Bondronat · 4.1 Therapeutic indications · 3

HOS-083190 · has-adverse-reaction-information · PDF-Seite 31

Summary of the safety profile The most serious reported adverse reactions are anaphylactic reaction/shock, atypical fractures of the femur, osteonecrosis for the jaw and ocular inflammation (see paragraph “description of selected adverse reactions”and section 4.4). Treatment of tumour induced hypercalcaemia is most frequently associated with a rise in body temperature. Less frequently, a decrease in serum calcium below normal range (hypocalcaemia) is reported. In most cases no specific treatment was required and the symptoms subsided after a couple of hours/days. In the prevention of skeletal events in patients with breast cancer and bone metastases, treatment is most frequently associated with asthenia followed by rise in body temperature and headache. Tabulated list of adverse reactions Table 1 lists adverse drug reactions from the pivotal phase III studies (Treatment of tumour induced hypercalcaemia: 311 patients treated with Bondronat 2 mg or 4 mg; Prevention of skeletal events in patients with breast cancer and bone metastases: 152 patients treated with Bondronat 6 mg), and from post-marketing experience. 31 Adverse reactions are listed according to MedDRA system organ class and frequency category. Frequency categories are defined using the following convention: very common (>1/10), common (≥ 1/100 to < 1/10), uncommon (≥ 1/1,000 to < 1/100), rare (≥ 1/10,000 to < 1/1,000), very rare (<1/10,000), not known (cannot be estimated from the available data). Within each frequency grouping, adverse reactions are presented in order of decreasing seriousness. Table 1 Adverse Reactions Reported for Intravenous Administration of Bondronat System Organ Common Uncommon Rare Very rare Not known Class Infections and Infection Cystitis, vaginitis, infestations oral candidiasis Neoplasms Benign skin benign, neoplasm malignant and unspecified Blood and Anaemia, blood lymphatic dyscrasia system disorders Immune system Hypersensitivit Asthma disorders y†, exacerbation bronchospasm†

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HOS-083178 · has-adverse-reaction-information · PDF-Seite 6

Summary of the safety profile The most serious reported adverse reactions are anaphylactic reaction/shock, atypical fractures of the femur, osteonecrosis for the jaw, and ocular inflammation (see paragraph “description of selected adverse reactions” and section 4.4). Treatment of tumour induced hypercalcaemia is most frequently associated with a rise in body temperature. Less frequently, a decrease in serum calcium below normal range (hypocalcaemia) is reported. In most cases no specific treatment is required and the symptoms subside after a couple of hours/days. In the prevention of skeletal events in patients with breast cancer and bone metastases, treatment is most frequently associated with asthenia followed by rise in body temperature and headache. Tabulated list of adverse reactions Table 1 lists adverse drug reactions from the pivotal phase III studies (Treatment of tumour induced hypercalcaemia: 311 patients treated with Bondronat 2 mg or 4 mg; Prevention of skeletal events in patients with breast cancer and bone metastases: 152 patients treated with Bondronat 6 mg), and from post-marketing experience. 6 Adverse reactions are listed according to MedDRA system organ class and frequency category. Frequency categories are defined using the following convention: very common (>1/10), common (≥ 1/100 to < 1/10), uncommon (≥ 1/1,000 to < 1/100), rare (≥ 1/10,000 to < 1/1,000), very rare (<1/10,000), not known (cannot be estimated from the available data). Within each frequency grouping, adverse reactions are presented in order of decreasing seriousness. Table 1 Adverse Reactions Reported for Intravenous Administration of Bondronat System Organ Common Uncommon Rare Very rare Not known Class Infections and Infection Cystitis, vaginitis, infestations oral candidiasis Neoplasms Benign skin benign, neoplasm malignant and unspecified Blood and Anaemia, blood lymphatic dyscrasia system disorders Immune system Hypersensitivit Asthma disorders y†, exacerbation bronchospasm†

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HOS-083184 · has-adverse-reaction-information · PDF-Seite 19

Summary of the safety profile The most serious reported adverse reactions are anaphylactic reaction/shock, atypical fractures of the femur, osteonecrosis of the jaw, gastrointestinal irritation, and ocular inflammation (see paragraph “Description of selected adverse reactions” and section 4.4).Treatment was most frequently associated with a decrease in serum calcium to below normal range (hypocalcaemia), followed by dyspepsia. Tabulated list of adverse reactions Table 1 lists adverse reactions from 2 pivotal phase III studies (Prevention of skeletal events in patients with breast cancer and bone metastases: 286 patients treated with Bondronat 50 mg administered orally), and from post-marketing experience. Adverse reactions are listed according to MedDRA system organ class and frequency category. Frequency categories are defined using the following convention: very common (>1/10), common (≥ 1/100 to < 1/10), uncommon (≥ 1/1,000 to < 1/100), rare (≥ 1/10,000 to < 1/1,000),very rare (<1/10,000), not known (cannot be estimated from the available data). Within each frequency grouping, adverse reactions are presented in order of decreasing seriousness. 19 Table 1 Adverse Drug Reactions Reported for Oral Administration of Bondronat System Organ Common Uncommon Rare Very rare Not known Class Blood and Anaemia lymphatic system disorders Immune system Hypersensitivity†, Asthma disorders bronchospasm†, exacerbation angioedema†, Anaphylactic reaction/shock†** Metabolism and Hypocalcaemia** nutrition disorders Nervous system Paraesthesia, disorders dysgeusia (taste perversion) Eye disorders Ocular inflammation†** Gastrointestinal Oesophagitis, Haemorrage, disorders abdominal pain, duodenal dyspepsia, nausea ulcer, gastritis,

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HOS-083186 · has-contraindication-information · PDF-Seite 29

- Hypersensitivity to the active substance or to any of the excipients listed in section 6.1 - Hypocalcaemia

HOS-083174 · has-contraindication-information · PDF-Seite 4

- Hypersensitivity to the active substance or to any of the excipients listed in section 6.1 - Hypocalcaemia

HOS-083180 · has-contraindication-information · PDF-Seite 16

- Hypersensitivity to ibandronic acid or to any of the excipients listed in section 6.1. - Hypocalcaemia - Abnormalities of the oesophagus which delay oesophageal emptying such as stricture or achalasia - Inability to stand or sit upright for at least 60 minutes

HOS-083185 · has-indication-information · PDF-Seite 27

Bondronat is indicated in adults for - Prevention of skeletal events (pathological fractures, bone complications requiring radiotherapy or surgery) in patients with breast cancer and bone metastases - Treatment of tumour-induced hypercalcaemia with or without metastases

HOS-083179 · has-indication-information · PDF-Seite 15

Bondronat is indicated in adults for the prevention of skeletal events (pathological fractures, bone complications requiring radiotherapy or surgery) in patients with breast cancer and bone metastases.

HOS-083173 · has-indication-information · PDF-Seite 2

Bondronat is indicated in adults for - Prevention of skeletal events (pathological fractures, bone complications requiring radiotherapy or surgery) in patients with breast cancer and bone metastases - Treatment of tumour-induced hypercalcaemia with or without metastases

HOS-083188 · has-interaction-information · PDF-Seite 31

Metabolic interactions are not considered likely, since ibandronic acid does not inhibit the major human hepatic P450 isoenzymes and has been shown not to induce the hepatic cytochrome P450 system in rats (see section 5.2). Ibandronic acid is eliminated by renal excretion only and does not undergo any biotransformation. Caution is advised when bisphosphonates are administered with aminoglycosides, since both substances can lower serum calcium levels for prolonged periods. Attention should also be paid to the possible existence of simultaneous hypomagnesaemia.

HOS-083182 · has-interaction-information · PDF-Seite 18

Medicinal product -Food Interactions Products containing calcium and other multivalent cations (such as aluminium, magnesium, iron), including milk and food, are likely to interfere with absorption of Bondronat tablets. Therefore, with such products, including food, intake must be delayed at least 30 minutes following oral administration. Bioavailability was reduced by approximately 75% when Bondronat tablets were administered 2 hours after a standard meal. Therefore, it is recommended that the tablets should be taken after an overnight fast (at least 6 hours) and fasting should continue for at least 30 minutes after the dose has been taken (see section 4.2). Interactions with other medicinal products Metabolic interactions are not considered likely, since ibandronic acid does not inhibit the major human hepatic P450 isoenzymes and has been shown not to induce the hepatic cytochrome P450 system in rats (see section 5.2). Ibandronic acid is eliminated by renal excretion only and does not undergo any biotransformation. H2-antagonists or other medicinal products that increase gastric pH. In healthy male volunteers and postmenopausal women, intravenous ranitidine caused an increase in ibandronic acid bioavailability of about 20% (which is within the normal variability of the bioavailability of ibandronic acid), probably as a result of reduced gastric acidity. However, no dosage adjustment is required when Bondronat is administered with H2-antagonists or medicinal products that increase gastric pH. Acetylsalicylic acid and NSAIDs Since Acetylsalicylic acid, Nonsteroidal Anti-Inflammatory medicinal products (NSAIDs) and bisphosphonates are associated with gastrointestinal irritation, caution should be taken during concomitant administration (see section 4.4). 18 Aminoglycosides Caution is advised when bisphosphonates are administered with aminoglycosides, since both substances can lower serum calcium levels for prolonged periods. Attention should also be paid to the possible existence of simultaneous hypomagnesaemia.

HOS-083176 · has-interaction-information · PDF-Seite 6

Metabolic interactions are not considered likely, since ibandronic acid does not inhibit the major human hepatic P450 isoenzymes and has been shown not to induce the hepatic cytochrome P450 system in rats (see section 5.2). Ibandronic acid is eliminated by renal excretion only and does not undergo any biotransformation. Caution is advised when bisphosphonates are administered with aminoglycosides, since both substances can lower serum calcium levels for prolonged periods. Attention should also be paid to the possible existence of simultaneous hypomagnesaemia.

HOS-083189 · has-pregnancy-information · PDF-Seite 31

Pregnancy There are no adequate data from the use of ibandronic acid in pregnant women. Studies in rats have shown reproductive toxicity (see section 5.3). The potential risk for humans is unknown. Therefore, Bondronat should not be used during pregnancy. Breast-feeding It is not known whether ibandronic acid is excreted in human milk. Studies in lactating rats have demonstrated the presence of low levels of ibandronic acid in the milk following intravenous administration. Bondronat should not be used during breast-feeding. Fertility There are no data on the effects of ibandronic acid in humans. In reproductive studies in rats by the oral route, ibandronic acid decreased fertility. In studies in rats using the intravenous route, ibandronic acid decreased fertility at high daily doses (see section 5.3).

HOS-083177 · has-pregnancy-information · PDF-Seite 6

Pregnancy There are no adequate data from the use of ibandronic acid in pregnant women. Studies in rats have shown reproductive toxicity (see section 5.3). The potential risk for humans is unknown. Therefore, Bondronat should not be used during pregnancy. Breast-feeding It is not known whether ibandronic acid is excreted in human milk. Studies in lactating rats have demonstrated the presence of low levels of ibandronic acid in the milk following intravenous administration. Bondronat should not be used during breast-feeding. Fertility There are no data on the effects of ibandronic acid in humans. In reproductive studies in rats by the oral route, ibandronic acid decreased fertility. In studies in rats using the intravenous route, ibandronic acid decreased fertility at high daily doses (see section 5.3).

HOS-083183 · has-pregnancy-information · PDF-Seite 19

Pregnancy There are no adequate data from the use of ibandronic acid in pregnant women. Studies in rats have shown reproductive toxicity (see section 5.3). The potential risk for humans is unknown. Therefore, Bondronat should not be used during pregnancy. Breast-feeding It is not known whether ibandronic acid is excreted in human milk. Studies in lactating rats have demonstrated the presence of low levels of ibandronic acid in the milk following intravenous administration. Bondronat should not be used during lactation. Fertility There are no data on the effects of ibandronic acid in humans. In reproductive studies in rats by the oral route, ibandronic acid decreased fertility. In studies in rats using the intravenous route, ibandronic acid decreased fertility at high daily doses (see section 5.3).

HOS-083187 · has-warning-information · PDF-Seite 29

Patients with disturbances of bone and mineral metabolism Hypocalcaemia and other disturbances of bone and mineral metabolism should be effectively treated before starting Bondronat therapy for metastatic bone disease. Adequate intake of calcium and vitamin D is important in all patients. Patients should receive supplemental calcium and/or vitamin D if dietary intake is inadequate. Anaphylactic reaction/shock Cases of anaphylactic reaction/shock, including fatal events, have been reported in patients treated with IV ibandronic acid. Appropriate medical support and monitoring measures should be readily available when Bondronat intravenous injection is administered. If anaphylactic or other severe hypersensitivity/allergic reactions occur, immediately discontinue the injection and initiate appropriate treatment. Osteonecrosis of the jaw Osteonecrosis of the jaw (ONJ) has been reported very rarely in the post marketing setting in patients receiving Bondronat for oncology indications (see section 4.8). The start of treatment or of a new course of treatment should be delayed in patients with unhealed open soft tissue lesions in the mouth. A dental examination with preventive dentistry and an individual benefit-risk assessment is recommended prior to treatment with Bondronat in patients with concomitant risk factors. The following risk factors should be considered when evaluating a patient’s risk of developing ONJ: - Potency of the medicinal product that inhibit bone resorption (higher risk for highly potent compounds), route of administration (higher risk for parenteral administration) and cumulative dose of bone resorption therapy - Cancer, co-morbid conditions (e.g. anaemia, coagulopathies, infection), smoking - Concomitant therapies: corticosteroids, chemotherapy, angiogenesis inhibitors, radiotherapy to head and neck - Poor oral hygiene, periodontal disease, poorly fitting dentures, history of dental disease, invasive dental procedures e.g. tooth extractions 29 All patients should be encouraged to maintain good oral hygiene, undergo routine dental check-ups, and immediately report any oral symptoms such as dental mobility, pain or swelling, or non-healing of sores or discharge during treatment with Bondronat. While on treatment, invasive dental procedures should be performed only after careful consideration and be avoided in close proximity to Bondronat ad

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HOS-083175 · has-warning-information · PDF-Seite 4

Patients with disturbances of bone and mineral metabolism Hypocalcaemia and other disturbances of bone and mineral metabolism should be effectively treated before starting Bondronat therapy for metastatic bone disease. Adequate intake of calcium and vitamin D is important in all patients. Patients should receive supplemental calcium and/or vitamin D if dietary intake is inadequate. Anaphylactic reaction/shock Cases of anaphylactic reaction/shock, including fatal events, have been reported in patients treated with intravenous ibandronic acid. Appropriate medical support and monitoring measures should be readily available when Bondronat intravenous injection is administered. If anaphylactic or other severe hypersensitivity/allergic reactions occur, immediately discontinue the injection and initiate appropriate treatment. Osteonecrosis of the jaw Osteonecrosis of the jaw (ONJ) has been reported very rarely in the post marketing setting in patients receiving Bondronat for oncology indications (see section 4.8). The start of treatment or of a new course of treatment should be delayed in patients with unhealed open soft tissue lesions in the mouth. A dental examination with preventive dentistry and an individual benefit-risk assessment is recommended prior to treatment with Bondronat in patients with concomitant risk factors. The following risk factors should be considered when evaluating a patient’s risk of developing ONJ: - Potency of the medicinal product that inhibit bone resorption (higher risk for highly potent compounds), route of administration (higher risk for parenteral administration) and cumulative dose of bone resorption therapy - Cancer, co-morbid conditions (e.g. anaemia, coagulopathies, infection), smoking - Concomitant therapies: corticosteroids, chemotherapy, angiogenesis inhibitors, radiotherapy to head and neck - Poor oral hygiene, periodontal disease, poorly fitting dentures, history of dental disease, invasive dental procedures e.g. tooth extractions 4 All patients should be encouraged to maintain good oral hygiene, undergo routine dental check-ups, and immediately report any oral symptoms such as dental mobility, pain or swelling, or non-healing of sores or discharge during treatment with Bondronat. While on treatment, invasive dental procedures should be performed only after careful consideration and be avoided in close proximity to Bon

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HOS-083181 · has-warning-information · PDF-Seite 16

Patients with disturbances of bone and mineral metabolism Hypocalcaemia and other disturbances of bone and mineral metabolism should be effectively treated before starting Bondronat therapy. Adequate intake of calcium and vitamin D is important in all patients. Patients should receive supplemental calcium and/or vitamin D if dietary intake is inadequate. Gastrointestinal irritation Orally administered bisphosphonates may cause local irritation of the upper gastrointestinal mucosa. Because of these possible irritant effects and a potential for worsening of the underlying disease, caution should be used when Bondronat is given to patients with active upper gastrointestinal problems (e.g. known Barrett’s oesophagus, dysphagia, other oesophageal diseases, gastritis, duodenitis or ulcers). Adverse experiences such as oesophagitis, oesophageal ulcers and oesophageal erosions, in some cases severe and requiring hospitalization, rarely with bleeding or followed by oesophageal stricture or perforation, have been reported in patients receiving treatment with oral bisphosphonates. The risk of severe oesophageal adverse experiences appears to be greater in patients who do not comply with the dosing instruction and/or who continue to take oral bisphosphonates after developing symptoms suggestive of oesophageal irritation. Patients should pay particular attention and be able to comply with the dosing instructions (see section 4.2). Physicians should be alert to any signs or symptoms signaling a possible oesophageal reaction and patients should be instructed to discontinue Bondronat and seek medical attention if they develop dysphagia, odynophagia, retrosternal pain or new or worsening heartburn. 16 While no increased risk was observed in controlled clinical trials there have been post-marketing reports of gastric and duodenal ulcers with oral bisphosphonate use, some severe and with complications. Acetylsalicylic acid and NSAIDs Since Acetylsalicylic acid, Nonsteroidal Anti-Inflammatory medicinal products (NSAIDs) and bisphosphonates are associated with gastrointestinal irritation, caution should be taken during concomitant administration. Osteonecrosis of the jaw Osteonecrosis of the jaw (ONJ) has been reported very rarely in the post marketing setting in patients receiving Bondronat for oncology indications (see section 4.8). The start of treatment or of a new course of treatment should be delayed in patien

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