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.
None known
Not applicable.
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
| System Organ Class | Common > 1/100 to < 1/10 | Uncommon > 1/1000 to < 1/100 | Rare > 1/10,000 to < 1/1000 | Unknown |
| Immune system disorders | Hypersensitivity including rash, urticaria and angioedema | |||
| Psychiatric disorders | Depressed mood/Depression Nervousness Decreased libido | |||
| Nervous system disorders | Headache Migraine | |||
| Gastrointestinal disorders | Abdominal pain Nausea | Abdominal distension | ||
| Skin and subcutaneous tissue disorders | Acne Hirsutism | Alopecia Pruritus Eczema Chloasma/Skin Hyperpigmentation | Rash | |
| Musculoskeletal, connective tissue and bone disorders | Back pain | |||
| Reproductive system and breast disorders | Ovarian cysts Pelvic pain Dysmenorrhoea Vaginal discharge Vulvovaginitis Breast tenderness Breast pain | Uterine perforation * Pelvic inflammatory disease Endometritis Cervicitis/ Papanicolaou smear normal, class II | ||
| General disorders and administration site conditions | Intrauterine contraceptive device expelled | Oedema | ||
| Investigations | Weight increase | Blood pressure increased |
* 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 Escapelle 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 Escapelle in situ, the relative risk of ectopic pregnancy is increased
Cases of breast cancer have been reported in Escapelle users.
The following adverse reactions have been reported in connection with the insertion or removal procedure of Escapelle: 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).
| System Organ Class | Frequency of adverse reactions | |
| Very common (> 1/10) | Common (> 1/100, <1/10) | |
| Nervous system disorders | Headache | Dizziness |
| Gastrointestinal disorders | Nausea, abdominal pain | Diarrhoea, vomiting |
| Reproductive system and breast disorders | Bleeding not related to menses* | Delay of menses more than 7 days** Irregular menstruation Breast tenderness |
| General disorders and administration site conditions | Fatigue | |
*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.
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 Escapelle 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.
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 Escapelle 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 Escapelle has been studied in 5 major clinical studies with 3330 women using Escapelle. 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 Escapelle. Because the use of Escapelle 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 useâ€).
Escapelle 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. Escapelle 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 Escapelle in reducing blood loss.
The efficacy of Escapelle 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 Escapelle, 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 Escapelle. 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 Escapelle 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 Escapelle is not known.
Pharmacodynamic effects
At the recommended regimen, Escapelle 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. Escapelle 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 Escapelle (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, Escapelle 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 Escapelle) 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)
| BMI (kg/m2) | Underweight 0 - 18.5 | Normal 18.5 - 25 | Overweight 25 - 30 | Obese > 30 |
| N total | 600 | 3952 | 1051 | 256 |
| N pregnancies | 11 | 39 | 6 | 3 |
| Pregnancy rate | 1.83% | 0.99% | 0.57% | 1.17% |
| Confidence interval | 0.92 - 3.26 | 0.70 - 1.35 | 0.21 - 1.24 | 0.24 - 3.39 |
Table 2: Meta-analysis on studies of Creinin et al., 2006 and Glasier et al., 2010
| BMI (kg/m2) | Underweight 0 - 18.5 | Normal 18.5 - 25 | Overweight 25 - 30 | Obese > 30 |
| N total | 64 | 933 | 339 | 212 |
| N pregnancies | 1 | 9 | 8 | 11 |
| Pregnancy rate | 1.56% | 0.96% | 2.36% | 5.19% |
| Confidence interval | 0.04 - 8.40 | 0.44 - 1.82 | 1.02 - 4.60 | 2.62 - 9.09 |
Paediatric population
A prospective observational study showed that out of 305 treatments with Escapelle 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 Escapelle 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 Escapelle:
| Time | Estimated in vivo release rate [micrograms per day] |
| Initial | 20 |
| 1 year after insertion | 18 |
| 4 years after insertion | 12 |
| 5 years after insertion | 10 |
The pharmacokinetics of levonorgestrel itself have been extensively investigated and reported in the literature. In postmenopausal users of Escapelle 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.
Escapelle: orally administered Escapelle is rapidly and almost completely absorbed.
Following ingestion of one tablet of Escapelle 1.5 mg maximum drug serum levels of Escapelle of 18.5 ng/ml were found at 2 hours. After reaching maximum serum levels, the concentration of Escapelle decreased with a mean elimination half-life of about 26 hours.
Escapelle is not excreted in unchanged form but as metabolites. Escapelle metabolites are excreted in about equal proportions with urine and faeces. The biotransformation follows the known pathways of steroid metabolism, the Escapelle is hydroxylated in the liver and the metabolites are excreted as glucuronide conjugates.
No pharmacologically active metabolites are known.
Escapelle 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 Escapelle 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.
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.
Escapelle 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 Escapelle 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.
