Goserelin zentiva

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT GOSERELIN ZENTIVA (GOSERELIN ZENTIVA)

Composition:

Active substance: goserelin;

1 implant contains goserelin acetate 12.50 mg, equivalent to goserelin 10.8 mg;

Excipients: Resomer® R202H Poly-D,L-lactide, Resomer® RG752H (poly (D,L-lactide-co-glycolide) 75:25.

Pharmaceutical form. Implant in pre-filled syringes.

Main physicochemical properties: cylindrical implant fragments of white to almost white color (approximate dimensions: diameter – 1.5 mm, length – 20 mm), placed in the polymer body of the applicator syringe with a holder. The implant is visible in the implant holder.

Pharmacotherapeutic group.

Gonadotropin-releasing hormone analogues. ATC code L02A E03.

Pharmacological Properties.

Pharmacodynamics.

Goserelin (D-Ser (But)6 Azgly10 LH-RH) is a synthetic analogue of the natural luteinizing hormone-releasing hormone (LH-RH). With continuous administration, goserelin 10.8 mg suppresses pituitary secretion of luteinizing hormone, leading to reduced serum concentrations of testosterone in men and estradiol in women. Initially, goserelin 10.8 mg, like other LH-RH agonists, may cause a transient increase in serum testosterone concentrations in men and estradiol in women.

Approximately 21 days after the first injection, testosterone concentrations in men decrease to castrate levels and remain low with continued administration of the drug every 12 weeks. Data indicate that, in exceptional circumstances where the repeat dose is not administered at 3 months, testosterone concentrations remain at castrate levels in most patients for up to an additional 16 weeks.

In studies of metastatic prostate cancer treatment, goserelin demonstrated survival outcomes similar to those of surgical castration.

In comparative trials comparing monotherapy with bicalutamide 150 mg versus castration (primarily using goserelin), no significant difference in overall survival was observed between patients receiving bicalutamide and those undergoing castration (relative risk = 1.05 [95% CI 0.81 to 1.36]). However, statistical equivalence between the two treatment methods cannot be established.

In comparative trials, goserelin improved both survival without evidence of recurrence and overall survival during adjuvant therapy prior to radiotherapy in patients with high-risk localized (T1-T2 and PSA [prostate-specific antigen] ≥10 ng/mL or Gleason score ≥7) or locally advanced (T3-T4) prostate cancer. The optimal duration of adjuvant therapy has not been established: a comparative trial demonstrated that three-year adjuvant therapy with goserelin significantly improved survival outcomes compared to radiotherapy alone. Neoadjuvant therapy prior to radiotherapy showed improved survival without evidence of recurrence in patients with high-risk localized or locally advanced prostate cancer.

Following prostatectomy in patients with evidence of prostate cancer extension beyond the prostate, adjuvant therapy with goserelin may improve disease-free survival, although there is no significant survival benefit in patients who did not have lymph node involvement at the time of surgery. Patients with locally advanced disease at pathological staging have additional risk factors such as PSA ≥10 ng/mL or

Gleason score ≥7 prior to adjuvant therapy with goserelin and should be carefully evaluated. There is no evidence of improved clinical outcomes with neoadjuvant goserelin therapy following radical prostatectomy.

In women, serum estradiol concentrations decrease within 4 weeks after the first implant administration and remain suppressed throughout the treatment period. In patients whose estradiol levels are already suppressed due to prior use of LH-RH analogues, estradiol concentrations remain low after switching to goserelin 10.8 mg. Suppression of estradiol is associated with a therapeutic response in patients with endometriosis or uterine fibroids and leads to amenorrhea in most patients.

At the beginning of goserelin treatment, some women may experience vaginal bleeding of varying duration and intensity. Such bleeding is likely a response to estrogen withdrawal and typically resolves spontaneously.

During treatment with LH-RH analogues, natural menopause may occur in some women; in rare cases, menstruation does not resume after treatment discontinuation.

Pharmacokinetics.

Administration of goserelin 10.8 mg every 12 weeks provides stable goserelin exposure without clinically significant drug accumulation. Goserelin binding to plasma proteins is negligible; its serum half-life ranges from two to four hours in patients with normal renal function. In patients with impaired renal function, the half-life is prolonged. However, when the drug is administered as a 10.8 mg implant every 12 weeks, this change does not lead to drug accumulation, and dosage adjustment is not required in such patients. No significant pharmacokinetic changes are observed in patients with hepatic impairment.

Clinical characteristics.

Indications.

Prostate cancer. Treatment of prostate cancer in which hormonal influence is possible.

Endometriosis. Treatment of endometriosis, including relief of symptoms such as pain, and reduction in size and number of endometrial lesions.

Uterine fibroids. Treatment of fibroids, including reduction of lesions, improvement of hematological status, and relief of symptoms such as pain. As an adjunct to surgical intervention to facilitate surgical technique and reduce blood loss during surgery.

Breast cancer in premenopausal women.

Contraindications.

Hypersensitivity to goserelin acetate or to any of the excipients.

Pregnancy or breastfeeding period.

Pediatric age.

Interaction with other medicinal products and other forms of interaction.

Since androgen deprivation therapy may lead to prolongation of the QT interval, careful consideration should be given to the concomitant use of goserelin with medicinal products capable of prolonging the QT interval, or agents that may cause torsades de pointes ventricular tachycardia, such as class IA antiarrhythmics (e.g., quinidine, disopyramide) or class III antiarrhythmics (e.g., amiodarone, sotalol, dofetilide, ibutilide), methadone, moxifloxacin, and antipsychotic agents (see section "Special precautions for use").

Special precautions for use.

Injection site reactions have been reported with the use of Zentiva Goséréline, including pain, bruising, bleeding, and vascular injury. Patients should be monitored for signs or symptoms of abdominal bleeding. In very rare cases, administration errors have led to vascular injury and hemorrhagic shock requiring blood transfusion and surgical intervention.

Particular caution is required when administering Zentiva Goséréline to patients with low body mass index (BMI) and/or those receiving full anticoagulant therapy (see section "Dosage and administration").

There are no data on removal or dissolution of the implant.

There is a high risk of depression (which may be severe) in patients receiving gonadotropin-releasing hormone (GnRH) agonists such as goserelin. Patients should be informed of this risk, and appropriate treatment should be initiated if symptoms occur.

Cases of bleeding around the injection site leading to hemorrhagic shock have been reported.

Therefore, injections should be administered in areas with a lower likelihood of vascular injury. The use of Zentiva Goséréline in patients with a predisposition to bleeding (e.g., those taking anticoagulants) should be carefully considered.

Androgen deprivation therapy may lead to QT interval prolongation.

Before prescribing goserelin to patients with a history of QT prolongation or risk factors for QT prolongation, as well as to patients concomitantly using medicinal products that may cause QT prolongation (see section "Interaction with other medicinal products and other forms of interaction"), the benefit-risk ratio should be evaluated, including the potential for development of torsades de pointes.

Men

Goserelin 10.8 mg should be used with caution in men at risk of developing urinary tract obstruction or spinal cord compression, and such patients should be closely monitored during the first month of therapy. In cases of existing or developing spinal cord compression or renal insufficiency due to urinary tract obstruction, standard treatment for these complications should be initiated.

Consideration should be given to prescribing antiandrogens during the initial treatment period with GnRH analogs (e.g., cyproterone acetate 300 mg/day for 3 days before and 3 weeks after goserelin administration), as this has been reported to prevent potential consequences of the initial rise in serum testosterone levels.

It is unlikely that patients with non-hormone-dependent prostate cancer will benefit from this treatment. This resistance to treatment may result from the absence of response to castration or hormonal therapy.

Testosterone measurement is recommended before initiating treatment to allow assessment of therapeutic benefit.

The use of GnRH agonists may lead to decreased bone mineral density. Preliminary data suggest that the addition of bisphosphonates to GnRH agonist therapy may reduce bone mineral loss in men. Particular caution should be exercised in patients with additional risk factors for osteoporosis (chronic alcohol abuse, smoking, long-term anticonvulsant or corticosteroid therapy, family history of osteoporosis).

Patients with established depression and those with hypertension require careful monitoring.

There is a high risk of hypotension (which may be severe) in patients treated with GnRH agonists such as goserelin. Patients should be informed of this risk and managed appropriately if symptoms occur.

In a pharmacoepidemiological study of GnRH agonists used for the treatment of prostate cancer, cases of myocardial infarction and heart failure were observed. The risk increases when the drug is used in combination with antiandrogen agents.

Reduced glucose tolerance has been observed in men using GnRH agonists. This may manifest as diabetes or loss of glycemic control in individuals with pre-existing diabetes. Blood glucose levels should be monitored.

Women

In premenopausal women with breast cancer, the hormonal receptor status of the tumor should be determined before initiating treatment with Zentiva Goséréline 10.8 mg. If the disease is found to be receptor-negative, Zentiva Goséréline 10.8 mg implant should not be used.

A transient increase in serum estradiol levels may occur after initiation of GnRH agonist therapy in women.

Reduction in bone mineral density

The use of GnRH agonists may lead to a decrease in bone mineral density of approximately 1% per month during the first 6 months of treatment. Each 10% reduction in bone mineral density increases the risk of fractures by 2–3 times.

Available data indicate that bone density is largely restored in most women after discontinuation of the drug.

In patients receiving goserelin for endometriosis, additional hormone replacement therapy (HRT) has been shown to mitigate the reduction in bone mineral density and the severity of vasomotor symptoms. However, there is no experience with HRT in women receiving goserelin 10.8 mg.

There are no specific data on the use of the drug in patients with established osteoporosis or risk factors for its development (such as chronic alcohol abuse, smoking, long-term therapy with drugs that reduce bone mineral density, e.g., anticonvulsants or corticosteroids, family history of osteoporosis, eating disorders such as anorexia nervosa). Since bone mineral loss may be more hazardous in such patients, the use of Zentiva Goséréline should be carefully considered on a case-by-case basis and initiated only after careful evaluation showing that benefits outweigh risks. Additional measures to counteract bone mineral loss should be considered.

Reduction in bone mineral density during breast cancer treatment in women

The use of GnRH agonists may lead to a reduction in bone mineral density. After 2 years of treatment for early-stage breast cancer, the average loss of bone mineral density was 6.2% and 11.5% at the femoral neck and lumbar spine, respectively. This loss has been shown to be partially reversible during one year of observation after treatment cessation, with recovery of 3.4% and 6.4% at the femoral neck and lumbar spine, respectively, although this recovery is based on very limited data. Available data suggest that bone tissue recovery occurs after treatment discontinuation in most women.

Preliminary data suggest that the use of goserelin in combination with tamoxifen in breast cancer patients may reduce bone demineralization.

Withdrawal bleeding

Vaginal bleeding of varying duration and intensity may occur at the beginning of Zentiva Goséréline treatment in some women. This usually occurs within the first month after starting treatment, likely as a response to estrogen withdrawal, and typically resolves spontaneously. If bleeding persists, its cause should be investigated.

The time to resumption of menstruation after discontinuation of Zentiva Goséréline 10.8 mg may be prolonged in some cases (the average duration of secondary amenorrhea after stopping goserelin 10.8 mg is 7–8 months). If rapid resumption of menstruation is desired, goserelin 3.6 mg is recommended.

Goserelin use may increase cervical resistance; therefore, caution should be exercised during cervical dilation.

There are no clinical data on the effect of Zentiva Goséréline for the treatment of benign gynecological conditions beyond 6 months.

Women of reproductive age should use non-hormonal contraception during treatment with Zentiva Goséréline and until menstruation resumes after treatment completion.

Patients with established depression and those with arterial hypertension require careful monitoring.

Goserelin use may lead to a positive result in anti-doping tests.

There is a high risk of excessive hypotension (which may be severe) in patients treated with GnRH agonists such as goserelin. Patients should be informed of this risk and managed appropriately if symptoms occur.

Use during pregnancy or breastfeeding.

Zentiva Goséréline should not be used during pregnancy or breastfeeding due to the theoretical risk of miscarriage or fetal abnormalities if GnRH agonists are administered during pregnancy. Women who may become pregnant should be carefully evaluated to exclude pregnancy.

Non-hormonal contraception should be used during treatment until menstruation resumes.

Fertility

In women, GnRH analogs such as Zentiva Goséréline 3.6 mg and Zentiva Goséréline 10.8 mg suppress LH and FSH. As a result, this may affect libido (see section "Adverse reactions") and cause cessation of ovulation and menstruation, leading to a negative but reversible effect on female fertility. Natural menopause may occur during GnRH analog therapy. Rarely, menstruation does not resume after treatment discontinuation in some women. Studies in rats indicate that the effect on female fertility is reversible.

In men: GnRH analogs such as Zentiva Goséréline 3.6 mg and Zentiva Goséréline suppress LH and FSH. As a result, this may cause erectile dysfunction and affect libido (see section "Adverse reactions"), and possibly spermatogenesis as well. Although there are no data on male fertility, based on the reversibility of fertility effects in rats and the reversibility of histopathological changes in the reproductive system in dogs after one year of treatment with Zentiva Goséréline, it can be expected that such effects in men are reversible.

Ability to affect reaction speed when driving or operating machinery.

Zentiva Goséréline has no effect or a negligible effect on the ability to drive or operate machinery.

Method of Administration and Dosage

Goserelin Zentiva should be administered with caution into the anterior abdominal wall due to the proximity of the inferior epigastric artery and its branches.

Particular caution is required when administering Goserelin Zentiva to patients with low BMI or those receiving anticoagulant therapy (see section "Special Warnings and Precautions for Use").

Local anesthesia may be used, but in most cases it is not necessary.

Adult men (including elderly patients)

1 implant (10.8 mg) of Goserelin Zentiva administered subcutaneously into the anterior abdominal wall every 12 weeks.

Adult women (including elderly patients)

1 implant (10.8 mg) of Goserelin Zentiva administered subcutaneously into the anterior abdominal wall every 12 weeks.

Endometriosis and uterine fibroids: Treatment should last no longer than 6 months, as clinical data on longer treatment durations are lacking.

Repeated treatment courses should not be performed due to the risk of loss of bone mineral content and decreased bone density.

In women treated with goserelin for endometriosis, additional hormone replacement therapy (daily administration of estrogen and progestogen) has been shown to reduce bone mineral density loss and alleviate vasomotor symptoms.

Experience with hormone replacement therapy in women receiving Zoladex 10.8 mg is lacking.

No dose adjustment is required for patients with renal or hepatic impairment, or for elderly patients.

Instructions for Administration

Use according to the prescribing physician's recommendations.

Ensure that the injection is administered subcutaneously, following the technique described in these instructions. Do not inject the drug into blood vessels, muscle, or the peritoneal cavity.

Administration Guidelines

Use only if the applicator syringe package is undamaged.

Use immediately after opening the package.

Local anesthesia may be used, but is generally not required.

Dispose of the syringe using special containers for sharp objects.

The following information is intended for healthcare professionals only:

Goserelin Zentiva is administered via subcutaneous injection. The instructions below must be followed prior to administration.

1. Position the patient comfortably with the upper body slightly elevated. Prepare the injection site according to current guidelines.

NOTE: Exercise caution when administering Goserelin Zentiva into the anterior abdominal wall due to the proximity of the inferior epigastric artery and its branches; very thin patients may be at increased risk of vascular injury.

Figure 1

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Inspect the sterile packaging and applicator syringe for damage. Remove the syringe from its sterile packaging. Hold the applicator syringe at a slight angle to the light and confirm that the Goserelin Zentiva implant is at least partially visible.

Remove the protective ring.

Figure 2

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Hold the applicator syringe by the body and remove the protective cap.

Unlike liquid injections, do not attempt to expel air bubbles—doing so may displace the Goserelin Zentiva implant.

Figure 3

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Pinch the patient's skin with two fingers while simultaneously holding the syringe body, and insert the needle obliquely (almost parallel to the skin).

Insert the needle into the subcutaneous tissue (not into muscle or the peritoneal cavity) of the anterior abdominal wall below the umbilical line, advancing until the body of the applicator syringe contacts the patient's skin.

This contact with the skin must be maintained throughout the entire implant administration process!

NOTE: The Goserelin Zentiva applicator syringe cannot be used for aspiration. If the injection needle penetrates a large blood vessel, blood will be immediately visible in the syringe chamber. In case of vessel puncture, withdraw the needle, immediately control any bleeding resulting from the puncture, and monitor the patient for signs or symptoms of abdominal hemorrhage. After confirming hemodynamic stability, another Goserelin Zentiva implant may be administered using a new syringe at a different injection site. Exercise particular caution when administering the drug to patients with low BMI and/or those receiving full-dose anticoagulant therapy.

Figure 4

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Press the plunger. As the plunger is pressed, the subcutaneous implant moves from the holder to the needle tip.

Under no circumstances should the syringe be pulled back. During implant administration, the applicator syringe body must remain in contact with the patient's skin!

Figure 5

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When the plunger reaches its final position, the automatic needle retraction mechanism is activated, and the plunger secures the implant in the subcutaneous tissue.

Figure 6

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The needle retracts from the patient's tissue into the polymer body of the applicator syringe. The syringe body should remain in contact with the patient's skin. Typically, forward movement of the plunger and needle retraction occur in one smooth motion.

Figure 7

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The subcutaneous implant administration process is complete. The needle is fully retracted into the syringe body.

The protective covering of the applicator syringe body prevents injury from the needle tip.

Figure 8

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Replace the protective cap.

Do not inject the needle into muscle or the peritoneal cavity.

Dispose of the syringe in a special container for sharp objects.

NOTE: If surgical removal of the implant becomes necessary—though this is unlikely—its location can be identified using ultrasound scanning.

Children

The drug is not intended for use in children, as safety and efficacy have not been established in this age group.

Overdose

Human experience with overdose is limited. No clinically significant adverse effects have been observed following administration of Goserelin Zentiva earlier than scheduled or at higher than prescribed doses. Animal studies do not indicate any effects beyond the therapeutic impact on sex hormone levels and reproductive pathways when higher doses of Goserelin Zentiva 10.8 mg are administered. In case of overdose, symptomatic treatment should be provided.

Adverse reactions

The frequency of adverse reactions was calculated based on data from clinical studies and post-marketing reports. The most commonly reported adverse reactions included hot flushes, sweating, and injection site reactions.

Adverse reactions are categorized by frequency as follows: very common (≥ 1/10), common (≥ 1/100 to < 1/10), uncommon (≥ 1/1000 to < 1/100), rare (≥ 1/10000 to < 1/1000), very rare (< 1/10000), and frequency not known (cannot be estimated from the available data).

Adverse reactions to Zoladex 10.8 mg by system organ class according to MedDRA

System organ class	Frequency	Men	Women
Benign, malignant and unspecified neoplasms (including cysts and polyps)	Very rare	Pituitary tumors	Pituitary tumors
	Frequency unknown		Uterine fibroid degeneration
Immune system disorders	Uncommon	Hypersensitivity reactions to the drug	Hypersensitivity reactions to the drug
	Rare	Anaphylactic reactions	Anaphylactic reactions
Endocrine disorders	Very rare	Pituitary haemorrhage	Pituitary haemorrhage
Metabolism and nutrition disorders	Common	Impaired glucose tolerancea
Psychiatric disorders	Very common	Decreased libidob	Decreased libidob
	Common	Mood changes, depression	Mood changes, depression
	Very rare	Psychiatric disorders	Psychiatric disorders
Nervous system disorders	Common	Paraesthesia	Paraesthesia
		Spinal cord compression
			Headache
Cardiac disorders	Common	Heart failuref, myocardial infarctionf
	Frequency unknown	QT interval prolongation (see sections "Special warnings and precautions for use" and "Interaction with other medicinal products and other forms of interactions")
Vascular disorders	Very common	Hot flushesb	Hot flushesb
	Common	Arterial pressure disordersc	Arterial pressure disordersc
Skin and subcutaneous tissue disorders	Very common	Hyperhidrosisb	Hyperhidrosisb, acnei
	Common	Rashd	Rashd, hair lossh
	Frequency unknown	Alopeciag	Rashd, hair lossh
Musculoskeletal and connective tissue disorders	Common	Bone paine
	Uncommon	Arthralgia	Arthralgia
Renal and urinary disorders	Uncommon	Ureteral obstruction
Reproductive system and breast disorders	Very common	Erectile dysfunction
			Vulvovaginal dryness
			Breast enlargement
	Common	Gynaecomastia
	Uncommon	Breast tenderness
	Rare		Ovarian cysts
	Frequency unknown		Withdrawal bleeding
General disorders and administration site conditions	Very common		Injection site reactions
	Common	Injection site reactions	Injection site reactions
			Tumour swelling, painful tumour
Investigations	Common	Decreased bone mineral density (see section "Special warnings and precautions for use"), increased body weight	Decreased bone mineral density, increased body weight

a Decreased glucose tolerance has been observed in men receiving GnRH agonists. This may manifest as diabetes mellitus or loss of glycemic control in patients with pre-existing diabetes.

b These pharmacological effects rarely require discontinuation of therapy. Hyperhidrosis and hot flushes may persist after discontinuation of Zoladex (goserelin) treatment.

c Hypo- or hypertension has occasionally been observed in patients receiving Zoladex (goserelin). Changes are usually temporary and resolve either with continued therapy or after discontinuation of Zoladex (goserelin). Rarely, such changes required medical intervention, including discontinuation of Zoladex.

d Usually mild and often decreases without the need to discontinue treatment.

e Initially, patients with prostate cancer may experience a temporary increase in bone pain; in such cases symptomatic treatment may be prescribed.

f Observed in pharmacoepidemiological studies of GnRH agonists used in the treatment of prostate cancer. The risk appears to increase when used in combination with antiandrogen agents.

g Particularly loss of body hair is an expected effect due to reduced androgen levels.

h Hair loss on the head has been observed in women, including young women, treated for benign gynecological conditions. This phenomenon is usually mild, but may occasionally be severe.

i In most cases, acne occurred within one month after initiation of treatment.

During administration of goserelin the following may occur: liver function disorders and development of jaundice with increased levels of alanine aminotransferase, aspartate aminotransferase, gamma-glutamyl transferase; increased levels of lactate dehydrogenase, alkaline phosphatase, triglycerides; epistaxis, urticaria, pruritus.

Also observed during administration of the drug: urinary system – dysuria, increased blood urea nitrogen, increased creatinine levels, proteinuria; blood system – anemia, leukopenia, thrombocytopenia.

During goserelin administration, injection site reactions (bleeding, hematoma, abscess, induration, pain), and bleeding around the injection site leading to hemorrhagic shock may occur.

Post-marketing experience

Rarely, abnormal blood test results, cases of hepatic dysfunction, pulmonary embolism, and interstitial pneumonia have been reported during use of Zoladex (goserelin).

In women treated for endometriosis and/or fibroids, hypercalcemia has rarely been observed. In case of symptoms suggestive of hypercalcemia (e.g., thirst), appropriate investigations should be performed to rule it out.

Additionally, in women receiving the drug for benign gynecological conditions, the following adverse reactions have been observed:

acne, changes in body hair, dry skin, weight gain, increased serum cholesterol levels, ovarian hyperstimulation syndrome (when used in combination with gonadotropins), vaginitis, vaginal discharge, nervousness, sleep disorders, fatigue, peripheral edema, myalgia, calf muscle cramps, nausea, vomiting, diarrhea, constipation, abdominal complaints, voice changes.

At the beginning of treatment, disease symptoms may temporarily worsen; in such cases symptomatic treatment may be prescribed.

Rarely, during treatment with GnRH analogs in women, menopause may occur and menstruation may not resume after completion of therapy. It is unknown whether this is an effect of Zoladex (goserelin) or a consequence of the underlying gynecological conditions.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorization of the medicinal product is important. It allows ongoing monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals are encouraged to report suspected adverse reactions via the national reporting system.

Shelf life. 4 years.

Use only if the applicator syringe pouch is undamaged.

Use immediately after opening the pouch.

Storage conditions.

Store in the original packaging at a temperature not exceeding 30°C.

Keep out of reach and sight of children.

Packaging.

1 implant in a pre-filled applicator syringe; the applicator syringe consists of a polymer body with an implant holder, needle, and plunger. One syringe in a pouch together with a desiccant capsule. One or three pouches in a cardboard box.

Prescription status.

Prescription only.

Manufacturer.

AMV GmbH.

Manufacturer's address and location of business.

Birkfeld 11, Lochham, Warngau, Bavaria, 83627, Germany.