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Alendronate and Cholecalciferol

Pronunciation

(a LEN droe nate & kole e kal SI fer ole)

Index Terms

  • Alendronate Sodium and Cholecalciferol
  • Cholecalciferol and Alendronate
  • Vitamin D3 and Alendronate

Dosage Forms

Excipient information presented when available (limited, particularly for generics); consult specific product labeling.

Tablet:

Fosamax Plus D 70/2800: Alendronate 70 mg and cholecalciferol 2800 units

Fosamax Plus D 70/5600: Alendronate 70 mg and cholecalciferol 5600 units

Brand Names: U.S.

  • Fosamax Plus D

Pharmacologic Category

  • Bisphosphonate Derivative
  • Vitamin D Analog

Pharmacology

See individual agents.

Use: Labeled Indications

Osteoporosis: Treatment of osteoporosis in postmenopausal females; increase bone mass in males with osteoporosis

Limitations of use: Not for use in the treatment of vitamin D deficiency.

Contraindications

Hypersensitivity to alendronate, vitamin D derivatives, or any component of the formulation; hypocalcemia; abnormalities of the esophagus (eg, stricture or achalasia) which delay esophageal emptying; inability to stand or sit upright for at least 30 minutes

Canadian labeling: Additional contraindications (not in US labeling): Renal insufficiency with CrCl <35 mL/minute

Dosing: Adult

Osteoporosis: Oral: One tablet (alendronate 70 mg/cholecalciferol 2,800 units or alendronate 70 mg/cholecalciferol 5,600 units) once weekly. Consider discontinuing after 3 to 5 years of use for osteoporosis in patients at low-risk for fracture. Supplemental calcium and vitamin D may be necessary if dietary intake is inadequate.

Missed doses: If a once-weekly dose is missed, it should be given the next morning after remembered; may then return to the original once-weekly schedule (original scheduled day of the week), however, do not give 2 doses on the same day.

Dosing: Geriatric

Refer to adult dosing.

Dosing: Renal Impairment

CrCl ≥35 mL/minute: No dosage adjustment necessary.

Clcr <35 mL/minute: Use is not recommended.

Dosing: Hepatic Impairment

Alendronate: No dosage adjustment necessary. Cholecalciferol: May not be adequately absorbed in patients who have malabsorption due to inadequate bile production.

Administration

Alendronate must be taken with plain water (6-8 oz) first thing in the morning and ≥30 minutes before the first food, beverage, or other medication of the day. Do not take with mineral water or with other beverages. Patient should be instructed to stay upright (not to lie down) for at least 30 minutes and until after first food of the day (to reduce esophageal irritation). The tablet should be swallowed whole; do not chew or suck.

Dietary Considerations

Ensure adequate calcium and vitamin D intake; if dietary intake is inadequate, dietary supplementation is recommended. Women and men should consume:

Calcium: 1,000 mg/day (men: 50 to 70 years) or 1,200 mg/day (women ≥51 years and men ≥71 years) (IOM, 2011; NOF [Cosman, 2014])

Vitamin D: 800 to 1,000 int. units daily (men and women ≥50 years) (NOF, 2014). Recommended Dietary Allowance (RDA): 600 int. units daily (men and women ≤70 years) or 800 int. units daily (men and women ≥71 years) (IOM, 2011).

Wait at least 30 minutes after taking alendronate with cholecalciferol before taking any supplement. Must be taken with at least 6 to 8 oz. plain water first thing in the morning and at least 30 minutes before the first food or beverage of the day. Administer with plain water only; do not administer with mineral-enriched water.

Storage

Store at 20°C to 25°C (68°F to 77°F); excursions permitted to 15°C to 30°C (59°F to 86°F). Protect from moisture and light. Keep sealed in blister container or original bottle (with desiccant) until use.

Drug Interactions

Aluminum Hydroxide: Vitamin D Analogs may increase the serum concentration of Aluminum Hydroxide. Specifically, the absorption of aluminum may be increased, leading to increased serum aluminum concentrations. Avoid combination

Aminoglycosides: May enhance the hypocalcemic effect of Bisphosphonate Derivatives. Monitor therapy

Antacids: May decrease the serum concentration of Bisphosphonate Derivatives. Management: Avoid administration of antacids containing polyvalent cations within: 2 hours before or after tiludronate/clodronate/etidronate; 60 minutes after oral ibandronate; or 30 minutes after alendronate/risedronate. Exceptions: Magaldrate; Sodium Bicarbonate. Consider therapy modification

Aspirin: May enhance the adverse/toxic effect of Alendronate. Specifically, the incidence of upper gastrointestinal adverse events may be increased Monitor therapy

Bile Acid Sequestrants: May decrease the serum concentration of Vitamin D Analogs. More specifically, bile acid sequestrants may impair absorption of Vitamin D Analogs. Management: Avoid concomitant administration of vitamin D analogs and bile acid sequestrants (e.g., cholestyramine). Separate administration of these agents by several hours to minimize the potential risk of interaction. Monitor plasma calcium concentrations. Consider therapy modification

Calcium Salts: May decrease the serum concentration of Bisphosphonate Derivatives. Management: Avoid administration of oral calcium supplements within: 2 hours before or after tiludronate/clodronate/etidronate; 60 minutes after oral ibandronate; or 30 minutes after alendronate/risedronate. Consider therapy modification

Cardiac Glycosides: Vitamin D Analogs may enhance the arrhythmogenic effect of Cardiac Glycosides. Monitor therapy

Danazol: May enhance the hypercalcemic effect of Vitamin D Analogs. Monitor therapy

Deferasirox: Bisphosphonate Derivatives may enhance the adverse/toxic effect of Deferasirox. Specifically, the risk for GI ulceration/irritation or GI bleeding may be increased. Monitor therapy

Iron Salts: May decrease the serum concentration of Bisphosphonate Derivatives. Management: Avoid administration of oral iron supplements within: 2 hours before or after tiludronate/clodronate/etidronate; 60 minutes after oral ibandronate; or 30 minutes after alendronate/risedronate. Exceptions: Ferric Carboxymaltose; Ferric Gluconate; Ferric Hydroxide Polymaltose Complex; Ferric Pyrophosphate Citrate; Ferumoxytol; Iron Dextran Complex; Iron Sucrose. Consider therapy modification

Magnesium Salts: May decrease the serum concentration of Bisphosphonate Derivatives. Management: Avoid administration of oral magnesium salts within: 2 hours before or after tiludronate/clodronate/etidronate; 60 minutes after oral ibandronate; or 30 minutes after alendronate/risedronate. Consider therapy modification

Mineral Oil: May decrease the serum concentration of Vitamin D Analogs. More specifically, mineral oil may interfere with the absorption of Vitamin D Analogs. Management: Avoid concomitant, oral administration of mineral oil and vitamin D analogs. Consider separating the administration of these agents by several hours to minimize the risk of interaction. Monitor plasma calcium concentrations. Consider therapy modification

Multivitamins/Fluoride (with ADE): May enhance the adverse/toxic effect of Vitamin D Analogs. Avoid combination

Multivitamins/Minerals (with ADEK, Folate, Iron): May enhance the adverse/toxic effect of Vitamin D Analogs. Avoid combination

Multivitamins/Minerals (with AE, No Iron): May decrease the serum concentration of Bisphosphonate Derivatives. Specifically, polyvalent cation-containing multivitamins may decrease the absorption of orally-administered bisphosphonate derivatives. Management: Avoid administration of polyvalent cation-containing multivitamins within: 2 hours before or after tiludronate/clodronate/etidronate; 60 minutes after oral ibandronate; or 30 minutes after alendronate/risedronate. Consider therapy modification

Nonsteroidal Anti-Inflammatory Agents: May enhance the adverse/toxic effect of Bisphosphonate Derivatives. Both an increased risk of gastrointestinal ulceration and an increased risk of nephrotoxicity are of concern. Monitor therapy

Orlistat: May decrease the serum concentration of Vitamin D Analogs. More specifically, orlistat may impair absorption of Vitamin D Analogs. Management: Monitor clinical response (including serum calcium) to oral vitamin D analogs closely if used with orlistat. If this combination must be used, consider giving the vitamin D analog at least 2 hrs before or after orlistat. Consider therapy modification

Parathyroid Hormone: Alendronate may diminish the therapeutic effect of Parathyroid Hormone. More specifically, Alendronate may interfere with normalization of blood calcium concentrations. Avoid combination

Proton Pump Inhibitors: May diminish the therapeutic effect of Bisphosphonate Derivatives. Monitor therapy

Sucralfate: Vitamin D Analogs may increase the serum concentration of Sucralfate. Specifically, the absorption of aluminum from sucralfate may be increased, leading to an increase in the serum aluminum concentration. Avoid combination

Systemic Angiogenesis Inhibitors: May enhance the adverse/toxic effect of Bisphosphonate Derivatives. Specifically, the risk for osteonecrosis of the jaw may be increased. Monitor therapy

Thiazide and Thiazide-Like Diuretics: May enhance the hypercalcemic effect of Vitamin D Analogs. Monitor therapy

Vitamin D Analogs: May enhance the adverse/toxic effect of other Vitamin D Analogs. Avoid combination

Test Interactions

Bisphosphonates may interfere with diagnostic imaging agents such as technetium-99m-diphosphonate in bone scans.

Adverse Reactions

See individual agents.

Warnings/Precautions

Concerns related to adverse effects:

• Bone fractures: Atypical femur fractures have been reported in patients receiving bisphosphonates for treatment/prevention of osteoporosis. The fractures include subtrochanteric femur (bone just below the hip joint) and diaphyseal femur (long segment of the thigh bone). Some patients experience prodromal pain weeks or months before the fracture occurs. It is unclear if bisphosphonate therapy is the cause for these fractures, although the majority of cases have been reported in patients taking bisphosphonates. Patients receiving long-term (>3-5 years) therapy may be at an increased risk. Discontinue bisphosphonate therapy in patients who develop a femoral shaft fracture.

• Bone/joint/muscle pain: Severe (and occasionally debilitating) bone, joint, and/or muscle pain have been reported during bisphosphonate treatment. The onset of pain ranged from a single day to several months. Consider discontinuing therapy in patients who experience severe symptoms; symptoms usually resolve upon discontinuation. Some patients experienced recurrence when rechallenged with same drug or another bisphosphonate; avoid use in patients with a history of these symptoms in association with bisphosphonate therapy.

• Gastrointestinal mucosa irritation: May cause irritation to upper gastrointestinal mucosa. Esophagitis, dysphagia, esophageal ulcers, esophageal erosions, and esophageal stricture (rare) have been reported with oral bisphosphonates; risk increases in patients unable to comply with dosing instructions. Use with caution in patients with dysphagia, esophageal disease, gastritis, duodenitis, or ulcers (may worsen underlying condition). Discontinue use if new or worsening symptoms develop.

• Ocular effects: Conjunctivitis, uveitis, episcleritis, and scleritis have been reported with alendronate; patients presenting with signs of ocular inflammation may require further ophthalmologic evaluation.

• Osteonecrosis of the jaw: Osteonecrosis of the jaw (ONJ), also referred to as medication-related osteonecrosis of the jaw (MRONJ), has been reported in patients receiving bisphosphonates. Known risk factors for MRONJ include invasive dental procedures (eg, tooth extraction, dental implants, boney surgery), cancer diagnosis, concomitant therapy (eg, chemotherapy, corticosteroids, angiogenesis inhibitors), poor oral hygiene, ill-fitting dentures, and comorbid disorders (anemia, coagulopathy, infection, preexisting dental or periodontal disease). Risk may increase with increased duration of bisphosphonate use. According to a position paper by the American Association of Maxillofacial Surgeons (AAOMS), MRONJ has been associated with bisphosphonates and other antiresorptive agents (denosumab), and antiangiogenic agents (eg, bevacizumab, sunitinib) used for the treatment of osteoporosis or malignancy; risk of MRONJ is significantly higher in cancer patients receiving antiresorptive therapy compared to patients receiving osteoporosis treatment (regardless of medication used or dosing schedule). MRONJ risk is also increased with intravenous antiresorptive use compared with the minimal risk associated with oral bisphosphonate use, although risk appears to increase with oral bisphosphonates when duration of therapy exceeds 4 years (AAOMS [Ruggiero 2014]). The manufacturer’s labeling states that in patients requiring invasive dental procedures, discontinuing bisphosphonates may reduce the risk of ONJ, and clinical judgment should guide the decision. However, the AAOMS suggests there is currently no evidence that interrupting oral bisphosphonate therapy alters the risk of ONJ following tooth extraction, and that in patients receiving oral bisphosphonates for <4 years who have no clinical risk factors, no alternations or delay in any procedure common to oral/maxillofacial surgeons, periodontists, and other dental providers is necessary (special considerations apply to patients receiving dental implants). Conversely, in patients receiving oral bisphosphonates for >4 years or in patients receiving oral bisphosphonates for <4 years who have also taken corticosteroids or antiangiogenic medications concomitantly, the AAOMS recommends considering a 2-month, drug-free period prior to invasive dental procedures (recommendation based on a theoretical benefit). Patients developing ONJ during therapy should receive care by an oral surgeon (AAOMS [Ruggiero 2014]). According to the manufacturer, discontinuation of the bisphosphonate therapy should be considered (based on risk/benefit evaluation) in patients who develop ONJ.

Disease-related concerns:

• Gastrointestinal malabsorption syndrome: Increased doses of vitamin D supplementation may be required in patients with GI malabsorption syndrome; consider monitoring 25-hydroxy vitamin D levels.

• Hypercalcemia: May exacerbate hypercalcemia and/or hypercalciuria in certain disease states (eg, leukemia, lymphoma, sarcoidosis); monitor serum and urine calcium levels.

• Hypocalcemia/vitamin D deficiency: Before therapy initiation hypocalcemia and/or vitamin D deficiency must be corrected; ensure adequate calcium and vitamin D intake. Do not use to treat vitamin D deficiency.

• Renal impairment: Use with caution in patients with renal impairment (not recommended for use in patients with CrCl <35 mL/minute).

Concurrent drug therapy issues:

• Drug-drug interactions: Potentially significant interactions may exist, requiring dose or frequency adjustment, additional monitoring, and/or selection of alternative therapy. Consult drug interactions database for more detailed information.

Other warnings/precautions:

• Duration of therapy: In the management of osteoporosis, re-evaluate the need for continued therapy periodically; the optimal duration of treatment has not yet been determined. Consider discontinuing after 3 to 5 years of use in patients at low-risk for fracture; following discontinuation, re-evaluate fracture risk periodically.

Monitoring Parameters

Bone mineral density (BMD) should be evaluated 1 to 2 years after initiating therapy and every 2 years thereafter (NOF [Cosman, 2014]); annual measurements of height and weight, assessment of chronic back pain; serum calcium and 25(OH)D; may consider monitoring biochemical markers of bone turnover

Pregnancy Risk Factor

C

Pregnancy Considerations

Animal reproduction studies have not been conducted with this combination. The Canadian labeling recommends avoiding use in pregnant women. See individual agents.

Patient Education

• Discuss specific use of drug and side effects with patient as it relates to treatment. (HCAHPS: During this hospital stay, were you given any medicine that you had not taken before? Before giving you any new medicine, how often did hospital staff tell you what the medicine was for? How often did hospital staff describe possible side effects in a way you could understand?)

• Patient may experience constipation or diarrhea. Have patient report immediately to prescriber signs of low calcium (muscle cramps or spasms, numbness and tingling, or seizures); black, tarry, or bloody stools; angina, coughing up blood; severe abdominal pain; heartburn; difficulty swallowing; pain when swallowing; pharyngitis; severe nausea; severe vomiting; vomiting blood; severe bone pain; severe joint pain; severe muscle pain; groin, hip, or thigh pain; mouth sores; or jaw pain or edema (HCAHPS).

• Educate patient about signs of a significant reaction (eg, wheezing; chest tightness; fever; itching; bad cough; blue skin color; seizures; or swelling of face, lips, tongue, or throat). Note: This is not a comprehensive list of all side effects. Patient should consult prescriber for additional questions.

Intended Use and Disclaimer: Should not be printed and given to patients. This information is intended to serve as a concise initial reference for healthcare professionals to use when discussing medications with a patient. You must ultimately rely on your own discretion, experience and judgment in diagnosing, treating and advising patients.

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