Ibandronic Acid Teva · 4.8 Undesirable effects · 1

HOS-154943 · has-adverse-reaction-information · PDF-Seite 18

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, ocular inflammation, (see paragraph “Description of selected adverse reactions” and section 4.4). The most frequently reported adverse reactions are arthralgia and influenza-like symptoms. These symptoms are typically in association with the first dose, generally of short duration, mild or moderate in intensity, and usually resolve during continuing treatment without requiring remedial measures (see paragraph “Influenza like illness”). Tabulated list of adverse reactions In table 1 a complete list of known adverse reactions is presented. The safety of oral treatment with ibandronic acid 2.5 mg daily was evaluated in 1251 patients treated in 4 placebo-controlled clinical studies, with the large majority of patients coming from the pivotal three year fracture study (MF 4411). In a two-year study in postmenopausal women with osteoporosis (BM 16549) the overall safety of ibandronic acid 150 mg once monthly and ibandronic acid 2.5 mg daily was similar. The overall proportion of patients who experienced an adverse reaction, was 22.7 % and 25.0 % for ibandronic acid 150 mg once monthly after one and two years, respectively. Most cases did not lead to cessation of therapy. 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 18 (<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 occurring in postmenopausal women receiving ibandronic acid 150 mg once monthly or ibandronic acid 2.5 mg daily in the phase III studies BM 16549 and MF 4411 and in post-marketing experience. System Organ Common Uncommon Rare Very rare Not known Class Immune Asthma Hypersensitivity Anaphylactic system exacerbation reaction reaction/shock*† disorders Metabolism Hypocalcaemia† and nutrition disorders N

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HOS-154937 · 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 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 ibandronic acid 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. Table 1 Adverse Drug Reactions Reported for Oral Administration of Ibandronic Acid System Organ Common Uncommon Rare Very rare Not known Class Blood and Anaemia lymphatic system disorders 6  System Organ Common Uncommon Rare Very rare Not known Class Immune Hypersensitivit Asthma system y†, exacerbation disorders bronchospasm †, angioedema†, anaphylactic reaction/shock †* Metabolism Hypocalcaemi and nutrition a* disorders Nervous Paraesthesia, system dysgeusia disorders

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HOS-154933 · has-contraindication-information · PDF-Seite 3

- 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-154939 · has-contraindication-information · PDF-Seite 15

- 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-154932 · has-indication-information · PDF-Seite 2

Ibandronic Acid Teva 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-154938 · has-indication-information · PDF-Seite 14

Treatment of osteoporosis in postmenopausal women at increased risk of fracture (see section 5.1). A reduction in the risk of vertebral fractures has been demonstrated, efficacy on femoral neck fractures has not been established.

HOS-154935 · has-interaction-information · PDF-Seite 5

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 Ibandronic Acid Teva 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 ibandronic acid 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 Ibandronic Acid Teva 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). Aminoglycosides 5 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-154941 · has-interaction-information · PDF-Seite 17

Medicinal product-Food Interaction Oral bioavailability of ibandronic acid is generally reduced in the presence of food. In particular, products containing calcium, including milk and other multivalent cations (such as aluminium, magnesium, iron), are likely to interfere with absorption of Ibandronic Acid Teva, which is consistent with findings in animal studies. Therefore, patients should fast overnight (at least 6 hours) before taking Ibandronic Acid Teva and continue fasting for 1 hour following intake of Ibandronic Acid Teva (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. Calcium supplements, antacids and some oral medicinal products containing multivalent cations Calcium supplements, antacids and some oral medicinal products containing multivalent cations (such as aluminium, magnesium, iron) are likely to interfere with the absorption of Ibandronic Acid Teva. Therefore, patients should not take other oral medicinal products for at least 6 hours before taking Ibandronic Acid Teva and for 1 hour following intake of Ibandronic Acid Teva. 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). H2 blockers or proton pump inhibitors Of over 1500 patients enrolled in study BM 16549 comparing monthly with daily dosing regimens of ibandronic acid, 14% and 18% of patients used histamine (H2) blockers or proton pump inhibitors after one and two years, respectively. Among these patients, the incidence of upper gastrointestinal events in the patients treated with ibandronic acid 150 mg once monthly was similar to that in patients treated with ibandronic acid 2.5 mg daily. In healthy male volunteers and postmenopausal women, intravenous administration of ranitidine caused an increase in ibandronic acid bioavailability of about 20%, probably as a result of reduced gastric acidity. However, since this increase is within the normal variability of the bioavailability of 17 iba

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HOS-154936 · 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, Ibandronic Acid Teva 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. Ibandronic Acid Teva 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-154942 · has-pregnancy-information · PDF-Seite 18

Pregnancy Ibandronic Acid Teva is only for use in postmenopausal women and must not be taken by women of childbearing potential. There are no adequate data from the use of ibandronic acid in pregnant women. Studies in rats have shown some reproductive toxicity (see section 5.3). The potential risk for humans is unknown. Ibandronic Acid Teva 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. Ibandronic Acid Teva should not be used during breast-feeding. Fertility There are no data on the effects of ibandronic acid from 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-154934 · has-warning-information · PDF-Seite 3

Patients with disturbances of bone and mineral metabolism Hypocalcaemia and other disturbances of bone and mineral metabolism should be effectively treated before starting Ibandronic Acid Teva 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 Ibandronic Acid Teva 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 Ibandronic Acid Teva and seek medical attention if they develop dysphagia, odynophagia, retrosternal pain or new or worsening heartburn. 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. 3 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 Ibandronic Acid Teva for oncology indications (see section 4.8). The start of treatment or of a new course o

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HOS-154940 · has-warning-information · PDF-Seite 15

Hypocalcaemia Existing hypocalcaemia must be corrected before starting Ibandronic Acid Teva therapy. Other disturbances of bone and mineral metabolism should also be effectively treated. Adequate intake of calcium and vitamin D is important in all patients. 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 Ibandronic Acid Teva is given to patients with active upper gastrointestinal problems (e.g. known Barrett’s oesophagus, dysphagia, other oesophageal diseases, gastritis, duodenitis or ulcers). Adverse reactions such as oesophagitis, oesophageal ulcers and oesophageal erosions, in some cases severe and requiring hospitalisation, 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 to 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 Ibandronic Acid Teva and seek medical attention if they develop dysphagia, odynophagia, retrosternal pain or new or worsening heartburn. 15 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. Since Nonsteroidal Anti-Inflammatory medicinal products and bisphosphonates are both 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 Ibandronic Acid Teva for osteoporosis (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-ris

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