ACIDE ALENDRONIQUE/CHOLECALCIFEROL (VITAMINE D3) CRISTERS 70 mg/5600 UI Cpr Plq/12

Tablet.

Rectangular tablet, white to off-white, engraved with a "5600" on one side, of 11,4 ± 0,2 mm long and 7,2 ± 0,2 mm wide.

Alendronic acid...................................................................................................................................... 70 mg

As alendronic acid monosodium trihydrate.

Cholecalciferol (vitamin D3)............................................................................. 140 micrograms (5600 IU)

For one tablet.

Excipients with known effect : each tablet contains up to 64 mg of anhydrous lactose and 27,5 mg of sucrose.

Excipients:

ALENDRONIC ACID/CHOLECALCIFEROL (VITAMIN D3) CRISTERS is indicated for the treatment of postmenopausal osteoporosis in women at risk of vitamin D insufficiency. It reduces the risk of vertebral and hip fractures.

Dosage

The recommended dose is one tablet once a week.

Patients should be advised that if they forget a dose of ALENDRONIC ACID/CHOLECALCIFEROL (VITAMIN D3) CRISTERS, they should take one tablet on the morning after they realise the mistake. They must not take two tablets on the same day, but should return to taking one tablet once a week, based on their originally chosen day.

Due to the pathophysiology of osteoporosis, ALENDRONIC ACID/CHOLECALCIFEROL (VITAMIN D3) CRISTERS is intended for long-term treatment. 

The optimal duration of bisphosphonate treatment for osteoporosis has not been established. The need to continue treatment should be reassessed regularly on a case-by-case basis, weighing the potential benefits and risks of ALENDRONIC ACID/CHOLECALCIFEROL (VITAMIN D3) CRISTERS, particularly after 5 years or more of treatment.

Treated patients should receive calcium supplementation if their dietary intake is insufficient (see section Warnings and precautions). Additional vitamin D should only be considered after individual assessment of patients, taking into account any vitamin D intake, whether from vitamin or dietary supplements.

The equivalence between the weekly intake of ALENDRONIC ACID/CHOLECALCIFEROL (VITAMIN D3) CRISTERS (equivalent to 5 600 IU of vitamin D3) and a daily dose of 800 IU of vitamin D has not been studied.

Elderly

Clinical studies have revealed no age-related differences in the efficacy and safety profiles of alendronate. Therefore, no dose adjustment is necessary in elderly patients.

Renal impairment

Due to lack of experience, ALENDRONIC ACID/CHOLECALCIFEROL (VITAMIN D3) CRISTERS is not recommended in patients with renal impairment characterised by a creatinine clearance of less than 35 ml/min. No dose adjustment is necessary in patients with a creatinine clearance above 35 ml/min.

Paediatric population

The safety and efficacy of ALENDRONIC ACID/CHOLECALCIFEROL (VITAMIN D3) CRISTERS in children under 18 years of age have not been established. This medicine must not be used in children under 18 years of age due to the absence of data for the alendronic acid/cholecalciferol combination. The data currently available for alendronic acid in the paediatric population are described in section Pharmacodynamics.

Method of administration

Oral use.

To ensure adequate absorption of alendronate:

ALENDRONIC ACID/CHOLECALCIFEROL (VITAMIN D3) CRISTERS must be taken at least 30 minutes before the first food, drink or medicine of the day (including antacids, medicines containing calcium and vitamins) with a large glass of tap water (not mineral water). Other drinks (including mineral water), food or certain medicines may reduce the absorption of alendronate (see sections Interactions and Adverse effects).

The following instructions must be strictly followed in order to reduce the risk of oesophageal irritation and the associated adverse effects (see section Warnings and precautions) :

• ALENDRONIC ACID/CHOLECALCIFEROL (VITAMIN D3) CRISTERS must be swallowed strictly after getting up, with a large glass of tap water (minimum 200 ml).
• Patients must swallow the ALENDRONIC ACID/CHOLECALCIFEROL (VITAMIN D3) CRISTERS tablet whole. Patients must neither crush nor chew the tablet nor let it dissolve in the mouth because of the potential risk of oropharyngeal ulceration.
• Patients must not lie down for at least 30 minutes after taking ALENDRONIC ACID/CHOLECALCIFEROL (VITAMIN D3) CRISTERS and until the first food of the day has been absorbed.
• ALENDRONIC ACID/CHOLECALCIFEROL (VITAMIN D3) CRISTERS must not be taken at bedtime or before getting up.

• Hypersensitivity to the active substances or to any of the excipients listed in section Composition.
• Abnormalities of the oesophagus and other factors that delay oesophageal transit such as stricture and achalasia.
• Inability to stand or sit upright for at least 30 minutes.
• Hypocalcaemia.

Alendronate

Adverse events of the upper gastrointestinal tract

Alendronate may cause local irritation of the upper oesophago-gastro-intestinal mucosa. Because of the possibility of worsening of an underlying disease, alendronate should be prescribed with caution in patients with active upper gastrointestinal disorders such as dysphagia, oesophageal disease, gastritis, duodenitis, ulcers, or patients with a recent history (within the past year) of a major gastrointestinal disorder such as peptic ulcer, active gastrointestinal bleeding or upper gastrointestinal surgery other than pyloroplasty (see section Contraindications). For patients in whom Barrett's oesophagus has been diagnosed, prescribers should assess the potential benefits and risks of alendronate on a case-by-case basis.

Oesophageal reactions (sometimes severe and requiring hospitalisation), such as oesophagitis, oesophageal ulcers and oesophageal erosions, rarely followed by oesophageal strictures, have been reported in patients treated with alendronate. Physicians should therefore be vigilant for any sign or symptom indicating a possible oesophageal reaction and instruct patients to stop alendronate and seek medical attention if they develop symptoms of oesophageal irritation such as dysphagia, odynophagia, retrosternal pain, or the onset or worsening of retrosternal heartburn (see section Adverse effects).

The risk of severe oesophageal adverse effects appears to be greater in patients who do not correctly follow the instructions for administration of alendronate and/or who continue to take alendronate after having developed symptoms suggestive of oesophageal irritation. It is very important that all instructions regarding administration of alendronate are given to and understood by the patient (see section Dosage and administration). Patients should be informed that if they do not strictly follow the administration instructions, the risk of oesophageal adverse effects may be increased.

Although no increased risk was observed in large clinical trials with alendronate, rare cases of gastric and duodenal ulcers have been reported since marketing, some of which were severe and accompanied by complications (see section Adverse effects).

Osteonecrosis of the jaw

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

The following risk factors should be taken into account when assessing an individual's risk of developing osteonecrosis of the jaw:

• the potency of the bisphosphonate (highest for zoledronic acid), the route of administration (see above) and cumulative doses;
• cancer, chemotherapy, radiotherapy, corticosteroids, angiogenesis inhibitors, smoking;
• history of dental disease, poor oral hygiene, periodontal disease, invasive dental procedures and ill-fitting dentures.

A dental examination with appropriate preventive dentistry should be considered before oral bisphosphonate treatment in patients with poor dentition.

During treatment, these patients should avoid invasive dental procedures where possible. Dental surgery may worsen the condition of patients who develop osteonecrosis of the jaw during bisphosphonate treatment. For patients requiring dental procedures, there are no data available suggesting that interrupting bisphosphonate treatment reduces the risk of osteonecrosis of the jaw. The treating physician's clinical judgement should guide management for each patient, based on assessment of the individual benefit/risk ratio.

During bisphosphonate treatment, each patient should be encouraged to maintain good oral hygiene, undergo regular dental check-ups and report any oral symptoms such as tooth mobility, pain or swelling.

Osteonecrosis of the external auditory canal

Osteonecrosis of the external auditory canal has been reported with bisphosphonates, especially 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, such as pain or discharge, or chronic ear infections.

Musculoskeletal pain

Bone, joint and/or muscle pain have been reported in patients taking bisphosphonates. Since marketing, these symptoms have rarely been severe and/or disabling (see section Adverse effects). The time to onset of symptoms ranged from one day to several months after the start of treatment. The symptoms in most patients resolved after discontinuation of treatment. In some of them, recurrence of these symptoms was observed when treatment was resumed with the same drug or with another bisphosphonate.

Atypical fractures of the femur

Subtrochanteric and diaphyseal atypical femoral fractures have been reported with bisphosphonates, mainly in patients treated long-term 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 area. These fractures occur after minimal or no trauma, and some patients present with thigh or groin pain, often associated with radiological signs of stress fractures, weeks or months before the femoral fracture. Fractures are often bilateral; therefore, the contralateral femur should be examined in bisphosphonate-treated patients who have had a diaphyseal femoral fracture. Poor healing of these fractures has also been reported. Discontinuation of bisphosphonate treatment in patients in whom an atypical femoral fracture is suspected should be considered, based on assessment of the benefit/risk for the patient. During bisphosphonate treatment, patients should be advised to report any thigh, hip or groin pain, and all patients presenting with such symptoms should be evaluated for an atypical femoral fracture.

Renal impairment

ALENDRONIC ACID/CHOLECALCIFEROL (VITAMIN D3) CRISTERS must not be administered to patients with renal impairment characterised by a creatinine clearance below 35 mL/min (see section Dosage and administration).

Mineral and bone metabolism

Causes of osteoporosis other than oestrogen deficiency and age should be taken into consideration.

Hypocalcaemia must be corrected before starting treatment with ALENDRONIC ACID/CHOLECALCIFEROL (VITAMIN D3) CRISTERS (see section Contraindications). Likewise, other disorders of bone metabolism (such as vitamin D deficiency and hypoparathyroidism) must be effectively corrected before starting treatment with ALENDRONIC ACID/CHOLECALCIFEROL (VITAMIN D3) CRISTERS. The vitamin D content of ALENDRONIC ACID/CHOLECALCIFEROL (VITAMIN D3) CRISTERS is not suitable for correcting vitamin D deficiency. In patients with these disorders, serum calcium and symptoms of hypocalcaemia must be monitored during treatment with ALENDRONIC ACID/CHOLECALCIFEROL (VITAMIN D3) CRISTERS.

Due to the positive effects of alendronate on bone mass increase, a decrease in serum calcium and phosphate may occur, particularly in patients taking glucocorticoids in whom calcium absorption may be reduced. It is usually mild and asymptomatic. However, there have been rare cases of symptomatic hypocalcaemia, sometimes severe and often occurring in patients with risk factors (for example hypoparathyroidism, vitamin D deficiency and calcium malabsorption) (see section Adverse effects).

Cholecalciferol

Vitamin D3 may increase the severity of hypercalcaemia and/or hypercalciuria when administered to patients with diseases associated with uncontrolled overproduction of calcitriol (e.g. leukaemia, lymphoma, sarcoidosis). Serum calcium and urinary calcium should be monitored in these patients.

Patients with malabsorption syndrome may not absorb vitamin D properly3.

Excipients

This medicine contains lactose and sucrose. Patients with rare hereditary problems of fructose or galactose intolerance, congenital galactosaemia, glucose-galactose malabsorption syndrome or sucrase-isomaltase insufficiency must not take this medicine.

Alendronate

When administered concomitantly, food and drinks (including mineral water), calcium-containing medicines, antacids, as well as other orally administered medicines are likely to interfere with the absorption of alendronate. Therefore, patients should wait at least 30 minutes after taking alendronate before taking any other oral medicine (see sections Dosage and administration and Pharmacokinetics).

Due to the gastrointestinal irritation associated with the intake of Non-Steroidal Anti-Inflammatory Drugs (NSAIDs), caution is required when alendronate is taken concomitantly.

Cholecalciferol

Olestra, mineral oils, orlistat and bile acid sequestrants (e.g. cholestyramine, colestipol) may reduce the absorption of vitamin D. Anticonvulsants, cimetidine and thiazide diuretics may increase the catabolism of vitamin D. Additional vitamin D intake should only be considered after individual assessment of patients.

ALENDRONIC ACID/CHOLECALCIFEROL (VITAMIN D3) CRISTERS is only indicated in postmenopausal women and therefore must not be used in pregnant or breast-feeding women.

Pregnancy

There are no or limited data on the use of alendronate in pregnant women. Animal studies have shown reproductive toxicity. Alendronate administered during pregnancy in rats caused dystocia related to hypocalcaemia (see section Preclinical safety). Studies in animals with high doses of vitamin D have shown hypercalcaemia and toxicity on reproductive function (see section Preclinical safety). ALENDRONIC ACID/CHOLECALCIFEROL (VITAMIN D3) CRISTERS must not be used during pregnancy.

Breast-feeding

It is not known whether alendronate/metabolites are excreted in human milk. A risk to newborns/infants cannot be excluded. Cholecalciferol and some of its active metabolites pass into breast milk. ALENDRONIC ACID/CHOLECALCIFEROL (VITAMIN D3) CRISTERS must not be used during breast-feeding.

Fertility

Bisphosphonates are incorporated into the bone matrix, from where they are gradually released over several years. The amount of bisphosphonate incorporated into adult bone, and hence the amount available to pass into the systemic circulation, is directly related to the dose and duration of bisphosphonate use (see section Pharmacokinetics). There are no human data on fetal risk. However, there is a theoretical risk of fetal impairment, mainly skeletal, if a woman becomes pregnant after treatment with bisphosphonates. The impact of variables on this risk, such as the time between cessation of bisphosphonate treatment and conception, the nature of the bisphosphonate used and the route of administration (intravenous versus oral), has not been studied.

ALENDRONIC ACID/CHOLECALCIFEROL (VITAMIN D3) CRISTERS has no or negligible direct effect on the ability to drive and use machines. Patients may experience certain adverse reactions (for example blurred vision, dizziness and severe bone, muscle or joint pain (see section Adverse effects) which may influence the ability to drive and use machines.

Summary of the safety profile

The most frequently reported adverse reactions concern the upper gastrointestinal tract, including abdominal pain, dyspepsia, oesophageal ulcer, dysphagia, abdominal distension and acid regurgitation (> 1%).

Tabulated list of adverse reactions

The following adverse reactions have been reported during clinical studies and/or since marketing of alendronate.

No additional adverse reactions were observed with the combination of alendronic acid and cholecalciferol.

Frequencies are defined as follows: 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).

System organ class	Frequency	Adverse effects
Immune system disorders	Rare	hypersensitivity reactions including urticaria and angioedema
Metabolism and nutrition disorders	Rare	symptomatic hypocalcaemia, often associated with risk factors§
Nervous system disorders	Common	headache, dizziness†
	Uncommon	dysgeusia†
Eye disorders	Uncommon	eye inflammation (uveitis, scleritis or episcleritis)
Ear and labyrinth disorders	Common	vertigo†
	Very rare	osteonecrosis of the external auditory canal (adverse effects of the bisphosphonate class)
Gastrointestinal disorders	Common	abdominal pain, dyspepsia, constipation, diarrhoea, flatulence, oesophageal ulcer*, dysphagia*, abdominal bloating, acid regurgitation
	Uncommon	nausea, vomiting, gastritis, oesophagitis*, oesophageal erosions*, melaena†
	Rare	oesophageal stricture*, oropharyngeal ulceration*, PUS (perforation, ulcers, bleeding) of the upper gastrointestinal tract§
Skin and subcutaneous tissue disorders	Common	alopecia†, pruritus†
	Uncommon	rash, erythema
	Rare	rash with photosensitivity, severe skin reactions, including Stevens-Johnson syndrome and toxic epidermal necrolysis† (Lyell's syndrome)
Musculoskeletal and systemic disorders	Very common	musculoskeletal pain (bone, muscle or joints), sometimes severe†§
	Common	joint swelling†
	Rare	osteonecrosis of the jaw‡§, atypical subtrochanteric and diaphyseal femoral fractures (class adverse effects of bisphosphonates)
General disorders and administration site conditions	Common	asthenia†, peripheral oedema†
	Uncommon	transient acute-reaction-type symptoms (myalgia, malaise and rarely fever), generally observed at the start of treatment†
§ See section Warnings and precautions. † The frequency was similar in clinical studies between the drug group and the placebo group. * See sections Dosage and administration and Warnings and precautions. ‡ This adverse event has been identified by pharmacovigilance since marketing. The rare frequency was estimated from appropriate clinical trials.

Reporting of suspected adverse reactions

Reporting 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 reaction via the national reporting system: National Agency for the Safety of Medicines and Health Products (ANSM) and the network of Regional Centres of Pharmacovigilance - Website: www.ansm.sante.fr.

Alendronate

Symptoms

Hypocalcaemia, hypophosphataemia and adverse effects of the upper gastrointestinal tract, such as indigestion, heartburn, oesophagitis, gastritis or ulcer, may occur in cases of oral overdose.

Management

No specific data are available on the management of overdose with alendronate. In case of overdose with ACIDE ALENDRONIQUE/CHOLECALCIFEROL (VITAMIN D3) CRISTERS, milk or antacids should be administered in order to chelate the alendronate. Because of the risk of oesophageal irritation, vomiting must not be induced and the patient must remain in an upright position.

Cholecalciferol

At doses below 10 000 IU per day, no vitamin D toxicity has been documented during long-term treatment in generally healthy adults. In one clinical study, in healthy adults, a daily dose of 4 000 IU of vitamin D3 for a period of up to 5 months was not associated with hypercalcaemia or hypercalciuria.

Pharmacotherapeutic class: Medicines for the treatment of bone diseases, Bisphosphonates, combinations, ATC code: M05BB03.

Mechanism of action

Alendronate

Monosodium alendronate is a bisphosphonate that inhibits bone resorption by osteoclasts without direct effect on bone formation. Preclinical studies have shown a preferential localisation of alendronate at active sites of resorption. The activity of osteoclasts is inhibited, but neither their recruitment nor their attachment is affected. During treatment with alendronate, the quality of the bone formed is normal.

Cholecalciferol (vitamin D3)

Vitamin D3 is produced by the skin through conversion of 7-dehydrocholesterol into vitamin D3 under the action of ultraviolet light. In the absence of sufficient exposure to sunlight, vitamin D3 is an essential dietary nutrient. Vitamin D3 is converted into 25-hydroxyvitamin D3 in the liver, and is stored there until use. Its conversion in the kidney into the active calcium-mobilising hormone, 1,25-dihydroxyvitamin D3 (calcitriol) is tightly regulated. The main action of 1,25-dihydroxyvitamin D3 is to increase intestinal absorption of calcium and phosphate and to balance calcium-phosphate homeostasis, bone formation and bone resorption.

Vitamin D3 is necessary for normal bone formation. Vitamin D insufficiency occurs when both sun exposure and dietary intake are inadequate. Insufficiency is associated with a negative calcium balance, bone loss and an increased risk of bone fracture. In severe cases, deficiency leads to secondary hyperparathyroidism, hypophosphataemia, proximal muscle weakness and osteomalacia, and an increased risk of falls and fractures in individuals with osteoporosis. Additional vitamin D intake reduces these risks and their consequences.

Osteoporosis is defined by a bone mineral density (BMD) at the spine or femoral neck 2,5 standard deviations below the mean of a young normal population, or by a history of fragility fracture, regardless of BMD.

Clinical efficacy and safety

Studies of alendronic acid/cholecalciferol

The effect of the lowest dosage of alendronic acid/cholecalciferol (70 mg alendronate/2 800 IU of vitamin D3) on vitamin D levels was demonstrated in an international study of 15 weeks in 682 women with post-menopausal osteoporosis (serum 25-hydroxyvitamin D at baseline: mean, 56 nmol/l or 22,3 ng/ml; range, 22,5-225 nmol/l or 9-90 ng/ml). Patients received once weekly either alendronic acid/cholecalciferol at the lowest dosage (70 mg/2 800 IU) (n = 350), or 70 mg of alendronate (n = 332); additional vitamin D supplementation was not permitted. After 15 weeks of treatment, mean serum levels of 25-hydroxyvitamin D were significantly higher (26 %) in the Alendronic acid/Vitamin D3 (70 mg/2 800 IU) (56 nmol/l or 23 ng/ml) group than in the alendronate-alone group (46 nmol/l or 18,2 ng/ml). The percentage of patients with vitamin D insufficiency (serum 25-hydroxyvitamin D < 37,5 nmol/l or < 15 ng/ml) was significantly reduced by 62,5 % with alendronic acid/cholecalciferol (70 mg/2 800 IU) versus alendronate alone (12 % versus 32 %, respectively) at week 15. The percentage of patients with vitamin D deficiency (serum 25-hydroxyvitamin D < 22,5 nmol/l or < 9 ng/ml) was significantly reduced by 92 % with alendronic acid/cholecalciferol (70 mg/2 800 IU) versus alendronate alone (1 % versus 13 %, respectively). In this study, mean levels of 25-hydroxyvitamin D in patients with vitamin D insufficiency at baseline (25-hydroxyvitamin D, 22,5 to 37,5 nmol/l or 9 to < 15 ng/ml) increased by 30 nmol/l or 12,1 ng/ml to 40 nmol/l or 15,9 ng/ml at week 15 in the alendronic acid/cholecalciferol group (70 mg/2 800 IU) (n = 75), and decreased by 30 nmol/l or 12,0 ng/ml at baseline to 26 nmol/l or 10,4 ng/ml at week 15 in the alendronate-alone group (n = 70). There was no difference between the mean values of serum calcium, serum phosphate or 24-hour urinary calcium between the treatment groups.

The effect of the lowest dosage of alendronic acid/cholecalciferol (70 mg alendronate/2 800 IU of vitamin D3) with the addition of 2 800 IU of vitamin D3, for a total of 5 600 IU (amount of vitamin D3 in the highest strength of Alendronic acid/Vitamin D3 once weekly was demonstrated during a study extension of 24 weeks, in 619 women with post-menopausal osteoporosis. Patients in the 2 800 IU of vitamin D3 received alendronic acid/cholecalciferol (70 mg/2 800 IU) (n = 299) and patients in the 5 600 IU of vitamin D3 received alendronic acid/cholecalciferol (70 mg/2 800 IU) with the addition of 2 800 IU of vitamin D3 (n = 309) once weekly; supplementary vitamin D intake was permitted. After 24 weeks of treatment, mean serum 25-hydroxyvitamin D levels were significantly higher in the 5 600 IU of vitamin D3 (69 nmol/l, i.e. 27,6 ng/ml) than in the 2 800 IU of vitamin D3 (64 nmol/l, i.e. 25,5 ng/ml). The percentage of patients with vitamin D insufficiency was 5,4% in the 2 800 IU of vitamin D3 versus 3,2% in the 5 600 IU of vitamin D3 during the study extension of 24 weeks. The percentage of patients with vitamin D deficiency was 0,3% in the 2 800 IU of vitamin D3 versus zero in the 5 600 IU of vitamin D3. There was no difference between the mean values of serum calcium, serum phosphorus or urinary calcium over 24 hours between treatment groups. The percentage of patients with hypercalciuria at the end of the 24-week extension period was not statistically different between treatment groups.

Alendronate studies

The therapeutic equivalence of alendronate 70 mg once weekly (n = 519) and alendronate 10 mg/day (n = 370) was demonstrated in a multicentre study lasting 1 year in postmenopausal women with osteoporosis. Mean increases in BMD at the lumbar spine at 1 year, compared with baseline values, were 5,1% (CI 95%: 4,8%-5,4%) in the alendronate 70 mg once weekly group and 5,4% (CI 95%: 5,0%-5,8%) in the alendronate 10 mg/day group. Mean increases in BMD in the 70 mg once weekly group and the 10 mg once daily group were 2,3% and 2,9% respectively at the femoral neck, and 2,9% and 3,1% respectively at the hip (femoral neck and trochanter). The two treatment groups were also similar in terms of BMD increase at the other skeletal sites.

The effects of alendronate on bone mass and fracture incidence in postmenopausal women were analysed in two initial efficacy studies, using an identical protocol (n = 994), as well as in the FIT (Fracture Intervention Trial) study (n = 6 459).

In the initial efficacy studies, alendronate at a dose of 10 mg per day produced mean increases in BMD at the spine, femoral neck and trochanter of 8,8%, 5,9% and 7,8% respectively at 3 years, compared with placebo. Whole-body BMD also increased significantly. There was a 48% reduction in the proportion of patients with one or more vertebral fractures in the alendronate group compared with the placebo group (alendronate 3,2% and placebo 6,2%). In the extension to 2 years of these studies, BMD at the spine and trochanter continued to increase, and BMD at the femoral neck and whole body was maintained.

The FIT trial comprised two controlled studies versus placebo with daily alendronate (5 mg per day for 2 years and 10 mg per day for one or two additional years):

• FIT 1: A 3-year study in 2 027 patients with at least one vertebral (compression) fracture at baseline. In this study, daily alendronate administration reduced the incidence of at least one new vertebral fracture by 47% (alendronate 7,9% versus placebo 15,0%). In addition, a statistically significant reduction was observed in the incidence of hip fractures (1,1% versus 2,2%, i.e. a reduction of 51%).
• FIT 2: A 4-year study in 4 432 patients with low bone mass but without vertebral fracture at baseline. In this study, in the analysis of the subgroup of osteoporotic women (37% of the overall population who met the above definition of osteoporosis), a significant difference was observed in the incidence of hip fractures (alendronate 1,0% versus placebo 2,2%, i.e. a reduction of 56%) and in the incidence of at least one vertebral fracture (2,9% versus 5,8%, i.e. a reduction of 50%).

Laboratory test results

In clinical studies, asymptomatic, mild and transient decreases in serum calcium and serum phosphorus were observed in approximately 18% and 10% respectively of patients taking alendronate 10 mg/day, compared with approximately 12% and 3% of patients taking placebo. However, the incidences of decreases in serum calcium to a level < 8,0 mg/dl (2,0 mmol/l) and of serum phosphorus to a level ≤ to 2,0 mg/dl (0,65 mmol/l) were similar in both treatment groups.

Paediatric population

Monosodium alendronate has been studied in a small number of patients under the age of 18 years with osteogenesis imperfecta. The results are insufficient to support its use in children with osteogenesis imperfecta.

Alendronate

Absorption

Compared with an intravenous reference dose, the mean oral bioavailability of alendronate in women is approximately 0,64% for doses ranging from 5 to 70 mg when administered fasting after an overnight fast and two hours before a normal breakfast. When alendronate is administered one hour or half an hour before a normal breakfast, bioavailability is similarly reduced, estimated at 0,46% and 0,39% respectively. In studies in osteoporosis, alendronate was effective when administered at least 30 minutes before the first food or drink of the day.

The alendronate in ALENDRONIC ACID/CHOLECALCIFEROL (VITAMIN D3) CRISTERS (70 mg/5600 IU) tablet (combination) is bioequivalent to the 70 mg alendronate tablet.

Bioavailability was almost nil when alendronate was administered during a normal breakfast or within two hours after it. Concomitant administration of alendronate with coffee or orange juice reduced its bioavailability by approximately 60 %.

In healthy subjects, oral administration of prednisone (20 mg given 3 times a day for 5 days) did not produce any clinically significant change in the oral bioavailability of alendronate (mean increase between 20 % and 44 %).

Distribution

Studies in rats at an intravenous dose of 1 mg/kg show that alendronate, initially distributed into soft tissues, is then rapidly redistributed to bone or excreted in the urine. The mean volume of distribution at equilibrium, excluding bone volume, is at least 28 L in humans. After administration of alendronate per os at therapeutic doses, plasma concentrations are too low to permit analytical detection (< 5 ng/ml). Plasma protein binding in humans is approximately 78 %.

Biotransformation

Nothing suggests that alendronate is metabolised in animals or in humans.

Elimination

Following intravenous administration of a single dose of alendronate labelled with [14C], approximately 50 % of the radioactivity is excreted in the urine within 72 hours. Little or no radioactivity is found in the faeces. Following a single intravenous dose of 10 mg, the renal clearance of alendronate is 71 ml/min, and systemic clearance does not exceed 200 ml/min. Plasma concentrations decrease by more than 95 % within 6 hours following intravenous administration. The terminal half-life in humans is estimated to be greater than 10 years, reflecting the release of alendronate from the skeleton. In rats, alendronate is not excreted by the renal acidic or basic transport systems. Therefore, alendronate is not expected to interfere with other medicinal substances on this excretion system in humans.

Cholecalciferol

Absorption

In healthy adult subjects (men and women), after administration of alendronic acid/cholecalciferol 70 mg/5 600 IU tablets fasted overnight and two hours before a meal, the mean area under the serum concentration-time curve (AUC0-80 hours) of vitamin D3 (unadjusted levels of endogenous vitamin D3 ) was 490,2 ng.h/ml. The mean maximum serum concentration (Cmax) of vitamin D3 was 12,2 ng/ml, and the median time to reach maximum serum concentration (Tmax) was 10,6 hours. The bioavailability of 5 600 IU of vitamin D3 contained in 70 mg/5 600 IU of alendronic acid/cholecalciferol is similar to that of 5 600 IU of vitamin D3 administered alone.

Distribution

After absorption, vitamin D3 bound to chylomicrons enters the bloodstream. Vitamin D3 is rapidly distributed largely to the liver, where it is metabolised to 25-hydroxyvitamin D3, which is the main storage form. Smaller amounts are distributed to adipose and muscle tissue and stored there as vitamin D3 which will be released later into the circulation. The circulating form of vitamin D3 is bound to the vitamin D-binding protein.

Biotransformation

Vitamin D3 is rapidly metabolised in the liver by hydroxylation to 25-hydroxyvitamin D3 and then to 1,25-dihydroxyvitamin D3 in the kidney, which represents the biologically active form. Further hydroxylation occurs before elimination. A small percentage of vitamin D3 is glucuronoconjugated before elimination.

Elimination

When administering radioactive vitamin D to healthy subjects,3 the mean urinary elimination of radioactivity after 48 hours was 2,4 % and the mean faecal elimination of radioactivity after 4 days was 4,9 %. In both cases, the radioactivity eliminated was almost exclusively that of metabolites. The mean half-life of vitamin D3 in serum after administration of an oral dose of alendronic acid/cholecalciferol (70 mg/2 800 IU) is approximately 24 hours.

Renal impairment

Preclinical studies show that the fraction of alendronate that does not deposit in bone is rapidly excreted in the urine. In animals, no evidence of saturation of bone uptake was demonstrated after intravenous administration in prolonged treatment with repeated doses up to 35 mg/kg. Although no clinical data are available, it is likely that, as in animals, renal elimination of alendronate is decreased in patients with renal impairment. Consequently, a slightly higher accumulation of alendronate in bone may be expected in patients with renal impairment (see section Dosage and administration).

No non-clinical study has been performed with the combination of alendronate and cholecalciferol.

Alendronate

The non-clinical data reveal no particular risk for humans, based on conventional studies of safety pharmacology, repeated-dose toxicity, genotoxicity, and carcinogenesis. Studies in rats have shown that treatment with alendronate during pregnancy was associated with dystocia in the offspring at parturition, related to hypocalcaemia. In studies, administration of high doses to rats showed an increased incidence of incomplete foetal ossification. The risk for humans is unknown.

Cholecalciferol

At doses much higher than those used therapeutically in humans, reproductive toxicity was observed in animals.

2 years.

Store in the original package, protected from moisture and light.

No special requirements for disposal.

List I

Marketing authorisation (AMM)

CIP 3400930109656 (Blister/4). CIP 3400930109663 (Blister/12).

Price:

5,85 euros (Blister/4). 15,75 euros (Blister/12).

Social Security reimbursement at 65% based on the TFR: 5.85 euros (Blister/4), 15.75 euros (Blister/12) in the indications:

• Post-menopausal osteoporosis (T-score <-2,5) in case of early menopause, fracture prevention treatment (Blister/4, Blister/12)
• Post-menopausal osteoporosis (T-score <-2,5) + family history of femoral neck fracture, fracture prevention treatment (Blister/4, Blister/12)
• Post-menopausal osteoporosis (T-score<-2,5) in women > 60 years, preventive treatment of fractures (Plq/4, Plq/12)
• Post-menopausal osteoporosis (T-score<-2,5) in case of corticosteroid therapy, preventive treatment of fractures (Plq/4, Plq/12)
• Post-menopausal osteoporosis, preventive treatment of fracture recurrence (of) (Plq/4, Plq/12)
• Post-menopausal osteoporosis (T-score<-3), preventive treatment of fractures (of) (Plq/4, Plq/12)
• Post-menopausal osteoporosis (T-score<-2,5) with a BMI < 19 kg/m2, preventive treatment of fractures (of) (Plq/4, Plq/12)

Collection.