Source: European Medicines Agency (EU) Revision Year: 2019 Publisher: Atnahs Pharma Netherlands B.V., Strawinskylaan 3127, 1077 ZX Amsterdam, Netherlands
Pharmaco-therapeutic group: Medicinal products for treatment of bone diseases, bisphosphonate
ATC Code: M05BA06
Ibandronic acid belongs to the bisphosphonate group of compounds which act specifically on bone. Their selective action on bone tissue is based on the high affinity of bisphosphonates for bone mineral. Bisphosphonates act by inhibiting osteoclast activity, although the precise mechanism is still not clear.
In vivo, ibandronic acid prevents experimentally-induced bone destruction caused by cessation of gonadal function, retinoids, tumours or tumour extracts. The inhibition of endogenous bone resorption has also been documented by 45Ca kinetic studies and by the release of radioactive tetracycline previously incorporated into the skeleton.
At doses that were considerably higher than the pharmacologically effective doses, ibandronic acid did not have any effect on bone mineralisation.
Bone resorption due to malignant disease is characterised by excessive bone resorption that is not balanced with appropriate bone formation. Ibandronic acid selectively inhibits osteoclast activity, reducing bone resorption and thereby reducing skeletal complications of the malignant disease.
Clinical studies in hypercalcaemia of malignancy demonstrated that the inhibitory effect of ibandronic acid on tumour-induced osteolysis, and specifically on tumour-induced hypercalcaemia, is characterised by a decrease in serum calcium and urinary calcium excretion.
In the dose range recommended for treatment, the following response rates with the respective confidence intervals have been shown in clinical trials for patients with baseline albumin-corrected serum calcium ≥3.0 mmol/l after adequate rehydration.
| Ibandronic acid dose | % of Patients with Response | 90% Confidence Interval |
|---|---|---|
| 2 mg | 54 | 44-63 |
| 4 mg | 76 | 62-86 |
| 6 mg | 78 | 64-88 |
For these patients and dosages, the median time to achieve normocalcaemia was 4 to 7 days. The median time to relapse (return of albumin-corrected serum calcium above 3.0 mmol/l) was 18 to 26 days.
Clinical studies in patients with breast cancer and bone metastases have shown that there is a dose dependent inhibitory effect on bone osteolysis, expressed by markers of bone resorption, and a dose dependent effect on skeletal events.
Prevention of skeletal events in patients with breast cancer and bone metastases with Bondronat 6 mg administered intravenously was assessed in one randomized placebo controlled phase III trial with a duration of 96 weeks. Female patients with breast cancer and radiologically confirmed bone metastases were randomised to receive placebo (158 patients) or 6 mg Bondronat (154 patients). The results from this trial are summarised below.
The primary endpoint of the trial was the skeletal morbidity period rate (SMPR). This was a composite endpoint which had the following skeletal related events (SREs) as sub-components:
The analysis of the SMPR was time-adjusted and considered that one or more events occurring in a single 12 week period could be potentially related. Multiple events were therefore counted only once for the purposes of the analysis. Data from this study demonstrated a significant advantage for intravenous Bondronat 6 mg over placebo in the reduction in SREs measured by the time-adjusted SMPR (p=0.004). The number of SREs was also significantly reduced with Bondronat 6 mg and there was a 40% reduction in the risk of a SRE over placebo (relative risk 0.6, p=0.003). Efficacy results are summarised in Table 2
Table 2. Efficacy Results (Breast Cancer Patients with Metastatic Bone Disease):
| All Skeletal Related Events (SREs) | |||
|---|---|---|---|
| Placebo n=158 | Bondronat 6 mg n=154 | p-value | |
| SMPR (per patient year) | 1.48 | 1.19 | p=0.004 |
| Number of events (per patient) | 3.64 | 2.65 | p=0.025 |
| SRE relative risk | - | 0.60 | p=0.003 |
A statistically significant improvement in bone pain score was shown for intravenous Bondronat 6 mg compared to placebo. The pain reduction was consistently below baseline throughout the entire study and accompanied by a significantly reduced use of analgesics. The deterioration in Quality of Life was significantly less in Bondronat treated patients compared with placebo. A tabular summary of these secondary efficacy results is presented in Table 3.
Table 3. Secondary Efficacy Results (Breast cancer Patients with Metastatic Bone Disease):
| Placebo n=158 | Bondronat 6 mg n=154 | p-value | |
|---|---|---|---|
| Bone pain* | 0.21 | -0.28 | p<0.001 |
| Analgesic use* | 0.90 | 0.51 | p=0.083 |
| Quality of Life* | -45.4 | -10.3 | p=0.004 |
* Mean change from baseline to last assessment.
There was a marked depression of urinary markers of bone resorption (pyridinoline and deoxypyridinoline) in patients treated with Bondronat that was statistically significant compared to placebo.
In a study in 130 patients with metastatic breast cancer the safety of Bondronat infused over 1 hour or 15 minutes was compared. No difference was observed in the indicators of renal function. The overall adverse event profile of ibandronic acid following the 15 minute infusion was consistent with the known safety profile over longer infusion times and no new safety concerns were identified relating to the use of a 15 minute infusion time.
A 15 minute infusion time has not been studied in cancer patients with a creatinine clearance of <50ml/min.
The safety and efficacy of Bondronat in children and adolescents below the age of 18 years have not been established. No data are available.
After a 2 hour infusion of 2, 4 and 6 mg ibandronic acid pharmacokinetic parameters are dose proportional.
After 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 87% at therapeutic concentrations, and thus interaction with other medicinal products, due to displacement is unlikely.
There is no evidence that ibandronic acid is metabolized in animals or humans.
The range of observed apparent half-lives is broad and dependent on dose and assay sensitivity, but the apparent terminal half-life is generally in the range of 10-60 hours. However, early plasma levels fall quickly, reaching 10% of peak values within 3 and 8 hours after intravenous or oral administration respectively. No systemic accumulation was observed when ibandronic acid was administered intravenously once every 4 weeks for 48 weeks to patients with metastatic bone disease.
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 of renal elimination does not appear to include known acidic or basic transport systems involved in the excretion of other active substances In addition, ibandronic acid does not inhibit the major human hepatic P450 isoenzymes and does not induce the hepatic cytochrome P450 system in rats.
Bioavailability and pharmacokinetics of ibandronic acid are similar in both men and women.
There is no evidence for clinically relevant interethnic differences between Asians and Caucasians in ibandronic acid disposition. There are only very few data available on patients with African origin.
Exposure to ibandronic acid in patients with various degrees of renal impairment is related to creatinine clearance (CLcr). In subjects with severe renal impairment (mean estimated CLcr=21.2 mL/min), dose-adjusted mean AUC0-24h was increased by 110% compared to healthy volunteers. In clinical pharmacology trial WP18551, after a single dose intravenous administration of 6 mg (15 minutes infusion), mean AUC0-24 increased by 14% and 86%, respectively, in subjects with mild (mean estimated CLcr=68.1 mL/min) and moderate (mean estimated CLcr=41.2 mL/min) renal impairment compared to healthy volunteers (mean estimated CLcr=120 mL/min). Mean Cmax was not increased in patients with mild renal impairment and increased by 12% in patients with moderate renal impairment. For patients with mild renal impairment (CLcr ≥50 and <80 mL/min) no dosage adjustment is necessary. For patients with moderate renal impairment (CLcr ≥30 and <50 mL/min) or severe renal impairment (CLcr <30 mL/min) being treated for the prevention of skeletal events in patients with breast cancer and metastatic bone disease an adjustment in the dose is recommended (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 since it is not metabolized but is cleared by renal excretion and by uptake into bone. Therefore dosage adjustment is not necessary in patients with hepatic impairment. Further, as protein binding of ibandronic acid is approximately 87% at therapeutic concentrations, hypoproteinaemia in severe liver disease is unlikely to lead to clinically significant increases in free plasma concentration.
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, this is the only factor that should be considered (see renal impairment section).
There are no data on the use of Bondronat in patients less than 18 years old.
Effects in non-clinical studies were observed only at exposures sufficiently in excess of the maximum human exposure indicating little relevance to clinical use. As with other bisphosphonates, the kidney was identified to be the primary target organ of systemic toxicity.
No indication of carcinogenic potential was observed. Tests for genotoxicity revealed no evidence of effects on genetic activity for ibandronic acid.
No evidence of direct foetal toxicity or teratogenic effects were observed for ibandronic acid in intravenously treated rats and rabbits. 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. Adverse effects of ibandronic acid in reproductive toxicity studies in the rat were those expected for this class of medicinal products (bisphosphonates). They include a decreased number of implantation sites, interference with natural delivery (dystocia), an increase in visceral variations (renal pelvis ureter syndrome) and teeth abnormalities in F1 offspring in rats.
© All content on this website, including data entry, data processing, decision support tools, "RxReasoner" logo and graphics, is the intellectual property of RxReasoner and is protected by copyright laws. Unauthorized reproduction or distribution of any part of this content without explicit written permission from RxReasoner is strictly prohibited. Any third-party content used on this site is acknowledged and utilized under fair use principles.
