Ganirelix gedeon richter

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT GANIRELIX GEDEON RICHTER

Composition:

Active substance: ganirelix;

1 pre-filled syringe contains 0.5 mL of aqueous solution with 0.25 mg of ganirelix;

Excipients: glacial acetic acid, mannitol (E 421), water for injections, sodium hydroxide.

Pharmaceutical form. Injection solution.

Main physicochemical properties: clear, colorless solution.

Pharmacotherapeutic group. Gonadotropin-releasing hormone antagonist.

ATC code H01C C01.

Pharmacological Properties

Pharmacodynamics

Mechanism of action

Ganirelix is a gonadotropin-releasing hormone (GnRH) antagonist that modulates the hypothalamic-pituitary-gonadal system by competitively binding to GnRH receptors in the pituitary gland. This results in rapid, complete, and reversible suppression of endogenous gonadotropin release, without prior stimulation, as observed with GnRH agonists. After repeated administration of 0.25 mg ganirelix to women, serum concentrations of luteinizing hormone (LH), follicle-stimulating hormone (FSH), and estradiol (E2) were maximally reduced by 74%, 32%, and 25% at 4, 16, and 16 hours after injection, respectively. Hormone levels returned to baseline within 2 days after the last injection.

Pharmacodynamic effects

The average duration of treatment with 0.25 mg ganirelix once daily in patients undergoing controlled ovarian stimulation is 5 days. During ganirelix treatment, the average incidence of LH surge (> 10 IU/L) accompanied by an increase in progesterone concentration (> 1 ng/mL) is 0.3–1.2%, which is comparable to that observed with GnRH agonists (0.8%). A trend toward increased incidence of LH and progesterone elevation has been observed in women with higher body weight (> 80 kg), although this did not affect clinical outcomes. However, based on the limited number of patients treated to date, such an effect cannot be excluded.

In cases of high ovarian response resulting from high gonadotropin exposure or high ovarian reactivity, premature LH surge may occur before day 6 of stimulation. Initiating ganirelix treatment on day 5 of stimulation may prevent such premature LH surges without adversely affecting clinical outcomes.

Clinical efficacy and safety

In controlled studies comparing ganirelix plus FSH with the long GnRH agonist protocol as the reference, treatment with the ganirelix regimen resulted in faster follicular growth during the initial days of stimulation, although the final number of growing follicles was slightly lower and they produced, on average, less estradiol. This difference in follicular growth pattern necessitates that FSH dose adjustments be based on the number and size of developing follicles rather than on circulating estradiol concentrations. Comparative studies of corifollitropin alfa using a GnRH antagonist or a long GnRH agonist protocol have not been conducted.

Pharmacokinetics

Pharmacokinetic parameters following multiple subcutaneous administrations of ganirelix (1 injection daily) are similar to those after a single subcutaneous dose. After repeated daily administration of 0.25 mg, a steady-state plasma concentration of approximately 0.6 ng/mL is achieved within 2–3 days.

Pharmacokinetic analysis indicates an inverse relationship between body weight and serum ganirelix concentration.

Absorption

Following a single subcutaneous dose of 0.25 mg ganirelix, serum concentration increases rapidly, reaching maximum levels (Cmax) of approximately 15 ng/mL within the first 1–2 hours (tmax). The bioavailability of ganirelix after subcutaneous administration is approximately 91%.

Metabolic profile

Ganirelix is the main component and compound present in plasma. Ganirelix is also the primary compound excreted in urine. Only metabolites are excreted in feces. The metabolites are small peptide fragments formed by enzymatic hydrolysis of ganirelix at specific sites. The metabolic profile of ganirelix in humans is similar to that observed in animals.

Elimination

The elimination half-life (t½) is approximately 13 hours, and clearance is approximately 2.4 L/h. The drug is eliminated via feces (approximately 75%) and urine (approximately 22%).

Preclinical safety data

Preclinical data indicate no specific risk for humans based on findings from studies of pharmacological safety, repeated-dose toxicity, and genotoxicity.

Reproductive toxicity studies conducted with ganirelix administered subcutaneously at doses of 0.1 to 10 µg/kg/day in rats and 0.1 to 50 µg/kg/day in rabbits showed increased fetal resorption rates at the highest dose levels. No teratogenic effects were observed.

Clinical characteristics.

Indications.

Prevention of premature luteinizing hormone (LH) surge in women undergoing controlled ovarian hyperstimulation (COH) as part of assisted reproductive technologies (ART).

In clinical studies, ganirelix was used in combination with recombinant human follicle-stimulating hormone (rFSH) or corifollitropin alfa, a prolonged follicle-stimulating agent.

Contraindications.

• Hypersensitivity to the active substance or to any of the excipients listed in the section "Composition".
• Hypersensitivity to GnRH or to other GnRH analogues.
• Moderate or severe renal or hepatic impairment.
• Pregnancy or breastfeeding.

Interaction with other medicinal products and other forms of interaction.

Studies on interactions between ganirelix and other medicinal products have not been conducted. The possibility of interactions with concurrently administered medicinal products cannot be excluded, including those that trigger histamine release.

Special precautions for use.

Hypersensitivity reactions

Particular caution is required when using the drug to treat women with signs and symptoms of active allergic conditions.

Cases of hypersensitivity reactions (both generalized and local) have been reported during post-marketing surveillance with the use of ganirelix, including upon administration of the first dose. These cases included anaphylaxis (including anaphylactic shock), angioedema, and urticaria (see section "Adverse reactions"). If a hypersensitivity reaction is suspected, administration of ganirelix should be discontinued and appropriate treatment initiated.

Due to the lack of clinical experience with ganirelix, its use is not recommended in women with severe allergic disorders.

Ovarian hyperstimulation syndrome (OHSS)

Ovarian hyperstimulation syndrome (OHSS) may occur during or after ovarian stimulation. The risk of this complication should be considered when performing gonadotropin stimulation. Symptomatic treatment is required in cases of OHSS (bed rest, intravenous administration of electrolyte or colloid solutions, heparin).

Ectopic pregnancy

Infertile women undergoing assisted reproductive procedures, particularly in vitro fertilization (IVF), often have impaired fallopian tube function, which may increase the risk of ectopic pregnancy. It is important to perform an ultrasound examination as early as possible to confirm intrauterine pregnancy.

Congenital malformations

The incidence of congenital malformations after assisted reproductive technology (ART) may be slightly higher than after spontaneous conception. This is believed to be related to certain parental characteristics (e.g., maternal age, sperm parameters) and the higher likelihood of multiple pregnancies following ART. In clinical studies involving over 1000 newborns, the rate of congenital malformations in children born after controlled ovarian stimulation (COS) with ganirelix was comparable to rates reported after COS with GnRH antagonists.

Women with body weight less than 50 kg or more than 90 kg

The safety and efficacy of ganirelix have not been established in women with body weight less than 50 kg or more than 90 kg (see sections "Pharmacodynamics" and "Pharmacokinetics").

Excipients

This medicinal product contains less than 1 mmol of sodium (23 mg) per injection, i.e., essentially "sodium-free".

Use during pregnancy or breastfeeding.

Pregnancy

There are no adequate data on the use of the drug during pregnancy.

In animal studies, administration of ganirelix during implantation resulted in embryo resorption (see section "Preclinical safety data"). The relevance of these findings to humans has not been established.

Breastfeeding period

It is unknown whether ganirelix is excreted in human breast milk.

The use of Ganirelix Gedeon Richter is contraindicated during pregnancy and breastfeeding (see section "Contraindications").

Fertility

Ganirelix is used to treat women undergoing controlled ovarian hyperstimulation as part of assisted reproductive technologies. Ganirelix is used to prevent premature LH surge, which might otherwise occur in these women during ovarian stimulation. For dosage and administration, see section "Dosage and administration".

Effect on ability to drive and use machines.

The effect of ganirelix on the ability to drive or operate machinery has not been studied.

Method of Administration and Dosage

The medicinal product Ganirelix Gedeon Richter should be prescribed only by a specialist experienced in the treatment of infertility.

Dosing

Ganirelix is used to prevent premature LH surge in women undergoing controlled ovarian stimulation. Controlled ovarian hyperstimulation with FSH or corifollitropin alfa may be initiated on day 2 or 3 of the menstrual cycle. Ganirelix Gedeon Richter (0.25 mg) should be administered subcutaneously once daily, starting on day 5 or 6 of corifollitropin alfa administration. The initiation of ganirelix treatment depends on ovarian response, including the number and size of developing follicles and/or circulating estradiol levels. Initiation of ganirelix may be delayed in the absence of follicular growth, although clinical experience is based on administration of the drug on day 5 or 6 of stimulation.

Ganirelix and FSH should be administered approximately at the same time. The drugs must not be mixed in the same syringe and should be injected into different body sites.

The FSH dose should be adjusted based on the number and size of developing follicles, not on serum estradiol concentration (see section "Pharmacological Properties").

Daily administration of ganirelix should be continued until a sufficient number of follicles of appropriate size have developed. Final follicular maturation can be triggered by administration of human chorionic gonadotropin (hCG).

Timing of the last injection

Considering the half-life of ganirelix, the interval between two ganirelix injections, as well as the interval between the last ganirelix injection and hCG injection, should not exceed 30 hours, as premature LH surge may occur if the interval is prolonged. Therefore, if the ganirelix solution is administered in the morning, this regimen should be maintained throughout the entire gonadotropin treatment period, including the day of ovulation induction. If ganirelix injections are administered in the afternoon, the last dose of ganirelix must be given in the afternoon, one day before ovulation induction.

Ganirelix is safe and effective in patients who have undergone multiple treatment cycles.

The need for luteal phase support in treatment cycles involving ganirelix has not been studied. In clinical trials, luteal phase support was provided according to the practice of the investigational centers or in accordance with the clinical protocol.

Special Patient Groups

Renal and Hepatic Impairment

There is no experience with the use of ganirelix in patients with renal or hepatic impairment, as such patients were excluded from clinical trials. Therefore, ganirelix is contraindicated in patients with moderate to severe renal impairment and in patients with hepatic impairment.

Children

Ganirelix Gedeon Richter is not indicated for use in children.

Route of Administration

Ganirelix Gedeon Richter should be administered subcutaneously, preferably in the thigh. The injection site should be rotated to prevent lipodystrophy. The patient or her partner may self-administer the drug provided that a healthcare professional has provided detailed instructions and the possibility of consulting a specialist is available.

Air bubbles may be visible in the pre-filled syringe. This is expected, and there is no need to remove the air bubbles.

Instructions for Administration

Before administration, inspect the solution. Use only clear solution free from foreign particles. Unused solution and waste materials must be disposed of according to local requirements.

Preparation of the Injection Site

Wash hands thoroughly with soap and water. To reduce bacteria on the skin surface, clean the injection site with an alcohol swab.

Needle Insertion

Remove the cap from the needle. Pinch the skin with the thumb and index finger. Insert the needle at a 45° angle into the base of the pinched skin. The injection site should be changed after each injection.

Checking Correct Needle Placement

Gently pull back the plunger to check correct needle placement. If blood appears in the syringe, this indicates that the needle has entered a blood vessel, and the drug should not be injected. The syringe and needle should be withdrawn, and an antiseptic swab should be applied to the injection site for 1–2 minutes.

Begin administration using a new syringe.

If the needle is correctly placed, slowly and evenly depress the plunger to inject the solution subcutaneously without causing tissue damage.

Quickly withdraw the syringe and needle and apply an antiseptic swab to the injection site. The syringe may be used only once.

Actions to Take if a Dose is Missed

Do not administer a double dose to compensate for a missed injection. If a patient misses a dose, it should be administered as soon as remembered. If the delay in administration exceeds 6 hours (i.e., the interval between two doses exceeds 30 hours), the patient should administer the dose and consult her physician for advice.

Children.

The drug is not indicated for use in children.

Overdose.

Overdose may prolong the drug's effect. In case of overdose, administration of ganirelix should be (temporarily) discontinued.

There are insufficient data on acute toxicity of ganirelix in humans. Clinical studies with subcutaneous administration of single doses up to 12 mg did not reveal systemic adverse reactions. In acute toxicity studies in rats and monkeys, symptoms of non-specific toxicity were observed only after intravenous administration of ganirelix at doses exceeding 1 mg/kg and 3 mg/kg, respectively.

Adverse reactions

General description of the safety profile

The table below lists all adverse reactions that occurred in women treated with ganirelix during clinical trials involving the use of r-hFSH for ovarian stimulation. Similar reactions are expected to occur when ganirelix is used in combination with corifollitropin alfa.

Table of adverse reactions

Adverse reactions are classified by system organ classes and frequency: very common (≥ 1/10), common (≥ 1/100 to < 1/10), uncommon (≥ 1/1000 to < 1/100). The frequency of hypersensitivity reactions (rare, < 1/10000) was determined from post-marketing surveillance.

1Cases have been reported after administration of the first dose in patients who received ganirelix.

2One case was reported after administration of the first dose of ganirelix.

3In clinical studies (within 1 hour after injection), the incidence of at least one local skin reaction (of moderate or severe intensity) was 12% in patients receiving ganirelix and 25% in patients receiving subcutaneous GnRH agonist. These local reactions usually resolved within 4 hours after administration of the drug.

Specific adverse reactions

Other adverse reactions were associated with controlled ovarian hyperstimulation during ART and included pelvic pain, abdominal distension, ovarian hyperstimulation syndrome (see section "Dosage and Administration"), ectopic pregnancy, and spontaneous abortion.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorization of the medicinal product is important. It allows continued monitoring of the benefit-risk balance of the medicinal product. Medical and pharmaceutical personnel, as well as patients or their legal representatives, should report all suspected adverse reactions and lack of efficacy through the automated pharmacovigilance information system at the following link: https://aisf.dec.gov.ua.

Shelf life. 3 years.

Storage conditions.

Store in the original packaging to protect from light. Do not freeze.

Incompatibilities.

Due to lack of compatibility studies, this medicinal product must not be mixed with other medicinal products.

Packaging.

1 ml of solution for injection in a glass syringe with a fixed stainless steel needle with a rigid cap, closed with a plunger stopper and rod. 1 or 6 pre-filled syringes with the instruction for medical use in a cardboard box.

Prescription status.

By prescription only.

Manufacturer.

JSC "Gedeon Richter", Hungary.

Manufacturer's address and location of business activity.

H-1103 Budapest, Demrédi street 19-21, Hungary.