Special Warning : אזהרת שימוש

4.4   Special warnings and precautions for use

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

Medical examination/consultation

Before insertion, a woman must be informed of the benefits and risks of Kyleena, including the signs and symptoms of perforation and the risk of ectopic pregnancy, see below. A physical examination including pelvic examination and examination of the breasts should be conducted. Cervical smear should be performed as needed, according to healthcare professional’s evaluation. Pregnancy and sexually transmitted diseases should be excluded. Genital infections should be successfully treated prior to insertion. The position of the uterus and the size of the uterine cavity should be determined. Fundal positioning of Kyleena is important in order to maximize the efficacy and reduce the risk of expulsion. The instructions for the insertion should be followed carefully.

Emphasis should be given to training in the correct insertion technique.

Insertion and removal may be associated with some pain and bleeding. The procedure may precipitate a vasovagal reaction (e.g. syncope, or a seizure in an epileptic patient).

A woman should be re-examined 4 to 6 weeks after insertion to check the threads and ensure that the system is in the correct position. Follow-up visits are recommended once a year thereafter, or more frequently if clinically indicated.

Kyleena is not for use as a post-coital contraceptive.

The use of Kyleena for the treatment of heavy menstrual bleeding or protection from endometrial hyperplasia during estrogen replacement therapy has not been established. Therefore it is not recommended for use in these conditions.

Ectopic pregnancy

In clinical trials, the overall incidence of ectopic pregnancy with Kyleena was approximately 0.20 per 100 women-years. Approximately half of the pregnancies that occur during Kyleena use are likely to be ectopic.
Women considering Kyleena should be counselled on the signs, symptoms and risks of ectopic pregnancy.
For women who become pregnant while using Kyleena, 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 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.
Because an ectopic pregnancy may impact future fertility the benefits and risks of using Kyleena should be carefully evaluated on an individual woman basis.

Effects on the menstrual bleeding pattern

Effects on the menstrual bleeding pattern are expected in most users of Kyleena. Those alterations are a result of the direct action of levonorgestrel on the endometrium and may not correlate with the ovarian activity.

Irregular bleeding and spotting are common in the first months of use. Thereafter, the strong suppression of the endometrium results in the reduction of the duration and volume of menstrual bleeding. Scanty flow frequently develops into oligomenorrhoea or amenorrhoea.

In clinical trials, infrequent bleeding and/or amenorrhoea developed gradually. By the end of the fifth year about 26.4% and 22.6% of the users developed infrequent bleeding and/or amenorrhoea, respectively.
Pregnancy should be considered if menstruation does not occur within 6 weeks of the onset of previous menstruation. A repeated pregnancy test is not necessary in subjects who remain amenorrhoeic unless indicated by other signs of pregnancy.

If bleeding becomes heavier and/or more irregular over time, appropriate diagnostic measures should be taken as irregular bleeding may be a symptom of endometrial polyps, hyperplasia or cancer and heavy bleeding may be a sign of unnoticed expulsion of the IUS.

Pelvic infection

Pelvic infection has been reported during use of any IUS or IUD. While Kyleena and the inserter are sterile they may, due to bacterial contamination during insertion, become a vehicle for microbial transport in the upper genital tract. In clinical trials, pelvic inflammatory disease (PID) was observed more frequently at the beginning of Kyleena use, which is consistent with published data for copper IUDs, where the highest rate of PID occurs during the first 3 weeks after insertion and decreases thereafter.

Before electing use of Kyleena, patients should be fully evaluated for risk factors associated with pelvic infection (e.g. multiple sexual partners, sexually transmitted infections, prior history of PID). Pelvic infections such as PID may have serious consequences and may impair fertility and increase the risk of ectopic pregnancy.

As with other gynecological or surgical procedures, severe infection or sepsis (including group A streptococcal sepsis) can occur following IUD insertion, although this is extremely rare.

If a woman experiences recurrent endometritis or pelvic inflammatory disease or if an acute infection is severe or does not respond to treatment, Kyleena must be removed.

Bacteriological examinations are indicated and monitoring is recommended, even with discrete symptoms indicative of infections.

Expulsion

In clinical trials with Kyleena, 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 Kyleena 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. As Kyleena 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
- Women with greater than normal BMI at the time of insertion; this risk increases gradually with increasing BMI

Women should be counselled on possible signs of expulsion and how to check the threads of Kyleena 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 Kyleena has been confirmed.
Partial expulsion may decrease the effectiveness of Kyleena.

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

Perforation

Perforation or penetration of the uterine corpus or cervix by an intrauterine contraceptive may occur, most often during insertion, although it may not be detected until sometime later, and may decrease the effectiveness of Kyleena. In case of a difficult insertion and/or exceptional pain or bleeding during or after insertion, appropriate steps should be taken immediately to exclude perforation, such as physical examination and ultrasound. Such a system must be removed; surgery may be required.

In a large prospective comparative non-interventional cohort study in users of other IUDs (N=61448 women) with a 1-year observational period, 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 of another levonorgestrel-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 2). Both risk factors were independent of the type of IUD inserted.

Table 2: Incidence of perforation per 1000 insertions for the entire study cohort observed over 1 year, stratified by breastfeeding and time since delivery at insertion (parous women) Breastfeeding                      Not breastfeeding at time of insertion               at time of insertion
Insertion ≤ 36 weeks      5.6                                1.7 after delivery            95% CI: 3.9-7.9,                   95% CI: 0.8-3.1, n=6047 insertions)                 n=5927 insertions)

Insertion > 36 weeks       1.6                               0.7 after delivery             (95% CI: 0.0-9.1,                 (95% CI: 0.5-1.1, n=608 insertions)                 n=41910 insertions)

Extending the observational period to 5 years in a subgroup of this study (N=39009 women inserted with another levonorgestrel-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. Breastfeeding 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 perforations may be increased in women with fixed retroverted uterus.

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

Lost threads

If the removal threads are not visible at the cervix on follow-up examinations, unnoticed expulsion and 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 the cervical canal with a suitable instrument. If they cannot be found, the possibility of expulsion or perforation should be considered. Ultrasound examination may be used to ascertain the position of the system. If ultrasound is not available or is not successful, X-ray may be used to locate Kyleena.

Ovarian cysts/enlarged ovarian follicles

Since the contraceptive effect of Kyleena is mainly due to its local effects within the uterus, there is generally no change in ovulatory function, including regular follicular development, oocyte release and follicular atresia 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. Ovarian cysts (including haemorrhagic ovarian cysts and ruptured ovarian cysts) have been reported over the course of the clinical trials as adverse event at least once in approximately 22.2% of women using Kyleena. Most of these cysts are asymptomatic, although some may be accompanied by pelvic pain or dyspareunia.

In most cases, the enlarged follicles resolve spontaneously over two to three months observation. Should an enlarged follicle fail to resolve spontaneously, continued ultrasound monitoring and other diagnostic/ therapeutic measures may be appropriate. Rarely, surgical intervention may be required.

Psychiatric disorders

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.

Effects on Driving

4.7    Effects on ability to drive and use machines

Kyleena has no known influence on the ability to drive or use machines.