Pharmacological properties : תכונות פרמקולוגיות

Pharmacodynamic Properties

5.1   Pharmacodynamic properties
Pharmacotherapeutic group:
Drugs affecting bone structure and mineralisation, bisphosphonates
ATC Code: M05B A04

Method of action
The active ingredient of Binosto 70 mg, alendronate sodium trihydrate, is a bisphosphonate that inhibits osteoclastic bone resorption with no direct effect on bone formation.
Preclinical studies have shown preferential localisation of alendronate to sites of active resorption. Activity of osteoclasts is inhibited, but recruitment or attachment of osteoclasts is not affected. The bone formed during treatment with alendronate is of normal quality.
Oesophageal toxicity associated with alendronate treatment is a multifactorial effect that seems predominately mediated by local irritations of the oesophageal mucosa through crystalline matter, which is also known as pill oesophagitis. Gastroesophageal acid reflux might be a concomitant factor, as acid blockage is one of the main treatments once alendronate-associated oesophagitis occurs. Binosto 70 mg effervescent tablet administered as a buffered solution was designed to fully solubilise alendronate in a drinkable solution of high pH and acid neutralising capacity, to minimise particulate alendronate from contacting the mucosa and to prevent strong stomach acid being present in the stomach, diminishing damage potential in cases of oesophageal reflux and thereby improving tolerance.

Treatment of post-menopausal osteoporosis
Osteoporosis is defined as BMD of the spine or hip 2.5 SD below the mean value of a normal young population or as a previous fragility fracture, irrespective of BMD.

The therapeutic equivalence of alendronate 70 mg once weekly (n=519) and alendronate 10 mg daily (n=370) was demonstrated in a one-year multicentre study of post-menopausal women with osteoporosis.

The mean increases from baseline in lumbar spine BMD at one year were 5.1% (95% CI: 4.8, 5.4%) in the 70 mg once-weekly group and 5.4% (95% CI: 5.0, 5.8%) in the 10 mg daily group. The mean BMD increases were 2.3% and 2.9% at the femoral neck and 2.9% and 3.1% at the total hip in the 70 mg once weekly and 10 mg daily groups, respectively. The two treatment groups were also similar with regard to BMD increases at other skeletal sites.

The effects of alendronate on bone mass and fracture incidence in post-menopausal women were examined in two initial efficacy studies of identical design (n=994) as well as in the Fracture Intervention Trial (FIT: n=6,459).

In the initial efficacy studies, the mean bone mineral density (BMD) increases with alendronate 10 mg/day relative to placebo at three years were 8.8%, 5.9% and 7.8% at the spine, femoral neck and trochanter, respectively. Total body BMD also increased significantly. There was a 48% reduction (alendronate 3.2% vs placebo 6.2%) in the proportion of patients treated with alendronate experiencing one or more vertebral fractures relative to those treated with placebo. In the two-year extension of these studies BMD at the spine and trochanter continued to increase and BMD at the femoral neck and total body were maintained.

FIT consisted of two placebo-controlled studies using alendronate daily (5 mg daily for two years and 10 mg daily for either one or two additional years):

• FIT 1: A three-year study of 2,027 patients who had at least one baseline vertebral (compression) fracture. In this study alendronate daily reduced the incidence of ≥ 1 new vertebral fracture by 47% (alendronate 7.9% vs. placebo 15.0%). In addition, a statistically significant reduction was found in the incidence of hip fractures (1.1% vs. 2.2%, a reduction of 51%).

• FIT 2: A four-year study of 4,432 patients with low bone mass but without a baseline vertebral fracture. In this study, a significant difference was observed in the analysis of the subgroup of osteoporotic women (37% of the global population who correspond with the above definition of osteoporosis) in the incidence of ≥1 vertebral fracture (2.9% vs. 5.8%, a reduction of 50%) and in the incidence of hip fractures (alendronate 1.0% vs. placebo 2.2%, a reduction of 56%).

Clinical efficacy of Binosto 70 mg, effervescent tablets for oral solution 
BC-118-07: A clinical study with Binosto 70 mg performed in 12 healthy female subjects. This clinical study evaluated gastric emptying and gastric pH after administration of a conventional tablet and Binosto 70 mg, effervescent tablet, with a high buffering capacity. The buffered solution has the potential for improving gastric tolerance. Both formulations tested, rapidly cleared the oesophagus and there were no statistically significant or physiologically relevant differences in gastric emptying times.
Mucosal exposure to alendronate at a pH less than 3 is irritating to gastro-oesophageal tissue. Ingestion of a conventional tablet resulted in alendronate being present in the stomach at a pH below 3 within minutes.
After dosing with Binosto 70 mg, the gastric pH generally increased to approximately 5 and remained at a plateau for 30 minutes then gradually decreased. The time taken for the gastric pH to drop below 3, after the ingestion of the medications was significantly higher with the effervescent tablets, in comparison to the conventional tablet.
Therefore, Binosto 70 mg minimises the possibility of exposing the oesophagus (in case of reflux) and the stomach to acidified alendronate.

Post-authorization safety study
A prospective, non-interventional, single-arm, safety study (GastroPASS) was conducted in post-menopausal women (n= 1084) treated with Binosto who were followed in routine clinical practice for 12 months (±3 months). The cumulative incidence of all related upper GI adverse events (AEs) was 9.6% (8.0% mild, 1.5% moderate, 0.2% of severe intensity). There have been no reports of oesophagitis, oesophageal or gastric ulcer and duodenitis nor of upper GI perforation, haemorrhage or stenosis. No serious side effects related to Binosto were observed throughout the study. The mean time on Binosto was 12.8 months. The mean overall compliance based on the number of tablets missed was 94.8.
Laboratory test findings
In clinical studies, asymptomatic, mild and transient decreases in serum calcium and phosphate were observed in approximately 18 and 10%, respectively, of patients taking alendronate 10 mg/day versus approximately 12 and 3% of those taking placebo.

However, the incidences of decreases in serum calcium to < 8.0 mg/dl (2.0 mmol/l) and serum phosphate to ≤ 2.0 mg/dl (0.65 mmol/l) were similar in both treatment groups.

Paediatric population
Alendronate sodium has been studied in a small number of patients with osteogenesis imperfecta under the age of 18 years. Results are insufficient to support the use of alendronate sodium in paediatric patients with osteogenesis imperfecta.

Pharmacokinetic Properties

5.2   Pharmacokinetic properties

Absorption
Relative to an intravenous reference dose, the oral mean bioavailability of alendronate tablets in women was 0.64% for doses ranging from 5 to 70 mg when administered after an overnight fast and two hours before a standardised breakfast. Bioavailability was decreased similarly to an estimated 0.46% and 0.39% when alendronate was administered one hour or half an hour before a standardised breakfast.

The bioavailability of Binosto 70 mg effervescent tablets is equivalent to that of alendronate tablets, but the intraindividual variation in excretion (and therefore in absorption) is smaller for the effervescent tablets (CV 32.0 vs 42.1% cumulative excretion in the first 48 hours, CV 37.5 vs 45.6% maximum excretion rate).

In osteoporosis studies, alendronate was effective when administered at least 30 minutes before the first food or beverage of the day.

Bioavailability was negligible whether alendronate was administered with, or up to two hours after, a standardised breakfast. Concomitant administration of alendronate with coffee or orange juice reduced bioavailability by approximately 60%.

In healthy subjects, oral prednisone (20 mg three times daily for five days) did not produce a clinically meaningful change in oral bioavailability of alendronate (a mean increase ranging from 20% to 44%).


Distribution
Studies in rats show that alendronate transiently distributes to soft tissues following 1 mg/kg intravenous administration but is then rapidly redistributed to bone or excreted in the urine. The mean steady-state volume of distribution, exclusive of bone, is at least 28 litres in humans. Concentrations of drug in plasma following therapeutic oral doses are too low for analytical detection (< 5 ng/ml). Protein binding in human plasma is approximately 78%.

Biotransformation
There is no evidence that alendronate is metabolised in animals or humans.

Elimination
Following a single intravenous dose of [14C]alendronate, approximately 50% of the radioactivity was excreted in the urine within 72 hours and little or no radioactivity was recovered in the faeces.
Following a single 10 mg intravenous dose, the renal clearance of alendronate was 71 ml/min, and systemic clearance did not exceed 200 ml/min.
Plasma concentrations fell by more than 95% within six hours following intravenous administration. The terminal half-life in humans is estimated to exceed ten years, reflecting release of alendronate from the skeleton. Alendronate is not excreted through the acidic or basic transport systems of the kidney in rats, and thus it is not anticipated to interfere with the excretion of other medicinal products by those systems in humans.

Renal Impairment
Preclinical studies show that the drug that is not deposited in bone is rapidly excreted in the urine. No evidence of saturation of bone uptake was found after chronic dosing with cumulative intravenous doses up to 35 mg/kg in animals. Although no clinical information is available, it is likely that, as in animals, elimination of alendronate via the kidney will be reduced in patients with impaired renal function.
Therefore, somewhat greater accumulation of alendronate in bone might be expected in patients with impaired renal function (see section 4.2).