When a pharmaceutical company changes an SPC or PIL, a new version is published on medicines.ie. For each version, we show the dates it was published on medicines.ie and the reasons for change.
Text Deleted:
The in-vivo dissolution rate is about 20 µg/24 hours initially and is reduced to about 11 µg/24 hours after five years. The mean dissolution rate of levonorgestrel is about 14 µg/24 hours over the time up to five years.
Additional text:
Mirena is not the method of first choice for young nulligravid women nor for postmenopausal women with advanced uterine atrophy. (See Section 4.4 Special Warnings and Precautions for use).
The failure rate (Pearl Index) was approximately 0.2 per 100 women at 1 year and the cumulative failure rate was approximately 0.7 per 100 women at 5 years. The failure rate also includes pregnancies due to undetected expulsions and perforations. (See Section 5.1, Pharmacodynamic Properties).
Mirena must be inserted using aseptic technique.
After removal of Mirena, the system should be checked to be intact. During difficult removals, single cases have been reported of the cylinder sliding over the horizontal arms and hiding them together 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.
4.4. Special Warnings and Precautions for Use
Mirena does not protect against HIV infection (AIDS) and other sexually transmitted diseases.
Medical examination/consultation
Mirena should only be inserted be physicians/health care professionals who are experienced in Mirena insertions and/or have undergone sufficient training for Mirena insertion. Mirena must be inserted using aseptic technique.
Updated text:
Pelvic infection
A decision to use Mirena must include consideration of the risks of pelvic inflammatory diseases (PID).
In general, pelvic infection is more likely to occur within the first 20 days following insertion and the rates of infection decrease thereafter to very low levels corresponding to that of non-users and remain low for the duration of use of the product.
Known risk factors for pelvic inflammatory disease are multiple sexual partners, frequent intercourse and young age. Pelvic infection may have serious consequences, including impairment of fertility, increase in the risk of ectopic pregnancy, and on rare occasions, hysterectomy.
During spontaneous post marketing reporting, Group A streptococcal sepsis (GAS) has been reported in less than one in one million users of Mirena. Group A streptococcal sepsis (GAS) is a condition which may occur after surgery, delivery, and from minor trauma.
PID can be asymptomatic but can still result in tubal damage and ectopic pregnancy, infertility.
Signs and symptoms of PID should be investigated appropriately and treated promptly.
Expulsion
Section updated:
Symptoms of the partial or complete expulsion of any IUD may include bleeding or pain. However, the system can be expelled from the uterine cavity without the woman noticing it leading to loss of contraceptive protection. Partial expulsion may decrease the effectiveness of Mirena. As Mirena decreases menstrual flow, increase of menstrual flow may be indicative of an expulsion.
After expulsion, Mirena may be replaced within 7 days from the onset of the next menstruation.
Ectopic pregnancy
An ectopic pregnancy may lead to a higher risk of a subsequent pregnancy being ectopic or to impaired fertility.
Mirena may not be suitable for use as a post-coital contraceptive.
4.6 Pregnancy and Lactation
Lactation
About 0.1 % of the levonorgestrel dose is transferred to the infant during breast-feeding. However, it is not likely that there will be a risk for the infant with the dose released from Mirena, when it is inserted in the uterine cavity.
Section updated/Additional text
The contraceptive efficacy of Mirena has been studied in 5 major clinical studies with 3330 women using Mirena. 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 perforations. Similar contraceptive efficacy has been observed in a large post-marketing study with more than 17000 women using Mirena. Because the use of Mirena 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”). The use of Mirena does not alter the course of future fertility. About 80% of women wishing to become pregnant conceived within 12 months after removal of the system.
The menstrual pattern is a result of the direct action of levonorgestrel on the endometrium and does not reflect the ovarian cycle. There is no clear difference in follicle development, ovulation or estradiol and progesterone production in women with different bleeding patterns. In the process of inactivation of the proliferation of the endometrium there can be an initial increase of spotting during the first months of use. Thereafter, the strong suppression of the endometrium results in the reduction of the duration and volume of menstrual bleeding during use of Mirena. Scanty flow frequently develops into oligomenorrhoea and amenorrhoea. Ovarian function is normal and estradiol levels are maintained, even when users of Mirena are amenorrhoeic.
Following insertion Mirena releases levonorgestrel without delay. The high local drug exposure in the uterine cavity which is important for the local action of Mirena on the endometrium, leads to a strong concentration gradient via the endometrium to the myometrium (gradient endometrium to myometrium >100-fold), and to low concentrations of levonorgestrel in serum (gradient endometrium to serum>1000-fold).
The in vivo release rate of levonorgestrel in the uterine cavity is initially approximately 20 µg/24 hours and declines to 10 µg/24 hours after 5 years. The mean dissolution rate of levonorgestrel is about 14 µg/24 hours over the time up to five years.
Distribution
Levonorgestrel is bound non-specifically to serum albumin and specifically to SHBG. About 1-2 % of the circulating levonorgestrel is present as free steroid and 42-62 % is specifically bound to SHBG. During the use of Mirena, the concentration of SHBG declines. Accordingly, the fraction bound to SHBG decreases during the treatment and the free fraction increases. The mean apparent volume of distribution of levonorgestrel is about 106 L.
After insertion of Mirena, levonorgestrel is detectable in serum after 1 hour. The maximum concentration is reached within 2 weeks after insertion. In correspondence with the declining release rate, the median serum concentration of levonorgestrel declines from 206 pg/ml (25th to 75th percentiles: 151 pg/ml to 264 pg/ml) at 6 months to 194 pg/ml (146 mg/ml to 266 pg/ml) at 12 months and to 131 pg/ml (113 pg/ml to 161 pg/ml) at 60 months in women of reproductive age weighing above 55 kg.
Body weight and serum SHBG concentration have been shown to affect systemic levonorgestrel concentration i.e. low body weight and/or a high SHBG level increase levonorgestrel concentration. In women of reproductive age with a low body weight (37 to 55 kg) the median serum concentration of levonorgestrel is about 1.5-fold higher.
In postmenopausal women using Mirena together with non-oral oestrogen treatment, the median serum concentration of levonorgestrel declines from 257 pg/ml (25th to 75th percentiles: 186 pg/ml to 326 pg/ml) at 12 months to 149 pg/ml (122 pg/ml to 180 pg/ml) at 60 months. When Mirena is used together with oral oestrogen treatment, the serum levonorgestrel concentration at 12 months is increased to approx. 478 pg/ml (25th to 75th percentiles: 341 pg/ml to 655 pg/ml) due to the induction of SHBG by oral oestrogen treatment.
Biotransformation
Levonorgestrel is extensively metabolized. The major metabolites in the plasma are the unconjugated and conjugated forms of 3a, 5b-tetrahydrolevonorgestrel. Based on in vitro and in vivo studies, CYP3A4 is the main enzyme involved in the metabolism of levonorgestrel, CYP2E1, CYP2C19 and CYP2C9 may also be involved, but to a smaller extent
Elimination
The total clearance of levonorgestrel from plasma is approximately 1.0 ml/min/kg. Only trace amounts of levonorgestrel are excreted in unchanged form. The metabolites are excreted with the faeces and urine at an excretion ratio of about 1. The excretion half-life which is mainly represented by metabolites, is about 1 day
Deleted wording:
With anti-estrogenic activity
None known
Store in the original package.
10.0 Date revision
Date of (Partial) Revision of the Text
December 2009
Addition of the following paragraph regarding the failure rate to Section 5.1:
'Mirena, when inserted according to the insertion instructions, has a failure rate of approximately 0.1% per year. The failure rate may increase in case of expulsion or perforation'
Section 2. Qualitative and Quantitative Composition
The following text was inserted:
“The in-vivo dissolution rate is about 20 µg/24 hours initially and is reduced to about 11 µg/24 hours after five years. The mean dissolution rate of levonorgestrel is about 14 µg/24 hours over the time up to five years.”
Section 3. Pharmaceutical Form
The following text was deleted:
“White or almost white intrauterine delivery system consisting of a T-shaped polyethylene body on the vertical section of which is mounted an elastomeric sleeve.”
“The levonorgestrel intrauterine delivery system consists of a white or almost white drug core covered with an opaque membrane, which is mounted on the vertical stem of a T-body. The T-body has a loop at one end of the vertical stem and two horizontal arms at the other end. Removal threads are attached to the loop. The vertical stem of the intrauterine delivery system is loaded in the insertion tube at the tip of the inserter.”
Section 6.6 Instructions for Use and Handling
“The exposed product should be handled with aseptic precautions.”
“For further information see also Section 4.2, Posology and Method of Administration, Insertion and removal/replacement
Any unused product or waste material should be disposed of in accordance with local requirements.”
Section 10. Date of Revision of the Text
The date was changed from “January 2007” to “April 2007”
Main Changes to the SPC include:
Section 4.2 Posology and method of administration
Addition of instructions for ‘Insertion and Removal/Replacement’ and ‘Instructions for Use and Handling’.
Section 4.3 Contraindications
Update of contraindications in line with the most recent safety information.
Deletion of the following contra-indications:
- Presence or history of severe hepatic disease as long as liver function values have not returned to normal
- Undiagnosed vaginal bleeding
Section 4.4 Special warnings and precautions for use
Revised/additional text regarding:
- Risk of breast cancer
- Risk of venous/ arterial thromboembolic events
- Use in women with diabetes
- Medical examination/ consultation
- Perforation
- Ectopic pregnancy
Instructions for ‘Insertion and Removal/Replacement’ have been revised and are now included in Section 4.2.
Section 4.5 Interaction with other medicinal products and other forms of interaction
Revised text regarding possible interaction with drugs which induce cytochrome P450 enzymes.
Section 4.6 Pregnancy and lactation
Revised text regarding the use of Mirena during lactation.
Section 4.8 Undesirable effects
Undesirable effects have been revised according to the most recently available information and have been tabulated according to the MedDRA System Organ Class affected and the frequency of occurrence.
The following possible undesirable effects have been newly included: vulvovaginitis, pelvic inflammatory disease. endometritis.
Section 5.2 Pharmacokinetic properties
Revised information regarding the metabolism of the active substance.