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

Composition:

Active substance: ibandronic acid;

1 film-coated tablet contains 150 mg of ibandronic acid in the form of 168.75 mg of sodium ibandronate monohydrate;

Excipients: povidone K25; lactose monohydrate; microcrystalline cellulose; crospovidone; stearic acid 95; colloidal anhydrous silicon dioxide; film coating: hypromellose, titanium dioxide (E 171), talc, macrogol 6000.

Pharmaceutical form. Film-coated tablets.

Main physicochemical properties: elongated-shaped tablets, white to almost white, with "BNVA" imprinted on one side and "150" on the other.

Pharmacotherapeutic group. Drugs used in the treatment of bone disorders. Drugs affecting bone structure and mineralization. Bisphosphonates. Ibandronic acid.

ATC code M05BA06.

Pharmacological properties.

Pharmacodynamics.

Mechanism of action

Ibandronic acid is a highly potent nitrogen-containing bisphosphonate that acts selectively on bone tissue and specifically inhibits osteoclast activity without having a direct effect on bone formation. The drug does not affect the replenishment of the osteoclast pool. In postmenopausal women, ibandronic acid reduces the elevated rate of bone turnover to premenopausal levels, resulting in progressive increases in bone mass and reduction in fracture frequency.

Pharmacodynamic effects

The pharmacodynamic action of ibandronic acid consists of inhibition of bone resorption. In vivo, ibandronic acid prevents bone destruction induced experimentally by blockade of gonadal function, retinoids, tumors, and tumor extracts. In young (rapidly growing) rats, increased bone resorption was also observed, leading to an increase in normal bone mass compared to untreated animals.

Animal models confirm that ibandronic acid is a highly potent inhibitor of osteoclast activity. In growing rats, no signs of impaired mineralization were observed even at doses exceeding more than 5,000 times the dose required for the treatment of osteoporosis.

Long-term daily administration and intermittent administration (with long intervals) over prolonged periods in rats, dogs, and monkeys were associated with formation of new bone of normal quality, with preserved or increased mechanical strength, even at doses within the toxic range.

The efficacy of daily and intermittent administration of ibandronic acid with dosing intervals of 9–10 weeks was confirmed in a clinical study (MF 4411) involving humans, in which ibandronic acid demonstrated efficacy in preventing fracture occurrence.

In animal models, ibandronic acid causes biochemical changes indicating dose-dependent inhibition of bone tissue resorption, including reduction in urinary levels of biochemical markers of bone collagen degradation (such as deoxypyridinoline and cross-linked N-telopeptide of type I collagen).

In a Phase I bioequivalence study involving 72 postmenopausal women, patients received oral Bonviva**®** 150 mg every 28 days (a total of 4 doses). In this study, a reduction in serum concentration of cross-linked C-telopeptide of type I collagen (CTX) was observed within the first 24 hours after the first dose (on average by 28%), with the mean maximum reduction (by 69%) observed on day 6. After the third and fourth doses, the mean maximum reduction in concentration 6 days after each dose was 74%, and 28 days after the fourth dose, the mean reduction in concentration was 56%. Upon discontinuation of further drug intake, the reduction in biochemical markers of bone resorption ceases.

Pharmacokinetics.

The primary pharmacological effect of ibandronic acid on bone is not directly related to actual plasma concentrations of ibandronic acid, as demonstrated in various studies in animals and humans.

Absorption.

After oral administration, ibandronic acid is rapidly absorbed in the upper gastrointestinal tract. Plasma concentration increases proportionally with increasing dose up to 50 mg orally, and increases significantly more with further dose escalation. Maximum plasma concentration is reached within 30 minutes to 2 hours (on average, 1 hour) when administered on an empty stomach. Absolute bioavailability is approximately 0.6%. Absorption is impaired when administered with food or beverages (other than plain water). Bioavailability decreases by approximately 90% when taken with a standard breakfast compared to administration on an empty stomach. No significant reduction in bioavailability occurs if ibandronic acid is taken 60 minutes before the first meal. Bioavailability and increase in bone mineral density are reduced when food or beverages are consumed less than 60 minutes after administration of ibandronic acid.

Distribution.

After initial systemic distribution, ibandronic acid rapidly binds to bone tissue or is excreted in urine. In humans, the apparent volume of distribution is at least 90 L, and approximately 40–50% of the circulating drug penetrates and accumulates in bone tissue. About 85–87% binds to plasma proteins (determined in vitro at therapeutic concentrations of ibandronic acid), thus indicating a low potential for interaction with other medicinal products due to displacement.

Metabolism.

There is no evidence that ibandronic acid is metabolized in animals or humans.

Excretion.

Ibandronic acid is eliminated from the bloodstream via bone uptake (approximately 40–50% in postmenopausal women), with the remainder excreted unchanged by the kidneys. The portion of ibandronic acid that is not absorbed is excreted unchanged in feces.

The range of apparent elimination half-life is wide, varying between 10–72 hours. Since calculated values depend significantly on study duration, administered dose, and analytical method sensitivity, the terminal half-life is likely considerably longer, as seen with other bisphosphonates. Initial plasma levels decline rapidly, reaching 10% of peak values within 3 hours and 8 hours after intravenous and oral administration, respectively.

Total clearance of ibandronic acid is low, averaging 84–160 mL/min. Renal clearance (approximately 60 mL/min in healthy postmenopausal women) accounts for 50–60% of total clearance and depends on creatinine clearance. The difference between apparent total and renal clearance reflects uptake of the drug by bone tissue.

Excretion pathways likely do not involve known acidic or basic transport systems involved in the elimination of other active substances. Furthermore, ibandronic acid does not inhibit major human hepatic P450 isoenzymes and does not induce the cytochrome P450 system in rats.

Pharmacokinetics in special populations.

Gender.

Bioavailability and pharmacokinetic parameters of ibandronic acid are similar in men and women.

Race.

There are no data indicating clinically significant inter-ethnic differences in the distribution of ibandronic acid between Mongoloid and Caucasian patients. Data on Negroid patients are insufficient.

Patients with renal impairment.

Renal clearance of ibandronic acid in patients with various stages of renal impairment is linearly dependent on creatinine clearance. Dose adjustment is not required in patients with mild to moderate renal impairment (creatinine clearance ≥ 30 mL/min), as demonstrated in study BM 16549, in which most patients had mild to moderate renal impairment.

In patients with severe renal impairment (creatinine clearance < 30 mL/min) receiving oral ibandronic acid 10 mg for 21 days, plasma concentrations were 2–3 times higher than in individuals with normal renal function, and total clearance of ibandronic acid was 44 mL/min. After intravenous administration of 0.5 mg ibandronic acid, total, renal, and non-renal clearances were reduced by 67%, 77%, and 50%, respectively, in patients with severe renal impairment, but no reduction in tolerability due to increased exposure was observed. Due to limited clinical experience with Bonviva® use, the drug is not recommended for patients with severe renal impairment (see sections "Dosage and administration", "Special precautions"). Pharmacokinetics of ibandronic acid in patients with end-stage renal disease has been evaluated only in a small number of hemodialysis patients; pharmacokinetics in non-dialysis patients is unknown. Due to limited data, ibandronic acid should not be used in patients with end-stage renal disease.

Patients with hepatic impairment (see section "Dosage and administration").

There are no data on the pharmacokinetics of ibandronic acid in patients with hepatic impairment. The liver does not play a significant role in the clearance of ibandronic acid, which is not metabolized but excreted by the kidneys and via uptake into bone tissue. Therefore, dose adjustment is not required in patients with hepatic impairment.

Elderly patients (see sections "Dosage and administration").

Multivariate analysis has shown that the studied pharmacokinetic parameters are not age-dependent. Since renal function declines with age, this is the only factor to consider (see section "Patients with renal impairment").

Paediatric population (see section "Dosage and administration").

There are no data on the use of Bonviva**®** in children.

Clinical characteristics.

Indications.

Treatment of osteoporosis in postmenopausal women with increased risk of fractures. Reduction in the risk of vertebral fractures has been demonstrated; efficacy in preventing hip fractures has not been established.

Contraindications.

Hypersensitivity to ibandronic acid or to any other component of the medicinal product (see section "Composition").

Hypocalcemia.

Esophageal disorders associated with delayed esophageal emptying, such as stricture or achalasia.

Inability to remain in an upright position (standing or sitting) for at least 60 minutes.

Interaction with other medicinal products and other forms of interaction.

Interaction of the medicinal product with food

The oral bioavailability of ibandronic acid is generally reduced in the presence of food. In particular, food products containing calcium, including milk, and other polyvalent cations (aluminum, magnesium, iron) may interfere with the absorption of Boniva® tablets, which is consistent with results obtained in animal studies. Therefore, Boniva® should be taken after an overnight fast (at least 6 hours) and the fasting state should be maintained for 1 hour after taking Boniva**®** (see section "Dosage and administration").

Interaction with other medicinal products

Metabolic interactions are considered unlikely, as ibandronic acid does not inhibit major human hepatic CYP450 isoenzymes and does not induce the hepatic cytochrome P450 system in rats (see section "Pharmacokinetics"). Ibandronic acid is eliminated via renal excretion and does not undergo biotransformation.

Calcium preparations (supplements), antacids, and certain other oral medicinal products containing polyvalent cations

Calcium preparations (supplements), antacids, and certain other oral medicinal products containing polyvalent cations (aluminum, magnesium, iron) may interfere with the absorption of Boniva**®. Therefore, patients should not take other oral medicinal products at least 6 hours before and 1 hour after taking Boniva®**.

Acetylsalicylic acid and NSAIDs

Since acetylsalicylic acid, nonsteroidal anti-inflammatory drugs (NSAIDs), and bisphosphonates may cause gastrointestinal irritation, caution is required when using NSAIDs concomitantly with Boniva**®** (see section "Special precautions for use").

H2-blockers and proton pump inhibitors

In study BM16549 involving over 1500 patients, dosing regimens of ibandronic acid (daily and once monthly) were compared; 14% and 18% of patients, respectively, also received H2-receptor blockers or proton pump inhibitors at one and two years, respectively. The incidence of upper gastrointestinal events in patients receiving Boniva**®** 150 mg once monthly was similar to that in patients receiving 2.5 mg ibandronic acid daily.

In a study involving healthy volunteers (men) and postmenopausal women, intravenous ranitidine increased the bioavailability of ibandronic acid by approximately 20%, possibly due to reduced gastric acidity. However, since this increase falls within the normal range of ibandronic acid bioavailability, dose adjustment of Boniva**®** is not required when co-administered with H2-receptor blockers or other agents that increase gastric pH.

Special precautions for use.

Hypocalcemia

Hypocalcemia must be corrected before initiating treatment with Boniva®. All other disturbances in bone metabolism and mineral homeostasis should also be effectively managed. Adequate intake of calcium and vitamin D is essential for all patients.

Gastrointestinal irritation

Oral bisphosphonates may cause local irritation of the upper gastrointestinal mucosa.

Due to these potential effects and the possibility of worsening underlying conditions, caution is required when administering Boniva® to patients with active upper gastrointestinal disorders (Barrett’s esophagus, dysphagia, other esophageal diseases, gastritis, duodenitis, or ulcers).

Cases of adverse reactions such as esophagitis, esophageal ulcers, and esophageal erosions have been reported with oral bisphosphonates. In some instances, these reactions were severe and required hospitalization, rarely with hemorrhage or subsequent development of esophageal stricture or perforation. The risk of severe esophageal adverse reactions is higher in patients who do not follow dosing instructions and/or in individuals who continue taking oral bisphosphonates after developing symptoms suggestive of esophageal irritation. Therefore, patients must pay particular attention to following the dosing instructions (see section "Dosage and administration").

Physicians should be vigilant for symptoms indicating possible esophageal reactions and should inform patients to discontinue Boniva® and seek medical advice if they experience dysphagia, pain on swallowing, retrosternal pain, heartburn, or worsening of heartburn. Although an increased risk was not observed in controlled clinical trials, postmarketing use of oral bisphosphonates has reported cases of gastric and duodenal ulcers. Some of these were severe and associated with complications.

Since nonsteroidal anti-inflammatory drugs (NSAIDs) and bisphosphonates may both cause gastrointestinal irritation, concomitant use of NSAIDs with Boniva® should be done with caution.

Osteonecrosis of the jaw

Osteonecrosis of the jaw has been reported very rarely during postmarketing use in patients receiving Boniva® for osteoporosis (see section "Adverse reactions").

Initiation or re-initiation of treatment should be delayed in patients with non-healing open soft tissue lesions in the oral cavity.

Prior to starting treatment with Boniva®, patients with concomitant risk factors should undergo a dental examination with appropriate preventive interventions and individual benefit-risk assessment.

When evaluating the risk of developing osteonecrosis of the jaw, the following risk factors should be considered:

Potency of the bone resorption-inhibiting agent (higher risk with more potent compounds), route of administration (higher risk with parenteral administration), and cumulative dose of bone resorption therapy.
Malignant neoplasms, concomitant medical conditions (e.g., anemia, coagulopathies, infection), and tobacco smoking.
Concomitant therapies: corticosteroids, chemotherapy, angiogenesis inhibitors, radiotherapy to the head and neck region.
Poor oral hygiene, periodontal disease, ill-fitting dentures, history of dental disease, invasive dental procedures such as tooth extractions.

All patients undergoing treatment with Boniva® should maintain good oral hygiene, undergo regular dental check-ups, and promptly report any oral symptoms such as loose teeth, pain, swelling, non-healing ulcers, or discharge. Invasive dental procedures should only be performed after careful consideration during treatment and should be avoided during and shortly after Boniva® administration.

Management of patients who develop osteonecrosis of the jaw should be planned in close collaboration with a dentist or an oral and maxillofacial surgeon experienced in treating osteonecrosis of the jaw. Consideration should be given to temporarily interrupting Boniva® treatment until improvement occurs and contributing risk factors are reduced.

Osteonecrosis of the external auditory canal

Osteonecrosis of the external auditory canal has been reported with bisphosphonate use, primarily with long-term therapy. Risk factors for osteonecrosis of the external auditory canal include steroid and chemotherapy use and/or local risk factors such as infection or trauma. The possibility of osteonecrosis of the external auditory canal should be considered in patients receiving bisphosphonates who present with ear symptoms, including chronic ear infections.

Atypical femoral fractures

Atypical subtrochanteric and diaphyseal femoral fractures have been reported with bisphosphonate therapy, particularly in patients receiving long-term osteoporosis treatment. These transverse or short oblique fractures may occur anywhere along the femur, from slightly below the lesser trochanter to just above the supracondylar ridge. These fractures occur with minimal or no trauma, and some patients experience thigh or groin pain, often associated with characteristic features of stress fractures, for several weeks to months before the fracture becomes a complete femoral fracture. Fractures are often bilateral; therefore, the contralateral femur should also be examined in patients receiving bisphosphonate therapy who have sustained a femoral shaft fracture. Poor healing of these fractures has also been reported. Until a patient's condition has been evaluated with individual benefit-risk assessment, consideration should be given to discontinuing bisphosphonate therapy in patients suspected of having atypical femoral fractures.

Patients receiving bisphosphonate therapy should be advised to report any thigh, hip, or groin pain. All patients with such symptoms should be evaluated for incomplete femoral fracture.

Renal impairment

Due to limited clinical experience, Boniva® is not recommended for patients with creatinine clearance below 30 mL/min (see section "Pharmacokinetics").

Galactose intolerance

The product contains lactose. Patients with rare hereditary problems of galactose intolerance, Lapp lactase deficiency, or glucose-galactose malabsorption should not take this medicine.

Disposal of unused medicine and expired products. Medicinal waste should be minimized to prevent environmental contamination. The medicine should not be disposed of via wastewater or household waste. Disposal should be carried out via a designated waste collection system, if available.

Use during pregnancy or breastfeeding.

Pregnancy

Boniva® is indicated only for postmenopausal women. The medicine should not be used in women of reproductive age.

There are no adequate data on the use of ibandronic acid in pregnant women. Reproductive toxicity was observed in rat studies. The potential risk in humans is unknown. Boniva® should not be used during pregnancy.

Breastfeeding

It is unknown whether ibandronic acid is excreted in human breast milk. Studies in lactating rats have shown low levels of ibandronic acid in milk after intravenous administration. Boniva® should not be used during breastfeeding.

Fertility

There are no data on the effect of ibandronic acid in humans. In reproductive studies in rats, ibandronic acid reduced fertility following oral administration. In rat studies, ibandronic acid reduced fertility following intravenous administration of high daily doses.

Ability to affect reaction speed when driving or operating machinery.

Considering the pharmacodynamic characteristics, pharmacokinetic profile, and reported adverse reactions, Boniva® is expected to have no effect or a negligible effect on the ability to drive or operate machinery.

Method of Administration and Dosage

Dosage

The recommended dose of Boniva^® for the treatment of osteoporosis is 1 tablet of 150 mg once monthly orally. Tablets should be taken on the same day each month.

Boniva^® should be taken after an overnight fast (at least 6 hours) and at least 60 minutes before the first intake of food, drink (other than water), or other oral medicinal products or supplements (including calcium) during the day (see section "Interaction with other medicinal products and other forms of interaction").

Patients should be advised that if a monthly dose is missed, they should take one 150 mg tablet of Boniva^® the following morning as soon as they remember, provided that the day for the next scheduled dose is not within the next 7 days. Subsequent doses should be taken on the previously established day of the month. If the day for the next scheduled dose falls within the next 7 days, the missed dose should be skipped, and the next dose should be taken on the scheduled day of the month, continuing with one tablet per month on the previously established day of the month. Two tablets should not be taken within one week.

Patients should take calcium and/or vitamin D supplements if their dietary intake is inadequate (see sections "Special Warnings and Precautions for Use", "Interaction with other medicinal products and other forms of interaction").

The optimal duration of treatment of osteoporosis with bisphosphonates has not been established. The need for continued treatment should be periodically reassessed for each individual patient, taking into account the benefits and potential risks of Boniva^®, particularly after 5 or more years of treatment.

Special Patient Groups

Patients with Renal Impairment

Due to limited clinical experience, Boniva^® is not recommended for patients with creatinine clearance below 30 mL/min (see sections "Special Warnings and Precautions for Use", "Pharmacokinetics").

Dose adjustment is not required in patients with mild or moderate renal impairment with creatinine clearance ≥30 mL/min.

Patients with Hepatic Impairment

Dose adjustment is not required (see section "Pharmacokinetics").

Elderly Patients (>65 years of age)

Dose adjustment is not required (see section "Pharmacokinetics").

Children

There is no relevant experience with the use of Boniva^® in children under 18 years of age. The use of Boniva^® in children under 18 years of age has not been studied (see sections "Pharmacodynamics", "Pharmacokinetics").

Method of Administration

Tablets should be swallowed whole with a full glass of plain water (180–240 mL), while sitting or standing in an upright position. Water with high calcium content should not be used. If there are concerns about potentially high calcium levels in drinking water (hard water), it is recommended to use bottled water with low mineral content.
Patients should remain upright (sitting or standing) for at least 60 minutes after taking Boniva^®.
Boniva^® should be taken only with plain water.
Patients should not chew or suck the tablet due to the risk of developing ulcers in the oropharyngeal mucosa.

Children

There is no experience with the use of Boniva^® in children under 18 years of age. The use of Boniva^® in children under 18 years of age has not been studied (see sections "Pharmacodynamics", "Pharmacokinetics").

Overdose

There is no specific information on the treatment of overdose with Boniva^®.

However, based on knowledge of bisphosphonates, oral overdose may result in adverse reactions affecting the upper gastrointestinal tract (such as gastrointestinal disturbances, dyspepsia, esophagitis, gastritis, ulceration) or hypocalcemia. To bind Boniva^®, milk or antacids should be administered, and any adverse reactions should be treated symptomatically. Due to the risk of esophageal irritation, vomiting should not be induced. Patients should remain in an upright position.

Adverse reactions.

Summary of safety profile

The most serious adverse reactions reported are anaphylactic reaction/shock, atypical femoral fractures, osteonecrosis of the jaw, gastrointestinal irritation, and eye inflammation (see "Description of selected adverse reactions" and section "Special warnings and precautions for use").

The most commonly reported adverse reactions were arthralgia and influenza-like symptoms. These symptoms were usually associated with the first dose, were generally transient, mild to moderate in severity, and typically resolved with continued treatment without requiring medical intervention (see "Description of selected adverse reactions").

The complete list of known adverse reactions is provided below.

The safety of ibandronic acid 2.5 mg once daily orally was evaluated in 1251 patients participating in four placebo-controlled clinical trials, with the majority of patients enrolled in the pivotal three-year fracture study (MF 4411).

In a two-year study in postmenopausal women with osteoporosis (VM 16549), the overall safety profile was similar for Bonviva® 150 mg once monthly and ibandronic acid 2.5 mg orally daily. The overall proportion of patients experiencing adverse reactions was 22.7% and 25% with Bonviva® 150 mg once monthly after 1 and 2 years of treatment, respectively. Most adverse reactions did not lead to discontinuation of treatment.

Adverse reactions listed below are classified according to the MedDRA system organ class and frequency categories. Adverse reactions are categorized by frequency as 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 available data). Within each frequency category, adverse reactions are listed in order of decreasing severity.

Adverse reactions observed during phase III studies VM16549 and MF4411 in postmenopausal women receiving Bonviva® 150 mg once monthly or ibandronic acid 2.5 mg orally daily, and during post-marketing use.

Immune system disorders: uncommon – exacerbation of bronchial asthma; rare – hypersensitivity reactions; very rare – anaphylactic reaction/shock*†.

Nervous system disorders: common – headache; uncommon – dizziness.

Eye disorders: rare – eye inflammation*†.

Gastrointestinal disorders: common – oesophagitis, gastritis, gastro-oesophageal reflux disease, dyspepsia, diarrhoea, abdominal pain, nausea; uncommon – oesophagitis, including oesophageal ulceration or stricture and dysphagia, vomiting, flatulence; rare – duodenitis.

Skin and subcutaneous tissue disorders: common – rash; rare – angioneurotic oedema, facial oedema, urticaria; very rare – Stevens-Johnson syndrome†, erythema multiforme†, bullous dermatitis†.

Musculoskeletal and connective tissue disorders: common – arthralgia, myalgia, musculoskeletal pain, muscle cramps, musculoskeletal stiffness; uncommon – back pain; rare – atypical subtrochanteric and diaphyseal femoral fractures†; very rare – osteonecrosis of the jaw*†, osteonecrosis of the external auditory canal (an adverse reaction characteristic of bisphosphonates as a class)†.

General disorders and administration site conditions: common – influenza-like illness*; uncommon – asthenia.

*See below.

†Identified during post-marketing use.

Description of selected adverse reactions

Gastrointestinal adverse reactions

Patients with a prior history of gastrointestinal disorders, including patients with peptic ulcer without recent bleeding or hospitalization, and patients with dyspepsia or reflux controlled with medication, were included in the once-monthly treatment studies. In these patients, there was no difference in the frequency of upper gastrointestinal adverse events with Bonviva® 150 mg once monthly compared to 2.5 mg daily.

Influenza-like illness

Influenza-like illness included symptoms such as acute phase reactions, or symptoms such as myalgia, arthralgia, fever, chills, fatigue, nausea, loss of appetite, and bone pain.

Osteonecrosis of the jaw

Cases of osteonecrosis of the jaw have been reported, primarily in patients with malignancies receiving treatment with bone resorption inhibitors, including ibandronic acid (see section "Special warnings and precautions for use"). Cases of osteonecrosis of the jaw have also been reported during post-marketing use of ibandronic acid.

Eye inflammation

Inflammatory eye disorders such as uveitis, episkleritis, and scleritis have been reported with ibandronic acid use. In some cases, these inflammatory disorders resolved only after discontinuation of ibandronic acid.

Anaphylactic reaction/shock

Cases of anaphylactic reaction/shock, including fatal cases, have been reported in patients receiving intravenous ibandronic acid.

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 are asked to report any suspected adverse reactions via the national pharmacovigilance system.

Shelf life.

5 years.

Storage conditions.

Keep out of the reach and sight of children. Store at temperatures not exceeding 30 ºC.

Packaging.

Film-coated tablets, 150 mg. Pack of 1 or 3 tablets in a blister.

One blister per cardboard box.

Prescription category.

Prescription only.

Manufacturer.

F. Hoffmann-La Roche Ltd.

Welwyn PL.

Manufacturer's address and location of its operations.

Grenzacherstrasse 124, 4070 Basel, Switzerland.

Sovereign House, Miles Gray Road, Basildon, SS14 3FR, United Kingdom.