Roche Products (Ireland) Ltd

Underlined text has been added, text with strike through deleted:

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

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

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.

MedDRA version 7.1

* 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.

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

Underlined text has been added, text with strike through deleted:

2.       QUALITATIVE AND QUANTITATIVE COMPOSITION

One pre-filled syringe of 3 ml solution contains 3 mg ibandronic acid (as 3.375 mg ibandronic acid, monosodium salt, monohydrate).

The concentration of ibandronic acid in the solution for injection is 1mg per ml.

For a full list of excipients, see section 6.1.

4.2     Posology and method of administration

Paediatric Ppopulation

Children and adolescents

There is no relevant use of Bonviva experience in children, and Bonviva was not studied in the paediatric population .

Method of Administration:

For intravenous use.

Strict adherence to the intravenous administration route is required (see section 4.4).

4.4     Special warnings and precautions for use

Administration failures

Strict adherence to the intravenous route of administration is required. Care must be taken not to administer Bonviva injection via intra-arterial or paravenous administration as this could lead to tissue damage.

Hypocalcaemia and Mineral Metabolism

Bonviva, like other bisphosphonates administered intravenously, may cause a transient decrease in serum calcium values.

Existing Hhypocalcaemia 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.

Route of administration

Strict adherence to the intravenous route of administration is required. Care must be taken not to administer Bonviva injection via intra-arterial or paravenous administration as this could lead to tissue damage.