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TRESOVELLE 20 MICROGRAMS/24 HOURS INTRAUTERINE DELIVERY SYSTEM
Active substance(s): LEVONORGESTREL / LEVONORGESTREL / LEVONORGESTREL
NAME OF THE MEDICINAL PRODUCT
Tresovelle 20 micrograms/24 hours Intrauterine Delivery System
QUALITATIVE AND QUANTITATIVE COMPOSITION
The active substance is Levonorgestrel.
The intrauterine delivery system contains 52 mg levonorgestrel. The initial release of
levonorgestrel is approximately 20 micrograms per day reducing to approximately 12
micrograms per day after 3 years.
For the full list of excipients, see section 6.1
Levonorgestrel Intrauterine delivery system (IUS).
The product consists of an inserter and levonorgestrel IUS, which is loaded at the tip
of the inserter. Inserter components are an insertion tube, plunger, flange, body and
slider. The device consists of a white or almost white hormone-elastomer core,
mounted on a T-body and covered in opaque tubing, which regulates the release of
levonorgestrel. The T-body has a loop at one end and two arms at the other end.
Removal threads are attached to the loop.
Heavy menstrual bleeding. Tresovelle may be particularly useful in women with heavy
menstrual bleeding requiring (reversible) contraception.
Posology and method of administration
In women of fertile age, Tresovelle 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
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. Tresovelle can
also be inserted immediately after the first trimester abortion.
Tresovelle is effective for three years in the indications for contraception and heavy
menstrual bleeding. Therefore it should be removed after 3 years of 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.
Before insertion, the patient must be informed about the efficacy, risks and sideeffects of Tresovelle. A gynaecological examination, including examination of the
breasts and exclusion of a pregnancy, should be performed. Cervical infection and
sexually transmitted diseases should be excluded. The position of the uterus and the
size of the uterine cavity should be determined. The instructions for insertion should
be followed carefully. The patient should be re-examined six weeks after insertion and
once a year thereafter, or more frequently if clinically indicated.
Tresovelle has not been studied in patients below 16 years of age. There is no relevant
indication for the use of Tresovelle before menarche.
Instructions for use and handling
Tresovelle is supplied in a sterile pack which should not be opened until required for
insertion. The exposed product should be handled with aseptic precautions. If the seal
of the sterile package is broken, the product should be discarded (see Section 6.6 for
How to insert Tresovelle
It is recommended that Tresovelle should only be inserted by physicians/health care
professionals who are experienced in levonorgestrel IUS insertions and/or have
undergone sufficient training for levonorgestrel IUS insertion.
In case of difficult insertion and/or exceptional pain or bleeding during or after
insertion, please refer to section 4.4.
• Tresovelle 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 shown on the label.
• Tresovelle is inserted with the provided inserter (figure 1) into the uterine cavity by
carefully following the insertion instructions.
The following insertion instruction will be provided in the box containing the IUS.
Conditions for use
1. In women of fertile age, Tresovelle is inserted within seven days of the onset
of menstruation. It can be replaced by a new system at any time of the cycle.
physicians/health care professionals who have undergone sufficient training
and have read carefully these instructions before Tresovelle insertion.
3. Tresovelle is supplied in a sterile pack. Do not use if the inner package is
damaged or open.
4. Determine the position (anteversion, retroversion) and size of the uterus by a
gynaecological examination. Exclude pregnancy and contraindications.
5. Place a speculum, use appropriate antiseptic solution to clean the vagina and
6. Use cervical dilators if cervical stenosis is diagnosed. Do not force to
7. Grasp the cervix with a Tenaculum forceps and apply a gentle traction in order
to straighten alignment of the cervical canal and uterine cavity.
8. Determine the uterine depth by hysterometry. If uterine depth is < 5.5 cm
discontinue the procedure.
Preparation for insertion
Introduce the plunger and the IUD in
the insertion tube
Partly open the blister (about 1/3 from
the bottom) and introduce the plunger in
the insertion tube. Extricate the threads
from the flange. Pull the thread to
introduce the IUD into the tube. The
arms of the IUD must stay in an
horizontal plan, parallel to the flat side
of the flange.
Position the lower edge of the flange at
the sounded value
Position the blue flange so as the lower
edge of the flange indicates the value
found by hysterometry. The flat sides of
the flange must always remain parallel
to the arms. This will allow the arms to
open correctly in the uterine cavity.
Adjust the position of the IUD in the
Hold the plunger firmly while pulling
the thread and moving the tube to adjust
the IUD´s position.
The knobs of the lateral arms must be
closely opposed to each other, slightly
above the upper extremity of the
insertion tube (see zoom 1) and the
distal edge of the tube must be aligned
with the first indent of the plunger (see
zoom 2). If the tube is not aligned with
the first indent of the plunger you must
pull the thread more firmly.
Introduce the device in the cervical
canal until the blue flange is in contact
with the cervix
Take the whole device out of the blister,
by holding firmly the plunger and tube
together in the correctly adjusted
Introduce the assembly into the cervical
canal until the blue flange is in contact
with the cervix.
Release the arms of the
Hold the plunger, release the thread and
pull the insertion tube down until its
lower extremity reaches the second
indent of the plunger.
Push the IUD against
To position the IUD in the uterine
cavity, push the insertion tube
simultaneously with the plunger, until
the blue flange is again in contact with
Tresovelle is then correctly placed in
the uterine cavity.
Release the IUD from the tube into the
Without moving the plunger, pull the
insertion tube down to the ring of the
A slight resistance marks the passage of
the bulge of the plunger. Nevertheless
pull down the tube to the ring of the
Tresovelle is then released completely
from the insertion tube.
Remove sequentially the inserter
components and cut the threads
Remove sequentially, first the plunger,
then the insertion tube.
Cut the threads at around 3 cm from the
In case of difficult insertion and/or exceptional pain or bleeding during or after
insertion, physical examination and ultrasound should be performed immediately to
exclude perforation of the uterine body or cervix. If necessary remove the system and
insert a new, sterile system.
Please report to our pharmacovigilance department any case of uterine perforation or
insertion difficulties: firstname.lastname@example.org or +32 (0)4 223 38 55.
How to remove Tresovelle
Tresovelle is removed by gently pulling on the threads with forceps. If the threads are
not visible and the device is in the uterine cavity, it may be removed using a narrow
tenaculum. This may require dilatation of the cervical canal.
After removal of Tresovelle, the device 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.
• Known or suspected pregnancy
• Current or recurrent pelvic inflammatory disease
• Current genital 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 genital bleeding
• Conditions associated with increased susceptibility to infections
• Active or previous severe arterial disease, such as stroke or myocardial infarction
• Current or suspected hormone dependent tumours such as breast cancer (see
• Hypersensitivity to the active substance or to any of the excipients listed in section
• Acute malignancies affecting the blood or leukaemias except when in remission
• Recent trophoblastic disease while hCG levels remain elevated
Special warnings and precautions for use
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 Tresovelle 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.
Conditions under which Tresovelle can be used with caution
Tresovelle 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 with aura
Unusually severe or unusually frequent headache
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
Severe or multiple risk factors for arterial disease
Thrombotic arterial or any current embolic disease
In general, women using Tresovelle should be encouraged to stop smoking.
Insertion / removal warnings and precautions
General Information: 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, physical examination and ultrasound should be performed immediately
to exclude perforation of the uterine corpus or cervix (see also ‘Perforation’). Physical
examination alone (including checking of threads) may not be sufficient to exclude
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), 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 Mirena cohort and 1.1 (95% CI: 0.7 - 1.6) per 1000 insertions in the copper
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). These risk factors were independent of the type of IUS/IUD inserted.
Table 1: Incidence of perforation per 1000 insertions for the entire study cohort,
stratified by breastfeeding and time since delivery at insertion (parous women)
Breastfeeding at time of
Insertion ≤ 36 weeks after 5.6
(95% CI 3.9-7.9; n=6047
Not breastfeeding at time
(95% CI 0.8-3.1; n=5927
Insertion > 36 weeks
(95% CI 0.5-1.1; n=41,910
(95% CI 0.0-9.1; n=608
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: 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.
For women using Tresovelle with symptoms and signs suggestive of pelvic infection
appropriate antibiotics should be started. There is no need to remove Tresovelle unless
the symptoms fail to resolve within the following 72 hours or unless the women
wishes Tresovelle to be removed. Tresovelle must be removed if the women
experiences recurrent endometritis or pelvic infection, or if an acute infection is
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.
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 Tresovelle.
As the device decreases menstrual flow, increase of menstrual flow may be indicative
of an expulsion. A displaced Tresovelle should be removed and a new system
inserted. The woman should be advised how to check the threads of Tresovelle.
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
pregnancy has been excluded, the threads may usually be located by gently probing
with a suitable instrument. If they cannot be found, they may have broken off, or the
device 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 meantime. 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.
Irregular bleeding: Tresovelle usually achieves a significant reduction in menstrual
blood loss within 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.
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 Tresovelle.
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
Treatment review advice for Menorrhagia: Tresovelle usually achieves a significant
reduction in menstrual blood loss within 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 users of levonorgestrel
IUS is low. However, when a woman becomes pregnant with Tresovelle 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 rate
of ectopic pregnancy in users of levonorgestrel IUS is 0.06 per 100 woman-years.
This rate is lower than the rate of 0.3-0.5 per 100 woman-years estimated for women
not using any contraception. The corresponding figure for the copper IUS is 0.12 per
100 woman years. Women with a previous history of ectopic pregnancy carry a higher
risk of a further ectopic pregnancy.
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. 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 Tresovelle, 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
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 oestrogenprogestogen 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 Tresovelle, 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.
Glucose tolerance: Low-dose levonorgestrel may affect glucose tolerance and blood
glucose concentrations should be monitored in diabetic users of Tresovelle.
Interaction with other medicinal products and other forms of interaction
The effects of Tresovelle may be impaired by drugs which induce liver enzymes,
including barbiturates, primidone, phenytoin, carbamazepine, griseofulvin and
rifampicin. No interaction studies on the influence of these drugs on the efficacy of
Tresovelle have been performed.
Fertility, pregnancy and lactation
Pregnancy: Tresovelle is not to be used during an existing or suspected pregnancy. In
case of an accidental pregnancy with Tresovelle in situ (see section 5:
pharmacological properties), ectopic pregnancy should be excluded (see section 4.4)
and the system must be removed and termination of the pregnancy should be
considered as there is a high risk for pregnancy complications (abortion, infection and
sepsis). Removal of Tresovelle or probing of the uterus may result in spontaneous
abortion. Should these procedures not be possible, 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:
Clinical experience of the outcomes of pregnancies with levonorgestrel IUS in situ is
limited. However, to date, there is no evidence of birth defects caused by local
levonorgestrel IUS use in cases where pregnancy continues to term with the IUS in
Breastfeeding: Levonorgestrel is excreted in very small quantities in breast milk after
use in levonorgestrel IUS. Since no risk for the child is expected, breast feeding can
be continued during use of Tresovelle.
Uterine bleeding has rarely been reported in women using a levonorgestrel IUS
Fertility: the use of levonorgestrel IUS does not alter the course of female fertility
after removal of the IUS.
Effects on ability to drive and use machines
Tresovelle has no known influence on the ability to drive or use machines.
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 (see
section 5.1) and benign ovarian cysts.
The frequency of benign ovarian cysts depends on the diagnostic method used, and in
clinical trials enlarged follicles have been diagnosed in 12% of the subjects using a
levonorgestrel IUS. Most of the follicles are asymptomatic and disappear within three
and breast disorders
≥1/100 to <1/10
≥1/1000 to <1/100
≥1/10000 to <1/1000
* This frequency is based on clinical trials that excluded breastfeeding women. In a
large prospective comparative non-interventional cohort study in IUS/IUD users, the
frequency of perforation in women who were breastfeeding or had an insertion up to
36 weeks after delivery was “uncommon” (see section 4.4).
Cases of sepsis (including group A streptococcal sepsis) have been reported following
IUD insertion (see section 4.4).
When a woman becomes pregnant with Tresovelle in situ, the relative risk of ectopic
pregnancy is increased (see ‘Special warnings and precautions for use’ and ‘Fertility,
pregnancy and lactation’).
In addition, cases of breast cancer have been reported in levonorgestrel IUS users
(frequency unknown, see section 4.4).
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 Yellow Card Scheme - Website: www.mhra.gov.uk/yellowcard.
Pharmacotherapeutic group: Intrauterine contraceptives, plastic IUD with
progestogen ATC code: G02BA03
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 IUS. This allows a very low
daily dosage, as the hormone is released directly into the target organ.
The contraceptive mechanism of action of the levonorgestrel IUS is based mainly on
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.
When inserted according to the insertion instructions, Tresovelle has a contraceptive
failure rate of approximately 0.19% (95% Cl: 0.05% - 0.75%) per year. The failure
rate may increase in case of the Levosert expulsion or perforation.
Levonorgestrel IUS may be particularly useful for contraception in patients with
heavy menstrual bleeding, and can be successfully used in the treatment of idiopathic
The volume of menstrual bleeding was decreased by 88% in menorrhagic women by
the end of three months of use. 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 levonorgestrel IUS in reducing blood loss.
Different kinds of bleeding changes (frequent, prolonged or heavy bleeding, spotting,
oligomenorrhea, amenorrhoea) are experienced by all users of levonorgestrel IUS. 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.
The initial release of levonorgestrel from Tresovelle is 20 micrograms/24 hours,
delivered directly into the uterine cavity. Because of the low plasma concentrations,
there are only minor effects on the metabolism.
The pharmacokinetics of levonorgestrel itself have been extensively investigated and
reported in the literature. 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
Preclinical safety data
Non-clinical data reveal no special hazard for humans other than the information
already included in other sections of the SmPC. These data are based on conventional
studies of safety pharmacology, repeated dose toxicity, genotoxicity, carcinogenic
potential and toxicity to reproduction and development.
List of excipients
Polyethylene T-frame with 20-24% barium sulphate
Copper phthalocyanine blue
Special precautions for storage
Store in the original package in order to protect from light.
Nature and contents of container
Tresovelle® IUS is individually packaged into a peel pouch bag. The peel pouches are
made of 2 sheets:
1. PerfecFlex TM (clear Polyester-based Non-forming film with CPT which is a
2. Tyvek® 1073B (polyetylene fiber)
Special precautions for disposal
As the insertion technique is different from intrauterine devices, special emphasis
should be given to training in the correct insertion technique. Special instructions for
insertion are in the package.
Tresovelle 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
Tresovelle and inserter should be disposed of in this manner. The outer carton
package and the inner blister package can be handled as household waste.
MARKETING AUTHORISATION HOLDER
Mithra Pharmaceuticals S.A.
Rue Saint Georges, 5
MARKETING AUTHORISATION NUMBER(S)
DATE OF FIRST AUTHORISATION/RENEWAL OF THE
DATE OF REVISION OF THE TEXT
Source: Medicines and Healthcare Products Regulatory Agency
Disclaimer: Every effort has been made to ensure that the information provided here is accurate, up-to-date and complete, but no guarantee is made to that effect. Drug information contained herein may be time sensitive. This information has been compiled for use by healthcare practitioners and consumers in the United States. The absence of a warning for a given drug or combination thereof in no way should be construed to indicate that the drug or combination is safe, effective or appropriate for any given patient. If you have questions about the substances you are taking, check with your doctor, nurse or pharmacist.