ADROVANCE 70mg / 5600UI tablets medication leaflet

ADROVANCE 70 mg/2,800 IU tablets

ADROVANCE 70 mg/5,600 IU tablets

ADROVANCE 70 mg/2,800 IU tablets

Each tablet contains 70 mg alendronic acid (as sodium trihydrate) and 70 micrograms (2,800 IU)colecalciferol (vitamin D3).

Each tablet contains 62 mg lactose (as lactose anhydrous) and 8 mg sucrose.

ADROVANCE 70 mg/5,600 IU tablets

Each tablet contains 70 mg alendronic acid (as sodium trihydrate) and 140 micrograms (5,600 IU)colecalciferol (vitamin D3).

Each tablet contains 63 mg lactose (as lactose anhydrous) and 16 mg sucrose.

For the full list of excipients, see section 6.1.

Tablet

ADROVANCE 70 mg/2,800 IU tablets

Modified capsule-shaped, white to off-white tablets, marked with an outline of a bone image on oneside, and '710' on the other.

ADROVANCE 70 mg/5,600 IU tablets

Modified rectangle-shaped, white to off-white tablets, marked with an outline of a bone image on oneside, and '270' on the other.

ADROVANCE is indicated for the treatment of postmenopausal osteoporosis in women at risk ofvitamin D insufficiency. It reduces the risk of vertebral and hip fractures.

The recommended dose is one tablet once weekly.

Patients should be instructed that if they miss a dose of ADROVANCE they should take one tablet onthe morning after they remember. They should not take two tablets on the same day but should returnto taking one tablet once a week, as originally scheduled on their chosen day.

Due to the nature of the disease process in osteoporosis, ADROVANCE is intended for long-term use.

The optimal duration of bisphosphonate treatment for osteoporosis has not been established. The needfor continued treatment should be re-evaluated periodically based on the benefits and potential risks of

ADROVANCE on an individual patient basis, particularly after 5 or more years of use.

Patients should receive supplemental calcium if intake from diet is inadequate (see section 4.4).

Additional supplementation with vitamin D should be considered on an individual basis taking intoaccount any vitamin D intake from vitamins and dietary supplements.

ADROVANCE 70 mg/2,800 IU tablets

The equivalence of intake of 2,800 IU of vitamin D3 weekly in ADROVANCE to daily dosing ofvitamin D 400 IU has not been studied.

ADROVANCE 70 mg/5,600 IU tablets

The equivalence of intake of 5,600 IU of vitamin D3 weekly in ADROVANCE to daily dosing ofvitamin D 800 IU has not been studied.

In clinical studies there was no age-related difference in the efficacy or safety profiles of alendronate.

Therefore no dose adjustment is necessary for the elderly.

ADROVANCE is not recommended for patients with renal impairment where creatinine clearance isless than 35 ml/min, due to lack of experience. No dose adjustment is necessary for patients with acreatinine clearance greater than 35 ml/min.

The safety and efficacy of ADROVANCE in children less than 18 years of age have not beenestablished. This medicinal product should not be used in children less than 18 years of age because nodata are available for the alendronic acid/colecalciferol combination. Currently available data foralendronic acid in the paediatric population is described in section 5.1.

Oral use.

To permit adequate absorption of alendronate:

ADROVANCE must be taken with water only (not mineral water) at least 30 minutes before the firstfood, beverage, or medicinal product (including antacids, calcium supplements and vitamins) of theday. Other beverages (including mineral water), food and some medicinal products are likely to reducethe absorption of alendronate (see section 4.5 and section 4.8).

The following instructions should be followed exactly in order to minimise the risk of oesophagealirritation and related adverse reactions (see section 4.4):

* ADROVANCE should only be swallowed after getting up for the day with a full glass of water(not less than 200 ml).

* Patients should only swallow ADROVANCE whole. Patients should not crush or chew thetablet or allow the tablet to dissolve in their mouths because of a potential for oropharyngealulceration.

* Patients should not lie down for at least 30 minutes after taking ADROVANCE and until afterthe first food of the day.

* ADROVANCE should not be taken at bedtime or before arising for the day.

- Hypersensitivity to the active substances or to any of the excipients listed in section 6.1.

- Abnormalities of the oesophagus and other factors which delay oesophageal emptying such asstricture or achalasia.

- Inability to stand or sit upright for at least 30 minutes.

- Hypocalcaemia.

Alendronate

Upper gastrointestinal adverse reactions

Alendronate can cause local irritation of the upper gastrointestinal mucosa. Because there is a potentialfor worsening of the underlying disease, caution should be used when alendronate is given to patientswith active upper gastrointestinal problems, such as dysphagia, oesophageal disease, gastritis,duodenitis, ulcers, or with a recent history (within the previous year) of major gastrointestinal diseasesuch as peptic ulcer, or active gastrointestinal bleeding, or surgery of the upper gastrointestinal tractother than pyloroplasty (see section 4.3). In patients with known Barrett's oesophagus, prescribersshould consider the benefits and potential risks of alendronate on an individual patient basis.

Oesophageal reactions (sometimes severe and requiring hospitalisation), such as oesophagitis,oesophageal ulcers and oesophageal erosions, rarely followed by oesophageal stricture, have beenreported in patients receiving alendronate. Physicians should therefore be alert to any signs orsymptoms signalling a possible oesophageal reaction and patients should be instructed to discontinuealendronate and seek medical attention if they develop symptoms of oesophageal irritation such asdysphagia, pain on swallowing or retrosternal pain or new or worsening heartburn (see section 4.8).

The risk of severe oesophageal adverse reactions appears to be greater in patients who fail to takealendronate properly and/or who continue to take alendronate after developing symptoms suggestiveof oesophageal irritation. It is very important that the full dosing instructions are provided to, and areunderstood by the patient (see section 4.2). Patients should be informed that failure to follow theseinstructions may increase their risk of oesophageal problems.

While no increased risk was observed in extensive clinical trials with alendronate, there have been rare(post-marketing) reports of gastric and duodenal ulcers, some of which were severe and withcomplications (see section 4.8).

Osteonecrosis of the jaw, generally associated with tooth extraction and/or local infection (includingosteomyelitis), has been reported in patients with cancer who are receiving treatment regimensincluding primarily intravenously administered bisphosphonates. Many of these patients were alsoreceiving chemotherapy and corticosteroids. Osteonecrosis of the jaw has also been reported inpatients with osteoporosis receiving oral bisphosphonates.

The following risk factors should be considered when evaluating an individual’s risk of developingosteonecrosis of the jaw:

* potency of the bisphosphonate (highest for zoledronic acid), route of administration (see above)and cumulative dose

* cancer, chemotherapy, radiotherapy, corticosteroids, angiogenesis inhibitors, smoking

* a history of dental disease, poor oral hygiene, periodontal disease, invasive dental proceduresand poorly fitting dentures

A dental examination with appropriate preventive dentistry should be considered prior to treatmentwith oral bisphosphonates in patients with poor dental status.

While on treatment, these patients should avoid invasive dental procedures if possible. For patientswho develop osteonecrosis of the jaw while on bisphosphonate therapy, dental surgery may exacerbatethe condition. For patients requiring dental procedures, there are no data available to suggest whetherdiscontinuation of bisphosphonate treatment reduces the risk of osteonecrosis of the jaw. Clinicaljudgement of the treating physician should guide the management plan of each patient based onindividual benefit/risk assessment.

During bisphosphonate treatment, all patients should be encouraged to maintain good oral hygiene,receive routine dental check-ups, and report any oral symptoms such as dental mobility, pain, orswelling.

Osteonecrosis of the external auditory canal

Osteonecrosis of the external auditory canal has been reported with bisphosphonates, mainly inassociation with long-term therapy. Possible risk factors for osteonecrosis of the external auditorycanal include steroid use and chemotherapy and/or local risk factors such as infection or trauma. Thepossibility of osteonecrosis of the external auditory canal should be considered in patients receivingbisphosphonates who present with ear symptoms such as pain or discharge, or chronic ear infections.

Musculoskeletal pain

Bone, joint, and/or muscle pain has been reported in patients taking bisphosphonates. Inpost-marketing experience, these symptoms have rarely been severe and/or incapacitating (seesection 4.8). The time to onset of symptoms varied from one day to several months after startingtreatment. Most patients had relief of symptoms after stopping treatment. A subset had recurrence ofsymptoms when rechallenged with the same medicinal product or another bisphosphonate.

Atypical fractures of the femur

Atypical subtrochanteric and diaphyseal femoral fractures have been reported with bisphosphonatetherapy, primarily in patients receiving long-term treatment for osteoporosis. These transverse or shortoblique, fractures can occur anywhere along the femur from just below the lesser trochanter to justabove the supracondylar flare. These fractures occur after minimal or no trauma and some patientsexperience thigh or groin pain, often associated with imaging features of stress fractures, weeks tomonths before presenting with a completed femoral fracture. Fractures are often bilateral; therefore thecontralateral femur should be examined in bisphosphonate-treated patients who have sustained afemoral shaft fracture. Poor healing of these fractures has also been reported. Discontinuation ofbisphosphonate therapy in patients suspected to have an atypical femur fracture should be consideredpending 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 andany patient presenting with such symptoms should be evaluated for an incomplete femur fracture.

ADROVANCE is not recommended for patients with renal impairment where creatinine clearance isless than 35 ml/min (see section 4.2).

Bone and mineral metabolism

Causes of osteoporosis other than oestrogen deficiency and ageing should be considered.

Hypocalcaemia must be corrected before initiating therapy with ADROVANCE (see section 4.3).

Other disorders affecting mineral metabolism (such as vitamin D deficiency and hypoparathyroidism)should also be effectively treated before starting this medicinal product. The content of vitamin D in

ADROVANCE is not suitable for correction of vitamin D deficiency. In patients with theseconditions, serum calcium and symptoms of hypocalcaemia should be monitored during therapy with

ADROVANCE.

Due to the positive effects of alendronate in increasing bone mineral, decreases in serum calcium andphosphate may occur especially in patients taking glucocorticoids in whom calcium absorption may bedecreased. These are usually small and asymptomatic. However, there have been rare reports ofsymptomatic hypocalcaemia, which have occasionally been severe and often occurred in patients withpredisposing conditions (e.g. hypoparathyroidism, vitamin D deficiency and calcium malabsorption)(see section 4.8).

Colecalciferol

Vitamin D3 may increase the magnitude of hypercalcaemia and/or hypercalciuria when administered topatients with disease associated with unregulated overproduction of calcitriol (e.g. leukaemia,lymphoma, sarcoidosis). Urine and serum calcium should be monitored in these patients.

Patients with malabsorption may not adequately absorb vitamin D3.

This medicinal product contains lactose and sucrose. Patients with rare hereditary problems of fructoseintolerance, galactose intolerance, total lactase deficiency, glucose-galactose malabsorption or sucrase-isomaltase insufficiency should not take this medicinal product.

This medicinal product contains less than 1 mmol sodium (23 mg) per tablet, that is to say essentially‘sodium-free’.

Alendronate

If taken at the same time, it is likely that food and beverages (including mineral water), calciumsupplements, antacids, and some oral medicinal products will interfere with absorption of alendronate.

Therefore, patients must wait at least 30 minutes after taking alendronate before taking any other oralmedicinal product (see sections 4.2 and 5.2).

Since Non Steroidal Anti-Inflammatory Drug (NSAID) use is associated with gastrointestinalirritation, caution should be used during concomitant use with alendronate.

Colecalciferol

Olestra, mineral oils, orlistat, and bile acid sequestrants (e.g. cholestyramine, colestipol) may impairthe absorption of vitamin D.

Anticonvulsants, cimetidine and thiazides may increase the catabolism of vitamin D. Additionalvitamin D supplements may be considered on an individual basis.

ADROVANCE is only intended for use in postmenopausal women and therefore it should not be usedduring pregnancy or in breast-feeding women.

There are no or limited amount of data from the use of alendronate in pregnant women. Studies inanimals have shown reproductive toxicity. Alendronate given during pregnancy in rats caused dystociarelated to hypocalcaemia (see section 5.3). Studies in animals have shown hypercalcaemia andreproductive toxicity with high doses of vitamin D (see section 5.3). ADROVANCE should not beused during pregnancy.

It is unknown whether alendronate/metabolites are excreted in human milk. A risk to thenewborns/infants cannot be excluded. Colecalciferol and some of its active metabolites pass intobreast milk. ADROVANCE should not be used during breast-feeding.

Bisphosphonates are incorporated into the bone matrix, from which they are gradually released over aperiod of years. The amount of bisphosphonate incorporated into adult bone, and hence, the amountavailable for release back into the systemic circulation, is directly related to the dose and duration ofbisphosphonate use (see section 5.2). There are no data on foetal risk in humans. However, there is atheoretical risk of foetal harm, predominantly skeletal, if a woman becomes pregnant after completinga course of bisphosphonate therapy. The impact of variables such as time between cessation ofbisphosphonate therapy to conception, the particular bisphosphonate used, and the route ofadministration (intravenous versus oral) on the risk has not been studied.

ADROVANCE has no or negligible direct influence on the ability to drive and use machines. Patientsmay experience certain adverse reactions (for example blurred vision, dizziness and severe bonemuscle or joint pain (see section 4.8)) that may influence the ability to drive and use machines.

The most commonly reported adverse reactions are upper gastrointestinal adverse reactions includingabdominal pain, dyspepsia, oesophageal ulcer, dysphagia, abdominal distension and acid regurgitation(> 1 %).

The following adverse reactions have been reported during clinical studies and/or post-marketing usewith alendronate.

No additional adverse reactions have been identified for the combination of alendronate andcolecalciferol.

Frequencies are defined as: 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).

System organ class Frequency Adverse reactions

Immune system disorders Rare hypersensitivity reactions including urticaria andangioedema

Metabolism and nutrition Rare symptomatic hypocalcaemia, often in associationdisorders with predisposing conditions§

Nervous system disorders Common headache, dizziness†

Uncommon dysgeusia†

Eye disorders Uncommon eye inflammation (uveitis, scleritis, or episcleritis)

Ear and labyrinth Common vertigo†disorders Very rare osteonecrosis of the external auditory canal(bisphosphonate class adverse reaction)

Gastrointestinal disorders Common abdominal pain, dyspepsia, constipation, diarrhoea,flatulence, oesophageal ulcer*, dysphagia*,abdominal distension, acid regurgitation

Uncommon nausea, vomiting, gastritis, oesophagitis*,oesophageal erosions*, melena†

Rare oesophageal stricture*, oropharyngeal ulceration*,upper gastrointestinal PUBs (perforation, ulcers,bleeding)§

Skin and subcutaneous Common alopecia†, pruritus†tissue disorders Uncommon rash, erythema

Rare rash with photosensitivity, severe skin reactionsincluding Stevens-Johnson syndrome and toxicepidermal necrolysis‡

Musculoskeletal and Very common musculoskeletal (bone, muscle or joint) pain which isconnective tissue disorders sometimes severe†§

Common joint swelling†

Rare osteonecrosis of the jaw‡§, atypical subtrochantericand diaphyseal femoral fractures (bisphosphonateclass adverse reaction)

General disorders and Common asthenia†, peripheral oedema†administration site Uncommon transient symptoms as in an acute-phase responseconditions (myalgia, malaise and rarely, fever), typically inassociation with initiation of treatment†§See section 4.4†Frequency in Clinical Trials was similar in the medicinal product and placebo group.

*See sections 4.2 and 4.4‡This adverse reaction was identified through post-marketing surveillance. The frequency of rare wasestimated based on relevant clinical trials.

Reporting suspected adverse reactions after authorisation of the medicinal product is important. Itallows continued monitoring of the benefit/risk balance of the medicinal product. Healthcareprofessionals are asked to report any suspected adverse reactions via the national reporting systemlisted in Appendix V.

Alendronate

Hypocalcaemia, hypophosphataemia and upper gastrointestinal adverse reactions, such as upsetstomach, heartburn, oesophagitis, gastritis, or ulcer, may result from oral overdose.

No specific information is available on the treatment of overdose with alendronate. In case of overdosewith ADROVANCE, milk or antacids should be given to bind alendronate. Owing to the risk ofoesophageal irritation, vomiting should not be induced and the patient should remain fully upright.

Colecalciferol

Vitamin D toxicity has not been documented during chronic therapy in generally healthy adults at adose less than 10,000 IU/day. In a clinical study of healthy adults a 4,000 IU daily dose of vitamin D3for up to five months was not associated with hypercalciuria or hypercalcaemia.

Pharmacotherapeutic group: Drugs for treatment of bone diseases, Bisphosphonates, combinations,

ATC code: M05BB03

Alendronate

Alendronate sodium is a bisphosphonate that inhibits osteoclastic bone resorption with no direct effecton bone formation. Preclinical studies have shown preferential localisation of alendronate to sites ofactive resorption. Activity of osteoclasts is inhibited, but recruitment or attachment of osteoclasts isnot affected. The bone formed during treatment with alendronate is of normal quality.

Colecalciferol (vitamin D3)

Vitamin D3 is produced in the skin by conversion of 7-dehydrocholesterol to vitamin D3 by ultravioletlight. In the absence of adequate sunlight exposure, vitamin D3 is an essential dietary nutrient.

Vitamin D3 is converted to 25-hydroxyvitamin D3 in the liver, and stored until needed. Conversion tothe active calcium-mobilising hormone 1,25-dihydroxyvitamin D3 (calcitriol) in the kidney is tightlyregulated. The principal action of 1,25-dihydroxyvitamin D3 is to increase intestinal absorption of bothcalcium and phosphate as well as regulate serum calcium, renal calcium and phosphate excretion, boneformation and bone resorption.

Vitamin D3 is required for normal bone formation. Vitamin D insufficiency develops when bothsunlight exposure and dietary intake are inadequate. Insufficiency is associated with negative calciumbalance, bone loss, and increased risk of skeletal fracture. In severe cases, deficiency results insecondary hyperparathyroidism, hypophosphataemia, proximal muscle weakness and osteomalacia,further increasing the risk of falls and fractures in osteoporotic individuals. Supplemental vitamin Dreduces these risks and their consequences.

Osteoporosis is defined as bone mineral density (BMD) of the spine or hip 2.5 standard deviations(SD) below the mean value of a normal young population or as a previous fragility fracture,irrespective of BMD.

ADROVANCE studies

The effect of the lower dose of ADROVANCE (alendronate 70 mg/vitamin D3 2,800 IU) on vitamin Dstatus was demonstrated in a 15-week, multinational study that enrolled 682 osteoporotic post-menopausal women (serum 25-hydroxyvitamin D at baseline: mean, 56 nmol/l [22.3 ng/ml]; range,22.5-225 nmol/l [9-90 ng/ml]). Patients received the lower strength (70 mg/2,800 IU) of

ADROVANCE (n=350) or FOSAMAX (alendronate) 70 mg (n=332) once a week; additionalvitamin D supplements were prohibited. After 15 weeks of treatment, the mean serum25-hydroxyvitamin D levels were significantly higher (26 %) in the ADROVANCE (70 mg/2,800 IU)group (56 nmol/l [23 ng/ml]) than in the alendronate-only group (46 nmol/l [18.2 ng/ml]). Thepercentage of patients with vitamin D insufficiency (serum 25-hydroxyvitamin D < 37.5 nmol/l[< 15 ng/ml]) was significantly reduced by 62.5 % with ADROVANCE (70 mg/2,800 IU) vs.alendronate-only (12 % vs. 32 %, respectively), through week 15. The percentage of patients withvitamin D deficiency (serum 25-hydroxyvitamin D < 22.5 nmol/l [< 9 ng/ml]) was significantlyreduced by 92 % with ADROVANCE (70 mg/2,800 IU) vs. alendronate-only (1 % vs 13 %,respectively). In this study, mean 25-hydroxyvitamin D levels in patients with vitamin D insufficiencyat baseline (25-hydroxyvitamin D, 22.5 to 37.5 nmol/l [9 to < 15 ng/ml]) increased from 30 nmol/l(12.1 ng/ml) to 40 nmol/l (15.9 ng/ml) at week 15 in the ADROVANCE (70 mg/2,800 IU) group(n=75) and decreased from 30 nmol/l (12.0 ng/ml) at baseline to 26 nmol/l (10.4 ng/ml) at week 15 inthe alendronate-only group (n=70). There were no differences in mean serum calcium, phosphate, or24-hour urine calcium between treatment groups.

The effect of the lower dose of ADROVANCE (alendronate 70 mg/vitamin D3 2,800 IU) plus anadditional 2,800 IU Vitamin D3 for a total of 5,600 IU (the amount of vitamin D3 in the higher dose of

ADROVANCE) once weekly was demonstrated in a 24-week, extension study that enrolled619 osteoporotic post-menopausal women. Patients in the Vitamin D3 2,800 group received

ADROVANCE (70 mg/2,800 IU) (n=299) and patients in the Vitamin D3 5,600 group received

ADROVANCE (70 mg/2,800 IU) plus an additional 2,800 IU vitamin D3 (n=309) once a week;additional vitamin D supplements were allowed. After 24-weeks of treatment, the mean serum25-hydroxyvitamin D levels were significantly higher in the Vitamin D3 5,600 group (69 nmol/l[27.6 ng/ml]) than in the Vitamin D3 2,800 group (64 nmol/l [25.5 ng/ml]). The percentage of patientswith vitamin D insufficiency was 5.4 % in the Vitamin D3 2,800 group vs. 3.2 % in the Vitamin D35,600 group through the 24-week extension. The percentage of patients with vitamin D deficiency was0.3 % in the Vitamin D3 2,800 group vs. zero in the Vitamin D3 5,600 group. There were nodifferences in mean serum calcium, phosphate, or 24-hour urine calcium between treatment groups.

The percentage of patients with hypercalciuria at the end of the 24-week extension was not statisticallydifferent between treatment groups.

Alendronate studies

The therapeutic equivalence of alendronate once weekly 70 mg (n=519) and alendronate 10 mg daily(n=370) was demonstrated in a one-year multicentre study of post-menopausal women withosteoporosis. 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 dailygroup. The mean BMD increases were 2.3 % and 2.9 % at the femoral neck and 2.9 % and 3.1 % at thetotal hip in the 70 mg once weekly and 10 mg daily groups, respectively. The two treatment groupswere 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 wereexamined 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 BMD increases with alendronate 10 mg/day relative to placeboat 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 % vsplacebo 6.2 %) in the proportion of patients treated with alendronate experiencing one or morevertebral 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 bodywere maintained.

FIT consisted of two placebo-controlled studies using alendronate daily (5 mg daily for two years and10 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 newvertebral fracture by 47 % (alendronate 7.9 % vs. placebo 15.0 %). In addition, a statisticallysignificant reduction was found in the incidence of hip fractures (1.1 % vs. 2.2 %, a reduction of51 %).

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

Laboratory test findings

In clinical studies, asymptomatic, mild and transient decreases in serum calcium and phosphate wereobserved in approximately 18 % and 10 %, respectively, of patients taking alendronate 10 mg/dayversus approximately 12 % and 3 % of those taking placebo. However, the incidences of decreases inserum calcium to < 8.0 mg/dl (2.0 mmol/l) and serum phosphate to ≤ 2.0 mg/dl (0.65 mmol/l) weresimilar in both treatment groups.

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

Alendronate

Relative to an intravenous reference dose, the oral mean bioavailability of alendronate in women was0.64 % for doses ranging from 5 to 70 mg when administered after an overnight fast and two hoursbefore a standardised breakfast. Bioavailability was decreased similarly to an estimated 0.46 % and0.39 % when alendronate was administered one hour or half an hour before a standardised breakfast.

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

The alendronate component in the ADROVANCE (70 mg/2,800 IU) combination tablet and the

ADROVANCE (70 mg/5,600 IU) combination tablet is bioequivalent to the alendronate 70 mg tablet.

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

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

Studies in rats show that alendronate transiently distributes to soft tissues following 1 mg/kgintravenous administration but is then rapidly redistributed to bone or excreted in the urine. The meansteady-state volume of distribution, exclusive of bone, is at least 28 litres in humans. Concentrations ofalendronate in plasma following therapeutic oral doses are too low for analytical detection (< 5 ng/ml).

Protein binding in human plasma is approximately 78 %.

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

Following a single intravenous dose of [14C]alendronate, approximately 50 % of the radioactivity wasexcreted 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, andsystemic clearance did not exceed 200 ml/min. Plasma concentrations fell by more than 95 % withinsix hours following intravenous administration. The terminal half-life in humans is estimated toexceed ten years, reflecting release of alendronate from the skeleton. Alendronate is not excretedthrough the acidic or basic transport systems of the kidney in rats, and thus it is not anticipated tointerfere with the excretion of other medicinal products by those systems in humans.

Colecalciferol

In healthy adult subjects (males and females), following administration of ADROVANCE70 mg/2,800 IU tablets after an overnight fast and two hours before a meal, the mean area under theserum-concentration-time curve (AUC0-120 hrs) for vitamin D3 (unadjusted for endogenous vitamin D3levels) was 296.4 ng*hr/ml. The mean maximal serum concentration (Cmax) of vitamin D3 was5.9 ng/ml, and the median time to maximal serum concentration (Tmax) was 12 hours. Thebioavailability of the 2,800 IU vitamin D3 in ADROVANCE is similar to 2,800 IU vitamin D3administered alone.

In healthy adult subjects (males and females), following administration of ADROVANCE70 mg/5,600 IU after an overnight fast and two hours before a meal, the mean area under the serum-concentration-time curve (AUC0-80 hrs) for vitamin D3 (unadjusted for endogenous vitamin D3 levels)was 490.2 ng*hr/ml. The mean maximal serum concentration (Cmax) of vitamin D3 was 12.2 ng/ml andthe median time to maximal serum concentration (Tmax) was 10.6 hours. The bioavailability of the5,600 IU vitamin D3 in ADROVANCE is similar to 5,600 IU vitamin D3 administered alone.

Following absorption, vitamin D3 enters the blood as part of chylomicrons. Vitamin D3 is rapidlydistributed mostly to the liver where it undergoes metabolism to 25-hydroxyvitamin D3, the majorstorage form. Lesser amounts are distributed to adipose and muscle tissue and stored as vitamin D3 atthese sites for later release into the circulation. Circulating vitamin D3 is bound to vitamin D-bindingprotein.

Vitamin D3 is rapidly metabolised by hydroxylation in the liver to 25-hydroxyvitamin D3, andsubsequently metabolised in the kidney to 1,25-dihydroxyvitamin D3, which represents thebiologically active form. Further hydroxylation occurs prior to elimination. A small percentage ofvitamin D3 undergoes glucuronidation prior to elimination.

When radioactive vitamin D3 was administered to healthy subjects, the mean urinary excretion ofradioactivity after 48 hours was 2.4 %, and the mean faecal excretion of radioactivity after 4 days was4.9 %. In both cases, the excreted radioactivity was almost exclusively as metabolites of the parent.

The mean half-life of vitamin D3 in the serum following an oral dose of ADROVANCE(70 mg/2,800 IU) is approximately 24 hours.

Preclinical studies show that alendronate 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 intravenousdoses up to 35 mg/kg in animals. Although no clinical information is available, it is likely that, as inanimals, elimination of alendronate via the kidney will be reduced in patients with impaired renalfunction. Therefore, somewhat greater accumulation of alendronate in bone might be expected inpatients with impaired renal function (see section 4.2).

Non-clinical studies with the combination of alendronate and colecalciferol have not been conducted.

Alendronate

Non-clinical data reveal no special hazard for humans based on conventional studies of safetypharmacology, repeated dose toxicity, genotoxicity and carcinogenic potential. Studies in rats haveshown that treatment with alendronate during pregnancy was associated with dystocia in dams duringparturition which was related to hypocalcaemia. In studies, rats given high doses showed an increasedincidence of incomplete foetal ossification. The relevance to humans is unknown.

Colecalciferol

At doses far higher than the human therapeutic range, reproductive toxicity has been observed inanimal studies.

Microcrystalline cellulose (E460)

Lactose anhydrous

Medium chain triglycerides

Gelatin

Croscarmellose sodium

Sucrose

Colloidal silicon dioxide

Magnesium stearate (E572)

Butylhydroxytoluene (E321)

Modified starch (maize)

Sodium aluminium silicate (E554)

Not applicable.

18 months.

Store in the original blister in order to protect from moisture and light.

ADROVANCE 70 mg/2,800 IU tablets

Aluminium/aluminium blisters, in cartons containing 2, 4, 6 or 12 tablets.

ADROVANCE 70 mg/5,600 IU tablets

Aluminium/aluminium blisters, in cartons containing 2, 4 or 12 tablets.

Not all pack sizes may be marketed.

No special requirements.

N.V. Organon

Kloosterstraat 65349 AB Oss

The Netherlands

ADROVANCE 70 mg/2,800 IU tablets

EU/1/06/364/001 - 2 tablets

EU/1/06/364/002 - 4 tablets

EU/1/06/364/003 - 6 tablets

EU/1/06/364/004 - 12 tablets

ADROVANCE 70 mg/5,600 IU tablets

EU/1/06/364/006 - 2 tablets

EU/1/06/364/007 - 4 tablets

EU/1/06/364/008 - 12 tablets

Date of first authorisation: 4 January 2007

Date of latest renewal: 21 November 2011

Detailed information on this medicinal product is available on the website of the European Medicines

Agency http://www.ema.europa.eu.