Get your patient on Miudella - Copper intrauterine Device (Copper)

• Miudella is supplied sterile in a sealed package with a sterile single use inserter for placement. Do not open the package until required for insertion. Do not use if the seal of the sterile package is broken or appears compromised.
• Before considering use of Miudella, make sure that the patient is an appropriate candidate for Miudella. Exclude pregnancy (consider the possibility of ovulation and conception) prior to use [see Contraindications (4) and Warnings and Precautions (5) ].
• Only a healthcare provider should insert Miudella. Healthcare providers should be thoroughly familiar with the product, product educational materials, product insertion instructions, and prescribing information before inserting Miudella.
• The IUS is provided preloaded in the inserter (see Figure A ).
• Remove Miudella on or before 3 years from the date of insertion.
• Replace Miudella at the time of removal with a new Miudella if continued contraceptive protection is desired.

Figure A : Miudella Intrauterine System (IUS) Preloaded Inserter

• Figure B: Detailed diagram of Miudella

• Miudella can be inserted at any time during the menstrual cycle. If switching to Miudella from another contraceptive, discontinue the previous method (see Table 1 ).

1. Ensure use of clean technique during the procedure.
2. Perform a bimanual exam to establish the size, shape, and position of the uterus and to rule out abnormalities that would preclude safe placement of Miudella.
3. Gently insert a speculum to visualize the cervix.
4. Thoroughly cleanse the cervix with chlorhexidine or povidone-iodine.
5. Apply a sterile tenaculum to the cervix. Apply traction with the tenaculum. Gently advance a sterile uterine sound to the fundus. Note any uterine anomaly and the depth in centimeters.

Step 1 – Open the Sterile Package
Remove the sterile packaging containing Miudella from the box. Inspect the packaging to confirm a sterile barrier is maintained. Do not use if the packaging is not intact or there are concerns of compromised sterility.
Peel back the paper lid ¾ of the way up the package to expose the inserter handle and flange.	c.
• Step 2 – Setting the Flange
Grasp the handle while maintaining your thumb or forefinger on the slider to restrict its movement. Gently lift the handle from the package, taking care not to bend or kink the insertion tube. Use the paper lid to hold the flange in the notch of the package, slowly pull the handle back, while keeping the flange in the notch, until the flange is set to the desired depth measured during sounding. Alternately, set the flange with sterile gloves after you have lifted the inserter out of the packaging. After setting the flange, remove the inserter from the package.	a.
Inspect the end of the inserter to confirm that Miudella is positioned as shown.	c.
• Step 3 – Inserter Placement
Continue applying upward pressure with the thumb/forefinger on the slider to avoid early deployment of the IUS. Maintain traction with the tenaculum and gently advance the inserter through the cervical canal. Progress slowly towards the fundus until the flange is at the level of the external cervical os and the tip of the inserter is at the fundus. CAUTION: Do not advance the flange beyond the external os, as this may result in fundal perforation. NOTE: Do not force the inserter into the external or internal cervical os. If necessary, consider use of an os finder or a small cervical dilator .	a.
Step 4 -Miudella Placement
Once the flange is at the level of the external os, gently withdraw the inserter back towards you 1–2 cm.	a.
With the inserter tip 1-2 cm from the fundus (i.e., with the flange 1-2 cm from the os), move the slider to position ①.	b.
Holding the slider securely in position ①, slowly re-advance the inserter until you feel the fundus.	c.
With the IUS at the fundus, hold the inserter steady and move the slider to position ②.	d.
Release Miudella from the inserter: Hold the inserter handle steady with one hand and grasp the end cap with the other hand.
While holding the inserter steady with one hand, twist the green end cap (labeled ③ ) ½ - ¾ turn to the left with the other hand.
Remove end cap. One end of the white release thread is attached to the end cap as shown in the diagram and removing the end cap initiates removal of the release thread.	iii.
Completely remove the white release thread from the inserter until you see the free end of the thread Do not cut the white release thread. The length of the release thread is approximately twice the length of the inserter.	iv.
Slowly remove the inserter from the cervix and vaginal cavity and properly dispose of the inserter and end cap with release thread.

• Step 5 – Confirm the Retrieval Thread Ends
  1. Confirm that the blue retrieval thread ends are visible past the external os. The retrieval thread ends are pre-cut to typically allow 3-4 cm of exposed thread in the vaginal cavity without the need for trimming, and hence cutting of excess thread length is generally not required.
  2. Should additional trimming of the thread ends be desired, cut the thread ends perpendicular to the thread length, for example, with sterile curved scissors, leaving the desired amount of visible length outside the cervix.
  3. Remove the tenaculum and achieve adequate hemostasis.
  4. Remove speculum from the vaginal cavity.
  5. Miudella placement is now complete.
• Important information to consider during and after placement:
  • If you suspect that Miudella is not in the correct position, check placement (for example, with transvaginal ultrasound). Remove Miudella if it is not positioned completely within the uterus. A removed Miudella must not be reused.
  • If there is clinical concern and/or exceptional pain or bleeding during or after placement, conduct appropriate and timely measures and assessments. For example, ultrasound should be performed to exclude perforation, embedment, or translocation.

Intrauterine system: 175 mm ² exposed copper surface area. Miudella is a copper-containing IUS that has a flexible nitinol frame with copper sleeves and monofilament polymer retrieval thread, preloaded in a sterile inserter with a tapered rounded tip and packaged in a sealed tray with lid.

The safety and effectiveness of Miudella have been established in females of reproductive potential. Efficacy is expected to be the same for postmenarcheal females regardless of age. Miudella is not indicated in females before menarche.

Miudella has not been studied in women over 65 years of age and is not indicated in this population.

Improper insertion of intrauterine systems, including Miudella, increases the risk of perforation, infection, undiagnosed abnormal bleeding, pregnancy loss (if pregnancy occurs with IUS in situ), and expulsion.

Proper training prior to first use of Miudella can minimize the risk of improper insertion. Miudella is available only through a restricted program under a REMS [see Warnings and Precautions (5.2) ].

Miudella is only available through a restricted program under a REMS called Miudella REMS Program to ensure healthcare providers are trained prior to first use [see Warnings and Precautions (5.1) ]. Notable requirements include the following:

• Healthcare providers must be certified with the program by enrolling and completing training on the proper insertion of Miudella prior to first use [see Warnings and Precautions (5.2) ].
• Pharmacies and healthcare settings that dispense Miudella must be certified by enrolling in the REMS and must only dispense Miudella to certified healthcare providers.

Further information is available at miudellarems.com and 1-855-337-0772.

Evaluate for possible ectopic pregnancy in any female who becomes pregnant while using Miudella because a pregnancy that occurs with Miudella in place is more likely to be ectopic than a pregnancy in the general population. However, because Miudella prevents most pregnancies, females who use Miudella have a lower risk of an ectopic pregnancy than sexually active females who do not use any contraception.

The incidence of ectopic pregnancy in the clinical trials with Miudella was approximately 0.3%. Ectopic pregnancy may require surgery and may result in loss of fertility.

Patients who use Miudella should be informed about recognizing the signs and symptoms of ectopic pregnancy and promptly reporting them to their healthcare professional, and about the associated risks of ectopic pregnancy (e.g., loss of fertility).

If intrauterine pregnancy occurs with Miudella in place and the thread ends are visible or can be retrieved from the cervical canal, remove Miudella. Leaving it in place may increase the risk of spontaneous abortion and preterm labor. Removal of Miudella may also result in spontaneous abortion. In the event of an intrauterine pregnancy with Miudella, consider the following:

Severe infection or sepsis, including Group A streptococcal sepsis (GAS), have been reported following insertion of IUSs. In some cases, severe pain occurred within hours of insertion followed by sepsis within days. Because death from GAS is more likely if treatment is delayed, it is important to be aware of these rare but serious infections. Aseptic technique during insertion of Miudella is essential to minimize serious infections such as GAS.

Promptly examine users with complaints of lower abdominal or pelvic pain, odorous discharge, unexplained bleeding, fever, genital lesions or sores. Remove Miudella in cases of recurrent pelvic inflammatory disease or endometritis, or if an acute pelvic infection is severe or does not respond to treatment.

Partial or total perforation of the uterine wall or cervix may occur during insertions, although the perforation may not be detected until sometime later. Perforation may also occur at any time during IUS use. Perforation that results in embedment or translocation may reduce contraceptive efficacy and result in pregnancy. The incidence of perforation during or following Miudella insertion in clinical trials was 0.1% (2 out of 1904).

A post-marketing safety study conducted in Europe (EURAS IUS) with IUSs, including copper IUSs, demonstrated an increased risk of perforation in postpartum and lactating women. The risk of perforation may be increased if an IUS, such as Miudella, is inserted when the uterus is fixed, retroverted or not completely involuted during the postpartum period.

If perforation is suspected or if known perforation occurs during placement, the IUS should be removed as soon as possible. Surgery may be required. Preoperative imaging followed by laparoscopy or laparotomy may be required to remove the IUS from the peritoneal cavity. Delayed detection or removal of Miudella in cases of perforation may result in migration outside the uterine cavity, adhesions, peritonitis, intestinal penetration, intestinal obstruction, abscesses and/or damage to adjacent organs.

Partial or complete expulsion of Miudella has been reported, resulting in the loss of contraceptive protection. The incidence of expulsion in the clinical trials with Miudella was 3.6% through 3 years of use. Consider further diagnostic imaging, such as x-ray, to confirm expulsion if the IUS is not found in the uterus on ultrasound.

Miudella should be placed no earlier than 4 weeks post-pregnancy to mitigate the risk of expulsion that may be increased when the uterus is not completely involuted at the time of insertion. Remove a partially expelled Miudella and do not attempt to push a partially expelled Miudella into the uterus. If expulsion has occurred, a new Miudella may be inserted when there is reasonable certainty the patient is not pregnant.

Miudella may exacerbate Wilson's disease, a rare genetic disease affecting copper excretion; therefore, the use of Miudella is contraindicated in females with Wilson's disease [see Contraindications (4) ] .

Miudella can alter the bleeding pattern and result in heavier and longer menstrual cycles with intermenstrual spotting.

In three clinical trials with Miudella [see Adverse Reactions (6.1) ] , menstrual changes were the most common medical reason for discontinuation. Discontinuation rates for pain and bleeding combined were highest in the first year of use and diminished thereafter. The percentage of females who discontinued Miudella because of bleeding problems or pain during this study ranged from 8.5% in the first year to 3.2% in Year 3. Females complaining of heavy vaginal bleeding should be evaluated and treated, and may need to discontinue Miudella [see Adverse Reactions (6.1) ] .

Medical equipment that contains high levels of Radiofrequency (RF) energy such as diathermy may cause health effects (by heating tissue) in females with a metal-containing IUS including Miudella. Avoid using high medical RF transmitter devices in females with Miudella.

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice.

The data described below reflect exposure of 1,904 healthy 17- to 45-year-old women (mean age 27.5 ± 5.72 years) to Miudella. These data come from two multi-center contraceptive trials with a 3-year duration and a single, multi-center comparative bioavailability study with a 3 year duration, all conducted in the United States, enrolling generally healthy, postmenarcheal females to 45 years old. In total 1,904 subjects were exposed to Miudella for one year and 916 completed three years. The data in these trials cover approximately 51,692 cycles of exposure.

The following adverse reactions have been observed in ≥5% of users in clinical trials with Miudella: heavy menstrual bleeding, dysmenorrhea, intermenstrual bleeding, pelvic discomfort, procedural pain, pelvic pain, post procedural hemorrhage, and dyspareunia.

Table 2 shows discontinuation rates from the 3 multi-center clinical studies by adverse reaction and year.

According to the safety analyses of these three studies, it was determined the incidence of expulsion of Miudella did not vary significantly by body mass index (BMI). There was no statistically significant difference in the incidence of expulsion of Miudella in normal weight versus obese females.

Miudella (copper intrauterine system) contains 99.99% pure copper for use as a contraceptive. Copper (Cu) has a molecular weight of 63.546 g/mol. Miudella consists of ten copper sleeves attached to a flexible nitinol (nickel-titanium alloy) frame measuring 32 mm horizontally and 30 mm vertically, and a polypropylene monofilament retrieval thread tied to the vertical stem. Miudella has a total exposed copper surface area of 175 mm ² and is provided sterile and preloaded in an inserter.

• Figure C: Diagram of Miudella

The inserter device provided with Miudella is a single use, disposable, sterile insertion system (insertion tube with a tapered rounded tip, depth markings and flange, and handle with slider and endcap); preloaded with the IUS for intrauterine administration. Once Miudella has been inserted, the inserter is discarded.

Figure D: Diagram of Inserter

Copper continuously released into the uterine cavity contributes to the contraceptive effectiveness of Miudella. Mechanism(s) by which copper enhances contraceptive efficacy include interference with sperm transport and fertilization of an egg.

The exposure-response relationship and time course of pharmacodynamic response for the safety and effectiveness of Miudella have not been fully characterized.

The pharmacokinetics (PK) of copper following insertion of Miudella were investigated in 20 healthy premenopausal female adult subjects. Table 3 shows PK parameters of serum copper with or without baseline-adjustment following 57 days after insertion, and serum copper concentrations during 3 years after insertion.

Adequate long-term studies in animals to assess the carcinogenic potential of a copper-containing IUS have not been performed.

A chemical characterization and toxicological risk assessment of the extractables derived from the copper-containing IUS were utilized to address carcinogenicity, mutagenicity and reproductive/developmental toxicity risks. The toxicological risk assessment indicates that the risks of carcinogenicity, mutagenicity and reproductive/developmental toxicity caused by the copper-containing IUS are negligible.

Store at 20°C to 25°C (68°F to 77°F); excursions permitted between 15°C to 30°C (59°F to 86°F) [see USP Controlled Room Temperature].