Mirena

/ Bayer

The initial release of levonorgestrel is approximately 20 micrograms per day.
This medical product is inserted into the uterine cavity and is effective for 5 years in the indications contraception and idiopathic menorrhagia. For contraception and idiopathic menorrhagia: the system should be removed after 5 years of use. If the user wishes to continue using the same method, a new system can be inserted at the same time, in which case no additional protection is required.
In the indication for protection from endometrial hyperplasia during oestrogen replacement therapy, clinical data (from clinical trials conducted in women of 18 years and over) beyond 4 years of use are limited. Therefore it should be removed after 4 years.
See prescribing information for full details.

Contraception, idiopathic menorrhea, protection from endometrial hyperplasia during estrogen replacement therapy.

Known or suspected pregnancy, genital infection, suspected or confirmed uterine/cervical malignant, undiagnosed abnormal uterine bleeding, congenital/ acquired uterine anomality including fibroids, acute liver disease, liver tumor, venous thrombo-embolism, acute/recurring pelvic inflammatory disease, previous bacterial endocarditis, severe pelvic infection with anomalic. cardiac lesion, prosthetic valve replacement, arterial disease, immunodeficiency, acute malignancy affecting blood, leukemia except when in remission, recent trophoblastic disease while HCG levels elevated.
See prescribing information for full details.

Conditions requiring cautious use
– Migraine with aura
– Unusually severe or unusually frequent headache
– Jaundice
– Marked increase in blood pressure
– Malignancies affecting the blood or leukaemias in remission
– Use of chronic corticosteroid therapy
– Past history of symptomatic functional ovarian cysts
– Active or previous severe arterial disease, such as stroke or myocardial infarction
– Severe or multiple risk factors for arterial disease
– Thrombotic arterial or any current embolic disease
– Acute venous thromboembolism
In general, women using hormonal contraception should be encouraged to give up smoking.
This medical product should be used with caution in postmenopausal women with advanced uterine atrophy.
Insertion/removal
Insertion and removal may be associated with some pain and bleeding. In case of difficult insertion and/or exceptional pain or bleeding during or after insertion, the possibility of perforation should be considered and appropriate steps should be taken, such as performing a physical examination and an ultrasound.
Vaginal ultrasound examination may be considered to ascertain the correct position of the system. In case IUD cannot be located in the uterine cavity, expulsion or complete perforation should be considered and X-ray may be used. Thereafter, re-examination should be performed once a year or more frequently if clinically indicated.
After removal, the system should be examined to ensure that it is intact and has been completely removed.
The procedure may precipitate fainting as a vasovagal reaction, or a seizure in an epileptic patient. In the event of early signs of a vasovagal attack, insertion may need to be abandoned or the system removed. The woman should be kept supine, the head lowered and the legs elevated to the vertical position if necessary in order to restore cerebral blood flow. A clear airway must be maintained; an airway should always be at hand. Persistent bradycardia may be controlled with intravenous atropine. If oxygen is available it may be administered.
Perforation: Perforation or penetration of the uterine corpus or cervix by an intrauterine contraceptive may occur, most commonly during insertion, although it may not be detected until sometime later, and may decrease the effectiveness. This may be associated with severe pain and continued bleeding. In some of these cases, the device may be located outside of the uterine cavity. If perforation is suspected the system should be removed as soon as possible; surgery may be required.
Pelvic infection: The insertion tube helps to prevent contamination with micro-organisms during the insertion and the inserter has been designed to minimise the risk of infections.
Symptoms and signs suggestive of pelvic infection, bacteriological examinations are indicated and monitoring is recommended, even with discrete symptoms, and appropriate antibiotics should be started. There is no need to remove the device unless the symptoms fail to resolve within the following 72 hours or unless the woman wishes to be removed. It must be removed if the woman experiences recurrent endometritis or pelvic infection, or if an acute infection is severe.
Complications leading to failure
Expulsion: In clinical trials in the indication contraception, the incidence of expulsion was low (<4% of insertions) and in the same range as that reported for other IUDs and IUSs. Symptoms of the partial or complete expulsion may include bleeding or pain. However, a system can be expelled from the uterine cavity without the woman noticing it, leading to loss of contraceptive protection. As the system decreases menstrual flow, increase of menstrual flow may be indicative of an expulsion. Partial expulsion may decrease the effectiveness of this medical product. A partially expelled device should be removed. A new system can be inserted at the time of removal, provided pregnancy has been excluded.
Risk of expulsion is increased in: Women with history of heavy menstrual bleeding (including women who use for treatment of heavy menstrual bleeding).
Women with greater than normal BMI at the time of insertion.
Lost threads: If the retrieval threads are not visible at the cervix on follow-up examination – first exclude pregnancy. The threads may have been drawn up into the uterus or cervical canal and may reappear during the next menstrual period. If they cannot be found, they may have broken off, the system may have been expelled, or rarely the device may be extrauterine after having perforated the uterus. A vaginal ultrasound should be arranged to locate the device and alternative contraception should be advised in the meantime. If an ultrasound cannot locate the device and there is no evidence of expulsion, a plain abdominal X-ray should be performed to exclude an extrauterine device.
Bleeding irregularities
A significant reduction in menstrual blood loss is typically observed within 3 to 6 months of treatment. Increased menstrual flow or unexpected bleeding may be indicative of expulsion. If menorrhagia persists then the woman should be re-
examined. An assessment of the uterine cavity should be performed using ultrasound scan. An endometrial biopsy should also be considered.
Risk in pre-menopausal women: Because irregular bleeding/spotting may occur during the first months of therapy in pre-menopausal women, it is recommended to exclude endometrial pathology before insertion.
Risk in post-menopausal women: If the woman continues the use of IUD inserted earlier for contraception, endometrial pathology has to be excluded if bleeding disturbances appear after commencing oestrogen replacement therapy. If bleeding irregularities develop during a prolonged treatment, appropriate diagnostic measures should also be taken as irregular bleeding may mask symptoms and signs of endometrial polyps or cancer.
When to check for pregnancy in women of child bearing potential: The possibility of pregnancy should be considered if menstruation does not occur within six weeks of the onset of previous menstruation and expulsion should be excluded. A repeated pregnancy test is not necessary in amenorrhoeic subjects unless indicated by other symptoms.
Ectopic pregnancy: The absolute risk of ectopic pregnancy is low. However, when a woman becomes pregnant with IUD in situ, the relative likelihood of ectopic pregnancy is increased. 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. In a large prospective comparative non-interventional cohort study with an observation period of 1 year, the ectopic pregnancy rate with this medical product was 0.02%. In clinical trials, the absolute rate of ectopic pregnancy was approximately 0.1% per year. This rate is lower than the rate of 0.3-0.5 % per year estimated for women not using any contraception.
Ovarian Cysts: Since the contraceptive effect 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. In most cases, the ovarian cysts 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.
Breast cancer:
Risk in pre-menopausal women: 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 (COCs), mainly using oestrogen-progestogen preparations. The excess risk gradually disappears during the course of the 10 years after cessation of COC use. Because breast cancer is rare in women under 40 years of age, the excess number of breast cancer diagnoses in current and recent COC users is small in relation to the overall risk of breast cancer.
The risk of having breast cancer diagnosed in users of progestogen-only methods (POPs, implants and injectables), including this medical product, is possibly of similar magnitude to that associated with COC. However, for progestogen-only contraceptive preparations, the evidence is based on much smaller populations of users and so is less conclusive than that for COCs.
Psychiatric disorders: Depressed mood and depression are well-known undesirable effects of hormonal contraceptive use. Depression can be serious and is a well-known risk factor for suicidal behaviour and suicide.
Glucose tolerance: Low-dose levonorgestrel may affect glucose tolerance, and the blood glucose concentration should be monitored in diabetic users.
Post-coital contraception: Limited experience suggests that this medical product is not suitable for use as a post-coital contraceptive.
See prescribing information for full details.

Common: Depressed mood/depression, Nervousness, Decreased libido, Headache, Migraine, Dizziness, Abdominal pain, Nausea, Acne, Hirsutism, Back pain, Ovarian cysts, Pelvic pain, Dysmenorrhoea, Vaginal discharge, Vulvovaginitis, Breast tenderness, breast pain, Intrauterine contraceptive device expelled, Weight increased.
See prescribing information for full details.

Effects of other medicinal products
Substances increasing the clearance of levonorgestrel, e.g.:
Phenytoin, barbiturates, primidone, carbamazepine, rifampicin and possibly also oxcarbazepine, topiramate, felbamate, griseofulvin and products containing St. John’s wort.
The influence of these drugs on the contraceptive efficacy has not been studied but is not believed to be of major importance due to the local mechanism of action.
Substances with variable effects on the clearance of levonorgestrel:
When co-administered with sex hormones, many HIV/HCV protease inhibitors and non-nucleoside reverse transcriptase inhibitors can increase or decrease plasma concentrations of the progestin.
Substances decreasing the clearance of levonorgestrel (enzyme inhibitors), e.g.:
Strong and moderate CYP3A4 inhibitors such as azole antifungals (e.g. fluconazole, itraconazole, ketoconazole, voriconazole), verapamil, macrolides (e.g. clarithromycin, erythromycin), diltiazem and grapefruit juice can increase plasma concentrations of the progestin.

Pregnancy: The use during an existing or suspected pregnancy is contraindicated. In case of an accidental pregnancy, the system should be removed as soon as possible, since any intrauterine contraceptive left in situ may increase the risk of abortion and preterm labour. Removal of IUD or probing of the uterus may also result in spontaneous abortion. Ectopic pregnancy should be excluded.
In addition, an increased risk of virilising effects in a female foetus because of the intrauterine exposure to levonorgestrel cannot be excluded. There have been isolated cases of masculinisation of the external genitalia of the female foetus following local exposure to levonorgestrel during pregnancy with an LNG-IUS in place.
Lactation: Levonorgestrel has been identified in the breast milk. About 0.1% of the levonorgestrel dose is transferred during breast-feeding, but it is not likely that there will be a risk for the child with the dose released from this medical product, when it is inserted in the uterine cavity.
There appear to be no deleterious effects on infant growth or development when using any progestogen-only method after six weeks postpartum. Progestogen-only methods do not appear to affect the quantity or quality of breast milk. Uterine bleeding has rarely been reported in women using this medical product during lactation.