Source: Medicines & Healthcare Products Regulatory Agency (GB) Revision Year: 2019 Publisher: Bayer plc, 400 South Oak Way, Reading, RG2 6AD
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:
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.
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.
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 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 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.
In clinical trials with Kyleena, the incidence of expulsion was low and in the same range as that reported for other IUDs and IUSs. Symptoms of the partial or complete expulsion of Kyleena may include bleeding or pain. However, partial or complete expulsion can occur without the woman noticing it, leading to decrease or loss of contraceptive protection. As Kyleena typically decreases menstrual bleeding over time, an increase of menstrual bleeding may be indicative of an expulsion.
A partially expelled Kyleena should be removed. A new system can be inserted at that time provided pregnancy has been excluded.
A woman should be advised how to check the threads of Kyleena and to contact her healthcare professional if the threads cannot be felt.
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 1). Both risk factors were independent of the type of IUD inserted.
Table 1. 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 at time of insertion | Not breastfeeding at time of insertion | |
|---|---|---|
| Insertion ≤36 weeks after delivery | 5.6 | 1.7 |
| (95% CI: 3.9-7.9, n=6047 insertions) | (95% CI: 0.8-3.1, n=5927 insertions) | |
| Insertion >36 weeks after delivery | 1.6 | 0.7 |
| (95% CI: 0.0-9.1, n=608 insertions) | (95% CI: 0.5-1.1, 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.
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.
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.
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.
Note: The prescribing information of concomitant medications should be consulted to identify potential interactions.
Interactions can occur with medicinal products that induce microsomal enzymes, which can result in increased clearance of sex hormones.
Substances increasing the clearance of levonorgestrel, e.g.:
Phenytoin, barbiturates, primidone, carbamazepine, rifampicin, and possibly also oxcarbazepine, topiramate, felbamate, griseofulvin, and products containing St. John’s wort.
The influence of these medicinal products on the contraceptive efficacy of Kyleena is not known, but it is not believed to be of major importance due to the local mechanism of action.
Substances with variable effects on the clearance of levonorgestrel, e.g.:
When co-administered with sex hormones, many HIV/HCV protease inhibitors and non-nucleoside reverse transcriptase inhibitors can increase or decrease plasma concentrations of the progestin.
Substances decreasing the clearance of levonorgestrel (enzyme inhibitors):
Strong and moderate CYP3A4 inhibitors such as azole antifungals (e.g. fluconazole, itraconazole, ketoconazole, voriconazole), verapamil, macrolides (e.g. clarithromycin, erythromycin), diltiazem and grapefruit juice can increase plasma concentrations of the progestin.
Non-clinical testing of another levonorgestrel-IUS with the same size silver ring and T-body has demonstrated that a patient can be scanned safely after placement of Kyleena (MR conditional) under the following conditions:
In non-clinical testing, the aforementioned levonorgestrel-IUS produced a temperature rise of equal to or less than 1.8°C at a maximum whole body averaged specific absorption rate (SAR) of 2.9 W/kg, for 15 minutes of MR scanning at 3 T using a transit/receive body coil.
A small amount of imaging artifact may occur if the area of interest is in the same area or relatively close to the position of Kyleena.
The use of a levonorgestrel-releasing intrauterine system does not alter the course of future fertility. Upon removal of the intrauterine system, women return to their normal fertility (see section 5.1).
The insertion of Kyleena in pregnant women is contraindicated (see section 4.3).
If a woman becomes pregnant while using Kyleena ectopic pregnancy should be excluded and timely removal of the system is recommended since any intrauterine contraceptive left in situ may increase the risk of abortion and preterm labour. Removal of Kyleena or probing of the uterus may also result in spontaneous abortion. If the woman wishes to continue the pregnancy and the system cannot be withdrawn, she 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. 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 levonorgestrel, the possible occurrence of virilizing effects in a female fetus should be taken into consideration. Clinical experience of the outcomes of pregnancies under Kyleena treatment is limited due to the high contraceptive efficacy. Women should be informed that, to date, there is no evidence of birth defects caused by a levonorgestrel-releasing intrauterine system use in cases where pregnancy has continued to term with the levonorgestrel-IUS in place.
In general, there appears to be no deleterious effect on infant growth or development when using any progestogen-only method after 6 weeks postpartum. A levonorgestrel-releasing intrauterine system does not affect the quantity or quality of breast milk. Small amounts of progestogen (about 0.1% of the levonorgestrel dose) pass into the breast milk in nursing mothers.
Kyleena has no known influence on the ability to drive or use machines.
The majority of women experience changes in menstrual bleeding pattern after insertion of Kyleena. Over time, the frequency of amenorrhoea and infrequent bleeding increases, and the frequency of prolonged, irregular and frequent bleeding decreases. The following bleeding patterns were observed in clinical trials:
Table 2. Bleeding patterns reported with Kyleena in clinical trials:
| Kyleena | First 90 days | Second 90 days | End of year 1 | End of year 3 | End of year 5 |
|---|---|---|---|---|---|
| Amenorrhoea | <1% | 5% | 12% | 20% | 23% |
| Infrequent bleeding | 10% | 20% | 26% | 26% | 26% |
| Frequent bleeding | 25% | 10% | 4% | 2% | 2% |
| Prolonged bleeding* | 57% | 14% | 6% | 2% | 1% |
| Irregular bleeding | 43% | 25% | 17% | 10% | 9% |
* Subjects with prolonged bleeding may also be included in one of the other categories (excluding amenorrhoea)
The frequencies of Adverse Drug Reactions (ADRs) reported with Kyleena are summarized in the table below. Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness. Frequencies are defined as:
very common (≥1/10),
common (≥1/100 to <1/10),
uncommon (≥1/1,000 to <1/100),
rare (≥1/10,000 to <1/1,000),
very rare (<1/10,000).
Common: Depressed mood/Depression
Very Common: Headache
Common: Migraine
Very Common: Abdominal/pelvic pain
Common: Nausea
Very Common: Acne/Seborrhoea
Common: Alopecia
Uncommon: Hirsutism
Very Common: Bleeding changes including increased and decreased menstrual bleeding, spotting, infrequent bleeding and amenorrhoea, Ovarian cyst*, Vulvovaginitis
Common: Upper genital tract infection, Dysmenorrhoea, Breast pain/discomfort, Device expulsion (complete and partial), Genital discharge
Uncommon: Uterine perforation**
* In clinical trials ovarian cysts had to be reported as AEs if they were abnormal, non-functional cysts and/or had a diameter >3 cm on ultrasound examination.
** This frequency is based on a large prospective comparative non-interventional cohort study with women using another levonorgestrel-IUS and copper IUDs which showed that breastfeeding at the time of insertion and insertion up to 36 weeks after giving birth are independent risk factors for perforation (see section 4.4 under Perforation). In clinical trials with Kyleena that excluded breastfeeding women the frequency of perforation was “rare”.
With the use of levonorgestrel-IUS, cases of hypersensitivity including rash, urticaria and angioedema have been reported.
If a woman becomes pregnant while using Kyleena, the relative likelihood of this pregnancy being ectopic is increased (see section 4.4 under Ectopic Pregnancy).
The removal threads may be felt by the partner during intercourse.
The following ADRs have been reported in connection with the insertion or removal procedure of Kyleena:
Procedural pain, procedural bleeding, insertion-related vasovagal reaction with dizziness or syncope. The procedure may precipitate a seizure in an epileptic patient.
Cases of sepsis (including group A streptococcal sepsis) have been reported following IUD insertion (see section 4.4 under Pelvic Infection).
The safety profile of Kyleena is expected to be the same for adolescents under the age of 18 as for users 18 years and older. For data on safety in adolescents, see section 5.1.
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 Yellow Card Scheme at: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in Google Play or Apple App Store.
Not applicable.
© All content on this website, including data entry, data processing, decision support tools, "RxReasoner" logo and graphics, is the intellectual property of RxReasoner and is protected by copyright laws. Unauthorized reproduction or distribution of any part of this content without explicit written permission from RxReasoner is strictly prohibited. Any third-party content used on this site is acknowledged and utilized under fair use principles.
