Its metabolites are excreted at a urinary to biliary ration of about 1:1. The half-life of metabolite excretion is about 1 day.
Steady-state conditions
Following daily ingestion drug serum levels increase about threefold reaching steady-state conditions during the second half of a treatment cycle. Levonorgestrel pharmacokinetics are influenced by SHBG levels, which are increased 1,5 to 1,6 fold when co-administered with ethinylestradiol. At steady-state, clearance rate and volume of distribution are slightly reduced to 0,7 mL/min/kg and about 100 L, respectively.
•        Ethinylestradiol
Absorption
Orally administered ethinylestradiol is completely absorbed. Peak serum concentrations of about 50 pg/mL are reached within 1 to 2 hours. During absorption and first liver passage, ethinylestradiol is metabolised extensively, resulting in a mean oral bioavailability of about 45% with a large interindividual variation of about 20 to 65%.
Distribution
Ethinylestradiol is highly but non-specifically bound to serum albumin (approximately 98%), and induces an increase in the serum concentrations of SHBG. An apparent volume of distribution of about 2,8 to 8,6 L/kg was reported.
Metabolism
Ethinylestradiol is subject to presystemic conjugation in both the small bowel mucosa and the liver. Ethinylestradiol is primarily metabolised by aromatic hydroxylation but a wide variety of hydroxylated and methylated metabolites are formed, and these are present as free metabolites and as conjugates with glucuronides and sulphate. The metabolic clearance rate was reported to be 2,3 to 7 mL/min/kg.
Elimination
Ethinylestradiol serum levels decrease in two disposition phases characterised by half-lives of about 1 hour and 10 to 20 hours, respectively. Unchanged drug is not excreted, ethinylestradiol metabolites are excreted at a urinary to biliary ratio of 4:6. The half-life of metabolite excretion is about 1 day.
Steady-state conditions
Ethinylestradiol serum concentrations increase about twofold after daily oral administration of Miranova. According to the variable half-life of the terminal disposition phase from serum and the daily ingestion, steady-state serum levels of ethinylestradiol will be reached after about one week.

INDICATIONS
Oral contraception.

CONTRA-INDICATIONS
Miranova should not be used in the presence of any of the conditions listed below. Should any of the conditions appear for the first time during the use of Miranova, it should be stopped immediately.

•	Presence or a history of venous or arterial thrombotic/thromboembolic events (eg deep venous thrombosis, pulmonary embolism, myocardial infarction) or of a cerebrovascular accident.
•	Presence or history of prodromi of a thrombosis (eg transient ischaemic attack, angina pectoris).
•	History of migraine with focal neurological symptoms.
•	Diabetes mellitus with vascular involvement.
•	The presence of a severe or multiple risk factor(s) for venous or arterial thrombosis may also constitute a contra-indication (see “Warnings”).
•	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 malignancies (eg of the genital organs or the breasts).
•	Undiagnosed vaginal bleeding.
•	Known or suspected pregnancy.
•	Hypersensitivity to the active substances or to any of the excipients.

WARNINGS
If any of the conditions/risk factors mentioned below are present, the benefits of using Miranova should be weighed against the possible risks for each individual woman and discussed with the woman before she decides to start using it. In the event of aggravation, exacerbation or first appearance of any of these conditions or risk factors, the woman should contact her physician. The physician should then decide on whether the use of Miranova should be discontinued.
Circulatory disorders
Epidemiological studies have suggested an association between the use of combined oral contraceptives 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.
Venous thromboembolism, manifesting as deep venous thrombosis and/or pulmonary embolism, may occur during the use of all combined oral contraceptives. The approximate incidence of venous thromboembolism in users of low estrogen dose (<0,05 mg ethinylestradiol) oral contraceptives is up to 4 per 10 000 woman years compared to 0,5 to 3 per 10 000 woman years in non-oral contraceptive users. The incidence of venous thromboembolism associated with pregnancy is 6 per 10 000 pregnant woman years.
Extremely rarely, thrombosis has been reported to occur in other blood vessels, eg hepatic, mesenteric, renal, cerebral or retinal veins and arteries, in combined oral contraceptive users. There is no consensus as to whether the occurrence of these events is associated with the use of combined oral contraceptives.
Symptoms of venous or arterial thrombotic/thromboembolic events or of a cerebrovascular accident can include: 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.
The risk of venous or arterial thrombotic/thromboembolic events or of a cerebrovascular accident increases with:

•	age;
•	smoking (with heavier smoking and increasing age the risk increases further, especially in women over 35 years of age);
•	a positive family history (ie venous or arterial thromboembolism ever in a sibling or parent at a relatively early age). If a hereditary predisposition is suspected, the woman should be referred to a specialist for advice before deciding about any combined oral contraceptive use;
•	obesity (body mass index over 30 kg/m²);
•	dyslipoproteinaemia;
•	hypertension;
•	migraine;
•	valvular heart disease;
•	atrial fibrillation;
•	prolonged immobilisation, major surgery, any surgery to the legs, or major trauma. In these situations it is advisable to discontinue combined oral contraceptive use (in the case of elective surgery at least four weeks in advance) and not to resume until two weeks after complete remobilisation.

There is no consensus about the possible role of varicose veins and superficial thrombophlebitis in venous thromboembolism.
The increased risk of thromboembolism in the puerperium must be considered (for information on “Pregnancy and lactation”see “Side effects and special precautions”).
Other medical conditions which have been associated with adverse circulatory events include diabetes mellitus, systemic lupus erythematosus, haemolytic uraemic syndrome, chronic inflammatory bowel disease (Crohn’s disease or ulcerative colitis) and sickle cell disease.
An increase in frequency or severity of migraine during combined oral contraceptive use (which may be prodromal of a cerebrovascular event) may be a reason for immediate discontinuation of the combined oral contraceptive.
Biochemical factors that may be indicative of a hereditary or acquired predisposition for venous or arterial thrombosis include Activated Protein C (APC) resistance, hyperhomocysteinaemia, antithrombin-III deficiency, protein C deficiency, protein S deficiency, antiphospholipid antibodies (anticardiolipin antibodies, lupus anticoagulant).
When considering risk/benefit, the physician should take into account that adequate treatment of a condition may reduce the associated risk of thrombosis and that the risk associated with pregnancy is higher than that associated with low-dose combined oral contraceptives (<0,05 mg ethinylestradiol).
Tumours
An increased risk of cervical cancer in long-term users of combined oral contraceptives has been reported in some epidemiological studies, but there continues to be controversy about the extent to which this finding is attributable to the confounding effects of sexual behaviour and other factors such as human papilloma virus.
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. The excess risk gradually disappears during the course of the 10 years after cessation of combined oral contraceptive use. Because breast cancer is rare in women under 40 years of age, the excess number of breast cancer diagnoses in current and recent combined oral contraceptive users is small in relation to the overall risk of breast cancer. These studies do not provide evidence for causation. The observed pattern of increased risk may be due to an earlier diagnosis of breast cancer in combined oral contraceptive users, the biological effects of combined oral contraceptives, or a combination of both. The breast cancers diagnosed in ever-users tend to be less advanced clinically than the cancers diagnosed in never-users.
In rare cases, benign liver tumours and, even more rarely, malignant liver tumours have been reported in users of combined oral contraceptives. In isolated cases, these tumours have led to life-threatening intra-abdominal haemorrhages. A hepatic tumour should be considered in the differential diagnosis when severe upper abdominal pain, liver enlargement or signs of intra-abdominal haemorrhage occur in women taking combined oral contraceptives.
Other conditions
Women with hypertriglyceridaemia, or a family history thereof, may be at an increased risk of pancreatitis when using combined oral contraceptives.
Although small increases in blood pressure have been reported in many women taking combined oral contraceptives, clinically relevant increases are rare. However, if a sustained clinically significant hypertension develops during the use of a combined oral contraceptive, then it is prudent for the physician to withdraw the combined oral contraceptive and treat the hypertension. Where considered appropriate, combined oral contraceptive use may be resumed if normotensive values can be achieved with antihypertensive therapy.
The following conditions have been reported to occur or deteriorate with both pregnancy and combined oral contraceptive use but the evidence of an association with combined oral contraceptive use is inconclusive: jaundice and/or pruritus related to cholestasis; gallstone formation; porphyria; systemic lupus erythematosus; haemolytic uraemic syndrome; Sydenham’s chorea; herpes gestationis; otosclerosis-related hearing loss.
Acute or chronic disturbances of liver function may necessitate the discontinuation of combined oral contraceptive use until markers of liver function return to normal. Recurrence of cholestatic jaundice which occurred first during pregnancy or previous use of sex steroids necessitates the discontinuation of combined oral contraceptives.
Although combined oral contraceptives may have an effect on peripheral insulin resistance and glucose tolerance, there is no evidence for a need to alter the therapeutic regimen in diabetics using low-dose combined oral contraceptives (containing <0,05 mg ethinylestradiol). However, diabetic women should be carefully observed while taking combined oral contraceptives.
Crohn’s disease and ulcerative colitis have been associated with combined oral contraceptive use.
Chloasma may occasionally occur, especially in women with a history of chloasma gravidarum. Women with a tendency to chloasma should avoid exposure to the sun or ultraviolet radiation whilst taking combined oral contraceptives.

INTERACTIONS
Interactions between Miranova and other drugs may lead to breakthrough bleeding and/or contraceptive failure. The following interactions have been reported in the literature.
Hepatic metabolism
Interactions can occur with drugs that induce microsomal enzymes which can result in increased clearance of sex hormones (eg phenytoin, barbiturates, primidone, carbamazepine, rifampicin, and possibly also oxcarbazepine, topiramate, felbamate, ritonavir, griseofulvin and products containing St John’s Wort).
Interference with Enterohepatic circulation
Some clinical reports suggest that enterohepatic circulation of estrogens may decrease when certain antibiotic agents are given, which may reduce ethinylestradiol concentrations (eg penicillins, tetracyclines).
Women on treatment with any of these drugs should temporarily use a barrier method in addition to Miranova or choose another method of contraception. With microsomal enzyme-inducing drugs, the barrier method should be used during the time of concomitant drug administration and for 28 days after their discontinuation. Women on treatment with antibiotics (except rifampicin and griseofulvin) should use the barrier method until 7 days after discontinuation. If the period during which the barrier method is used runs beyond the end of the active tablets in the Miranova pack, the inactive tablets should be omitted and the next combined oral contraceptive pack be started.
Miranova may interfere with the metabolism of other drugs. Accordingly, plasma and tissue concentrations may be affected (eg cyclosporin).
Note: The prescribing information of concomitant medications should be consulted to identify potential interactions.
•        Laboratory tests
The use of Miranova may influence the results of certain laboratory tests, including biochemical parameters of liver, thyroid, adrenal and renal function, plasma levels of (carrier) proteins, eg corticosteroid binding globulin and lipid/lipoprotein fractions, parameters of carbohydrate metabolism and parameters of coagulation and fibrinolysis. Changes generally remain within the normal laboratory range.

PREGNANCY AND LACTATION
Miranova is not indicated during pregnancy. If pregnancy occurs during treatment with Miranova, further intake should be stopped.
Lactation may be influenced by Miranova as it may reduce the quantity and change the composition of breast milk. Therefore, the use of Miranova should generally not be recommended until the nursing mother has completely weaned her child. Small amounts of the contraceptive steroids and/or their metabolites may be excreted with the milk.

DOSAGE AND DIRECTIONS FOR USE
Medical examination/consultation
A complete medical history and physical examination should be taken prior to the initiation or reinstitution of Miranova use, guided by the “Contra-indications”and “Warnings” and should be repeated periodically. Periodic medical assessment is also of importance because contra-indications (eg a transient ischaemic attack, etc) or risk factors (eg a family history of venous or arterial thrombosis) may appear for the first time during the use of a combined oral contraceptive. The frequency and nature of these assessments should be based on established practice guidelines and be adapted to the individual woman, but should generally include special reference to blood pressure, breasts, abdomen and pelvic organs, including cervical cytology.
How to take Miranova
The first course of Miranova is started on the first day of the menstrual period (day 1 of the cycle) from the silver section of the pack by selecting the appropriate tablet for that day of the week (eg "MO" for Monday). The tablet is swallowed whole with some liquid. Thereafter one tablet must be taken daily for 28 days following the direction shown by the arrows. It does not matter at what time of the day the tablet is taken, but once the patient has selected a particular time, the tablet should be taken as near as possible at the same time each day. Withdrawal bleeding usually starts on day 2 to 3 after starting the inactive tablets and may not have finished before the next pack is started. Each subsequent pack is started the day after the last tablet of the current pack. If a patient starts Miranova during the latter part of the week, the very first cycle may be slightly shortened.
How to start Miranova
No preceding hormonal contraceptive use (in the past month)
Tablet-taking has to start on day 1 of the woman’s natural cycle (ie the first day of her menstrual bleeding). Starting on days 2 to 5 is allowed. During the first cycle a barrier method (such as condoms and spermicide) is recommended in addition for the first 7 days of tablet-taking.
Changing from another combined oral contraceptive
The woman should start with Miranova preferably on the day after the last active tablet of her previous combined oral contraceptive, but at the latest on the day following the usual tablet-free or inactive tablet interval of her previous combined oral contraceptive.
Changing from a progestogen-only-method (minipill, injection, implant) or from a progestogen-releasing intrauterine system
The woman may switch any day from theminipill (from an implant or the intrauterine system on the day of its removal, from an injectable when the next injection would be due), but should in all of these cases be advised to additionally use a barrier method for the first 7 days of tablet-taking.
Following first trimester abortion
The woman may start immediately. When doing so, she need not take additional contraceptive measures.
Following delivery or second-trimester abortion
For breastfeeding women see “Side effects and special precautions”.
Women should be advised to start at day 21 to 28 after delivery or second-trimester abortion. When starting later, the woman should be advised to additionally use a barrier method for the first 7 days of tablet-taking. However, if intercourse has already occurred, pregnancy should be excluded before the actual start of combined oral contraceptive use or the woman must wait for her first menstrual period.
Management of missed tablets
The large white tablets are inactive tablets and missing these can be disregarded. However, they should be discarded to avoid unintentionally prolonging the inactive tablet phase. The following advice only refers to missed active tablets (pink tablets).
If the user is less than 12 hours late in taking any active tablet, contraceptive protection is not reduced. The woman should take the tablet as soon as she remembers and should take further tablets at the usual time.
If she is more than 12 hours late in taking any active tablet, contraceptive protection may be reduced. The management of missed tablets can be guided by the following two basic rules:

•	Tablet-taking must never be discontinued for longer than 7 days.
•	7 days of uninterrupted active tablet-taking are required to attain adequate suppression of the hypothalamic-pituitary-ovarian-axis.

Accordingly the following advice can be given in daily practice:
If you are less than 12 hours late in taking your Miranova tablet, you are still protected against pregnancy. Take the tablet as soon as you remember and take the next one at your usual time. This may mean that you are taking 2 tablets in one day.
If you are more than 12 hours late in taking your Miranova tablet you will not be protected. Take the tablet as soon as you remember and take the next one at your normal time. This may mean taking 2 tablets in one day. You must take extra contraceptive precautions and you must follow the 7 day rule. Read the sections on “Extra contraceptive precautions”and “The 7 day rule”carefully.
If you have forgotten to take your Miranova tablets for a few days, consult your doctor to be sure you are not pregnant, then discard the missed tablets and follow the 7 day rule.

Extra contraceptive precautions When you need extra contraceptive precautions, either: -        don’t have sex; or -        use a cap plus spermicide, or a condom. Don’t use the rhythm or temperature methods as extra contraceptive precautions. This is because oral contraceptives disrupt the usual menstrual cycle changes such as changes in temperature and cervical mucous.

The 7 day rule
If:
-        you are more than 12 hours late in taking a tablet; or
-        you have vomiting; or
-        your doctor advises you to follow the 7 day rule because you are taking certain medicines;
continue to take your tablets as usual.
However, take extra contraceptive precautions during the next 7 days, BUT - if these days run beyond the end of the small pink active tablets in your pack - the 7 large white inactive tablets must NOT be taken (ie discard the current pack after taking the last small pink tablet on “FR”). Start a new pack the next day with the “SA” tablet from the silver section. You can now continue pill taking as before. Read the section “Extra contraceptive precautions”carefully.
Do not leave a gap between packs. Your menstrual period will occur after you have completed the second pack. If the period does not occur, consult your doctor before resuming the next pack.
If the woman missed tablets and subsequently has no withdrawal bleed in the first inactive tablet phase, the possibility of a pregnancy should be considered.
Advice in case of gastro-intestinal disturbances
In case of severe gastro-intestinal disturbances, absorption may not be complete and additional contraceptive measures should be taken.
If vomiting occurs within 3 to 4 hours after active tablet-taking, the advice concerning missed tablets under the “Management of missed tablets” is applicable. If the woman does not want to change her normal tablet-taking schedule, she has to take the extra tablet(s) needed from another pack.
How to shift periods or how to delay a period
To delay a period the woman should continue with another pack of Miranova without taking the inactive tablets from her current pack. The extension can be carried on for as long as wished until the end of the active tablets in the second pack. During the extension the woman may experience breakthrough bleeding or spotting. Regular intake of Miranova is then resumed after the inactive tablet phase.
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 inactive tablet phase by as many days as she likes. The shorter the interval, the higher the risk that she will not have a withdrawal bleed and will experience breakthrough-bleeding and spotting during the second pack (just as when delaying a period).
Reduced cycle control
Irregular bleeding (spotting or breakthrough bleeding) may occur, especially during the first months of use. Therefore, the evaluation of any irregular bleeding is only meaningful after an adaptation interval of about three cycles.
If bleeding irregularities persist or occur after previously regular cycles, then non-hormonal causes should be considered and adequate diagnostic measures are indicated to exclude malignancy or pregnancy. These may include curettage.
In some women withdrawal bleeding may not occur during the inactive tablet phase. If Miranova has been taken according to the directions described in “Dosage and directions for use”, it is unlikely that the woman is pregnant. However, if Miranova has not been taken according to these directions prior to the first missed withdrawal bleed or if two withdrawal bleeds are missed, pregnancy must be ruled out before the use of Miranova is continued.

SIDE EFFECTS AND SPECIAL PRECAUTIONS
Side effects
The most serious undesirable effects associated with the use of combined oral contraceptives including Miranova are listed under “Warnings”.
Other side effects that have been reported in users of combined oral contraceptives but for which the association has been neither confirmed or refuted are: breast tenderness, pain, enlargement, secretion; headache; migraine; changes in libido; depressive moods/mood changes; nausea, vomiting, and other gastro-intestinal complaints; various skin disorders (eg rash, erythema, nodosum, erythema multiforme); changes in vaginal secretion; contact lens intolerance; fluid retention; change in body weight; hypersensitivity reaction.
Special precautions
Women should be advised that oral contraceptives do not protect against HIV infections (AIDS) and other sexually transmissible diseases.
Reduced efficacy
The efficacy of combined oral contraceptives may be reduced in the event of eg missed active tablets, gastro-intestinal disturbances during active tablet-taking or concomitant medication.

KNOWN SYMPTOMS OF OVERDOSAGE AND PARTICULARS OF ITS TREATMENT
There have been no reports of serious deleterious effects from overdose. Symptoms that may occur in case of taking an overdose of active tablets are: nausea; vomiting; and, in young girls, slight vaginal bleeding. There are no antidotes and further treatment should be symptomatic.

IDENTIFICATION
21 pink coated tablets (hormonal) and 7 white coated tablets (inactive).

PRESENTATION
Cartons with 1 or 3 PVC/aluminium blister packs each containing 28 tablets.

STORAGE INSTRUCTIONS
In original packs at room temperature (below 30°C). Protect from light. Store all medicines out of reach of children.

REGISTRATION NUMBER
37/21.8.2/0541

NAME AND BUSINESS ADDRESS OF THE HOLDER OF THE CERTIFICATE OF REGISTRATION
Schering (Pty) Ltd
(Reg No: 1964/009072/07)
106 Sixteenth Road
Randjespark
Midrand        1685
P O Box 5278
Halfway House        1685

DATE OF PUBLICATION OF THE PACKAGE INSERT
7 May 2004

SCHERING (PTY) LTD
(Reg No: 1964/009072/07)
Subsidiary of
Schering AG        Germany

New addition to this site: January 2005
Source: Pharmaceutical Industry
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