Zoladex capsules for subcutaneous administration, prolonged action, 10.8 mg, syringe applicator No. 1

Instructions for Zoladex capsules for subcutaneous administration of prolonged action 10.8 mg syringe applicator No. 1

Composition

active ingredient: 1 capsule for subcutaneous administration of prolonged action contains goserelin acetate equivalent to 10.8 mg of goserelin base;

excipients: lactide and glycolide copolymer.

Dosage form

Capsule for subcutaneous administration of prolonged action.

Main physicochemical properties: pieces of solid polymer of cylindrical shape from white to cream color, free or practically free of visible particles.

Pharmacotherapeutic group

Gonadotropin-releasing hormone analogues. ATX code L02A E03.

Pharmacological properties

Pharmacodynamics

Zoladex (D-Ser (But)6Azgly10LH-RH) is a synthetic analogue of the natural luteinizing hormone-releasing hormone (LH-RH). With continuous use, Zoladex 10.8 mg inhibits the secretion of luteinizing hormone by the pituitary gland, which leads to a decrease in serum testosterone concentrations in men and estradiol in women. At the initial stage, Zoladex 10.8 mg, like other LH-RH agonists, may cause a temporary increase in serum testosterone concentrations in men and estradiol in women.

In men, testosterone concentrations fall to castrate levels by approximately 21 days after the first capsule and remain reduced with subsequent administration every 12 weeks. Evidence suggests that, unless re-administration occurs in exceptional circumstances after 3 months, testosterone concentrations remain at castrate levels in most patients for up to 16 weeks.

In comparative clinical trials in the treatment of metastatic prostate cancer, the drug Zoladex showed survival results similar to the effect of surgical castration.

In a pooled analysis of 2 randomized controlled trials comparing bicalutamide 150 mg monotherapy and castration (mainly in the form of Zoladex), there was no significant difference in overall survival between patients with prostate cancer who received bicalutamide and those who received castration (relative risk = 1.05 [confidence interval (CI) 0.81 to 1.36]). However, the equivalence of the two treatments could not be assessed statistically.

In comparative studies, Zoladex improved recurrence-free survival and overall survival when given as adjuvant therapy before radiotherapy in patients with high-risk localized prostate cancer (T1–T2 and PSA (prostate-specific antigen) at least 10 ng/mL or Gleason score 7) or locally advanced (T3–T4) prostate cancer. The optimal duration of adjuvant therapy has not been established; the comparative trial showed that adjuvant therapy with Zoladex for 3 years significantly improved survival compared with radiotherapy alone. Neoadjuvant use of Zoladex before radiotherapy improved recurrence-free survival in patients with high-risk localized or locally advanced prostate cancer.

After prostatectomy in patients with advanced prostate cancer, adjuvant therapy with Zoladex may improve disease-free survival, although there is no significant improvement in survival if patients are node-negative at surgery. Patients with locally advanced disease with histopathologically staged disease who have additional risk factors such as a PSA level of at least 10 ng/mL or a Gleason score of 7 prior to adjuvant therapy with Zoladex should be carefully evaluated. There is no evidence that neoadjuvant therapy with Zoladex after radical prostatectomy improves clinical outcomes.

In women, serum estradiol concentrations decrease within 4 weeks after administration of the first capsule and remain decreased until the end of the treatment period. In patients whose estradiol levels are already decreased by the use of LH-RG analogues, concentrations remain decreased when transferred to Zoladex 10.8 mg. Estradiol suppression is accompanied by a response in patients with endometriosis or uterine fibroids and results in amenorrhea in the majority of patients.

When starting Zoladex, some women may experience vaginal bleeding of varying duration and intensity. This bleeding is likely to be a reaction to estrogen withdrawal and usually resolves on its own.

During treatment with LH-RG analogues, patients may experience natural menopause; in rare cases, menstruation does not resume after treatment is completed.

Administration of Zoladex 10.8 mg every 12 weeks provides stable exposure to goserelin without clinically significant accumulation of the drug. Zoladex is poorly bound to proteins; its serum half-life is two to four hours in patients with normal renal function. In patients with impaired renal function, the half-life is increased. When the drug is administered as a 10.8 mg capsule every 12 weeks, this change does not lead to accumulation of the drug, and there is no need for dose adjustment in such patients. No significant changes in pharmacokinetics are observed in patients with hepatic insufficiency.

Indication

Prostate cancer. Therapy of prostate cancer, in which hormonal influence is possible.

Endometriosis. Treatment of endometriosis, including relief of symptoms such as pain and reduction of the 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 surgery to facilitate surgical technique and reduce blood loss during surgery.

Breast cancer in premenopausal women.

Contraindication

Hypersensitivity to goserelin acetate or to any of the excipients.

Pregnancy or breastfeeding.

Childhood.

Interaction with other medicinal products and other types of interactions

Since androgen deprivation therapy may prolong the QT interval, the concomitant use of Zoladex with medicinal products known to prolong the QT interval or medicinal products that may induce torsades de pointes, such as class IA (e.g. quinidine, disopyramide) or class III (e.g. amiodarone, sotalol, dofetilide, ibutilide) antiarrhythmics, methadone, moxifloxacin, antipsychotics, etc., should be carefully evaluated (see section 4.4).

Application features

Injection site reactions, including pain, hematoma, bleeding and vascular injury, have been reported with Zoladex. Patients with these reactions should be monitored for signs or symptoms of abdominal bleeding. In very rare cases, administration errors have resulted in vascular injury and hemorrhagic shock requiring blood transfusion and surgery. Particular caution should be exercised when administering Zoladex to patients with a low body mass index (BMI) and to patients receiving full anticoagulation (see section 4.2).

There are no data on capsule removal or dissolution.

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

Cases of bleeding around the injection site leading to hemorrhagic shock have been reported. The following precautions should be taken into account when using Zoladex:

Injections should be made in an area with a lower probability of vascular damage. The possibility of using the drug Zoladex in patients with a tendency to bleeding (for example, those using anticoagulants) should be carefully considered.

Androgen deprivation therapy may lead to prolongation of the QT interval.

Before prescribing Zoladex to patients with a history of QT prolongation or risk factors for QT prolongation, or to patients receiving concomitant medications that may prolong the QT interval (see Interactions with other medicinal products and other forms of interaction), the benefit-risk balance should be assessed, including the potential for torsades de pointes.

Men

Zoladex 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. If spinal cord compression or renal failure due to urinary tract obstruction is present or develops, standard treatment for such complications should be used.

Patients with non-hormonal prostate cancer are unlikely to benefit from this treatment. This resistance to treatment may be the result of a lack of response to castration or hormonal treatment.

Recommended dosage of testosterone therapy before treatment initiation to allow assessment of therapeutic benefit.

Use of LH-GH agonists may result in decreased bone mineral density. Preliminary evidence suggests that the use of bisphosphonates in addition to LH-GH agonists in men may reduce bone mineral loss. Particular caution should be exercised in patients with additional risk factors for osteoporosis (such as chronic alcohol abuse, smoking, long-term anticonvulsant or corticosteroid therapy, family history of osteoporosis).

Patients with established depression and patients with hypertension require close supervision.

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

In a pharmacoepidemiological study of LH-GH agonists used for the treatment of prostate cancer, cases of myocardial infarction and heart failure were observed. The risk is increased when the drug is used in combination with antiandrogens.

Impaired glucose tolerance has been reported in men treated with LH-GH agonists. This may manifest as diabetes or loss of glycemic control in individuals with pre-existing diabetes. Therefore, monitoring of blood glucose levels is necessary.

Women

In the case of breast cancer in premenopausal women, before starting Zoladex 10.8 mg, the hormone receptor status of the tumor should be determined. If the disease is found to be receptor-negative, Zoladex 10.8 mg prolonged-release subcutaneous capsules should not be used.

After starting therapy with LH-RG agonists, a temporary increase in blood estradiol levels is observed in women.

Decreased bone mineral density

The use of LH-GH agonists can lead to a decrease in bone mineral density of approximately 1% per month during the 6-month treatment period. Each 10% decrease in bone mineral density increases the risk of fracture 2-3-fold.

Existing evidence suggests that in most women, bone density recovers after stopping the drug.

In patients taking Zoladex for the treatment of endometriosis, additional hormone replacement therapy (HRT) attenuated the decrease in bone mineral density and the severity of vasomotor symptoms. There is no experience with the use of HRT in women taking Zoladex 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, e.g. anorexia nervosa). Since the decrease in bone mineral density in such patients may be more dangerous, the use of Zoladex should be considered on a case-by-case basis and therapy should be initiated only if, after careful assessment, the benefits outweigh the risks. Additional measures to counteract bone mineral loss should be taken.

Decreased bone mineral density in the treatment of breast cancer in women

The use of GnRH (gonadotropin-releasing hormone) agonists may cause a decrease in bone mineral density. After 2 years of treatment for early breast cancer, the mean bone mineral density loss was 6.2% and 11.5% at the hip and lumbar spine, respectively. This loss was found to be partially reversible, with a recovery of 3.4% and 6.4% from baseline at the hip and lumbar spine, respectively, during a one-year follow-up without treatment, although this recovery is based on very limited data. For most women, the data available to date suggest that recovery of bone loss occurs after cessation of treatment.

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

Withdrawal bleeding

At the beginning of treatment with Zoladex, some patients may experience vaginal bleeding of varying duration and intensity. This bleeding usually occurs within the first month after starting treatment, is likely to be a reaction to estrogen withdrawal, and is usually self-limiting. If the bleeding persists, the cause should be investigated.

The time to the resumption of menstruation after discontinuation of Zoladex 10.8 mg therapy may be prolonged in some cases (the average duration of secondary amenorrhea after discontinuation of Zoladex 10.8 mg is 7-8 months). If rapid resumption of menstruation is required, Zoladex 3.6 mg is recommended.

The use of Zoladex may lead to increased cervical resistance, so caution should be exercised when dilating the cervix.

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

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

The use of Zoladex may lead to a positive reaction to an anti-doping test.

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

Envelope usage guide
Use only if the envelope with the syringe applicator is intact. Use immediately after opening the envelope.

Ability to influence reaction speed when driving vehicles or other mechanisms

Zoladex has no or negligible influence on the speed of reaction when driving or operating other mechanisms.

Use during pregnancy or breastfeeding

Zoladex should not be used during pregnancy or breast-feeding because there is a theoretical risk of miscarriage or foetal abnormalities when LH-RH agonists are used during pregnancy. Women of childbearing potential should be carefully examined to exclude pregnancy.

During treatment, non-hormonal methods of contraception should be used until menstruation resumes.

Fertility

In women, LH-GH analogues such as Zoladex 3.6 mg and Zoladex 10.8 mg are intended to suppress LH and FSH. As a result, this may affect libido (see section 4.8) and cause cessation of ovulation and menstruation, with a negative but reversible effect on female fertility. During treatment with GnRH analogues, menopause may occur naturally. Rarely, some women do not resume menstruation after stopping treatment. Studies in rats show that the effect on female fertility is reversible.

For men: LH-RH analogues such as Zoladex 3.6 mg and Zoladex 10.8 mg are designed to suppress LH and FSH. As a result, this may cause erectile dysfunction and affect libido (see section 4.8) and possibly spermatogenesis. Although there are no data on male fertility, based on the reversibility of the effects on fertility in rats and the reversibility of histopathological changes in the reproductive system in dogs after one year of treatment with Zoladex, it is expected that such effects in men are reversible.

Method of administration and doses

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 should be exercised when using Zoladex in patients with low BMI or those receiving anticoagulants (see section "Special warnings and precautions for use").

Local anesthesia is permitted, but in most cases it is not necessary.

Adult males (including elderly patients).

1 capsule (10.8 mg) of Zoladex should be injected subcutaneously into the anterior abdominal wall every 12 weeks.

Adult women (including elderly patients).

1 capsule (10.8 mg) of Zoladex should be injected subcutaneously into the anterior abdominal wall every 12 weeks.

Endometriosis and uterine fibroids: treatment should only last 6 months, as clinical data on longer periods of use are lacking.

Repeated courses of treatment should not be carried out due to the risk of loss of some mineral components and a decrease in bone density.

In patients taking goserelin for the treatment of endometriosis, additional hormone replacement therapy (daily estrogen and progestin) reduced bone mineral density loss and the severity of vasomotor symptoms.

There is no experience with the use of hormone replacement therapy in women receiving Zoladex 10.8 mg.

There is no need to adjust the dose for patients with renal or hepatic insufficiency, as well as for elderly patients.

Instructions for use

Use according to the recommendations of the doctor who prescribed the drug.

Care should be taken to ensure that the injection is performed subcutaneously, following the procedure described in the administration instructions. Do not inject into blood vessels, muscle or the abdominal cavity.

If surgical removal of the Zoladex capsule is necessary, its location can be determined using ultrasound.

Instructions for use

Use only if the envelope with the syringe applicator is intact. Use immediately after opening the envelope.

Dispose of the syringe using special containers for sharps.

The following information is intended for medical or healthcare professionals only:

Zoladex is administered by subcutaneous injection. Please read the instructions below before use.

NOTE: Caution should be exercised when administering Zoladex 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.

2. Inspect the foil envelope and syringe for damage. Remove the syringe from the opened foil envelope. Hold the syringe at a slight angle to the light. Make sure that the Zoladex capsule is at least partially visible (Figure 1).

3. Pull the plastic safety tab to separate it from the syringe and discard it (Figure 2). Remove the protective cap from the needle. Unlike liquid injections, there is no need to remove air bubbles – attempting to do so may dislodge the Zoladex capsule.

4. Holding the syringe by the protective sheath and observing the rules of aseptic technique, pinch the patient's skin and insert the needle at a slight angle (30–45°) to the skin. Holding the needle with the opening upwards, insert the needle into the subcutaneous tissue of the anterior abdominal wall below the umbilicus so that the protective sheath touches the patient's skin (Figure 3).

NOTE: The Zoladex syringe should not be used for aspiration. If the injection needle enters a major vessel, blood will be immediately visible in the syringe chamber. If a vessel is punctured, the needle should be removed, any bleeding resulting from the puncture should be stopped immediately, and the patient should be observed for signs or symptoms of abdominal bleeding. Once the patient is hemodynamically stable, another Zoladex capsule may be administered using a new syringe to a different body site. Particular caution should be exercised when administering the drug to patients with low BMI and/or those receiving full-dose anticoagulant therapy.

5. Do not insert the needle into the muscle or abdominal cavity. Incorrect syringe grip and angle of insertion are shown in Fig.

6. Push the plunger of the syringe all the way in to insert the capsule and activate the safety mechanism. You will hear a click and feel the safety cover automatically slide down to cover the needle. If the plunger is not pushed in all the way in, the safety cover will not activate.

NOTE: The needle does not retract.

7. Holding the syringe as shown in Fig. 5, remove the needle and allow the needle guard to fully cover it. Discard the syringe in a sharps container.

NOTE: If the capsule needs to be surgically removed, which is unlikely, its location can be determined using an ultrasound scan.

Children

Zoladex is not indicated for use in children because safety and efficacy in this patient group have not been established.

Overdose

There is insufficient data on overdose in humans. In the case of administration of Zoladex before the planned time or in a dose higher than the prescribed, no clinically significant undesirable effects were observed. The results of studies in animals do not indicate any effect, other than therapeutic, on the concentration of sex hormones and the genital tract when using higher doses of Zoladex 10.8 mg. In case of overdose, symptomatic treatment should be provided.

Adverse reactions

The frequency of adverse reactions was calculated from clinical trial reports of Zoladex and post-marketing reports. The most common adverse reactions were hot flushes, increased sweating, and injection site reactions.

The following gradation was used to classify the frequency: very common (≥ 1/10), common (≥ 1/100 to < 1/10), uncommon (≥ 1/1000 to < 1/100), rare (≥ 1/10,000 to < 1/1000), very rare (< 1/10,000), frequency unknown (cannot be estimated from the available data).

Table: Adverse reactions to Zoladex 10.8 mg by MedDRA system organ class.

QT prolongation (see sections "Special warnings and precautions for use" and "Interaction with other medicinal products and other types of interactions")

Decreased bone density (see section "Special warnings and precautions for use"), weight gain

a Impaired glucose tolerance has been reported in men treated with LH-GH agonists. This may present as diabetes mellitus or loss of glycaemic control in individuals with pre-existing diabetes mellitus.

b These pharmacological effects rarely require discontinuation of therapy. Hyperhidrosis and hot flashes may persist after discontinuation of Zoladex.

c Hypotension or hypertension has occasionally been reported in patients receiving Zoladex. These changes are usually transient and resolve either with continued therapy or upon discontinuation of Zoladex. These changes have occasionally required medical intervention, including discontinuation of Zoladex.

d Usually minor, often resolves without the need to discontinue treatment.

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

f Observed in pharmacoepidemiological studies of LH-GH agonists used for the treatment of prostate cancer. The risk appears to be increased when used with antiandrogens.

g In particular, loss of body hair is an expected effect of reduced androgen levels.

h Hair loss on the scalp has been observed in women, including young women, treated for benign gynecological conditions. It is usually mild but can sometimes be severe.

and In most cases, acne was observed within a month of starting use.

When using goserelin, the following are possible: impaired liver function and the development of jaundice with increased levels of ALT (alanine aminotransferase), AST (aspartate aminotransferase), GGTP (gamma-glutamine transpeptidase); increased levels of LDH (lactate dehydrogenase), alkaline phosphatase, triglycerides; nosebleeds, vaginal bleeding, urticaria, itching.

Also, when using the drug, the following may be observed: from the urinary system - dysuria, increased blood urea nitrogen, increased creatinine, proteinuria; from the blood - anemia, leukopenia, thrombocytopenia.

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

Post-marketing experience

Abnormal blood test results, cases of liver dysfunction, pulmonary embolism and interstitial pneumonia have been observed rarely with the use of Zoladex.

Hypercalcemia has been reported rarely in women treated for endometriosis and/or fibroids. If symptoms of hypercalcemia (e.g. thirst) occur, evaluation should be performed to rule it out.

In addition, the following adverse reactions were observed in women receiving the drug for benign gynecological conditions:

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, signs and symptoms of the disease may temporarily worsen - in this case, symptomatic treatment may be prescribed.

Occasionally, during treatment with LH-RG analogues, women may experience menopause and menstruation may not resume after the end of therapy. Whether this is due to the effects of Zoladex or to the patients' gynecological conditions is unknown.

Reporting suspected adverse reactions after a medicinal product has been authorised is important. This allows for continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals should report any suspected adverse reactions.

Expiration date

3 years.

Storage conditions

Store at a temperature not exceeding 25 ° C. Keep out of the reach of children.

Packaging

1 capsule in a syringe applicator with a protective mechanism; 1 syringe in an envelope with an attached annotation flag with a moisture-absorbing capsule; 1 envelope in a cardboard box.

Vacation category

According to the recipe.

Producer

AstraZeneca UK Limited.

Location of the manufacturer and its business address

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