Levonorgestrel 19.5mg (Intrauterine Delivery System)

Registered South African indications:

• Contraception for up to 5 years in women 18 years and older

Contraindications

Registered contraindications in South Africa & other jurisdictions

• Hypersensitivity to the active ingredient or any of its excipients
• Pregnancy
• Acute or recurrent pelvic inflammatory disease or conditions associated with increased risk of pelvic infections, including gonorrhoea and other sexually transmitted infection
• Acute cervicitis or vaginitis
• Postpartum endometritis or infected abortion during the past three months
• Cervical neoplasm
• Uterine or cervical malignancy
• Progestogen-dependent tumours
• Abnormal uterine bleeding of unknown aetiology
• 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)
• Acute liver disease or liver tumour

Cautions

Recommendations in South Africa & other jurisdictions

Caution in the following patient groups

• Renal impairment

Medical examination/consultation

• Before insertion of the levonorgestrel IUD, inform the patient of benefits and risks, and perform a physical exam including pelvic and breast examination, as well as cervical smear if needed
• Exclude pregnancy and sexually transmitted diseases; ensure any genital infections are treated prior to insertion
• Assess the position and size of the uterine cavity, and ensure fundal placement for maximum efficacy and reduced risk of expulsion
• Insertion should be performed only by trained and experienced healthcare professionals following correct procedure
• Use with caution after specialist consultation, or consider removal, if the patient has or develops migraine (especially with focal neurological symptoms), severe headache, jaundice, marked increase of blood pressure, or severe arterial disease (such as stroke or myocardial infarction)

Diabetes/glucose tolerance

• Low-dose levonorgestrel may affect glucose tolerance; monitor blood glucose levels in diabetic users

Infrequent bleeding and amenorrhoea

• Infrequent bleeding and/or amenorrhoea may develop gradually during levonorgestrel IUD use, with about 26.4% and 22.6% of users affected at five years, respectively
• Pregnancy should be considered if menstruation does not occur within six weeks of the previous menstrual period; repeat testing is not needed unless other pregnancy signs appear
• Irregular bleeding and spotting are common in the first month after insertion
• If bleeding becomes heavier or more irregular over time, further diagnostic evaluation is advised, as this may indicate endometrial polyps, hyperplasia, or cancer

Pelvic infection

• Pelvic infection, including pelvic inflammatory disease, may occur, especially shortly after levonorgestrel IUD insertion, due to potential bacterial contamination during the procedure
• Patients should be evaluated for risk factors (e.g., multiple sexual partners, STIs, prior history of PID) before insertion
• Pelvic infections can have serious consequences, including impaired fertility and increased risk of ectopic pregnancy
• Severe infections or sepsis (including group A streptococcal sepsis) have been reported after insertion
• The levonorgestrel IUD must be removed if recurrent endometritis, pelvic inflammatory disease, or severe/untreatable infection occurs
• Bacteriological testing and close monitoring are recommended even if symptoms are mild

Expulsion

• Expulsion occurs in approximately 3.5% of users; symptoms may include bleeding or pain, but can also be asymptomatic
• Unnoticed expulsion can lead to decreased or loss of contraceptive protection
• An increase in menstrual bleeding may indicate expulsion, as the levonorgestrel IUD typically reduces menstrual bleeding over time
• A partially expelled device should be removed; a new IUD can be inserted after excluding pregnancy
• Women should be advised to check for the IUD threads and contact their healthcare provider if the threads cannot be felt

Perforation

• Perforation or penetration of the uterine corpus or cervix by the levonorgestrel IUD may occur, most often during insertion, and may reduce contraceptive effectiveness. The device must be removed if perforation occurs
• Insertion during breastfeeding or within 36 weeks postpartum increases the risk of perforation
• The incidence of perforation per 1000 insertions is higher among breastfeeding women and those inserted ≤36 weeks after delivery
• Additional risk may be present in women with a fixed retroverted uterus

Ectopic pregnancy

• Women with a previous history of ectopic pregnancy, tubal surgery, or pelvic infection are at higher risk of ectopic pregnancy
• The possibility of ectopic pregnancy should be considered in cases of lower abdominal pain, especially if associated with missed periods or new bleeding in amenorrhoeic women
• Women who become pregnant while using the levonorgestrel IUD should be evaluated for ectopic pregnancy, as its relative likelihood is increased
• The overall incidence of ectopic pregnancy with the levonorgestrel IUD is approximately 0.20 per 100 woman-years

Lost threads

• If the removal threads are not visible at the cervix during follow-up, exclude unnoticed expulsion and pregnancy
• The threads may have been drawn up into the uterus or cervical canal and could reappear during a subsequent menstrual period
• If pregnancy has been excluded, attempt to locate the threads by gently probing the cervical canal with a suitable instrument
• If threads cannot be found, consider the possibility of expulsion or uterine perforation
• Ultrasound examination should be used to determine the position of the levonorgestrel IUD; if ultrasound is unavailable or unsuccessful, X-ray may be considered to locate the device

Ovarian cysts/enlarged ovarian follicles

• Ovarian cysts or enlarged follicles, which cannot be clinically distinguished from one another, may develop in approximately 22.2% of women using the levonorgestrel IUD
• Most cysts are asymptomatic, but some may be associated with pelvic pain or dyspareunia
• Generally, these cysts resolve spontaneously within two to three months of observation
• If an enlarged follicle does not resolve, ongoing ultrasound monitoring and other diagnostic or therapeutic measures may be required
• Rarely, surgical intervention may be needed

Effects on ability to drive or use machines

• No known influence on driving or machine use

Additional precautions applicable to South Africa

Cardiac disorders

• Use the levonorgestrel IUD with caution in women with congenital or valvular heart disease who are at risk of infective endocarditis

Additional precautions applicable to other jurisdictions

Psychiatric disorders

• Depressed mood and depression may occur with hormonal contraceptive use, including the levonorgestrel IUD
• Depression can be serious and increases the risk of suicidal behaviour and suicide
• Women should be advised to contact a healthcare professional if they experience mood changes or depressive symptoms, including those that arise soon after starting treatment

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

Forms avail. in SA and covered in this monograph: iud

South African registered indications and dosages

Contraception
- For up to 5 years in women 18 years and older

• Intrauterine (IUD): First insertion: 19.5mg (one device) placed inside the uterine cavity within 7 days of the onset of menstruation; Replacement: Can be replaced by a new system at any time in the cycle; Can be also inserted immediately after first trimester abortion (see Additional Prescribing Points for more on insertion and removal/replacement)

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Instructions for use/handling
Levonorgestrel IUD 19.5mg is supplied in a sterile package within an integrated inserter that enables single handed loading. The package should not be opened until required for insertion
The exposed product should be handled using aseptic techniques. If the seal of the sterile package is broken, or appears compromised, the product should not be used. 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 four to twelve weeks after insertion and once a year thereafter, or more frequently if clinically indicated. Levonorgestrel IUD 19.5mg is not for use as a post-coital contraceptive

Not established for use in women below 18 years

Pregnancy

South African recommendations

• Contraindicated
• The insertion of levonorgestrel IUD in pregnant women is contraindicated
• If the woman becomes pregnant when using levonorgestrel IUS, removal of the system is recommended since any intrauterine contraceptive left in situ may increase the risk of abortion and preterm labour
• Removal of levonorgestrel IUD or probing of the uterus may result in spontaneous abortion. Ectopic pregnancy should be excluded. If the woman wishes to continue the pregnancy and the system cannot be withdrawn, the woman 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 local exposure to levonorgestrel, the possible occurrence of virilising effects in a female foetus should be taken into consideration
• Clinical experience of the outcome of pregnancies under levonorgestrel IUS treatment is limited

Recommendations in other jurisdictions

• Contraindicated
• The use of levonorgestrel IUS during an existing or suspected pregnancy is contraindicated
• If the woman becomes pregnant while using levonorgestrel IUS the system should be removed as soon as possible, since any intrauterine contraceptive left in situ may increase the risk of abortion and preterm labour
• Removal of levonorgestrel IUS or probing of the uterus may also result in spontaneous abortion. Ectopic pregnancy should be excluded
• 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
• 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 levonorgestrel IUS in place

Breastfeeding

Recommendations below are applicable to South Africa and other jurisdictions

• Safe
• In general, there appear to be no deleterious effects on infant growth or development when using any progestogen-only method after six weeks post-partum
• Levonorgestrel IUS does not affect the quantity or quality of breast milk. About 0.1% of the levonorgestrel dose passes into the breast milk in nursing mothers

Fertility

Recommendations below are applicable to South Africa and other jurisdictions

• The use of levonorgestrel IUS does not alter the course of future fertility. Upon removal of the levonorgestrel IUS, women usually return to their normal fertility

Recommendations below are applicable to South Africa and other jurisdictions

• Caution; no information available
  Levonorgestrel IUS has not been studied in women with renal impairment

Recommendations below are applicable to South Africa and other jurisdictions

• Acute liver disease or liver tumour: Contraindicated
  Levonorgestrel IUS has not been studied in women with hepatic impairment

Recommendations below are applicable to South Africa and other jurisdictions

• Not indicated for use in postmenopausal women

Psychiatric Disorders

Common

• Depressed mood/Depression
• Decreased libido

Nervous System Disorders

Very common

• Headache

Common

• Migraine

Vascular Disorders

Common

• Dizziness

Gastrointestinal Disorders

Very common

• Abdominal/pelvic pain

Common

• Nausea

Skin and Subcutaneous Tissue Disorders

Very common

• Acne/Seborrhoea

Common

• Alopecia

Uncommon

• Hirsutism

Reproductive System and Breast Disorders

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**

Investigations

Common

• Increased weight

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* 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. In clinical trials with levonorgestrel IUS that excluded breastfeeding women the frequency of perforation was "rare"

• Substances increasing the clearance of levonorgestrel
• Phenytoin
• Barbiturates
• Primidone
• Carbamazepine
• Rifampicin
• Oxcarbazepine
• Topiramate
• Felbamate
• Griseofulvin
• Substances with variable effects on the clearance of levonorgestrel
• HIV/HCV protease inhibitors
• Non-nucleoside reverse transcriptase inhibitors
• Substances decreasing the clearance of levonorgestrel (enzyme inhibitors)
• Strong and moderate CYP3A4 inhibitors
• Azole antifungals
• Fluconazole
• Itraconazole
• Ketoconazole
• Voriconazole
• Verapamil
• Macrolides
• Clarithromycin
• Erythromycin
• Diltiazem

Other interactions

• St. John's wort
• Grapefruit juice

• Bacteriological examination
• Physical examination
• Pelvic examination
• Breast examination
• Pregnancy status
• Sexually transmitted diseases screening
• Post-insertion examination

Specific cases may require

• Blood glucose
• Ultrasound monitoring and other diagnostic/ therapeutic measures
• Cervical smear

Insertion and removal/replacement

• Levonorgestrel IUD 19.5mg is to be inserted into the uterine cavity within seven days of the onset of menstruation. Levonorgestrel IUD 19.5mg can be replaced by a new system at any time in the cycle
• Levonorgestrel IUD 19.5mg can also be inserted immediately after first-trimester abortion. Postpartum insertions should be postponed until the uterus is fully involuted, however not earlier than six weeks after delivery
• If involution is substantially delayed, consider waiting until 12 weeks postpartum
• 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 and ultrasound examination
• Levonorgestrel IUD 19.5mg can be identified by the combination of the visibility of the silver ring on ultrasound and the blue colour of the removal threads
• The T-frame of levonorgestrel IUD 19.5mg contains barium sulphate which makes it visible in X-ray examination
• Levonorgestrel IUD 19.5mg is removed by gently pulling on the thread with a forceps. If the threads are not visible and the system is found to be in the uterine cavity on ultrasound examination, it may be removed using a narrow forceps. This may require dilatation of the cervical canal or surgical intervention
• Levonorgestrel IUD 19.5mg should be removed no later than the end of the fifth year. If the woman wishes to continue using the same method, a new levonorgestrel IUD 19.5mg can be inserted immediately following removal of the original system
• If pregnancy is not desired, the removal should be carried out within seven days of the onset of menstruation, provided the woman is still experiencing regular menses
• If levonorgestrel IUD 19.5mg is removed at some other time during the cycle or the woman does not experience regular menses and the woman has had intercourse within a week, she is at risk of pregnancy
• To ensure continuous contraception a new system should be immediately inserted or an alternative contraceptive method should have been initiated. After removal of levonorgestrel IUD 19.5mg, the system should be examined to ensure that it is intact

Levonorgestrel IUS has mainly local progestogenic effects in the uterine cavity. The high levonorgestrel concentration in the endometrium down-regulates endometrial oestrogen and progesterone receptors. The endometrium becomes relatively insensitive to the circulating estradiol and a strong antiproliferative effect is seen. Morphological changes of the endometrium and a weak local foreign body reaction are observed during use. Thickening of the cervical mucus prevents passage of the sperm through the cervical canal. The local milieu of the uterus and of the fallopian tubes inhibits sperm mobility and function, preventing fertilisation.