unofem HEXAL

Contraception.

Idiopathic menorrhagia. unofem HEXAL may be particularly useful in women with idiopathic menorrhagia requiring (reversible) contraception.

Protection from endometrial hyperplasia during oestrogen replacement therapy.

Emergency contraception within 72 hours of unprotected sexual intercourse or failure of a contraceptive method.

Starting treatment

- Contraception and idiopathic menorrhagia

In women of fertile age, unofem HEXAL 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.

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. unofem HEXAL can also be inserted immediately after the first trimester abortion.

unofem HEXAL is effective for 5 years in the indications for contraception and idiopathic menorrhagia so should be removed after 5 years use. If the user wishes to continue using the same method, a new system can be inserted at the same time, in which case no additional protection is required.

If pregnancy is not desired, the removal should be carried out within 7 days of the onset of menstruation in women of fertile age, provided the woman is experiencing regular menses. If the system 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 (e.g. condoms) starting at least 7 days before the removal.

- Protection from endometrial hyperplasia during oestrogen replacement therapy.

When used for endometrial protection during oestrogen replacement therapy, unofem HEXAL can be inserted at any time in an amenorrhoeic woman, or during the last days of menstruation or withdrawal bleeding.

In the indication for protection from endometrial hyperplasia during oestrogen replacement therapy, clinical data (from clinical trials conducted in women of 18 years and over) beyond 4 years of use are limited. unofem HEXAL should therefore be removed after 4 years.

unofem HEXAL provides the progestogen component of hormone therapy (HRT). Therefore in women receiving HRT, unofem HEXAL can be used in combination with oral or transdermal oestrogen preparations without additional exogenous progestogens. The product information of the oestrogen component of the HRT should be consulted prior to the use of unofem HEXAL as the important risk factors associated with HRT use should be considered, such as the risk of endometrial cancer, breast cancer and venous thromboembolisms.

Instructions for use and handling

Only to be inserted by a trained healthcare professional using aseptic technique.

unofem HEXAL is supplied within an inserter in a sterile package which should not be opened until needed for insertion.).

How to Insert unofem HEXAL

It is strongly recommended that unofem HEXAL should only be inserted by physicians/healthcare professionals who are experienced in unofem HEXAL insertions and/or have undergone sufficient training for unofem HEXAL insertion.

In case of difficult insertion and/or exceptional pain or bleeding during or after insertion, please refer to section 4.4.

- unofem HEXAL is supplied sterile having been sterilised with ethylene oxide. Do not resterilise. For single use only. Do not use if the inner package is damaged or open. Insert before the month and year shown on the label.

- unofem HEXAL is inserted with the provided inserter (figure 1) into the uterine cavity by carefully following the insertion instructions.

Preparation for insertion

- Examine the patient to establish the size and position of the uterus, in order to detect any signs of acute genital infections or other contraindications for the insertion of unofem HEXAL and to exclude pregnancy.

- Insert a speculum, visualise the cervix and then thoroughly cleanse the cervix and vagina with a suitable antiseptic solution.

- Use an assistant as necessary.

- Grasp the anterior lip of the cervix with a tenaculum or other forceps to stabilise the uterus. If the uterus is retroverted, it may be more appropriate to grasp the posterior lip of the cervix. Gentle traction on the forceps can be applied to straighten the cervical canal. The forceps should remain in position and gentle counter traction on the cervix should be maintained throughout the insertion procedure.

- Advance a uterine sound through the cervical canal to the fundus to measure the depth and confirm the direction of the uterine cavity and to exclude any evidence of intrauterine abnormalities (e.g. septum, submucous fibroids) or a previously inserted intrauterine contraceptive which has not been removed. If difficulty is encountered, consider dilatation of the canal. If cervical dilatation is required, consider using analgesics and/or a paracervical block.

Insertion

Removal/ replacement

unofem HEXAL is removed by gently pulling on the 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 or other surgical intervention.

After removal of unofem HEXAL, the system should be checked to ensure it is intact. During difficult removals, single cases have been reported of the hormone cylinder sliding over the horizontal arms and hiding them inside the cylinder. This situation does not require further intervention once completeness of the IUS has been ascertained. The knobs of the horizontal arms usually prevent complete detachment of the cylinder from the T-body.

Information on special populations

Paediatric population

There are no relevant indications for use of unofem HEXAL before menarche.

Geriatric patients

unofem HEXAL has not been studied in women over the age of 65 years.

Patients with hepatic impairment

unofem HEXAL is contraindicated in women with acute liver disease or liver tumour (see

Posology

One tablet should be taken as soon as possible, preferably within 12 hours, and no later than 72 hours after unprotected intercourse.

If vomiting occurs within three hours of taking the tablet, another tablet should be taken immediately.

unofem HEXAL can be used at any time during the menstrual cycle unless menstrual bleeding is overdue.

After using emergency contraception it is recommended to use a barrier method (e.g. condom, diaphragm or cap) until the next menstrual period starts. The use of unofem HEXAL does not contraindicate the continuation of regular hormonal contraception.

Women who have used enzyme-inducing drugs during the last 4 weeks and need emergency contraception are recommended to use a non-hormonal EC, i.e. Cu-IUD or take a double dose of unofem HEXAL (i.e. 2 tablets taken together) for those women unable or unwilling to use Cu-IUD.

Paediatric population: There is no relevant use of unofem HEXAL for children of prepubertal age in the indication emergency contraception

Method of administration

unofem HEXAL should be taken orally.

Patients with renal impairment

unofem HEXAL has not been studied in women with renal impairment.

- Known or suspected pregnancy

- Confirmed or suspected hormone dependent tumours including breast cancer

- Current or recurrent pelvic inflammatory disease

- Cervicitis

- Current genital infection

- Postpartum endometritis, infected abortion during the past three months

- Conditions associated with increased susceptibility to infections

- Cervical dysplasia

- Uterine or cervical malignancy

- Undiagnosed abnormal genital bleeding

- Congenital or acquired abnormality of the uterus including fibroids if they distort the uterine cavity

- Liver tumour or other acute or severe liver disease

- Acute malignancies affecting the blood or leukaemias except when in remission

- Recent trophoblastic disease while hCG levels remain elevated

- Hypersensitivity to the active substance or to any of the excipients.

Active or previous severe arterial disease, such as stroke or myocardial infarction is a contraindication when unofem HEXAL is used in conjunction with an oestrogen for HRT use.

Medical Examination

Before insertion, a complete personal and family medical history should be taken. Physical examination should be guided by this and by the contraindications and warnings for use. Pulse and blood pressure should be measured and a bimanual pelvic examination performed to establish the orientation of the uterus. The patient should be re-examined six weeks after insertion and further examinations should be performed where clinically indicated and adapted to the individual woman rather than as routine procedure. Prior to insertion pregnancy should be excluded and genital infection should be successfully treated. Women should be advised that unofem HEXAL does not protect against HIV (AIDs) and other sexually transmitted disease (please refer to the section below on pelvic infections).

Women should be encouraged to attend cervical and breast screening as appropriate for their age.

For the treatment of postmenopausal symptoms, HRT should only be initiated for symptoms that adversely affect quality of life. In all cases, a careful appraisal of the risks and benefits should be undertaken at least annually and HRT should only be continued as long as the benefit outweighs the risk. The contraindications and warnings for the oestrogen component should also be considered prior to commencing the HRT regimen.

Conditions under which unofem HEXAL can be used with caution

Should any of the following conditions exist or arise for the first time during treatment, removal of the system should be considered:

- Migraine with aura

- Unusually severe or unusually frequent headache

- Jaundice

- Marked increase in blood pressure

- Malignancies affecting the blood or leukaemias in remission

- Use of chronic corticosteroid therapy

- Past history of symptomatic functional ovarian cysts

- ).

- Severe or multiple risk factors for arterial disease

- Thrombotic arterial or any current embolic disease

- Acute venous thromboembolism

In general, women using hormonal contraception should be encouraged to give up smoking.

unofem HEXAL should be used with caution in postmenopausal women with advanced uterine atrophy.

Insertion/removal warnings and precautions

General Information: As the insertion technique is different from other intrauterine devices, special emphasis should be given to training in the correct insertion technique. Instructions for insertion are in the package.

Insertion and removal may be associated with some pain and bleeding. In case of difficult insertion and/or exceptional pain or bleeding during or after insertion, the possibility of perforation should be considered and appropriate steps should be taken, such as performing a physical examination and an ultrasound (see also 'Perforation'). Physical examination alone (including checking of threads) may not be sufficient to exclude partial perforation.

The procedure may precipitate fainting as a vasovagal reaction, or a seizure in an epileptic patient. In the event of early signs of a vasovagal attack, insertion may need to be abandoned or the system removed. The woman should be kept supine, the head lowered and the legs elevated to the vertical position if necessary in order to restore cerebral blood flow. A clear airway must be maintained; an airway should always be at hand. Persistent bradycardia may be controlled with intravenous atropine. If oxygen is available it may be administered.

Perforation: Perforation of the uterine corpus or cervix may occur, most commonly during insertion, although it may not be detected until sometime later. This 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.

In a large prospective comparative non-interventional cohort study in IUS/IUD users (N = 61,448 women), with a 1-year observational period, the incidence of perforation was 1.3 (95% CI: 1.1 - 1.6) per 1000 insertions in the entire study cohort; 1.4 (95% CI: 1.1 - 1.8) per 1000 insertions in the unofem HEXAL cohort and 1.1 (95% CI: 0.7 - 1.6) per 1000 insertions in the copper IUD cohort.

The study showed that both breastfeeding at the time of insertion and insertion up to 36 weeks after giving birth were associated with an increased risk of perforation (see Table 1). Both risk factors were independent of the type of IUS/IUD inserted.

Table 1: Incidence of perforation per 1000 insertions for the entire study cohort observed over 1 year, stratified by breastfeeding and time since delivery at insertion (parous women)

Extending the observational period to 5 years in a subgroup of this study (N = 39,009 women inserted with unofem HEXAL or copper IUD, 73% of these women had information available over the complete 5 years of follow-up), the incidence of perforation detected at any time during the entire 5-year period was 2.0 (95% CI: 1.6 - 2.5) per 1000 insertions. Breastfeeding at the time of insertion and insertion up to 36 weeks after giving birth were confirmed as risk factors also in the subgroup that were followed up for 5 years.

The risk of perforation may be increased in women with a fixed retroverted uterus.

Re-examination after insertion should follow the guidance given above under the heading "Medical examination" above, which may be adapted as clinically indicated in women with risk factors for perforation.

Pelvic infection: The insertion tube helps to prevent unofem HEXAL from contamination with micro-organisms during the insertion and the unofem HEXAL inserter has been designed to minimise the risk of infections. In users of copper intrauterine devices (IUDs), the highest rate of pelvic infections occurs during the first month after insertion and decreases later.

Known risk factors for pelvic inflammatory disease are multiple sexual partners, frequent intercourse and young age. Pelvic infection may have serious consequences as it may impair fertility and increase the risk of ectopic pregnancy.

As with other gynaecological or surgical procedures, severe infection or sepsis (including group A streptococcal sepsis) can occur following IUS insertion, although this is extremely rare.

For women using unofem HEXAL with symptoms and signs suggestive of pelvic infection, bacteriological examinations are indicated and monitoring is recommended, even with discrete symptoms, and appropriate antibiotics should be started. There is no need to remove unofem HEXAL unless the symptoms fail to resolve within the following 72 hours or unless the woman wishes unofem HEXAL to be removed. unofem HEXAL must be removed if the woman experiences recurrent endometritis or pelvic infection, or if an acute infection is severe.

Complications leading to failure

Expulsion: Symptoms of the partial or complete expulsion of any IUS may include bleeding or pain. However, a system can be expelled from the uterine cavity without the woman noticing it. Partial expulsion may decrease the effectiveness of unofem HEXAL. As the system decreases menstrual flow, increase of menstrual flow may be indicative of an expulsion. A displaced unofem HEXAL should be removed and a new system inserted. The woman should be advised how to check the threads of unofem HEXAL.

Lost threads: If the retrieval threads are not visible at the cervix on follow-up examination - first exclude pregnancy. The threads may have been drawn up into the uterus or cervical canal and may reappear during the next menstrual period. If they cannot be found, they may have broken off, the system may have been expelled, or rarely the device may be extrauterine after having perforated the uterus. An ultrasound should be arranged to locate the device and alternative contraception should be advised in the mean time. If an ultrasound cannot locate the device and there is no evidence of expulsion, a plain abdominal X-ray should be performed to exclude an extrauterine device.

Bleeding irregularities

Irregular bleeding: unofem HEXAL usually achieves a significant reduction in menstrual blood loss in 3 to 6 months of treatment. Increased menstrual flow or unexpected bleeding may be indicative of expulsion. If menorrhagia persists then the woman should be re-examined. An assessment of the uterine cavity should be performed using ultrasound scan. An endometrial biopsy should also be considered.

Risk in pre-menopausal women

Because irregular bleeding/spotting may occur during the first months of therapy in pre-menopausal women, it is recommended to exclude endometrial pathology before insertion of unofem HEXAL.

Risk in post-menopausal women

If the woman continues the use of unofem HEXAL inserted earlier for contraception, endometrial pathology has to be excluded if bleeding disturbances appear after commencing oestrogen replacement therapy. If bleeding irregularities develop during a prolonged treatment, appropriate diagnostic measures should also be taken as irregular bleeding may mask symptoms and signs of endometrial polyps or cancer.

When to check for pregnancy in women of child bearing potential: The possibility of pregnancy should be considered if menstruation does not occur within six weeks of the onset of previous menstruation and expulsion should be excluded. A repeated pregnancy test is not necessary in amenorrhoeic subjects unless indicated by other symptoms. In a study in women who used unofem HEXAL for contraception (n=130), oligomenorrhoea and amenorrhoea were reported in 57% and 16% of women respectively at the end of the first year of use.

Treatment review advice for Menorrhagia: unofem HEXAL usually achieves a significant reduction in menstrual blood loss in 3 to 6 months of treatment. If significant reduction in blood loss is not achieved in these time-frames, alternative treatments should be considered.

Other risks during use

Ectopic pregnancy: The absolute risk of ectopic pregnancy in unofem HEXAL users is low. However, when a woman becomes pregnant with unofem HEXAL 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. In a large prospective comparative non-interventional cohort study with an observation period of 1 year, the ectopic pregnancy rate with unofem HEXAL was 0.02%. In clinical trials, the absolute rate of ectopic pregnancy in users of unofem HEXAL was approximately 0.1% per year. This rate is lower than the rate of 0.3-0.5 % per year estimated for women not using any contraception. Women with a previous history of ectopic pregnancy carry a higher risk of a further ectopic pregnancy.

Ovarian Cysts: Since the contraceptive effect of unofem HEXAL 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. Data from clinical trials suggest that ovarian cysts have been reported as an adverse drug reaction in approximately 7% of women using unofem HEXAL, however some published studies have reported a higher incidence of ovarian cysts (which could have been influenced by factors including frequency and criteria of ultrasound scanning, and patient population). Most of these follicles are asymptomatic, although some may be accompanied by pelvic pain or dyspareunia.

In most cases, the ovarian cysts disappear spontaneously during two to three months' observation. Should this not happen, continued ultrasound monitoring and other diagnostic/therapeutic measures are recommended. Rarely, surgical intervention may be required.

Breast cancer:

Risk in pre-menopausal women

A meta-analysis from 54 epidemiological studies reported that there is a slightly increased relative risk (RR = 1.24) of having breast cancer diagnosed in women who are currently using combined oral contraceptives (COCs), mainly using oestrogen-progestogen preparations. The excess risk gradually disappears during the course of the 10 years after cessation of COC use. 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 in relation to the overall risk of breast cancer.

The risk of having breast cancer diagnosed in users of progestogen-only methods (POPs, implants and injectables), including unofem HEXAL, is possibly of similar magnitude to that associated with COC. However, for progestogen-only contraceptive preparations, the evidence is based on much smaller populations of users and so is less conclusive than that for COCs.

Risk in post-menopausal women

The risk of breast cancer is increased in post-menopausal women using systemic (i.e. oral or transdermal) hormone replacement therapy (HRT). This risk is higher with combined oestrogen-progestogen HRT than with oestrogen-only HRT. The risk of breast cancer when unofem HEXAL is prescribed to provide the progestogen component of HRT is not yet known. The product information of the oestrogen component of the treatment should also be consulted for additional information.

General Information

Glucose tolerance: Low-dose levonorgestrel may affect glucose tolerance, and the blood glucose concentration should be monitored in diabetic users of unofem HEXAL.

Post-coital contraception: Limited experience suggests that unofem HEXAL is not suitable for use as a post-coital contraceptive.

unofem HEXAL is not recommended in patients with severe hepatic dysfunction.

Severe malabsorption syndromes, such as Crohn's disease, might impair the efficacy of unofem HEXAL.

unofem HEXAL contains lactose monohydrate. Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicine.

After unofem HEXAL intake, menstrual periods are usually normal and occur at the expected date. They can sometimes occur earlier or later than expected by a few days. Women should be advised to make a medical appointment to initiate or adopt a method of regular contraception. If no withdrawal bleed occurs in the next pill-free period following the use of unofem HEXAL after regular hormonal contraception, pregnancy should be ruled out.

Repeated administration within a menstrual cycle is not advisable because of the possibility of disturbance of the cycle.

unofem HEXAL is not as effective as a conventional regular method of contraception and is suitable only as an emergency measure. Women who present for repeated courses of emergency contraception should be advised to consider long-term methods of contraception.

Use of emergency contraception does not replace the necessary precautions against sexually transmitted diseases.

Limited and inconclusive data suggest that there may be reduced efficacy of unofem HEXAL with increasing body weight or body mass index (BMI). In all women, emergency contraception should be taken as soon as possible after unprotected intercourse, regardless of the woman's body weight or BMI.

There are no known effects on the ability to drive or use machines.

No studies on the effect on the ability to drive and use machines have been reported.

Undesirable 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 uterine/vaginal bleeding including spotting, oligomenorrhoea, amenorrhoea.

The frequency of benign ovarian cysts depends on the diagnostic method used but has been estimated from clinical trial data to occur in 7% of users.

Table 2: Adverse Drug Reactions

* 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 unofem HEXAL that excluded breastfeeding women the frequency of perforation was "rare".

Cases of sepsis (including group A streptococcal sepsis) have been reported following IUD insertion.

When a woman becomes pregnant with unofem HEXAL in situ, the relative risk of ectopic pregnancy is increased

Cases of breast cancer have been reported in unofem HEXAL users.

The following adverse reactions have been reported in connection with the insertion or removal procedure of unofem HEXAL: pain, bleeding and insertion-related vasovagal reaction with dizziness or syncope. The procedure may also precipitate a seizure in patients with epilepsy.

The removal threads may be felt by the partner during intercourse.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the Yellow Card Scheme at: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.

The most commonly reported undesirable effect was nausea. The following undesirable effects were observed in two different studies.

Very common (> 1/10), Common (> 1/100, <1/10), Uncommon (> 1/1,000, <1/100), Rare (> 1/10,000, <1/1,000) and Very rare (<1/10,000), Not known (cannot be estimated from the available data).

*Bleeding patterns may be temporarily disturbed, but most women will have their next menstrual period within 7 days of the expected time.

**If the next menstrual period is more than 5 days overdue, pregnancy should be excluded.

From Post-marketing surveillance additionally, the following adverse events have been reported:

Gastrointestinal disorders

Very rare (<1/10,000): abdominal pain

Skin and subcutaneous tissue disorders

Very rare (<1/10,000): rash, urticaria, pruritus,

Reproductive system and breast disorders

Very rare (<1/10,000): pelvic pain, dysmenorrhoea

General disorders and administration site conditions

Very rare (<1/10,000): face oedema

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the internet at www.mhra.gov.uk/yellowcard.

Not applicable.

Serious undesirable effects have not been reported following acute ingestion of large doses of oral contraceptives. Overdose may cause nausea, and withdrawal bleeding may occur. There are no specific antidotes and treatment should be symptomatic.

ATC Code: G02BA03

Pharmacotherapeutic group: Plastic IUD with progestogen

Levonorgestrel is a progestogen used in gynaecology in various ways: as the progestogen component in oral contraceptives, in hormonal replacement therapy or alone for contraception in minipills and subdermal implants. Levonorgestrel can also be administered directly into the uterine cavity as an intrauterine system. This allows a very low daily dosage, as the hormone is released directly into the target organ.

The contraceptive mechanism of action of unofem HEXAL is based on mainly hormonal effects producing the following changes:

- Prevention of proliferation of the endometrium

- Thickening of the cervical mucus thus inhibiting the passage of sperm

- Suppression of ovulation in some women.

The physical presence of the system in the uterus would also be expected to make a minor contribution to its contraceptive effect.

. The contraceptive efficacy of unofem HEXAL has been studied in 5 major clinical studies with 3330 women using unofem HEXAL. The failure rate (Pearl Index) was approximately 0.2% at 1 year and the cumulative failure rate was approximately 0.7% at 5 years. The failure rate also includes pregnancies due to undetected expulsions and perforation. Similar contraceptive efficacy has been observed in a large post-marketing study with more than 17000 women using unofem HEXAL. Because the use of unofem HEXAL does not require daily intake compliance by the users, the pregnancy rates in “typical use” are similar to those observed in controlled clinical trials (“perfect use”).

unofem HEXAL may be particularly useful for contraception in patients with excessive menstrual bleeding, and can be successfully used in the treatment of idiopathic menorrhagia. Results from three comparative studies indicate that in menorrhagic women, menstrual blood loss decreased by 62-94% at the end of three months and by 71-95% at the end of six months of use. unofem HEXAL appears to have similar effects to endometrial ablation/resection in reducing the menstrual blood loss up to two years. Menorrhagia caused by submucosal fibroids may respond less favourably. Reduced bleeding promotes the increase of blood haemoglobin in patients with menorrhagia.

In idiopathic menorrhagia, prevention of proliferation of the endometrium is the probable mechanism of action of unofem HEXAL in reducing blood loss.

The efficacy of unofem HEXAL in preventing endometrial hyperplasia during continuous oestrogen treatment is the same when oestrogen is administered orally or transdermally. The observed hyperplasia rate under oestrogen therapy alone is as high as 20%. In clinical studies with a total of 634 perimenopausal and postmenopausal users of unofem HEXAL, no cases of endometrial hyperplasia were reported up to four years.

Bleeding Patterns:

Different kinds of bleeding changes (frequent, prolonged or heavy bleeding, spotting, oligomenorrhoea, amenorrhoea) are experienced by all users of unofem HEXAL. In fertile women the average number of spotting days/month decreases gradually from nine to four days during the first six months of use. The percentage of women with prolonged bleeding (more than eight days) decreases from 20% to 3% during the first three months of use. In clinical studies during the first year of use, 17% of women experienced amenorrhoea of at least three months duration.

When used in combination with oestrogen replacement therapy, perimenopausal users of unofem HEXAL may experience spotting and irregular bleeding during the first months of the treatment. The amount of bleeding becomes minimal during the first year, and 30-60% of users are totally free of bleedings.

Pharmacotherapeutic group: Emergency contraceptives, ATC code: G03AD01

Mechanism of action

The precise mode of action of unofem HEXAL is not known.

Pharmacodynamic effects

At the recommended regimen, unofem HEXAL is thought to work mainly by preventing ovulation and fertilisation if intercourse has taken place in the preovulatory phase, when the likelihood of fertilisation is the highest. It may also cause endometrial changes that discourage implantation. unofem HEXAL is not effective once the process of implantation has begun.

Clinical efficacy and safety

Results from a recent clinical study (Lancet 2002; 360: 1803-1810) showed that a 1500 microgram single dose of unofem HEXAL (taken within 72 hours of unprotected sex) prevented 84% of expected pregnancies (compared with 79% when the two 750 microgram tablets were taken 12 hours apart).

At the recommended regimen, unofem HEXAL is not expected to induce significant modification of blood clotting factors, and lipid and carbohydrate metabolism.

There is limited and inconclusive data on the effect of high body weight/high BMI on the contraceptive efficacy. In three WHO studies no trend for a reduced efficacy with increasing body weight/BMI was observed (Table 1), whereas in the two other studies (Creinin et al., 2006 and Glasier et al., 2010) a reduced contraceptive efficacy was observed with increasing body weight or BMI (Table 2). Both meta-analyses excluded intake later than 72 hours after unprotected intercourse (i.e. off-label use of unofem HEXAL) and women who had further acts of unprotected intercourse.

Table 1: Meta-analysis on three WHO studies (Von Hertzen et al., 1998 and 2002; Dada et al., 2010)

Table 2: Meta-analysis on studies of Creinin et al., 2006 and Glasier et al., 2010

Paediatric population

A prospective observational study showed that out of 305 treatments with unofem HEXAL emergency contraceptive tablets, seven women became pregnant resulting in an overall failure rate of 2.3%. The failure rate in women under 18 years (2.6% or 4/153) was comparable to the failure rate in women 18 years and over (2.0% or 3/152).

The active ingredient of unofem HEXAL is levonorgestrel. Levonorgestrel is delivered directly into the uterine cavity. Estimated in vivo release rates for different points in time are provided in table 3. Because of the low plasma concentrations, there are only minor effects on the metabolism.

Table 3: Estimated in vivo release rates for unofem HEXAL:

The pharmacokinetics of levonorgestrel itself have been extensively investigated and reported in the literature. In postmenopausal users of unofem HEXAL who were receiving non-oral concomitant oestrogen, plasma levonorgestrel concentrations have been 276 ±119 pg/ml, 196 ± 87pg/ml and 177 ± 70 pg/ml at 56 weeks, 24 months and 48 months respectively. A half life of 20 hours is considered the best estimate although some studies have reported values as short as 9 hours and others as long as 80 hours. Another important finding, although one in agreement with experience with other synthetic steroids, has been marked differences in metabolic clearance rates among individuals, even when administration was by the intravenous route. Levonorgestrel is extensively bound to proteins (mainly sex hormone binding globulin (SHBG) and extensively metabolised to a large number of inactive metabolites.

unofem HEXAL: orally administered unofem HEXAL is rapidly and almost completely absorbed.

Following ingestion of one tablet of unofem HEXAL 1.5 mg maximum drug serum levels of unofem HEXAL of 18.5 ng/ml were found at 2 hours. After reaching maximum serum levels, the concentration of unofem HEXAL decreased with a mean elimination half-life of about 26 hours.

unofem HEXAL is not excreted in unchanged form but as metabolites. unofem HEXAL metabolites are excreted in about equal proportions with urine and faeces. The biotransformation follows the known pathways of steroid metabolism, the unofem HEXAL is hydroxylated in the liver and the metabolites are excreted as glucuronide conjugates.

No pharmacologically active metabolites are known.

unofem HEXAL is bound to serum albumin and sex hormone binding globulin (SHBG). Only about 1.5% of the total serum levels are present as free steroid, but 65% are specifically bound to SHBG.

The absolute bioavailability of unofem HEXAL was determined to be almost 100% of the dose administered.

About 0.1% of the maternal dose can be transferred via milk to the nursed infant.

Levonorgestrel is a well established progestogen with anti-oestrogenic activity. The safety profile following systemic administration is well documented. A study in monkeys with intrauterine delivery of levonorgestrel for 12 months confirmed local pharmacological activity with good local tolerance and no signs of systemic toxicity. No embryotoxicity was seen in the rabbit following intrauterine administration of levonorgestrel.

Animal experiments with unofem HEXAL have shown virilisation of female foetuses at high doses.

Preclinical data reveal no special hazard for humans based on conventional studies of safety pharmacology, repeat dose toxicity, mutagenicity and carcinogenicity potential, beyond the information included in other sections of the SmPC.

None known

Not applicable.

unofem HEXAL is supplied in a sterile pack which should not be opened until required for insertion. Each system should be handled with aseptic precautions. If the seal of the sterile envelope is broken, the system inside should be disposed of in accordance with the local guidelines for the handling of biohazardous waste. Likewise, a removed unofem HEXAL and inserter should be disposed of in this manner. The outer carton package and the inner blister package can be handled as household waste.

No special requirements.