Avibela 52 mg Intrauterine System/Device

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

Posology
One unit is inserted into the uterine cavity. AVIBELA is effective for six years in the indications for contraception and heavy menstrual bleeding. Therefore, it should be removed after 6 years of use. 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, AVIBELA can be removed at any time; however, a contraception method should be started prior to removal of AVIBELA. Counsel your patient that she is at risk of pregnancy if she has intercourse in the week prior to removal without use of a backup contraceptive method. Removal may be associated with some pain and/or bleeding or vasovagal reactions (e.g. syncope, bradycardia, or seizure), especially in patients with a predisposition to these conditions.

Starting Treatment
In women of fertile age, AVIBELA 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. AVIBELA can also be inserted immediately after a first trimester abortion. If AVIBELA is not inserted during the first 7 days of the menstrual cycle and if the provider can be reasonably certain the woman is not pregnant, abstinence or a barrier method of contraception (such as condoms and spermicide) should be used for 7 days to prevent pregnancy.

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.

Timing of Insertion
Refer to Table 1 for instructions on when to start use of AVIBELA.

Table 1: When to insert AVIBELA
Starting AVIBELA in women not currently using hormonal or intrauterine contraception
u2022 AVIBELA can be inserted any time the provider can be reasonably certain the woman is not pregnant. Consider the possibility of ovulation and conception prior to initiation of this product
u2022 if AVIBELA is inserted after the first 7 days of the menstrual cycle, the patient should use a barrier method of contraception (such as condoms and spermicide) or abstain from vaginal intercourse for 7 days after insertion to prevent pregnancy.

Switching to AVIBELA from an oral, transdermal or vaginal hormonal contraceptive
u2022 AVIBELA may be inserted at any time.
u2022 may be inserted during the hormone-free interval of the previous method
u2022 if inserted during active use of the previous method, continue that method for seven days after AVIBELA insertion or until the end of the current treatment cycle.
u2022 if using continuous hormonal contraception, discontinue that method seven days after AVIBELA insertion.

Switching to AVIBELA from an injectable progestin contraceptive
u2022 AVIBELA may be inserted at any time
u2022 if AVIBELA is inserted more than 3 months (13 weeks) after the last injection, a barrier method of contraception (such as condoms and spermicide) should also be used for 7 days after insertion.

Switching to AVIBELA from a contraceptive implant or another IUD
u2022 insert AVIBELA on the same day the implant or IUD is removed
u2022 AVIBELA may be inserted at any time during the menstrual cycle.

Inserting AVIBELA after abortion or miscarriage
u2022 First- trimester
u2022 AVIBELA may be inserted immediately after a first-trimester abortion or miscarriage.
u2022 Second- trimester
u2022 do not insert AVIBELA until a minimum of 4 weeks after second-trimester abortion or miscarriage, or until the uterus is fully involuted. If involution is delayed, wait until involution is complete before insertion
u2022 if the woman has not yet had a period, consider the possibility of ovulation and conception occurring prior to insertion of AVIBELA. AVIBELA can be inserted any time the provider can be reasonably certain the woman is not pregnant
u2022 if AVIBELA is not inserted during the first 7 days of the menstrual cycle, a barrier method of contraception should be used or the patient should abstain from vaginal intercourse for 7 days after insertion to prevent pregnancy.

Inserting AVIBELA after childbirth
u2022 do not insert AVIBELA until a minimum of 4 weeks after delivery, or until the uterus is fully involuted. If involution is delayed, wait until involution is complete before insertion
u2022 if the woman has not yet had a period, consider the possibility of ovulation and conception occurring prior to insertion of AVIBELA. AVIBELA can be inserted any time the provider can be reasonably certain the woman is not pregnant
u2022 if AVIBELA is not inserted during the first 7 days of the menstrual cycle, a barrier method of contraception should be used or the patient should abstain from vaginal intercourse for 7 days after insertion to prevent pregnancy
u2022 there appears to be an increased risk of perforation in lactating women.

Paediatric population
AVIBELA has not been studied in patients below 16 years of age. AVIBELA is not indicated for use before menarche.

Special populations
Elderly
AVIBELA has not been studied in elderly women.
Hepatic impairment
AVIBELA is contraindicated in patients with liver tumour or acute or severe liver disease (see section 4.3). AVIBELA has not been studied in women with hepatic impairment.

Method of administration
Instructions for use and handling
AVIBELA is supplied in a tray, sealed with a peel-off lid and is inserted into the uterine cavity with the provided inserter (Figure 1b) by carefully following the insertion instructions. Do not use if the seal of the sterile package is broken or appears compromised. Use strict aseptic techniques throughout the insertion procedure [see section 4.4 u2013 Pelvic infection]. AVIBELA is for single use only.

AVIBELA is contraindicated in the following conditions:
u2022 hypersensitivity to levonorgestrel or to any of the ingredients of AVIBELA listed in section 6.1
u2022 known or suspected pregnancy
u2022 lower genital tract infection
u2022 current or recurrent pelvic inflammatory disease or conditions associated with increased risk of pelvic infections, including gonorrhoea and other sexually transmitted infections
u2022 postpartum endometritis
u2022 infected abortion during the past three months
u2022 acute cervicitis or vaginitis
u2022 cervical dysplasia or neoplasm
u2022 uterine or cervical malignancy
u2022 progestogen-dependent tumours, known or suspected breast cancer or other hormone-sensitive cancer, now or in the past (see section 4.4)
u2022 undiagnosed abnormal uterine bleeding
u2022 congenital or acquired uterine anomaly including fibroids which would interfere with insertion and/or retention of the intrauterine system i.e. if they distort the uterine cavity
u2022 acute or severe liver disease or liver tumour
u2022 a previously inserted IUD that has not been removed
u2022 conditions associated with increased susceptibility to infections
u2022 acute malignancies affecting the blood or leukaemia except when in remission recent trophoblastic disease while human chorionic gonadotropin (hCG) levels remain elevated.

Medical examination
Obtain a complete medical and social history, including partner status, to determine conditions that might influence the selection of an IUD for contraception and/or heavy menstrual bleeding. Before insertion, the woman must be informed of the benefits and risks of AVIBELA. Exclude underlying endometrial pathology (e.g., polyps or cancer) prior to the insertion of AVIBELA in women with persistent or uncharacteristic bleeding because irregular bleeding/spotting is common during the first months of AVIBELA use and may preclude adequate assessment after insertion. AVIBELA is contraindicated in women with uterine bleeding of unknown aetiology. Exclude underlying congenital or acquired uterine anomalies, including fibroids, that distort the uterine cavity and would be incompatible with correct IUD placement. Ensure a previously inserted IUD has been removed prior to insertion of AVIBELA. Assess whether the woman is at increased risk of infection (e.g. leukaemia, acquired immune deficiency syndrome [AIDS], intravenous [IV] substance abuse), or has a history of pelvic inflammatory disease (PID) unless there has been a subsequent intrauterine pregnancy. AVIBELA does not protect against human immunodeficiency virus (HIV)/STI transmission.

Conditions under which AVIBELA can be used with caution
u2022 use AVIBELA with caution after careful assessment if any of the following conditions exist, and consider removal of the IUD if any of them arise during use: migraine, focal migraine with asymmetrical visual loss or other symptoms indicating transient cerebral ischaemia
u2022 exceptionally severe or frequent headache
u2022 marked increase of blood pressure
u2022 severe arterial disease such as stroke or myocardial infarction
u2022 coagulopathy or use of anticoagulants. Consider removing AVIBELA if any of the following conditions arise during use:
u2022 uterine or cervical malignancy
u2022 jaundice.

Vascular effects
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. Symptoms of venous or arterial thrombosis can include: unilateral leg pain and/or swelling; sudden severe pain in the 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; u201cacuteu201d abdomen. Symptoms or signs indicating retinal thrombosis are: unexplained partial or complete loss of vision, onset of proptosis or diplopia, papilledema, or retinal vascular lesions.

There is no consensus about the possible role of progestogens in patients with varicose veins and superficial thrombophlebitis in the causation of venous thromboembolism.

Cardiac effects
AVIBELA 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 women when inserting or removing the intrauterine system. Syncope or bradycardia may occur in some women during insertion or removal of an intrauterine system. In the event of early signs of a vasovagal attack, insertion may need to be abandoned or the system removed.

Blood glucose effects
Low-dose levonorgestrel may affect glucose tolerance, and the blood glucose concentration should be monitored in diabetic users of AVIBELA.

Bleeding irregularities
Use of AVIBELA can alter the menstrual bleeding pattern and may result in spotting, irregular bleeding, heavy bleeding, oligomenorrhea or amenorrhea. During the first three to six months of AVIBELA use, the number of bleeding and spotting days may increase, and irregular bleeding patterns may develop. Thereafter, the number of bleeding and spotting days usually decreases but bleeding may remain irregular. In the AVIBELA contraception clinical trial, amenorrhea developed in approximately 19 % of AVIBELA users 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 the trial, 2,3 % of AVIBELA subjects discontinued due to bleeding complaints.

In the AVIBELA contraception clinical trial, 537 of 538 (99,8%) women evaluated experienced menses after AVIBELA removal. This excludes fourteen women who became pregnant (9 women), had a hysterectomy (3 women), were considered menopausal after removal (1 woman), or had ovulatory dysfunction (1 woman). Increased menstrual flow or unexplained bleeding, especially with increased cramping, may be indicative of expulsion and clinical evaluation should be performed as indicated. If a significant change in bleeding develops during prolonged use, take appropriate diagnostic measures to rule out endometrial pathology. Consider the possibility of pregnancy if menstruation does not occur within six weeks of the onset of a previous menstruation. Once pregnancy has been excluded, repeated pregnancy tests are generally not necessary in amenorrhoeic women unless indicated, for example, by other signs of pregnancy or by pelvic pain.

The effect of hormonal contraceptives may be impaired by medicines which induce liver enzymes which may result in increased clearance of sex hormones. Substances increasing the clearance of levonorgestrel include primidone, barbiturates, phenytoin, carbamazepine, rifampicin and oxcarbazepine, topiramate, felbamate, griseofulvin, rifabutin, nevirapine, efavirenz and products containing St. Johnu2019s wort. The influence of these medicines on the contraceptive efficacy of AVIBELA has not been studied but is not believed to be of major importance due to the mainly local mechanisms of contraceptive action. No drug-drug interaction studies have been conducted with AVIBELA. The contraceptive effect of AVIBELA is mediated via the direct release of levonorgestrel into the uterine cavity and is unlikely to be affected by drug interactions via enzyme induction or inhibition.

Pregnancy
The use of AVIBELA during an existing or suspected pregnancy is contraindicated (see section 4.3). If the woman becomes pregnant with AVIBELA in situ (see section 5), advise a woman of the increased risks for pregnancy complications, including miscarriage, premature labour, premature delivery, infection and sepsis. Ectopic pregnancy should be excluded (see section 4.4) and removal of the system should be considered. Removal of AVIBELA 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. Prenatal care should include counselling about these risks and that she should report immediately any flu-like symptoms, fever, chills, cramping, pain, bleeding, vaginal discharge or leakage of AVIBELA fluid, or any other symptom that suggests complications of the pregnancy.

Clinical experience of the outcomes of pregnancies with levonorgestrel IUD in situ is limited. However, to date, there is no evidence of birth defects caused by local levonorgestrel IUD use in cases where pregnancy continues to term with the IUD in place.

Breastfeeding
Levonorgestrel has been identified in the breast milk of lactating women using IUDs. The quantity and quality of breast milk are however not affected. About 0,1 % of the levonorgestrel dose passes into the breast milk in nursing mothers.

Fertility
The use of AVIBELA does not alter the course of future fertility. Upon removal of the AVIBELA, women usually return to their normal fertility (see section 4.4). In the clinical trial of women using AVIBELA for contraception, 99,8 % of women had a rapid return of menses after IUD removal. This excludes fourteen women who became pregnant (9 women), had a hysterectomy (3 women), were considered menopausal after removal (1 woman), or had ovulatory dysfunction (1 woman). Of 191 women who desired pregnancy after study discontinuation, 79 % conceived within 6 months after removal of AVIBELA, and 85 % conceived within 12 months after removal of AVIBELA.

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

a. Summary of the safety profile
Side-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 vaginal bacterial infections, vulvovaginal mycotic infections, nausea or vomiting, and acne.

b. Tabulated list of adverse effects
The table below reports adverse reactions assessed as related to 52 mg levonorgestrel intrauterine delivery system by investigator, by MedDRA system organ class (MedDRA SOCs).

Organ System
Very common: u22651/10
Common: u22651/100 to <1/10
Uncommon: u22651/1000 to <1/100
Rare: u22651/10000 to <1/1000
Infections and infestations
Vaginal bacterial infections, vulvovaginal mycotic infections
Pelvic inflammatory disease, endometritis
Psychiatric disorders
Anxiety, depression, mood changes, insomnia, libido decreased
Exacerbation of bipolar disorder, Suicidality
Nervous system disorders
Headache, migraine, presyncope, dizziness, syncope
Gastrointestinal disorders
Abdominal pain/discomfort, abdominal distension, constipation, dyspepsia, diarrhoea, vomiting
Skin and subcutaneous tissue disorders
Acne
Alopecia
Greasy hair, hirsuitism
Musculoskeletal and connective tissue disorders
Back pain, pain in extremity
Pregnancy, puerperium and perinatal conditions
Ectopic pregnancy
Reproductive system and breast disorders
Uterine/ vaginal bleeding including spotting, oligomenorrhea, amenorrhea, menstrual cycle prolonged
Ovarian cysts, dysmenorrhoea, breast tenderness/pain, pelvic discomfort/pain, uterine spasm, vaginal discharge, vulvovaginal dryness/ discomfort, ovarian cyst, menorrhagia, coital bleeding, vaginal odour, vaginal haemorrhage, bleeding menstrual heavy
Parametritis, pelvic pain, salpingo- oophoritis, polymenorrhoea
General disorders and Administration site conditions
Oedema abdomen, peripheral oedema
Investigations
Weight increase, ultrasound ovary abnormal
Injury, poisoning and procedural complications
Procedural bleeding
Intrauterine contraceptive device expelled, intrauterine contraceptive device migration, procedural pain
Perforation
Cases of sepsis (including group A streptococcal sepsis) have been reported following insertions with hormonal IUDs (see section 4.4).

a. Description of selected adverse reactions
Changes in menstrual bleeding
The most common adverse effect of IUDs, like AVIBELA, is a change in menstrual bleeding patterns. The changes may include spotting, shorter or longer menstrual periods, irregular bleeding, oligomenorrhea, amenorrhea, heavy flow, back pain and dysmenorrhoea. The average number of spotting days decreased gradually during the first six months of use.

Combination with estrogen replacement therapy
When used in combination with estrogen replacement therapy, perimenopausal users of AVIBELA may experience spotting and irregular bleeding during the first months of the treatment. A non-bleeding pattern gradually develops in most women during the first year.

Reporting of suspected adverse reactions
Reporting suspected adverse reactions after authorisation of the medicine is important. It allows continued monitoring of the benefit/risk balance of the medicine. Healthcare professionals are requested to report any suspected adverse drug reactions to SAHPRA via the Med Safety APP (Medsafety X SAHPRA) and eReporting platform (who-umc.org) found on SAHPRA website. An email can be sent directly to the company, [email protected], to ensure safety of the product.

Not applicable