Goserelin zentiva

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

Composition:

active substance: goserelin;

1 implant contains goserelin acetate 4.10 mg equivalent to goserelin 3.6 mg;

excipients: Resomer® RG 502H (poly (D,L-lactide-co-glycolide) 50:50.

Pharmaceutical form. Implant in pre-filled syringes.

Main physicochemical characteristics: cylindrical implant fragments of white to almost white color (approximate dimensions: width about 1.2 mm, length about 13 mm), placed in the polymer body of the syringe-applicator with an implant holder. The implant is visible in the implant holder.

Pharmacotherapeutic group.

Gonadotropin-releasing hormone analogues. ATC code L02A E03.

Pharmacological Properties

Pharmacodynamics

Mechanism of action

Goserelin (D-Ser(But)^6 Azgly^10 LH-RH) is a synthetic analogue of the natural luteinizing hormone-releasing hormone (LH-RH). With continuous administration, goserelin inhibits pituitary secretion of LH, resulting in decreased serum testosterone concentrations in men and decreased serum estradiol concentrations in women. This effect is reversible upon discontinuation of therapy. Initially, like other LH-RH agonists, goserelin may cause a transient increase in serum testosterone concentrations in men and serum estradiol concentrations in women.

In men, serum testosterone concentrations decrease to castrate levels by approximately day 21 after the first implant administration and remain suppressed with continuous monthly dosing every 28 days. This testosterone suppression leads to tumor regression and symptomatic improvement in the majority of patients with prostate cancer.

In clinical studies, goserelin has demonstrated efficacy comparable to that of surgical castration in the treatment of patients with metastatic prostate cancer.

In trials comparing monotherapy with bicalutamide 150 mg versus castration (primarily using goserelin), no significant difference in overall survival was observed between patients with locally advanced prostate cancer receiving bicalutamide and those undergoing castration (hazard ratio = 1.05 [95% CI: 0.81–1.36]). However, statistical equivalence between the two treatment approaches cannot be established.

Goserelin has been reported to improve disease-free survival and overall survival when used as adjuvant therapy combined with radiotherapy in patients with localized intermediate-risk (T1–T2 with 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 definitively established; however, studies have shown that 3 years of adjuvant goserelin therapy provides a significant survival benefit compared to radiotherapy alone. Neoadjuvant goserelin in combination with radiotherapy has been shown to improve disease-free survival in patients with localized or locally advanced prostate cancer.

Following radical prostatectomy in patients with locally advanced prostate cancer, adjuvant therapy with Zoladex may improve recurrence-free survival, although a significant overall survival benefit has not been demonstrated in patients who did not have lymph node involvement at surgery. Patients with locally advanced disease confirmed histopathologically and additional risk factors such as pre-adjuvant PSA levels ≥10 ng/mL or Gleason score of 7 should undergo careful evaluation before initiating Zoladex adjuvant therapy. There is no evidence of improved clinical outcomes with neoadjuvant goserelin therapy following radical prostatectomy.

In women, serum estradiol concentrations decrease to postmenopausal levels by approximately day 21 after the first implant and remain suppressed with continuous monthly administration every 28 days. This suppression provides therapeutic benefit in hormone-dependent breast cancer, uterine fibroids, endometriosis, and by inhibiting ovarian follicular development. It also leads to endometrial thinning and amenorrhea in most patients.

During treatment with LH-RH analogues, some women may enter menopause. Rarely, menstruation does not resume after therapy is discontinued.

Goserelin in combination with iron supplements has been shown to induce amenorrhea, thereby increasing hemoglobin levels and improving hematological parameters compared to iron therapy alone. This combination resulted in a mean hemoglobin concentration 1 g/dL higher than that achieved with iron therapy alone.

Pharmacokinetics

Goserelin has nearly complete bioavailability. Administration of the implant every 4 weeks maintains effective drug concentrations. No significant tissue accumulation occurs. Goserelin is poorly protein-bound, and its elimination half-life from serum is 2–4 hours in patients with normal renal function. The half-life is prolonged in patients with impaired renal function. However, this change is not considered clinically significant with monthly dosing, and therefore dose adjustment is not required in patients with renal impairment. No significant pharmacokinetic changes are observed in patients with hepatic insufficiency.

Clinical characteristics.

Indications.

Prostate cancer.

Treatment of prostate cancer in the following cases:

• treatment of metastatic prostate cancer – administration of goserelin has a favorable effect on survival, similar to that of surgical castration;
• treatment of locally advanced prostate cancer as an alternative to surgical castration – administration of goserelin has a favorable effect on survival, similar to that of antiandrogen therapy;
• as adjuvant therapy to radiotherapy in patients with localized high-risk prostate cancer or locally advanced prostate cancer – administration of goserelin improves disease-free survival and overall survival;
• as neoadjuvant therapy prior to radiotherapy in patients with localized high-risk prostate cancer or locally advanced prostate cancer – administration of goserelin improves disease-free survival;
• as adjuvant therapy following radical prostatectomy in patients with locally advanced prostate cancer and high risk of disease progression – administration of goserelin improves disease-free survival.

Breast cancer. Treatment of advanced hormone-responsive breast cancer in premenopausal and perimenopausal women.

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

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

Endometrial thinning. For pretreatment endometrial thinning prior to endometrial 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 prior to superovulation stimulation.

Contraindications.

Hypersensitivity to the active substance or to any of the excipients.

Pregnancy or breastfeeding.

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 goserelin with medicinal products capable of prolonging the QT interval or causing torsades de pointes ventricular tachycardia should be carefully considered. Such products include 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 warnings and 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 if symptoms occur.

Androgen deprivation therapy may lead to QT interval prolongation.

Before prescribing goserelin to patients with a history of QT interval prolongation or risk factors for QT prolongation, as well as to patients concurrently using 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, hematoma, bleeding, and vascular injury, have been reported with the use of Goserelin Zentiva. 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 Goserelin Zentiva to patients with low body mass index (BMI) and/or those receiving full anticoagulant therapy (see section "Method of administration and dosage").

Men

Goserelin should be used with caution in men at risk of urinary tract obstruction or spinal cord compression, and such patients should be closely monitored during the first month of therapy. Standard treatment for these complications should be initiated if spinal cord compression or renal insufficiency due to urinary tract obstruction occurs.

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 it has been reported that this may prevent potential consequences of the initial rise in serum testosterone levels.

It is unlikely that treatment will be beneficial in patients with non-hormone-dependent prostate cancer. This resistance to treatment may result from lack of response to castration or hormonal therapy.

Recommended testosterone measurement prior to initiating treatment to allow assessment of therapeutic benefit.

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 is advised in patients with additional risk factors for osteoporosis (chronic alcohol abuse, smoking, long-term anticonvulsant or corticosteroid therapy, family history of osteoporosis).

Mood changes, including depression, have been reported. Patients with pre-existing depression and patients with hypertension require careful monitoring.

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

In a pharmacoepidemiological study of GnRH agonists used in 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 antiandrogenic agents.

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

Women

Breast cancer as an indication

Reduction in bone mineral density

Use of GnRH agonists may lead to decreased bone mineral density. After 2 years of treatment for early-stage breast cancer, mean reductions in femoral neck and lumbar spine bone mineral density in women were 6.2% and 11.5%, respectively. These losses have been shown to be partially reversible: one year after treatment cessation, bone mineral density loss 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, bone mass is restored in most women after treatment discontinuation.

Preliminary data suggest that the use of goserelin in combination with tamoxifen in breast cancer patients 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 approximately 1% every 6 months of treatment. A 10% reduction in bone mineral density approximately doubles or triples the risk of fractures. According to available data, bone mass recovers in most women after treatment discontinuation.

In patients receiving goserelin for endometriosis treatment, additional hormone replacement therapy has been shown to reduce the decline in bone mineral density 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 reduction in bone mineral density may be more hazardous in such patients, the appropriateness of goserelin use should be evaluated on a case-by-case basis, and therapy should only be initiated if benefits outweigh the risks. Additional measures to counteract bone mineral loss should be considered.

Withdrawal bleeding

At the beginning of goserelin treatment, some patients may experience vaginal bleeding of varying duration and intensity. This usually occurs within the first month after starting treatment, likely as a response to estrogen withdrawal, and resolves spontaneously. If bleeding persists, its cause should be investigated.

There are no clinical data on the use of goserelin for the treatment of benign gynecological conditions beyond 6 months.

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

Goserelin should only be used in assisted reproduction 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 goserelin 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, administration of human chorionic gonadotropin (hCG) should be discontinued.

Goserelin should be used with caution in fertility procedures in patients with polycystic ovary syndrome, as a large number of follicles may be stimulated.

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

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

Goserelin use may result in a positive anti-doping test.

Use during pregnancy or breastfeeding.

Goserelin Zentiva should not be used during pregnancy, as there is a theoretical risk of miscarriage or fetal abnormalities with the use of GnRH agonists 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 (see also precautions regarding the time required for menstruation recovery in the "Special precautions for use" section).

Pregnancy must be excluded before administering Goserelin Zentiva for fertility purposes. There are no clinical data indicating a causal relationship between goserelin use and any subsequent oocyte, pregnancy, or pregnancy outcome abnormalities.

Use of Goserelin Zentiva during breastfeeding is not recommended.

Menopause may naturally occur during treatment with GnRH analogs. Rarely, menstruation does not resume in some women after treatment discontinuation.

Ability to influence reaction speed when driving or operating machinery.

The medicinal product has no effect or has a negligible effect on the ability to drive or operate machinery.

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 Precautions").

The injection must be performed subcutaneously according to the technique described in the administration instructions. Do not inject the drug into blood vessels, muscle, or the abdominal cavity.

If surgical removal of the goserelin implant becomes necessary, its location can be identified using ultrasound imaging.

Adults

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

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

In vitro fertilization

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

Controlled ovarian hyperstimulation with gonadotropins should be initiated once desensitization has been achieved. Desensitization induced by agonist implant administration 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. Treatment monitoring, oocyte retrieval, and fertilization procedures should be performed according to standard practices at each treatment center.

Endometriosis should be treated for no more than 6 months, as clinical data on longer treatment durations are currently lacking. Repeat treatment courses are not recommended due to the risk of decreased bone mineral density. It has been demonstrated that in patients receiving goserelin for endometriosis treatment, additional hormone replacement 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 4 or 8 weeks. A second capsule may be required if the uterus is large or if the timing of surgical intervention is uncertain.

Uterine fibroids

Women with anemia caused by uterine fibroids may receive Goserelin Zentiva 3.6 mg in combination with iron supplements for 3 months prior to planned surgery.

Administration Instructions

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

Instructions for Use

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

Dispose of the syringe using special sharps containers.

The following information is intended solely for healthcare professionals:

Goserelin Zentiva is administered via subcutaneous injection. The instructions below should be reviewed 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

Inspect the pouch and the applicator syringe for damage.

Remove the applicator syringe from its sterile packaging.

Ensure the subcutaneous implant is properly positioned within the applicator syringe. Hold the syringe at a slight angle to the light to verify.

Figure 2

Grasp the syringe by the body and remove the protective cap.

Unlike liquid injections, do not expel air bubbles.

Figure 3

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 abdominal cavity) of the anterior abdominal wall below the umbilical line, advancing until the body of the applicator syringe contacts the patient’s skin.

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

NOTE: The Goserelin Zentiva applicator syringe cannot be used for aspiration. If the injection needle enters a large vessel, blood will immediately be 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. Once hemodynamic stability is confirmed, 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

Press the plunger. As pressure is applied, the subcutaneous implant moves from the holder to the tip of the needle.

Under no circumstances should the syringe be pulled back. The body of the applicator syringe must remain in contact with the patient’s skin during implant administration!

Figure 5

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

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

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

Replace the protective cap.

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

Children

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

Overdose

Human experience with overdose is limited. No clinically significant adverse effects have been observed following administration of goserelin earlier than scheduled or in doses higher than prescribed.

Animal studies do not indicate any effects beyond the therapeutic impact on sex hormone concentrations and reproductive organs when higher doses of goserelin are administered.

Treatment: Symptomatic therapy.

Adverse Reactions

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

Adverse events are categorized by frequency as follows: 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), and frequency not known (cannot be estimated from the available data).

Adverse reactions to Gosorelin Zentiva 3.6 mg by organ system 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		Degeneration of uterine fibroids
Immune system disorders	Uncommon	Hypersensitivity reactions to the drug	Hypersensitivity reactions to the drug
	Rare	Anaphylactic reactions	Anaphylactic reactions
Endocrine system disorders	Very rare	Pituitary hemorrhage	Pituitary hemorrhage
Metabolism and nutrition disorders	Common	Impaired glucose tolerancea
	Uncommon		Hypercalcemia
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	Paresthesia	Paresthesia
		Spinal cord compression
			Headache
Cardiac disorders	Common	Heart failuref, myocardial infarctionf
	Frequency unknown	QT interval prolongation (see sections "Special precautions" and "Interaction with other medicinal products and other forms of interaction")	QT interval prolongation (see sections "Special precautions" and "Interaction with other medicinal products and other forms of interaction")
Vascular disorders	Very common	Flushingb	Flushingb
	Common	Arterial pressure disturbancesc	Arterial pressure disturbancesc
Skin and subcutaneous tissue disorders	Very common	Hyperhidrosisb	Hyperhidrosisb, acnei
	Common	Rashd	Rashd, alopeciag
	Frequency unknown	Alopeciah	(see Common)
Musculoskeletal and connective tissue disorders	Common	Bone paine
	Uncommon	Arthralgia	(see Common)
Renal and urinary disorders	Uncommon	Ureteral obstruction
Reproductive system and breast disorders	Very common	Erectile dysfunction
			Vulvovaginal dryness
			Breast enlargement
	Common	Gynecomastia
	Uncommon	Breast tenderness
	Rare		Ovarian cysts
			Ovarian hyperstimulation syndrome (when used in combination with gonadotropins)
	Frequency unknown		Withdrawal bleeding (see section "Special precautions")
General disorders and administration site conditions	Very common	(see frequency "Common")	Injection site reactions
	Common	Injection site reactions	(see very common)
			Tumor flare (increase in tumor size, painful tumor at the beginning of treatment)
Investigations	Common	Decreased bone mineral density (see section "Special precautions"), increased body weight	Decreased bone mineral density (see section "Special precautions"), 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 cessation of goserelin administration.

c Hypo- or hypertension have occasionally been reported in patients receiving goserelin. These changes usually resolve either with continued therapy or after discontinuation of Zoladex Zentiva. Rarely, such changes required medical intervention, including discontinuation of goserelin.

d Usually mild and does not require discontinuation of treatment.

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

f Observed in pharmacoepidemiological studies of GnRH agonists used for the treatment of prostate cancer. The risk clearly increases when used in combination with antiandrogens.

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

In women treated for endometriosis and/or fibroids, rare cases of hypercalcemia have been reported. If symptoms of hypercalcemia (e.g., thirst) occur, investigations should be performed to exclude this condition.

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, 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 disorders, 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, hypercalcemia should be ruled out.

Rarely, hypercalcemia has developed at the beginning of treatment in patients with metastatic breast cancer. If symptoms suggestive of hypercalcemia (e.g., thirst) are present, hypercalcemia should be excluded.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorization of the medicinal product is important. It allows continuous 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 pouch containing the applicator syringe 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.

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

Prescription category.

Prescription only.

Manufacturer.

AMV GmbH.

Manufacturer's address and location of operation.

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