Ganirelix-Richter (Solution) Instructions for Use

Marketing Authorization Holder

Gedeon Richter, Plc. (Hungary)

Contact Information

GEDEON RICHTER JSC (Hungary)

ATC Code

H01CC01 (Ganirelix)

Active Substance

Ganirelix (Rec.INN registered by WHO)

Dosage Form

Ganirelix-Richter

Solution for subcutaneous administration 0.25 mg/0.5 ml: syringes 0.5 ml 1 or 6 pcs.

Dosage Form, Packaging, and Composition

Solution for subcutaneous administration transparent, colorless.

* each pre-filled syringe contains: Ganirelix – 0.25 mg (as ganirelix acetate 0.27 mg-0.31 mg).

Excipients : mannitol, glacial acetic acid, sodium hydroxide for pH adjustment to 5.0, water for injections.

0.5 ml – disposable syringes of colorless glass (1) – cardboard packs^×.
0.5 ml – disposable syringes of colorless glass (6) – cardboard packs^×.

^× the pack may additionally bear a first-opening control.

Clinical-Pharmacological Group

Gonadotropin-releasing hormone antagonist

Pharmacotherapeutic Group

Pituitary and hypothalamic hormones and their analogues; hypothalamic hormones; antigonadotropin-releasing hormones

Pharmacological Action

Mechanism of action

Ganirelix is a competitive antagonist of GnRH receptors, controls the secretion of gonadotropins – luteinizing hormone (LH) and follicle-stimulating hormone (FSH), inhibits the secretion of LH and FSH by the pituitary gland (the effect is dose-dependent). In the absence of prior stimulation, the onset of inhibition of pituitary secretory function occurs immediately after drug administration and is maintained with continued such treatment. With sequential administration of multiple doses of ganirelix 0.25 mg to female volunteers, the greatest decrease in serum concentrations of LH, FSH, and estradiol was 74%, 32%, and 25% at 4, 16, and 16 hours after administration, respectively. Serum hormone levels returned to baseline within two days after the last injection.

Pharmacodynamic effects

The average duration of ganirelix use at a dose of 0.25 mg/day for controlled ovarian stimulation is 5 days. When using the drug at a dose of 0.25 mg/day, the average incidence of LH level increase (more than 10 IU/l) with a concomitant increase in progesterone concentration (more than 1 ng/ml) is 1.2%, which is comparable to the similar rate of 0.8% for GnRH agonists. Sometimes, even before the start of ganirelix therapy, by day 6 of ovarian stimulation with gonadotropic drugs, women with a pronounced ovarian response experienced an increase in LH levels, which subsequently did not significantly affect clinical outcomes. LH secretion in these patients was rapidly suppressed immediately after the first administration of ganirelix.

Pharmacokinetics

Pharmacokinetic parameters after multiple subcutaneous administrations of ganirelix (once daily) were similar to those after a single administration. After repeated administration at a dose of 0.25 mg/day, steady-state concentrations of approximately 0.6 ng/ml were reached within 2-3 days.

Pharmacokinetic analysis demonstrates an inverse relationship between body weight and ganirelix plasma concentrations.

Absorption

After a single subcutaneous administration of 0.25 mg of the drug, the plasma concentration of ganirelix increases rapidly and reaches C_max of about 15 ng/ml within 1-2 hours (T_max). The bioavailability of ganirelix after subcutaneous administration is about 91%.

Metabolism

The main compound circulating in plasma is Ganirelix. Ganirelix is also the main compound found in urine. The feces contain only metabolites formed by enzymatic hydrolysis of ganirelix to form small peptide fragments. The metabolic profile of ganirelix in humans is similar to that in animals.

Excretion

T_1/2 is approximately 13 hours, clearance is approximately 2.4 l/h.

The drug is excreted in feces (about 75%) and urine (about 22%).

Indications

• Prevention of premature peak secretion of luteinizing hormone (LH) in women during induction of ovulation (superovulation) in infertility treatment programs using assisted reproductive technologies (ART).

ICD codes

Dosage Regimen

The drug Ganirelix-Richter should be prescribed only by a specialist experienced in the treatment of infertility.

Controlled ovarian hyperstimulation with FSH or corifollitropin alfa may be initiated on day 2 or 3 of the menstrual cycle.

The drug Ganirelix-Richter at a dose of 0.25 mg is administered subcutaneously once daily, starting on the 5th or 6th day of FSH or corifollitropin alfa administration.

The initiation of therapy with Ganirelix-Richter depends on the ovarian response, i.e., the number and size of growing follicles and/or the amount of circulating estradiol. The initiation of therapy with Ganirelix-Richter may be delayed in the absence of follicular growth, although clinical experience is based on initiating ganirelix on day 5 or 6 of stimulation.

Ganirelix-Richter and FSH should be administered at approximately the same time. However, the drugs should not be mixed and must be administered at different body sites.

FSH dose adjustment should be based on the number and size of growing follicles, not on the amount of circulating estradiol (see section “Pharmacological Action”).

Daily administration of Ganirelix-Richter should continue until a sufficient number of follicles of appropriate size are formed. Final follicular maturation may be initiated by administration of human chorionic gonadotropin (hCG).

Timing of the last injection

Considering the T_1/2 of ganirelix, the interval between Ganirelix-Richter injections, as well as the time between the last Ganirelix-Richter injection and the hCG injection, should not exceed 30 hours, otherwise a premature LH peak may occur. Therefore, if Ganirelix-Richter is administered in the morning, its use should be continued throughout the entire period of gonadotropin treatment, including the day of ovulation triggering. If Ganirelix-Richter is administered in the afternoon, the last injection should be given in the afternoon preceding the day of ovulation triggering.

Ganirelix-Richter has shown safety and efficacy in women undergoing multiple treatment cycles.

The need for luteal phase support during treatment cycles with Ganirelix-Richter has not been studied. In clinical studies, luteal phase support was provided according to the practice of the research centers and the clinical protocol.

Special patient groups

Patients with renal impairment

There is no experience with ganirelix in patients with renal failure, as they were excluded from clinical studies. Accordingly, the use of Ganirelix-Richter in patients with moderate or severe renal impairment is contraindicated (see section “Contraindications”).

Patients with hepatic impairment

There is no experience with ganirelix in patients with hepatic failure, as they were excluded from clinical studies. Accordingly, the use of Ganirelix-Richter in patients with moderate or severe hepatic impairment is contraindicated (see section “Contraindications”).

Method of administration

Ganirelix-Richter should be administered subcutaneously, preferably into the anterior thigh. The injection site should be rotated to prevent lipoatrophy.

The patient may self-administer the drug provided she is properly instructed and can consult with a specialist.

Precautions for drug preparation and administration

Before using the drug, read the instructions for administration of Ganirelix-Richter, which describes the administration procedure.

The syringe should be inspected before use. Use only syringes with a clear solution without visible impurities and from undamaged containers.

When inspecting the syringe, small air bubbles may be seen. This effect is expected; removal of air bubbles from the syringe is not required.

Injection site preparation

Wash hands with soap. Treat the injection site (an area of skin approximately 5 cm in diameter around where the needle will enter) with an alcohol swab and allow to dry for at least 1 minute.

Needle insertion

Remove the needle cap. Pinch a skin fold between the index finger and thumb.

Insert the needle into the base of the skin fold at a 45°C (113°F) angle to its surface.

After each injection, the injection site should be changed.

Checking the correct needle position

Gently pull back on the plunger to check if the needle is correctly positioned. If blood is present in the syringe, do not inject the drug, remove the syringe, and apply an alcohol swab to the injection site for 1-2 minutes. Do not use this syringe. Begin administration with a new syringe.

Solution administration

If the needle is correctly positioned, slowly press the plunger and inject the solution subcutaneously.

Syringe removal

Remove the syringe and immediately apply an alcohol swab, pressing it against the injection site. Use the syringe only once.

If a dose is missed

Do not administer a double dose to make up for a missed injection. If the patient remembers that she forgot to administer the drug injection, the drug should be administered as soon as possible. If the delay in administering Ganirelix-Richter is more than 6 hours (i.e., the interval between administrations is more than 30 hours), the patient should immediately administer the drug and consult a doctor as soon as possible.

Children

The use of Ganirelix-Richter in children is not related to the indication.

Special precautions for the disposal of used medicinal product or waste generated from the use of the medicinal product, and other handling of the drug

Inspect the syringe before use. Use only syringes with a clear solution without visible impurities and from undamaged containers.

Before the first use of the drug, the patient should carefully read the instructions for administration of Ganirelix-Richter.

Each pre-filled syringe is for single use only.

Adverse Reactions

The table below lists adverse reactions that were observed in women receiving Ganirelix in clinical studies using recombinant FSH for ovarian stimulation. Adverse reactions with the use of ganirelix and corifollitropin alfa for ovarian stimulation are expected to be similar.

Adverse reactions are presented according to the MedDRA system-organ class classification and frequency of occurrence: very common (≥1/10), common (≥1/100 to <1/10), uncommon (≥1/1000 to <1/100). The frequency of hypersensitivity reactions (very rare, <1/10000) is based on post-marketing experience.

¹ Cases have been reported as early as after the first dose in patients receiving ganirelix treatment.

² Reported in one patient after the first dose of ganirelix.

³ In clinical studies, 1 hour after drug injection, the frequency of moderate or severe local skin reactions (according to patient reports) during the treatment course was 12% in patients receiving ganirelix treatment and 25% in patients using subcutaneous GnRH agonist. Local reactions usually disappear within 4 hours after drug administration.

Description of selected adverse reactions

Other reported adverse reactions are related to treatment aimed at achieving controlled ovarian stimulation using ART, especially pelvic pain, abdominal bloating, OHSS (see section “Special Precautions”), ectopic pregnancy and spontaneous abortion.

Reporting of suspected adverse reactions

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

Contraindications

• Hypersensitivity to ganirelix or to any of the excipients included in the drug;
• Hypersensitivity to GnRH or any other GnRH analogue;
• Moderate or severe renal impairment;
• Moderate or severe hepatic impairment;
• Pregnancy;
• Breastfeeding period.

Use in Pregnancy and Lactation

The use of Ganirelix-Richter is contraindicated during pregnancy and breastfeeding (see section “Contraindications”).

Use in Hepatic Impairment

Contraindication: moderate or severe hepatic impairment.

Use in Renal Impairment

Contraindication: moderate or severe renal impairment.

Pediatric Use

The use of Ganirelix-Richter in children is not related to the indication.

Geriatric Use

The use of Ganirelix-Richter in elderly patients is not related to the indication.

Special Precautions

Hypersensitivity reactions

Women with signs and symptoms of active allergic conditions should exercise particular caution. During post-marketing surveillance, cases of hypersensitivity reactions (both generalized and local) have been reported after the first dose of ganirelix. These reactions included anaphylaxis (including anaphylactic shock), angioedema and urticaria (see section “Adverse Reactions”).

If a hypersensitivity reaction is suspected, the use of Ganirelix-Richter should be discontinued and appropriate treatment instituted. Due to lack of clinical experience, treatment with Ganirelix-Richter is not recommended in women with severe allergic conditions.

Ovarian hyperstimulation syndrome

Ovarian hyperstimulation syndrome (OHSS) may occur during or after ovulation induction. The risk of developing OHSS should be considered when stimulating with gonadotropin. Treatment of OHSS is symptomatic, e.g., rest, intravenous infusions of electrolyte or colloid solutions and heparin.

Ectopic pregnancy

Since women with infertility undergoing treatment using assisted reproduction, especially in vitro fertilization (IVF), often have tubal pathology, the incidence of ectopic pregnancy may be increased. Therefore, an ultrasound examination should be performed early in pregnancy to confirm intrauterine pregnancy.

Congenital malformations

The incidence of congenital malformations after ART may be higher than after natural conception. This is associated with parental characteristics (e.g., maternal age, sperm characteristics) and the increased frequency of multiple pregnancies. In clinical studies (more than 1000 newborns), it has been demonstrated that the incidence of congenital malformations in children born after COH therapy with ganirelix is comparable to the incidence noted after COH therapy with GnRH agonists.

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.

Excipient

The drug contains less than 1 mmol sodium (23 mg) per injection, i.e., essentially sodium-free.

Effect on ability to drive and operate machinery

No studies have been conducted to evaluate the effect of the drug on the ability to drive and operate machinery.

Overdose

Symptoms overdose of ganirelix may lead to an increase in its duration of action.

Treatment in case of overdose, administration of Ganirelix-Richter should be (temporarily) discontinued and the patient should consult a doctor.

Drug Interactions

Interaction studies have not been conducted.

The possibility of interaction of ganirelix with widely used medicinal products, including histaminomimetics, cannot be excluded.

Ganirelix-Richter should not be mixed with any other medicines.

Storage Conditions

The syringe should be stored in the outer packaging to protect it from light.

Do not freeze.

Shelf Life

The shelf life is 3 years.

Dispensing Status

The drug is 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.