Mirena®

Active ingredient: Levonorgestrel 52mg. The initial release rate is 20 micrograms/24hours

For excipients, see 6.1

Levonorgestrel Intrauterine System (IUS).

The product consists of an inserter and levonorgestrel intrauterine system, which is loaded at the tip of the inserter. Inserter components are an insertion tube, plunger, flange, body and slider. The system consists of a white or almost white hormone-elastomer core, mounted on a T-body and covered in opaque tubing, which regulates the release of levonorgestrel. The T-body has a loop at one end and two arms at the other end. Removal threads are attached to the loop.

Contraception.

Idiopathic menorrhagia. Mirena may be particularly useful in women with idiopathic menorrhagia requiring (reversible) contraception.

Protection from endometrial hyperplasia during oestrogen replacement therapy.

The initial release of levonorgestrel is about 20 micrograms/24 hours.

Mirena is effective for five years in the indications for contraception and idiopathic menorrhagia.

In the indication for protection from endometrial hyperplasia during oestrogen replacement therapy, clinical data beyond 4 years of use are limited. Mirena should therefore be removed after 4 years.

Clinical trials were conducted in women of 18 years and over.

Before insertion, the patient must be informed of the efficacy, risks and side-effects of Mirena. A gynaecological examination, including examination of the breasts and exclusion of a pregnancy, should be performed. Cervical infection and sexually transmitted diseases should be excluded. The position of the uterus and the size of the uterine cavity should be determined. The instructions for insertion should be followed carefully. The patient should be re-examined six weeks after insertion and once a year thereafter, or more frequently if clinically indicated.

Special instructions for insertion are in the package.

Insertion:

In women of fertile age, Mirena is inserted into the uterine cavity within seven days of the onset of menstruation. It can be replaced by a new system at any time of the cycle.

Mirena can also be inserted immediately after the first trimester abortion by curettage. Postpartum insertions should be postponed until six weeks after delivery.

In women under hormonal replacement therapy, Mirena can be used in combination with oral or transdermal oestrogen preparations without progestogens.

When used for endometrial protection during oestrogen 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 may occur 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 if bleeding disturbances appear after commencing oestrogen replacement therapy. If bleeding irregularities develop during a prolonged treatment, appropriate diagnostic measures should also be taken.

Removal:

The system should be removed after five years in the indications for contraception and menorrhagia and after 4 years for endometrial protection. If the user wishes to continue using the same method, a new system can be inserted at the same time.

Mirena is removed by gently pulling on the 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.

If pregnancy is not desired, removal should be carried out during menstruation in women of fertile age, provided that there appears to be a menstrual cycle. If the system is removed mid-cycle and the woman has had intercourse within a week, she is at risk of pregnancy unless a new system is inserted immediately following removal.

After removal of Mirena, the system should be checked to ensure it is intact. During difficult removals, single cases have been reported of the hormone cylinder sliding over the horizontal arms and hiding them inside the cylinder. This situation does not require further intervention once completeness of the IUS has been ascertained. The knobs of the horizontal arms usually prevent complete detachment of the cylinder from the T-body.

Known or suspected pregnancy; undiagnosed abnormal genital bleeding; congenital or acquired abnormality of the uterus including fibroids if they distort the uterine cavity; current genital infection; current or recurrent pelvic inflammatory disease; postpartum endometritis, infected abortion during the past three months; cervicitis; cervical dysplasia; uterine or cervical malignancy; past attack of bacterial endocarditis or of severe pelvic infection in a woman with an anatomical lesion of the heart or after any prosthetic valve replacement; active or previous severe arterial disease, such as stroke or myocardial infarction; liver tumour or other acute or severe liver disease; conditions associated with increased susceptibility to infections; acute malignancies affecting the blood or leukaemias except when in remission; recent trophoblastic disease while hCG levels remain elevated; 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 cerebral ischaemia

- Unusually severe or unusually frequent headache

- Jaundice

- Marked increase of blood pressure

- Confirmed or suspected hormone dependent neoplasia including breast cancer

- Malignancies affecting the blood or leukaemias in remission

- Use of chronic corticosteroid therapy

- Past history of symptomatic functional ovarian cysts

- Severe or multiple risk factors for arterial disease

- Thrombotic arterial or any current embolic disease

- Venous thromboembolism.

In general, women using hormonal contraception should be encouraged to give up smoking.

Menorrhagia: Mirena usually achieves a significant reduction in menstrual blood loss in 3 to 6 months of treatment. If significant reduction in blood loss is not achieved in these time-frames, alternative treatments should be considered.

Patients with congenital or acquired cardiac valve defects may be given antibiotic prophylaxis at the time of IUS insertion or removal to prevent endocarditis.

Ectopic pregnancy: Women with a previous history of ectopic pregnancy carry a higher risk of a further 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 is 0.06 per 100 woman-years. This rate is lower than the rate of 0.3-0.5 per 100 woman-years estimated for women not using any contraception. The corresponding figure for the copper IUD is 0.12 per 100 woman years.

Irregular bleeding may mask symptoms and signs of endometrial cancer.

Functional ovarian cysts have been diagnosed in about 10-12% of patients, and these are also common with progestogen-only contraception. 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.

Use with caution in postmenopausal women with advanced uterine atrophy.

Low-dose levonorgestrel may affect glucose tolerance, and the blood glucose concentration should be monitored in diabetic users of Mirena.

Insertion and removal may be associated with some pain and bleeding. If the pain is unusually severe, or if bleeding continues, the possibility of perforation of the uterine corpus or cervix must be considered (see also special warnings and precautions for use 'Perforation'). 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.

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.

Pelvic infection: Known risk factors for pelvic inflammatory disease are multiple sexual partners, frequent intercourse and young age. Mirena must be removed if the woman experiences recurrent endometritis or pelvic infection, or if an acute infection is severe or does not respond to treatment within a few days. Pelvic infection may have serious consequences as it may impair fertility and increase the risk of ectopic pregnancy.

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.

Expulsion: Symptoms of the partial or complete expulsion of any IUS 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 the system decreases menstrual flow, increase of menstrual flow may be indicative of an expulsion. A displaced Mirena should be removed and a new system inserted. The woman should be advised how to check the threads of Mirena.

Perforation: Perforation of the uterine corpus or cervix may occur, most commonly during insertion. This may be associated with severe pain and continued bleeding. If perforation is suspected the system should be removed as soon as possible.

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 pregnancy has been excluded, the threads may usually be located by gently probing with a suitable instrument. If they cannot be found, they may have broken off, or the system may have been expelled. Ultrasound or X-ray may be used to locate Mirena.

Post-coital contraception: Limited experience suggests that Mirena is not suitable for use as a post-coital contraceptive.

The effect of hormonal contraceptives may be impaired by drugs which induce liver enzymes, including barbiturates, primidone, phenytoin, carbamazepine, griseofulvin and rifampicin. The influence of these drugs on the contraceptive efficacy of Mirena has not been studied.

Pregnancy: Mirena is not to be used during an existing or suspected pregnancy. In case of an accidental pregnancy with Mirena in situ, the system must be removed and termination of the pregnancy should be considered. Removal of Mirena or probing of the uterus may result in spontaneous abortion. Should these procedures not be possible, the woman should be informed about increased risk of spontaneous abortion or premature labour observed during the use of copper and plastic IUDs. Accordingly, such pregnancies should be closely monitored. Ectopic pregnancy should be excluded. The woman should be instructed to report all symptoms that suggest complications of the pregnancy, like cramping abdominal pain with fever.

Because of the intrauterine administration and the local exposure to the hormone, teratogenicity (especially virilisation) cannot be completely excluded. It can be expected that the systemic hormone exposure of the foetus through the maternal circulation is lower than with any other hormonal contraceptive method. Clinical experience of the outcomes of pregnancies with Mirena in situ is limited. However, the woman should be informed that, to date, there is no evidence of birth defects caused by Mirena use in cases where pregnancy continues to term with Mirena in place.

Lactation: Levonorgestrel has been identified in the breast milk, but it is not likely that there will be a risk for the child with the dose released from Mirena, 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 Mirena during lactation.

There are no known effects on the ability to drive or use machines.

Undesirable effects are more common during the first months after the insertion, and subside during prolonged use. In addition to the adverse effects listed in section 4.4 “Special warnings and special precautions for use” the following undesirable effects have been reported in users of Mirena, although a causal relationship with Mirena could not always be confirmed.

Ectopic pregnancy in case of method failure should be ruled out (see section 4.4).

Very common undesirable effects (occurring in more than 10% of users) include bleeding changes and ovarian cysts.

Different kinds of bleeding changes (frequent, prolonged or heavy bleeding, spotting, oligomenorrhoea, amenorrhoea) are experienced by all users of Mirena. In fertile women the average number of spotting days/month decreases gradually from nine to four days during the first six months of use. The percentage of women with prolonged bleeding (more than eight days) decreases 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 oestrogen replacement therapy, perimenopausal users of Mirena may experience spotting and irregular bleeding during the first months of the treatment. The amount of bleeding becomes minimal during the first year, and 30-60% of users are totally free of bleedings.

The frequency of benign ovarian cysts depends on the diagnostic method used, and in clinical trials enlarged follicles have been diagnosed in 12% of the subjects using Mirena. Most of the follicles are asymptomatic and disappear within three months.

Not applicable

Levonorgestrel is a progestogen used in gynaecology in various ways: as the progestogen component in oral contraceptives, in hormonal replacement therapy or alone for contraception in minipills and subdermal implants. Levonorgestrel can also be administered directly into the uterine cavity as an intrauterine system. This allows a very low daily dosage, as the hormone is released directly into the target organ.

The contraceptive mechanism of action of Mirena is based on mainly hormonal effects producing the following changes:

- Prevention of proliferation of the endometrium

- Thickening of the cervical mucus thus inhibiting the passage of sperm

- Suppression of ovulation in some women.

The physical presence of the system in the uterus would also be expected to make a minor contribution to its contraceptive effect.

Studies on contraceptive efficacy have suggested a pregnancy rate (Pearl Index) of less than 1 per 100 woman-years.

Mirena may be particularly useful for contraception in patients with excessive menstrual bleeding, and can be successfully used in the treatment of idiopathic menorrhagia. The volume of menstrual bleeding was decreased by 88% in menorrhagic women by the end of three months of use. Menorrhagia caused by submucosal fibroids may respond less favourably. Reduced bleeding promotes the increase of blood haemoglobin in patients with menorrhagia.

In idiopathic menorrhagia, prevention of proliferation of the endometrium is the probable mechanism of action of Mirena in reducing blood loss.

The efficacy of Mirena in preventing endometrial hyperplasia during continuous oestrogen treatment is the same when oestrogen is administered orally or transdermally. The observed hyperplasia rate under oestrogen therapy alone is as high as 20%. In clinical studies with 201 perimenopausal and 259 postmenopausal users of Mirena, no cases of endometrial hyperplasia were reported in the postmenopausal group during the observation period up to 4 years.

The pharmacokinetics of levonorgestrel itself have been extensively investigated and reported in the literature. One key finding is that the bioavailability of levonorgestrel administered orally is almost 90 per cent. In postmenopausal users of Mirena, plasma levonorgestrel concentrations have been 184±54 pg/ml, 188±47 pg/ml and 134±30 pg/ml, respectively. A half life of 20 hours is considered the best estimate although some studies have reported values as short as 9 hours and others as long as 80 hours. Another important finding, although one in agreement with experience with other synthetic steroids, has been marked differences in metabolic clearance rates among individuals, even when administration was by the intravenous route. Levonorgestrel is extensively bound to proteins (mainly sex hormone binding globulin (SHBG) and extensively metabolised to a large number of inactive metabolites.

The initial release of levonorgestrel from Mirena is 20 micrograms/24 hours, delivered directly into the uterine cavity. Because of the low plasma concentrations, there are only minor effects on the metabolism.

Levonorgestrel is a well established progestogen with anti-oestrogenic activity. The safety profile following systemic administration is well documented. A study in monkeys with intrauterine delivery of levonorgestrel for 12 months confirmed local pharmacological activity with good local tolerance and no signs of systemic toxicity. No embryotoxicity was seen in the rabbit following intrauterine administration of levonorgestrel.

Polydimethylsiloxane elastomer, polydimethylsiloxane tubing, polyethylene, barium sulphate, iron oxide

None known

Three years

Not applicable.

The product is individually packed into a thermoformed blister package with a peelable lid.

As the insertion technique is different from intrauterine devices, special emphasis should be given to training in the correct insertion technique. Special instructions for insertion are in the package.

Mirena is supplied in a sterile pack which should not be opened until required for insertion. Each system should be handled with aseptic precautions. If the seal of the sterile envelope is broken, the system inside should be disposed of in accordance with the local guidelines for the handling of biohazardous waste. Likewise, a removed Mirena and inserter should be disposed of in this manner. The outer carton package and the inner blister package can be handled as household waste.

Bayer plc

Bayer House

Strawberry Hill

Newbury

Berkshire RG14 1JA

Trading as Bayer plc, Bayer Schering Pharma

00010/0547

1 May 2008

24 February 2009