Glucophage xr

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT GLUCOPHAGE XR (GLUCOPHAGE® XR)

Composition:

Active substance: metformin;

One coated tablet contains 1000 mg of metformin hydrochloride;

Excipients: sodium carmellose, hypromellose 100,000 cPs, magnesium stearate.

Pharmaceutical form. Prolonged-release tablets.

Main physicochemical properties: white or almost white, capsule-shaped, biconvex tablets, engraved with "1000" on one side and "MERCK" on the other.

Pharmacotherapeutic group. Oral hypoglycaemic agents, excluding insulin.

ATC code A10BA02.

Pharmacological Properties.

Pharmacodynamics.

Metformin hydrochloride is a biguanide with an antihyperglycemic effect: it reduces glucose levels both in the fasting state and after food intake. It does not stimulate insulin secretion and does not cause hypoglycemia. Metformin reduces fasting hyperinsulinemia and, when used in combination with insulin, reduces insulin requirements.

Metformin exerts its antihyperglycemic effect through several mechanisms:

• reduces glucose production in the liver;
• enhances peripheral glucose uptake and utilization, partly by increasing insulin action;
  • alters glucose metabolism in the intestine: absorption into the bloodstream increases, while absorption from food decreases. Additional intestinal mechanisms include increased release of glucagon-like peptide-1 (GLP-1) and reduced bile acid resorption. Metformin alters the gut microbiome;
  • may improve lipid profile in patients with hyperlipidemia.

In clinical trials, patients' body weight remained stable or moderately decreased during metformin treatment.

Metformin is an activator of adenosine monophosphate-activated protein kinase (AMPK) and enhances the transport capacity of all types of glucose membrane transporters (GLUT).

Clinical efficacy.

Reduction of risk or delay in onset of type 2 diabetes mellitus.

The Diabetes Prevention Program (DPP) in adults was a multicenter, randomized, controlled clinical trial evaluating the effectiveness of lifestyle intervention or metformin use in preventing or delaying the development of type 2 diabetes mellitus. Inclusion criteria included age ≥25 years, BMI ≥24 kg/m² (≥22 kg/m² for Asian Americans), and impaired glucose tolerance plus fasting plasma glucose levels of 95–125 mg/dL (or ≤125 mg/dL for American Indians). Participants were assigned to intensive lifestyle intervention, 2×850 mg metformin plus standard lifestyle modifications, or placebo plus standard lifestyle modifications.

Baseline characteristics of DPP participants (n=3,234 over 2.8 years) were as follows: mean age 50.6±10.7 years, fasting plasma glucose 106.5±8.3 mg/dL, 2-hour plasma glucose after oral glucose load 164.6±17.0 mg/dL, and BMI 34.0±6.7 kg/m². Intensive lifestyle intervention and metformin significantly reduced the risk of developing type 2 diabetes compared to placebo: 58% (95% CI 48–66%) and 31% (95% CI 17–43%), respectively.

The benefit of lifestyle intervention over metformin was greater in older patients.

Patients who benefited most from metformin treatment were aged ≥45 years with BMI ≥35 kg/m², baseline 2-hour glucose levels of 9.6–11.0 mmol/L, baseline HbA1c ≥6.0%, or those with a history of gestational diabetes.

To prevent one case of type 2 diabetes over three years in the DPP cohort, 6.9 patients needed to be treated with lifestyle intervention and 13.9 with metformin. The time to reach a cumulative incidence of diabetes of 50% was delayed by approximately three years in the metformin group compared to placebo.

The Diabetes Prevention Program Outcomes Study (DPPOS) is a long-term follow-up of DPP, including more than 87% of the original DPP participants for extended observation.

Among DPPOS participants (n=2,776), the cumulative incidence of diabetes at 15 years was 62% in the placebo group, 56% in the metformin group, and 55% in the lifestyle intervention group. Overall incidence rates were 7.0, 5.7, and 5.2 cases of diabetes per 100 patient-years in the placebo, metformin, and lifestyle groups, respectively. Compared to placebo, the risk of diabetes was reduced by 18% in the metformin group (hazard ratio [HR] 0.82, 95% CI 0.72–0.93; p=0.001) and by 27% in the lifestyle group (HR 0.73, 95% CI 0.65–0.83; p<0.0001). Regarding the composite microvascular endpoint of nephropathy, retinopathy, and neuropathy, there were no significant differences between groups. However, among participants who did not develop diabetes during DPP/DPPOS, the prevalence of microvascular complications was 28% lower than in those who developed diabetes (hazard ratio 0.72, 95% CI 0.63–0.83; p<0.0001). There are no comparative data on the effect of metformin on macrovascular complications in patients with impaired glucose tolerance (IGT) and/or impaired fasting glucose (IFG) and/or elevated HbA1c.

Published risk factors for type 2 diabetes include: Mongoloid or Negroid ethnicity, age over 40 years, dyslipidemia, hypertension, obesity or overweight, age, family history (first-degree relative with diabetes), history of gestational diabetes, and polycystic ovary syndrome (PCOS).

Treatment of type 2 diabetes mellitus.

The prospective randomized UKPDS study demonstrated the benefit of intensive glucose control in overweight patients with type 2 diabetes receiving immediate-release metformin hydrochloride as first-line therapy after diet failed. Analysis of outcomes in overweight patients receiving metformin hydrochloride after diet failure showed:

• a significant reduction in the absolute risk of any diabetes-related complication in the metformin hydrochloride group (29.8 events/1000 patient-years) compared to the diet-only group (43.3 events/1000 patient-years), p=0.0023, and compared to combined therapy with sulfonylurea and insulin monotherapy (40.1 events/1000 patient-years), p=0.0034;
• a significant reduction in diabetes-related mortality: metformin hydrochloride 7.5 events/1000 patient-years vs. diet-only 12.7 events/1000 patient-years, p=0.017;
• a significant reduction in overall mortality: 13.5 events/1000 patient-years in the metformin hydrochloride group compared to 20.6 events/1000 patient-years in the diet-only group (p=0.011), and compared to combined sulfonylurea therapy and insulin monotherapy: 18.9 events/1000 patient-years (p=0.021);
• a significant reduction in the risk of myocardial infarction: 11 events/1000 patient-years with metformin hydrochloride vs. 18 events/1000 patient-years with diet alone (p=0.01).

For metformin hydrochloride used as second-line therapy in combination with sulfonylurea, clinical benefit has not been demonstrated.

In type 1 diabetes, the combination of metformin hydrochloride and insulin has been used in individual patients, but the clinical benefit of this combination has not been formally established.

Pharmacokinetics.

Absorption.

After oral administration of one Glucophage XR 1000 mg tablet with or without food, maximum plasma concentration reaches 1214 ng/mL, achieved on average at 5 hours (range: 4–10 hours).

Maximum concentration (Cmax) and area under the curve (AUC) of Glucophage XR 1000 mg are bioequivalent to a 1000 mg dose of Glucophage XR 500 mg in healthy volunteers, both with and without food.

A bioequivalent product has the following properties.

At steady state, as with immediate-release tablets, Cmax and AUC increase disproportionately relative to the administered internal dose. AUC after single 2000 mg oral dose of metformin hydrochloride in extended-release tablets is comparable to the AUC observed after 1000 mg metformin hydrochloride in immediate-release tablets twice daily.

Variability in Cmax and AUC among individuals after administration of extended-release metformin hydrochloride tablets is comparable to variability observed after immediate-release metformin hydrochloride tablets.

After administration of 1000 mg extended-release tablets with food, AUC increased by 77% (Cmax increased by 26% and Tmax prolonged by 1 hour).

Absorption of metformin hydrochloride from extended-release tablets is not affected by food composition. No accumulation occurs with repeated dosing up to 2000 mg metformin hydrochloride in extended-release tablets.

Distribution.

Plasma protein binding is negligible. Metformin penetrates into erythrocytes. Maximum blood concentration is lower than maximum plasma concentration and is reached approximately at the same time. Erythrocytes likely represent a secondary distribution compartment. Mean volume of distribution (Vd) ranges from 63 to 276 L.

Metabolism.

Metformin is excreted unchanged in urine. No metabolites have been identified in humans.

Elimination.

Renal clearance of metformin is >400 mL/min, indicating that metformin is eliminated by glomerular filtration and tubular secretion. After oral administration, elimination half-life is approximately 6.5 hours. In renal impairment, renal clearance decreases proportionally to creatinine clearance, resulting in prolonged elimination half-life and increased plasma metformin levels.

Special patient populations.

Renal impairment.

Limited data are available in patients with moderate renal impairment; therefore, systemic exposure to metformin in this patient group compared to those with normal renal function cannot be precisely determined. Dose adjustment is required based on clinical efficacy and tolerability (see section "Dosage and administration").

Clinical characteristics.

Indications.

• Reduction of risk or delay in the onset of type 2 diabetes mellitus in adult patients with overweight and with IGT* and/or IFG* and/or elevated HbA1C levels, who have:
  • a high risk of developing overt (manifest) type 2 diabetes mellitus (see section "Pharmacodynamics");
  • progressive disturbances in carbohydrate metabolism despite lifestyle modifications over a period of 3 to 6 months.

Treatment with Glucophage XR should be based on risk assessment, including appropriate measures for glycemic control and evidence of high cardiovascular risk.

Alongside initiation of metformin therapy, lifestyle modifications should be continued, except in cases where the patient is unable to make such changes for medical reasons.

*IGT: Impaired glucose tolerance; IFG: Impaired fasting glucose.

• Treatment of type 2 diabetes mellitus in adults, particularly in patients with excess body weight, when diet and physical exercise alone do not provide adequate glycemic control.

Glucophage XR may be used as monotherapy or in combination with other oral antidiabetic agents, or concomitantly with insulin.

Contraindications.

• Hypersensitivity to metformin or to any other component of the medicinal product;
• any type of acute metabolic acidosis (e.g., lactic acidosis, diabetic ketoacidosis);
• diabetic precoma;
• severe renal impairment (glomerular filtration rate (GFR) < 30 mL/min);
• acute conditions associated with risk of renal function impairment, such as: dehydration, severe infections, shock;
• diseases that may lead to tissue hypoxia (especially acute conditions or exacerbations of chronic disease): decompensated heart failure, respiratory failure, recent myocardial infarction, shock;
• hepatic impairment, acute alcohol intoxication, alcoholism.

Interaction with other medicinal products and other forms of interaction.

Combinations not recommended.

Alcohol. Alcohol intoxication is associated with an increased risk of lactic acidosis, particularly in cases of fasting or adherence to a low-calorie diet, as well as in the presence of hepatic impairment.

Iodinated contrast media. Metformin should be discontinued before or during radiological procedures involving iodinated contrast agents and should not be restarted earlier than 48 hours after the procedure, and only after reassessment and confirmation of normal renal function (see sections "Dosage and administration" and "Special precautions").

Combinations requiring caution. Certain medicinal products, such as non-steroidal anti-inflammatory drugs (NSAIDs), including selective cyclooxygenase (COX)-2 inhibitors, angiotensin-converting enzyme (ACE) inhibitors, angiotensin II receptor antagonists, and diuretics, especially loop diuretics, may negatively affect renal function, thereby increasing the risk of lactic acidosis. Careful monitoring of renal function is required when initiating treatment with these medicinal products or when used concomitantly with metformin.

Medicinal products with hyperglycemic effects (systemic and local glucocorticoids, sympathomimetics).

Blood glucose levels should be monitored more frequently, especially at the beginning of treatment. Dose adjustment of Glucophage XR may be necessary during and after discontinuation of such concomitant therapy.

Organic cation transporters (OCT)

Metformin is a substrate of both OCT1 and OCT2 transporters.

Concomitant use of metformin with:

• OCT1 inhibitors (such as verapamil) may reduce metformin efficacy;
• OCT1 inducers (such as rifampicin) may increase gastrointestinal absorption and efficacy of metformin;
• OCT2 inhibitors (such as cimetidine, dolutegravir, ranolazine, trimethoprim, vandetanib, isavuconazole) may reduce renal elimination of metformin, leading to increased plasma metformin concentrations;
• inhibitors of both OCT1 and OCT2 (such as crizotinib, olaparib) may affect both efficacy and renal excretion of metformin.

Therefore, particular caution is recommended when co-administering these agents with metformin, especially in patients with impaired renal function, as plasma metformin concentrations may increase. Dose adjustment of metformin should be considered if necessary, since OCT inhibitors/inducers may affect metformin efficacy.

Special precautions for use.

Lactic acidosis.

Lactic acidosis is a very rare but serious metabolic complication, most commonly occurring in acute worsening of renal function, cardiopulmonary disease, or sepsis. In acute worsening of renal function, metformin accumulates, increasing the risk of lactic acidosis.

In cases of dehydration (severe diarrhea or vomiting, fever, or reduced fluid intake), temporary discontinuation of metformin is recommended, and medical advice should be sought.

When patients are receiving metformin, initiating treatment with agents that may acutely impair renal function (e.g., antihypertensive drugs, diuretics, and NSAIDs) should be done with caution. Other risk factors for lactic acidosis include excessive alcohol intake, hepatic insufficiency, poorly controlled diabetes, ketosis, prolonged fasting, and any conditions associated with hypoxia, as well as concomitant use of medicinal products that may lead to lactic acidosis (see sections "Contraindications" and "Interaction with other medicinal products and other forms of interaction").

Patients and/or caregivers should be informed about the risk of developing lactic acidosis. Characteristic symptoms of lactic acidosis include acidotic dyspnea, abdominal pain, muscle cramps, asthenia, and hypothermia, with possible progression to coma. If any symptoms suggestive of lactic acidosis occur, the patient should discontinue metformin immediately and seek medical attention without delay.

Diagnostic laboratory findings include decreased blood pH (< 7.35), elevated serum lactate concentration (> 5 mmol/L), increased anion gap, and elevated lactate/pyruvate ratio.

Renal impairment.

eGFR should be assessed before initiating treatment and regularly thereafter (see section "Dosage and administration"). Metformin is contraindicated in patients with eGFR < 30 mL/min and should be temporarily discontinued in the presence of conditions affecting renal function (see section "Contraindications").

Cardiac function.

Patients with heart failure have an increased risk of developing hypoxia and renal impairment. Metformin may be used in patients with stable chronic heart failure under regular monitoring of cardiac and renal function. Metformin is contraindicated in patients with acute or unstable heart failure (see section "Contraindications").

Elderly patients.

Due to limited data on therapeutic efficacy in reducing the risk of developing type 2 diabetes or delaying its onset in patients aged 75 years and older, metformin is not recommended for this age group.

Iodinated contrast agents.

Intravascular administration of iodinated contrast media may induce contrast-induced nephropathy, leading to metformin accumulation and increased risk of lactic acidosis. Metformin should be discontinued before or during the procedure and should not be restarted earlier than 48 hours after the procedure, and only after re-evaluation and confirmation of normal renal function (see sections "Dosage and administration" and "Interaction with other medicinal products and other forms of interaction").

Surgical procedures.

Metformin should be discontinued during surgical procedures performed under general, spinal, or epidural anesthesia and should not be restarted earlier than 48 hours after surgery or until oral nutrition is re-established, and only after assessment and confirmation of normal renal function.

Other precautions.

Patients should adhere to a diet with evenly distributed carbohydrate intake throughout the day. Overweight patients should continue a low-calorie diet. Regular monitoring of blood glucose levels is necessary.

Metformin may decrease serum vitamin B12 levels. The risk of low vitamin B12 levels increases with higher metformin doses, longer duration of treatment, and/or the presence of known risk factors for vitamin B12 deficiency. If vitamin B12 deficiency is suspected (e.g., anemia or neuropathy), serum vitamin B12 levels should be monitored. Patients with risk factors for vitamin B12 deficiency may require periodic monitoring of vitamin B12 levels. Metformin therapy should be continued as long as it is well tolerated and not contraindicated, and appropriate corrective treatment for vitamin B12 deficiency should be administered according to current clinical guidelines.

Monotherapy with metformin does not cause hypoglycemia; however, caution is required when metformin is used concomitantly with insulin or other oral hypoglycemic agents (e.g., sulfonylureas or meglitinides). The presence of tablet coating fragments in feces may occur. This is a normal phenomenon and has no clinical significance.

This medicinal product contains less than 1 mmol sodium (23 mg) per dose unit, i.e., it is considered "essentially sodium-free."

Use during pregnancy or breastfeeding.

Pregnancy. Uncontrolled hyperglycemia in the preconception period and during pregnancy is associated with an increased risk of congenital anomalies, pregnancy loss, gestational hypertension, preeclampsia, and perinatal mortality. It is important to maintain blood glucose levels as close to normal as possible throughout pregnancy to reduce the risk of adverse outcomes of hyperglycemia for both mother and child.

Metformin crosses the placenta in amounts that may be as high as maternal concentrations.

A large amount of data from pregnant women (over 1000 pregnancy outcomes) from registry-based cohort studies, published meta-analyses, and clinical trials indicate no increased risk of congenital anomalies or fetal/neonatal toxicity due to metformin exposure during the periconceptional period and/or during pregnancy.

There are limited unconfirmed data on the long-term effect of metformin on the weight of children exposed in utero. Metformin appears not to affect motor and social development in children up to 4 years of age who were exposed in utero, although data on long-term outcomes are limited.

If clinically necessary, metformin may be used during pregnancy and in the preconception period, either as an adjunct or as an alternative to insulin.

Breastfeeding. Metformin is excreted in breast milk, but no adverse effects have been observed in breastfed newborns/infants. However, due to insufficient data on the safety of the drug, breastfeeding is not recommended during metformin therapy. The decision to discontinue breastfeeding should be made considering the benefits of breastfeeding and the potential risk of adverse effects for the infant.

Fertility. Metformin had no effect on fertility in animals when administered at doses of 600 mg/kg/day, which is almost three times the maximum recommended human daily dose based on body surface area.

Ability to influence reaction rate when driving or operating machinery.

Glucophage XR does not affect the ability to drive or operate machinery, as monotherapy with this medicinal product does not cause hypoglycemia.

However, caution should be exercised when using metformin in combination with other hypoglycemic agents (sulfonylureas, insulin, meglitinides) due to the risk of hypoglycemia.

Method of Administration and Dosage.

Adult patients with normal renal function (eGFR ≥ 90 mL/min).

Reduction of risk or delay in onset of type 2 diabetes mellitus.

Metformin should only be prescribed when lifestyle modifications over a period of 3–6 months have not provided adequate glycemic control.

• Treatment should be initiated with one tablet of Glucophage XR 500 mg once daily with the evening meal.
• After 10–15 days of treatment, the dose should be adjusted according to blood glucose measurements (OGTT (oral glucose tolerance test) values and/or fasting plasma glucose and/or HbA1c should be within normal range). Gradual dose escalation may improve gastrointestinal tolerability. The maximum recommended dose of Glucophage XR 1000 mg is 2 tablets (2000 mg) once daily with the evening meal.
• It is recommended to monitor glycemic status regularly (every 3–6 months) (OGTT values and/or fasting plasma glucose and/or HbA1c), as well as risk factors, to determine whether continuation, modification, or discontinuation of treatment is necessary.
• Re-evaluation of treatment is also required if the patient subsequently improves diet and/or physical activity or if changes in the patient’s health status allow for lifestyle modifications.

Monotherapy or combination therapy with other oral antihyperglycemic agents.

Glucophage XR 1000 mg should be administered once daily with the evening meal. The maximum recommended dose is 2 tablets per day.

Glucophage XR 1000 mg may be used as maintenance therapy in patients already treated with metformin hydrochloride at a dose of 1000 mg or 2000 mg. When switching, the daily dose of Glucophage XR should be equivalent to the current daily dose of metformin hydrochloride.

Patients currently receiving metformin hydrochloride at doses exceeding 2000 mg per day should not be switched to Glucophage XR therapy.

Patients receiving Glucophage XR should not exceed a daily dose of 2000 mg.

For patients initiating treatment, the usual starting dose of Glucophage XR is 500 mg once daily with the evening meal. After 10–15 days of treatment, the dose should be adjusted based on blood glucose measurements. Gradual dose escalation helps reduce gastrointestinal side effects.

If adequate glycemic control cannot be achieved with the maximum daily dose of Glucophage XR (2000 mg) taken once daily, this dose may be divided into two doses per day (once in the morning and once in the evening, with meals).

If glycemic targets remain unmet, Glucophage film-coated tablets may be used at the maximum recommended daily dose of 3000 mg.

When switching from another antidiabetic therapy to Glucophage XR 1000 mg, dose titration should begin with Glucophage XR 500 mg.

Combination therapy with insulin.

Metformin and insulin may be used together in combination therapy to achieve better blood glucose control. The usual starting dose of Glucophage XR is 500 mg once daily with the evening meal, and the insulin dose should then be adjusted based on blood glucose monitoring.

Glucophage XR, 1000 mg prolonged-release tablets, may be used after appropriate dose titration.

In elderly patients.

Renal function may decline with age; therefore, the metformin dose should be adjusted based on assessment of renal function, which should be performed regularly (see section "Special Warnings and Precautions for Use").

The benefit of reducing the risk of or delaying the onset of type 2 diabetes has not been established in patients aged 75 years and older (see section "Pharmacodynamics"); therefore, metformin is not recommended in these patients (see section "Special Warnings and Precautions for Use").

Renal impairment.

eGFR should be assessed before initiating treatment with metformin-containing medicinal products and at least annually thereafter. In patients at increased risk of worsening renal function and in elderly patients, renal function should be monitored more frequently, e.g., every 3–6 months.

eGFR (mL/min)	Maximum recommended daily dose	Additional recommendations
60–89	2000 mg	In case of reduced renal function, dose reduction should be considered.
45–59	2000 mg	Risk factors for lactic acidosis should be assessed prior to initiating metformin therapy (see section "Special warnings and precautions for use"). The initial dose should not exceed half of the maximum daily dose.
30–44	1000 mg
< 30	-	Metformin is contraindicated.

Children. The drug should not be used in children, as there are no clinical data available for this age group of patients.

Overdose.

When the drug was administered at a dose of 85 g, hypoglycemia was not observed. However, in this case, lactic acidosis did develop. A significant overdose of metformin or concomitant risk factors may lead to the development of lactic acidosis. Lactic acidosis is a medical emergency. If lactic acidosis occurs, treatment with Glucophage XR must be discontinued and the patient should be urgently hospitalized. Hemodialysis is the most effective measure for removing lactate and metformin from the body.

Adverse Reactions

According to post-marketing and controlled clinical studies, adverse reactions in patients treated with Glucophage XR were similar in nature and severity to those observed in patients treated with Glucophage (immediate-release formulation).

The most common adverse reactions at the beginning of treatment are nausea, vomiting, diarrhea, abdominal pain, and loss of appetite. These symptoms usually resolve spontaneously in most cases.

Adverse effects are classified by frequency of occurrence into the following categories:

very common (> 1/10), common (> 1/100 and < 1/10), uncommon (> 1/1,000 and < 1/100), rare (> 1/10,000 and < 1/1,000), very rare (< 1/10,000).

Disorders of metabolism

Common: vitamin B12 deficiency/low levels (see section "Special Warnings and Precautions for Use").

Very rare: lactic acidosis (see section "Special Warnings and Precautions for Use").

From the nervous system

Common: taste disturbances.

From the gastrointestinal tract

Very common: gastrointestinal disorders such as nausea, vomiting, diarrhea, abdominal pain, and loss of appetite. These adverse effects most commonly occur at the beginning of treatment and usually disappear spontaneously in most cases. To help prevent gastrointestinal adverse effects, a gradual increase in the dose of the medication is recommended.

From the hepatobiliary system

Very rare: isolated reports of abnormal liver function tests or hepatitis, which completely resolved after discontinuation of metformin.

From the skin and subcutaneous tissue

Very rare: skin allergic reactions, including erythema, pruritus, and urticaria.

Reporting of suspected adverse reactions

Reporting of suspected adverse reactions after marketing authorization of the medicinal product is important. It allows ongoing monitoring of the benefit-risk balance of the medicinal product. Medical and pharmaceutical professionals, as well as patients or their legal representatives, should report any suspected adverse reactions and lack of efficacy through the Automated Pharmacovigilance Information System at the following link: https://aisf.dec.gov.ua/.

Shelf life

4 years.

Storage conditions

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

Packaging

10 tablets in a blister; 3 or 6 blisters per cardboard box.

Prescription status

Prescription only.

Manufacturer

Merck Sante, France / Merck Sante, France.

Merck Healthcare KGaA, Germany / Merck Healthcare KGaA, Germany.

Manufacturer's address and location of business activity

2 rue du Pressoir Vert, 45400 Semoy, France / 2 rue du Pressoir Vert, 45400 Semoy, France.

Frankfurter Strasse 250, 64293 Darmstadt, Germany / Frankfurter Strasse 250, 64293 Darmstadt, Germany.