Contraception.

Treatment of heavy menstrual bleeding. Levosert may be particularly useful in women with heavy menstrual bleeding requiring (reversible) contraception.

Starting treatment

In women of fertile age, Levosert 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.

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.

Contraception:

Levosert is effective for six years in the indication contraception.

Post-partum insertion: To reduce the risk of perforation, postpartum insertions should be postponed until the uterus is fully involuted. Do not insert earlier than six weeks after delivery. If the patient is experiencing significant post-partum bleeding and/or pain then infection or other causes should be excluded before insertion. Levosert can also be inserted immediately after the first trimester abortion.

Heavy menstrual bleeding:

Levosert has a demonstrated efficacy for 3 years for the indication heavy menstrual bleeding. Clinical trial data to support efficacy beyond this are not available. Levosert should be removed or exchanged if heavy or bothersome menstrual bleeding returns or no later than 6 years if used clinically in line with contraceptive effectiveness.

Paediatric population

Levosert has not been studied in patients below 16 years of age. Levosert should not be used before menarche.

Hepatic impairment

Levosert is contraindicated in patients with liver tumour or other acute or severe liver disease (see section 4.3).

Instructions for use and handling

Levosert 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 seal of the sterile package is broken, the product should be discarded (see section 6.6 for disposal instructions).

How to insert Levosert

It is strongly recommended that Levosert should only be inserted by physicians/health care professionals who are experienced in levonorgestrel IUS insertions and/or have undergone sufficient training for levonorgestrel IUS insertion.

In case of difficult insertion and/or exceptional pain or bleeding during or after insertion, please refer to section 4.4.

• Levosert is supplied sterile having been sterilised with ethylene oxide. Do not resterilise. For single use only. Do not use if the inner package is damaged or open. Insert before the last day of the month shown on the label.

• Levosert is inserted with the provided inserter into the uterine cavity by carefully following the insertion instructions.

The following insertion instruction will be provided in the box containing the IUS.

Please read the following instructions for use carefully as there may be some difference in the type of inserter device compared with other intrauterine devices (IUDs) you have used previously.

Description

Conditions for use

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

2. It is strongly recommended that Levosert should only be inserted by physicians/health care professionals who have undergone sufficient training and have read carefully these instructions before Levosert insertion.

3. Levosert is supplied in a sterile pack which should not be opened until required for insertion. The exposed product should be handled with aseptic precautions. Do not use if the inner package is damaged or open.

4. Determine the position (anteversion, retroversion) and size of the uterus by a gynaecological examination. Exclude pregnancy and contraindications.

5. Place a speculum, use appropriate antiseptic solution to clean the vagina and cervix.

6. Use cervical dilators if cervical stenosis is diagnosed. Do not force to overcome resistance. If cervical dilatation is required, consider using analgesics and/or a paracervical block.

7. Grasp the cervix with a Tenaculum forceps and apply a gentle traction in order to straighten alignment of the cervical canal and uterine cavity.

8. Determine the uterine depth by hysterometry. If uterine depth is < 5.5 cm discontinue the procedure.

Preparation for insertion

Insertion of Levosert is now complete.

Important information to consider during or after insertion:

- If you suspect the IUS is not in the correct position:

IMPORTANT!

In case of difficult insertion and/or exceptional pain or bleeding during or after insertion, physical examination and ultrasound should be performed immediately to exclude perforation of the uterine body or cervix. If necessary remove the system and insert a new, sterile system.

Please report any case of uterine perforation or insertion difficulties via the MHRA Yellow Card Scheme (www.mhra.gov.uk/yellowcard) or search for MHRA Yellow Card in the Google Play or Apple App Store.

How to remove Levosert

Levosert is removed by gently pulling on the threads with forceps. If the threads are not visible and the device 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, 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 a week, she is at a risk of pregnancy unless a new system is inserted immediately following removal.

After removal of Levosert, the device 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 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.

- 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;

- Suspected or confirmed uterine or cervical malignancy;

- Liver tumour or other acute or severe liver disease;

- Congenital or acquired abnormality of the uterus including fibroids if they distort the uterine cavity;

- Undiagnosed abnormal uterine bleeding;

- Conditions associated with increased susceptibility to infections;

- Current or suspected hormone dependent tumours such as breast cancer (see section 4.4);

- Acute malignancies affecting the blood or leukaemias except when in remission,

- Recent trophoblastic disease while hCG levels remain elevated;

- Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.

Medical examination

Before insertion, a complete personal and family medical history should be taken. Physical examination should be guided by this and by the contraindications and warnings for use. Pulse and blood pressure should be measured and a bimanual pelvic examination performed to establish the orientation of the uterus. The patient should be re-examined six weeks after insertion and further examinations should be performed where clinically indicated and adapted to the individual woman rather than as routine procedure. Prior to insertion pregnancy should be excluded and genital infection should be successfully treated. Women should be advised that Levosert does not protect against HIV (AIDS) and other sexually transmitted disease (please refer to the section below on pelvic infections).

Women should be encouraged to attend cervical and breast screening as appropriate for their age.

Conditions under which Levosert can be used with caution

Levosert 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 during treatment:

- Migraine, focal migraine with asymmetrical visual loss or other symptoms indicating transient cerebral ischemia

- Unusually severe or unusually frequent headache

- Jaundice

- Marked increase of 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.

Levosert may be used with caution in women who have congenital heart disease or valvular heart disease at risk of infective endocarditis.

Irregular bleedings may mask some symptoms and signs of endometrial polyps or cancer, and in these cases diagnostic measures have to be considered.

In general, women using Levosert should be encouraged to stop smoking.

Insertion / removal warnings and precautions

General information: 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, physical examination and ultrasound should be performed immediately to exclude perforation of the uterine corpus or cervix (see also '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.

Perforation: Perforation of the uterine corpus or cervix may occur, most commonly during insertion, although it may not be detected until sometime later. This may be associated with severe pain and continued bleeding. If perforation is suspected the system should be removed as soon as possible; surgery may be required.

The incidence of perforation during or following Levosert insertion in the clinical trial, which excluded breastfeeding women, was 0.1%

In a large prospective comparative non-interventional cohort study in IUS/IUD users (N = 61,448 women), the incidence of perforation was 1.3 (95% CI: 1.1-1.6) per 1000 insertions in the entire study cohort; 1.4 (95% CI: 1.1-1.8) per 1000 insertions in the cohort for another LNG-IUS and 1.1 (95% CI: 0.7-1.6) per 1000 insertions in the copper IUD cohort.

The study showed that both breastfeeding at the time of insertion and insertion up to 36 weeks after giving birth were associated with an increased risk of perforation (see Table 1). These risk factors were independent of the type of IUS/IUD inserted.

Table 1: Incidence of perforation per 1000 insertions for the entire study cohort, stratified by breastfeeding and time since delivery at insertion (parous women)

Extending the observational period to 5 years in a subgroup of this study (N = 39,009 women inserted with another LNG-IUS or copper IUD, 73% of these women had information available over the complete 5 years of follow-up), the incidence of perforation detected at any time during the entire 5-year period was 2.0 (95% CI: 1.6-2.5) per 1000 insertions. Breast-feeding at the time of insertion and insertion up to 36 weeks after giving birth were confirmed as risk factors also in the subgroup that were followed up for 5 years.

The risk of perforation may be increased in post-partum insertions (see section 4.2), in lactating women and in women with a fixed retroverted uterus.

Re-examination after insertion should follow the guidance given above under the heading "Medical examination" above, which may be adapted as clinically indicated in women with risk factors for perforation.

Pelvic infection: In users of copper IUDs, 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, frequent intercourse and young age. Pelvic infection may have serious consequences as it may impair fertility and increase the risk of ectopic pregnancy. As with other gynaecological or surgical procedures, severe infection or sepsis (including group A streptococcal sepsis) can occur following IUS insertion, although this is extremely rare.

For women using Levosert with 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 Levosert unless the symptoms fail to resolve within the following 72 hours or unless the women wishes Levosert to be removed. Levosert must be removed if the women experiences recurrent endometritis or pelvic infection, or if an acute infection is severe.

Complications leading to failure

Expulsion: In clinical trials with Levosert in the indication contraception, the incidence of expulsion was low (<4% of insertions) and in the same range as reported for other IUDs and IUSs. Symptoms of partial or complete expulsion of Levosert 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 Levosert decreases menstrual flow, increase of menstrual flow may be indicative of an expulsion.

Risk of expulsion is increased in

• Women with history of heavy menstrual bleeding (including women who use Levosert for treatment of heavy menstrual bleeding)

• Women with greater than normal BMI at the time of insertion; this risk increases gradually with increasing BMI

Woman should be counselled on possible signs of expulsion and how to check the threads of Levosert and advised to contact a healthcare professional if the threads cannot be felt. A barrier contraceptive (such as a condom) should be used until the location of Levosert has been confirmed.

Partial expulsion may decrease the effectiveness of Levosert.

A partially expelled Levosert should be removed. A new system can be inserted at the time of removal, provided pregnancy has been excluded.

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 extra-uterine after having perforated the uterus. An 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 extra-uterine device.

Bleeding irregularities

Irregular bleeding: Levosert usually achieves a significant reduction in menstrual blood loss 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 of Levosert.

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. In women of fertile age, oligomenorrhoea and/or amenorrhoea develops gradually in about 20% of the users.

Treatment review advice for menorrhagia: Levosert usually achieves a significant reduction in menstrual blood loss within 3 to 6 months of treatment. If significant reduction in blood loss is not achieved in these time-frames, alternative treatments should be considered.

Other risks during use

Ectopic pregnancy: The absolute risk of ectopic pregnancy in users of levonorgestrel IUS is low. However, when a woman becomes pregnant with Levosert 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 the conducted clinical study, the overall incidence of ectopic pregnancy with Levosert was approximately 0.12 per 100 woman-years. Women considering Levosert should be counselled on the signs, symptoms and risks of ectopic pregnancy. For women who become pregnant while using Levosert, the possibility of an ectopic pregnancy must be considered and evaluated.

Women with a previous history of ectopic pregnancy, tubal surgery or pelvic infection carry an increased risk of ectopic pregnancy. The risk of ectopic pregnancy in women who have a history of ectopic pregnancy and use Levosert is unknown. 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. Ectopic pregnancy may require surgery and may result in loss of fertility.

Ovarian Cysts: 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. Most of these follicles are asymptomatic, although some may be accompanied by pelvic pain or dyspareunia.

In a clinical trial of Levosert that enrolled 280 women presenting with heavy menstrual bleeding of which 141 received Levosert, ovarian cyst (symptomatic and asymptomatic) was reported in 9.9% patients within 12 months of insertion. In a clinical trial of Levosert which enrolled 1,751 subjects, symptomatic ovarian cysts occurred in approximately 4.5% of subjects using Levosert, and 0.3 % of subjects discontinued use of Levosert because of an ovarian cyst.

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.

Depressed mood and depression are well-known undesirable effects of hormonal contraceptive use (see section 4.8). Depression can be serious and is a well-known risk factor for suicidal behaviour and suicide. Women should be advised to contact their physician in case of mood changes and depressive symptoms, including shortly after initiating the treatment.

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 Levosert, 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.

General information

Glucose tolerance: Low-dose levonorgestrel may affect glucose tolerance and blood glucose concentrations should be monitored in diabetic users of Levosert.

Post-coital contraception: Levosert is not for use as a post-coital contraceptive.

The T-frame of Levosert contains barium sulphate so that it can be seen on X-rays.

The metabolism of progestagens may be increased by concomitant use of substances known to induce drug-metabolizing enzymes, specifically cytochrome P450 enzymes, such as anticonvulsants (e.g., phenobarbital, phenytoin, carbamazepine) and anti-infectives (e.g. griseofulvin, rifampicin, rifabutin, nevirapine, efavirenz). On the other hand, substances known to inhibit drug-metabolizing enzymes (e.g. itraconazole, ketoconazole) may increase serum concentrations of levonorgestrel. The influence of these drugs on the contraceptive efficacy of Levosert is not known, but it is not believed to be of major importance due to the local mechanism of action.

Pregnancy: Levosert is not to be used during an existing or suspected pregnancy. In case of an accidental pregnancy with Levosert in situ (see section 5), ectopic pregnancy should be excluded (see section 4.4) and the system should be removed as soon as possible, as there is a high risk for pregnancy complications (abortion, preterm labor, infection and sepsis). Removal of Levosert or probing of the uterus may also result in spontaneous abortion. Should these procedures not be possible or if the woman wishes to continue the pregnancy, the woman should be informed about these risks, and accordingly, such pregnancies should be closely monitored. The woman should be instructed to report all symptoms that suggest complications of the pregnancy, like cramping abdominal pain with fever.

Local exposure to levonorgestrel:

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.

Breastfeeding: Levonorgestrel is excreted in very small quantities in breast milk after use in levonorgestrel IUS. Since no risk for the child is expected, breast feeding can be continued during use of Levosert. Uterine bleeding has rarely been reported in women using a levonorgestrel IUS during lactation.

Fertility: the use of levonorgestrel IUS does not alter the course of female fertility after removal of the IUS.

Levosert has no known influence 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.

Very common undesirable effects (occurring in more than 10% of users) include uterine/vaginal bleeding including spotting, oligomenorrhoea, amenorrhoea (see section 5.1) and benign ovarian cysts.

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 a levonorgestrel IUS. Most of the follicles are asymptomatic and disappear within three months.

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

*This frequency is based on a large prospective comparative non-interventional cohort study in IUS/IUD users, which showed that breast feeding at the time of insertion and insertion up to 36 weeks after giving birth are independent risk factors for perforation (see section 4.4). In clinical trials with levonorgestrel IUS that excluded breast-feeding women the frequency of perforation was "rare".

Infections and infestations

Cases of sepsis (including group A streptococcal sepsis) have been reported following IUS insertion (see section 4.4)

Pregnancy, puerperium and perinatal conditions

When a woman becomes pregnant with Levosert in situ, the relative risk of ectopic pregnancy is increased (see 'Special warnings and precautions for use' and 'Fertility, pregnancy and lactation').

Reproductive system and breast disorders

Cases of breast cancer have been reported in levonorgestrel IUS users (frequency unknown, see section 4.4).

The following adverse reactions have been reported in connection with the insertion or removal procedure of Levosert: pain, bleeding, and insertion-related vasovagal reaction with dizziness or syncope (see section 4.4). The procedure may also precipitate a seizure in patients with epilepsy.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the MHRA Yellow Card Scheme (www.mhra.gov.uk/yellowcard) or search for MHRA Yellow Card in the Google Play or Apple App Store.

Not applicable.

Pharmacotherapeutic group: Intrauterine contraceptives, plastic IUD with progestogen ATC code: G02BA03

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 IUS. This allows a very low daily dosage, as the hormone is released directly into the target organ.

The contraceptive mechanism of action of the levonorgestrel IUS is based mainly on 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.

Clinical Efficacy

Contraception Trial

When inserted according to the insertion instructions, Levosert offers contraceptive protection. Contraceptive efficacy of Levosert was investigated in a large clinical trial. The cumulative pregnancy rate calculated as the Pearl Index (PI) in women aged 16 to 35 years, inclusive, was 0.15 (95% CI: 0.02, 0.55) at the end of year 1 and 0.18 (95% CI: 0.08, 0.33) at the end of year 6.

19% of Levosert users became amenorrhoeic by the end of the first year of use, 27% by the end of the second year of use, 37% by the end of the third year of use, 37% by the end of the fourth year of use, 40% by the end of the fifth year of use, and 40% by the end of the sixth year of use.

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

Heavy Menstrual Bleeding

In the clinical trial evaluating women with heavy menstrual bleeding (≥ 80 mL per menstrual cycle), Levosert achieved a significant reduction in menstrual blood loss within 3 to 6 months of treatment. The volume of menstrual bleeding was decreased by 88% in women with heavy menstrual bleeding by the end of three months of use and 82% reduction was sustained for the duration of the study (12 months). The effect was maintained during the extension phase of the study (up to 36 months). Heavy menstrual bleeding caused by submucosal fibroids may respond less favourably. Reduced bleeding promotes an increase of blood haemoglobin in patients with heavy menstrual bleeding.

The initial in vivo release rate of 20.1 micrograms/day levonorgestrel from Levosert decreases to 17.5 micrograms/day during the first year and 8.6 micrograms /day during the sixth year. Levonorgestrel is delivered directly into the uterine cavity with low plasma concentrations (252 ± 123 pg/mL 7 days after insertion and 93 ± 45 pg/mL after 6 years) resulting in only minor systemic effects.

The pharmacokinetics of levonorgestrel itself have been extensively investigated and reported in the literature. 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.

Non-clinical data reveal no special hazard for humans other than the information already included in other sections of the SmPC. These data are based on conventional studies of safety pharmacology, repeated dose toxicity, genotoxicity, carcinogenic potential and toxicity to reproduction and development.

Polydimethylsiloxane (PDMS) reservoir

Polydimethylsiloxane (PDMS) membrane

Low density polyethylene T-frame with 20-24% barium sulphate

Polypropylene thread

Copper phthalocyanine blue

Not applicable

5 years

Store in the original package. Keep the pouch in the outer carton in order to protect from light.

Levosert IUS with the inserter device is individually packed into a thermoformed blister (polyester) package with a peelable lid (TYVEK-Polyethylene).

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.

Levosert 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 Levosert and inserter should be disposed of in this manner. The outer carton package and the inner blister package can be handled as household waste.