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4.6      Fertility, Ppregnancy and lactation

Pregnancy

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 lactation.

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).

5.3      Preclinical safety data

Toxic effects, e.g. signs of renal damage, were observed in dogs only at exposures considered sufficiently in excess of the maximum human exposure, indicating little relevance to clinical use.

Mutagenicity/Carcinogenicity:

No indication of carcinogenic potential was observed. Tests for genotoxicity revealed no evidence of genetic activity for ibandronic acid.

Reproductive toxicity:

Specific studies for the 3-monthly dosing regimen have not been performed. In studies with daily i.v. dosing regimen, there was no evidence for a direct foetal toxic or teratogenic effect of ibandronic acid in rats and rabbits. Body weight gain was decreased in F₁ offspring in rats. In reproductive studies in rats by the oral route effects on fertility consisted of increased preimplantation losses at dose levels of 1 mg/kg/day and higher. In reproductive studies in rats by the intravenous route, ibandronic acid decreased sperm counts at doses of 0.3 and 1 mg/kg/day and decreased fertility in males at 1 mg/kg/day and in females at 1.2 mg/kg/day. Other adverse reactions to ibandronic acid in reproductive toxicity studies in the rat were those observed with bisphosphonates as a class. They include a decreased number of implantation sites, interference with natural delivery (dystocia), and an increase in visceral variations (renal pelvis ureter syndrome).

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4.2      Posology and method of administration

Posology

The recommended dose of ibandronic acid is 3 mg, administered as an intravenous injection over 15 - 30 seconds, every three months.

Patients must receive supplemental calcium and vitamin D (see section 4.4 and section 4.5)

If a dose is missed, the injection should be administered as soon as convenient. Thereafter, injections should be scheduled every 3 months from the date of the last injection.

The optimal duration of bisphosphonate treatment for osteoporosis has not been established.  The need for continued treatment should be re-evaluated periodically based on the benefits and potential risks of Bonviva on an individual patient basis, particularly after 5 or more years of use.

Special populations

Patients with renal impairment

No dose adjustment is necessary for patients with mild or moderate renal impairment where serum creatinine is equal or below 200 μmol/l (2.3 mg/dl) or where creatinine clearance (measured or estimated) is equal or greater than 30 ml/min.

Bonviva injection is not recommended for use in patients who have a serum creatinine above 200 μmol/l (2.3 mg/dl) or who have a creatinine clearance (measured or estimated) below 30 ml/min, because of limited clinical data available from studies including such patients (see section 4.4 and section 5.2)

Patients with hepatic impairment

No dose adjustment is required (see section 5.2).

Elderly population

No dose adjustment is required (see section 5.2).

Paediatric population

There is no relevant use of Bonviva 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

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.

Atypical fractures of the femur

Atypical subtrochanteric and diaphyseal femoral fractures have been reported with bisphosphonate therapy, primarily in patients receiving long-term treatment for osteoporosis. These transverse or short oblique fractures can occur anywhere along the femur from just below the lesser trochanter to just above the supracondylar flare. These fractures occur after minimal or no trauma and some patients experience thigh or groin pain, often associated with imaging features of stress fractures, weeks to months before presenting with a completed femoral fracture. Fractures are often bilateral; therefore the contralateral femur should be examined in bisphosphonate-treated patients who have sustained a femoral shaft fracture. Poor healing of these fractures has also been reported. Discontinuation of bisphosphonate therapy in patients suspected to have an atypical femur fracture should be considered pending evaluation of the patient, based on an individual benefit risk assessment.

During bisphosphonate treatment patients should be advised to report any thigh, hip or groin pain and any patient presenting with such symptoms should be evaluated for an incomplete femur fracture.

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).

Osteonecrosis of the jaw

Osteonecrosis of the jaw, generally associated with tooth extraction and/or local infection (including osteomyelitis) has been reported in patients with cancer receiving treatment regimens including primarily intravenously administered bisphosphonates. Many of these patients were also receiving chemotherapy and corticosteroids. Osteonecrosis of the jaw has also been reported in patients with osteoporosis receiving oral bisphosphonates.

A dental examination with appropriate preventive dentistry should be considered prior to treatment with bisphosphonates in patients with concomitant risk factors (e.g. cancer, chemotherapy, radiotherapy, corticosteroids, poor oral hygiene).

While on treatment, these patients should avoid invasive dental procedures if possible. For patients who develop osteonecrosis of the jaw while on bisphosphonate therapy, dental surgery may exacerbate the condition. For patients requiring dental procedures, there are no data available to suggest whether discontinuation of bisphosphonate treatment reduces the risk of osteonecrosis of the jaw. Clinical judgement of the treating physician should guide the management plan of each patient based on individual benefit/risk assessment.

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 (MF 4411). The overall safety profile of ibandronic acid 2.5 mg daily in all these studies was similar to that of placebo.

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. The majority of adverse reactions were mild to moderate in intensity. Most cases of adverse reactions did not lead to cessation of therapy.

The most commonly reported adverse reaction was influenza like illness.

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 drug 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 postmarketing experience.

*See further information below

†Identified in postmarketing experience.

Influenza-like illness

Transient, influenza-like symptoms have been reported in patients receiving intravenous injection of Bonviva 3 mg every 3 months, typically in association with the first dose.

Influenza-like illness includes events reported as acute phase reaction or symptoms, including myalgia, arthralgia, fever, chills, fatigue, nausea, loss of appetite, and bone pain. Such symptoms were generally of short duration, mild or moderate in intensity, and resolved during continuing treatment without requiring remedial measures.

Osteonecrosis of jaw

Osteonecrosis of the jaw has been reported in patients treated by bisphosphonates. The majority of the reports refer to cancer patients, but such cases have also been reported in patients treated for osteoporosis. Osteonecrosis of the jaw is generally associated with tooth extraction and / or local infection (including osteomyelitis). Diagnosis of cancer, chemotherapy, radiotherapy, corticosteroids and poor oral hygiene are also deemed as risk factors (see section 4.4).

Ocular inflammation

Ocular inflammation events such as uveitis, episcleritis and scleritis have been reported with ibandronic acid. In some cases, these events did not resolve until the ibandronic acid was discontinued.

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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 1 mg per ml.

Excipients: Sodium (less than 1 mmol per dose).

For a full list of excipients, see section 6.1.

4.3     Contraindications

-        Hypocalcaemia (see section 4.4)

-        Hypersensitivity to ibandronic acid or to any of the excipients.

-        Hypocalcaemia

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.

[…]

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 (MF 4411). The overall safety profile of ibandronic acid 2.5 mg daily in all these studies was similar to that of placebo.

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. The majority of adverse reactions were mild to moderate in intensity. Most cases of adverse reactions did not lead to cessation of therapy.

The most commonly reported adverse reaction was influenza like illness.

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 drug reactions occurring in postmenopausal women receiving Bonviva 33 mg injection every 3 months or ibandronic acid 2.55 mg daily in the phase III studies BM16550 and MF 4411 and in postmarketing experience.

MedDRA version 8.0

*See further information below

†Identified in postmarketing experience.

Influenza-like illness

Transient, influenza-like symptoms have been reported in patients receiving intravenous injection of Bonviva 3 mg every 3 months, typically in association with the first dose.

Influenza-like illness includes events reported as acute phase reaction or symptoms, including myalgia, arthralgia, fever, chills, fatigue, nausea, loss of appetite, and bone pain. Such symptoms were generally of short duration, mild or moderate in intensity, and resolved during continuing treatment without requiring remedial measures.

Laboratory test findings

In the pivotal three-year study with oral ibandronic acid 2.5 mg daily (MF 4411) there was no difference compared with placebo for laboratory abnormalities indicative of hepatic or renal dysfunction, impaired haematologic system, hypocalcaemia or hypophosphataemia. Similarly, no differences were noted between the groups in the pivotal study with Bonviva 3 mg injection every 3 months (BM 16550).

Post-marketing Experience

Osteonecrosis of jaw

Osteonecrosis of the jaw has been reported in patients treated by bisphosphonates. The majority of the reports refer to cancer patients, but such cases have also been reported in patients treated for osteoporosis. Osteonecrosis of the jaw is generally associated with tooth extraction and / or local infection (including osteomyelitis). Diagnosis of cancer, chemotherapy, radiotherapy, corticosteroids and poor oral hygiene are also deemed as risk factors (see section 4.4).

Ocular inflammation

Ocular inflammation events such as uveitis, episcleritis and scleritis have been reported with ibandronic acid. In some cases, these events did not resolve until the ibandronic acid was discontinued.

5.1       Pharmacodynamic properties

Pharmacotherapeutic group: Drugs for treatment of bone diseases, Bbisphosphonates, ATC code: M05B A06

[…]

Paediatric population

Bonviva was not studied in the paediatric population, therefore no efficacy or safety data are available for this patient population.

[…]

6.6       Special precautions for disposal

Where the product is administered into an existing intravenous infusion line, the infusate should be restricted to either isotonic saline or 50 mg/ml (5 %) glucose solution. This also applies to solutions used to flush butterfly and other devices.

Any unused solution for injection, syringe and injection needle should be disposed of in accordance with local requirements. The release of pharmaceuticals in the environment should be minimized.

The following points should be strictly adhered to regarding the use and disposal of syringes and other medicinal sharps:

·     Needles and syringes should never be reused.

·     Place all used needles and syringes into a sharps container (puncture-proof disposable container).

·     Keep this container out of the reach of children.

·     Placing used sharps containers in the household waste should be avoided.

·     Dispose of the full container according to local requirements or as instructed by your healthcare provider

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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

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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.