Mirena 52 mg

Interactions with herbal products have not been established.

The effect of MIRENA on the ability to drive or to use machines has not been studied. Patients should be advised not to drive or use machines until they know how they react to MIRENA.

Interactions with food have not been established.

The effect of hormonal contraceptives may be impaired by drugs which induce liver enzymes, including primidone, barbiturates, phenytoin, carbamazepine, rifampicin and griseofulvin. The influence of these drugs on the efficacy of MIRENA (levonorgestrel-releasing intrauterine system) has not been studied, but it is not believed to be of major importance due to the local action of MIRENA.

Interactions with laboratory tests have not been established.

Pathologists should be advised of MIRENA therapy when specimens obtained from surgical procedures and Pap smears are submitted for examination.

The use of sanitary pads is recommended. If tampons are used, they should be changed carefully to avoid inadvertently pulling the MIRENA removal threads.

Visualize the cervix with the aid of a speculum and thoroughly cleanse the cervix and vagina with a suitable antiseptic solution.

Following insertion into the uterine cavity, MIRENA (levonorgestrel-releasing intrauterine system) is effective for up to five years. The in vivo dissolution rate is approximately 20 μg levonorgestrel per day initially, and diminishes over time to approximately 11 μg per day after five years. The mean dissolution rate is approximately 14 μg per day over five years.

If after 5 years, continued use of MIRENA is desired a new MIRENA system should be inserted immediately after the old one is removed.

Symptoms of the partial or complete expulsion of MIRENA may include bleeding or pain, however, a system may be expelled from the uterine cavity without the patient noticing it. Partial expulsion may decrease the effectiveness of MIRENA. Since MIRENA decreases menstrual flow, an increase in menstrual flow may indicate an expulsion. A displaced system should be removed. A new system can be inserted at that time and the patient should be advised on how to check for the presence of the system by feeling for the removal threads.

In a five-year clinical trial, the net cumulative expulsion rate ranged from 3.4 per 100 women in year one to 4.9 in year five. Expulsion rates for MIRENA are comparable to those observed for copper IUDs.

In the same clinical trial, the net cumulative removal rate due to pain ranged from 1.6 per 100 women in the first year to 4.2 in the fifth year.

MIRENA should be removed after 5 years. If the user wishes to continue using MIRENA, a new system can be inserted replacing the old system. If the system has been used for a longer period of time than 5 years, pregnancy should be ruled out before insertion of a new system.

If the removal threads are not visible upon follow-up examination, 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 be located by gently probing with a suitable instrument. If they cannot be found, the system may have been expelled or displaced (see Expulsion). Ultrasound or X-rays may be used to locate a displaced system (MIRENA is radiopaque).

In women of fertile age, MIRENA should be inserted within seven days of the onset of menstruation. MIRENA may be replaced by a new system at any time during the cycle. The system can also be inserted immediately after first trimester abortion. Postpartum insertions should be postponed until the uterus is fully involuted, and 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, physical examination and ultrasound should be performed immediately to exclude perforation.

MIRENA is not suitable for use as a post-coital contraceptive.

Because irregular bleeding is common during the first months of therapy, it is recommended to exclude endometrial pathology before insertion of MIRENA. If bleeding irregularities develop during prolonged treatment, appropriate diagnostic measures should be undertaken.

MIRENA can be removed by gently pulling on the removal threads with forceps. If the threads are not visible and the system is in the uterine cavity, it may be removed using a narrow tenaculum. This may require dilatation of the cervical canal.

The system should be removed after five years of use. If the patient wishes to continue using MIRENA, a new system can be inserted at the time of removal of the old one. If pregnancy is not desired, removal should be carried out during menstruation in women of fertile age provided that there appears to be a menstrual cycle. If the system is removed mid-cycle and the patient has had intercourse within a week, she is at risk of pregnancy unless a new system is inserted immediately following removal.

Insertion and removal may be associated with some pain and bleeding. The procedure may cause a fainting spell or precipitate a seizure in an epileptic patient. It is recommended to wait 24 to 48 hours before having sexual intercourse in the event of general discomfort after insertion of MIRENA.

Before insertion, the patient must be informed of the efficacy, risks and side effects of MIRENA. A physical examination including pelvic examination, examination of the breasts and cervical smear should be performed. Pregnancy and sexually transmitted diseases should be excluded and any genital infections must be successfully treated. The position of the uterus and the size of the uterine cavity should be determined. Fundal positioning of MIRENA is particularly important in order to ensure uniform exposure of the endometrium to the progestogen, prevent expulsion and maximize efficacy. The instructions for insertion should be followed carefully. The patient should be re-examined 4 to 12 weeks after insertion and once-a-year thereafter, or more frequently if clinically indicated.

Open the sterile package completely. Wearing sterile gloves, grab the shaft and rotate the inserter so that the centimetre scale marked on the insertion tube is facing upwards. Release the threads. Make sure that the slider is in the furthermost position (nearest the cervical end). Check that the arms of the system are in a horizontal position (shape of a T). If they are not, align them on a sterile surface.

If there is any doubt that the system is not in the correct position, verify with ultrasound or X-ray. Remove the system if it is not positioned properly in the intrauterine cavity, and insert a new one. A removed system must never be re-inserted.

Because the insertion technique is different from intrauterine devices, it is important that physicians receive training on the correct insertion technique.

Physicians should become thoroughly familiar with the insertion instructions in their entirety before attempting insertion of MIRENA.

MIRENA is supplied in a sterile pouch which should not be opened until required for insertion. It is sterilized with ethylene oxide. Do not resterilize. For single use only. Do not use if the seal of the sterile pouch is broken, or if the pouch is damaged or opened. The exposed product should be handled with aseptic precautions. Insert before the date indicated on the label.

MIRENA is inserted into the uterine cavity using the enclosed inserter within seven days of the onset of menstruation by carefully following these insertion instructions. It can be replaced by a new system at any time during the menstrual cycle.

Conduct a gynecological examination of the patient to establish the size and position of the uterus and to exclude pregnancy or other genital tract contraindications for the use of MIRENA.

MIRENA can be removed by pulling the threads with forceps.

A MIRENA system should not remain in the uterus longer than 5 years.

vaginal discharge, breast tension, mastalgia, uterine perforation, pelvic pain, breast cancer.

lactation nonpuerperal, amenorrhoea.

Additional adverse events reported in clinical trials with MIRENA occurring at a rate of less than 1.0% after either 3 or 60 months of use were:

IUD complication.

Based on approximately 12.7 million insertions, the reporting rate for suspected uterine perforation with MIRENA is 0.21 per 1000 insertions.

Undesirable effects are more common during the first months after insertion and subside during prolonged use. In addition to the adverse events observed in clinical trials, the following undesirable effects have been reported in users of MIRENA, although a causal relationship with MIRENA could not always be confirmed.

expulsion.

hypertension, arrhythmia.

asthma.

dizziness, vertigo, sciatica, migraine.

dysuria, urinary incontinence, changes in micturition frequency.

sweating increased, hypertrichosis, alopecia, eczema, seborrhoea, dry skin, skin disorder, pruritus.

unspecified surgical/medical procedure.

weight increase.

breast neoplasm (benign), vaginal neoplasm (benign).

tendonitis.

otitis media (externa), pneumonia, pharyngitis, infection, fever, mastitis, cystitis.

genital infections.

hirsutism, rash, urticaria, chloasma.

The most commonly occurring adverse events (ie, in greater than 10% of users) that are observed post-marketing with MIRENA (levonorgestrel-releasing intrauterine system) are uterine/vaginal bleeding (including frequent, prolonged or heavy bleeding, spotting, oligomenorrhea, amenorrhea) and benign ovarian cysts.

allergic reaction, allergy.

abdominal bloating.

nervousness, altered mood.

Women using MIRENA who require surgery associated with prolonged immobilization should be followed closely for signs and symptoms of thromboembolism.

Visual changes or changes in contact lens tolerance may occur in users of MIRENA. If this occurs, an ophthalmologist should be consulted. Temporary or permanent cessation of wear may be advised.

Because irregular menstrual bleeding or spotting is common during the first few months of use, endometrial pathology should be excluded prior to insertion of MIRENA. Irregular bleeding patterns in users of MIRENA could mask the signs and symptoms of cervical or endometrial cancer. If bleeding irregularities develop after prolonged use, appropriate diagnostic measures should be undertaken.

Prolonged menstrual bleeding may occur during the first few months, however with continued use, bleeding patterns vary from regular scanty menstruation in some women to oligomenorrhea or amenorrhea in others. Oligomenorrhea or amenorrhea develop gradually in about 20% of users. Reduced bleeding increases the level of blood hemoglobin.

The possibility of pregnancy should be considered if menstruation does not occur after six weeks or more of amenorrhea, following a pattern of regular menses. A pregnancy test is not necessary in amenorrheic women unless indicated by other symptoms.

MIRENA is not to be used during an existing or suspected pregnancy. If a patient becomes pregnant while using MIRENA, removal of the system is recommended since any intrauterine system left in place may increase the risk of abortion and preterm labour. Removal of MIRENA or probing of the uterus may result in spontaneous abortion. If the system cannot be gently removed, termination of the pregnancy may be considered. If the patient wishes to continue the pregnancy and the system cannot be withdrawn, she should be informed about the risks to the infant of premature birth. The course of such a pregnancy should be closely monitored. Ectopic pregnancy should be excluded. The patient should be instructed to report all symptoms that suggest complications of the pregnancy, such as cramping abdominal pain with fever.

Because of the local exposure of the fetus to levonorgestrel, teratogenicity (especially virilization) cannot be completely excluded.

Due to the high contraceptive efficacy of MIRENA, clinical experience with MIRENA during full term pregnancy is limited. However, the patient should be informed that there is no evidence of birth defects associated with MIRENA in cases where pregnancy has continued to term with the system in place.

Steroid hormones may be poorly metabolized in patients with impaired liver function. Acute or chronic disturbances of liver function may necessitate the discontinuation of hormonal contraceptive use until markers of liver function return to normal (see Contraindications).

To date, no studies have examined whether the avoidance of the first-pass effect through the liver, as with non-oral hormonal contraceptives, lessens concerns in women with liver conditions.

Before insertion, the woman must be informed of the efficacy, risks, and side effects of MIRENA. As well, before MIRENA is inserted, a thorough history and physical examination should be performed, including a blood pressure determination. Breasts, liver, extremities, and pelvic organs should be examined. A Papanicolaou smear should be taken if the patient has been sexually active. Pregnancy and sexually transmitted diseases should be excluded, and genital infections have to be successfully treated.

Women should be re-examined 4 to 12 weeks after insertion and at least once a year thereafter, or more frequently if clinically indicated. At each annual visit, examination should include those procedures that were done at the initial visit as outlined above or per recommendations of the Canadian Task Force on the Periodic Health Examination.

See also Dosage and Administration, Medical Examination/Consultation.

Cigarette smoking increases the risk of serious cardiovascular side effects and mortality. Hormonal contraceptives increase this risk, especially with increasing age.

Other women who are independently at high risk for cardiovascular disease include those with diabetes, hypertension, abnormal lipid profile, or a family history of these risk factors.

MIRENA should be used with caution in women who have migraine, focal migraine with asymmetrical visual loss or other symptoms indicating transient cerebral ischemia, severe headache, marked increase in blood pressure or confirmed or suspected hormone dependent neoplasia including breast cancer, or active or previous severe arterial disease such as stroke or myocardial infarction. See Warnings and Precautions, Cardiovascular; Hematologic; Neurologic. Removal of MIRENA should be considered if any of the above conditions occur during use.

Cases of breast cancer have been reported in users of MIRENA. See Warnings and Precautions, Carcinogensis and Mutagenesis.

MIRENA is not the contraceptive method of first choice for young, nulligravid women. Controlled clinical trials were done in previously parous women aged mainly over 18 years.

MIRENA is intended for use only in women of child-bearing age.

MIRENA is not suitable for use as a post-coital contraceptive.

MIRENA is not the contraceptive method of first choice for young, nulligravid women. Controlled clinical trials were done in previously parous women aged mainly over 18 years. Use of this product before menarche is not indicated.

If a significant elevation of blood pressure in previously normotensive or hypertensive subjects occurs at any time during MIRENA use, MIRENA removal should be considered.

Cases of breast cancer have been reported in users of MIRENA. See Adverse Reactions.

The incidence rate of breast cancer in association with MIRENA use has been analyzed in a large Finnish epidemiological study using hospital registry data and cancer diagnoses derived from the Finnish Cancer Registry. In this study, the incidence rate of breast cancer in 17 360 MIRENA users (a total of >58 000 women years with MIRENA, and >150 000 women years of follow-up) was not statistically significantly different compared to the occurrence of breast cancer in 4863 control women. In addition, the incidence rate of breast cancer among these MIRENA users has been compared to the average breast cancer incidence rates in Finland. There was no indication of a statistically significant difference between the MIRENA users and average Finnish female population in any of the age group of women studied (30-54 years). Although these studies do not support a causal relationship between MIRENA and the development of breast cancer, an elevated breast cancer risk cannot be totally excluded, since these studies did not control for confounding factors such as use of oral hormonal contraception by control subjects, genetics and lifestyle and environmental factors such as smoking and alcohol.

Increasing age, inherited mutations, and a strong family history are the most significant risk factors for the development of breast cancer. Other established risk factors include nulliparity, first full-term pregnancy after the age of 30, menarche before the age of 12, never breast-fed a child, and daily alcohol consumption. In some women, the use of hormonal contraceptives may accelerate the growth of an existing but undiagnosed breast cancer. More thorough studies are needed to determine the definitive link between hormonal contraceptive use and the potential risk of breast cancer. There is currently no conclusive evidence of an association between MIRENA use and development of breast cancer or progression of subclinical breast cancer. There is no reason to change prescribing habits at present.

Breast self-examination should be discussed with women receiving hormonal contraceptives. Women should be instructed to notify their physicians whenever any masses are detected.

Patients who have had jaundice should be given hormonal contraceptives only with great care and under close observation. If jaundice develops in a patient using MIRENA, consideration should be given to removing the system. Hormonal contraceptive-related cholestasis has been described in women with a history of pregnancy-related cholestasis. This condition may recur with subsequent hormonal contraceptive use. (See Contraindications.)

MIRENA should be used with caution in women with a history of migraine headache, including migraine with focal neurological symptoms. The onset or exacerbation of migraine or the development of headaches with a new pattern that is recurrent, persistent or severe requires evaluation of the cause and consideration to remove MIRENA. (See Warnings and Precautions, General; Cardiovascular.)

Other generalized risk factors for venous thromboembolism include but are not limited to a personal history, a family history (the occurrence of VTE in a direct relative at a relatively early age may indicate genetic predisposition), severe obesity (body mass index ≥30 kg/m²) and systemic lupus erythematosus. The risk of VTE also increases with age and smoking. The risk of VTE may be temporarily increased with prolonged immobilization, major surgery, or trauma. Also patients with varicose veins and leg cast should be closely monitored.

The inserter provided with MIRENA helps protect the system from contamination with micro-organisms during insertion, thereby minimizing the risk of pelvic infection. The exposed product should be handled with aseptic precautions. See Dosage and Administration, Insertion Instructions. Known risk factors for pelvic inflammatory disease include multiple sexual partners, frequent intercourse and young age. Less common causes of pelvic inflammatory disease include pelvic actinomycosis and pelvic tuberculosis, both of which are extremely rare. There is an increased risk of PID during 20 days following the insertion of IUDs related to the insertion procedure. Thereafter, the risk of PID during the use of IUDs or MIRENA is small. Patients should be advised to report to their physicians promptly if they experience symptoms suggestive of PID.

If recurrent endometritis or pelvic infections are experienced, or if an acute infection does not respond to treatment within a few days, MIRENA must be removed.

Since the contraceptive action of MIRENA is due mainly to its local effect on the uterus, 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.

Enlarged follicles were diagnosed in about 12% of women using MIRENA in one study involving 50 women. In a larger clinical trial (n=2246), the rate of functional ovarian cysts was 1.2 per 100 woman-years. Cysts are usually small and disappear spontaneously within a few months.

Most of these follicles are asymptomatic, although some may be accompanied by pelvic pain or dyspareunia. In most cases, the enlarged follicles disappear spontaneously over a two to three month period. Should this not occur, continued ultrasound monitoring and other diagnostic or therapeutic measures are recommended. Rarely, surgical intervention may be required.

Patients with a history of emotional disturbances, especially the depressive type, may be more prone to have a recurrence of depression while using MIRENA. In cases of a serious recurrence, consideration should be given to removing MIRENA, since the depression may be drug-related.

MIRENA is not indicated for use in postmenopausal women.

An individual benefit-risk assessment in relation to continued use of MIRENA should be carried out in the event of thrombosis. In particular, removal of MIRENA should be considered if venous thromboembolic disease such as deep vein thrombosis or pulmonary embolism occurs. Women with a history of thromboembolic disorders should be made aware of the possibility of a recurrence. See Warnings and Precautions, Cardiovascular and Adverse Reactions, Post-Market Adverse Drug Reactions. There have been postmarketing reports of arterial and venous thromboembolism (ATE, VTE) in women using MIRENA, although a causal relationship with MIRENA could not be clearly established in such cases. Epidemiological studies have indicated that women using progestogen-only oral contraceptives may have a slightly increased risk of venous thromboembolism; however, the results are not statistically significant.

Appropriate diagnostic and therapeutic measures should be undertaken immediately if there are symptoms or signs of thrombosis in users of MIRENA. Symptoms of thromboembolism 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 part of the body, motor disturbances and acute abdomen. Symptoms or signs of retinal thrombosis are: unexplained partial or complete loss of vision, onset of proptosis or diplopia, papilledema, or retinal vascular lesions.

Combination and progestogen-only oral contraceptives, including those containing levonorgestrel, may affect glucose tolerance in some users. Diabetic patients, and those with a family history of diabetes, should be observed closely to detect any alterations in carbohydrate metabolism. Young diabetic patients whose disease is of recent origin, well-controlled and not associated with hypertension or other signs of vascular disease such as ocular fundal changes, should be closely observed. One published clinical study indicated no change in mean daily insulin requirements in women with Type 1 diabetes using MIRENA over a 12-month period.

MIRENA should be used with caution in women with congenital or valvular heart disease who are at risk of infective endocarditis. Antibiotic prophylaxis should be administered to such patients when inserting or removing MIRENA.

There have been very rare postmarket reports of Group A streptococcal sepsis temporally associated with MIRENA insertion.

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 association with missed periods, or if an amenorrheic woman starts bleeding.

Ectopic pregnancies with MIRENA are very rare. However, when a woman becomes pregnant with MIRENA in situ, the relative likelihood of ectopic pregnancy is increased. In one clinical trial with 1821 women using MIRENA, the reported rate of ectopic pregnancy was 0.02 per 100 woman-years.

Combined data from prospective clinical trials with MIRENA reveal an overall rate of ectopic pregnancy of 0.06 per 100 woman-years. A similar ectopic pregnancy rate has been reported in a postmarketing surveillance study with data from over 17 000 women using MIRENA. These rates are lower than the estimated rate of 0.3 to 0.5 per 100 woman-years for women using no contraceptive method.

Perforation or penetration of the uterus or cervix is rare (occurring at a rate of between 1/1000 and 1/10 000), most often occurring during insertion. MIRENA should be removed as soon as possible if this occurs. The number of uterine perforations is linked to the experience of the person inserting the system. The risk of perforation may be increased in post-partum insertions, in lactating women, and in women with a fixed retroverted uterus. To reduce the possibility of perforation, it is important to follow the recommended insertion technique. (See Adverse Reactions, Post-Market Adverse Drug Reactions and Dosage and Administration, Insertion Instructions.)

Hormonal contraceptives are not recommended as the contraceptive method of first choice in breast-feeding women. A published study indicated that during lactation, 0.1% of the daily maternal dose of levonorgestrel could be transferred to the newborn via milk. Although levonorgestrel has been found in the breast milk of women using MIRENA, there does not appear to be a detrimental effect on growth or development of breast-fed infants whose mothers started using the product after six weeks postpartum. Progestogen-only contraceptive methods do not appear to affect the quantity and quality of breast milk.

An individual benefit-risk assessment in relation to continued use of MIRENA should be carried out in the event of arterial thrombosis. In particular, removal of MIRENA should be considered if severe arterial disease such as stroke or myocardial infarction occurs. In addition, MIRENA should be used with caution in patients with a previous history of severe arterial disease such as stroke or myocardial infarction. Women with a history of thromboembolic disorders should be made aware of the possibility of a recurrence. See Warnings and Precautions, Hematologic and Adverse Reactions, Post-Market Adverse Drug Reactions. There have been postmarket reports of cardiovascular events, including myocardial infarction and stroke in women using MIRENA, although a causal relationship with MIRENA could not be clearly established in these cases.

The drug can be detected in plasma within 15 minutes of insertion and maximum concentrations are seen within a few hours. Following intrauterine insertion of MIRENA, the initial release rate of levonorgestrel is 20 μg per day. This provides stable plasma levonorgestrel concentrations which, after the first few weeks, stabilize at between 150 to 200 pg/mL in women of fertile age. After 12, 24 and 60 months of use in young women, plasma levonorgestrel concentrations of 180±66 pg/mL, 192±140 pg/mL, and 159±60 pg/mL were observed, respectively. Because of the low drug levels in plasma, the systemic effects of the progestogen are minimized.

Orally administered levonorgestrel is rapidly and completely absorbed and the absolute bioavailability is about 90%. Levonorgestrel is bound to serum albumin and to sex hormone-binding globulin (SHBG). The relative distribution (free, albumin-bound, SHBG-bound) depends on the SHBG concentration in the serum. Only about 2.5% of the total serum drug levels are present as free steroid, but 47.5% and 50% are bound to SHBG and albumin respectively. For levonorgestrel, a mean volume of distribution of approximately 137 L and a metabolic clearance rate from serum of about 5.7 L/hr were reported.

The intrauterine release of levonorgestrel results in the absorption of the drug into the systemic circulation.

MIRENA (levonorgestrel-releasing intrauterine system) consists of a small polyethylene T-shaped frame with a cylindrical reservoir containing levonorgestrel around the vertical arm of the T frame. After insertion into the uterus, MIRENA releases levonorgestrel continuously for up to five years. Intrauterine administration allows a very low daily dosage, as the hormone is released directly to the target organ. MIRENA contains a total of 52 mg levonorgestrel and has an initial intrauterine release rate of 20 μg per day that diminishes over time to approximately 11 μg per day after 5 years.

The terminal half-life in serum is in the range of 14-20 hours after single-dose administration.

Levonorgestrel is excreted as metabolites at about equal proportion in urine and feces. The metabolites have little or no pharmacological activity. The principal metabolite in urine is tetrahydronorgestrel which accounts for approximately 25% of the radioactivity recovered from the urine after administration of radiolabeled levonorgestrel. A published study indicated that during lactation, 0.1% of the daily maternal dose of levonorgestrel could be transferred to the newborn via milk.

The altered menstrual bleeding pattern that occurs with MIRENA use is a result of the direct action of levonorgestrel on the endometrium and is not due to the suppression of the ovulatory cycle. There is no clear difference in follicle development, ovulation, or estradiol and progesterone production in women with different bleeding patterns. Ovarian function is normal and estradiol levels are maintained even when users of MIRENA are amenorrheic.

The effect of MIRENA on ovarian function depends on plasma levonorgestrel levels achieved. While marked interindividual variation is observed, plasma concentrations are relatively constant within each individual. Patterns of ovarian function in women using MIRENA include normal ovulatory cycles, anovulatory cycles with some inhibition of estradiol production, anovulation with high follicular activity and ovulation with an inadequate luteal phase. In general, anovulatory cycles correlate with higher plasma levels of levonorgestrel, and are more frequent in the first year of MIRENA use. Functional ovarian cysts may occur in relation to pre-ovulatory arrest of follicular development in any woman, and are associated with progestogen-only methods of contraception.

Endometrial histology has been investigated in clinical studies examining the intrauterine release of levonorgestrel at rates ranging from 10 to 40 μg/day. Subjects with anywhere from 3 to 84 months of exposure to continuous levonorgestrel release showed endometrial glandular atrophy and decidualized stroma throughout the period. Local inflammation and focal necrosis compatible with the intrauterine mode of administration were observed.

In one study, cervical histology was evaluated by examining cervical smears from 1,355 women using MIRENA over a period of five years. A total of twelve smears indicated moderate to severe cervical dysplasia. Large multi-centre studies have not detected differences in cervical cytology between women using MIRENA and those using copper IUDs.