PosologyThe 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.
Patients with renal impairmentBonviva 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).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.
Patients with hepatic impairmentNo dose adjustment is required (see section 5.2).
Elderly population (>65 years)No dose adjustment is required (see section 5.2).
Paediatric populationThere is no relevant use of Bonviva in children below 18 years, and Bonviva was not studied in this population (see section 5.1 and 5.2).
Method of administrationFor intravenous use over 15 - 30 seconds, every three months.Strict adherence to the intravenous administration route is required (see section 4.4).
Administration failuresCare must be taken not to administer Bonviva injection via intra-arterial or paravenous administration as this could lead to tissue damage.
HypocalcaemiaBonviva, 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/shockCases 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 impairmentPatients 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 impairmentOverhydration should be avoided in patients at risk of cardiac failure.
Osteonecrosis of the jawOsteonecrosis 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 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-morbid conditions (e.g. anaemia, coagulopathies, infection), smoking- Concomitant therapies: corticosteroids, chemotherapy, angiogenesis inhibitors, radiotherapy to head and neck- Poor oral hygiene, periodontal disease, poorly fitting dentures, history of dental disease, invasive dental procedures e.g. tooth extractionsAll patients should be encouraged to maintain good oral hygiene, undergo routine dental check-ups, and immediately report any oral symptoms such as dental mobility, pain or swelling, or non-healing of sores or discharge during treatment with Bonviva. While on treatment, invasive dental procedures should be performed only after careful consideration and be avoided in close proximity to Bonviva administration.The management plan of the patients who develop ONJ should be set up in close collaboration between the treating physician and a dentist or oral surgeon with expertise in ONJ. Temporary interruption of Bonviva treatment should be considered until the condition resolves and contributing risk factors are mitigated where possible.
Osteonecrosis of the external auditory canalOsteonecrosis of the external auditory canal has been reported with bisphosphonates, mainly in association with long-term therapy. Possible risk factors for osteonecrosis of the external auditory canal include steroid use and chemotherapy and/or local risk factors such as infection or trauma. The possibility of osteonecrosis of the external auditory canal should be considered in patients receiving bisphosphonates who present with ear symptoms including chronic ear infections.
Atypical fractures of the femurAtypical 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.Bonviva is essentially sodium free.
PregnancyBonviva 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-feedingIt 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.
FertilityThere 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).
Summary of the safety profileThe 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 reactionsIn 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.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 Class||Common||Uncommon||Rare||Very rare|
|Immune system disorders||Asthma exacerbation||Hypersensitivity reaction||Anaphylactic reaction/shock*|
|Nervous system disorders||Headache|
|Eye disorders||Ocular inflammation*|
|Vascular disorders||Phlebitis/ thrombophlebitis|
|Gastrointestinal disorders||Gastritis, Dyspepsia, Diarrhoea, Abdominal pain, Nausea, Constipation|
|Skin and subcutaneous tissues disorders||Rash||Angioedema, Facial swelling/oedema, Urticaria||Stevens-Johnson Syndrome, Erythema Multiforme, Dermatitis Bullous|
|Musculoskeletal and , connective tissue disorders||Arthralgia, Myalgia, Musculoskeletal pain, Back pain||Bone pain||Atypical subtrochanteric and diaphyseal femoral fractures||Osteonecrosis of jaw* Osteonecrosis of the external auditory canal (bisphosphonate class adverse reaction)|
|General disorders and administration site conditions||Influenza like illness*, Fatigue||Injection site reactions, Asthenia|
Description of selected adverse reactions
Influenza-like illnessInfluenza-like illness includes events reported as acute phase reaction or symptoms, including myalgia, arthralgia, fever, chills, fatigue, nausea, loss of appetite, and bone pain.
Osteonecrosis of the jawCases of osteonecrosis of the jaw have been reported, predominantly in cancer patients treated with medicinal products that inhibit bone resorption, such as ibandronic acid (see section 4.4.) Cases of ONJ have been reported in the post marketing setting for ibandronic acid.
Ocular inflammationOcular 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.
Anaphylactic reaction/shockCases of anaphylactic reaction/shock, including fatal events, have been reported in patients treated with intravenous ibandronic acid.
Reporting of suspected adverse reactionsReporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions (see details below).
IrelandHPRA PharmacovigilanceEarlsfort Terrace IRL - Dublin 2Tel: +353 1 6764971Fax: +353 1 6762517Website: www.hpra.iee-mail:email@example.com
MaltaADR ReportingWebsite: www.medicinesauthority.gov.mt/adrportal
United KingdomYellow Card SchemeWebsite: www.mhra.gov.uk/yellowcard
Mechanism of actionIbandronic acid is a highly potent bisphosphonate belonging to the nitrogen-containing group of bisphosphonates, which act selectively on bone tissue and specifically inhibit osteoclast activity without directly affecting bone formation. It does not interfere with osteoclast recruitment. Ibandronic acid leads to progressive net gains in bone mass and a decreased incidence of fractures through the reduction of elevated bone turnover towards premenopausal levels in postmenopausal women.
Pharmacodynamic effectsThe pharmacodynamic action of ibandronic acid is inhibition of bone resorption. In vivo, ibandronic acid prevents bone destruction experimentally induced by cessation of gonadal function, retinoids, tumours or tumour extracts. In young (fast growing) rats, the endogenous bone resorption is also inhibited, leading to increased normal bone mass compared with untreated animals.Animal models confirm that ibandronic acid is a highly potent inhibitor of osteoclastic activity. In growing rats, there was no evidence of impaired mineralisation even at doses greater than 5,000 times the dose required for osteoporosis treatment.Both daily and intermittent (with prolonged dose-free intervals) long-term administration in rats, dogs and monkeys was associated with formation of new bone of normal quality and maintained or increased mechanical strength even at doses in the toxic range. In humans, the efficacy of both daily and intermittent administration with a dose-free interval of 9 - 10 weeks of ibandronic acid was confirmed in a clinical trial (MF 4411), in which ibandronic acid demonstrated anti-fracture efficacy.In animal models ibandronic acid produced biochemical changes indicative of dose-dependent inhibition of bone resorption, including suppression of urinary biochemical markers of bone collagen degradation (such as deoxypyridinoline, and cross-linked N-telopeptides of type I collagen (NTX)).Both daily, intermittent (with a dose-free interval of 9 - 10 weeks per quarter) oral doses as well as intravenous doses of ibandronic acid in postmenopausal women produced biochemical changes indicative of dose-dependent inhibition of bone resorption.Bonviva intravenous injection decreased levels of serum C-telopeptide of the alpha chain of Type I collagen (CTX) within 3 - 7 days of starting treatment and decreased levels of osteocalcin within 3 months.Following treatment discontinuation, there is a reversion to the pathological pre-treatment rates of elevated bone resorption associated with postmenopausal osteoporosis.The histological analysis of bone biopsies after two and three years of treatment of postmenopausal women with doses of oral ibandronic acid 2.5 mg daily and intermittent intravenous doses of up to 1 mg every 3 months showed bone of normal quality and no indication of a mineralisation defect. An expected decrease in bone turnover, normal quality of bone and absence of defects in mineralization were also seen after two years of treatment with Bonviva 3 mg injection.
Clinical efficacyIndependent risk factors, for example, low BMD, age, the existence of previous fractures, a family history of fractures, high bone turnover and low body mass index should be considered in order to identify women at increased risk of osteoporotic fractures.
Bonviva 3 mg injection every 3 months
Bone mineral density (BMD)Bonviva 3 mg intravenous injection, administered every 3 months, was shown to be at least as effective as oral ibandronic acid 2.5 mg daily in a 2-year, randomised, double-blind, multicentre, non-inferiority study (BM16550) of postmenopausal women (1386 women aged 55 - 80) with osteoporosis (lumbar spine BMD T-score below -2.5 SD at baseline). This was demonstrated in both the primary analysis at one year and in the confirmatory analysis at two years endpoint (Table 2).The primary analysis of data from study BM16550 at one year and the confirmatory analysis at 2 years demonstrated the non-inferiority of 3 mg every 3 months injection dosing regimen compared to 2.5 mg oral daily dosing regimen, in terms of mean increases in BMD at lumbar spine, total hip, femoral neck and trochanter (Table 2).Table 2: Mean relative change from baseline of lumbar spine, total hip, femoral neck and trochanter BMD after one year (primary analysis) and two years of treatment (Per-Protocol Population) in study BM 16550.
|One year data in study BM 16550||Two year data in study BM 16550|
|Mean relative changes from baseline % [95% CI]||ibandronic acid 2.5 mg daily (N=377)||Bonviva 3 mg injection every 3 months (N=365)||ibandronic acid 2.5 mg daily (N=334)||Bonviva 3 mg injection every 3 months (N=334)|
|Lumbar spine L2-L4 BMD||3.8 [3.4, 4.2]||4.8 [4.5, 5.2]||4.8 [4.3, 5.4]||6.3 [5.7, 6.8]|
|Total hip BMD||1.8 [1.5, 2.1]||2.4 [2.0, 2.7]||2.2 [1.8, 2.6]||3.1 [2.6, 3.6]|
|Femoral neck BMD||1.6 [1.2, 2.0]||2.3 [1.9, 2.7]||2.2 [1.8, 2.7]||2.8 [2.3, 3.3]|
|Trochanter BMD||3.0 [2.6, 3.4]||3.8 [3.2, 4.4]||3.5 [3.0, 4.0]||4.9 [4.1, 5.7]|
Biochemical markers of bone turn-overClinically meaningful reductions in serum CTX levels were observed at all time points measured. At 12 months median relative changes from baseline were 58.6 % for the intravenous injection of 3 mg every 3 months regimen and 62.6 % for oral 2.5 mg daily regimen. In addition, 64.8 % of patients receiving 3 mg every 3 months injection were identified as responders (defined as a decrease ≥50 % from baseline), compared with 64.9 % of patients receiving 2.5 mg daily orally. Serum CTX reduction was maintained over the 2 years, with more than half of the patients identified as responders in both treatment groups.Based on the results of study BM 16550, Bonviva 3 mg intravenous injection, administered every 3 months is expected to be at least as effective in preventing fractures as the oral regimen of ibandronic acid 2.5 mg daily.
Ibandronic acid 2.5 mg daily tabletsIn the initial three-year, randomised, double-blind, placebo-controlled, fracture study (MF 4411), a statistically significant and medically relevant decrease in the incidence of new radiographic morphometric and clinical vertebral fractures was demonstrated (table 3). In this study, ibandronic acid was evaluated at oral doses of 2.5 mg daily and 20 mg intermittently as an exploratory regimen. Ibandronic acid was taken 60 minutes before the first food or drink of the day (post-dose fasting period). The study enrolled women aged 55 to 80 years, who were at least 5 years postmenopausal, who had a BMD at the lumbar spine of -2 to -5 SD below the premenopausal mean (T-score) in at least one vertebra [L1-L4], and who had one to four prevalent vertebral fractures. All patients received 500 mg calcium and 400 IU vitamin D daily. Efficacy was evaluated in 2,928 patients. Ibandronic acid 2.5 mg administered daily, showed a statistically significant and medically relevant reduction in the incidence of new vertebral fractures. This regimen reduced the occurrence of new radiographic vertebral fractures by 62 % (p=0.0001) over the three year duration of the study. A relative risk reduction of 61 % was observed after 2 years (p=0.0006). No statistically significant difference was attained after 1 year of treatment (p=0.056). The anti-fracture effect was consistent over the duration of the study. There was no indication of a waning of the effect over time. The incidence of clinical vertebral fractures was also significantly reduced by 49 % after 3 years (p=0.011). The strong effect on vertebral fractures was furthermore reflected by a statistically significant reduction of height loss compared to placebo (p<0.0001).Table 3: Results from 3 years fracture study MF 4411 (%, 95 % CI)
|Placebo (N=974)||ibandronic acid 2.5 mg daily (N=977)|
|Relative risk reduction New morphometric vertebral fractures||62% (40.9, 75.1)|
|Incidence of new morphometric vertebral fractures||9.56% (7.5, 11.7)||4.68% (3.2, 6.2)|
|Relative risk reduction of clinical vertebral fracture||49% (14.03, 69.49)|
|Incidence of clinical vertebral fracture||5.33% (3.73, 6.92)||2.75% (1.61, 3.89)|
|BMD mean change relative to baseline lumbar spine at year 3||1.26% (0.8, 1.7)||6.54% (6.1, 7.0)|
|BMD mean change relative to baseline total hip at year 3||-0.69% (-1.0, -0.4)||3.36% (3.0, 3.7)|
|Placebo (N=587)||ibandronic acid 2.5 mg daily (N=575)|
|Relative Risk Reduction New morphometric vertebral fractures||59% (34.5, 74.3)|
|Incidence of new morphometric vertebral fractures||12.54% (9.53, 15.55)||5.36% (3.31, 7.41)|
|Relative risk reduction of clinical vertebral fracture||50% (9.49, 71.91)|
|Incidence of clinical vertebral fracture||6.97% (4.67, 9.27)||3.57% (1.89, 5.24)|
|BMD mean change relative to baseline lumbar spine at year 3||1.13% (0.6, 1.7)||7.01% (6.5, 7.6)|
|BMD mean change relative to baseline total hip at year 3||-0.70% (-1.1, -0.2)||3.59% (3.1, 4.1)|
DistributionAfter initial systemic exposure, ibandronic acid rapidly binds to bone or is excreted into urine. In humans, the apparent terminal volume of distribution is at least 90 l and the amount of dose reaching the bone is estimated to be 40 50 % of the circulating dose. Protein binding in human plasma is approximately 85 % - 87 % (determined in vitro at therapeutic ibandronic acid concentrations), and thus there is a low potential for interaction with other medicinal products due to displacement.
BiotransformationThere is no evidence that ibandronic acid is metabolised in animals or humans.
EliminationIbandronic acid is removed from the circulation via bone absorption (estimated to be 40 50 % in postmenopausal women) and the remainder is eliminated unchanged by the kidney. The range of observed apparent half-lives is broad, the apparent terminal half-life is generally in the range of 10 - 72 hours. As the values calculated are largely a function of the duration of study, the dose used, and assay sensitivity, the true terminal half-life is likely to be substantially longer, in common with other bisphosphonates. Early plasma levels fall quickly, reaching 10 % of the peak values within 3 and 8 hours after intravenous or oral administration, respectively. Total clearance of ibandronic acid is low with average values in the range 84 - 160 ml/min. Renal clearance (about 60 ml/min in healthy postmenopausal females) accounts for 50 60 % of total clearance, and is related to creatinine clearance. The difference between the apparent total and renal clearances is considered to reflect the uptake by bone.The secretory pathway appears not to include known acidic or basic transport systems involved in the excretion of other active substances.(see section 4.5). In addition, ibandronic acid does not inhibit the major human hepatic P450 isoenzymes and does not induce the hepatic cytochrome P450 system in rats.
Pharmacokinetics in special clinical situations
GenderPharmacokinetics of ibandronic acid are similar in men and women.
RaceThere is no evidence for any clinically relevant inter-ethnic differences between Asians and Caucasians in ibandronic acid disposition. There is limited data available on patients of African origin.
Patients with renal impairmentRenal clearance of ibandronic acid in patients with various degrees of renal impairment is linearly related to creatinine clearance (CLcr). No dose adjustment is necessary for patients with mild or moderate renal impairment (CLcr equal or above 30 ml/min). Subjects with severe renal impairment (CLcr less than 30 ml/min) receiving daily oral administration of 10 mg ibandronic acid for 21 days, had 2 - 3 fold higher plasma concentrations than subjects with normal renal function and total clearance of ibandronic acid was 44 ml/min. After intravenous administration of 0.5 mg of ibandronic acid, total, renal, and non-renal clearances decreased by 67 %, 77 % and 50 %, respectively, in subjects with severe renal failure, but there was no reduction in tolerability associated with the increase in exposure. Due to the limited clinical experience, Bonviva is not recommended in patients with severe renal impairment (see section 4.2 and section 4.4). The pharmacokinetics of ibandronic acid in patients with end-stage renal disease was only assessed in a small number of patients managed by haemodialysis, therefore, the pharmacokinetics of ibandronic acid in the patients not undergoing haemodialysis is unknown. Due to the limited data available, ibandronic acid should not be used in all patients with end-stage renal disease.
Patients with hepatic impairment (see section 4.2)There are no pharmacokinetic data for ibandronic acid in patients who have hepatic impairment. The liver has no significant role in the clearance of ibandronic acid, which is not metabolised but is cleared by renal excretion and by uptake into bone. Therefore dose adjustment is not necessary in patients with hepatic impairment.
Elderly population (see section 4.2)In a multivariate analysis, age was not found to be an independent factor of any of the pharmacokinetic parameters studied. As renal function decreases with age, renal function is the only factor to take into consideration (see renal impairment section).
Paediatric population (see section 4.2 and section 5.1)There are no data on the use of Bonviva in these age groups.
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).
Roche Products Limited
Address : Hexagon Place, 6 Falcon Way, Shire Park, Welwyn Garden City, Hertfordshire, AL7 1TW
Telephone : +44 (0)1707 366 000
Fax : +44 (0)1707 338 297
Medical Information Direct Line : +44 (0)800 328 1629
Medical Information e-mail : firstname.lastname@example.org
Customer Care direct line : +44 (0)800 731 5711
Medical Information Fax : +44 (0)1707 384555
Patient Information Leaflets (PILs):