Donasert^® Uno (Intrauterine System) Instructions for Use

Marketing Authorization Holder

Gedeon Richter, Plc. (Hungary)

Manufactured By

Gedeon Richter, Plc. (Hungary)

Or

Odyssea Pharma, SPRL (Belgium)

Contact Information

GEDEON RICHTER Plc. (Hungary)

ATC Code

G02BA03 (Plastic IUDs with gestagens)

Active Substance

Levonorgestrel (Rec.INN registered by WHO)

Dosage Form

Donasert® Uno

Therapeutic intrauterine system 20 mcg/24 hours: 1 pc.

Dosage Form, Packaging, and Composition

Therapeutic intrauterine system (IUS) consists of a white reservoir covered by a membrane, mounted on the vertical part of the T-shaped frame. A double blue thread is attached to the loop on the T-shaped frame. The vertical part of the T-shaped frame and the thread are placed in an insertion tube, which is graduated from 5 (at the top) to 12 (at the bottom) with the unit of measurement (“cm”). A movable blue indicator ring is located on the insertion tube. The handle of the inserter contains a blue slider marked with the number “1”, and a green slider marked with the number “2”. The white handle body is marked with the number “3”. The thread is located inside along the entire length of the insertion device and exits from the rear end of the handle.

The release rate of levonorgestrel from the therapeutic intrauterine system is approximately 20 mcg per day.

Excipients: polydimethylsiloxane elastomer: silicone base, tetra-n-propyl silicate, stannous octoate; polydimethylsiloxane membrane; T-shaped frame made of low-density polyethylene with 20-24% barium sulfate; polypropylene thread dyed with copper phthalocyanine.

1 IUS – sterile trays made of transparent thermoformed film (1) with an insertion device* – cardboard packs with first-opening control.

* insertion device, consisting of: high-density polyethylene insertion tube with a graduated scale applied by tampon printing; low-density polyethylene indicator ring; acetal plunger; polystyrene handle (made of two parts); main polystyrene slider (made of two parts) and polybutylene terephthalate thread slider.
A transparent self-adhesive film for first-opening control is applied to the valves of the cardboard pack.

Clinical-Pharmacological Group

Gestagen

Pharmacotherapeutic Group

Other agents used in gynecology; contraceptives for topical use; intrauterine contraceptives

Pharmacological Action

Mechanism of action

The Donasert^® Uno IUS, which releases Levonorgestrel, exerts primarily a local gestagenic effect. The gestagen (Levonorgestrel) is released directly into the uterine cavity, allowing it to be used in an extremely low daily dose. High concentrations of levonorgestrel in the endometrium contribute to a decrease in the sensitivity of its estrogen and progesterone receptors, making the endometrium unresponsive to estradiol and exerting a strong antiproliferative effect.

When using the levonorgestrel-releasing IUS, morphological changes in the endometrium and a mild local reaction to the presence of a foreign body in the uterus are observed. An increase in the viscosity of cervical mucus prevents the penetration of sperm into the uterine cavity, and due to reduced sperm motility and changes in the endometrium, the likelihood of egg fertilization decreases. In some women, ovulation is suppressed.

Pharmacodynamic effects

In the first months of using the levonorgestrel-releasing IUS, an initial increase in “spotting” vaginal bleeding may be observed due to the process of inhibiting endometrial proliferation. Following this, pronounced suppression of endometrial proliferation leads to a reduction in the duration and volume of menstrual bleeding in women using the levonorgestrel-releasing IUS. Scanty bleeding often transforms into oligo- or amenorrhea. Ovarian function and plasma estradiol concentrations remain normal.

Clinical efficacy and safety

The Donasert^® Uno IUS can be used for the treatment of idiopathic menorrhagia, i.e., menorrhagia in the absence of hyperplastic processes in the endometrium (endometrial cancer, metastatic lesions of the uterus, submucous or large interstitial myomatous node leading to deformation of the uterine cavity, adenomyosis), endometritis, extragenital diseases and conditions accompanied by severe hypocoagulation (e.g., von Willebrand disease, severe thrombocytopenia), the symptoms of which include menorrhagia. In a clinical study of women with heavy menstrual bleeding (≥80 ml per menstrual cycle), the use of the Donasert^® Uno IUS led to a significant reduction in menstrual blood loss within 3-6 months. The volume of menstrual blood loss in women with heavy menstruation decreased by 63% by the end of the third month of use, and an 82% reduction in blood loss was maintained throughout the study (12 months). A less favorable response to treatment is possible in menorrhagias caused by submucous uterine fibroids. Reducing menstrual blood loss lowers the risk of iron deficiency anemia.

Among women using the Donasert^® Uno IUS, menstrual bleeding ceases in 19% after 1 year of use, 27% after 2 years of use, 37% after 3 years of use, 37% after 4 years of use, 40% after 5 years of use, and 40% after 6 years of use.

In the case of idiopathic menorrhagia, the probable mechanism of action of the levonorgestrel-releasing IUS aimed at reducing blood loss is the prevention of endometrial proliferation.

When correctly inserted according to the instructions for medical use, the Donasert^® Uno IUS provides a contraceptive effect. The contraceptive efficacy of the Donasert^® Uno IUS was studied in a large clinical trial. The cumulative pregnancy rate, calculated as the Pearl Index, in women aged 16 to 35 years inclusive was 0.15 (95% confidence interval (CI) 0.02-0.55) after 1 year and 0.18 (95% CI 0.08-0.33) after 6 years.

Previous use of the levonorgestrel-releasing IUS does not affect reproductive function. Results from the contraceptive evaluation study demonstrated rapid return of menstruation (96.7%) within 3 months after removal of the Donasert^® Uno IUS and restoration of fertility (pregnancy occurred in more than 50% of the population for fertility restoration assessment within 4 months after removal of the Donasert^® Uno IUS, and in 85.3% within 12 months). Approximately 85% of women who wished to have a child became pregnant within 12 months after IUS removal (see section “Pregnancy and lactation”).

Pharmacokinetics

The active substance of the Donasert^® Uno IUS is Levonorgestrel. Levonorgestrel is released directly into the uterine cavity. The calculated in vivo release rate at various time points is presented in Table 1.

Table 1. Calculated in vivo release rate for Donasert^® Uno IUS

Absorption

After insertion of the Donasert^® Uno IUS, Levonorgestrel begins to be released immediately into the uterine cavity, as evidenced by measurable plasma concentrations. The in vivo release rate of levonorgestrel from the Donasert^® Uno IUS is initially 20.1 mcg/day and subsequently decreases to 17.5 mcg/day in the first year and to 8.6 mcg/day in the 6th year of use. Levonorgestrel is released directly into the uterine cavity, which ensures low plasma concentrations (252 ± 123 pg/ml 7 days after IUS insertion and 93 ± 45 pg/ml after 6 years) with minimal severity of systemic effects.

The high local drug exposure in the uterine cavity, necessary for the local effect of the levonorgestrel-releasing IUS on the endometrium, provides a high concentration gradient from the endometrium to the myometrium (the concentration of levonorgestrel in the endometrium is more than 100 times higher than its concentration in the myometrium) and low concentrations of levonorgestrel in plasma (the concentration of levonorgestrel in the endometrium is more than 1000 times higher than its concentration in plasma).

Distribution

Levonorgestrel binds non-specifically to plasma albumin and specifically to sex hormone-binding globulin (SHBG). Less than 2% of circulating levonorgestrel is present as free steroid. Levonorgestrel binds to SHBG with high affinity. Therefore, changes in SHBG concentration in plasma lead to an increase (with higher SHBG concentration) or decrease (with lower SHBG concentration) in the total plasma concentration of levonorgestrel.

It has been shown that body weight and plasma SHBG concentration affect the systemic concentration of levonorgestrel, i.e., concentration of levonorgestrel is higher with low body weight and/or high SHBG concentration.

Metabolism

Levonorgestrel is extensively metabolized. The most important metabolic pathways are reduction of the Δ4-3-oxo group and hydroxylation at the 2α, 1β, and 16β positions followed by conjugation. CYP3A4 is the main enzyme involved in the oxidative metabolism of levonorgestrel. Available in vitro data suggest a minor significance of CYP-mediated biotransformation reactions for levonorgestrel compared to reduction and conjugation.

Excretion

The total clearance of levonorgestrel from plasma is approximately 1.0 ml/min/kg. Levonorgestrel is excreted unchanged only in trace amounts. Metabolites are excreted via the intestine and kidneys with an excretion ratio of approximately 1.77.

The T_1/2 in the terminal phase, represented mainly by metabolites, is about one day.

Linearity/non-linearity

The pharmacokinetics of levonorgestrel depend on SHBG concentration, which in turn is influenced by estrogen and androgen concentrations. A decrease in SHBG concentration leads to a decrease in the total plasma concentration of levonorgestrel, indicating non-linearity of levonorgestrel pharmacokinetics over time. Given the primarily local action of the Donasert^® Uno IUS, the influence of changes in systemic levonorgestrel concentrations on the efficacy of the Donasert^® Uno IUS is unlikely.

Indications

For adults over 18 years of age for

• Contraception;
• Treatment of idiopathic menorrhagia.

ICD codes

Dosage Regimen

The initial release rate of levonorgestrel is approximately 20 mcg/day and gradually decreases to approximately 8.6 mcg/day after 6 years. The average in vivo release rate of levonorgestrel over the 6-year period is approximately 14.3 mcg/day.

The therapeutic intrauterine system (IUS) Donasert^® Uno is inserted into the uterine cavity and remains effective for 6 years for the indication of contraception and for 3 years for the indication of idiopathic menorrhagia.

With correct insertion of the Donasert^® Uno IUS, performed in accordance with the instructions for use and handling, the Pearl Index (an indicator reflecting the number of pregnancies per 100 women using the contraceptive for 1 year) is approximately 0.18%.

In the case of idiopathic menorrhagia, if there are no symptoms of the disease after 3 years of use, the possibility of continuing use can be considered. The Donasert^® Uno IUS should be removed or replaced no later than 6 years after insertion.

After a gynecological examination, a speculum is inserted into the vagina and the cervix is treated with an antiseptic solution. Then the Donasert^® Uno IUS is inserted into the uterine cavity using the inserter included with the system, strictly following the instructions.

A woman may feel the insertion of the system, but it should not cause severe pain. Before insertion, if necessary, a paracervical block and/or analgesics can be used.

In some cases, patients may have cervical stenosis. Excessive force should not be used when inserting the Donasert^® Uno IUS in such patients.

Sometimes after insertion of the IUS, pain, dizziness, sweating, and pallor of the skin are observed. Women are advised to rest for some time after insertion of the Donasert^® Uno IUS. If these phenomena do not subside after half an hour in a calm position, the intrauterine system may be incorrectly positioned. A gynecological examination should be performed; if necessary, the system is removed. In some women, the use of the levonorgestrel-releasing IUS causes skin allergic reactions.

For women of reproductive age, the Donasert^® Uno IUS should be inserted into the uterine cavity within 7 days of the start of menstruation.

The Donasert^® Uno IUS can be replaced with a new IUS on any day of the menstrual cycle. The IUS can also be inserted immediately after a first-trimester abortion, provided there are no inflammatory diseases of the genital organs.

Insertion of the Donasert^® Uno IUS in the postpartum period should be performed only after complete involution of the uterus, but not earlier than 6 weeks after delivery. In case of prolonged subinvolution of the uterus, postpartum endometritis and other causes of significant delay in involution must be excluded, and the decision to insert the Donasert^® Uno IUS should be postponed until uterine involution is complete. Due to the high risk of uterine perforation in the postpartum period, insertion of the Donasert^® Uno IUS is preferably performed 12 weeks after delivery.

For detailed information on the removal/post-removal process of the IUS, see the subsection “Removal of the Donasert^® Uno IUS”.

The system used for the indication of contraception should be removed 6 years after insertion or 3 years after insertion if the system is used for the indication of idiopathic menorrhagia. If there are no symptoms of the disease after 3 years of use, the possibility of continuing use can be considered. The Donasert^® Uno IUS should be removed or replaced no later than 6 years after insertion. If a woman wishes to continue using the same method, a new system can be inserted immediately after removal of the previous one.

If further contraception is required in women of reproductive age, removal of the IUS should be performed within 7 days of the start of menstruation, provided the menstrual cycle is preserved. If the system is removed at another time in the cycle, or if the woman has irregular menstruation and has had sexual intercourse during the preceding week, the woman is at risk of becoming pregnant. To ensure continuous contraception, a new IUS must be inserted immediately after removal of the previous IUS, or an alternative method of contraception must be initiated.

Special patient groups

Elderly patients

The Donasert^® Uno IUS has not been studied in women over 65 years of age, therefore the use of the Donasert^® Uno IUS is not recommended for this patient group (see section “Contraindications”).

The Donasert^® Uno IUS is not a first-choice drug for postmenopausal women under 65 years of age with severe uterine atrophy.

Patients with impaired liver function

The Donasert^® Uno IUS is contraindicated in women with acute liver diseases and liver tumors (see section “Contraindications”).

Patients with impaired renal function

The use of the Donasert^® Uno IUS in women with impaired renal function has not been studied.

Children

The drug is contraindicated for use in children (efficacy and safety of use in children have not been established to date).

Method of administration

The Donasert^® Uno IUS is inserted into the uterine cavity.

Instructions for use and handling of the Donasert^® Uno IUS

The Donasert^® Uno IUS is supplied in sterile packaging that must not be opened until the start of the system insertion procedure. Aseptic techniques should be observed when handling the opened system. If the sterility of the packaging is compromised, the IUS should be discarded.

The outer cardboard packaging of the Donasert^® Uno IUS contains a user card. This card should be filled out and given to the patient after IUS insertion.

Insertion of the Donasert^® Uno IUS

It is strongly recommended that the Donasert^® Uno IUS be inserted only by a physician experienced in inserting levonorgestrel-releasing IUS and/or well-trained in performing this procedure.

In case of difficulties during system insertion and/or in case of unusual pain or bleeding during or after insertion, see information in the “Special Instructions” section.

The Donasert^® Uno IUS is supplied sterile after sterilization with ethylene oxide. Do not re-sterilize. For single use only. Do not use if the inner packaging is damaged or opened. Do not insert the system after the last day of the month indicated on the packaging.

The Donasert^® Uno IUS (Figure 1a) is supplied in a tray sealed with a peel-off lid and is inserted into the uterine cavity using the provided inserter (Figure 1b) strictly following the insertion instructions.

The instructions for system insertion are included in the box with the IUS.

The physician should carefully read the following instructions for use, as the type of inserter may differ somewhat from other IUSs the physician has used previously.

Description

• Figure 1a. Donasert^® Uno Therapeutic Intrauterine System (IUS)

• Figure 1b: Donasert^® Uno IUD with inserter

The Donasert^® Uno IUD is packaged partially pre-loaded into the inserter. The threads are passed through the insertion tube and exit through the slit at the end of the handle.

The inserter handle contains a BLUE slider, marked with number 1, and a GREEN slider, marked with number 2. The handle is marked with number 3. The sliders are marked with numbers 1 and 2 and the handle is marked with number 3 to facilitate the insertion process (Figure 2). Moving the sliders provides the positions necessary to complete the IUD insertion.

• Figure 2. Inserter sliders

Conditions for use

1. In women of reproductive age, the Donasert^® Uno IUD should be inserted within 7 days of the onset of menstruation. Replacement of the system with a new one can be performed on any day of the menstrual cycle.
2. Perform a gynecological examination to determine the position (anteversion, retroversion) and size of the uterus. Exclude pregnancy and contraindications for IUD insertion.
3. Insert a speculum, and treat the cervix and vagina with a suitable antiseptic solution.
4. In case of cervical canal stenosis, use a dilator. Force should not be used to overcome resistance.

The anterior lip of the cervix should be grasped with a tenaculum and, by gently pulling on the tenaculum, the cervical canal should be straightened in relation to the uterine cavity.

1. Determine the depth of the uterine cavity by sounding. If the depth of the uterine cavity is less than 5.5 cm, the procedure should be discontinued.

Preparation for insertion

Opening the sterile packaging of the Donasert^® Uno IUD

1. Remove the sealed tray with the Donasert^® Uno IUD from the box.
2. Inspect the sealed tray; the system should not be used if the packaging, inserter, or IUD is damaged.
3. Place the tray on a flat surface with the peel-off lid facing up.
4. Remove the peel-off lid.

Loading the Donasert^® Uno IUD into the inserter

To remove the inserter from the tray, grasp the handle below the sliders and gently twist (Figure 3).

Note. Do not attempt to remove the inserter by pulling on the tube.

• Figure 3. Removing the inserter from the tray

1. Ensure that both sliders (marked with numbers 1 and 2) are fully advanced forward (Figure 4)

• The BLUE slider (marked with number 1) has a single line marking that aligns with the single line on the handle;
• The GREEN slider (marked with number 2) has a double line marking that aligns with the double line on the handle;

1. Grasp the handle, placing your thumb in the recess of the BLUE slider (at number 1), and push forward, ensuring that both sliders are fully advanced forward.

• Figure 4. Sliders fully advanced forward for loading the Donasert^® Uno IUD

Loading the Donasert^® Uno IUD into the inserter

1. Ensure that the arms of the IUD are horizontal (aligned with the horizontal plane of the handle and the flange); if necessary, adjust the position of the IUD by rotating it, using the flat sterile surface of the tray.
2. While continuing to push the blue slider forward, gently pull the threads straight back to load the Donasert^® Uno IUD into the insertion tube. Ensure that both threads are pulled with equal tension. Pull the threads up or down to secure them in the slit at the lower end of the handle (Figure 5). It is necessary to secure the threads in the handle slit to prevent the IUD from exiting the top of the insertion tube. After the threads are secured in the slit, release the threads.

• Figure 5. Securing the threads in the handle slit

1. After loading the IUD, continue to push the BLUE slider forward to maintain the hemispherical shape of the tip with the IUD arms.
2. When loaded correctly, the IUD is completely inside the insertion tube, and the ends of the arms form a hemispherical dome at the top end of the tube (Figure 6).

• Figure 6. Enlarged view of the hemispherical dome at the end of the tube

1. If the IUD is loaded incorrectly, do not attempt to insert it into the uterus.
2. To reload the Donasert^® Uno IUD, perform the following steps

• To release the IUD, pull the BLUE slider back with your thumb until the recess aligns with the GREEN slider;
• Manually pull the threads out of the handle slit;
• Return the BLUE slider to the forward position and repeat the loading steps.

1. Adjust the position of the flange according to the uterine depth measured by sounding. To adjust, place the flange with its flat side into the notch of the tray (Figure 7) or on the sterile inner edge of the tray. Slide the insertion tube to move the flange to the required position. Ensure that the flat sides of the flange are in the same horizontal plane as the handle. If it becomes necessary to touch the flange or any other sterile surface at any stage, sterile gloves should be used.

• Figure 7. Adjusting the flange

1. If it is necessary to adjust the curvature of the insertion tube to match the anatomical position of the uterus, the insertion tube can be bent or straightened, but it should only be touched above the flange while wearing sterile gloves. The tube should be bent with a large radius to prevent kinking.
2. After setting the flange to the required position, avoid contact with objects that may displace it (e.g., the tray, speculum, tenaculum, etc.).

Insertion of the Donasert^® Uno IUD into the uterus

1. Gently pull on the tenaculum on the cervix and insert the insertion tube with the loaded IUD through the external os of the cervix, while continuing to press the BLUE slider forward. Advance the tube until the upper edge of the flange is 1.5-2 cm from the external os of the cervix (Figure 8). Maintain pressure on the BLUE slider in the forward direction throughout the insertion process.

• DO NOT ADVANCE the flange towards the cervix at this time.
• DO NOT USE force when inserting the inserter. Perform cervical dilation if necessary.
• Figure 8. Advance the insertion tube until the flange is 1.5-2 cm from the external os of the cervix

Using your thumb or index finger, gently move only the BLUE slider backward. When moving the BLUE slider from its initial position, slight resistance will be felt initially. Continue moving the BLUE slider backward until slight resistance is felt again; at this point, the BLUE and GREEN sliders will align, forming a common recess. Do not move the BLUE slider more than necessary to create the common recess. Hold the GREEN slider so that the double lines on the slider and the inserter handle remain aligned (Figure 9). This will allow the IUD arms to open in the lower segment of the uterus. After this, do not pull the sliders back further, as this may lead to premature release of the IUD in the wrong location.

• Figure 9. Releasing and opening the IUD arms
1. Move the BLUE slider down
1. Wait 10-15 seconds for the IUD arms to fully open.
2. Without moving the sliders, advance the inserter until the flange touches the cervix. If resistance from the uterine fundus is encountered, stop advancing the inserter. The Donasert^® Uno IUD is now in the fundal position (Figure 10).

Notethe fundal position of the IUD is important for preventing expulsion.

• Figure 10. Move the Donasert^® Uno IUD to the fundal position

Releasing the Donasert^® Uno IUD and completing the procedure

Holding the inserter steady and maintaining its position relative to the cervix, move both sliders (BLUE and GREEN) together, maintaining the common recess of the sliders, down towards the number 3 on the handle (Figure 11), until a click is heard and a GREEN indicator appears at the bottom of the handle (Figure 12).

• Figure 11. Releasing the Donasert^® Uno IUD from the inserter

Look at the handle slit to ensure that the threads have been released correctly (Figure 12); if the threads are not released or a click is not heard, grasp the threads and gently pull them out of the handle slit.

• Figure 12. Green indicator visible and threads released from the handle slit
1. Remove the inserter from the uterus.
2. Using sharp scissors with blunt ends, cut the IUD threads perpendicular to their length, so that the threads protrude from the cervix by approximately 3 cm (Figure 13).

Notedo not cut the threads at an angle, as sharp ends may form.

1. When cutting, do not pull or tug on the threads to prevent displacement of the IUD.
• Figure 13. Cut the threads approximately 3 cm from the cervix

Insertion of the Donasert^® Uno IUD is complete.

Important information to consider during or after IUD insertion

If incorrect IUD position is suspected, perform the following actions

• Check the position of the inserted IUD using ultrasound or a suitable radiological method;
• If incorrect placement is suspected, remove the Donasert^® Uno IUD; it is prohibited to reinsert the same Donasert^® Uno IUD that was removed.

Important information

In case of difficulties during insertion and/or if unusual pain or bleeding occurs during or after IUD insertion, a physical and ultrasound examination should be performed immediately to exclude perforation of the uterine body or cervix. If necessary, remove the system and insert a new sterile system.

Any case of uterine perforation or difficulties during IUD insertion should be reported through the national adverse reaction reporting systems of the member states of the Eurasian Economic Union (see the “Adverse Reactions” section).

Removal of the Donasert^® Uno IUD

The Donasert^® Uno IUD is removed by gently pulling on the threads grasped with forceps. If the threads are not visible and the system is in the uterine cavity, it can be removed using a narrow clamp. Cervical dilation may be required.

If pregnancy is not desired, in women of reproductive age, IUD removal should be performed during menstruation provided there are visible signs of the menstrual cycle. If the system is removed mid-cycle and the woman has had sexual intercourse during the preceding week, she is at risk of pregnancy, unless a new system was inserted immediately after removal of the old one.

After removal of the Donasert^® Uno IUD, its integrity should be checked. In cases of difficult removal, isolated cases of the hormone reservoir slipping onto the horizontal arms, resulting in them being concealed inside the reservoir, have been observed. Provided the integrity of the IUD is confirmed, this situation does not require additional intervention. The bumps on the horizontal arms usually prevent complete detachment of the reservoir from the T-shaped body.

Since the insertion techniques for different IUDs differ, special attention should be paid to practicing the correct insertion technique for the specific system. Specific insertion instructions are included in the packaging.

The Donasert^® Uno IUD is supplied in sterile packaging, which must not be opened until the start of the system insertion procedure. Aseptic techniques must be observed when handling the opened system. If the sterility of the packaging is compromised, the IUD should be disposed of in accordance with local regulatory requirements for handling hazardous biological waste. Similarly, the Donasert^® Uno IUD and inserter removed from the uterus should be disposed of.

The outer cardboard packaging and the inner blister packaging should be disposed of as household waste.

Adverse Reactions

Summary of the safety profile

Most women experience a change in the pattern of cyclic bleeding after insertion of a levonorgestrel-releasing IUD.

Among women using the Donasert^® Uno IUD, menstrual bleeding ceases in approximately 19% after 1 year of use, 27% after 2 years of use, approximately 37% after 3 years of use, 37% after 4 years of use, 40% after 5 years of use, and 40% after 6 years of use.

Tabulated summary of adverse reactions

Adverse reactions (ARs) were classified by system organ class and frequency using the following categories: very common (≥1/10), common (≥1/100 to <1/10), uncommon (≥1/1,000 to <1/100), rare (≥1/10,000 to <1/1,000), very rare (<1/10,000), frequency not known (cannot be estimated from the available data).

* The frequency values provided are based on the results of a large prospective comparative non-interventional cohort study involving women using the levonorgestrel-releasing IUD, which demonstrated that breastfeeding at the time of insertion and insertion up to 36 weeks after delivery are independent risk factors for uterine perforation (see the “Special Instructions” section). In clinical studies of the levonorgestrel-releasing IUD, which did not include women during breastfeeding, cases of perforation were reported with “rare” frequency.

Description of selected adverse reactions

Clinical studies were conducted using the Donasert^® Uno IUD for 2 indications (contraception, idiopathic menorrhagia).

A large multicenter open-label Phase III clinical study for the contraception indication was conducted, involving 1751 women aged 16 to 45 years who used the Donasert^® Uno IUD for 6 years.

The most frequently reported ARs associated with the use of the Donasert^® Uno IUD in this study were acne, IUD expulsion, menorrhagia, dyspareunia, breast tenderness, and uterine cramping.

Two large Phase III studies were conducted for the idiopathic menorrhagia indication: a multicenter randomized single-blind clinical trial in parallel groups, involving 280 women, of whom 141 were in the Donasert^® Uno IUD treatment group (study duration up to 3 years), and a multicenter single-blind randomized non-inferiority study with an active control in parallel groups, involving 312 women, of whom 158 were in the Donasert^® Uno IUD treatment group (study duration 6 months).

The most common ARs associated with the use of the Donasert^® Uno IUD in the first study were: prolonged menstrual cycle, intermenstrual spotting, amenorrhea, ovarian cyst, and post-procedural pain.

The most common ARs associated with the use of the Donasert^® Uno IUD in the second study were: metrorrhagia, oligomenorrhea, polymenorrhea, amenorrhea, breast pain, delayed menses, vaginal bleeding, dysmenorrhea, menstrual disorder, weight increased.

Infections and infestations

Cases of sepsis (including group A streptococcus sepsis) have been reported following IUD insertion (see the “Special Instructions” section).

Pregnancy, puerperium and perinatal conditions

If a woman with a levonorgestrel-releasing IUD in place becomes pregnant, the relative risk of ectopic pregnancy increases (see the “Special Instructions” section).

Reproductive system and breast disorders

Cases of breast cancer have been reported in women using the levonorgestrel-releasing IUD (frequency not known, see the “Special Instructions” section).

The following ARs have been described during IUD insertion and removal procedures: pain during the procedure, bleeding during the procedure, vasovagal reaction associated with the IUD insertion procedure, accompanied by dizziness or fainting, associated with the IUD insertion procedure (see the “Dosage and Administration” section). The procedure may also trigger seizures in patients with epilepsy.

The partner may feel the threads during sexual intercourse.

Reporting of suspected adverse reactions

It is important to report suspected adverse reactions after authorization of the medicinal product to ensure continuous monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals are requested to report any suspected adverse reactions of the medicinal product through the national adverse reaction reporting systems of the member states of the Eurasian Economic Union.

Contraindications

• Hypersensitivity to levonorgestrel or to any of the excipients of the drug;
• Pregnancy or suspected pregnancy (see the “Pregnancy and Lactation” section);
• acute or recurrent inflammatory diseases of the pelvic organs;
• infections of the external and internal genital organs;
• postpartum endometritis;
• septic abortion within the last 3 months;
• cervicitis;
• diseases accompanied by increased susceptibility to infections;
• cervical dysplasia;
• diagnosed or suspected malignant neoplasm of the uterus or cervix;
• diagnosed progestogen-dependent tumors or suspicion of them, including breast cancer;
• bleeding from the genital tract of unclear etiology;
• congenital or acquired uterine anomalies, including fibroids leading to deformation of the uterine cavity;
• acute liver diseases or tumors;
• The IUD Donasert^® Uno has not been studied in women over 65 years of age, therefore the use of the IUD Donasert^® Uno is not recommended for this group of patients.

Use in Pregnancy and Lactation

Pregnancy

The use of the IUD Donasert^® Uno is contraindicated in suspected or confirmed pregnancy (see section “Contraindications”). Pregnancy in women with a levonorgestrel-releasing IUD is an extremely rare occurrence. But if the IUD is expelled from the uterine cavity, the woman is no longer protected from pregnancy and should use other methods of contraception until consultation with a doctor.

If pregnancy occurs in a woman using the IUD Donasert^® Uno, an ectopic pregnancy must be ruled out (see section “Special Precautions”) and the IUD should be removed as soon as possible due to the high risk of pregnancy complications (spontaneous abortion, premature birth, infection or sepsis). Removal of the IUD Donasert^® Uno or uterine sounding can also lead to spontaneous abortion. If careful removal of the intrauterine contraceptive is not possible, the advisability of medical abortion should be discussed. If a woman wishes to continue the pregnancy and the IUD cannot be removed, she should be informed about the probable risks, in particular, the possible risk of septic abortion in the second trimester of pregnancy, postpartum purulent-septic diseases that can be complicated by sepsis, septic shock and death, as well as possible consequences of premature birth for the child. In such cases, careful monitoring of the pregnancy is necessary. The woman should be explained that she must report all symptoms possibly related to the development of complications, such as the appearance of cramping abdominal pain with fever.

Isolated cases of masculinization of the external genitalia of a female fetus as a result of local exposure to levonorgestrel during pregnancy, in which the IUD was not removed, have been described.

Lactation period

Breastfeeding a child while using the IUD Donasert^® Uno is not contraindicated. A small amount of levonorgestrel may enter the child’s body during breastfeeding. However, it is unlikely to pose a risk to the child at the doses released into the uterine cavity after insertion of the IUD Donasert^® Uno. It is believed that the use of a levonorgestrel-releasing IUD 6 weeks after childbirth does not have a harmful effect on the growth and development of the child. Monotherapy with progestogens does not affect the quantity and quality of breast milk.

Fertility

After removal of the IUD Donasert^® Uno, fertility is restored in women.

Use in Hepatic Impairment

The IUD Donasert^® Uno is contraindicated in women with acute liver diseases and tumors.

Use in Renal Impairment

The use of the IUD Donasert^® Uno in women with impaired renal function has not been studied.

Pediatric Use

The drug is contraindicated for use in children (efficacy and safety of use in children have not been established at this time).

Geriatric Use

The IUD Donasert^® Uno has not been studied in women over 65 years of age, therefore the use of the IUD Donasert^® Uno is not recommended for this group of patients.

Special Precautions

Due to the risk of developing bacterial endocarditis, the IUD Donasert^® Uno should be used only for strict indications in the presence of current congenital or acquired heart defects or valve defects.

Levonorgestrel in low doses may affect glucose tolerance, therefore its plasma concentration should be regularly monitored in women with diabetes mellitus using the IUD Donasert^® Uno. As a rule, no adjustment of the dose of hypoglycemic drugs is required.

Some manifestations of polyposis or endometrial cancer may be masked by irregular bleeding. In such cases, additional examination is necessary to clarify the diagnosis.

The IUD Donasert^® Uno should not be considered as a first-choice method in the postmenopausal period in women with severe uterine atrophy.

Available data indicate that the use of a levonorgestrel-releasing IUD does not increase the risk of developing breast cancer in postmenopausal women under 50 years of age.

The advisability of removing the installed IUD should be considered in the presence or development of any of the following conditions

• Migraine, focal migraine with asymmetric vision loss or other symptoms indicating transient cerebral ischemia;
• Unusually severe or unusually frequent headache;
• Jaundice;
• Significant increase in blood pressure;
• Malignant diseases affecting blood counts or leukemias in remission;
• Long-term use of corticosteroids;
• History of functional ovarian cysts with clinical manifestations;
• Severe circulatory disorders, including stroke and myocardial infarction;
• Serious or multiple risk factors for arterial disease;
• Arterial thrombosis or the presence of any thromboembolic disease;
• Acute venous thromboembolism.

Medical examinations/consultations

Before insertion of the IUD Donasert^® Uno, the woman should be informed about the effectiveness, risks and adverse reactions of using the IUD. A general and gynecological examination should be performed, including examination of the pelvic organs and mammary glands. If necessary, as decided by the doctor, a cervical smear test should be performed. Pregnancy and sexually transmitted diseases should be ruled out, and inflammatory diseases of the pelvic organs must be completely cured.

It must be borne in mind that the IUD Donasert^® Uno does not protect against HIV infection and other sexually transmitted diseases.

The position of the uterus and the dimensions of its cavity are determined. If visualization of the uterus is necessary before insertion of the IUD Donasert^® Uno, a pelvic ultrasound should be performed.

Correct placement of the IUD Donasert^® Uno in the fundus of the uterus is especially important, as it ensures uniform exposure of the endometrium to the progestogen, prevents expulsion of the IUD and creates conditions for its maximum effectiveness. Therefore, the requirements of the instructions for insertion of the IUD Donasert^® Uno should be carefully followed. Since the insertion technique for different IUDs varies, special attention should be paid to practicing the correct insertion technique for this specific system.

Insertion and removal of the IUD may be accompanied by certain pain sensations and bleeding. The procedure may cause fainting due to a vasovagal reaction, bradycardia or a seizure in patients with epilepsy, especially if there is a predisposition to these conditions or in case of cervical stenosis.

Some women experience pain (resembling menstrual cramps) in the first 2-3 weeks after IUD insertion. The patient should be advised to seek consultation if she feels severe pain or if the pain continues for more than 3 weeks after insertion of the system.

The woman should be re-examined 4-12 weeks after insertion, and then once a year or more often if clinically indicated. Before insertion of the IUD Donasert^® Uno, pathological processes in the endometrium should be ruled out, since irregular bleeding/”spotting” is often observed in the first months of its use. Appropriate diagnostic measures should also be taken when irregular bleeding develops during long-term treatment.

The IUD Donasert^® Uno is not used for postcoital contraception.

Menstrual bleeding disorders

In women of fertile age, the use of the IUD Donasert^® Uno leads to a gradual reduction in the duration of menstruation and the volume of blood loss (in more than half of women within the first year of use), and in some women, menstruation may stop. In the first 3-6 months after insertion of the IUD Donasert^® Uno, many women experience, in addition to their regular periods, frequent spotting or scanty bleeding. In some cases, very heavy or prolonged bleeding is noted during this period.

If menstruation is absent for 6 weeks after the start of the last menstruation, pregnancy should be ruled out. Repeated pregnancy tests for amenorrhea are not necessary if there are no other signs of pregnancy.

Pelvic inflammatory disease (PID)

The insertion tube helps protect the IUD Donasert^® Uno from infection during insertion, and the IUD Donasert^® Uno inserter is specifically designed to minimize the risk of infection. PID in women using intrauterine contraception is often caused by sexually transmitted infections. It has been established that having multiple sexual partners for a woman or multiple sexual partners for her partner is a risk factor for PID. PID can have serious consequences: it can impair reproductive function and increase the risk of ectopic pregnancy.

As with other gynecological or surgical procedures, severe infection or sepsis (including group A streptococcal sepsis) can develop after IUD insertion, although this happens extremely rarely.

In case of recurrent endometritis or PID, as well as in severe or acute infections that are resistant to treatment for several days, the IUD Donasert^® Uno should be removed. If a woman develops persistent lower abdominal pain, chills, fever, pain associated with sexual intercourse (dyspareunia), prolonged or heavy spotting/vaginal bleeding, or a change in the nature of vaginal discharge, she should consult a doctor immediately. Severe pain or fever that appears shortly after IUD insertion may indicate the presence of a severe infection that requires immediate treatment. Even in cases where only isolated symptoms indicate the possibility of infection, bacteriological examination and monitoring are indicated.

Expulsion

Uterine muscle contractions during menstruation sometimes lead to displacement of the IUD or even its expulsion from the uterus, which leads to the cessation of the contraceptive effect. Possible signs of partial or complete expulsion of any IUD are bleeding and pain, however, expulsion of the IUD Donasert^® Uno can also occur unnoticed. Since the IUD Donasert^® Uno reduces menstrual blood loss, an increase in it may indicate expulsion of the IUD.

The risk of expulsion is increased

• In women with a history of heavy menstrual bleeding;
• In women with a body mass index (BMI) above normal at the time of insertion; this risk gradually increases with increasing BMI.

The woman should be told about the possible signs of expulsion and how to check the threads of the IUD Donasert^® Uno, and advised to consult a doctor if she cannot feel the threads. It is necessary to avoid sexual intercourse or use barrier methods of contraception (for example, a condom) until the correct position of the IUD Donasert^® Uno is confirmed.

Partial expulsion may reduce the effectiveness of the IUD Donasert^® Uno.

In case of partial expulsion of the IUD Donasert^® Uno, it should be removed. A new system can be inserted immediately after removal, provided that possible pregnancy is excluded.

Perforation and penetration

Perforation or penetration of the body or cervix by the IUD can occur mainly during insertion, although it may not be detected for some time after insertion and reduces the effectiveness of the IUD Donasert^® Uno. In these cases, the system should be removed. If perforation is diagnosed late and the IUD migrates, complications such as adhesions, peritonitis, intestinal obstruction, intestinal perforation, abscesses or erosions of adjacent internal organs may be observed.

The risk of perforation increases when the IUD is inserted during breastfeeding, as well as if the IUD is inserted within 36 weeks after childbirth, regardless of the type of IUD used (see also the “Adverse Reactions” section).

There is an increased risk of perforation during IUD insertion in women with a fixed malposition of the uterus (retroversion and retroflexion).

Ectopic pregnancy

Women with a history of ectopic pregnancy, those who have undergone tubal surgery or pelvic infection are at higher risk of ectopic pregnancy. The possibility of ectopic pregnancy should be considered in case of lower abdominal pain, especially if it is combined with cessation of menstruation, or when a woman with amenorrhea begins to bleed. In a conducted clinical study, the overall incidence of ectopic pregnancy with the use of the IUD Donasert^® Uno over 6 years was approximately 0.12 per 100 patient-years. The absolute risk of ectopic pregnancy in women using the IUD Donasert^® Uno is low. However, if a woman with an installed IUD Donasert^® Uno becomes pregnant, the relative probability of an ectopic pregnancy is higher (see the “Adverse Reactions” section). Women planning to use the IUD Donasert^® Uno should be explained the symptoms and risks of ectopic pregnancy.

Loss of threads

If the threads for removing the IUD cannot be found in the cervical area during a gynecological examination, pregnancy must be ruled out. The threads may be retracted into the uterine cavity or into the cervical canal and become visible again after the next menstruation. If pregnancy is excluded, the location of the threads can usually be determined by careful probing with an appropriate instrument. If the threads cannot be found, perforation of the uterine wall or expulsion of the IUD from the uterine cavity is possible. To determine the correct position of the system, ultrasound can be used. If it is unavailable or unsuccessful for locating the IUD Donasert^® Uno, an X-ray examination is used.

The use of sanitary pads is recommended. If tampons or menstrual cups are used, women should change them carefully so as not to pull on the threads of the IUD Donasert^® Uno.

Ovarian cysts

Since the contraceptive effect of the IUD Donasert^® Uno is mainly due to its local action, women of fertile age usually have ovulatory cycles with follicle rupture. Sometimes follicle atresia is delayed and their development may continue. Such enlarged follicles are clinically indistinguishable from ovarian cysts. In most cases, these follicles do not cause any symptoms, although sometimes they are accompanied by lower abdominal pain or pain during sexual intercourse. As a rule, ovarian cysts disappear spontaneously within 2-3 months of observation. If this does not happen, it is recommended to continue ultrasound monitoring, as well as to carry out other diagnostic/therapeutic measures. In rare cases, surgical intervention may be required (see also the “Adverse Reactions” section).

Excipients

The T-shaped body of the IUD Donasert^® Uno contains barium sulfate, which allows the IUD to be visualized on X-ray images.

Effect on ability to drive vehicles and mechanisms

No effect of the IUD Donasert^® Uno on the ability to drive vehicles and mechanisms has been observed.

Overdose

Not applicable.

Drug Interactions

Effect of other medicinal products on the IUD Donasert^® Uno

Interaction with medicinal products that induce or inhibit liver microsomal enzymes is possible, which may increase or decrease the clearance of sex hormones.

Substances that increase the clearance of levonorgestrel, for example

• Phenytoin, barbiturates, primidone, carbamazepine, rifampicin, and possibly also oxcarbazepine, topiramate, felbamate, griseofulvin, as well as preparations containing St. John’s wort.

The effect of these substances on the contraceptive efficacy of the IUD Donasert^® Uno is unknown, but it is assumed to be not significant due to the local mechanism of action.

Substances with varying effects on the clearance of levonorgestrel

• When used concomitantly with sex hormones, many HIV or hepatitis C virus protease inhibitors and non-nucleoside reverse transcriptase inhibitors can either increase or decrease the plasma concentration of the progestogen.

Substances that reduce the clearance of levonorgestrel (enzyme inhibitors), for example

• Strong and moderate CYP3A4 inhibitors such as azole antifungals (e.g., fluconazole, itraconazole, ketoconazole, voriconazole), verapamil, macrolides (e.g., clarithromycin, erythromycin), diltiazem and grapefruit juice may increase plasma concentrations of the progestogen.

Storage Conditions

The medicinal product does not require special temperature storage conditions. Store the tray in the cardboard pack to protect from light.

Shelf Life

Shelf life – 5 years.

Dispensing Status

Dispensed by prescription.

Important Safety Information

This information is for educational purposes only and does not replace professional medical advice. Always consult your doctor before use. Dosage and side effects may vary. Use only as prescribed.