Fosamax Plus D

Oral Bisphosphonates in Combination with Vitamins

Administer after the patient has risen for the day. The patient should be sitting or standing. Do not administer alendronate; cholecalciferol to the patient while the patient is lying down.
Administer in the morning with a full glass (180 to 240 mL or 6 to 8 ounces) of plain water only and at least 30 minutes before the first food, beverage, or other medications of the day. At least 30 minutes should elapse after the dose before taking any other drugs or supplements.
To avoid esophageal irritation, the patient should not lie down for at least 30 minutes after the dose and until after their first food of the day.
Do not administer at bedtime or before the patient has risen for the day.
Missed doses: If a once-weekly dose is missed, instruct the patient to take the dose on the morning after they remember. They should not take 2 doses on the same day but should return to taking 1 dose once a week, as originally scheduled on their chosen day.
Ensure adequate intake of calcium and vitamin D to reduce the risk of treatment-related hypocalcemia.

esophageal ulceration / Delayed / 0.1-1.5
peptic ulcer / Delayed / 0-1.1
atrial fibrillation / Early / Incidence not known
GI bleeding / Delayed / Incidence not known
esophageal stricture / Delayed / Incidence not known
GI perforation / Delayed / Incidence not known
Stevens-Johnson syndrome / Delayed / Incidence not known
toxic epidermal necrolysis / Delayed / Incidence not known
angioedema / Rapid / Incidence not known
visual impairment / Early / Incidence not known
uveitis / Delayed / Incidence not known
osteonecrosis / Delayed / Incidence not known
hypervitaminosis D / Delayed / Incidence not known
bone fractures / Delayed / Incidence not known

bone pain / Delayed / 0.4-4.1
constipation / Delayed / 0-3.1
gastritis / Delayed / 0.2-1.1
dysphagia / Delayed / 0.1-1.0
oral ulceration / Delayed / Incidence not known
esophagitis / Delayed / Incidence not known
peripheral edema / Delayed / Incidence not known
hypocalcemia / Delayed / Incidence not known
erythema / Early / Incidence not known
conjunctivitis / Delayed / Incidence not known
ocular inflammation / Early / Incidence not known
hyperphosphatemia / Delayed / Incidence not known
hypophosphatemia / Delayed / Incidence not known

abdominal pain / Early / 0.9-6.6
flatulence / Early / 0-4.1
musculoskeletal pain / Early / 0.4-4.1
myalgia / Early / 0.4-4.1
arthralgia / Delayed / 0.4-4.1
nausea / Early / 0-3.6
dyspepsia / Early / 1.1-3.6
diarrhea / Early / 0.6-3.1
gastroesophageal reflux / Delayed / 0.7-2.8
vomiting / Early / 0.2-1.0
dysgeusia / Early / 0.1-0.5
fever / Early / Incidence not known
dizziness / Early / Incidence not known
asthenia / Delayed / Incidence not known
vertigo / Early / Incidence not known
malaise / Early / Incidence not known
rash / Early / Incidence not known
pruritus / Rapid / Incidence not known
alopecia / Delayed / Incidence not known
photosensitivity / Delayed / Incidence not known
urticaria / Rapid / Incidence not known
ocular pain / Early / Incidence not known

Fosamax Plus D

Rx

Oral fixed-dose once-weekly regimen of a bisphosphonate (alendronate) with vitamin D3 supplement (cholecalciferol)
Used to treat osteoporosis in men or postmenopausal women
Helps meet recommended dietary intake for vitamin D; supplement patient with calcium and additional vitamin D if intake inadequate

1 tablet PO once weekly. For most patients, the appropriate dose is alendronate 70 mg with cholecalciferol 140 mcg (5,600 International Units) PO once weekly. A dose of alendronate 70 mg with cholecalciferol 70 mcg (2,800 International Units) PO once weekly is also available. Supplement calcium and with additional vitamin D if dietary intake is inadequate. Reevaluate periodically.[36897] Continue an oral bisphosphonate for up to 10 years in postmenopausal women who are initially at very high risk of fracture and remain at high risk. Consider discontinuation after 5 years of stability in high-risk postmenopausal women. For those patients at low or moderate risk for fracture, consider stopping alendronate; cholecalciferol after 3 to 5 years. After discontinuation of therapy, continue to periodically reassess fracture risk.[36897] Bisphosphonates are first-line therapy for the treatment of osteoporosis in postmenopausal women; the drug is additionally effective in men with osteoporosis.[62806]

No dosage adjustment is needed.

CrCl 35 mL/minute or more: No dosage adjustment is necessary.
CrCl less than 35 mL/minute: Not recommended.

Acetaminophen; Aspirin, ASA; Caffeine: (Minor) Monitor for gastrointestinal adverse events during concurrent use of alendronate and aspirin. Both medications have been associated with gastrointestinal irritation although data suggest concomitant use introduces little additional risk for adverse effects for most patients.
Acetaminophen; Aspirin: (Minor) Monitor for gastrointestinal adverse events during concurrent use of alendronate and aspirin. Both medications have been associated with gastrointestinal irritation although data suggest concomitant use introduces little additional risk for adverse effects for most patients.
Acetaminophen; Aspirin; Diphenhydramine: (Minor) Monitor for gastrointestinal adverse events during concurrent use of alendronate and aspirin. Both medications have been associated with gastrointestinal irritation although data suggest concomitant use introduces little additional risk for adverse effects for most patients.
Aluminum Hydroxide: (Moderate) Separate administration of alendronate and aluminum hydroxide by at least 30 minutes. Aluminum-containing antacids will interfere with the absorption of alendronate.
Aluminum Hydroxide; Magnesium Carbonate: (Moderate) Separate administration of alendronate and aluminum hydroxide by at least 30 minutes. Aluminum-containing antacids will interfere with the absorption of alendronate.
Aluminum Hydroxide; Magnesium Hydroxide: (Major) Avoid vitamin D coadministration with magnesium hydroxide in persons on chronic hemodialysis due to the risk for hypermagnesemia. (Moderate) Separate administration of alendronate and aluminum hydroxide by at least 30 minutes. Aluminum-containing antacids will interfere with the absorption of alendronate.
Aluminum Hydroxide; Magnesium Hydroxide; Simethicone: (Major) Avoid vitamin D coadministration with magnesium hydroxide in persons on chronic hemodialysis due to the risk for hypermagnesemia. (Moderate) Separate administration of alendronate and aluminum hydroxide by at least 30 minutes. Aluminum-containing antacids will interfere with the absorption of alendronate.
Aluminum Hydroxide; Magnesium Trisilicate: (Moderate) Separate administration of alendronate and aluminum hydroxide by at least 30 minutes. Aluminum-containing antacids will interfere with the absorption of alendronate.
Aspirin, ASA: (Minor) Monitor for gastrointestinal adverse events during concurrent use of alendronate and aspirin. Both medications have been associated with gastrointestinal irritation although data suggest concomitant use introduces little additional risk for adverse effects for most patients.
Aspirin, ASA; Butalbital; Caffeine: (Minor) Monitor for gastrointestinal adverse events during concurrent use of alendronate and aspirin. Both medications have been associated with gastrointestinal irritation although data suggest concomitant use introduces little additional risk for adverse effects for most patients.
Aspirin, ASA; Caffeine: (Minor) Monitor for gastrointestinal adverse events during concurrent use of alendronate and aspirin. Both medications have been associated with gastrointestinal irritation although data suggest concomitant use introduces little additional risk for adverse effects for most patients.
Aspirin, ASA; Caffeine; Orphenadrine: (Minor) Monitor for gastrointestinal adverse events during concurrent use of alendronate and aspirin. Both medications have been associated with gastrointestinal irritation although data suggest concomitant use introduces little additional risk for adverse effects for most patients.
Aspirin, ASA; Carisoprodol: (Minor) Monitor for gastrointestinal adverse events during concurrent use of alendronate and aspirin. Both medications have been associated with gastrointestinal irritation although data suggest concomitant use introduces little additional risk for adverse effects for most patients.
Aspirin, ASA; Carisoprodol; Codeine: (Minor) Monitor for gastrointestinal adverse events during concurrent use of alendronate and aspirin. Both medications have been associated with gastrointestinal irritation although data suggest concomitant use introduces little additional risk for adverse effects for most patients.
Aspirin, ASA; Citric Acid; Sodium Bicarbonate: (Moderate) Sodium bicarbonate can reduce the absorption of the oral bisphosphonates. Wait at least 30 minutes after oral alendronate, 1 hour after ibandronate, and 2 hours after oral etidronate, risedronate, or tiludronate before taking a sodium bicarbonatecontaining product. (Minor) Monitor for gastrointestinal adverse events during concurrent use of alendronate and aspirin. Both medications have been associated with gastrointestinal irritation although data suggest concomitant use introduces little additional risk for adverse effects for most patients.
Aspirin, ASA; Dipyridamole: (Minor) Monitor for gastrointestinal adverse events during concurrent use of alendronate and aspirin. Both medications have been associated with gastrointestinal irritation although data suggest concomitant use introduces little additional risk for adverse effects for most patients.
Aspirin, ASA; Omeprazole: (Minor) Monitor for gastrointestinal adverse events during concurrent use of alendronate and aspirin. Both medications have been associated with gastrointestinal irritation although data suggest concomitant use introduces little additional risk for adverse effects for most patients.
Aspirin, ASA; Oxycodone: (Minor) Monitor for gastrointestinal adverse events during concurrent use of alendronate and aspirin. Both medications have been associated with gastrointestinal irritation although data suggest concomitant use introduces little additional risk for adverse effects for most patients.
Bumetanide: (Moderate) When the intravenous formulation of alendronate is used for the treatment of hypercalcemia of malignancy, combination therapy with loop diuretics should be used with caution in order to avoid hypocalcemia. In patients with hypercalcemia of malignancy, the initial treatment typically includes the use of loop diuretics, in combination with saline hydration, however, diuretic therapy should not be employed prior to correction of hypovolemia and dehydration.
Butalbital; Aspirin; Caffeine; Codeine: (Minor) Monitor for gastrointestinal adverse events during concurrent use of alendronate and aspirin. Both medications have been associated with gastrointestinal irritation although data suggest concomitant use introduces little additional risk for adverse effects for most patients.
Calcium (oral): (Moderate) Separate administration of alendronate and calcium-containing supplements by at least 30 minutes. Calcium will interfere with the absorption of alendronate.
Castor Oil: (Moderate) Absorption of fat-soluble vitamins may be decreased with coadministration of castor oil.
Cholestyramine: (Moderate) Cholestyramine can decrease the intestinal absorption of fat and fat-soluble vitamins. If used concurrently, administration of the two agents should be staggered for the longest time interval possible.
Colesevelam: (Moderate) It is not known if colesevelam can reduce the absorption of oral vitamin supplements including fat soluble vitamins A, D, E, and K. To minimize potential interactions, administer vitamins at least 4 hours before colesevelam.
Colestipol: (Moderate) Separate administration of fat-soluble vitamins by 1 hour before or 4 hours after a colestipol dose to limit effects on oral absorption. Because it sequesters bile acids, colestipol may interfere with normal fat absorption and thus may reduce absorption of fat-soluble vitamins.
Deferasirox: (Moderate) Because gastric ulceration and GI bleeding have been reported in patients taking deferasirox, use caution when coadministering with other drugs known to increase the risk of peptic ulcers or gastric hemorrhage including alendronate.
Ethacrynic Acid: (Moderate) When the intravenous formulation of alendronate is used for the treatment of hypercalcemia of malignancy, combination therapy with loop diuretics should be used with caution in order to avoid hypocalcemia. In patients with hypercalcemia of malignancy, the initial treatment typically includes the use of loop diuretics, in combination with saline hydration, however, diuretic therapy should not be employed prior to correction of hypovolemia and dehydration.
Food: (Major) Absorption of alendronate is very poor; oral bioavailability is less than 1%. Because of this, food interactions can be very significant. Alendronate oral absorption becomes almost negligible if alendronate is taken within 2 hours of breakfast. Even orange juice or coffee can reduce bioavailability by about 60%. To achieve maximum possible bioavailability alendronate must be taken in the fasting state and at least 2 hours before a standard breakfast.
Furosemide: (Moderate) When the intravenous formulation of alendronate is used for the treatment of hypercalcemia of malignancy, combination therapy with loop diuretics should be used with caution in order to avoid hypocalcemia. In patients with hypercalcemia of malignancy, the initial treatment typically includes the use of loop diuretics, in combination with saline hydration, however, diuretic therapy should not be employed prior to correction of hypovolemia and dehydration.
Hydantoins: (Moderate) Phenytoin and fosphenytoin can decrease the activity of vitamin D (e.g., cholecalciferol) by increasing its metabolism. In rare cases, this has caused anticonvulsant-induced rickets and osteomalacia. Vitamin D supplementation or dosage adjustments may be required in patients who are receiving chronic treatment with anticonvulsants.
Iron Sucrose, Sucroferric Oxyhydroxide: (Moderate) Separate administration of alendronate and iron supplements by at least 30 minutes. Iron will interfere with the absorption of alendronate.
Iron: (Moderate) Separate administration of alendronate and iron supplements by at least 30 minutes. Iron will interfere with the absorption of alendronate.
Isoniazid, INH; Pyrazinamide, PZA; Rifampin: (Moderate) Rifampin is a potent inducer of the cytochrome P450 hepatic enzyme system and can decrease the plasma concentrations and possibly the efficacy of cholecalciferol, Vitamin D3. In some cases, reduced concentrations of circulating vitamin D and 1,25-dihydoxy vitamin D have been accompanied by decreased serum calcium and phosphate, and elevated parathyroid hormone. Dosage adjustments of cholecalciferol, Vitamin D3 may be required.
Isoniazid, INH; Rifampin: (Moderate) Rifampin is a potent inducer of the cytochrome P450 hepatic enzyme system and can decrease the plasma concentrations and possibly the efficacy of cholecalciferol, Vitamin D3. In some cases, reduced concentrations of circulating vitamin D and 1,25-dihydoxy vitamin D have been accompanied by decreased serum calcium and phosphate, and elevated parathyroid hormone. Dosage adjustments of cholecalciferol, Vitamin D3 may be required.
Lanthanum Carbonate: (Moderate) To limit absorption problems, the oral bisphosphonates should not be taken within 2 hours of dosing with lanthanum carbonate. Oral drugs known to interact with cationic antacids, like the oral bisphosphonates, may also be bound by lanthanum carbonate. Separating times of administration will maximize absorption and clinical benefit of the bisphosphonate. Separate the times of administration appropriately. Monitor the patient's clinical status and bone density as recommended to ensure the appropriate response to bisphosphonate therapy is obtained.
Levothyroxine: (Moderate) Separating times of administration of alendronate from levothyroxine and other medications will maximize alendronate absorption and clinical benefit. For example, administering the levothyroxine dose at bedtime can avoid this interaction with alendronate. The bioavailability of alendronate was slightly decreased when alendronate and levothyroxine were co-administered to healthy subjects The mean AUC and Cmax of alendronate decreased by 7% and 9%, respectively. Alendronate should always be administered upon arising for the day and at least 30 minutes before the first food, beverage, or other medication of the day. To minimize interactions, levothyroxine is also best taken on an empty stomach with a glass of water.
Levothyroxine; Liothyronine (Porcine): (Moderate) Separating times of administration of alendronate from levothyroxine and other medications will maximize alendronate absorption and clinical benefit. For example, administering the levothyroxine dose at bedtime can avoid this interaction with alendronate. The bioavailability of alendronate was slightly decreased when alendronate and levothyroxine were co-administered to healthy subjects The mean AUC and Cmax of alendronate decreased by 7% and 9%, respectively. Alendronate should always be administered upon arising for the day and at least 30 minutes before the first food, beverage, or other medication of the day. To minimize interactions, levothyroxine is also best taken on an empty stomach with a glass of water.
Levothyroxine; Liothyronine (Synthetic): (Moderate) Separating times of administration of alendronate from levothyroxine and other medications will maximize alendronate absorption and clinical benefit. For example, administering the levothyroxine dose at bedtime can avoid this interaction with alendronate. The bioavailability of alendronate was slightly decreased when alendronate and levothyroxine were co-administered to healthy subjects The mean AUC and Cmax of alendronate decreased by 7% and 9%, respectively. Alendronate should always be administered upon arising for the day and at least 30 minutes before the first food, beverage, or other medication of the day. To minimize interactions, levothyroxine is also best taken on an empty stomach with a glass of water.
Loop diuretics: (Moderate) When the intravenous formulation of alendronate is used for the treatment of hypercalcemia of malignancy, combination therapy with loop diuretics should be used with caution in order to avoid hypocalcemia. In patients with hypercalcemia of malignancy, the initial treatment typically includes the use of loop diuretics, in combination with saline hydration, however, diuretic therapy should not be employed prior to correction of hypovolemia and dehydration.
Magnesium Citrate: (Major) Avoid vitamin D coadministration with magnesium citrate in persons on chronic hemodialysis due to the risk for hypermagnesemia. (Moderate) Separate administration of alendronate and magnesium-containing supplements by at least 30 minutes. Magnesium will interfere with the absorption of alendronate.
Magnesium Hydroxide: (Major) Avoid vitamin D coadministration with magnesium hydroxide in persons on chronic hemodialysis due to the risk for hypermagnesemia.
Magnesium Salts: (Moderate) Separate administration of alendronate and magnesium-containing supplements by at least 30 minutes. Magnesium will interfere with the absorption of alendronate.
Magnesium: (Major) Avoid vitamin D coadministration with magnesium-containing products, such as antacids, in persons on chronic hemodialysis due to the risk for hypermagnesemia. (Moderate) Separate administration of alendronate and magnesium-containing supplements by at least 30 minutes. Magnesium will interfere with the absorption of alendronate.
Mineral Oil: (Moderate) Absorption of fat-soluble vitamins is reported to be decreased with prolonged oral administration of mineral oil. However, despite warnings in various texts, there is little direct evidence that the interaction is of practical/clinical importance with limited use as directed. It may be prudent for those taking dietary supplements of Vitamin A, D, E, or K to separate administration by 1 hour before or 4 hours after a mineral oil oral dosage to help limit absorption interactions. Theoretically, the effect on fat-soluble vitamin absorption may more likely occur with prolonged or chronic administration of mineral oil.
Nonsteroidal antiinflammatory drugs: (Minor) Monitor for gastrointestinal adverse events during concurrent use of alendronate and nonsteroidal antiinflammatory drugs. Both medications have been associated with gastrointestinal irritation although data suggest concomitant use introduces little additional risk for adverse effects for most patients.
Omeprazole; Sodium Bicarbonate: (Moderate) Sodium bicarbonate can reduce the absorption of the oral bisphosphonates. Wait at least 30 minutes after oral alendronate, 1 hour after ibandronate, and 2 hours after oral etidronate, risedronate, or tiludronate before taking a sodium bicarbonatecontaining product.
Orlistat: (Moderate) Orlistat reduced the absorption of fat-soluble vitamins during clinical trials. The bioavailability of orally administered vitamin D may also be decreased. In patients receiving orally-administered vitamin D with orlistat, close monitoring is recommended. In addition, the manufacturer recommends that fat-soluble vitamins be administered at least 2 hours before or after the administration of orlistat to limit effects on oral absorption.
Parathyroid Hormone: (Moderate) Coadministration of alendronate with parathyroid hormone (PTH) is not recommended as concomitant use leads to a reduction in the calcium sparing effect, which can interfere with the normalization of serum calcium. The use of PTH alone was superior to use in combination with alendronate in clinical trials. In clinical trials, there was no evidence of synergy between PTH and alendronate. Changes in the volumetric density of trabecular bone, the cortical volume at the hip, and levels of markers of bone turnover suggest that the concurrent use of alendronate may reduce the anabolic effects of PTH. Concurrent use with other bisphosphonates is also controversial. However, sequential use (e.g., PTH followed by anti-resorptive treatment with bisphosphonates) appears to be beneficial and to help maintain beneficial bone effects.
Phosphorus: (Major) High intake of phosphates concomitantly with vitamin D or vitamin D analogs may lead to hyperphosphatemia. Dose adjustment of vitamin D or vitamin D analogs may be necessary during coadministration with phosphorus salts. Additionally, serum calcium concentrations should be monitored frequently. Monitor more frequently in patients with a history of hypercalcemia.
Polycarbophil: (Moderate) Coadministration of alendronate with calcium polycarbophil can interfere with the oral absorption of alendronate; do not administer calcium polycarbophil within 30 minutes of alendronate. Each 625 mg of calcium polycarbophil contains a substantial amount of calcium (approximately 125 mg).
Proton pump inhibitors: (Moderate) Proton pump inhibitors (PPIs) are widely used and are frequently coadministered in users of oral bisphosphonates. A national register-based, open cohort study of 38,088 elderly patients suggests that those who use proton pump inhibitors in conjunction with alendronate have a dose-dependent loss of protection against hip fracture. While causality was not investigated, the dose-response relationship noted during the study suggested that PPIs may reduce oral alendronate efficacy, perhaps through an effect on absorption or other mechanism, and therefore PPIs may not be optimal agents to control gastrointestinal complaints. It is not yet clear if all bisphosphonates would exhibit a loss of efficacy when PPIs are coadministered, but the results suggest that the interaction may occur across the class.
Rifampin: (Moderate) Rifampin is a potent inducer of the cytochrome P450 hepatic enzyme system and can decrease the plasma concentrations and possibly the efficacy of cholecalciferol, Vitamin D3. In some cases, reduced concentrations of circulating vitamin D and 1,25-dihydoxy vitamin D have been accompanied by decreased serum calcium and phosphate, and elevated parathyroid hormone. Dosage adjustments of cholecalciferol, Vitamin D3 may be required.
Sodium Bicarbonate: (Moderate) Sodium bicarbonate can reduce the absorption of the oral bisphosphonates. Wait at least 30 minutes after oral alendronate, 1 hour after ibandronate, and 2 hours after oral etidronate, risedronate, or tiludronate before taking a sodium bicarbonatecontaining product.
Sodium Sulfate; Magnesium Sulfate; Potassium Chloride: (Moderate) Separate administration of alendronate and magnesium-containing supplements by at least 30 minutes. Magnesium will interfere with the absorption of alendronate.
Sucralfate: (Moderate) Concomitant administration of oral alendronate with aluminum-containing medications (e.g., sucralfate) may interfere with the absorption of alendronate. Separation of administration is advised. At least 30 minutes should elapse after an alendronate dose before taking aluminum-containing drugs.
Thiazide diuretics: (Moderate) Dose adjustment of vitamin D or vitamin D analogs may be necessary during coadministration with thiazide diuretics. Additionally, serum calcium concentrations should be monitored frequently. Monitor more frequently in patients with a history of hypercalcemia. Hypercalcemia may be exacerbated by coadministration of vitamin D or vitamin D analogs and thiazide diuretics. Thiazide diuretics are known to induce hypercalcemia by reducing the excretion of calcium in the urine.
Torsemide: (Moderate) When the intravenous formulation of alendronate is used for the treatment of hypercalcemia of malignancy, combination therapy with loop diuretics should be used with caution in order to avoid hypocalcemia. In patients with hypercalcemia of malignancy, the initial treatment typically includes the use of loop diuretics, in combination with saline hydration, however, diuretic therapy should not be employed prior to correction of hypovolemia and dehydration.

Alendronate Sodium, Cholecalciferol/Alendronic Acid, Cholecalciferol/Fosamax Plus D Oral Tab: 70-2800IU, 70-5600IU

1 tablet/week PO with a maximum of 70 mg/week PO alendronate and 140 mcg/week (5,600 International Units/week) PO cholecalciferol.

1 tablet/week PO with a maximum of 70 mg/week PO alendronate and 140 mcg/week (5,600 International Units/week) PO cholecalciferol.

Safety and efficacy have not been established.

Safety and efficacy have not been established.

Safety and efficacy have not been established.

The bisphosphonates (e.g., alendronate) increase skeletal mineralization and thus improve bone density and reduce fracture risk. Insufficiency of vitamin D is associated with negative calcium balance, increased parathyroid hormone levels, bone loss, and increased risk of skeletal fracture. In severe cases, deficiency results in more severe hyperparathyroidism, hypophosphatemia, proximal muscle weakness, bone pain, and osteomalacia. Thus, adequate vitamin D and calcium intake are essential for the proper treatment of osteoporosis with bisphosphonate therapy.[50514] [36897]
Alendronate: Alendronate is a second-generation bisphosphonate that binds to bone hydroxyapatite and specifically inhibits the activity of osteoclasts, the bone-resorbing cells. Alendronate reduces bone resorption with no direct effect on bone formation, although the latter process is ultimately reduced because bone resorption and formation are coupled during bone turnover. Animal studies have indicated the following mode of action. At the cellular level, alendronate shows preferential localization to sites of bone resorption, specifically under osteoclasts. The osteoclasts adhere normally to the bone surface but lack the ruffled border that is indicative of active resorption. Alendronate does not interfere with osteoclast recruitment or attachment, but it does inhibit osteoclast activity. Studies in mice on the localization of radioactive alendronate in bone showed about 10-fold higher uptake on osteoclast surfaces than on osteoblast surfaces. Bones examined 6 and 49 days after radioactive alendronate administration in rats and mice, respectively, showed that normal bone was formed on top of the alendronate, which was incorporated inside the matrix. While incorporated in bone matrix, alendronate is not pharmacologically active. Thus, alendronate must be continuously administered to suppress osteoclasts on newly formed resorption surfaces. Histomorphometry in baboons and rats showed that alendronate treatment reduces bone turnover (i.e., the number of sites at which bone is remodeled). In addition, bone formation exceeds bone resorption at these remodeling sites, leading to progressive gains in bone mass.[36897] [26651] [50514]
Cholecalciferol (Vitamin D3): Adequate vitamin D serum concentrations are necessary for normal bone formation. If vitamin D concentrations are insufficient, a negative calcium balance, increased parathyroid hormone concentrations, bone loss, and increased skeletal fracture risk may occur. Vitamin D3 is produced in the skin by photochemical conversion of 7-dehydrocholesterol to previtamin D3 by ultraviolet light. This is followed by non-enzymatic isomerization to vitamin D3. In the absence of adequate sunlight exposure, vitamin D3 is an essential dietary nutrient. Vitamin D3 from the diet is absorbed into chylomicrons and converted to 25-hydroxyvitamin D3 in the liver. In the kidney, 25-hydroxyvitamin D3 is converted to 1,25-dihydroxyvitamin D3 (calcitriol) under the influence of parathyroid hormone and hypophosphatemia. 1,25-dihydroxyvitamin D3 (calcitriol) increases intestinal absorption of calcium and phosphorus and regulates serum calcium concentrations, renal calcium, and phosphorus excretion, bone formation, and bone resorption.[36897] [52900]

Alendronate; cholecalciferol is administered orally.
 
Alendronate: Transient distribution into soft tissue is rapidly followed by redistribution to bone or urinary excretion. Alendronate is approximately 78% bound to protein in human plasma. There is no evidence that any metabolism takes place. Elimination from plasma is rapid, falling 95% within 6 hours of an IV dose. Approximately 50% of a single IV dose is excreted in the urine within 72 hours. Once alendronate is bound to bone, the half-life is more than 10 years. Inhibition of bone resorption diminishes after completion of treatment, suggesting that not all the alendronate sequestered in bone is biologically active.[24426] Estimations suggest that the amount of alendronate released from the skeleton daily after 10 years of daily dosing with 10 mg of alendronate is 25% of that absorbed from the GI tract. Bone resorption in individual remodeling units normally continues for approximately 2 weeks. Due to the long half-life of alendronate in the bone, weekly administration of alendronate should inhibit bone resorption and provide benefits on bone mass and strength to a similar extent as daily administration.[26290]
 
Cholecalciferol: Cholecalciferol enters the blood as part of chylomicrons. Vitamin D3 is rapidly and primarily distributed to the liver. Some vitamin D3 is stored in adipose tissue. In the liver, vitamin D3 is metabolized to 25-hydroxyvitamin D3, which is the major storage form. Circulating vitamin D3 is bound to vitamin D-binding protein. Vitamin D3 is hydroxylated by the liver to 25-hydroxyvitamin D3. In the kidney, 25-hydroxyvitamin D3 is further converted to 1,25-dihydroxyvitamin D3. Glucuronidation and further hydroxylation occur before elimination. The mean urinary excretion of radioactivity 48 hours after radioactive vitamin D3 administration was 2.4% of the dose. The mean fecal excretion was 4.9% of the dose. The mean half-life of vitamin D3 in the serum after a single oral dose of 70 mcg (2,800 International Units) is approximately 14 hours.

The alendronate provided in the Fosamax Plus D tablet is equally bioavailable as compared with the alendronate in the Fosamax 70 mg tablet. Also, the bioavailability of 70 or 140 mcg (2,800 or 5,600 International Units) of cholecalciferol is similar when administered as Fosamax Plus D or individually (without alendronate).
 
Alendronate: Administration is poor with oral bioavailability of less than 1%. Cations (e.g., calcium, magnesium) reduce bioavailability. If alendronate is taken within 2 hours of breakfast, its bioavailability becomes almost negligible. Orange juice or coffee can reduce bioavailability by about 60%. To achieve maximum possible bioavailability, alendronate must be taken in the fasting state and at least 2 hours before a standard breakfast.
 
Cholecalciferol: The mean time to the maximum vitamin D3 serum concentration after an oral dose of alendronate; cholecalciferol given 2 hours before a meal was 10.6 hours.

Alendronate; cholecalciferol is not indicated in women of reproductive potential. It is prudent to avoid alendronate use during pregnancy unless the potential benefit to the mother justifies any possible risk to the fetus. Bisphosphonates are incorporated into the bone matrix, from which they are gradually released over a period of years. The amount of bisphosphonate incorporated into adult bone, and hence, the amount available for release back into the systemic circulation, is directly related to the dose and duration of bisphosphonate use. There are no data on fetal risk due to alendronate in humans. However, there is a theoretical risk of fetal harm (predominantly skeletal) if a woman becomes pregnant after completing a course of bisphosphonate therapy. The impact of variables such as time between cessation of bisphosphonate therapy to conception, the particular bisphosphonate used, and the route of administration (intravenous versus oral) on the risk has not been studied. Bisphosphonates do cause fetal harm (predominantly skeletal) in animals, suggesting the uptake of bisphosphonates into fetal bone is greater than into maternal bone. Animal reproductive studies indicate alendronate may induce fetal skeletal changes, a decrease in maternal serum calcium and protracted parturition, as well as a possible effect on fetal viability. No data are available for cholecalciferol (vitamin D3) specifically. Use of cholecalciferol within the recommended daily dietary intakes for pregnant women are generally recognized as safe; however, hypercalcemia during pregnancy has been associated with suppression of parathyroid hormone in the neonate. Administration of high doses (10,000 international units/every other day or more) of ergocalciferol (vitamin D2) to rabbits resulted in abortions and an increased incidence of fetal aortic stenosis. Administration of vitamin D2 (40,000 international units/day) to rats resulted in neonatal death, decreased fetal weight, and impaired osteogenesis of long bones postnatally.

Alendronate; cholecalciferol is not indicated in women of reproductive potential. Caution should be exercised when alendronate; cholecalciferol is given to a woman who is breast-feeding. Cholecalciferol and some of its active metabolites pass into breast milk. It is not known whether alendronate is excreted in human milk.[36897] Use of cholecalciferol (vitamin D3) within the recommended daily dietary intakes for lactating women is generally recognized as safe.[52900] Serum calcium concentrations in the infant should be monitored when using high doses of vitamin D in a nursing mother, since hypercalcemia has been reported with high dose maternal use.[30166]