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4.3 Contraindications
- Abnormalities of the oesophagus which delay oesophageal emptying such as stricture or achalasia
- Inability to stand or sit upright for at least 60 minutes
- Hypocalcaemia (see section 4.4)
- Hypersensitivity to ibandronic acid or to any of the excipients.
See also section 4.4.
4.4 Special warnings and precautions for use
Gastrointestinal Disorders
Bisphosphonates have been associated with dysphagia, oesophagitis and oesophageal or gastric ulcers. Therefore patients, especially those with a history of prolonged oesophageal transit time, should pay particular attention to and be able to comply with the dosing instructions (see section 4.2).
Physicians should be alert to signs or symptoms signalling a possible oesophageal reaction during therapy, and patients should be instructed to discontinue Bonviva and seek medical attention if they develop symptoms of oesophageal irritation such as new or worsening dysphagia, pain on swallowing, retrosternal pain, or heartburn.
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 experiences 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 signalling 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.
6.3 Shelf life
3 years5 years.
10. DATE OF REVISION OF THE TEXT
2 July 200911 December 2009
4.8 Undesirable effects
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). ; 73 % of these patients came from the pivotal three-year treatment study (MF 4411). The overall safety profile of ibandronic acid 2.5 mg daily in all these studies was similar to that of placebo. The overall proportion of patients who experienced an adverse reaction, i.e. adverse event with a possible or probable relationship to trial medication, in the pivotal treatment study (MF 4411) was 19.8 % for ibandronic acid and 17.9 % for placebo.
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 and 21.5 % and 22.5 % for ibandronic acid 2.5 mg daily after one and two years, respectively. The majority of adverse reactions were mild to moderate in intensity. Most cases did not lead to cessation of therapy.
The most commonly reported adverse reaction was arthralgia.
Table 1 and table 2 list adverse reactions occurring in more than 1 % of patients treated with Bonviva 150 mg monthly or 2.5 mg daily in study BM 16549 and in patients treated with ibandronic acid 2.5 mg daily in study MF 4411. The tables show the adverse reactions in the two studies that occurred with a higher incidence than in patients treated with placebo in study MF 4411. Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness.
Data at one year from BM 16549 are represented in Table 1 and cumulative data for the two years from BM 16549 are represented in table 2.
Table 1: Common adverse reactions (>1/100, ≤ 1/10) in phase III osteoporosis studies that were considered by the investigator to be possibly or probably related to treatment - One year data from study BM 16549 and three year data from placebo-controlled fracture study MF 4411
One year data in study BM 16549
Three year data in study MF 4411
System Organ Class/ Adverse reaction
Bonviva 150 mg once monthly
(N=396)
(%)
ibandronic acid 2.5 mg daily
(N=395)
(N=977)
Placebo
(N=975)
Gastrointestinal system
Gastro-oesophageal reflux disease
0.5
1.0
0.4
0.1
Diarrhoea
2.5
1.8
1.4
Abdominal pain
3.5
2.8
2.1
2.9
Dyspepsia
3.3
5.8
4.3
Nausea
2.3
Flatulence
0.7
Nervous system
Headache
0.8
1.5
0.6
General disorders
Influenza like illness*
0.3
0.2
Fatigue
Musculoskeletal system
Arthralgia
Myalgia
Skin disorders
Rash
1.2
MedDRA version 6.1
* Transient, influenza-like symptoms have been reported with Bonviva 150 mg once monthly, typically in association with the first dose. Such symptoms were generally of short duration, mild or moderate in intensity, and resolved during continuing treatment without requiring remedial measures. Influenza-like illness includes events reported as acute phase reaction or symptoms including myalgia, arthralgia, fever, chills, fatigue, nausea, loss of appetite, or bone pain.
Table 2: Cumulative common adverse reactions (>1/100, ≤ 1/10) in Phase III osteoporosis studies that were considered by the investigator to be possibly or probably related to treatment - Two year data from study BM 16549 and three year data from placebo-controlled fracture study MF 4411
Two year cumulative data in study BM 16549
Gastritis
Oesophagitis
0
2.0
4.0
3.0
6.3
2.7
Muscle cramp
Musculoskeletal pain
Musculoskeletal stiffness
MedDRA version 7.1
Adverse reactions considered by investigators to be causally related to Bonviva are listed below by System Organ Class.
Frequencies are defined as common (≥ 1/100 to < 1/10), uncommon (≥ 1/1,000 to < 1/100), and rare (≥ 1/10,000 to < 1/1,000). Within each frequency grouping, adverse reactions are presented in order of decreasing seriousness.
Table 1: Adverse reactions occurring in postmenopausal women receiving Bonviva 150mg once monthly or ibandronic acid 2.5mg daily in the phase III studies BM16549 and MF4411.
System Organ Class
Frequency
Adverse reactions
Immune system disorders
Rare
Hypersensitivity reaction
Nervous system disorders
Common
Uncommon
Dizziness
Gastrointestinal disorders
Oesophagitis, Gastritis, Gastro oesophageal reflux disease, Dyspepsia, Diarrhoea, Abdominal pain, Nausea
Oesophagitis including oesophageal ulcerations or strictures and dysphagia, Vomiting, Flatulence
Duodenitis
Skin and subcutaneous tissues disorders
Angioedema, Face oedema, Urticaria
Musculoskeletal, connective tissue and bone disorders
Arthralgia, Myalgia, Musculoskeletal pain, Muscle cramp, Musculoskeletal stiffness
Back pain
General disorders and administration site conditions
Adverse reactions occurring at a frequency of less than or equal to 1 %
The following list provides information on adverse reactions reported in study MF 4411 occurring more frequently with ibandronic acid 2.5 mg daily than with placebo and study BM 16549 occurring more frequently with Bonviva 150 mg once monthly than with ibandronic acid 2.5 mg daily. Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness:
Uncommon (1/100 – 1/1,000)
Gastro-intestinal Disorders: gastritis, oesophagitis including oesophageal
ulcerations or strictures, vomiting,
dysphagia
Nervous System Disorders: dizziness
Musculoskeletal and Connective Tissue Disorders: back pain
Rare (1/1,000 – 1/10,000)
Gastro-intestinal Disorders: duodenitis
Immune System Disorders: hypersensitivity reactions
Skin and Subcutaneous Tissue Disorders: angioedema, face oedema, urticaria
4.2 Posology and method of administration
Tablets should be swallowed whole with a glass of plain water (180 to 240 ml) while the patient is sitting or standing in an upright position. Patients should not lie down for 1 hour after taking Bonviva.
Plain water is the only drink that should be taken with Bonviva. Please note that some mineral waters may have a higher concentration of calcium and therefore, should not be used.
Patients should not chew or suck the tablet, because of a potential for oropharyngeal ulceration.
Paediatric Population
Children and adolescents
There is no relevant useexperience of Bonviva in children, and Bonviva was not studied in the paediatric population.
Method of Administration:
For oral use.
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.
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.
Renal impairment
Due to limited clinical experience, Bonviva is not recommended for patients with a creatinine clearance below 30 ml/min (see section 5.2).
Due to limited clinical experience, Bonviva is not recommended for patients with a creatinine clearance below 30 ml/min (see section 4.2 and section 5.2).
4.5 Interaction with other medicinal products and other forms of interaction
Drug-Food Interactions
Oral bioavailability of ibandronic acid is generally reduced in the presence of food. In particular, products containing calcium and other multivalent cations (such as aluminium, magnesium, iron), including milk, 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.
Drug-Drug Interactions
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.
Pharmacokinetic interaction studies in postmenopausal women have demonstrated the absence of any interaction potential with tamoxifen or hormone replacement therapy (oestrogen). No interaction was observed when co-administered with melphalan/prednisolone in patients with multiple myeloma.
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 ibandronic acid, no dosage adjustment is considered necessary when Bonviva is administered with H2-antagonists or other active substances which increase gastric pH.
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 ibandronic acid, no dose adjustment is considered necessary when Bonviva is administered with H2-antagonists or other active substances which increase gastric pH.
Pharmacokinetic interaction studies in postmenopausal women have demonstrated the absence of any interaction potential with tamoxifen or hormone replacement therapy (oestrogen).
No interaction was observed when co-administered with melphalan/prednisolone in patients with multiple myeloma.
6.5 Nature and contents of container
Bonviva 150 mg film-coated tablets are supplied in blisters (Aluminium/Aluminium) (PVC/PVDC) containing 1 or 3 tablets.
Underlined text has been added, text with strike-through deleted
2 years.3 years.
Updated: October 2006