CLASSES

Oral Bisphosphonates in Combination with Vitamins

DEA CLASS

Rx

DESCRIPTION

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

COMMON BRAND NAMES

Fosamax Plus D

HOW SUPPLIED

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

DOSAGE & INDICATIONS

MAXIMUM DOSAGE

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.

DOSING CONSIDERATIONS

No dosage adjustment is needed.

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

ADMINISTRATION

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.

STORAGE

Generic:
- Protect from light
- Protect from moisture
- Store between 68 to 77 degrees F, excursions permitted 59 to 86 degrees F
Fosamax Plus D:
- Protect from light
- Protect from moisture
- Store between 68 to 77 degrees F, excursions permitted 59 to 86 degrees F
- Store in a dry place
- Store in original package until time of use

CONTRAINDICATIONS / PRECAUTIONS

NOTE: This monograph discusses the use of alendronate and cholecalciferol together. Consult the individual alendronate monograph for more detailed information.

Alendronate; cholecalciferol is contraindicated in patients with a known hypersensitivity to the drug or to any ingredients in the product formulation. Alendronate; cholecalciferol tablets contain lactose; patients with lactase deficiency should take appropriate precautions with use.

A history of GI disease is an independent risk factor for the development of GI adverse reactions during alendronate therapy.[26144] Severe reactions requiring hospitalization have occurred. Alendronate; cholecalciferol should be used with caution in patients with esophageal and GI disease including dysphagia, esophagitis, gastritis, gastroesophageal reflux disease (GERD), hiatal hernia, duodenitis, ulcers, or GI perforation. Alendronate; cholecalciferol is contraindicated in patients with abnormalities of the esophagus that delay esophageal emptying such as esophageal stricture or achalasia. Further, use is contraindicated in patients with an inability to stand or sit upright for at least 30 minutes after dose administration as the risk of esophagitis and esophageal ulceration/erosion appears to be greater in patients who lay down after taking this medicine. Prescribers and health care professionals should closely monitor patients for any signs or symptoms an esophageal reaction. Advise patients to discontinue alendronate; cholecalciferol and seek medical attention if they develop dysphagia, odynophagia, or retrosternal pain. The risk of esophageal reactions increases in patients who do not follow the administration instructions. It is very important that patients understand and follow these instructions; direct observation may be required in those who cannot independently follow dosing instructions due to mental disability. In 2011, the FDA announced an ongoing review of data from published studies to evaluate whether use of oral bisphosphonate drugs is associated with an increased risk of esophageal cancer. There have been conflicting findings from studies evaluating this risk. At the time of the announcement, FDA states that the benefits of oral bisphosphonate drugs in reducing the risk of serious fractures in people with osteoporosis continue to outweigh their potential risks.

Geriatric patients may be at increased risk for the development of adverse GI reactions during alendronate; cholecalciferol therapy. Increased age has been identified as an independent risk factor particularly for GI perforations, ulcers, or bleeding but not necessarily esophageal events. A few published reports have suggested that the absorption of orally administered vitamin D may be attenuated in elderly as compared with younger individuals. Dietary requirements of vitamin D3 are increased in the elderly. Additional vitamin D supplementation beyond the amount provided by alendronate; cholecalciferol is recommended for patients who are over 70 years of age, nursing home bound, or chronically ill, as these patients are at increased risk for vitamin D insufficiency.

The risk versus benefit of alendronate; cholecalciferol therapy in patients who are receiving corticosteroid therapy (systemic prednisone doses < 7.5 mg/day or other corticosteroid equivalent) has not been established. Before initiating therapy, the hormonal status of both men and women should be determined and appropriate replacement therapy started, if needed. Bone mineral density measurements should be done at baseline and after 6—12 months of combined corticosteroid and alendronate; cholecalciferol therapy (see Interactions). The efficacy of alendronate in the treatment of corticosteroid-induced osteoporosis has been shown in patients with a median bone mineral density that is 1.2 standard deviations below the mean for healthy young adults.

Alendronate can decrease serum calcium concentrations. Preexistent hypocalcemia is a contraindication to use of alendronate; cholecalciferol and must be corrected before initiating therapy. Similarly, vitamin D deficiency must also be corrected. In clinical trials, patients with 25-hydroxyvitamin D3 concentrations less than 9 ng/mL were excluded. Adequate intake of calcium and vitamin D during treatment are essential.

Alendronate; cholecalciferol should be used cautiously in patients with hyperphosphatemia due to the risk of metastatic calcification. Furthermore, alendronate; cholecalciferol should be avoided in patients with renal osteodystrophy with hyperphosphatemia. Alendronate can decrease serum phosphate concentrations, and calcitriol increases phosphate absorption (see Mechanism of Action). Alendronate; cholecalciferol may be initiated after stabilization of phosphorus concentrations. Monitor patients for symptoms of hypophosphatemia or hyperphosphatemia during alendronate; cholecalciferol receipt.

Alendronate; cholecalciferol should not be given to patients with hypercalcemia or hypervitaminosis D. Hypercalcemia, hypercalciuria, anorexia, nausea, vomiting, polyuria, polydipsia, weakness, and lethargy are possible signs and symptoms of vitamin D toxicity. Cases of vitamin D toxicity have been reported in patients receiving at least 250 mcg (10,000 International Units) daily for at least a month. Chronic hypercalcemia can lead to soft tissue calcification, nephrocalcinosis, and other toxicities. The serum calcium times phosphate (Ca x P) product should not exceed 70. Radiographic evaluation of suspect areas may be useful in the early detection of soft tissue calcification. Monitor the patient's serum and urine calcium concentrations if vitamin D toxicity is suspected. Treatment may include hydration and dietary calcium restriction. Systemic glucocorticoids may be necessary for patients with severe hypercalcemia.

About 50% of a single IV dose of alendronate is excreted in the urine. Studies in animals indicated that any alendronate not deposited in bone was rapidly excreted. No human study results are available, but it is likely that patients with severe renal impairment will accumulate alendronate. In addition, patients with renal insufficiency will have a decreased ability to form the active 1,25-dihydroxyvitamin D3 metabolite. Use of excessive cholecalciferol doses acutely or for a prolonged period can result in vitamin D-induced hypercalcemia manifest as nephrocalcinosis and other calcifications. These adverse reactions can be significant in patients with renal failure, even with usual dosages. Cholecalciferol should be used with caution in patients with renal disease or renal stones (nephrolithiasis). No dosage adjustment of alendronate; cholecalciferol is recommended by the manufacturer if creatinine clearance is > 35 mL/min (mild to moderate renal insufficiency). Due to an absence of data, alendronate; cholecalciferol is not recommended for patients with creatinine clearance < 35 mL/min (renal failure).

Alendronate; cholecalciferol is not indicated for use in children. Bisphosphonates have been used successfully in children for treatment of specific disease states (i.e., hypercalcemia of malignancy, idiopathic or glucocorticoid induced osteoporosis, osteogenesis imperfecta, Paget's disease). The efficacy and safety of alendronate in children aged 4—18 years of age with osteogenesis imperfecta has been evaluated. In a 2-year study, 109 patients were randomized to either 5 mg of alendronate once daily (weight < 40 kg) or 10 mg of alendronate once daily (weight >= 40 kg), and 30 patients were randomized to placebo. The mean change in BMD Z-score from baseline was 1.3 in the alendronate-treated groups and 0.1 in the placebo group; treatment with alendronate did not reduce fracture rates. Of the patients who sustained a radiologically-confirmed fracture by month 12 of the study, 16% of alendronate-treated compared with only 9% of placebo-treated patients had delayed fracture healing or fracture non-union when assessed radiographically at month 24. In addition, at month 24, patients treated with alendronate demonstrated decreased bone turnover and delayed mineralization time. There were no differences between the alendronate-treated and the placebo-treated patients with respect to bone pain. Extreme caution must be used to ensure appropriate use in children; excessive doses of bisphosphonates may compromise skeletal quality during growth, despite concomitant increases in bone density. In a case report, inappropriate and excessive doses of pamidronate in a child resulted in osteopetrosis (abnormally dense and misshapen bone predisposed to fracture). It may be advisable to monitor biochemical markers of skeletal turnover when bisphosphonates are used in children to help assure clinicians that skeletal resorption is not excessively suppressed.

Alendronate; cholecalciferol should be used with caution in patients with hypoparathyroidism. Calcium, dihydrotachysterol, or parathyroid hormone may need to be added to therapy.

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]

Alendronate; cholecalciferol is contraindicated in patients with alendronate hypersensitivity or hypersensitivity to any of the components in the formulation. Alendronate should be used cautiously in patients with known phosphonate hypersensitivity.

Sunlight (UV) exposure should be limited in patients receiving alendronate; cholecalciferol. Alendronate may cause a rash that is worsened by exposure to the sun.

Osteonecrosis of the jaw may occur with alendronate; cholecalciferol. It has been reported in patients with cancer receiving treatment regimens which included bisphosphonates (most commonly pamidronate and zoledronic acid), but also occasionally in patients receiving chronic oral bisphosphonate therapy for osteoporosis including alendronate. The risk may increase with duration of exposure to the bisphosphonate. In patients with cancer receiving intravenous bisphosphonates, many patients were also receiving chemotherapy and corticosteroids. The majority of reported cases have been associated with dental procedures, such as tooth extraction, and many of these patients had signs of local infection including osteomyelitis; however, cases have appeared spontaneously. It would be prudent for all patients including those with concomitant risk factors (e.g. anemia, cancer, chemotherapy, coagulopathy, corticosteroid therapy, dental disease, infection, poor oral hygiene) initiating bisphosphonate therapy to receive a dental examination with appropriate preventive dentistry and correction of dental complications prior to beginning treatment. Preventive measures such as these as well as continued regular follow-up with a dentist during bisphosphonate therapy are recommended by the American Academy of Oral Medicine as the best way to minimize the risk of osteonecrosis. Invasive dental procedures should be avoided, if possible, during treatment, but if they are necessary, should be performed by an experienced dentist with close patient follow-up. If osteonecrosis of the jaw does develop during bisphosphonate therapy, it should be noted that dental surgery may exacerbate the condition. For patients requiring dental work, no data are available to suggest whether discontinuation of bisphosphonate treatment reduces the risk of osteonecrosis of the jaw. In addition, discontinuing the bisphosphonate once osteonecrosis develops is controversial as the estimated half-life of bisphosphonates in the bone is years.

Patients with a malabsorption syndrome may not have adequate vitamin D3 absorption due to inadequate bile production. Additional vitamin D supplementation beyond the amount provided by alendronate; cholecalciferol may be needed for patients with gastrointestinal malabsorption syndromes. Determination of serum 25-hydroxyvitamin D concentrations may be advisable.

Lymphoma, leukemia, and sarcoidosis are conditions that are associated with unregulated 1,25-dihydroxyvitamin D overproduction. Administration of alendronate; cholecalciferol to patients with one of these conditions may cause or worsen hypercalcemia or hypercalciuria. Monitoring of urine and serum calcium concentrations is recommended.

ADVERSE REACTIONS

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

DRUG INTERACTIONS

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; Butalbital; 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.
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.
Aspirin, ASA; Pravastatin: (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.
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.

PREGNANCY AND LACTATION

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]

MECHANISM OF ACTION

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]

PHARMACOKINETICS

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.