Alendronate;Cholecalciferol

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Alendronate;Cholecalciferol Quick Reference
Alendronate
Alendronate;Cholecalciferol
IUPAC Name
Sodium [4-amino-1-hydroxy-1-(hydroxy-oxido-phosphoryl)- butyl]phosphonic acid trihydrate
Chemical Information
Empirical Formula Alendronate: C4H18NNaO10P2

Cholecalciferol: C27H44O

Molecular Weight Alendronate: 325.124

Cholecalciferol: 384.6

General Drug Information
Classification Bisphosphonates, Vitamin D Analog
Schedule Legend
How Supplied Oral Tablets: 70 mg/2800 IU
Trade Names Fosamax Plus D
Pregnancy Category C
Breast Feeding No data available regarding the secretion of alendronate into breast milk. Caution should be used.
Generic Availability Generic not available
Patent Expiration Date Jun 02,2013
Administration Information
Route(s) Oral
Method(s) Take one tablet at least 30 minutes before the first food, beverage or medication. This medications should be taken once weekly in the morning.
Pharmacokinetic Information
Absorption Alendronate:F = ~60%(coffee or orange juice can decrease F by~60%)

Cholecalciferol: F= similar to taking cholecalciferol alone (F is unknown).

Alendronate: tmax = unavailable

Cholecalciferol: tmax = ~11 hours

Distribution Alendronate: Vd = ~28L

Cholecalciferol: Rapidly distributed to liver

Alendronate: Protein binding =~78%

Cholecalciferol: Binds to vitamin D-binding protein

Metabolism Alendronate: None Known

Cholecalciferol: metabolized in the liver first then in the kidney

Excretion Alendronate: T1/2 = >10 years

Cholecalciferol: T1/2 =~ 14 hours

Alendronate: Urine

Cholecalciferol: Urine (2.4%) and feces (4.9%) as metabolites

Contents

Brand/Trade Names of Drug

Fosamax Plus D

Generic Name of Drug

Alendronate (a LEN droe nate) Alendronate Pronunciation Click Here

Cholecalciferol (kole e kal SI fer ole) Cholecalciferol Pronunciation Click Here

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Description

Alendronate belongs to a class of medications known as the bisphosphonates. This medication is a second generation bisphosphonate which strengthens bones in addition to preventing bone loss. It inhibits osteoclast-mediated bone resorption.[1]

Cholecalciferol is a precusor of a calcium-regulating hormone, 1,25 dihydroxyvitamin D3. Higher concentrations of 25 dihydroxyvitamin D3 can lead to lower concentrations of parathyroid hormone in the blood. As a result, the bone mineral density will be increased. The combination of alendronate and cholecalciferol was approved by the FDA for the treatment of osteoporosis and to increase bone mass in men with osteoporosis.

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Mechanism of action

Bisphosphonates are antiresorptive agents. They prevent the transformation of calcium phosphate into hydroxyapatite. In addition, bisphosphonates inhibits osteoclast mediated bone reabsorption through an unknown mechanism. Current theories suggest that alendronate is incorporated into osteoclasts and disrupts the cellular ruffed border. As a result, active bone resorption is reduced. [2].

Cholecalciferol is vitamin D3, which is required for normal bone formation. It is converted to 25-hydroxyvitamin D3 in the liver and then further converted to 1,25-dihydroxyvitamin D3 (calcitriol) in the kidney. This conversion is stimulated by parathyroid hormone and hypophosphatemia. As a result, 1,25-dihydroxyvitamin D3 increases the absorption of calcium and phosphate in the intestines.[3]

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Time Required for Therapeutic Response

  • Data not available.[3]

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Pharmacokinetics

Absorption

The bioavailability of alendronate is about 60%. Coadministration with food decreases the bioavailability of alendronate by about 40%. Coffee or orange juice can decrease the bioavailability of alendronate by about 60%. The Tmax of cholecalciferol is about 11 hours.[3]

Distribution

Approximately 78% of the circulating drug is bounded to plasma protein. The volume of distribution is approximately 28L (exclusively contained within bone).[1] Cholecalciferol is rapidly distributed to the liver and undergoes further conversion to 25-hydroxyvitamin D3. Cholecalciferol binds to vitamin D-binding protein in the circulation.[3]

Metabolism

None known for alendronate. Cholecalciferol is metabolized in the liver to 25-hydroxyvitamin D3 through hydroxylation and further metabolized in the kidney to 1,25-dihydroxyvitamin D3. A small portion of cholecalciferol undergoes glucuronidation.[3]

Excretion

About 50% of alendronate recovered in the urine. The terminal half-life (t1/2) of alendronate is >10 years. The half-live (t1/2 of cholecalciferol is about 14 hours.[1]


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Special Population Pharmacokinetics

  • Renal insufficiency

Alendronate is not recommended for use in patients with creatinine clearance less than 35ml/min. The production of 1,25-dihydroxyvitamin D3 may also be reduced in these patients.[3]

  • Hepatic insufficiency

There is no evidence that alendronate is metabolized through the liver. No dosage adjustment is needed for hepatic insufficiency. The absorption of cholecalciferol may be reduced in patints with inadequate bile production.[3]

  • Hemodialysis

Data not available.[3]

  • Geriatric

No dosage adjustment for alendronate is needed for elderly patients. Elderly may have a higher dietary requirement for cholecalciferol.[3]

  • Pediatric

Data not available for patients younger than 18 years old.[3]

  • Gender

No dosage adjustment is needed.[3]

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Indications

FDA Approved Indications

  • Treatment to increase bone mass in men with osteoporosis

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Dosage

  • Treatment of osteoporosis in postmenopausal women[3]
    • Starting & Maintenance Dose: One 70mg/2800IU tablet once a week
  • Treatment to increase bone mass in men with osteoporosis[3]
    • Starting & Maintenance Dose: One 70mg/2800IU tablet once a week


  • Maximum Dosage Limits[3]
    • Adults: One 70mg/2800IU tablet once a week
    • Elderly: One 70mg/2800IU tablet once a week
    • Adolescents and children: Unknown; safety and efficacy has not been established in this population.
  • Dosage Adjustment[3]
    • Renal insufficiency: No adjustment is necessary if creatinine clearance is >35ml/min. The use of alendronate is not recommended in patients with creatinine clearance <= 35ml/min.
    • Hepatic insufficiency: No adjustment is necessary.
    • Hemodialysis: Unknown.
    • Geriatric: No adjustment is necessary.
    • Gender: No adjustment is necessary.


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Administration

  • Route: Oral[3]
  • Method:[3]
    • Take at least 30 minutes before the first food, beverage or medication of the day. This medication should be administered once a week in the morning.
    • Swallow the tablet with a full glass (8oz.) of plain water. (2oz. of plain water is sufficient for the liquid formulation)
    • Do not lie down for at least 30 minuties and until after the first food consumption.

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Monitoring Parameters

  • Serum alkaline phosphatase
  • Serum calcium
  • Serum creatinine and BUN(patients with renal insufficiency)
  • Bone mineral density

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Contraindications/Precautions

Contraindications


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Precautions

  • Musculoskeletal pain
  • Vitamin D deficiency
  • Osteonecrosis of the jaw
  • Renal insufficiency
  • Glucocorticoid therapy

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Pregnancy indications

  • Pregnancy category: Category C[3]
  • Teratogenicity: Animal reproduction studies have shown adverse effects on the fetus including slightly increased offspring mortality and growth retardation. Alendronate;cholecalciferol may be used during pregnancy if the potential benefits justify the potential risks to the fetus.[3]

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Breast-feeding indications

  • Secretion into breast milk: No data available. Alendronate;cholecalciferol may be used in nursing mother if the potential benefits of the mother justify the potential risks to the infant.[3]


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Drug-Drug Interactions

Alendronate;Cholecalciferol Drug/Drug Interaction Chart
Severity Level Click here to see Severity Level Legend Increased Effect/Toxicity Decreased Effect
4 None Known None Known
3 aspirin[3] The risk of upper GI side effects is increased when alendronate;cholecalciferol is co-administered with ASA. Nonsteroidal antiinflammatory drugs (NSAIDs)[3] The risk of upper GI side effects is increased when alendronate;cholecalciferol is co-administered with NSAIDs.magaldrate[4][5] The concentration of magnesium may be increased by vitamin D analog when alendronate;cholecalciferol is co-administered with magaldrate.magnesium citrate[4][5] The concentration of magnesium may be increased by vitamin D analogs when alendronate;cholecalciferol is co-administered with magnesium citrate.magnesium hydroxide[4][5] The concentration of magnesium may be increased by vitamin D analogs when alendronate;cholecalciferol is co-administered with magnesium hydroxide.phosphorus salts[4][5] The risk of hyperphosphatemia increased by vitamin D analogs when alendronate;cholecalciferol is co-administered with phosphorus salts.vitamin D analogs[4][5] The risk of hyperphosphatemia is increased by vitamin D analogs when alendronate;cholecalciferol is co-administered with other vitamin D analogs. aluminum hydroxide[3] The absorption of alendronate is decreased when alendronate;cholecalciferol is co-administered with aluminum hydroxide.antacids[3] The absorption of alendronate is decreased when alendronate;cholecalciferol is co-administered with antacids.calcium carbonate[3] The absorption of alendronate is decreased when alendronate;cholecalciferol is co-administered with calcium carbonate.calcium salts[3] The absorption of alendronate is decreased when alendronate;cholecalciferol is co-administered with calcium salts.iron salts[3] The absorption of alendronate is decreased when alendronate;cholecalciferol is co-administered with iron salts.magnesium salts[3] The absorption of alendronate is decreased when alendronate;cholecalciferol is co-administered with magnesium salts.polysaccharide-iron complex[3] The absorption of alendronate is decreased when alendronate;cholecalciferol is co-administered with polysaccharide-iron complex.
2 gastric mucosal agents[3] The risk of upper GI side effects is increased when alendronate;cholecalciferol is co-administered with gastric mucosal agents by affecting the bioavailability of alendronate.H2-blockers[3] The risk of upper GI side effects is increased when alendronate;cholecalciferol is co-administered with H2-blockers by affecting the bioavailability of alendronate.Proton pump inhibitors (PPIs)[3] The risk of upper GI side effects is increased when alendronate;cholecalciferol is co-administered with PPIs by affecting the bioavailability of alendronate. barbiturates[6] The metabolism of cholecalciferol is increased when alendronate;cholecalciferol is co-administered with barbiturates.phenytoin[6] The metabolism of cholecalciferol is increased when alendronate;cholecalciferol is co-administered with phenytoin.fosphenytoin[6] The metabolism of cholecalciferol is increased when alendronate;cholecalciferol is co-administered with fosphenytoin.thiazide diuretics[3] The metabolism of cholecalciferol is increased when alendronate;cholecalciferol is co-administered with thiazide diuretics.cholestyramine[7] The absorption of vitamin D is reduced when alendronate;cholecalciferol is co-administered with cholestyramine.colestipol[8] The absorption of vitamin D is reduced when alendronate;cholecalciferol is co-administered with colestipol.mineral oil[9] The absorption of vitamin D is reduced when alendronate;cholecalciferol is co-administered with mineral oil.orlistat[10] The absorption of vitamin D is reduced when alendronate;cholecalciferol is co-administered with orlistat.ketoconazole[4] The conversion of cholecalciferol to calcitriol may be reduced when alendronate;cholecalciferol is co-administered with ketoconazole.
1 corticosteroids[11] Corticosteroids decrease the absorption of calcium, which opposes the effect of cholecalciferol. teriparatide[12][13] The anabolic activity of teriparatide is decreased when it is co-administered with alendronate;cholecalciferol.


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Drug-Food-Herb Interactions

Alendronate;Cholecalciferol Drug/Food/Herb Interaction Chart
Severity Level Click here to see Severity Level Legend Increased Effect/Toxicity Decreased Effect
4 None Known None Known
3 None Known Food[3] The absorption of cholecalciferol is decreased when co-administered with certain food eg. olestra.
2 None Knownn None Known
1 None Known None Known

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Adverse Reactions/Side Effects

Alendronate Adverse Reactions Chart[14]
Incidence Body System Adverse Reactions
> 10 % Endocrine & metabolic Hypocalcemia (transient, mild, 18%); hypophosphatemia (transient, mild, 10%)
1-10% CNS Headache (up to 3%)
GI Abdominal pain (1% to 7%), acid reflux (1% to 4%), dyspepsia (1% to 4%), nausea (1% to 4%), flatulence (up to 4%), diarrhea (1% to 3%), gastroesophageal reflux disease (1% to 3%), constipation (up to 3%), esophageal ulcer (up to 2%), abdominal distension (up to 1%), gastritis (up to 1%), vomiting (up to 1%), dysphagia (up to 1%), gastric ulcer (1%), melena (1%)
Neuromuscular & skeletal Arthralgia, limb pain, muscle cramp, myalgia, neck/shoulder pain, paresthesia, tremor
< 1% All Postmarketing, and/or case reports: Anastomotic ulcer, angioedema; bone, muscle, or joint pain (occasionally severe, considered incapacitating in rare cases); dizziness, duodenal ulcer, episcleritis, erythema, esophageal erosions, esophageal perforation, esophageal stricture, esophagitis, fever, flu-like syndrome, hypersensitivity reactions, hypocalcemia (symptomatic), joint swelling, lymphocytopenia, malaise, myalgia, oropharyngeal ulceration, osteonecrosis (jaw), peripheral edema, photosensitivity (rare), pruritus, rash, scleritis (rare), Stevens-Johnson syndrome, taste perversion, toxic epidermal necrolysis, urticaria, uveitis (rare), vertigo, weakness


Cholecalciferol Adverse Reactions Chart ( Frequency not defined.[14])
Body System Adverse Reactions
CNS Irritability, headache, somnolence, overt psychosis (rare)
Cardiovascular Arrhythmia, hyper-/hypotension, cardiac arrhythmia
Dermatologic Pruritus
Endocrine & metabolic Polydipsia
GI Nausea, vomiting, anorexia, pancreatitis, metallic taste, dry mouth, constipation, weight loss
Neuromuscular & skeletal Bone pain, myalgia, weakness, muscle pain
Genitourinary Albuminuria, polyuria
Hepatic Increased liver function test
Ocular Conjunctivitis, photophobia
Renal Azotemia, nephrocalcinosis

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Overdosage Measures

Symptoms of overdose include hypocalcemia, hypophosphatemia, and upper GI adverse affects.

  • Treatment:
    • Give patient milk or antacids to bind alendronate.
    • Keep patient fully upright.[3]


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Product Information and Distribution

Alendronate;Cholecalciferol Product Availability Information
Name Manufacturer Dosage Form Strength Quantity NDC Storage
Fosamax Plus D[3] Merck and Co Inc Oral Tablets 70 mg/2800IU 4 00006-0710-44 15-30°C (59-86°F)
4 bottles 00006-0710-04
12 bottles 00006-0710-12
20 unit-dose box 00006-0710-21


  • Manufacturers/Distributors

Manufactured by: Merck & Co Inc, Whitehouse Station, United States

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Pharmacogenomic information

Alendronate Pharmacogenomic Information

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Patient Information

  • Take as directed.
  • Take one tablet at least 30 minutes before the first food, beverage or medication in the morning.
  • Swallow the tablet with a full glass (8oz.) of plain water.
  • Do not lie down for at least 30 minuties and until after the first food consumption.
  • Avoid OTC medications unless instructed by your physician.
  • Possible side effects include flatulence, bloating, nausea, acid regurgitation. Small frequent meals may help reducing the side effects.
  • Report acute headache or gastric pain, unresolved GI upset, or acid stomach.
  • Inform your doctor if you are or intend to become pregnant.

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References

  1. ↑ 1.0 1.1 1.2 Fosamax® (alendronate sodium) package insert. Whitehouse Station, NJ; Merck & Co.Inc; 2006 Nov.
  2. ↑ Dipiro JT, Talbert RL, Yee GC, Matzke GR, Wells BG, Posey LM. Pharmacotherapy: A Pathophysiologic Approach. 5th Edition ed. New York, NY: The McGraw-Hill Companies, Inc 2002.
  3. ↑ 3.00 3.01 3.02 3.03 3.04 3.05 3.06 3.07 3.08 3.09 3.10 3.11 3.12 3.13 3.14 3.15 3.16 3.17 3.18 3.19 3.20 3.21 3.22 3.23 3.24 3.25 3.26 3.27 3.28 3.29 3.30 3.31 3.32 3.33 3.34 3.35 3.36 Fosamax Plus D® (alendronate sodium and cholecalciferol) package insert.Whitehouse Station. NJ;Merck & Co.Inc; 2006 Feb.
  4. ↑ 4.0 4.1 4.2 4.3 4.4 4.5 Rocaltrol® (calcitriol) package insert. Nutley, NJ: Roche Laboratories, Inc.; 2004 Jul.
  5. ↑ 5.0 5.1 5.2 5.3 5.4 Hectorol® (doxercalciferol) package insert. Middleton, WI: Bone Care International, Inc.; 2005 Jun.
  6. ↑ 6.0 6.1 6.2 McNamara JO. Drugs effective in the therapy of the epilepsies.Gilman AG, Hardman JG, Limbird LE, (eds.) In: Goodman and Gilman's The Pharmacological Basis of Therapeutics. 10th ed., New York, McGraw-Hill Companies. 2001:530—2.
  7. ↑ Questran® and Questran® Light (cholestyramine) package insert. Spring Valley, NY: Par Pharmaceutical Inc; 2002 July.
  8. ↑ Colestid® and Flavored Colestid® (colestipol) package insert. Kalamazoo, MI: Pharmacia & Upjohn Company; 2002 July.
  9. ↑ Drisdol® (ergocalciferol) package insert. New York, NY: Sanofi-Synthelabo, Inc.; 2003 Dec.
  10. ↑ Xenical® (orlistat) package insert. Nutley, NJ: Roche Laboratories Inc.; 2005 Jan.
  11. ↑ Drisdol® (ergocalciferol) package insert. New York, NY: Sanofi-Synthelabo, Inc.; 2003 Dec.
  12. ↑ Black DM, Greenspan SL, Ensrud KE, et al. The effects of parathyroid hormone and alendronate alone or in combination in postmenopausal osteoporosis. N Engl J Med 2003;349:1207—15.
  13. ↑ Finkelstein JS, Hayes A, Hunzelman JL, et al. The effects of parathyroid hormone, alendronate or both in men with osteoporosis. N Engl J Med 2003;349:1216—26.
  14. ↑ 14.0 14.1 Lexi-Comp (2003). Drug Information Handbook. 11th Edition., APhA.

PUBMED References

Efficacy Trial Articles

  1. Millonig G, Graziadei IW, Eichler D, Pfeiffer KP, Finkenstedt G, Muehllechner P, Koenigsrainer A, Margreiter R, Vogel W.Alendronate in combination with calcium and vitamin D prevents bone loss after orthotopic liver transplantation: a prospective single-center study.Liver Transpl. 2005 Aug;11(8):960-6.
  2. Mondy K, Powderly WG, Claxton SA, Yarasheski KH, Royal M, Stoneman JS, Hoffmann ME, Tebas P.Alendronate, vitamin D, and calcium for the treatment of osteopenia/osteoporosis associated with HIV infection.J Acquir Immune Defic Syndr. 2005 Apr 1;38(4):426-31.
  3. Recker R, Lips P, Felsenberg D, Lippuner K, Benhamou L, Hawkins F, Delmas PD, Rosen C, Emkey R, Salzmann G, He W, Santora AC.Alendronate with and without cholecalciferol for osteoporosis: results of a 15-week randomized controlled trial.Curr Med Res Opin. 2006 Sep;22(9):1745-55.
  4. Sambrook PN, Kotowicz M, Nash P, Styles CB, Naganathan V, Henderson-Briffa KN, Eisman JA, Nicholson GC.Prevention and treatment of glucocorticoid-induced osteoporosis: a comparison of calcitriol, vitamin D plus calcium, and alendronate plus calcium.J Bone Miner Res. 2003 May;18(5):919-24.

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Therapeutic Class Comparison Articles

  1. Ringe JD, Farahmand P, Schacht E, Rozehnal A.Superiority of a combined treatment of Alendronate and Alfacalcidol compared to the combination of Alendronate and plain vitamin D or Alfacalcidol alone in established postmenopausal or male osteoporosis (AAC-Trial).Rheumatol Int. 2007 Jan 11.

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Drug Interaction Articles

  1. Black DM, Greenspan SL, Ensrud KE, et al. The effects of parathyroid hormone and alendronate alone or in combination in postmenopausal osteoporosis. N Engl J Med 2003;349:1207—15.
  2. Finkelstein JS, Hayes A, Hunzelman JL, et al. The effects of parathyroid hormone, alendronate or both in men with osteoporosis. N Engl J Med 2003;349:1216—26.

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Adverse Effects Articles

  1. Aki S, Eskiyurt N, Akarirmak U, Tuzun F, Eryavuz M, Alper S, Arpacioglu O, Atalay F, Kavuncu V, Kokino S, Kuru O, Nas K, Ozerbil O, Savas G, Sendur OF, Soy D, Akyuz G; Turkish Osteoporosis Society.Gastrointestinal side effect profile due to the use of alendronate in the treatment of osteoporosis.Yonsei Med J. 2003 Dec 30;44(6):961-7.
  2. Coleman CI, Perkerson KA, Lewis A.Alendronate-induced auditory hallucinations and visual disturbances.Pharmacotherapy. 2004 Jun;24(6):799-802.
  3. Yanik B, Turkay C, Atalar H.Hepatotoxicity induced by alendronate therapy.Osteoporos Int. 2007 Jan 17.

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Compliance Articles

  1. Segal E, Tamir A, Ish-Shalom S.Compliance of osteoporotic patients with different treatment regimens.Isr Med Assoc J. 2003 Dec;5(12):859-62.

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Pharmacoeconomics articles

  1. Buckley LM, Hillner BE.A cost effectiveness analysis of calcium and vitamin D supplementation, etidronate, and alendronate in the prevention of vertebral fractures in women treated with glucocorticoids.J Rheumatol. 2003 Jan;30(1):132-8.

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External Links


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Monograph created by Khlee3

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