Levonorgestrel 52mg (Intrauterine Delivery System)

Registered South African indications:

• Contraception
• Idiopathic menorrhagia
• Protection from endometrial hyperplasia during oestrogen replacement therapy

Registered South African contraindications

• Hypersensitivity to the active ingredient or any of its excipients
• Known or suspected pregnancy
• Current or recurrent pelvic inflammatory disease
• Lower genital tract infection
• Postpartum endometritis
• Septic (infected) abortion during the past three months
• Cervicitis
• Cervical dysplasia
• Uterine or cervical malignancy
• Undiagnosed abnormal uterine bleeding
• Progestogen-dependent tumours
• Congenital or acquired uterine anomaly including fibroids if they distort the uterine cavity
• Conditions associated with increased susceptibility to infections
• Acute liver disease or liver tumour

Contraindications registered in other jurisdictions

• Hypersensitivity to the active ingredient or any of its excipients
• Known or suspected pregnancy
• Current or recurrent pelvic inflammatory disease
• Lower genital tract infection
• Postpartum endometritis
• Infected abortion during the past three months
• Cervicitis, cervical dysplasia
• Suspected or confirmed uterine or cervical malignancy
• Liver tumour or other acute or severe liver disease
• Congenital or acquired abnormality of the uterus including fibroids if they distort the uterine cavity
• Undiagnosed abnormal uterine bleeding
• Conditions associated with increased susceptibility to infections
• Current or suspected hormone dependent tumours such as breast cancer
• Acute malignancies affecting the blood or leukaemias except when in remission
• Recent trophoblastic disease while hCG levels remain elevated

South African recommendations

Caution in the following patient groups

• Renal impairment
• Elderly

Levonorgestrel IUS 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 ischaemia
• Severe headache
• Jaundice
• Marked increase of blood pressure
• Severe arterial disease such as stroke or myocardial infarction

Vascular effects

• There is no consensus about the possible role of progestogens, as in levonorgestrel IUS, in patients with varicose veins and superficial thrombophlebitis in the causation of venous thromboembolism

Cardiac effects

• Levonorgestrel IUS should 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 delivery system

Blood glucose effects

• Low-dose levonorgestrel may affect glucose tolerance
• Blood glucose concentration should be monitored in diabetic users of levonorgestrel IUS

Breast cancer

• The available data are not sufficient to confirm or refute a risk for breast cancer when levonorgestrel IUS is used in the indication protection from endometrial hyperplasia during oestrogen replacement therapy

Oligo/amenorrhoea

• In women of fertile age, oligomenorrhoea and amenorrhoea develops in 57% and 16% of women respectively
• The possibility of 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 amenorrhoea subjects unless indicated by other signs of pregnancy
• When levonorgestrel IUS is used in combination with continuous oestrogen replacement therapy, a non-bleeding pattern gradually develops in most women during the first year

Pelvic infection

• The insertion tube helps to reduce contamination of the levonorgestrel IUS with micro-organisms during insertion
• The highest rate of pelvic infections occurs during the first month after insertion and decreases later
• Severe infections or sepsis (including group A streptococcal sepsis) can occur following IUD insertion, such as with the levonorgestrel IUS
• If the woman experiences recurrent endometritis or pelvic infections, or if an acute infection is severe or does not respond to treatment within a few days, the levonorgestrel IUS must be removed
• Bacteriological examinations are indicated and monitoring is recommended, even with discrete symptoms indicative of infections

Expulsion

• Symptoms of the partial or complete expulsion of the levonorgestrel IUS 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
• Partial expulsion may decrease the effectiveness of the levonorgestrel IUS
• As the levonorgestrel IUS decreases menstrual flow, an increase of menstrual flow may be indicative of an expulsion
• A displaced levonorgestrel IUS should be removed
• A new system can be inserted at that time
• The woman should be advised how to check the threads of the levonorgestrel IUS

Perforation

• Perforation or penetration of the uterine corpus or cervix by the levonorgestrel IUS may occur, most often during insertion, and may decrease its effectiveness
• If this occurs, the levonorgestrel IUS must be removed
• In a large European prospective comparative non-interventional cohort study in IUD users (N = 61448 women), the incidence of perforation was 1.3 (95% CI: 1.1 to 1.6) per 1000 insertions
• Breastfeeding at the time of insertion and insertion up to 36 weeks after giving birth were associated with an increased risk of perforation
• The risk of perforations may be increased in women with a fixed retroverted uterus

Ectopic pregnancy

• Women with a previous history of ectopic pregnancy, tubal surgery, or pelvic infection carry a higher 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
• In clinical trials, the ectopic pregnancy rate with the levonorgestrel IUS was approximately 0.1% per year
• In a large prospective comparative non-interventional cohort study with an observation period of 1 year, the ectopic pregnancy rate with the levonorgestrel IUS was 0.02%
• This rate is lower than in women not using any contraception (0.3 to 0.5% per year)
• When a woman becomes pregnant with the levonorgestrel IUS in situ, the relative likelihood of ectopic pregnancy is increased

Lost threads

• If the retrieval threads are not visible at the cervix on follow-up examinations, 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 with a suitable instrument
• If they cannot be found, the possibility of expulsion or perforation should be considered
• Ultrasound diagnosis may be used to ascertain the correct position of the system
• If ultrasound is not available or successful, X-ray may be used to locate the levonorgestrel IUS

Ovarian cysts

• Since the contraceptive effect of the levonorgestrel IUS is mainly due to its local effect, 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
• Ovarian cysts have been reported as adverse drug reactions in approximately 7% of women using the levonorgestrel IUS
• Most of these cysts are asymptomatic, although some may be accompanied by pelvic pain or dyspareunia
• In most cases, the cysts disappear spontaneously during two to three months observation
• Should this not happen, continued ultrasound monitoring and other diagnostic/therapeutic measures are recommended
• Surgical intervention may be required

Effects on ability to drive and use machines

• Not known

Recommendations in other jurisdictions

Caution in the following patient groups

• Renal impairment

Medical examination

• A complete personal and family medical history should be taken before insertion, physical examination should be guided by medical history, contraindications, and warnings
• Pulse and blood pressure should be measured, and a bimanual pelvic examination performed to determine uterine orientation
• Pregnancy should be excluded prior to insertion
• Genital infection should be successfully treated before insertion
• Women should be informed that levonorgestrel IUS does not protect against HIV (AIDS) and other sexually transmitted diseases
• A follow-up examination should occur 4 to 6 weeks after insertion to check threads and device position
• Further examinations should be based on clinical indication and the individual woman's needs, not as a routine
• Women should be encouraged to attend cervical and breast screening appropriate for their age
• Levonorgestrel IUS is not for post-coital contraception

Levonorgestrel IUS 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 ischaemia
• 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

Cardiac conditions

• Levonorgestrel IUS may be used with caution in women who have congenital heart disease or valvular heart disease at risk of infective endocarditis

Endometrial pathology

• Irregular bleeding may mask symptoms of endometrial polyps or cancer, requiring consideration of diagnostic measures

Smoking

• In general, women using levonorgestrel IUS should be encouraged to stop smoking

Insertion or removal pain and bleeding

• Insertion and removal may be associated with some pain and bleeding
• In case of difficult insertion, exceptional pain, or bleeding during or after, immediate physical examination and ultrasound are needed to rule out uterine or cervical perforation

Vasovagal attack or seizure

• The procedure may cause fainting (vasovagal reaction) or seizure in epileptic patients. In early signs of a vasovagal attack, insertion may need to be stopped or the system removed
• If a vasovagal attack occurs, the woman should be supine with head lowered and legs elevated to restore cerebral blood flow
• Maintain a clear airway, and have an airway readily available. Persistent bradycardia may be controlled with intravenous atropine. If available, oxygen may be administered

Uterine or cervical perforation

• Perforation may occur, most commonly during insertion, and may not be immediately detected
• 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 in the clinical trial (excluding breastfeeding women) was 0.1%
• A larger study reported an incidence of 1.3 per 1,000 insertions overall
• Breastfeeding at insertion and insertion up to 36 weeks postpartum are associated with increased risk
• Risk may also be increased in postpartum insertions, lactating women, and women with a fixed retroverted uterus
• Re-examination after insertion should follow the guidelines under "Medical examination above," adapted for women with perforation risk factors

Pelvic infection risk

• The highest rate of pelvic infections with copper IUDs occurs in the first month after insertion and decreases later
• Known risk factors include multiple sexual partners, frequent intercourse, and young age
• Pelvic infection can have serious consequences, including impaired fertility and increased ectopic pregnancy risk
• Severe infection or sepsis (including group A streptococcal sepsis) can occur after IUS insertion, although extremely rare

Management of suspected pelvic infection

• For women with symptoms of pelvic infection, bacteriological examinations are indicated, and monitoring with antibiotic treatment is recommended even with mild symptoms
• Levonorgestrel IUS does not need to be removed unless symptoms don't resolve within 72 hours or if the woman desires removal
• Levonorgestrel IUS must be removed in cases of recurrent endometritis or pelvic infection, or if an acute infection is severe

Expulsion

• Incidence was low (<4% of insertions) in contraception clinical trials, similar to other IUDs and IUSs
• Symptoms may include bleeding or pain
• Can occur without the woman noticing, leading to loss of contraceptive protection
• Increased menstrual flow may indicate expulsion as levonorgestrel IUS typically decreases flow
• Risk is increased in women with a history of heavy menstrual bleeding (including those using levonorgestrel IUS for treatment of heavy menstrual bleeding)
• Risk increases gradually with increasing BMI at insertion
• Women should be counselled on expulsion signs, how to check threads, and to contact a healthcare professional if threads cannot be felt
• A barrier contraceptive should be used until levonorgestrel IUS location is confirmed
• Partial expulsion may reduce effectiveness
• A partially expelled levonorgestrel IUS should be removed, and a new one can be inserted at removal if pregnancy is excluded

Lost threads

• If threads are not visible at follow-up, first exclude pregnancy
• Threads may have retracted into the uterus or cervical canal and reappear during the next menses
• If not found, threads may have broken off, the system may have been expelled, or rarely the device may be extra-uterine after perforation
• Ultrasound should be arranged to locate the device, and alternative contraception advised in the meantime
• If ultrasound doesn't locate it and no expulsion evidence, a plain abdominal X-ray should be done to exclude an extra-uterine device

Bleeding irregularities

• Levonorgestrel IUS usually significantly reduces menstrual blood loss within 3 to 6 months of treatment
• Increased menstrual flow or unexpected bleeding may indicate expulsion
• If menorrhagia persists, the woman should be re-examined, and uterine cavity assessment via ultrasound and endometrial biopsy should be considered
• In pre-menopausal women, endometrial pathology should be excluded before insertion due to potential irregular bleeding or spotting in the first months

Pregnancy risk and amenorrhoea

• Consider pregnancy if menstruation doesn't occur within six weeks of the previous one, and exclude expulsion
• Repeated pregnancy tests are unnecessary in amenorrhoeic women unless other symptoms suggest pregnancy
• Oligomenorrhoea and/or amenorrhoea gradually develops in about 20% of users of childbearing potential

Treatment review for menorrhagia

• If a significant reduction in menstrual blood loss isn't achieved within 3 to 6 months, alternative treatments should be considered

Ectopic pregnancy

• The absolute risk of ectopic pregnancy in users of levonorgestrel IUS is low
• However, when a woman becomes pregnant with levonorgestrel IUS 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
• The overall incidence of ectopic pregnancy with levonorgestrel IUS in the clinical study was approximately 0.12 per 100 woman-years
• Women considering levonorgestrel IUS should be counselled on the signs, symptoms, and risks of ectopic pregnancy
• For women who become pregnant while using levonorgestrel IUS, 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 levonorgestrel IUS is unknown
• 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, presenting as enlarged follicles that cannot be clinically distinguished from ovarian cysts
• Most of these follicles are asymptomatic, though some may be accompanied by pelvic pain or dyspareunia
• In a clinical trial for heavy menstrual bleeding, ovarian cysts (symptomatic and asymptomatic) were reported in 9.9% of patients within 12 months of insertion
• In another clinical trial, symptomatic ovarian cysts occurred in approximately 4.5% of subjects using levonorgestrel IUS, with 0.3% discontinuing use due to an ovarian cyst
• In most cases, ovarian cysts disappear spontaneously within two to three months of observation
• If cysts persist, continued ultrasound monitoring and other diagnostic/therapeutic measures are recommended
• Rarely, surgical intervention may be required

Depressed mood and depression

• Depressed mood and depression are well-known undesirable effects of hormonal contraceptive use
• 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 of 54 epidemiological studies reported a slightly increased relative risk (RR = 1.24) of breast cancer diagnosis in women currently using combined oral contraceptives (COCs), mainly oestrogen-progestogen preparations
• The excess risk gradually disappears over 10 years after COC cessation
• 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 compared to the overall risk of breast cancer
• The risk of breast cancer diagnosis in users of progestogen-only methods (POPs, implants, and injectables), including levonorgestrel IUS, is possibly of similar magnitude to that associated with COCs
• However, evidence for progestogen-only contraceptive preparations is based on smaller user populations and is less conclusive than for COCs

Glucose tolerance

• Low-dose levonorgestrel may affect glucose tolerance
• Blood glucose concentrations should be monitored in diabetic users of levonorgestrel IUS

Excipients

• The T-frame of levonorgestrel IUS contains barium sulphate so that it can be seen on X-rays

Effects on ability to drive and use machines

• Levonorgestrel IUS has no known influence on the ability to drive or use machines

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

South African registered indications and dosages

Contraception
Idiopathic menorrhagia
Protection from endometrial hyperplasia during oestrogen replacement therapy

• Intrauterine (IUD): First insertion: 52mg (one device) placed inside the uterine cavity within 7 days of the onset of menstruation; One admin. is effective for 5 years; Replacement: Can be replaced by a new system at any time in the cycle; Can also be inserted immediately after first trimester abortion (see Additional Prescribing Points for more on insertion and removal/replacement)

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The in vivo dissolution rate is about 20µg/24 hours initially and is reduced to about 11µg/24hrs after 5 years. The mean dissolution rate of levonorgestrel is about 14µg/24hrs over the time up to 5 years

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In women under hormonal replacement therapy, levonorgestrel IUS can be used in combination with oral or transdermal oestrogen preparations without progestogens. Levonorgestrel IUS, when inserted according to the insertion instructions, has a failure rate of approximately 0.2% at 1 year and accumulative failure rate of approximately 0.7% at 5 years. The failure rate may increase in case of expulsion or perforation

Not indicated for use in premenarchal children

Pregnancy

South African recommendations

• Contraindicated
• The use of levonorgestrel IUS (LNG-IUS) during an existing or suspected pregnancy is contraindicated
• If the woman becomes pregnant when using LNG-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 LNG-IUS or probing of the uterus may result in spontaneous abortion. If the intrauterine contraceptive cannot be gently removed, termination of pregnancy may be considered
• 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
• Ectopic pregnancy should be excluded. 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 the hormone, the possible occurrence of virilising effects in the foetus should be taken into consideration

Recommendations in other jurisdictions

• Contraindicated
• LNG-IUS is contraindicated during an existing or suspected pregnancy
• In case of an accidental pregnancy with LNG-IUS in situ, ectopic pregnancy should be excluded and the system should be removed as soon as possible, as there is a high risk for pregnancy complications (abortion, preterm labour, infection and sepsis)
• Removal of LNG-IUS or probing of the uterus may also 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:

• 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 LNG-IUS in place

Breastfeeding

South African recommendations

• Safe
• About 0.1% levonorgestrel dose is transferred to the infant during breastfeeding. Progestogen-only methods do not appear to affect the quantity or quality of breast milk
• Non-hormonal contraceptive methods/devices are the methods of choice during lactation
• However, if progestogen only contraception is judged as appropriate for lactating women, LNG-IUS may be used. Uterine bleeding has been reported in women using LNG-IUS during lactation

Recommendations in other jurisdictions

• Safe
• Levonorgestrel is excreted in very small quantities in breast milk after use in LNG-IUS. Since no risk for the child is expected, breastfeeding can be continued during use
• Uterine bleeding has rarely been reported in women using a LNG-IUS during lactation

Fertility

South African recommendations

• Upon removal of LNG-IUS, women usually return to their normal fertility

Recommendations in other jurisdictions

• The use of LNG-IUS does not alter the course of female fertility after removal of the IUS

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

• Liver tumour or other acute or severe liver disease: Contraindicated

South African recommendations

• Caution; no information available
  Levonorgestrel IUS has not been studied in women over the age of 65 years

Recommendations in other jurisdictions

• Not indicated for use in postmenopausal women

Infections and Infestations

Very common

• Vaginal bacterial infections
• Vulvovaginal mycotic infections

Immune System Disorders

Rare

• Hypersensitivity including rash, urticaria and angioedema

Psychiatric Disorders

Common

• Depressive mood
• Nervousness
• Decreased libido

Nervous System Disorders

Common

• Headache
• Migraine
• Presyncope

Uncommon

• Syncope

Vascular Disorders

Common

• Dizziness

Gastrointestinal Disorders

Common

• Abdominal pain/discomfort
• Nausea
• Abdominal distension
• Vomiting

Skin and Subcutaneous Tissue Disorders

Very common

• Acne

Uncommon

• Alopecia
• Hirsutism
• Pruritus
• Eczema
• Chloasma/skin hyperpigmentation

Rare

• Rash
• Urticaria

Musculoskeletal and Connective Tissue Disorders

Common

• Back pain

Pregnancy, Puerperium and Perinatal Conditions

Uncommon

• Ectopic pregnancy

Reproductive System and Breast Disorders

Very common

• Uterine/vaginal bleeding including spotting, oligomenorrhea, amenorrhoea
• Benign ovarian cysts

Common

• Pelvic pain
• Dysmenorrhoea
• Vaginal discharge
• Vulvovaginitis
• Breast tenderness
• Breast pain
• Dyspareunia
• Uterine spasm

Uncommon

• Uterine perforation*
• Pelvic inflammatory disease
• Endometritis
• Cervicitis
• Papanicolaou smear normal, class II

General Disorders and Administration Site Conditions

Very common

• Procedural pain
• Procedural bleeding

Common

• Intrauterine contraceptive device expelled

Uncommon

• Oedema

Investigations

Common

• Weight increased

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*This frequency is based on a large prospective comparative non-interventional cohort study in IUS/IUD users, 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 known to induce drug-metabolising enzymes, specifically cytochrome P450 enzymes
• Anticonvulsants
• Phenobarbital
• Phenytoin
• Carbamazepine
• Anti-infectives
• Griseofulvin
• Fluconazole
• Rifampicin
• Rifabutin
• Nevirapine
• Efavirenz
• Substances known to inhibit drug-metabolising enzymes
• Itraconazole
• Ketoconazole

• Bacteriological examination
• Blood pressure
• Pulse
• Pelvic examination
• Pregnancy status
• Post-insertion examination
• Cervical and breast screening

Specific cases may require

• Blood glucose
• Ultrasound
• Physical examination

Levonorgestrel is a progestogen with anti-oestrogenic activity. Levonorgestrel intrauterine system has mainly local progestogenic effects in the uterine cavity. The high levonorgestrel concentrations in the endometrium down-regulate oestrogen and progesterone receptors, making the endometrium 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 of the levonorgestrel intrauterine system. Thickening of the cervical mucous prevents passage of the sperm through the cervical canal. The local milieu of the uterus and of the ovarian tubes inhibits sperm mobility and function, preventing fertilisation. Ovulation is inhibited in some women.