Re: presspack to go with website/petition

Awesome! So glad you are doing this. I fowarded similar packet to all my doctors and have been wanting to copy similar to the media (even local San Francisco chronical).

It would be great to add the report by the manufacturer for the canadian "FDA" (not sure what they're called). It used to be accessible on the internet but looks like Bayer pulled it since it did indeed list potential side effects that previously were not listed on the american FDA (although I think many of the side effects are now listed recently added in this past year). I can't figure out how to attach it here so I'll copy the report:


M20606EP Page 1







PRODUCT MONOGRAPH




Pr
MIRENA®

Levonorgestrel-releasing Intrauterine System (52 mg) to deliver
up to 20 µg levonorgestrel per day

Progestogen










Berlex Canada Inc.
334 Avro Avenue,
Pointe-Claire, Quebec
H9R 5W5

http://www.berlex.ca


Submission Control No. : 101300
Date of Preparation: November 27, 2000

Date of Revision: June 27, 2006



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Table of Contents


PART I: HEALTH PROFESSIONAL INFORMATION.........................................................3
SUMMARY PRODUCT INFORMATION........................................................................3
INDICATIONS AND CLINICAL USE..............................................................................3
CONTRAINDICATIONS...................................................................................................4
WARNINGS AND PRECAUTIONS..................................................................................4
ADVERSE REACTIONS....................................................................................................8
DRUG INTERACTIONS..................................................................................................11
DOSAGE AND ADMINISTRATION..............................................................................12
ACTION AND CLINICAL PHARMACOLOGY............................................................29
STORAGE AND STABILITY..........................................................................................34
DOSAGE FORMS, COMPOSITION AND PACKAGING.............................................34
PART II: SCIENTIFIC INFORMATION...............................................................................35
PHARMACEUTICAL INFORMATION..........................................................................35
CLINICAL TRIALS..........................................................................................................36
DETAILED PHARMACOLOGY.....................................................................................36
TOXICOLOGY.................................................................................................................37
REFERENCES..................................................................................................................40
PART III: CONSUMER INFORMATION..............................................................................41




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Pr
MIRENA®

Levonorgestrel-releasing Intrauterine System


PART I: HEALTH PROFESSIONAL INFORMATION


SUMMARY PRODUCT INFORMATION

Route of
Administration Dosage Form /
Strength Clinically Relevant Nonmedicinal
Ingredients
Intra-uterine Intrauterine system /
52 mg levonorgestrel barium sulphate, iron oxide,
polydimethylsiloxane, polyethylene, silica

For a complete listing see Dosage Forms,
Composition and Packaging section.


INDICATIONS AND CLINICAL USE

MIRENA (levonorgestrel-releasing intrauterine system) is indicated for: conception control



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CONTRAINDICATIONS

MIRENA (levonorgestrel-releasing intrauterine system) is contraindicated in patients with the
following conditions:

• known or suspected pregnancy
• current or recurrent pelvic inflammatory disease
• lower genital tract infection
• postpartum endometritis
• undiagnosed abnormal uterine bleeding
• uterine anomalies including fibroids if they distort the uterine cavity
• uterine or cervical malignancy
• cervicitis
• cervical dysplasia
• acute liver disease or liver tumour
• septic abortion within the previous three months
• hypersensitivity to levonorgestrel or any of the other ingredients in the formulation or
component of the container components of MIRENA. For a complete listing, see the Dosage
Forms, Composition and Packaging section of the product monograph.
• bacterial endocarditis
• established immunodeficiency
• acute malignancies affecting blood or leukemias
• recent trophoblastic disease while hCG levels are elevated


WARNINGS AND PRECAUTIONS

Serious Warnings and Precautions

Patients should be counseled that MIRENA (levonorgestrel-releasing intrauterine system) does
not protect against HIV infection (AIDS) and other sexually transmitted diseases (STDs). For
protection against STDs, patients should be counseled to use latex condoms.

General
MIRENA should be used with caution in women who have migraine, focal migraine with
asymmetrical visual loss or other symptoms indicating transient cerebral ischemia, severe
headache, marked increase in blood pressure or confirmed or suspected hormone dependent
neoplasia including breast cancer, or active or previous severe arterial disease such as stroke or
myocardial infarction. Removal of MIRENA should be considered if any of the above
conditions occur during use.

MIRENA is not the contraceptive method of first choice for young, nulligravid women.
Controlled clinical trials were done in previously parous women aged mainly over 18 years.

MIRENA is intended for use in women of child-bearing age.



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The effects of MIRENA on the ability to drive and use machines have not been studied.

MIRENA is not suitable for use as a post-coital contraceptive.

Cardiovascular
MIRENA should be used with caution in women with congenital or valvular heart disease who
are at risk of infective endocarditis. Antibiotic prophylaxis should be administered to such
patients when inserting or removing MIRENA.

Endocrine and Metabolism
Glucose Tolerance
Combination and progestogen-only oral contraceptives, including those containing
levonorgestrel, may affect glucose tolerance in some users. Diabetic patients, and those with a
family history of diabetes, should be observed closely to detect any alterations in carbohydrate
metabolism. Young diabetic patients whose disease is of recent origin, well-controlled and not
associated with hypertension or other signs of vascular disease such as ocular fundal changes,
should be closely observed.

Genitourinary
Bleeding irregularities
Because irregular menstrual bleeding or spotting is common during the first few months of use,
endometrial pathology should be excluded prior to insertion of MIRENA. Irregular bleeding
patterns in users of MIRENA could mask the signs and symptoms of cervical or endometrial
cancer. If bleeding irregularities develop after prolonged use, appropriate diagnostic measures
should be undertaken.

Prolonged menstrual bleeding may occur during the first few months, however with continued
use, bleeding patterns vary from regular scanty menstruation in some women to oligomenorrhea
or amenorrhea in others. Oligomenorrhea or amenorrhea develop gradually in about 20% of
users. Reduced bleeding increases the level of blood hemoglobin.

The possibility of pregnancy should be considered if menstruation does not occur after six weeks
or more of amenorrhea, following a pattern of regular menses. A pregnancy test is not
necessary in amenorrheic women unless indicated by other symptoms.

Hematologic
Thromboembolism
Epidemiological studies have indicated that women using progestogen-only oral contraceptives
may have a slightly increased risk of venous thromboembolism; however, the results are not
statistically significant. Appropriate diagnostic and therapeutic measures should be undertaken
immediately if there are symptoms or signs of thrombosis in users of MIRENA. Symptoms of
thromboembolism include: unilateral leg pain and/or swelling, sudden severe pain in the chest
whether or not it radiates to the left arm, sudden breathlessness, sudden onset of coughing, any
unusual severe prolonged headache, sudden partial or complete loss of vision, diplopia, slurred
speech or aphasia, vertigo, collapse with or without focal seizure, weakness or very marked

M20606EP Page 6
numbness suddenly affecting one side or part of the body, motor disturbances and acute
abdomen. Symptoms or signs of retinal thrombosis are: unexplained partial or complete loss of
vision, onset of proptosis or diplopia, papilledema, or retinal vascular lesions.

Hepatic/Biliary/Pancreatic
If jaundice develops in a patient using MIRENA, consideration should be given to removing the
system. Steroid hormones may be poorly metabolized in patients with impaired liver function.

Sexual Function/Reproduction
Ovarian Cysts (Delayed Follicular Atresia)
Since the contraceptive action of MIRENA is due mainly to its local effect on the uterus,
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.

Enlarged follicles were diagnosed in about 12% of women using MIRENA in one study
involving 50 women. In a larger clinical trial (n=2,246), the rate of functional ovarian cysts was
1.2 per 100 woman-years. Cysts are usually small and disappear spontaneously within a few
months.

Most of these follicles are asymptomatic, although some may be accompanied by pelvic pain or
dyspareunia. In most cases, the enlarged follicles disappear spontaneously over a two to three
month period. Should this not occur, continued ultrasound monitoring and other diagnostic or
therapeutic measures are recommended. Rarely, surgical intervention may be required.

Ectopic Pregnancy
Women with a previous history of ectopic pregnancy, tubal surgery or pelvic infection carry a
higher risk of ectopic pregnancy. The possibility of ectopic pregnancy should be considered in
the case of lower abdominal pain, especially in association with missed periods.

Ectopic pregnancies with MIRENA are very rare. In one clinical trial with 1,821 women using
MIRENA, the reported rate of ectopic pregnancy was 0.02 per 100 woman-years. This rate is
significantly lower than the estimated rate of 1.2 to 1.6 for women using no contraceptive
method.

Combined data from prospective clinical trials with MIRENA reveal an overall rate of ectopic
pregnancy of 0.06 per 100 woman-years. A post-marketing surveillance study with data from
over 17,000 women using MIRENA also indicated an ectopic pregnancy rate of 0.08 per 100
woman-years.

Pelvic Infection
The inserter provided with MIRENA helps protect the system from contamination with micro-
organisms during insertion, thereby minimizing the risk of pelvic infection. Known risk factors
for pelvic inflammatory disease include multiple sexual partners, frequent intercourse and young
age.

If recurrent endometritis or pelvic infections are experienced, or if an acute infection does not


M20606EP Page 7

respond to treatment within a few days, MIRENA must be removed.

Perforation
Perforation or penetration of the uterus or cervix is rare (occurring at a rate of between 1/1,000
and 1/10,000), most often occurring during insertion. MIRENA should be removed as soon as
possible if this occurs. The number of uterine perforations is linked to the experience of the
person inserting the system5. To reduce the possibility of perforation, it is important to follow
the recommended insertion technique. (See Post-market Adverse Drug Reactions and Dosage
and Administration: Insertion Instructions.)

Sexually Transmitted Diseases
Patients should be counseled that MIRENA does not protect against HIV infection (AIDS) and
other sexually transmitted diseases (STDs). For protection against STDs, patients should be
counseled to use latex condoms.

Opthalmologic
Contact Lenses
Visual changes or changes in contact lens tolerance may occur in users of MIRENA. If this
occurs an ophthalmologist should be consulted.

Psychiatric
Patients with a history of emotional disturbances, especially the depressive type, may be more
prone to have a recurrence of Depression while using MIRENA. In cases of a serious recurrence,
consideration should be given to removing MIRENA since the Depression may be drug-related.

Special Populations
Pregnant Women: MIRENA is not to be used during an existing or suspected pregnancy. If a
patient becomes pregnant while using MIRENA, removal of the system is recommended since
any intrauterine system left in place may increase the risk of abortion and preterm labour.
Removal of MIRENA or probing of the uterus may result in spontaneous abortion. If the system
cannot be gently removed, termination of the pregnancy may be considered. If the patient
wishes to continue the pregnancy and the system cannot be withdrawn, she should be informed
about the risks to the infant of premature birth. The course of such a pregnancy should be
closely monitored. Ectopic pregnancy should be excluded. The patient should be instructed to
report all symptoms that suggest complications of the pregnancy, such as cramping abdominal
pain with fever.

Because of the local exposure of the fetus to levonorgestrel, teratogenicity (especially
virilization) cannot be completely excluded.

Due to the high contraceptive efficacy of MIRENA, clinical experience with MIRENA during
full term pregnancy is limited. However, the patient should be informed that there is no evidence
of birth defects associated with MIRENA in cases where pregnancy has continued to term with
the system in place.


M20606EP Page 8

Nursing Women: Hormonal contraceptives are not recommended as the contraceptive method
of first choice in breast-feeding women. Although levonorgestrel has been found in the breast
milk of women using MIRENA, there does not appear to be a detrimental effect on growth or
development of breast-fed infants whose mothers started using the product after six weeks
postpartum. Progestogen-only contraceptive methods do not appear to affect the quantity and
quality of breast milk.

Pediatrics (< 18 years of age): MIRENA is not the contraceptive method of first choice for
young, nulligravid women. Controlled clinical trials were done in previously parous women
aged mainly over 18 years.


ADVERSE REACTIONS

Adverse Drug Reaction Overview
The most commonly occurring adverse events (i.e., in greater than 10% of users) that are
observed postmarketing include menstrual bleeding changes and benign ovarian cysts.

Different kinds of bleeding changes (frequent, prolonged or heavy bleeding, spotting,
oligomenorrhea, amenorrhea) are experienced by all users of MIRENA (levonorgestrel-releasing
intrauterine system).

Clinical Trial Adverse Drug Reactions
Because clinical trials are conducted under very specific conditions the adverse reaction rates
observed in the clinical trials may not reflect the rates observed in practice and should not be
compared to the rates in the clinical trials of another drug. Adverse drug reaction information
from clinical trials is useful for identifying drug-related adverse events and for approximating
rates.

In clinical studies, the most common adverse event occurring with MIRENA is a change in
menstrual bleeding patterns (see Action and Clinical Pharmacology). The changes may
include spotting, shorter or longer menstrual periods, irregular bleeding, oligomenorrhea,
amenorrhea, heavy flow, back pain and dysmenorrhea.

In one large clinical trial with MIRENA, the gross cumulative removal rate for bleeding was
13.7 per 100 women at five years. During the first year after insertion, 16.8% of MIRENA users
experienced an interval of amenorrhea lasting at least 90 days. The cumulative net removal rate
for amenorrhea was 4.3 per 100 women, with removals for this reason more frequent among
younger women than older women.

Ectopic pregnancy has been reported with MIRENA. Pelvic inflammatory disease may also
occur. The system or parts of it may perforate the uterine wall, but this is very rare. Enlarged
follicles (functional ovarian cysts) may develop.

Adverse events are most common during the first months after insertion of MIRENA; their
frequency subsides subsequently. In clinical trials, reported conditions elicited by non-specific


M20606EP Page 9

questioning in 2,213 women at three months and in 902 women at sixty months after insertion of
MIRENA, are listed in the following table:

Table 1: Adverse events reported in MIRENA clinical trials occurring at a rate of more than 1%
Incidence (%)

Reported adverse event After 3 Months
(n=2,213) After 60 Months
(n=902)
Infections and infestations:
upper respiratory tract infection
sinusitis
candidiasis
bronchitis
urinary tract infection
rhinitis

0.9
0.6
0.5
0.2
0.1
0

1.7
1.0
1.2
1.8
1.0
1.3
Gastrointestinal disorders:
abdominal pain
nausea

11.0
2.2

4.5
0.3
Musculoskeletal and connective tissue disorders:
back pain
musculoskeletal pain

3.5
0.3

1.8
1.0
Psychiatric disorders:
Depression 2.1 1.0
Nervous system disorders:
headache 5.8 6.5
Reproductive system and breast disorders:
menstrual disorder
breast pain
genital discharge
ovarian cyst
vaginal infection
fibroadenoma of breast

29.4
3.2
1.3
0.6
0.4
0.2

5.2
1.6
0.7
1.3
1.3
1.1
Skin and subcutaneous tissue disorders:
Acne 2.8 0.9

M20606EP Page 10
Less Common Clinical Trial Adverse Drug Reactions
Additional adverse events reported in clinical trials with MIRENA occurring at a rate of less than
1.0% after either 3 or 60 months of use were:

Cardiac disorders: hypertension, arrhythmia
Endocrine disorders: lactation nonpuerperal, amenorrhoea
Gastrointestinal disorders: diarrhea, toothache, tooth disorder, haemorrhoids,
abdomen enlarged
General disorders and administration
site conditions: fatigue, edema, leg pain, influenza-like symptoms,
pain
Immune system disorders: allergic reaction, allergy
Injury, poisoning and procedural
complications: IUD complication
Infections and infestations: otitis media (externa), pneumonia, pharyngitis,
infection, fever, mastitis, cystitis
Metabolism and nutritional disorders: weight increase
Musculoskeletal and connective
tissue disorders: tendonitis
Neoplasms benign, malignant
and unspecified (incl. cysts and polyps): breast neoplasm (benign), vaginal neoplasm
(benign)
Nervous system disorders: dizziness, vertigo, sciatica, migraine
Psychiatric disorders: nervousness, emotional lability
Renal and urinary disorders: dysuria, urinary incontinence, changes in
micturition frequency
Reproductive system and breast disorders: pre-menstrual tension, intermenstrual bleeding,
ovarian disorder, endometritis, endometriosis,
cervicitis, libido decreased, vulva disorder, uterine
disorder (unspecified), dyspareunia,
dysmenorrhoea, uterine fibroid, genital pruritis
Respiratory, thoracic and mediastinal
disorders: asthma
Skin and subcutaneous tissue
disorders: sweating increased, hypertrichosis, alopecia,
eczema, seborrhoea, dry skin, skin disorder, pruritis
Surgical and medical procedures: unspecified surgical/medical procedure


M20606EP Page 11

Post-Market Adverse Drug Reactions
Since market introduction in Canada in February 2001, 30 reports of suspected uterine
perforation with MIRENA have been reported in over 111,000 units of MIRENA sold, for a
reporting rate of 0.27/1000.

Undesirable effects are more common during the first months after insertion and subside during
prolonged use. In addition to the adverse events observed in clinical trials, the following
undesirable effects have been reported in users of MIRENA, although a causal relationship with
MIRENA could not always be confirmed.

Infections: genital infections
Gastrointestinal disorders: pelvic pain, abdominal bloating
General disorders and administration
site conditions: expulsion
Reproductive system and breast disorders: vaginal discharge, breast tension, mastalgia,
uterine perforation
Skin and subcutaneous disorders: hirsutism, rash, urticaria


DRUG INTERACTIONS

Drug-Drug Interactions
The effect of hormonal contraceptives may be impaired by drugs which induce liver enzymes,
including primidone, barbiturates, phenytoin, carbamazepine, rifampicin and griseofulvin. The
influence of these drugs on the efficacy of MIRENA (levonorgestrel-releasing intrauterine
system) has not been studied, but it is not believed to be of major importance due to the local
action of MIRENA.

Drug-Food Interactions
Interactions with food have not been established.

Drug-Herb Interactions
Interactions with herbal products have not been established.

Drug-Laboratory Test Interactions
Interactions with laboratory tests have not been established.



M20606EP Page 12
DOSAGE AND ADMINISTRATION

Recommended Dose
Following insertion into the uterine cavity, MIRENA (levonorgestrel-releasing intrauterine
system) is effective for up to five years. The in vivo dissolution rate is approximately 20 µg
levonorgestrel per day initially, and diminishes over time to approximately 11 µg per day after
five years. The mean dissolution rate is approximately 14 µg per day over five years.

If after 5 years, continued use of MIRENA is desired a new MIRENA system should be inserted
immediately after the old one is removed.

Administration
Insertion, Removal and Replacement
Before insertion, the patient must be informed of the efficacy, risks and side effects of MIRENA.
A physical examination including pelvic examination, examination of the breasts and cervical
smear should be performed. Pregnancy and sexually transmitted diseases should be excluded
and any genital infections must be successfully treated. The position of the uterus and the size of
the uterine cavity should be determined. Fundal positioning of MIRENA is particularly
important in order to ensure uniform exposure of the endometrium to the progestogen, prevent
expulsion and maximize efficacy. The instructions for insertion should be followed carefully.
The patient should be re-examined 4 to 12 weeks after insertion and once-a-year thereafter, or
more frequently if clinically indicated.

In women of fertile age, MIRENA should be inserted within seven days of the onset of
menstruation. MIRENA may be replaced by a new system at any time during the cycle. The
system can also be inserted immediately after first trimester abortion. Postpartum insertions
should be postponed until six weeks after delivery. MIRENA is not suitable for use as a post-
coital contraceptive.

Because irregular bleeding is common during the first months of therapy, it is recommended to
exclude endometrial pathology before insertion of MIRENA. If bleeding irregularities develop
during prolonged treatment, appropriate diagnostic measures should be undertaken.

MIRENA can be removed by gently pulling on the removal 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.

The system should be removed after five years of use. If the patient wishes to continue using
MIRENA, a new system can be inserted at the time of removal of the old one. If pregnancy is
not desired, removal should be carried out during menstruation in women of fertile age provided
that there appears to be a menstrual cycle. If the system is removed mid-cycle and the patient
has had intercourse within a week, she is at risk of pregnancy unless a new system is inserted
immediately following removal.

Insertion and removal may be associated with some pain and bleeding. The procedure may
cause a fainting spell or precipitate a seizure in an epileptic patient.


M20606EP Page 13


Expulsion
Symptoms of the partial or complete expulsion of MIRENA may include bleeding or pain,
however, a system may be expelled from the uterine cavity without the patient noticing it.
Partial expulsion may decrease the effectiveness of MIRENA. Since MIRENA decreases
menstrual flow, an increase in menstrual flow may indicate an expulsion. A displaced system
should be removed. A new system can be inserted at that time and the patient should be advised
on how to check for the presence of the system by feeling for the removal threads.

In a five-year clinical trial, the net cumulative expulsion rate ranged from 3.4 per 100 women in
year one to 4.9 in year five. Expulsion rates for MIRENA are comparable to those observed for
copper IUDs.

In the same clinical trial, the net cumulative removal rate due to pain ranged from 1.6 per 100
women in the first year to 4.2 in the fifth year.

Lost Removal Threads
If the removal threads are not visible upon follow-up examination, pregnancy must be excluded.
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 be located by
gently probing with a suitable instrument. If they cannot be found, the system may have been
expelled or displaced (See Expulsion). Ultrasound or X-rays may be used to locate a displaced
system (MIRENA is radiopaque).


Insertion Instructions


Because the insertion technique is different from intrauterine devices, it is important that
physicians receive training on the correct insertion technique.


Physicians should become thoroughly familiar with the insertion instructions in their
entirety before attempting insertion of MIRENA.

MIRENA is supplied sterile. It is sterilized with ethylene oxide. Do not resterilize. For single
use only. Do not use if the pouch is damaged or open. Insert before the date indicated on the
label.

MIRENA is to be inserted with the enclosed inserter into the uterine cavity within seven days of
the onset of menstruation by carefully following these insertion instructions (Figure 1). It can be
replaced by a new system at any time during the menstrual cycle.

M20606EP Page 14




Figure 1



M20606EP Page 15

Conduct a gynecological examination of the patient to establish the size and position of the
uterus and to exclude pregnancy or other genital tract contraindications for the use of MIRENA.

Preparation for Insertion

1. Visualize the cervix by means of a speculum and thoroughly cleanse the cervix and
vagina with a suitable antiseptic solution. Grasp the upper lip of the cervix with a suitable
holding forceps.

2. Gentle traction on the holding forceps has been shown to align the cervical canal with the
uterine cavity. The forceps should remain in position throughout the insertion procedure
to maintain gentle traction on the cervix against the pushing force of the insertion.

3. Gently move a uterine sound into the uterine cavity to the fundus to determine the
direction of the cervical canal and the depth of the uterine cavity, and to exclude a uterine
septum, synechiae and submucosal fibroids. Should the cervical canal be too narrow,
consider the need for dilatation and the use of analgesics or paracervical block.

M20606EP Page 16
Insertion

1. Open the sterile package enough to reveal the shaft of the inserter. Wearing sterile
gloves, make sure that the slider is in the furthermost position. Grasp the shaft as
illustrated in Figure 2 and check that the arms of the system are in a horizontal position
(shape of a T). If they are not, align them on the sterile surface of the MIRENA
packaging tray (Figure 2).



M20606EP Page 17



Figure 2


M20606EP Page 18
2. Pull on the threads to position the arms of the MIRENA system into the inserter tube
(Figure 3). Note that the knobs at the end of the arms now close the open end of the
inserter.



M20606EP Page 19


















Figure 3






M20606EP Page 20
3. Fix the threads tightly in the cleft at the end of the inserter shaft (Figure 4).




Figure 4



M20606EP Page 21

4. Ensure that the arms are in the correct position and that they will fold out horizontally.
If not, open the arms by pulling the slider back to the raised mark on the shaft (Figure 5).
Align the open arms on a sterile surface as shown in Figure 2. Return the slider to its
previous position. Check that the threads are still tight and that the arms have moved
back into the inserter.


M20606EP Page 22


















Figure 5


M20606EP Page 23


5. Set the flange at a distance from the knobs on MIRENA corresponding to the uterine
sound measure by using the scale marked on the insertion tube (Figure 6). Note that this
measurement is from the end of the inserter to the top edge of the flange.








Figure 6

M20606EP Page 24
6. MIRENA is now ready to be inserted. Hold the slider with the forefinger or thumb
firmly in the most distal position. Move the inserter carefully through the cervical canal
into the uterus until the flange is situated at a distance of about 1.5 – 2 cm from the cervix
to give sufficient space for the arms to open (Figure 7). Do not force the inserter.
























Figure 7


M20606EP Page 25


7. While holding the inserter steady, release the arms of MIRENA (Figure 8) by pulling the
slider back until it reaches the raised mark on the shaft (Figure 5).


























Figure 8

M20606EP Page 26
8. Holding the slider firmly, push the inserter gently inward until the flange touches the
cervix. MIRENA should now be at the fundus (Figure 9).


























Figure 9


M20606EP Page 27


9. Holding the inserter firmly in position, release MIRENA by pulling the slider all the way
back. The threads will uncleat automatically (Figure 10).








Figure 10

M20606EP Page 28

10. Remove the inserter from the uterus. Cut the threads to leave about 2 cm visible outside
the cervix (Figure 11).


















Figure 11


M20606EP Page 29


If there is any doubt that the system is not in the correct position, verify with ultrasound or
X-ray. If necessary, remove the system and insert a new one. A removed system must never
be re-inserted.


Use of sanitary pads
The use of sanitary pads is recommended. If tampons are used, they should be changed carefully
to avoid inadvertantly pulling the MIRENA removal threads.

Removal of MIRENA
MIRENA can be removed by pulling the threads with forceps.

A MIRENA system should not remain in the uterus longer than 5 years.


ACTION AND CLINICAL PHARMACOLOGY

Mechanism of Action
MIRENA (levonorgestrel-releasing intrauterine system) consists of a small polyethylene T-
shaped frame with a cylindrical reservoir containing levonorgestrel around the vertical arm of the
T frame. After insertion into the uterus, MIRENA releases levonorgestrel continuously for up to
five years. Intrauterine administration allows a very low daily dosage, as the hormone is
released directly to the target organ. MIRENA contains a total of 52 mg levonorgestrel and has
an initial intrauterine release rate of 20 µg per day that diminishes over time to approximately 11
µg per day after 5 years.


M20606EP Page 30






polyethylene T-shaped frame



cylindrical reservoir containing levonorgestrel






polyethylene removal threads












MIRENA
(levonorgestrel-releasing intrauterine system)



M20606EP Page 31

Pharmacodynamics
The contraceptive action of MIRENA is due mainly to the local progestogenic effect of
levonorgestrel on the uterine cavity. It produces a strong antiproliferative effect on the
endometrium and causes a thickening of the cervical mucus which prevents passage of sperm
through the cervical canal. Ovulation is inhibited in some women. Clinical trials with MIRENA
were performed in parous women mainly over the age of 18 years; results from these studies
involving more than 7,600 woman-years of use indicate an overall Pearl index of 0.11. The 5-
year cumulative gross pregnancy rates in these trials ranged from 0 to 1.2 per 100 women.

Normal menstruation returns quickly after removal of MIRENA. After five years of use in
clinical trials, the return of normal cyclical endometrial morphology was observed to occur from
one to three months after removal of MIRENA. The use of MIRENA does not alter the course
of future fertility; nearly 90% of women wishing to become pregnant conceive within 24 months
after removal of the system.

The duration and volume of menstrual bleeding and menstrual blood loss gradually decreases
during the first few months of use. With continued use, bleeding patterns vary from regular
scanty menstruation in some women to oligomenorrhea or amenorrhea in others.

The menstrual bleeding patterns of 1,495 women enrolled in a clinical trial were examined for
the first 12 months after MIRENA insertion. The number of combined days of vaginal bleeding
or spotting decreased from a mean of 16.1 days during the first month, to a mean of 3.8 days
during the 12th month (see Table 2).





M20606EP Page 32

Table 2: Number of Combined Vaginal Bleeding / Spotting Days During the first 12 Months After MIRENA Insertion


Interval (in 30-day segments)
Days



1 - 30

31 - 60

61 - 90

91 - 120

121 - 150

151 - 180

181 - 210

211 - 240

241 - 270

271 - 300

301 - 330

331 - 360

N

1,495

1,472

1,422

1,297

1,237

1,199

1,168

1,142

1,113

1,079

1,055

988

mean

16.1

11.2

8.5

7.1

6.4

5.8

5.2

4.8

4.5

4.3

4.1

3.8



M20606EP Page 33

The altered menstrual bleeding pattern that occurs with MIRENA use is a result of the direct action
of levonorgestrel on the endometrium and is not due to the suppression of the ovulatory cycle.
There is no clear difference in follicle development, ovulation, or estradiol and progesterone
production in women with different bleeding patterns. Ovarian function is normal and estradiol
levels are maintained even when users of MIRENA are amenorrheic.

The effect of MIRENA on ovarian function depends on plasma levonorgestrel levels achieved.
While marked interindividual variation is observed, plasma concentrations are relatively constant
within each individual. Patterns of ovarian function in women using MIRENA include normal
ovulatory cycles, anovulatory cycles with some inhibition of estradiol production, anovulation with
high follicular activity and ovulation with an inadequate luteal phase. In general, anovulatory
cycles correlate with higher plasma levels of levonorgestrel, and are more frequent in the first year
of MIRENA use. Functional ovarian cysts may occur in relation to pre-ovulatory arrest of
follicular development in any woman, and are associated with progestogen-only methods of
contraception.

Endometrial histology has been investigated in clinical studies examining the intrauterine release
of levonorgestrel at rates ranging from 10 to 40 µg/day. Subjects with anywhere from 3 to 84
months of exposure to continuous levonorgestrel release showed endometrial glandular atrophy
and decidualized stroma throughout the period. Local inflammation and focal necrosis compatible
with the intrauterine mode of administration were observed.

In one study, cervical histology was evaluated by examining cervical smears from 1,355 women
using MIRENA over a period of five years. A total of twelve smears indicated moderate to severe
cervical dysplasia. Large multi-centre studies have not detected differences in cervical cytology
between women using MIRENA and those using copper IUDs.

Pharmacokinetics
Absorption
The intrauterine release of levonorgestrel results in the absorption of the drug into the systemic
circulation.

Distribution
The drug can be detected in plasma within 15 minutes of insertion and maximum concentrations
are seen within a few hours. Following intrauterine insertion of MIRENA, the initial release rate
of levonorgestrel is 20 µg per day. This provides stable plasma levonorgestrel concentrations
which, after the first few weeks, stabilize at between 150 to 200 pg/mL in women of fertile age.
After 12, 24 and 60 months of use in young women, plasma levonorgestrel concentrations of 180 ±
66 pg/mL, 192 ± 140 pg/mL, and 159 ± 60 pg/mL were observed, respectively. Because of the
low drug levels in plasma, the systemic effects of the progestogen are minimized.

Orally administered levonorgestrel is rapidly and completely absorbed and the absolute
bioavailability is about 90%. Levonorgestrel is bound to serum albumin and to sex hormone-
binding globulin (SHBG). The relative distribution (free, albumin-bound, SHBG-bound) depends
on the SHBG concentration in the serum. Only about 2.5% of the total serum drug levels are


M20606EP Page 34
present as free steroid, but 47.5% and 50% are bound to SHBG and albumin respectively. For
levonorgestrel, a mean volume of distribution of approximately 137 litres and a metabolic
clearance rate from serum of about 5.7 L/hr were reported.

Metabolism and Excretion
The terminal half-life in serum is in the range of 14-20 hours after single-dose administration.
Levonorgestrel is excreted as metabolites at about equal proportion in urine and feces. The
metabolites have little or no pharmacological activity. The principal metabolite in urine is
tetrahydronorgestrel which accounts for approximately 25% of the radioactivity recovered from
the urine after administration of radiolabeled levonorgestrel. About 0.1% of the dose is excreted in
breast milk.



STORAGE AND STABILITY

Store at room temperature (between 15°C and 30°C). Protect from moisture and direct sunlight.


DOSAGE FORMS, COMPOSITION AND PACKAGING

Each MIRENA (levonorgestrel-releasing intrauterine system) contains 52 mg of levonorgestrel
USP in a cylindrical-shaped reservoir composed of a matrix of levonorgestrel and
polydimethylsiloxane. The reservoir is mounted on the vertical arm of a T-shaped frame made of
polyethylene and covered with a rate-controlling membrane of polydimethylsiloxane and silica.
The T-frame is pigmented with barium sulphate. The polyethylene removal threads attached to the
T-frame are pigmented with black iron oxide.

MIRENA is available in a carton of one sterile unit. Each MIRENA is packaged in a pouch within
an inserter.


M20606EP Page 35

PART II: SCIENTIFIC INFORMATION

PHARMACEUTICAL INFORMATION

Drug Substance

Proper name: levonorgestrel

Chemical name: 18,19-Dinorpregn-4-en-20-yn-3-one, 13-ethyl-17-hydroxy-,(17α)(-)

Molecular formula: C21 H28 O2

Molecular Mass: 312.45

Structural formula:
















Physicochemical properties: Levonorgestrel is a white to off-white crystalline powder, practically
insoluble in water and slightly soluble in ethanol, in vegetable oils,
in chloroform, in ether and in alkaline solutions. The melting range
is between 232°C and 239°C.





M20606EP Page 36
CLINICAL TRIALS

Contraceptive Efficacy
Clinical studies with MIRENA consistently show high contraceptive efficacy. The contraceptive
efficacy of MIRENA was studied in three clinical trials in which a total of 2,379 women were
enrolled. One trial compared MIRENA (n=1,821) to a copper IUD (n=937) over a period of 5
years with a resultant Pearl index of 0.09 for MIRENA and 1.26 for the copper IUD. After
completion of this trial, 168 women from the MIRENA group enrolled in a second clinical trial
and had a new MIRENA system inserted for four years. Results after 6,404 woman-months of
experience revealed a Pearl index of 0. A third MIRENA trial was non-comparative, and enrolled
390 women for 5 years with a resultant Pearl index of 0.24. Combined data from three clinical
trials provides 91,133 woman-months of experience. There were a total of 8 pregnancies, giving a
Pearl rate of 0.11.

Continuation Rate
The continuation rate for MIRENA in a five-year clinical trial in 390 women, was 56%. The
desire to become pregnant was the most common reason for discontinuing MIRENA (about 20%
of all discontinuations). Other discontinuations were due to medical reasons (predominantly
hormonal, menstrual problems and pain).


DETAILED PHARMACOLOGY

Pharmacodynamics
Levonorgestrel is a 19-nortestosterone derivative with potent progestogenic effects, but no
significant estrogenic activity.

In rabbits, evidence of transformation of the endometrium was observed after subcutaneous
administration of 0.01 mg levonorgestrel corresponding to 2 µg/kg/day. Transformative effects are
also histologically recognizable in the rabbit endometrium when levonorgestrel is administered
orally in doses ranging from 0.03 to 0.3 mg per animal corresponding to approximately 6 to 60
µg/kg/day.

In pregnant rats, ovariectomized within the first 4 days after conception, the subcutaneous
administration of 0.002 mg levonorgestrel had a blastocyst-maintaining effect. The anti-estrogenic
or progestogenic activity of levonorgestrel has also been demonstrated in various test models in
rats and mice, the potency of levonorgestrel is significantly higher than progesterone and about 83
times stronger than chlormadinone acetate.

Levonorgestrel does not have any significant estrogenic activity and androgenic effects are only
detectable after large doses. Levonorgestrel also influences the gonadotrophic function of the
anterior lobe of the pituitary gland in all experimental tests.

Like other progestogens, relative large doses of levonorgestrel lead to increases in insulin secretion
in rats and dogs.


M20606EP Page 37



TOXICOLOGY

Toxicology studies were performed on all the components of MIRENA: the "unfilled polymer",
the "levonorgestrel-releasing reservoir", the "membrane tubing", the polyethylene "T-body" and
the polyethylene "removal threads".

The unfilled polymer is the polydimethylsiloxane (PDMS) polymer after peroxide catalysis. The
unfilled polymer is mixed in an equal ratio with levonorgestrel, to form the levonorgestrel-
releasing reservoir. The unfilled polymer is also mixed with inert colloidal silica to form the
membrane tubing, which covers the levonorgestrel reservoir and serves to control the release rate
of levonorgestrel from MIRENA.

Acute Toxicology
The USP systemic injection test in mice on the unfilled polymer, membrane tubing, T-body and
removal threads did not show any signs of toxicity.

Mutagenicity
Extracts of the unfilled polymer, membrane tubing, T-body and removal threads were evaluated
for mutagenic potential in the following in vitro and in vivo tests: reverse gene mutation in vitro in
four Salmonella typhimurium and one Escherichia coli strains of bacteria, TK mutation test in
mouse lymphoma L5178Y cells in vitro, chromosomal aberrations in human peripheral blood
lymphocytes in vitro, and the induction of micronuclei in the bone marrow of mice.

Extracts of the unfilled polymer did not show any evidence of mutagenic or clastogenic activity in
vitro and did not induce chromosomal changes or other damage to micronucleus formation in
polychromatic erythrocytes in vivo after intraperitoneal administration to mice.

Saline and aqueous extracts of the levonorgestrel-releasing reservoir were negative except for the
chromosomal aberration test in CHO cells. Treatment of cultures of CHO cells with the highest
dose of DMSO extracts of the levonorgestrel-releasing reservoir, which were also precipitating,
resulted in small increases in the number of cells with aberrations (attributed to polyploidy) in a
single culture at the 20 and 44 hour sampling times during the second of two independent
experiments. Pure levonorgestrel was not mutagenic or clastogenic in any of the tests. No
clastogenic effect was detected for saline or arachis oil extracts tested in vivo in the mouse
micronucleus test. The results of these studies indicate that it is very unlikely that the materials
used in the levonorgestrel-releasing reservoir of MIRENA would cause genetic damage in humans
under the conditions of clinical use.

Saline and non-aqueous extracts of the T-body containing low-density polyethylene (with 20-24%
barium sulphate), and of removal threads containing high-density polyethylene (with 1% iron
oxide) were not mutagenic or clastogenic in vitro and did not induce chromosomal changes or


M20606EP Page 38
other damage to micronucleus formation in polychromatic erythrocytes in vivo after intraperitoneal
administration to mice.

Local Tolerance Studies
Saline and non-aqueous extracts of the unfilled polymer, membrane tubing, T-body and removal
threads were evaluated for biocompatibility using the following in vitro and in vivo test systems:
cytotoxicity test in mouse fibroblasts, guinea pig maximization test, intracutanous test in rabbits,
systemic injection test in mice, pyrogen testing, muscle implantation test in rabbits and a test for
hemolysis.

The results of these tests indicated acceptable biocompatibility of both the unfilled polymer and
the membrane tubing. No remarkable in vitro cytotoxicity or hemolysis was detected. There was
no evidence of delayed contact hypersensitivity, intracutaneous injection site irritation or test
article-related clinical signs of systemic toxicity including pyrogenicity, after treatment with saline
or sesame oil extracts.

In the muscle implantation test for the unfilled polymer, very thin encapsulation was observed on
the test article implants and in one of the negative control implants. This was correlated with
minimal microscopic changes (few to moderate inflammatory cells) in both test and control
implants, indicating that the unfilled polymer was well tolerated.

A similar result was observed in the muscle implantation test for the membrane tubing, a very thin
encapsulation of the test and control implants which was detected at necropsy on Day 90 was
correlated with minor microscopic changes (fibrosis), indicating that the membrane tubing was
well tolerated.

With regard to the low-density polyethylene T-body, no remarkable in vitro cytotoxicity or
hemolysis was detected. There was no evidence of delayed contact hypersensitivity,
intracutaneous injection site irritation or test article-related clinical signs of systemic toxicity,
including pyrogenicity after treatment with saline or sesame oil extracts. In the muscle
implantation test for the T-body, a very thin encapsulation of one test article implant which was
detected at necropsy on Day 90 was correlated with only minor microscopic changes (minimal to
slight fibrosis, minimal necrosis and minimal hemorrhage). The same test for the removal threads
showed a very thin encapsulation of the test article and USP negative control plastic implants
which were detected at necropsy on Day 90, and were correlated with only minor histology
(minimal to slight fibrosis). The results of these tests indicate that both the T-body and the
removal thread were well tolerated.

Long-term Toxicity
A one-year intrauterine toxicity study of MIRENA was conducted in Rhesus monkeys using a
smaller modified version of the system delivering 12.3 µg levonorgestrel per day. The raw
materials were the same as those used in the formulation of MIRENA with the exception that the
polydimethylsiloxane polymer was catalyzed using stannous octoate rather than peroxide. The


M20606EP Page 39

system caused suppression of ovulation in four of eight monkeys, reduced uterine weights and
resulted in the expected decidual endometrial changes. Cervical morphology was within normal
limits and there was a slight shortening of partial thromboplastin time (which was also seen in the
monkeys implanted with inert devices). Plasma levels of levonorgestrel varied between 0.1 and
0.4 ng/mL.

Overall, there was no significant difference observed between the monkeys with the
levonorgestrel-releasing intrauterine system and those with the inert intrauterine system used in the
study.

Reproduction and Teratology
A smaller modified version of MIRENA was used for a reproductive toxicology study in rabbits.
It consisted of a cylinder (diameter 2.4 mm, length 7 mm) with an inner core (5 mm) containing 12
mg levonorgestrel mixed with polydimethylsiloxane polymer, with a polydimethylsiloxane
polymer membrane fitted over the core for release rate control. The release rate was calculated to
be 3.5 µg levonorgestrel per day. One system was put into each uterine horn of the pregnant
rabbits.

Treatment did not have any adverse effect on litter parameters such as body weight and gross
pathology, embryonic or fetal development. One rabbit in the treatment group had a hemorrhagic
endometrium observed at Caesarean section. No treatment-related adverse effects were observed.



M20606EP Page 40
REFERENCES

1. Andersson, K. et al. Levonorgestrel-releasing and Copper-releasing (Nova T) IUDs
During Five Years of Use: A Randomised Comparative Trial. Contraception 1994; 49:56-
72.

2. Nilsson, C.G. and Lahteenmaki, P. Recovery of Ovarian Function After the Use of a
d-Norgestrel-releasing IUD. Contraception 1977; 15:389-400.

3. Silverberg, S.G. et al. Endometrial Morphology During Long-Term Use of
Levonorgestrel-Releasing Intrauterine Devices. International Journal of Gynecological
Pathology 1986; 5:235-241.

4. Sturridge, R. and J. Guillebaud. A Risk-Benefit Assessment of the Levonorgestrel-
Releasing Intrauterine System. Drug Safety 1996; 15:430-440.

5. Gupta, S. Non-oral Hormonal Contraception. Current Obstetrics & Gynecology 2003;
13:30-37.




IMPORTANT: PLEASE READ

M20606EP Page 41

PART III: CONSUMER INFORMATION

MIRENA
Levonorgestrel-releasing Intrauterine System

This leaflet is part III of a three-part "Product Monograph"
published when MIRENA was approved for sale in Canada
and is designed specifically for Consumers. This leaflet is a
summary and will not tell you everything about MIRENA.
Contact your doctor or pharmacist if you have any questions
about the drug.


ABOUT THIS MEDICATION

What the medication is used for:
$ to prevent pregnancy

For preventing pregnancy, MIRENA is as effective as oral
contraceptives. Clinical trials found that there were about 2
pregnancies per year for every 1,000 women using MIRENA.

What it does:
MIRENA is an intrauterine system which prevents pregnancy by
slowly releasing small amounts of a synthetic sex hormone known
as levonorgestrel into the uterus. Levonorgestrel is a hormone
commonly used in combination oral contraceptives (the “Pill”) and
is similar to progesterone, a sex hormone produced naturally by the
body.

MIRENA works by slowly releasing levonorgestrel into the uterus
at a rate of approximately 20 micrograms per day. This small
amount of levonorgestrel prevents pregnancy by:
• reducing the normal monthly thickening of the lining of the
uterus.
• thickening the cervical mucus which prevents passage of
sperm through the cervical canal (opening to the uterus).

MIRENA contains a total of 52 mg of levonorgestrel which is
enough hormone to prevent pregnancy for five years.

When it should not be used:
• if you are pregnant, or if you suspect that you may be
pregnant.
• if you have or have had pelvic inflammatory disease (see the
paragraph in this leaflet titled “Infections”)
• if you have an infection of your lower genital tract
• if you have had a womb infection after delivering a baby
• if you have bleeding from the vagina that has not been
explained
• if you have a condition of the uterus that distorts the uterine
cavity, such as large fibroids
• if you have an infection of the cervix (neck of the womb)
• if you have cell abnormalities in the cervix (your doctor can
tell you if you have this)
• if you have liver problems, including liver cancer
• have had a womb infection after having an abortion during
the past 3 months
• have any allergies to the hormone levonorgestrel, or to any of
the other ingredients of MIRENA, or to components of the
container (see the section in this leaflet titled “What the
important nonmedicinal ingredients are”)
• if you have bacterial endocarditis (a doctor will have told you
if you have this)
• if you have immunodeficiency (a doctor will have told you if
you have this)
• if you have cancer affecting the blood, or if you have
leukemia
• if you have or have had trophoblastic disease (a doctor will
have told you if you have this).

What the medicinal ingredient is:
levonorgestrel

What the important nonmedicinal ingredients are:
barium sulphate, iron oxide, polydimethysiloxane, polyethylene,
silica.

What dosage form it comes in:
Each MIRENA (levonorgestrel-releasing intrauterine system)
contains 52 mg of levonorgestrel to deliver up to 20µg
levonorgestrel per day, and is packaged in a pouch within an
insertion device.

WARNINGS AND PRECAUTIONS

Serious Warnings and Precautions

MIRENA DOES NOT PROTECT against sexually
transmitted diseases (STDs), including HIV/AIDS. For
protection against STDs, it is advisable to use latex condoms.


BEFORE you use MIRENA, talk to your doctor or
pharmacist if you:
• are breast-feeding
• have ever had an ectopic pregnancy (development of a
fertilized egg outside the uterus) (see the paragraph in this
leaflet titled “Ectopic pregnancy”).
• have had surgery on your fallopian tubes.
• have a history of ovarian cysts (see the paragraph in this
leaflet titled “Cysts on the ovary”)
• have an unusual menstrual bleeding pattern.
• have an unusual or unpleasant (e.g. smelly) vaginal discharge
or vaginal itching.
• have had a stroke, heart attack or any heart problems.
• have or have had jaundice (a yellowing of the whites of the
eyes and/or nails)
• are diabetic or have a family history of diabetes (see the
following paragraph in this leaflet titled “Diabetes”), have
IMPORTANT: PLEASE READ


M20606EP Page 42

high blood pressure or abnormal blood lipid levels.
• have a history of blood clots (thrombosis).
• are on long-term steroid therapy or are taking any other
medications.
• have a history of migraine, dizziness or blurred vision.
• have severe headaches.
• have a history of depression
• wear contact lenses
• have an abnormality of your heart or if you have any problem
with your heart valves

MIRENA is not the method of first choice for young women who
have never been pregnant, nor for postmenopausal women with
shrinking of the womb.
Diabetes
In diabetic users of MIRENA, the blood glucose concentration
should be monitored.

Infections
A serious pelvic infection called pelvic inflammatory disease
(PID) may occur in some users of MIRENA. PID is usually
sexually transmitted. You have a higher chance of getting PID if
you or your partner have sex with other partners. PID can cause
serious problems such as infertility, ectopic pregnancy, or constant
pelvic pain. PID is usually treated with Antibiotics , however, more
serious cases of PID may require surgery. Tell your doctor right
away if you have any of these signs of PID: long-lasting or heavy
bleeding, unusual vaginal discharge, low abdominal (stomach area)
pain, painful sex, chills or fever.

Ectopic pregnancy
Ectopic pregnancy (development of a fertilized egg outside the
uterus) is possible, as it is in women using no contraception, but is
highly unlikely. You should tell your doctor if you have lower
abdominal (tummy) pain especially if you have missed a period or
have unexpected bleeding. This might be a sign of ectopic
pregnancy.

Cysts on the ovary
Cysts on the ovary commonly occur in women using MIRENA.
These cysts usually disappear on their own within a few months.
However, cysts can sometimes cause pain and may need medical
attention.

Driving or Using Machines
The effects of MIRENA on the ability to drive or to use machines
have not been studied.

Uterine Perforations
In rare cases (occurring at a rate of between 1/1,000 and 1/10,000),
and most often during insertion, MIRENA may penetrate or
perforate the wall of the uterus. If this happens, the system must
be removed.


Abnormal Blood Clotting
Some studies have suggested that women who use progestogen-
only oral contraceptives might have a slightly higher risk of blood
clots, however the results are not certain. You should discuss risk
factors for blood clots with your doctor since blood clots can be
life threatening or cause serious disability.

Can I breast-feed while using MIRENA?
Small quantities of levonorgestrel, the medicinal ingredient in
MIRENA, have been found in the milk of breast-feeding women
using MIRENA; however, there does not appear to be a
detrimental effect on growth or development of breast-fed infants
whose mothers started using the product six weeks after delivery.

How will MIRENA affect my periods?
MIRENA will affect your menstrual cycle. You might experience
frequent spotting (a small amount of blood loss) or light bleeding
in addition to your periods for the first 3 to 6 months. In some
cases, you may have heavy or prolonged bleeding during this
time.

Overall, you are likely to have a gradual reduction in the number
of bleeding days and in the amount of blood loss each month.
Some women using MIRENA eventually find that their periods
stop altogether.

When the system is removed, periods return to normal.

What if I stop having periods?
Gradually, over time, your menstrual period may disappear. This
is because of the effect of the hormone on the lining of the uterus.
The normal monthly thickening of the uterine lining with blood
does not happen, therefore there is little or no bleeding, as
happens during a usual menstrual period. It does not necessarily
mean you have reached menopause or are pregnant. Your own
hormone levels remain normal.

If, however, you are having regular menstrual periods and then do
not have one for 6 weeks or longer, it is possible that you may be
pregnant. You should speak to your doctor.


INTERACTIONS WITH THIS MEDICATION

Please inform your doctor or pharmacist if you are taking or have
recently taken any other drugs or herbal products, even those
without a prescription.

Hormonal contraceptives may become less reliable if you are also
taking drugs that affect the liver (such as primidone, barbiturates,
phenytoin, carbamazepine, rifampicin and griseofulvin) at the
same time. The influence of these drugs on the reliability of
MIRENA has not been studied, but is unlikely since MIRENA
releases a very small amount of hormone, and delivers inside the
uterus.

IMPORTANT: PLEASE READ

M20606EP Page 43

The T-frame of MIRENA contains barium sulphate, which makes
it visible in X-ray examinations.


PROPER USE OF THIS MEDICATION

Usual Dose

What it looks like:




MIRENA consists of a small white T-shaped frame made from
soft, flexible plastic. The vertical and horizontal arms of the T are
approximately 3 cm in length. The vertical arm is surrounded by a
narrow cylindrical shaped reservoir that contains levonorgestrel.
Two fine plastic threads are attached to the tip of the vertical arm.
These threads are intended to be used for removal of the system
and also serve to check its presence once it is in place.


How is MIRENA inserted?
Before MIRENA is inserted, your doctor should perform an
examination, which may include a Pap smear, a breast examination
and other tests, e.g., a test to make sure you aren’t pregnant, and
tests for infections, including sexually transmitted diseases, as
necessary. Infections must be successfully treated before
MIRENA is inserted.

You will also have a pelvic examination to determine the position
and size of your uterus. Following this, your doctor will insert the
thin flexible plastic tube of the insertion device containing
MIRENA into your uterus. At this point you may feel a little
discomfort.

Once MIRENA is in the correct position, your doctor will
withdraw the tube leaving the system in place in the uterus.
Finally, your doctor will trim the removal threads to a suitable
length.

After insertion you may feel some cramp-like menstrual pain;
however, this usually disappears within a few days.

Most women find that the insertion procedure causes minor
discomfort, however, for some it may be more uncomfortable. If
concerned, you may wish to discuss the need for a painkiller or
local anesthetic with your doctor. Some women may feel faint
after the system is inserted, but this feeling subsides after a short
rest. The insertion procedure may precipitate a seizure in epileptic
patients.

It is uncommon but, part or all of the system may penetrate the
wall of the uterus during insertion and come to rest outside the
uterus. If this happens the system must be removed.

When should MIRENA be inserted?
The system should be inserted during your period or within seven
days of it starting. When replacing an existing system for a new
one, it is not necessary to wait for your period.

Following childbirth, MIRENA should not be fitted until 6 weeks
after delivery.

How long does insertion take?
The insertion procedure usually takes a few minutes after your
doctor has completed the pelvic examination.

How quickly does MIRENA start to work?
You will be protected from pregnancy as soon as insertion of the
system is complete, however, it is best to wait 24 to 48 hours
before having sexual intercourse.

How often should I have MIRENA checked?
You should have the system checked approximately 6 weeks after
it is fitted, again at 12 months and then once-a-year until it is
removed. MIRENA can stay in place for 5 years before it must
be removed.

You should see your doctor if:
• you cannot feel the threads anymore.
• you can feel the lower end of the system.
• you think you are pregnant.
• you have persistent abdominal pain, fever or unusual
discharge from the vagina.
• you or your partner feels pain or discomfort during sexual
intercourse.
• there are sudden changes in your menstrual periods, for
example, if your menstrual periods stop completely and then
you have persistent bleeding or pain, or if you have little or
no menstrual bleeding and then you start bleeding heavily.
• you have other medical problems, such as migraine
headaches or intense headaches that recur, sudden problems
with vision, jaundice (a yellowing of the whites of the eyes or
skin) or any of the other symptoms listed in the table titled
Serious Side Effects in this leaflet, or if you are told you have
high blood pressure.
IMPORTANT: PLEASE READ


M20606EP Page 44

• you are diagnosed with any of the medical conditions listed in
the “Who should not use this medication” and “Warnings and
precautions” sections of this leaflet.

How can I check if MIRENA is in place?
After each menstrual period or about once a month, you should
check by feeling if the two threads are still in place. Your doctor
will show you how to do this. Do not pull on the threads as you
may accidentally pull the system out.

If you cannot feel the threads, see your doctor and in the meantime
use another method of contraception. You should also see your
doctor if you can feel the lower end of the system itself.

Can I become pregnant while using MIRENA?
Although it is very rare, it is possible for you to become pregnant
with MIRENA in place.

If you do not have your period at the normal time and have other
symptoms of pregnancy (e.g. nausea, tiredness, breast tenderness),
you should see your doctor for an examination and pregnancy test.

If you become pregnant with MIRENA in place, you should have
it removed as soon as possible. If it is left in place during
pregnancy, the chances of having a miscarriage or premature
delivery increases. The effect of levonorgestrel on a developing
infant is not well known, therefore a detrimental effect cannot be
completely ruled out. You may wish to consider termination of the
pregnancy. Your doctor will advise you.

What if I want a baby?
If you want a baby, ask your doctor to remove MIRENA. Your
usual level of fertility will return very quickly after the system is
removed. Nearly 90% of women wishing to become pregnant
conceive within 24 months after removal of the system.

Will MIRENA interfere with sexual intercourse?
During sexual intercourse, you or your partner should not be able
to feel MIRENA. If you can feel MIRENA, or any pain or
discomfort that you suspect may be caused by it, then you should
not have sexual intercourse until you see your doctor to verify it is
still in the correct position.

Can tampons be used?
Use of sanitary pads is recommended. If tampons are used, you
should change them with care so as not to pull the threads of
MIRENA.

Can MIRENA fall out?
It is unlikely, but possible that MIRENA can come out either
completely or partially. If this happens you are not protected
against pregnancy.

An unusual increase in the amount of bleeding during your period
might be a sign that this has happened. You can check that
MIRENA is in place by feeling for the threads as explained by
your doctor.

If you think it has come out, use another method of contraception
until you see your doctor.

Removal of MIRENA
You should see your doctor when you want to have MIRENA
taken out. You can do this at any time and removal is very easy,
however, you should be aware that you may become pregnant
upon removal of the system if you have had sexual intercourse
during the previous week.

Tell your doctor if you have had sexual intercourse during the
preceding week.


SIDE EFFECTS AND WHAT TO DO ABOUT THEM

Cysts on the ovary and menstrual bleeding irregularity (or of
increased amount), are the most common side effects of MIRENA
during the first months after the system is inserted, but these
effects should decrease over time. Other side effects might
include lower abdominal pain, headache, Acne or other skin
problems, tender breasts, backache, depression, a feeling of
sickness, or menstrual pain.

The following side effects generally do not require medical
attention, and will usually go away as your body adjusts to
MIRENA:

Common: changes in bleeding (frequent, prolonged or
heavy bleeding, spotting) nausea (feeling sick),
acne, breast pain or swelling, weight gain.

Uncommon: Hair loss or excessive body hair, decreased
sexual desire.

If you think you are reacting poorly to MIRENA or are having
other problems, please tell your doctor.

















IMPORTANT: PLEASE READ

M20606EP Page 45

SERIOUS SIDE EFFECTS, HOW OFTEN THEY HAPPEN,
AND WHAT TO DO ABOUT THEM
Talk with your doctor
or pharmacist
Symptom / effect
Only if
severe In all
cases
Common

Vaginal bleeding
Symptoms of vaginal
infection, such as itching,
or unusual or increased
vaginal discharge
Headache
Dizziness
Abdominal pain
Pelvic or back pain
Feeling depressed or
nervous
Skin rash, hives, eczema
(itchy skin lesions)
Expulsion of MIRENA



























SERIOUS SIDE EFFECTS, HOW OFTEN THEY HAPPEN,
AND WHAT TO DO ABOUT THEM
Talk with your doctor
or pharmacist
Symptom / effect
Only if
severe In all
cases
Uncommon

Severe lower abdominal
pain which may be
together with bleeding,
possibly meaning
perforation of the uterus.
Migraine
Feeling of fullness or
tightness in the abdomen
Itching of the skin
Persistent lower
abdominal pain, together
with fever or unusual
discharge from the
vagina, possibly meaning
pelvic infection.
Persistent lower
abdominal pain, together
with nausea or breast
tenderness and/or vaginal
bleeding, possibly
meaning intrauterine
pregnancy, miscarriage,
or extrauterine pregnancy.





































This is not a complete list of side effects. For any unexpected
effects while taking MIRENA, contact your doctor or
pharmacist.



IMPORTANT: PLEASE READ


M20606EP Page 46

REPORTING SUSPECTED SIDE EFFECTS

To monitor drug safety, Health Canada collects
information on serious and unexpected effects of drugs. If
you suspect you have had a serious or unexpected reaction
to this drug you may notify Health Canada by:

toll-free telephone: 866-234-2345
toll-free fax 866-678-6789
By email: cadrmp@hc-sc.gc.ca

By regular mail:
Canadian Adverse Drug Reaction Monitoring Program
(CARDMP)
Marketed Health Products Safety and Effectiveness
Information Division
Marketed Health Products Directorate
Tunney’s Pasture, AL 0701C
Ottawa ON K1A 0K9

NOTE: Before contacting Health Canada, you should
contact your physician or pharmacist.

MORE INFORMATION

This document plus the full product monograph, prepared for
health professionals can be found at:
http://www.berlex.ca

or by contacting the sponsor, Berlex Canada Inc., at:
1 800 361-0240

This leaflet was prepared by Berlex Canada Inc.

Last revised: June 27, 2006. Tweet