- alendronate sodium trihydrate
POM: Prescription only medicine
This information is intended for use by health professionals
PosologyThe recommended dose is one 70 mg effervescent tablet once weekly. Patients should be instructed that if they miss a dose of Binosto 70 mg, they should take one effervescent tablet on the morning after they remember. They should not take two effervescent tablets on the same day but should return to taking one effervescent tablet once a week, as originally scheduled on their chosen day. 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 Binosto on an individual patient basis, particularly after 5 or more years of use.
Use in the elderly:In clinical studies there was no age related difference in the efficacy or safety profiles of alendronate. Therefore no dosage adjustment is necessary for the elderly.
Use in renal impairment:No dosage adjustment is necessary for patients with GFR greater than 35 ml/min. Alendronate is not recommended for patients with renal impairment where GFR is less than 35 ml/min, due to lack of experience.
Paediatric populationAlendronate sodium is not recommended for use in children under the age of 18 years due to insufficient data on safety and efficacy in conditions associated with paediatric osteoporosis (also see section 5.1).
Method of administration
To permit adequate absorption of alendronate:Binosto 70 mg must be taken at least 30 minutes before the first food, beverage, or medicinal product of the day with plain water only. Other beverages (including mineral water), food and some medicinal products are likely to reduce the absorption of alendronate (see section 4.5).
To facilitate delivery to the stomach and thus reduce the potential for local and oesophageal irritation/adverse experiences (see section 4.4):• Binosto 70 mg should only be taken upon arising for the day dissolved in half a glass of plain water (not less than 120 ml or 4.2 fl.oz.). Dissolving the tablet in water yields a buffered solution of pH 4.8 5.4. The buffered solution should be drunk, once the fizzing has subsided and the effervescent tablet has completely dissolved to give a clear, colourless, buffered solution, followed by at least 30 ml (one sixth of a glass) of plain water. Additional plain water may be taken. • Patients should not swallow the undissolved effervescent tablet, should not chew the effervescent tablet or allow the effervescent tablet to dissolve in their mouths because of the risk for oropharyngeal irritation (see sections 4.4 and 4.8). • If the tablet does not dissolve completely, the buffered solution may be stirred until it is clear and colourless. • Patients should not lie down until after their first food of the day, which should be at least 30 minutes after drinking the oral solution. • Patients should not lie down for at least 30 minutes after taking Binosto 70 mg. • Binosto 70 mg should not be taken at bedtime or before arising for the day. • Binosto 70 mg can be given to patients who are unable or unwilling to swallow tablets Patients should receive supplemental calcium and vitamin D if dietary intake is inadequate (see section 4.4). Binosto 70 mg has not been investigated in the treatment of glucocorticoid-induced osteoporosis.
Paediatric populationAlendronate sodium is not recommended for use in children under the age of 18 years due to insufficient data on safety and efficacy in conditions associated with paediatric osteoporosis (also see sections 4.2 and 5.1).Causes of osteoporosis other than oestrogen deficiency and ageing or glucocorticoid use should be considered. Hypocalcaemia must be corrected before initiating therapy with alendronate (see section 4.3). Other disorders affecting mineral metabolism (such as vitamin D deficiency and hypoparathyroidism) should also be effectively treated before starting Binosto treatment. In patients with these conditions, serum calcium and symptoms of hypocalcaemia should be monitored during therapy with Binosto 70 mg. Due to the positive effects of alendronate in increasing bone mineral, decreases in serum calcium and phosphate may occur especially in patients taking glucocorticoids in whom calcium absorption may be decreased. These are usually small and asymptomatic. However, there have been rare reports of symptomatic hypocalcaemia, which have occasionally been severe and often occurred in patients with predisposing conditions (e.g. hypoparathyroidism, vitamin D deficiency and calcium malabsorption). Ensuring adequate calcium and vitamin D intake is particularly important in patients receiving glucocorticoids. Excipients This medicinal product contains 26.2 mmol (or 602.54 mg) sodium per dose. To be taken into consideration by patients on a controlled sodium diet.
PregnancyAlendronate should not be used during pregnancy. There are no adequate data from the use of alendronate in pregnant women. Animal studies do not indicate direct harmful effects with respect to pregnancy, embryonal/foetal development, or postnatal development. Alendronate given during pregnancy in rats caused dystocia related to hypocalcemia (see section 5.3).
BreastfeedingIt is unknown whether alendronate is excreted into human breast milk. Given the indication, alendronate should not be used by breast-feeding women.
FertilityBisphosphonates are incorporated into the bone matrix, from which they are gradually released over a period of years. The amount of bisphosphonate incorporated into adult bone, and hence, the amount available for release back into the systemic circulation, is directly related to the dose and duration of bisphosphonate use (see section 5.2). There are no data on fetal risk in humans. However, there is a theoretical risk of fetal harm, predominantly skeletal, if a woman becomes pregnant after completing a course of bisphosphonate therapy. The impact of variables such as time between cessation of bisphosphonate therapy to conception, the particular bisphosphonate used, and the route of administration (intravenous versus oral) on the risk has not been studied.
|ONE-YEAR STUDY||THREE-YEAR STUDIES|
|alendronate Once Weekly 70 mg (n=519) %||alendronate 10 mg/day (n=370) %||alendronate 10mg/day (n=196) %||placebo (n=397) %|
|musculoskeletal pain (bone, muscle or joint)||2.9||3.2||4.1||2.5|
|Very Common (≥1/10)||Common (≥ 1/100, < 1/10)||Uncommon (≥1/1,000, <1/100)||Rare (≥1/10,000, <1/1,000)||Very Rare(<1/10,000)|
|Immune system disorders||hypersensitivity reactions including urticaria and angioedema|
|Metabolism and nutrition disorders||symptomatic hypocalcaemia, often in association with predisposing conditions#.|
|Nervous system disorders||headache, dizziness§||dysgeusia§|
|Eye disorders||eye inflammation (uveitis, scleritis, episcleritis)|
|Ear and labyrinth disorders||vertigo§|
|Gastrointestinal disorders||abdominal pain, dyspepsia, constipation, diarrhoea, flatulence, oesophageal ulcer*, dysphagia*, abdominal distension, acid regurgitation||nausea, vomiting, gastritis, oesopha-gitis*, oesophageal erosions*, melena§||oesophageal stricture*, oropharyngeal ulceration*, upper gastrointestinal PUBs (perforation, ulcers, bleeding)#|
|Skin and subcutaneous tissue disorders||alopecia§, pruritus§||rash, erythema||rash with photosensitivity, severe skin reactions including Stevens-Johnson syndrome and toxic epidermal necrolysis+|
|Musculoskeletal, connective tissue and bone disorders:||musculoskeletal (bone, muscle or joint) pain, which is sometimes severe#§||joint swelling§||Atypical subtrochanteric and diaphyseal femoral fractures (bisphosphonate class adverse reaction) # Osteonecrosis of the jaw§+, stress fractures of the proximal femoral shaft§+||Osteonecrosis of the external auditory canal (bisphosphonate class adverse reaction)|
|General disorders and administration site condition||asthenia§, peripheral oedema§||transient symptoms as in an acute-phase response (myalgia, malaise and rarely, fever) typically in association with initiation of treatment§.|
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 to the Yellow Card Scheme: www.mhra.gov.uk/yellowcard.
Treatment of post-menopausal osteoporosisOsteoporosis 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 solutionBC-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.
Laboratory test findingsIn 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 populationAlendronate 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.
AbsorptionRelative 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%.
DistributionStudies 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%.
BiotransformationThere is no evidence that alendronate is metabolised in animals or humans.
EliminationFollowing 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.
Characteristics in patientsPreclinical 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).
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