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

SCHEDULING STATUS:
S4

PROPRIETARY NAME
(and dosage form):

MIRENA
Levonorgestrel intrauterine system

COMPOSITION
Levonorgestrel intrauterine system 20 micrograms/24 hours. Each sterile intrauterine system contains levonorgestrel 52 mg.

PHARMACOLOGICAL CLASSIFICATION
A. 34. Other.

PHARMACOLOGICAL ACTION
Levonorgestrel is a progestogen. The contraceptive and therapeutic effects of Mirena are mainly based on local progestogenic effects in the uterine cavity. Levonorgestrel has an antiproliferative effect on the endometrium and it inhibits the endometrial synthesis of estrogen receptors, making the endometrium insensitive to the circulating estradiol. Morphological changes of the endometrium and a weak local foreign body reaction are observed during use of Mirena. Thickening of the cervical mucous prevents passage of the sperm through the cervical canal, and the changes in the uterus and the ovarian tubes inhibit sperm mobility and function, preventing fertilisation. Ovulation is inhibited in some women.
The pharmacokinetics of levonorgestrel itself have been extensively studied and reported in the literature. Orally administered levonorgestrel is rapidly and completely absorbed and the absolute bioavailability is about 90%. Levonorgestrel is bound to serum albumin and to sex hormone-binding globulin (SHBG). The relative distribution (free, albumin-bound, SHBG-bound) depends on the SHBG concentration in the serum. Only about 2,5% of the total serum drug levels are present as free steroid, but 47,5% and 50% are bound to SHBG and albumin, respectively. For levonorgestrel, a mean volume of distribution of approximately 137 litres and a metabolic clearance rate from serum of about 5,7 L/h were reported. A terminal half-life of levonorgestrel in serum in the range of about 14 to 20 hours can be observed after single dose administration. Levonorgestrel is excreted as metabolites at about equal proportions with urine and faeces. The metabolites have only weak or no pharmacological activity.
About 0,1% of the maternal dose of levonorgestrel can be transferred via milk to the infant.

INDICATIONS
Contraception; idiopathic menorrhagia.
Protection from endometrial hyperplasia during estrogen replacement therapy.

CONTRA-INDICATIONS
Known or suspected pregnancy; lower genital tract infection; current or recurrent pelvic inflammatory disease; postpartum endometritis; infected abortion during the past three months; cervicitis; cervical dysplasia; uterine or cervical malignancy; undiagnosed abnormal uterine bleeding; congenital or acquired uterine anomaly including fibroids if they distort the uterine cavity; conditions associated with increased susceptibility to infections; acute liver disease or liver tumour; hypersensitivity to the constituents of the preparation.

WARNINGS
Mirena may be used with caution after specialist consultation, or removal of the system should be considered, if any of the following conditions exist or arise for the first time:

•	migraine, crescendo migraine, focal migraine with asymmetrical visual loss or other symptoms indicating transient cerebral ischaemia;
•	exceptionally severe headache;
•	jaundice;
•	marked increase in blood pressure;
•	confirmed or suspected hormone dependent neoplasias including breast cancer;
•	severe arterial disease such as stroke or myocardial infarction.

In women using progestogen-only pills some recent epidemiological studies indicated that there may be a slightly increased risk of venous thromboembolism, but the results were statistically not significant. However, appropriate diagnostic and therapeutic measures should be undertaken immediately if there are symptoms or signs of thrombosis. Symptoms of venous or arterial thrombosis 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. Symptoms or signs indicating retinal thrombosis are: unexplained partial or complete loss of vision, onset of proptosis or diplopia, papilledema, or retinal vascular lesions.
There is no consensus about the possible role of progestogens in patients with varicose veins and superficial thrombophlebitis in the causation of venous thromboembolism.
Mirena may be used with caution in women who have congenital heart disease or valvular heart disease at risk of infective endocarditis. Antibiotic prophylaxis should be administered to these women when inserting or removing the intrauterine system.
Low-dose levonorgestrel may affect glucose tolerance, and the blood glucose concentration should be monitored in diabetic users of Mirena.
Irregular bleedings may mask some symptoms and signs of endometrial polyps or cancer, and in these cases diagnostic measures have to be considered.
Mirena is not the method of first choice for nulligravid women, nor for postmenopausal women with advanced uterine atrophy.

DOSAGE AND DIRECTIONS FOR USE
One unit is inserted into the uterine cavity. One administration is effective for five years.
Instructions for use/handling
Mirena is supplied in a sterile pack which should not be opened until required for insertion. The exposed product should be handled with aseptic precautions. If the seam of the sterile package is broken, the intrauterine system should be discarded as medicinal waste. A removed intrauterine system should likewise be handled as medicinal waste, since it may contain hormone remnants. The inserter should be handled as hospital waste, and the outer carton package as well as the inner blister package can be handled as household waste. Special instructions for insertion are in the package.
Insertion and removal/replacement
Before insertion, the woman must be informed of the efficacy, risks and side effects of Mirena. A physical examination including pelvic examination, examination of the breasts, and a cervical smear should be performed. Pregnancy and sexually transmitted diseases should be excluded, and genital infections have to be successfully treated. The position of the uterus and the size of the uterine cavity should be determined. Fundal positioning of Mirena is particularly important in order to ensure uniform exposure of the endometrium to the progestogen, prevent expulsion and maximise efficacy. Therefore, the instructions for the insertion should be followed carefully. The woman should be re-examined 4 to 12 weeks after insertion and once a year thereafter, or more frequently if clinically indicated.
In women of fertile age Mirena is to be inserted into the uterine cavity within seven days of the onset of menstruation. Mirena can be replaced by a new system at any time in the cycle. The system can also be inserted immediately after first trimester abortion. Postpartum insertions should be postponed until six weeks after delivery. Mirena is not suitable for use as a post-coital contraceptive.
When used for endometrial protection during estrogen replacement therapy, Mirena can be inserted at any time in an amenorrhoeic woman, or during the last days of menstruation or withdrawal bleeding.
Because irregular bleeding/spotting is common during the first months of therapy, it is recommended to exclude endometrial pathology before insertion of Mirena. If the woman continues the use of Mirena inserted earlier for contraception, endometrial pathology has to be excluded in case bleeding disturbances appear after commencing estrogen replacement therapy. If bleeding irregularities develop during a prolonged treatment, appropriate diagnostic measures should also be taken.
The system should be removed after five years. If the user wishes to continue using the same method, a new system can be inserted at the same time. If pregnancy is not desired, the removal should be carried out during the menstruation in women of fertile age, provided that there appears to be a menstrual cycle. If the system is removed in the mid-cycle and the woman has had intercourse within the previous week, she is at a risk of pregnancy unless a new system is inserted immediately following removal.
Insertion and removal may be associated with pain and bleeding. The procedure may precipitate fainting as a vasovagal reaction, or a seizure in an epileptic woman.
Insertion instructions
See separate enclosed insertion instruction leaflet.
Important
Should you suspect that the system is not in the correct position, remove it and insert a new one.
Removal of Mirena
Mirena can be removed by pulling the removal threads with forceps. If the threads are not visible and the system is in the uterine cavity, it may be removed using a narrow tenaculum. This may require dilatation of the cervical canal. Unless a pregnancy is desired, the system should not be removed after the fifth day of the menstrual cycle in a sexually active woman.

SIDE EFFECTS AND SPECIAL PRECAUTIONS
Side effects
Side effects are more common during the first months after the insertion, and subside during prolonged use. Menstrual problems are the most often reported adverse events as described below. The following adverse events have been reported in the order of frequency of occurrence: headache, lower abdominal pain, back pain, skin disorders, vaginal discharge, mastalgia and other benign breast conditions, vaginitis, depression and other mood changes, nausea and oedema. Other adverse events such as weight gain, hair loss or greasy hair, and hirsutism were reported in individual cases.
The most common adverse effect of Mirena is a change in menstrual bleeding patterns. The changes may include spotting, shorter or longer menstrual periods, irregular bleeding, oligomenorrhoea, amenorrhoea, heavy flow, back pain and dysmenorrhoea.
The average number of spotting days decreased gradually during the first six months of use. The percentage of women with prolonged bleeding (more than eight days) decreased from 20% to 3% during the first three months of use. In clinical studies during the first year of use, 17% of women experienced amenorrhoea of at least three months’duration.
When used in combination with estrogen replacement therapy, perimenopausal users of Mirena experience spotting and irregular bleeding during the first months of the treatment. A non-bleeding pattern gradually develops in most women during the first year.
Pregnancy in the case of failure may be ectopic. Pelvic inflammatory disease which may be serious can occur in a user of Mirena. The system or parts of it may perforate the uterine wall. Enlarged follicles (functional ovarian cysts) may develop, and have been diagnosed in about 12% of women using Mirena.
Special precautions
Syncope or bradycardia may occur in some women during insertion or removal of an intrauterine system. In the event of early signs of a vasovagal attack, insertion may need to be abandoned or the system removed.
Pelvic infection: The inserter protects Mirena from contamination with micro-organisms during the insertion. The highest rate of pelvic infections occurs during the first month after insertion and decreases later. Known risk factors for pelvic inflammatory disease are multiple sexual partners. Mirena should be removed if the woman experiences recurrent endometritis or pelvic infection, or if an acute infection does not respond to treatment within a few days.
Bacteriological examinations are indicated and monitoring is recommended, even with discrete symptoms indicative of infections.
Expulsion: Symptoms of the partial or complete expulsion of the intrauterine system may include bleeding or pain. However, a system can be expelled from the uterine cavity without the woman noticing it. Partial expulsion may decrease the effectiveness of Mirena. As Mirena decreases menstrual flow, increase of menstrual flow may be indicative of an expulsion.
A displaced Mirena should be removed. A new system can be inserted at that time.
The woman should be advised how to check the threads of Mirena.
Perforation: Perforation of the uterus or cervix may occur, most often during insertion. The system must be removed.
Ectopic pregnancy: Women with a previous history of ectopic pregnancy, tubal surgery or pelvic infection carry a higher risk of ectopic pregnancy. The possibility of ectopic pregnancy should be considered in the case of lower abdominal pain - especially in connection with missed periods or if an amenorrhoeic woman starts bleeding.The rate of ectopic pregnancy in users of Mirena has been 0,05 per 100 woman-years. This rate is significantly lower than the rate of 1,2 to 1,6 estimated for women not using any contraception.
Lost threads: If the retrieval thread is not visible at the cervix on follow-up examinations, pregnancy must be excluded. The threads may have been drawn up into the uterus or cervical canal and may reappear during the next menstrual period. If pregnancy has been excluded, the threads may usually be located by gently probing with a suitable instrument. If they cannot be found, the system may have been expelled. Ultrasound or x-ray may be used to locate Mirena.
Oligo/amenorrhoea: In women of fertile age oligomenorrhoea and/or amenorrhoea develops gradually in about 20% of the users. The possibility of pregnancy should be considered if menstruation does not occur within 6 weeks of the onset of previous menstruation.A repeated pregnancy test is not necessary in amenorrhoeic subjects unless indicated by other signs of pregnancy.
When Mirena is used in combination with continuous estrogen replacement therapy, a non-bleeding pattern gradually develops in most women during the first year.
Delayed follicular atresia: Since the contraceptive effect of Mirena is mainly due to its local effect, ovulatory cycles with follicular rupture usually occur in women of fertile age. Sometimes atresia of the follicle is delayed and folliculogenesis may continue. These enlarged follicles cannot be distinguished clinically from ovarian cysts. Enlarged follicles have been diagnosed in about 12% of the subjects using Mirena. Most of these follicles are asymptomatic, although some may be accompanied by pelvic pain or dyspareunia.
In most cases, the enlarged follicles disappear spontaneously during two to three months’ observation. Should this not happen, continued ultrasound monitoring and other diagnostic/therapeutic measures are recommended. Rarely, surgical intervention may be required.
Pregnancy and lactation
Pregnancy: Mirena is not to be used during an existing or suspected pregnancy. If the woman becomes pregnant when using Mirena, removal of the system is recommended since any intrauterine contraceptive left in situ may increase the risk of abortion and preterm labour. Removal of Mirena or probing of the uterus may result in spontaneous abortion. If the intrauterine contraceptive cannot be gently removed, termination of the pregnancy may be considered. If the woman wishes to continue the pregnancy and the system cannot be withdrawn, she should be informed about the risks and the possible consequences of premature birth to the infant. The course of such a pregnancy should be closely monitored. Ectopic pregnancy should be excluded. The woman should be instructed to report all symptoms that suggest complications of the pregnancy, such as cramping abdominal pain with fever.
Because of the intrauterine administration and the local exposure to the hormone, teratogenicity (especially virilisation) cannot be excluded.
Lactation: Levonorgestrel has been identified in the breast milk of lactating women using Mirena. The quantity and quality of breast milk are however not affected. Non-hormonal contraceptive methods/devices are the methods of choice during lactation. However, if progestogen only contraception is judged as appropriate for lactating women, Mirena may be used.
Interaction with other medicines and other forms of interaction
The effect of hormonal contraceptives may be impaired by drugs which induce liver enzymes, including primidone, barbiturates, phenytoin, carbamazepine, rifampicin and oxcarbazepine; griseofulvin is also suspected. The influence of these drugs on the contraceptive efficacy of Mirena has not been studied,but is not believed to be of major importance due to the mainly local mechanisms of contraceptive action.

KNOWN SYMPTOMS OF OVERDOSAGE AND PARTICULARS OF ITS TREATMENT
Not applicable.

IDENTIFICATION
Mirena consists of an inserter and levonorgestrel intrauterine system, which is loaded at the tip of the inserter. The inserter components are an insertion tube, plunger, flange, T-body and slider. The system consists of a white or almost white hormone sleeve, mounted on a T-body and covered with an opaque tubing. The body has a loop at one end and two arms at the other end. Removal threads are attached to the loop. The system is essentially free from visible impurities.

PRESENTATION
The system with accessories are packed into a heat sealed sterilisation pouch.

STORAGE INSTRUCTIONS
Store below 30°C. Protect from moisture and direct sunlight. Keep out of reach of children.

REGISTRATION NUMBER
32/34/0332

NAME AND BUSINESS ADDRESS OF THE APPLICANT
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 THIS PACKAGE INSERT
29 July 2002

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

Updated on this site: April 2003
Source: Pharmaceutical Industry
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