Bonviva · 4.6 Fertility, pregnancy and lactation · 1

HOS-093636 · 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, 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 (MF4411). In a two-year study in postmenopausal women with osteoporosis (BM 16549) the overall safety of Bonviva 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 Bonviva 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 (<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. 6 Table 1: Adverse reactions occurring in postmenopausal women receiving Bonviva 150 mg once monthly or ibandronic acid 2.5 mg daily in the phase III studies BM16549 and MF4411 and in post- marketing experience. System Organ Common Uncommon Rare Very rare Not known Class Immune system Asthma Hypersensitivi Anaphylactic disorders exacerbation ty reaction reaction/shock*† Metabolism and hypocalcaemia nutrition disorders Nervous system Headache Dizziness di

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HOS-093642 · 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 for the jaw and 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 (please 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 the pivotal two-year study in postmenopausal women with osteoporosis (BM16550), the overall safety of intravenous injection of Bonviva 3 mg every 3 months and oral ibandronic acid 2.5 mg daily were shown to be similar. The overall proportion of patients who experienced an adverse reaction was 26.0 % and 28.6 % for Bonviva 3 mg injection every 3 months after one year and two years, respectively. Most cases of adverse reactions did not lead to cessation of therapy. 19 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 occurring in postmenopausal women receiving Bonviva 3 mg injection every 3 months or ibandronic acid 2.5 mg daily in the phase III studies BM16550 and MF 4411, and in post-marketing experience. System Organ Common Uncommon Rare Very rare Not Class known Immune system Asthma Hypersensitivity Anaphylactic disorders ex

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HOS-093638 · has-contraindication-information · PDF-Seite 17

- Hypersensitivity to ibandronic acid or to any of the excipients listed in section 6.1 - Hypocalcaemia

HOS-093632 · 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-093631 · has-indication-information · PDF-Seite 2

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-093637 · has-indication-information · PDF-Seite 16

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-093640 · has-interaction-information · PDF-Seite 19

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.

HOS-093634 · has-interaction-information · PDF-Seite 5

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 Bonviva, which is consistent with findings in animal studies. Therefore, patients should fast overnight (at least 6 hours) before taking Bonviva and continue fasting for 1 hour following intake of Bonviva (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 Bonviva. Therefore, patients should not take other oral medicinal products for at least 6 hours before taking Bonviva and for 1 hour following intake of Bonviva. 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 Bonviva 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 5 gastric acidity. However, since this increase is within the normal variability of the bioavailability of ibandronic acid, no dose adjustment is considered necessary when Bonviva is administer

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HOS-093635 · has-pregnancy-information · PDF-Seite 6

Pregnancy Bonviva 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. Bonviva 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. Bonviva 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-093641 · has-pregnancy-information · PDF-Seite 19

Pregnancy Bonviva is only for use in postmenopausal women and must not be taken by women of child bearing 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. Bonviva 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. Bonviva should not be used during breastfeeding. 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-093639 · has-warning-information · PDF-Seite 17

Administration failures Care must be taken not to administer Bonviva injection via intra-arterial or paravenous administration as this could lead to tissue damage. Hypocalcaemia Bonviva, like other bisphosphonates administered intravenously, may cause a transient decrease in serum calcium values. Existing hypocalcaemia must be corrected before starting Bonviva injection therapy. Other disturbances of bone and mineral metabolism should also be effectively treated before starting Bonviva injection therapy. All patients must receive adequate supplemental calcium and vitamin D. 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 Bonviva intravenous injection is administered. If anaphylactic or other severe hypersensitivity/allergic reactions occur, immediately discontinue the injection and initiate appropriate treatment. Renal impairment Patients with concomitant diseases, or who use medicinal products which have potential for undesirable effects on the kidney, should be reviewed regularly in line with good medical practice during treatment. Due to limited clinical experience, Bonviva injection is not recommended for patients with a serum creatinine above 200 μmol/l (2.3 mg/dl) or with a creatinine clearance below 30 ml/min (see section 4.2 and section 5.2). Patients with cardiac impairment Overhydration should be avoided in patients at risk of cardiac failure. Osteonecrosis of the jaw Osteonecrosis of the jaw (ONJ) has been reported very rarely in the post marketing setting in patients receiving Bonviva for osteoporosis (see section 4.8). 17 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 Bonviva 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-mo

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HOS-093633 · has-warning-information · PDF-Seite 3

Hypocalcaemia Existing hypocalcaemia must be corrected before starting Bonviva 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 Bonviva 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). 3 Physicians should be alert to any signs or symptoms signaling a possible oesophageal reaction and patients should be instructed to discontinue Bonviva 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. 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 Bonviva 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-risk assessment is recommended prior to treatment with Bo

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