MIRENA®
Product concept
MIRENA® in contraception
Pirjo Inki, MD,PhD
Specialist in Ob&Gyn
Senior Medical Adviser
The current indications are valid as of October 11, 2005
107
102
92
Oral contraceptives Intrauterine devices
• Highly effective • No daily motivation
• Reduction of menstrual loss • Long-acting
• Reduction of pelvic • Estrogen-free
inflammatory disease
• Rapidly reversible
Levonorgestrel
intrauterine system
The Intra Uterine System
The 1st IUS (Intra Uterine System) is Progestasert® ,
38 mg of progesterone, with a release rate of 65 µg
of progesterone per day.
Approved by FDA in 1976, it was manufactured by
ALZA Corporation, USA.
Marketing of Progestasert® ended in the summer of
2001, and it is no longer available
MIRENA®
T-frame 32 x 32mm, impregnated with Barium Sulphate
Hormone cylinder 19mm in length, covered with a PDMS membrane
Total amount of Levonorgestrel 52mg
2 polyethylene removal threads
The levonorgestrel intrauterine system
Hor mone cylinder
Rate-controlling
membrane
Levonor gestrel
intrauterine
system
Detail
Uter ine Section of
wall system
Mirena®: Mode of Action
Prevention Thickening Local effects Effects on Minor effect
of of the in the ovum on the
endometrial cervical endometrium fertilization, ovarian
proliferation mucus without function
complete
suppression
of ovulation
Nilsson et al 1984; Silverberg et al Int J Gynecol Pathol 1986;
Ortiz et al Contraception 1987 Barbosa et al Contraception 1990;
Mandelin et al Hum Repr 1997
Mode of action: the
endometrium
After a few weeks, the endometrium becomes inactive.
Morphological changes are uniform from the 1st month
LNG IUS
Days
Menstrual cycle
Days
Nilsson et al., 1978
Pharmacokinetics of levonorgestrel
after Mirena® insertion
• Continuous drug delivery
– Mirena® does not cause ‘peaks and troughs’, as
with oral progestogen dosing
• Much higher endometrial levels of the progestogen
than with oral preparation:
Levonorgestrel concentration
(ng/g wet tissue)
LNG-IUS Oral preparation
(30μg/day) (250μg)
Endometrium 808 3.5
Nilsson et al., 1982
LNG IUS
Bleeding per month in 1st year
Mean number of days
16
LNG IUS (n = 1495)
12 Nova-T (n = 739)
8
Bleeding & spotting days
4 per month
0
8
Mean number of days
p < 0.001
6
4 Bleeding days per month
2
0
0 2 4 6 8 10 12
Months
Andersson, Contraception 1994;49:56–72
Mirena®: Changes in bleeding pattern
0–3 months 3–6 months After 6 months
Much spotting Less spotting and Amenorrhea
which progressively less menstrual (± 20%) or
decreases blood loss oligomenorrhea
Bleeding pattern during 5 years of use
Amenorrhea
26%
Infrequent Regular
3.7% 70.3%
Rönnerdag M, Odlind V. Acta Obstet Gynecol Scand 1999;78:716–21
Mirena® vs Cu IUD
• Discontinuation due to heavy or prolonged
bleeding is more common with Cu IUD
rates per 100 subjects
Mirena
Five-year cumulative
12
10 Nova T
8
6
4
2
0
Frequent Heavy Prolonged Spotting Other
irregular menstrual menstrual bleeding
bleeding bleeding bleeding problems
Andersson et al. Contraception 1994; 49: 56–72
Problems
• Prolonged spotting: advice
encouragement
bleeding diary
• Late bleedings: ultrasonography
hysteroscopy
histology
Ultrasound detection of MIRENA®
MIRENA® on X-ray examination
Contraceptive efficacy of LNG IUS
• Overall pregnancy rate: 0.16 per 100 woman-
years
• European multicentre study: cumulative gross
pregnancy rate
– 1-year rate LNG IUS: 0.1% Cu IUD: 1.0%
– 5-year rate LNG IUS: 0.5% Cu IUD: 5.9%
• Risk of ectopic pregnancy: 0.06 per 100 woman-
years.
Ectopic rate for women not using any
contraception: 0.3-0.5 per 100 woman-years
Comparison of Mirena® and sterilization
Mirena Sterilization
Efficacy +++ +++
Reversibility Yes No
Bleeding Reduced No effect
Pain Reduced No effect
Cost Low High
Complications Rare Rare
Pakarinen et al. Semin in Repr Med 2001;19:365-71
Return of fertility after Mirena® use
• Cyclic ovarian function is immediately restored
• The endometrium recovers quickly and normal
menstruation is established within 30 days
• Overall fertility is unaffected
• Cumulative conception rate after removal
– 79─96 per 100 women after 12 months
• Pregnancies progress as normal
Andersson K, et al. Contraception 1992; 45: 575–584
Sivin I, et al. Am J Obstet Gynecol. 1992; 166: 1208–13
Belhadj H, et al. Contraception. 1986; 34: 261–7
Return of fertility after removal of the
levonorgestrel intrauterine system
Levonorgestrel
100
intrauterine system
Cumulative pregnancy rate (%)
80
Copper IUD
60
40
20
0
3 6 9 12
Months
Andersson et al ., 1992
The levonorgestrel intrauterine system and
copper-releasing IUD during 5 years of use
a randomized comparative trial
Participants: 10 clinics in Denmark,
Finland, Norway, Sweden and
Hungary
Number: Nova T, n = 937
Levonorgestrel intrauterine
system, n = 1821
Andersson et al ., 1994
5-year cumulative gross termination rates
Nova T Levonorgestrel p
intrauterine system
Pregnancy 5.9 0.5 ***
Expulsion 6.7 5.8 ns
Bleeding problems 20.9 13.7 **
Absence of bleeding 0 6.0 ***
Pain 5.8 5.9 ns
Hormonal 2.0 12.1 ***
Pelvic inflammatory d isease 2.2 0.8 *
Other medical 10.6 7.7 ns
Personal 5.9 4.4 ns
Continuation rate 53.1 55.5
*p < 0.05; **p < 0.01; *** p < 0.001
Andersson et al., 1994
Hormonal reasons
5-year cumulative gross termination rates
Nova T Levonorgestrel
intrauterine system
Depression 0 2.9 ***
Acne 0.4 2.3 *
Headache 0.2 1.9 **
Weight change 0 1.5 **
Breast tenderness 0 0.8 *
* p < 0.05; ** p < 0.01; *** p < 0.001
Perforation rate
• Incidence in Mirena clinical studies < 1 / 1000
• Perforation rate is similar with all IUDs/IUSs.
• Lack of experience is associated with higher risk
• Some reports on increased perforation rate with
IUDs in postpartum/during lactation, data
inconsistent
• No increased risk in insertions after abortion,
after previous CS
Andersson Contraception1998;57:251-5;
Chi Contracept Deliv Syst 1984;5:123-130;
Grimes 2003.The Cochrane Library, Issue 3;
Chi Contraception 1984;30:209-214
WHO recommendation on progestin-only
contraception during lactation
• to be started ≥ 6 wk post partum to diminish the
exposition of the baby to steroids
• Does not have a negative influence in the milk
production when initiated after 6 weeks postpartum
• Progestins are transferred into the breast milk and
the infant. No deleterious effects on infant growth or
development
• Insertion of IUD ≥ 4 wk after delivery
WHO: Medical eligibility criteria for contraceptive use,2004
WHO Contraception 1994;50:35-68
MIRENA® after delivery
• Insertion should be postponed ≥ 6 weeks after
delivery
• Bleeding pattern compared to CuIUD: with the
exception of the first month post-insertion,
menses-like bleeding significantly more common
in the Cu-IUD users, compared to both LNG-IUD
users. However, initial spotting observed more
frequently observed in the LNG-IUD users
Heikkila et al. Contraception 1982:25:561-72
MIRENA® after delivery
• Randomized comparative trial of Mirena
(n=163) vs CuT380A (n=157) in breast-feeding
women: no difference between the groups in
– Continuation of breast-feeding (full or part-
time)
– Weaning
– Continuation rate of the method
– Infant growth and development (physical
parameters & developmental tests)
Sharmaash et al Contraception 2005:72:346-51
Postabortal insertion of Mirena®
• Fears: uterine perforation, expulsion or
infection (PID)
• No increased risk of perforation or PID
• Menstrual pattern similar to interval insertion.
• Expulsion risk slightly higher than after interval
insertion
Heikkilä et al. Contraception 1982;26:245-59, Andersson et al.
Contraception 1994;49:56-72, Ortayli et al Contraception
2001;63:309-14, Pakarinen et al. Contraception 2003;68:31-4
Postabortal insertion of Mirena®:
Cumulative discontinuation rate /100 women at 5 years
Reason Cu IUD Mirena® P
Pregnancy 9.5 0.8 0.00004
Expulsion 15.4 10.5 ns
Bleeding 22.6 13.7 ns
Amenorrh. 0 2.1 ns
Pain 10.8 5.5 ns
PID 2.3 0.7 ns
Hormonal 3.9 15.9 0.0054
Pakarinen P et al. Contraception 2003;68:31-4
Postabortal insertion of Mirena® : Conclusions
• Safe
• Effective
• Special attention should be paid to the insertion
technique
• Motivation for effective contraception high after
termination of pregnancy
• High rate of removals for planning pregnancy
highlight the importance of reversibility
Pakarinen P et al., Contraception 2003 68:31-4
Mirena® in clinical practice
Mirena® use is associated with high user
satisfaction in clinical practice
100
Percent of users
80
60
40
20
0
Moderate to very satisfied Fairly to very dissatisfied
Backman et al. Obstet Gynecol 2002; 99: 608–13
MIRENA® Continuation Rate is high
• In early clinical studies continuation at 5 years ca. 50%
• Cumulative continuation rates according to Backman et al 2000
100 % 93 %
90 % 87 %
81 %
80 % 75 %
70 % 65 %
60 %
50 %
40 %
30 %
20 %
10 %
0%
1 Year 2 Year 3 Year 4 Year 5 Year
• Yearly continuation rate over 90% in every year
• Relevant counselling significantly increases the continuation
Backman et al. 1992
Long-term use of Mirena®
• Amenorrhea rate increases in long-term use
• Continuation rates very high
• Weight and blood pressure change
consistently with aging
• No difference in body weight increase
compared to Cu IUD
Rönnerdag Acta Obstet Gynecol Scand 1999;78:716-21
.
Body weight in a randomized comparative
trial Mirena ® vs Cu IUD
65
64
Copper IUD
Weight (kg)
LNG-IUS
63
62
61
0 12 24 36 48 60
Months
Andersson Contraception 1994;49:56–72
MIRENA®:
• No difference in body weight compared to Cu
IUD
• Endogenous estradiol levels within normal limits
irrespective of bleeding pattern
• No adverse effect on bone mineral density
• Minimal metabolic effects on
– carbohydrate metabolism
– lipid profile
Rönnerdag Acta Obstet Gynecol Scand 1999;78:716–21; Luukkainen Ann Med 1990;
Bahamondes Hum Repr 2006 in press; Rogovskaya Obstet Gynecol 2005;105:811-5;
Raudaskoski BJOG 2002;109:136-44
