LEVOSERT Intrauterine delivery system (IUS) Ref.[27903] Active ingredients: Levonorgestrel

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 intrauterine devices (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: 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 leading to loss of contraceptive protection. Partial expulsion may decrease the effectiveness of Levosert. As the device decreases menstrual flow, increase of menstrual flow may be indicative of an expulsion. A displaced Levosert should be removed and a new system inserted. The woman should be advised how to check the threads of Levosert and that she should immediately see her doctor if she cannot feel the threads.

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 over 6 years 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 must be removed and termination of the pregnancy should be considered as there is a high risk for pregnancy complications (abortion, infection and sepsis). Removal of Levosert or probing of the uterus may 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

Because of the intrauterine administration and the local exposure to hormone, the possible occurrence of virilising effects in the foetus should be taken into consideration. Clinical experience of the outcomes of pregnancies with levonorgestrel IUS in situ 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 local levonorgestrel IUS use in cases where pregnancy continues to term with the 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.