(and dosage form):
Levonorgestrel intrauterine system
Levonorgestrel intrauterine system 20 micrograms/24 hours. Each sterile intrauterine system contains levonorgestrel
A. 34. Other.
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
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.
Contraception; idiopathic menorrhagia.
Protection from endometrial hyperplasia during estrogen replacement therapy.
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.
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
• exceptionally severe headache;
• marked increase in blood pressure;
• 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
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
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