Bayer Limited

Mirena 52 mg Intrauterine Delivery System

Active substance:

Levonorgestrel 52mg.

The in-vivo dissolution rate is about the 20 µg/24 hours initially and is reduced to about 11 µg/24 hours after five years. The mean dissolution rate of levonorgestrel is about 14 µg/24 hours over the time up to five years.

For a full list of excipients, see Section 6.1.

Intrauterine delivery system.

The levonorgestrel intrauterine delivery system consists of a white or almost white drug core covered with an opaque membrane, which is mounted on the vertical stem of a T-body. The T-body has a loop at one end of the vertical stem and two horizontal arms at the other end. Removal threads are attached to the loop. The vertical stem of the intrauterine delivery system is loaded in the insertion tube at the tip of the inserter.

Contraception.

Idiopathic menorrhagia.

Protection from endometrial hyperplasia during oestrogen replacement therapy.

Mirena is inserted into the uterine cavity and is effective for five years.

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

Mirena is not the method of first choice for young nulligravid women nor for postmenopausal women with advanced uterine atrophy. (See Section 4.4 Special Warnings and Precautions for use).

The failure rate (Pearl Index) was approximately 0.2 per 100 women at 1 year and the cumulative failure rate was approximately 0.7 per 100 women at 5 years. The failure rate also includes pregnancies due to undetected expulsions and perforations. (See Section 5.1, Pharmacodynamic Properties).

Insertion and removal/replacement

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 the uterus is fully involuted, however not earlier than six weeks after delivery. If involution is substantially delayed, consider waiting until 12 weeks postpartum. In case of a difficult insertion and/or exceptional pain or bleeding during or after insertion, physical examination and ultrasound should be performed immediately to exclude perforation.

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.

It is recommended that Mirena should only be inserted by physicians/health care professionals who are experienced in Mirena insertions and/or have undergone sufficient training for Mirena insertion. Mirena must be inserted using aseptic technique.

Mirena is removed by gently pulling on the threads with a 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.

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 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 a week, she is at a risk of pregnancy unless a new system is inserted immediately following removal.

After removal of Mirena, the system should be checked to be intact. During difficult removals, single cases have been reported of the hormone cylinder sliding over the horizontal arms and hiding them together 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.

Instructions for use and 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 product should be discarded.

• Known or suspected pregnancy,

• Current or recurrent pelvic inflammatory disease,

• Lower genital tract infection,

• Postpartum endometritis,

• Infected abortion during the past three months,

• Cervicitis,

• Cervical dysplasia,

• Uterine or cervical malignancy,

• Progestogen-dependent tumours,

• 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, focal migraine with asymmetrical visual loss or other symptoms indicating transient cerebral ischemia;

• exceptionally severe headache;

• jaundice;

• marked increase of blood pressure;

• 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. An individual benefit-risk assessment in relation to continued use of Mirena should be carried out in the event of thrombosis. Discontinuation of Mirena should also be considered in case of long-term immobilisation due to surgery or illness. Women with a history of thrombo-embolic disorders should be made aware of the possibility of a recurrence.

Symptoms of venous or arterial thrombosis can include: unilateral leg pain and/or swelling; sudden severe pain in 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, papilloedema, or retinal vascular lesions.

There is no consensus about the possible role of varicose veins and superficial thrombophlebitis in 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 patients when inserting or removing the IUS.

Low-dose levonorgestrel may affect glucose tolerance, and the blood glucose concentration should be monitored in diabetic users of Mirena. However, there is generally no need to alter the therapeutic regimen in diabetics using Mirena.

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 using 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 young nulligravid women nor for postmenopausal women with advanced uterine atrophy.

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 progestogen-only pill users is possibly of similar magnitude to that associated with COCs. However, for progestogen-only preparations, the evidence is based on much smaller populations of users and so is less conclusive than that for COCs. 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 OC users, the biological effects of OCs 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. Since a biological effect cannot be excluded, an individual benefit-risk assessment should be made in women in whom breast cancer is diagnosed while using Mirena. Removal of Mirena should be considered.

Since a biological effect of progestogens on liver cancer cannot be excluded, an individual benefit-risk assessment should be made in women with liver cancer.

Mirena does not protect against HIV infection (AIDS) and other sexually transmitted diseases.

Medical examination/consultation

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 maximize efficacy. Therefore, the instructions for insertion should be followed carefully. Because the insertion technique is different from other intrauterine devices, special emphasis should be given to training in the correct insertion technique (See Section 4.2 Posology and Method of Administration). Mirena should only be inserted be physicians/health care professionals who are experienced in Mirena insertions and/or have undergone sufficient training for Mirena insertion. Mirena must be inserted using aseptic technique. Insertion and removal may be associated with some pain and bleeding. The procedure may precipitate fainting as a vasovagal reaction, or a seizure in an epileptic patient.

The woman should be reexamined 4 to 12 weeks after insertion and once a year thereafter or more frequently if clinically indicated.

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 oestrogen replacement therapy. If bleeding irregularities develop during prolonged treatment, appropriate diagnostic measures should also be taken.

Oligo/amenorrhoea

In women of fertile age, oligomenorrhoea and/or amenorrhoea develops gradually in about 20 % of users. The possibility of pregnancy should be considered if menstruation does not occur within six 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 oestrogen replacement therapy, a non-bleeding pattern gradually develops in most women during the first year.

Pelvic infection

A decision to use Mirena must include consideration of the risks of pelvic inflammatory diseases (PID).

The insertion tube helps protect Mirena from contamination with micro-organisms during the insertion and the Mirena inserter has been designed to minimise the risk of infections.

In general, pelvic infection is more likely to occur within the first 20 days following insertion and the rates of infection decrease thereafter to very low levels corresponding to that of non-users and remain low for the duration of use of the product.

Known risk factors for pelvic inflammatory disease are multiple sexual partners, frequent intercourse and young age. Pelvic infection may have serious consequences, including impairment of fertility, increase in the risk of ectopic pregnancy, and on rare occasions, hysterectomy.

During spontaneous post marketing reporting, Group A streptococcal sepsis (GAS) has been reported in less than one in one million users of Mirena. Group A streptococcal sepsis (GAS) is a condition which may occur after surgery, delivery, and from minor trauma.

Actinomycosis has been associated with IUDs. Symptomatic women should have the IUD removed and should receive antibiotics.

If the woman experiences recurrent endometritis or pelvic infections or if an acute infection is severe or does not respond to treatment within a few days, Mirena must be removed.

PID can be asymptomatic but can still result in tubal damage and ectopic pregnancy, infertility.

Signs and symptoms of PID should be investigated appropriately and treated promptly.

Expulsion

Symptoms of the partial or complete expulsion of any IUD may include bleeding or pain. However, the system can be expelled from the uterine cavity without the woman noticing it leading to loss of contraceptive protection. Partial expulsion may decrease the effectiveness of Mirena. As Mirena decreases menstrual flow, increase of menstrual flow may be indicative of an expulsion.

After expulsion, Mirena may be replaced within 7 days from the onset of the next menstruation.

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, partial perforation (e.g. embedment in the myometrium) or penetration of the uterine corpus or cervix by an intrauterine contraceptive may occur rarely, most often during insertion and may decrease the effectiveness of Mirena. Such a system must be removed. The risk of perforations may be increased in post-partum insertions (see Section 4.2, Posology and method of administration), in lactating women and in women with fixed retroverted uterus.

Removal of a perforated device may require surgery and may be associated with complications such as adhesions, peritonitis or intestinal perforations.

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 ectopic pregnancy rate with Mirena is approximately 0.1% per year. This rate is lower than in women not using any contraception (0.3-0.5% per year). The absolute risk of ectopic pregnancy in Mirena users is low. However, when a woman becomes pregnant with Mirena in situ, the relative likelihood of ectopic pregnancy is increased and up to half of pregnancies that occur with Mirena in place are ectopic. An ectopic pregnancy may lead to a higher risk of a subsequent pregnancy being ectopic or to impaired fertility.

Lost threads

If the retrieval threads are 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 diagnosis may be used to ascertain the correct position of the system. If ultrasound is not available or successful, X-ray may be used to locate Mirena.

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 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.

The metabolism of progestogens may be increased by concomitant use of substances known to induce drug-metabolising enzymes, specifically cytochrome P450 enzymes, such as anticonvulsants (e.g. phenobarbital, phenytoin, carbamazepine) and anti-infectives (e.g. rifampicin, rifabutin, nevirapine, efavirenz). The influence of these drugs on the contraceptive efficacy of Mirena is not known, but it is not believed to be of major importance due to the local mechanism of action.

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, the woman 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, like cramping abdominal pain with fever.

Because of the intrauterine administration and the local exposure to the hormone the possible occurrence of virilising effects in the foetus should be taken into consideration. Clinical experience of the outcomes of pregnancies under Mirena is limited due to the high contraceptive efficacy,but 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

About 0.1 % of the levonorgestrel dose is transferred to the infant during breast-feeding. However, it is not likely that there will be a risk for the infant with the dose released from Mirena, when it is inserted in the uterine cavity.

Hormonal contraceptives are not recommended as the contraceptive method of choice during lactation.

There appear to be no deleterious effects on infant growth or development when using Mirena 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.

Not known

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.

Very common undesirable effects (occurring in more than 10% of users) include uterine/vaginal bleeding including spotting, oligomenorrhoea, amenorrhoea and benign ovarian cysts.

In fertile women the average number of spotting days/months 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, most peri- and postmenopausal users of Mirena experienced spotting and irregular bleeding during the first months of treatment. Thereafter bleeding and spotting decreased and about 40% of users became totally free of bleeding during the last three months of the first year of treatment. Bleeding disturbances were more frequent in perimenopausal women when compared with postmenopausal women.

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

The table below reports adverse reactions by MedDRA system organ classes (MedDRA SOCs). The frequencies are based on clinical trial data.

The most appropriate MedDRA term is used to describe a certain reaction and its synonyms and related conditions.

Pregnancy, puerperium and perinatal conditions:

When a woman becomes pregnant with Mirena in situ, the relative risk of ectopic pregnancy is increased.

Reproductive system and breast disorders:

In addition, cases of breast cancer have been reported (frequency unknown, see section 4.4, Special Warnings and Precautions for use).

Not relevant.

ATC code: G02BA03

Pharmacotherapeutic group: Plastic IUD with Progestogen

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

Mirena has mainly local progestogenic effects in the uterine cavity. The high levonorgestrel concentration in the endometrium down-regulates endometrial oestrogen and progesterone receptors, making the endometrium insensitive to the circulating estradiol and a strong antiproliferative effect is seen. Morphological changes of the endometrium and a weak local foreign body reaction are observed during use of Mirena. Thickening of the cervical mucus prevents passage of the sperm through the cervical canal. The local milieu of the uterus and of the ovarian tubes inhibits sperm mobility and function, preventing fertilisation. Ovulation is inhibited in some women.

The contraceptive efficacy of Mirena has been studied in 5 major clinical studies with 3330 women using Mirena. The failure rate (Pearl Index) was approximately 0.2 % at 1 year and the cumulative failure rate was approximately 0.7 % at 5 years. The failure rate also includes pregnancies due to undetected expulsions and perforations. Similar contraceptive efficacy has been observed in a large post-marketing study with more than 17000 women using Mirena. Because the use of Mirena does not require daily intake compliance by the users, the pregnancy rates in “typical use” are similar to those observed in controlled clinical trials (“perfect use”). The use of Mirena does not alter the course of future fertility. About 80% of women wishing to become pregnant conceived within 12 months after removal of the system.

The menstrual pattern is a result of the direct action of levonorgestrel on the endometrium and does not reflect the ovarian cycle. There is no clear difference in follicle development, ovulation or estradiol and progesterone production in women with different bleeding patterns. In the process of inactivation of the proliferation of the endometrium there can be an initial increase of spotting during the first months of use. Thereafter, the strong suppression of the endometrium results in the reduction of the duration and volume of menstrual bleeding during use of Mirena. Scanty flow frequently develops into oligomenorrhoea and amenorrhoea. Ovarian function is normal and estradiol levels are maintained, even when users of Mirena are amenorrhoeic.

Mirena 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 increases the concentration of blood haemoglobin. Mirena also alleviates dysmenorrhoea.

The efficacy of Mirena in preventing endometrial hyperplasia during continuous oestrogen treatment has been equally good when administering oestrogen either 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 endometrial hyperplasias were reported in the postmenopausal group during the observation period up to five years.

Following insertion Mirena releases levonorgestrel without delay. The high local drug exposure in the uterine cavity which is important for the local action of Mirena on the endometrium, leads to a strong concentration gradient via the endometrium to the myometrium (gradient endometrium to myometrium>100-fold), and to low concentrations of levonorgestrel in serum (gradient endometrium to serum >1000-fold).

The in vivo release rate of levonorgestrel in the uterine cavity is initially approximately 20 µg/24 hours and declines to 10 µg/24 hours after 5 years. The mean dissolution rate of levonorgestrel is about 14 µg/24 hours over the time up to five years.

Distribution

Levonorgestrel is bound non-specifically to serum albumin and specifically to SHBG. About 1-2 % of the circulating levonorgestrel is present as free steroid and 42-62 % is specifically bound to SHBG. During the use of Mirena, the concentration of SHBG declines. Accordingly, the fraction bound to SHBG decreases during the treatment and the free fraction increases. The mean apparent volume of distribution of levonorgestrel is about 106 L.

After insertion of Mirena, levonorgestrel is detectable in serum after 1 hour. The maximum concentration is reached within 2 weeks after insertion. In correspondence with the declining release rate, the median serum concentration of levonorgestrel declines from 206 pg/ml (25^th to 75^th percentiles: 151 pg/ml to 264 pg/ml) at 6 months to 194 pg/ml (146 mg/ml to 266 pg/ml) at 12 months and to 131 pg/ml (113 pg/ml to 161 pg/ml) at 60 months in women of reproductive age weighing above 55 kg.

Body weight and serum SHBG concentration have been shown to affect systemic levonorgestrel concentration i.e. low body weight and/or a high SHBG level increase levonorgestrel concentration. In women of reproductive age with a low body weight (37 to 55 kg) the median serum concentration of levonorgestrel is about 1.5-fold higher.

In postmenopausal women using Mirena together with non-oral oestrogen treatment, the median serum concentration of levonorgestrel declines from 257 pg/ml (25^th to 75^th percentiles: 186 pg/ml to 326 pg/ml) at 12 months to 149 pg/ml (122 pg/ml to 180 pg/ml) at 60 months. When Mirena is used together with oral oestrogen treatment, the serum levonorgestrel concentration at 12 months is increased to approx. 478 pg/ml (25^th to 75^th percentiles: 341 pg/ml to 655 pg/ml) due to the induction of SHBG by oral oestrogen treatment.

Biotransformation

Levonorgestrel is extensively metabolized. The major metabolites in the plasma are the unconjugated and conjugated forms of 3α, 5β-tetrahydrolevonorgestrel. Based on in vitro and in vivo studies, CYP3A4 is the main enzyme involved in the metabolism of levonorgestrel, CYP2E1, CYP2C19 and CYP2C9 may also be involved, but to a smaller extent

Elimination

The total clearance of levonorgestrel from plasma is approximately 1.0 ml/min/kg. Only trace amounts of levonorgestrel are excreted in unchanged form. The metabolites are excreted with the faeces and urine at an excretion ratio of about 1. The excretion half-life which is mainly represented by metabolites, is about 1 day

The preclinical safety evaluations revealed no special hazard for humans based on studies of safety pharmacology, toxicity, genotoxicity and carcinogenic potential of levonorgestrel. Levonorgestrel is a well-established progestogen with anti-estrogenic 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. The safety evaluation of the elastomer components of the hormone reservoir, polyethylene materials of the product, and combination of elastomer and levonorgestrel, based on both the assessment of genetic toxicology in standard in vitro and in vivo test systems and on biocompatibility tests in mice, guinea pigs, rabbits and in vitro test systems has not revealed bio-incompatibility.

Polydimethylsiloxane elastomer

Polydimethylsiloxane tubing

Polyethylene

Barium sulphate

Iron oxide

None known

Three years

Store in the original package to protect from moisture and direct sunlight.

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

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 envelope is broken, the product inside should be discarded. Special instructions for insertion are in the package. For further information see also Section 4.2, Posology and Method of Administration, Insertion and removal/replacement

Any unused product or waste material should be disposed of in accordance with local requirements.

Bayer Limited

The Atrium

Blackthorn Road

Dublin 18

PA 1410/8/1

Date of first authorisation: 28^th August 1998

Date of last renewal: 28^th August 2008

December 2009