Zoladex

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT ZOLADEX® (ZOLADEX)

Composition:

Active substance: 1 prolonged-release subcutaneous implant contains goserelin acetate equivalent to 3.6 mg goserelin base;

Excipients: copolymer of lactide and glycolide.

Pharmaceutical form. Prolonged-release subcutaneous implant.

Main physicochemical properties: solid cylindrical polymer pieces of white to creamy color.

Pharmacotherapeutic group. Gonadotropin-releasing hormone analogues.

ATC code: L02AE03.

Pharmacological properties.

Pharmacodynamics.

Zoladex (D-Ser(But)6 Azgly10 LH-RH) is a synthetic analogue of the natural luteinizing hormone-releasing hormone (LH-RH). With continuous administration, Zoladex inhibits pituitary secretion of LH, leading to a reduction in serum testosterone concentration in men and serum estradiol concentration in women. This effect is reversible upon discontinuation of therapy. Initially, like other LH-RH agonists, Zoladex may cause a transient increase in serum testosterone concentration in men and serum estradiol concentration in women.

In men, serum testosterone concentration decreases to castrate levels by approximately day 21 after the first implant administration and remains suppressed with continuous treatment every 28 days. This testosterone suppression leads to regression of prostate tumor and symptomatic improvement in most patients.

In comparative clinical trials of metastatic prostate cancer treatment, Zoladex demonstrated survival outcomes similar to those of surgical castration.

In a combined analysis of two randomized controlled trials comparing monotherapy with bicalutamide 150 mg versus castration (mostly with Zoladex), no significant difference was observed in overall survival between patients receiving bicalutamide and those undergoing castration (relative risk = 1.05 [confidence interval (CI) 0.81–1.36]). However, statistical equivalence between the two treatment modalities cannot be established.

In comparative studies, Zoladex improved both recurrence-free and overall survival when used as adjuvant therapy prior to radiotherapy in patients with high-risk localized prostate cancer (T1–T2 and PSA (prostate-specific antigen) ≥10 ng/mL or Gleason score of 7) or locally advanced (T3–T4) prostate cancer. The optimal duration of adjuvant therapy has not been established; however, a comparative study demonstrated that adjuvant treatment with Zoladex for 3 years significantly improved survival compared to radiotherapy alone. The use of Zoladex as neoadjuvant therapy improved recurrence-free survival in patients with high-risk localized or locally advanced prostate cancer compared to radiotherapy alone.

Following prostatectomy in patients with locally advanced prostate cancer, adjuvant therapy with Zoladex may improve recurrence-free survival, although significant survival benefit is not observed in patients without lymph node involvement at the time of surgery. Patients with locally advanced disease and confirmed histopathological stage who have additional risk factors, such as pre-adjuvant PSA ≥10 ng/mL or Gleason score of 7, should undergo careful evaluation. There is no evidence of improved clinical outcomes with neoadjuvant Zoladex therapy following radical prostatectomy.

In women, serum estradiol concentration decreases to postmenopausal levels by approximately day 21 after the first implant and remains suppressed with continuous treatment every 28 days. This suppression provides beneficial effects in hormone-dependent breast cancer, uterine fibroids, endometriosis, and inhibition of ovarian follicular development. It also causes endometrial thinning and amenorrhea in most patients.

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

Zoladex in combination with iron preparations has been shown to induce amenorrhea, resulting in increased hemoglobin levels and improvement in hematological parameters in women with uterine fibroids and concomitant anemia. This combination leads to an additional 10 g/dL increase in hemoglobin concentration compared to iron therapy alone.

Pharmacokinetics.

Zoladex has nearly complete bioavailability. Administration of the implant every four weeks maintains effective drug concentrations, with no tissue accumulation. Zoladex is poorly protein-bound, and its serum half-life is two to four hours in individuals with normal renal function. The half-life increases in patients with impaired renal function. However, this change is not expected to have significant consequences with monthly administration; therefore, dose adjustment is not necessary in such patients. No significant changes in pharmacokinetic parameters are observed in patients with hepatic impairment.

Clinical characteristics.

Indications.

Prostate cancer.

Treatment of prostate cancer in the following cases:

• treatment of metastatic prostate cancer – administration of Zoladex favorably influenced survival, similar to the effect of surgical castration;
• treatment of locally advanced prostate cancer as an alternative to surgical castration – administration of Zoladex favorably influenced survival, similar to the effect of antiandrogen use;
• as adjuvant therapy to radiotherapy in patients with localized high-risk prostate cancer or locally advanced prostate cancer – administration of Zoladex improved disease-free survival and overall survival;
• as neoadjuvant therapy preceding radiotherapy in patients with localized high-risk prostate cancer or locally advanced prostate cancer – administration of Zoladex improved disease-free survival;
• as adjuvant therapy to radical prostatectomy in patients with locally advanced prostate cancer and high risk of disease progression – administration of Zoladex improved disease-free survival.

Breast cancer. Treatment of advanced hormone-sensitive breast cancer in pre- and perimenopausal women.

As an alternative to chemotherapy in the standard treatment of pre- and perimenopausal women with estrogen receptor (ER) positive early breast cancer.

Endometriosis. Alleviates symptoms including pain, and reduces the size and number of endometrial lesions.

Endometrial thinning. For prior thinning of the endometrium before its ablation or resection.

Uterine fibroids. In combination with iron therapy to improve hematological status in anemic patients with fibroids prior to surgical intervention.

In vitro fertilization. Pituitary desensitization in preparation for superovulation stimulation.

Contraindications.

Hypersensitivity to the active substance 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 QT interval prolongation, concomitant use of Zoladex with medicinal products capable of prolonging the QT interval or those 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, antipsychotic agents, should be carefully evaluated (see section "Special precautions for use").

Special precautions for use.

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

Androgen deprivation therapy may lead to QT interval prolongation.

Before prescribing Zoladex to patients with a history of QT interval prolongation or risk factors for QT prolongation, as well as to patients concomitantly receiving medicinal products that may cause QT prolongation (see section "Interaction with other medicinal products and other forms of interaction"), physicians must evaluate the benefit-risk ratio, including the potential risk of developing torsades de pointes ventricular tachycardia.

Cases of injection site reactions, including pain, bruising, bleeding, and vascular injury, have been reported with the use of Zoladex. 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 should be exercised when administering Zoladex to patients with a low body mass index (BMI) and/or those receiving full anticoagulant therapy (see section "Method of administration and dosage").

Men

Zoladex 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 at the beginning of therapy with GnRH analogues (e.g., cyproterone acetate 300 mg daily for three days before and three weeks after Zoladex therapy), as it has been reported that this may prevent potential consequences of the initial rise in serum testosterone levels.

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

Patients with pre-existing depression and patients with hypertension require careful monitoring.

Reduced glucose tolerance has been observed in men receiving GnRH agonists. This may manifest as diabetes mellitus or loss of glycemic control in individuals with pre-existing diabetes. Therefore, monitoring of blood glucose levels is necessary.

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.

Women

Breast cancer as an indication

Reduction in bone mineral density

The use of GnRH agonists may lead to decreased bone mineral density. After two years of treatment for early-stage breast cancer, the mean reduction in bone mineral density at the femoral neck and lumbar spine in women was 6.2% and 11.5%, respectively. These losses have been shown to be partially reversible: one year after discontinuation of treatment, the loss of bone mineral density at the femoral neck and lumbar spine was 3.4% and 6.4% less, respectively, than before treatment initiation, although data on bone mass recovery are very limited. According to available data, in most women bone mass recovers after discontinuation of treatment.

Preliminary data indicate that the use of Zoladex in combination with tamoxifen in patients with breast cancer may reduce bone mineral loss.

Benign conditions as an indication

Loss of bone mineral density

GnRH agonists may cause a reduction in bone mineral density by an average of 1% per month during a six-month treatment period. A 10% decrease in bone mineral density approximately doubles to triples the risk of fractures. According to current data, in most women bone mass recovers after discontinuation of treatment.

It has been demonstrated that in patients receiving Zoladex for endometriosis treatment, additional hormone replacement therapy reduces bone mineral density loss and the severity of vasomotor symptoms.

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 reduced bone mineral density in such patients may be more hazardous, the use of Zoladex should be carefully considered on a case-by-case basis and initiated only after thorough evaluation confirming that benefits outweigh risks. Additional measures to counteract bone mineral density loss should be implemented.

Withdrawal bleeding

At the beginning of Zoladex treatment, some women may experience vaginal bleeding of varying duration and intensity. This usually occurs during the first month after treatment initiation, is likely a response to estrogen withdrawal, and resolves spontaneously. If bleeding persists, its cause should be investigated.

There are no clinical data on the effect of Zoladex use for the treatment of benign gynecological conditions for more than six months.

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

Zoladex should be used in assisted reproduction only under the supervision of a specialist experienced in this field.

As with other GnRH agonists, cases of ovarian hyperstimulation syndrome (OHSS) have been reported with the use of Zoladex 3.6 mg in combination with gonadotropins. The stimulation cycle should be carefully monitored to identify patients at risk of OHSS. If OHSS risk is present, human chorionic gonadotropin (hCG) should be withheld if possible.

Zoladex should be used with caution in fertility procedures for patients with polycystic ovary syndrome, as stimulation of a large number of follicles is possible.

Women of reproductive age must use non-hormonal contraception during Zoladex therapy and until menstruation resumes after treatment completion.

Careful monitoring is required for patients with pre-existing depression and patients with hypertension.

Zoladex use may result in a positive doping test.

Instructions for use of the pouch

Use only if the pouch containing the syringe-applicator is undamaged. Use immediately after opening the pouch.

Use during pregnancy or breastfeeding.

Zoladex should not be used during pregnancy or breastfeeding, as there is a 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.

During treatment, non-hormonal contraception should be used until menstruation resumes (see also the warnings regarding the time required for menstruation recovery in the "Special precautions for use" section).

Pregnancy should be excluded before initiating Zoladex for infertility treatment. There are no clinical data indicating a causal relationship between Zoladex use and any subsequent oocyte, pregnancy, or pregnancy outcome abnormalities.

The use of Zoladex during breastfeeding is not recommended.

Natural menopause may occur during treatment with GnRH analogues. Rarely, in some women, menstruation does not resume after discontinuation of treatment.

Ability to influence reaction rate when driving or operating machinery.

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

Method of Administration and Dosage

Zoladex 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 Zoladex to patients with low BMI or those receiving anticoagulant therapy (see section "Special Warnings and Precautions for Use").

Ensure that the injection is performed subcutaneously according to the technique described in the administration instructions. Do not inject the drug into blood vessels, muscle, or the peritoneal cavity.

If surgical removal of the Zoladex implant is required, its location can be identified using ultrasound imaging.

Adults

One 3.6 mg Zoladex implant should be administered subcutaneously into the anterior abdominal wall every 28 days.

Dose adjustment is not necessary for patients with renal or hepatic impairment, or for elderly patients.

In Vitro Fertilization (IVF)

Zoladex 3.6 mg is indicated for pituitary desensitization, determined by serum estradiol levels and corresponding to early follicular phase levels (approximately 150 pmol/L). This typically occurs between day 7 and day 21 of the menstrual cycle.

Controlled ovarian hyperstimulation with gonadotropins should begin once desensitization has been achieved. Desensitization induced by the agonist implant is more profound, which may necessitate higher gonadotropin doses in some cases. When appropriate follicular development is reached, gonadotropin administration is discontinued and human chorionic gonadotropin (hCG) is administered to induce ovulation. Monitoring of treatment, oocyte retrieval, and fertilization procedures should follow the standard protocols of the individual treatment center.

Endometriosis

Treatment should be limited to six months, as clinical data on longer treatment durations are currently unavailable. Repeated courses of treatment are not recommended due to the risk of decreased bone mineral density. It has been demonstrated that in patients receiving Zoladex for endometriosis, add-back hormone therapy (daily administration of estrogen and progestogen) reduces bone mineral density loss and alleviates vasomotor symptoms.

For endometrial thinning

The drug should be administered for four or eight weeks of treatment. In cases of large uterine size or uncertainty regarding the timing of surgery, a second implant may be required.

Uterine fibroids

Women with anemia caused by uterine fibroids may be treated with Zoladex 3.6 mg in combination with iron supplements for three months prior to surgical intervention.

Administration Instructions

Use only as directed by the prescribing physician. Exercise particular caution when administering Zoladex to patients with low BMI and/or those receiving full-dose anticoagulant therapy (see section "Special Warnings and Precautions for Use").

Instructions for Use

Use only if the syringe applicator pouch is undamaged. Use immediately after opening the pouch.

Dispose of the syringe using special sharps containers.

The following information is intended exclusively for healthcare professionals:

Zoladex is administered by subcutaneous injection. The instructions below should be read carefully before administration.

Children.

Zoladex is not indicated for use in children, as the safety and efficacy of use in this patient group have not been established.

Overdose.

Data regarding overdose in humans are insufficient. No clinically significant adverse effects have been observed following administration of Zoladex earlier than planned or in higher than prescribed doses. Results from animal studies do not indicate any effects other than the therapeutic ones on sex hormone concentrations and reproductive pathways when higher doses of Zoladex were administered. In case of overdose, symptomatic treatment should be provided.

Adverse Reactions

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

The following classification was used to define frequency: 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), frequency not known (cannot be estimated from the available data).

Table. Adverse reactions to Zoladex 3.6 mg by organ system classes according to MedDRA.

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 stopping Zoladex treatment.

c. Hypo- or hypertension has occasionally been reported in patients receiving Zoladex. Changes are usually transient and resolve either during continued therapy or after discontinuation of Zoladex. Rarely, such changes required medical intervention, including discontinuation of Zoladex.

d. Usually mild, and often diminishes 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 for the treatment of prostate cancer. The risk appears to increase when used concomitantly with antiandrogens.

g. Hair loss has been observed in women, including young women, treated for benign gynecological conditions. This effect is usually mild, but may occasionally be severe.

h. Particularly, loss of body hair is an expected effect due to decreased androgen levels.

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

Post-marketing experience

Rare cases of abnormal blood test results, hepatic dysfunction, pulmonary embolism, and interstitial pneumonia have been reported during post-marketing use of Zoladex.

Additionally, in women treated for benign gynecological conditions, the following adverse reactions have been reported:

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 spasms, nausea, vomiting, diarrhea, constipation, abdominal complaints, voice changes.

At the beginning of treatment, patients with breast cancer may experience a temporary worsening of signs and symptoms; symptomatic treatment may be prescribed in such cases.

Rarely, hypercalcemia has developed at the beginning of treatment in patients with metastatic breast cancer. If symptoms suggestive of hypercalcemia (e.g., thirst) occur, this condition should be ruled out.

Rarely, menopause may occur during treatment with GnRH analogues in women, and menstruation may not resume after completion of therapy. It is unclear whether this is due to the effect of Zoladex or the underlying gynecological conditions of the patients.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after medicine authorization is important. It allows continued monitoring of the benefit-risk balance of the medicine. Healthcare professionals should report any suspected adverse reactions.

Shelf life.

3 years.

Storage conditions.

Store at temperatures not exceeding 25 °C. Keep out of reach of children.

Packaging.

1 capsule in a syringe-applicator with a safety mechanism; 1 syringe in a pouch with an attached label and a moisture-absorbing capsule; 1 pouch in a cardboard box.

Prescription status.

Prescription only.

Manufacturer.

AstraZeneca UK Limited.

Manufacturer's address.

Silk Road Business Park, Macclesfield, SK10 2NA, United Kingdom.