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________________________________________CGH Pharmacy & Therapeutics Committee__

ALENDRONATE / COLECALCIFEROL (FOSAMAX PLUS, MERCK & CO.)

This drug monograph is for Fosamax Plus

70 mg / 2800 units oral tablets, as officially applied for byAssocProf Lam Khee Sien (Senior Consultant, Dept of Orthopaedic Surgery)

INTRODUCTION

Osteoporosis is a disease affecting many millions of people around the world. It is characterizedby low bone mass and micro-architectural deterioration of bone tissue, leading to bone fragilityand a consequent increase in risk of fracture.1

Osteoporosis is likely to increase as the population of Singapore is aging rapidly. In 1990 only6% of the population was above the age of 65, but by 2030, this figure is projected to rise to19%.2 Hence, it is important to consistently strive for more effective management ofosteoporosis, to decrease the related morbidity.

Fosamax Plus

is a combination product of alendronate and colecalciferol. Alendronate isavailable in CGH as a once-weekly 70 mg-tablet and a once-daily 10 mg-tablet. Vitamin D is

available mainly in combination with calcium carbonate.

PHARMACOKINETICS3-7

Oral bioavailability of alendronate is poor. Only about 0.64% of the dose is absorbed even afteran overnight fast and 2 hours before a standardised meal. Bioavailabilty decreases with food, butin osteoporosis studies, alendronate was effective when administered at least 30 minutes beforethe first food or beverage of the day. Colecalciferol (Vitamin D3) is well absorbed with or withoutfood. Absorption is impaired in the presence of biliary or hepatic dysfunction or fat malabsorptionsyndromes.5

Alendronate transiently distributes to soft tissues but is then rapidly redistributed to bone or

excreted in the urine. It adheres to bone surface, with preferential localisation at resorptive sitesof active bone turnover. Protein binding is approximately 78%. Vitamin D3 distributed rapidlymostly to the liver where it undergoes metabolism to 25-hydroxyvitamin D3, the major storageform. Circulating Vitamin D3 is bound to vitamin D-binding protein.

There is no evidence that alendronate is metabolised. Colecalciferol is converted to 25-hydroxyvitamin D3 in the liver. Further conversion to its active form, calcitriol (1,25-dihydroxyvitamin D3) takes place in the kidney. Patients with impaired renal function and hepaticfunction may exhibit a decreased ability to form the active metabolite.

Alendronate that is not retained in bones is renally cleared. Elimination half-life is up to 10 yearsfor alendronate bound to bones. Colecalciferol is excreted in the urine and faeces as metabolites.Storage and slow release of colecalciferol from tissues occurs, and the terminal half-life may

exceed 3 weeks.

There is no published pharmacokinetic equivalence study done on Fosamax Plus

. However,data on file shows that oral bioavailability of alendronate and colecalciferol in combination aresimilar to when they are administered separately.3,6,8

MECHANISM OF ACTION/PHARMACODYNAMICS

Alendronate sodium is a bisphosphonate that acts as a potent, specific inhibitor of osteoclast-mediated bone resorption. Bisphosphonates are synthetic analogues of pyrophosphate that bindto the hydroxyapatite found in bone.3 It decreases bone turnover and does not seem to impairbone quality in post-menopausal women with osteoporosis. Moreover, increases in bone mineraldensity (BMD) and bone strength associated with alendronate appear to be caused by increasedbone mineralisation rather than increased bone volume.6

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Colecalciferol is a secosterol that is the natural precursor of the calciumregulating hormonecalcitriol (1,25-dihydroxyvitamin D3).3 Colecalciferol is converted to 25-hydroxyvitamin D3 in theliver. Further conversion to its active form, calcitriol, takes place in the kidney. Conversion tocalcitriol is stimulated by PTH, oestrogen, hypocalcemia, and hypophosphatemia, and isregulated via negative feedback. Calcitriol increases intestinal absorption and renal reabsorption

of both calcium and phosphorous, increasing their serum concentration. To a smaller extent, thismay inhibit parathyroid hormone (PTH) secretion, thus inducing bone formation and reducingbone resorption.3,6 It had also been reported that Vitamin D increases lower-extremityneuromuscular function, thereby reducing the risk of falling.4

CLINICAL EFFICACY

In randomised controlled trials, alendronate demonstrates greater fracture risk reduction versusplacebo.9,10 For postmenopausal women with and without fractures at baseline, there was a 63%(p= 0.014) reduction in risk of hip fracture at 18 months, a 59% (p= 0.03) reduction in risk ofclinical vertebral fractures at 12 months, and a 90% (p


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osteoporosis who are home-bound or who are inadequately exposed to sunlight. This isdone without changing the anti-resorptive effects of once-weekly alendronate. Thesebeneficial effects may be more prominent for patients with serum 25-OHD of more than 9ng/ml at baseline, normal serum PTH and total alkaline phosphatase levels, and who aretaking daily calcium supplements.

TOLERABILITY3,6-7,15

The adverse effect profile of Fosamax Plus

comprises those observed with its individualcomponents. The incidence of treatment-related GI adverse events and discontinuation due totreatment-related adverse events were similar for patients taking the combination product oralendronate alone. Treatment-related upper GI adverse events were reported in 8.3% ofrecipients of the combination product as compared to 9.2% in those taking alendronate alone.

Local irritation of the upper GI mucosa and esophageal adverse experiences are possible sideeffects related to the alendronate component, especially if full administration instructions are notfollowed. Other safety concerns are localised osteonecrosis of the jaw that has been reportedrarely with oral bisphosphonates, and bone, joint, and/or muscle pain that have rarely been

severe and/or incapacitating, that may set in from one day to several months after startingtreatment.

Adverse events due to colecalciferol are mainly GI in nature (nausea, diarrhoea, and epigastricpain). Hypercalciuria and hypercalcemia related to the vitamin D3 component was rare.Nevertheless, urine and serum calcium should be monitored in patients with diseases associatedwith unregulated overproduction of calcitriol. Circulating vitamin D-binding protein levels areabout 20 times higher than concentrations of vitamin D compounds, and thus limit the possibilityof vitamin D toxicity. No toxicity has been associated with daily doses of colecalciferol as high as10000 units.

DRUG INTERACTIONS3

Specific interaction studies have not been done for Fosamax Plus

. If taken at the same time, it islikely that calcium supplements, antacids, and other oral medications will interfere with theabsorption of alendronate. Alendronate has also been used in studies with a wide range ofcommonly prescribed drugs without evidence of clinical adverse interactions.

Olestra, mineral oils, orlistat, and bile acids sequestrants may impair the absorption of vitamin D.Administration of enzyme inducers and thiazides may increase the catabolism of vitamin D.

DOSAGE AND ADMINISTRATION3

Recommended dosage is one 70 mg/2800 units tablet once weekly. No dosage adjustment isnecessary for the elderly or for patients with mild-to-moderate renal insufficiency. Fosamax Plus

is not recommended for patients with moderate-to-severe renal insufficiency with creatinineclearance of less than 35 ml/min.

Patients should receive supplemental calcium and/or vitamin D if intake is inadequate, especiallyin cases of gastrointestinal malabsorption syndromes.

Fosamax Plus

has not been studied in pregnant women, nursing mothers, and in children.

Fosamax Plus

must be taken at least 30 minutes before the first food, beverage, or medicationof the day with plain water only. It is to be swallowed whole upon rising for the day with a fullglass of water, and patients should be instructed not to lie down for at least 30 minutes and until

after their first food of the day.

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ROLE IN THERAPY

The anti-resorptive effect of Fosamax Plus

seems to be due to the alendronate component. Thevitamin D component, serves to enhance the GI absorption and renal reabsorption of calcium,thus helping in calcium homeostasis. The MOH recommended daily intake of vitamin D for adultsabove 65 years old is 800 units. The main advantage that Fosamax Plus

offers is improving

vitamin D status and suppressing increases in serum PTH levels in patients with osteoporosiswho are home-bound or who are inadequately exposed to sunlight.

Because of the long binding of alendronate to osteoclasts and the storage of 25-OHD in thetissues, there is no need for daily administration of alendronate nor colecalciferol.4,7 FosamaxPlus

incorporates the recommended weekly requirement of Vitamin D3, with the weekly dose ofalendronate in one tablet, allowing a convenient regimen for patients, without changing the anti-resorptive effects nor adverse effect profile of alendronate.15 It is also safe for use in patients withnormal vitamin D levels, as the amount of vitamin D in Fosamax Plus

will not cause vitamin Dtoxicity if given with usual doses of calcium and vitamin D supplements.

Currently, Fosamax Plus

is priced at parity with Fosamax

. Therefore, Fosamax Plus

may be analternative to replace once-weekly Fosamax

, especially for patients who need the extra vitaminD. However, it should be noted that Fosamax Plus

is formulated mainly to extend the patent ofMSDs alendronate products as generic alendronate may soon be available in Europeanmarkets.

COST

Drug Cost per dosage

form

Cost per 4weeks oftherapy

Usage(Nov 05-Oct

06)

Usage DDE*(Nov 05-Oct

06)Calcitonin nasal spray[200 units x 14 doses](Miacalcic

, Novartis)

$63.27/bottle $126.54(200 units/day)

1162 sprays 2324 pt-weeks

Raloxifene 60 mg tab

(Evista

, Eli Lily)

$3.47/tab $97.16(60 mg/day)

14311 tabs 2044 pt-weeks

Etidronate 200 mg tab

(Difosfen

, Zyfas)

$0.80/tab $22.40**(400 mg/day for

first 14 days)


Risedronate 35 mg tab(Actonel

, Sanofi-Aventis)$16.75/tab $67

(35 mg/week)9176 tabs 9176 pt-weeks

Strontium ranelate 2 gsachet (Protos

, Servier)#$3.81/sachet $106.68

(2g/day)1049 sachets 150 pt-weeks

Teriparatide 750 mcg/3 mLmultidose injection pen

(Forteo

, Eli Lily)##

$993.70/pen $993.70(20 mcg/day)

0 0

Alendronate 10 mg tab(Fosamax

, MSD)$2.30/tab $64.40

(10 mg/day)12126 tab 1732 pt-weeks

Alendronate 70 mg tab

(Fosamax

, MSD)

$17.27/tab $69.08(70 mg /week)


Alendronate 70 mg/Colecalciferol 2800 units

tab (Fosamax Plus, MSD)

$17.27/tab $69.08(70 mg/ 2800 units

/week)

N.A. N.A.

* Daily dose equivalents (DDE) a representation of the number of defined doses prescribed forpatients within a given time scale (e.g., patient-days, patient-year, etc); value acts as a common

denominator when comparing the usage volume of 2 or more drugs with varying dosagerequirement.

** Based on cyclical quarterly treatment schedule: 400 mg/day for 14 days followed by calcium & vitaminD for the next 2 and a half months.

# Approved in Sept 06. Usage shown is from approval date.## Approved in Apr 06.

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REFERENCES

Anonymous. Osteoporosis. World Health Organisation.http://www.who.int/dietphysicalactivity/publications/trs916/en/gsfao_osteo.pdf(Last accessed5th December 2006).

1. Ministry of Health, Singapore. Osteoporosis. MOH Clinical Practice Guidelines 02/2002.

http://www.moh.gov.sg/cmaweb/attachments/publication/osteo_pdf.pdf(Last accessed 5

th

December2006).

2. Fosamax Plus

. Alendronate/Colecalciferol. Local product circular. Merck & Co., Inc., WhitehouseStation, New Jersey, USA.

3. Heaney RP. Alendronate plus colecaciferol for the treatment of osteoporosis. Womens Health 2006;2(1): 23-27.

4. Colecalciferol (Drug evaluation). In: Klasco RK (Ed): DRUGDEX

System. Thomson Micromedex,Greenwood Village, Colorado (Edition expires 31 Dec 2006).

5. Reynolds NA, Curran MP. Alendronate/colecalciferol. Treat Endocrinol2005; 4(6): 371-377.

6. Epstein S. The problem of low levels of vitamin D and osteoporosis: Use of combination therapy withalendronic acid and colecalciferol (vitamin D3). Drugs Aging2006; 23(8): 617-625.

7. Data on file, MSD Singapore.

8. Black DM, Thompson DE, Bauer DC, et al. Fracture risk reduction with alendronate in women with

osteoporosis: The fracture intervention trial (FIT). J Clin Endocrinol Metab 2000; 85(1): 231-236.

9. Black DM, Thompson DE, Bauer DC, et al. Randomised trial of effect of alendronate on risk of fracturein women with existing vertebral fractures. Lancet1996; 348: 1535-1541.

10. Cranney A, Guyatt G, Wells G, et al. Summary of meta-analyses of therapies for postmenopausalosteoporosis. Endocr Rev2002; 23(4): 570-578.

11. Rosen CJ, Hochberg MC, Bonnick SL, et al. Treatment with once weekly alendronate 70 mg comparedwith once-weekly risedronate 35 mg in women with postmenopausal osteoporosis. J Bone Miner Res2005; 20(1): 141-151.

12. Sambrook PN, Geusens P, Ribot C, et al. Alendronate produces greater effects than raloxifene onbone density and bone turnover in postmenopausal women with low bone density: Results fromEFFECT. J Intern Med2004; 255:503-511.

13. Bone HG, Hosking D, Devogelaer JP, et al. Ten years experience with alendronate for the treatment of

osteoporosis in postmenopausal women. N Engl J MedMarch 18, 2004; 350:11-21.14. Recker R, Lips P, Felsenberg D, et al. Alendronate with and without colecalciferol for osteoporosis:

Results of a 15-week randomised controlled trial. Curr Med Res Opin 2006; 22(9): 1745-1755.

Monograph prepared by:

Cordelia Chen, B Sc (Pharm) (Hons)Pre-Registration Pharmacist

9th Dec 2006

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http://www.who.int/dietphysicalactivity/publications/trs916/en/gsfao_osteo.pdfhttp://www.who.int/dietphysicalactivity/publications/trs916/en/gsfao_osteo.pdfhttp://www.moh.gov.sg/cmaweb/attachments/publication/osteo_pdf.pdfhttp://www.who.int/dietphysicalactivity/publications/trs916/en/gsfao_osteo.pdfhttp://www.moh.gov.sg/cmaweb/attachments/publication/osteo_pdf.pdf

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