Alendronate and cholecalciferol:

MEDICATION SAFETY ISSUES
Sound-alike/look-alike issues:
Fosamax Plus D™ may be confused with Fosamax®

SPECIAL ALERTS
Bisphosphonates: Safety Update Regarding Possible Association With Atrial Fibrillation - November 2008

The Food and Drug Administration (FDA) has been reviewing placebo-controlled trials of the 7 bisphosphonates currently marketed in the US. This review is in response to study results associating an increased incidence of atrial fibrillation (AF) with alendronate or zoledronic acid use in women (65-89 years of age) with osteoporosis.

The FDA reviewed all the submitted data (19,687 bisphosphonate-treated patients and 18,358 placebo-treated patients) from these studies. Overall, the occurrence of AF was rare in each study with an absolute difference in event rates between each of the bisphosphonate and placebo arms of 0-3 per 1000. A zoledronic acid study showed a statistically significant increase in the rate of AF in the active treatment arm. However, no clear association between bisphosphonate use and AF could be established. In this study, AF events were diagnosed more than 30 days after receiving zoledronic acid in 47 of the 50 patients diagnosed with AF. According to the FDA, healthcare providers should not alter their prescribing patterns for bisphosphonates and patients should not stop taking their medication.

The FDA will continue monitoring the safety of bisphosphonates through postmarketing reports and is assessing the need for additional epidemiologic studies.

Further information is available at http://www.fda.gov/Drugs/DrugSafety/PostmarketDrugSafetyInformationforPatientsandProviders/DrugSafetyInformationforHeathcareProfessionals/ucm136201.htm

U.S. BRAND NAMES — Fosamax Plus D™

PHARMACOLOGIC CATEGORY
Bisphosphonate Derivative
Vitamin D Analog

DOSING: ADULTS — Osteoporosis: Oral: One tablet (alendronate 70 mg/cholecalciferol 2800 int. units or alendronate 70 mg/cholecalciferol 5600 int. units) once weekly. Appropriate dose in most osteoporotic women or men: Alendronate 70 mg/cholecalciferol 5600 int. units once weekly.

DOSING: ELDERLY — Refer to adult dosing.

DOSING: RENAL IMPAIRMENT
Clcr 35-60 mL/minute: No adjustment needed.

Clcr <35 mL/minute: Not recommended.

DOSING: HEPATIC IMPAIRMENT — Alendronate: None necessary. Cholecalciferol: May not be adequately absorbed in patients who have malabsorption due to inadequate bile production.

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

DOSAGE FORMS: CONCISE
Tablet:
Fosamax Plus D™ 70/2800: Alendronate 70 mg and cholecalciferol 2800 int. units
Fosamax Plus D™ 70/5600: Alendronate 70 mg and cholecalciferol 5600 int. units

GENERIC EQUIVALENT AVAILABLE — No

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. 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).

USE — Treatment of osteoporosis in postmenopausal females; increase bone mass in males with osteoporosis

ADVERSE REACTIONS SIGNIFICANT — See individual agents.

CONTRAINDICATIONS — Hypersensitivity to alendronate, other bisphosphonates, vitamin D derivatives, or any component of the formulation; hypocalcemia; abnormalities of the esophagus which delay esophageal emptying such as stricture or achalasia; inability to stand or sit upright for at least 30 minutes

WARNINGS / PRECAUTIONS
Concerns related to adverse effects: 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. Osteonecrosis of the jaw: Bisphosphonate therapy has been associated with osteonecrosis, primarily of the jaw; this has been observed mostly in cancer patients, but also in patients with postmenopausal osteoporosis and other diagnoses. Risk factors include a diagnosis of cancer, with concomitant chemotherapy, radiotherapy, or corticosteroids; anemia, coagulopathy, infection or pre-existing dental disease. Most reported cases occurred after I.V. bisphosphonate therapy; however, cases have been reported following oral therapy. Symptoms included nonhealing extraction socket or an exposed jawbone. There are no data addressing whether discontinuation of therapy reduces the risk of developing osteonecrosis. However, as a precautionary measure, dental exams and preventative dentistry should be performed prior to placing patients with risk factors on chronic bisphosphonate therapy. Invasive dental procedures should be avoided during treatment.

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 Clcr <35 mL/minute).

Special populations: Pediatrics: Safety and efficacy have not been established in children.

DRUG INTERACTIONS
Aminoglycosides: May enhance the hypocalcemic effect of Bisphosphonate Derivatives. Risk C: Monitor therapy

Antacids: May decrease the absorption of Bisphosphonate Derivatives. Antacids containing aluminum, calcium, or magnesium are of specific concern. Exceptions: Magaldrate; Sodium Bicarbonate. Risk D: Consider therapy modification

Aspirin: May enhance the adverse/toxic effect of Alendronate. Specifically gastrointestinal adverse events. Risk C: Monitor therapy

Calcium Salts: May decrease the absorption of Bisphosphonate Derivatives. Risk D: Consider therapy modification

Iron Salts: May decrease the absorption of Bisphosphonate Derivatives. Only oral iron salts are of concern. Exceptions: Ferric Gluconate; Ferumoxytol; Iron Dextran Complex; Iron Sucrose. Risk D: Consider therapy modification

Magnesium Salts: May decrease the absorption of Bisphosphonate Derivatives. Only oral magnesium salts are of concern. Risk D: 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. Risk C: Monitor therapy

Phosphate Supplements: Bisphosphonate Derivatives may enhance the hypocalcemic effect of Phosphate Supplements. Risk C: Monitor therapy

ETHANOL / NUTRITION / HERB INTERACTIONS — See individual agents.

PREGNANCY RISK FACTOR — C (show table)

PREGNANCY IMPLICATIONS — Animal studies have shown delays in delivery and fetal/neonatal death (secondary to hypocalcemia). Bisphosphonates are incorporated into the bone matrix and gradually released over time. Theoretically, there may be a risk of fetal harm when pregnancy follows the completion of therapy. No animal data are available for the use of cholecalciferol in pregnancy; however, high-dose ergocalciferol has demonstrated abortifacient properties and aortic abnormalities in rabbits. There are no adequate and well-controlled studies in pregnant women.

LACTATION — Cholecalciferol enters breast milk; excretion of alendronate in breast milk unknown/use caution

DIETARY CONSIDERATIONS — Ensure adequate calcium and vitamin D intake; supplemental calcium should be provided in patients whose dietary intake is inadequate. Recommended intake of vitamin D is 400-800 int. units daily. Certain patients may require additional vitamin D supplementation, particularly patients at risk for vitamin D deficiency (eg, malabsorption syndromes, chronically ill, >70 years of age). Consider monitoring 25-hydroxy vitamin D in patients with malabsorption syndromes. Wait at least 30 minutes after taking alendronate with cholecalciferol before taking any supplement. Must be taken with at least 6-8 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.

PRICING — (data from drugstore.com)
Tablets (Fosamax Plus D)
70-2800 mg-unit (4): $93.00
70-5600 mg-unit (4): $91.93

MONITORING PARAMETERS — Alkaline phosphatase (measured periodically); urine and serum calcium, serum phosphorus, serum 25-hydroxy vitamin D; monitor pain and fracture rate; hormonal status (male and female) prior to therapy; bone mineral density (should be done prior to initiation of therapy and after 6-12 months of combined glucocorticoid and alendronate treatment)

REFERENCE RANGE
Calcium (total): Adults: 9.0-11.0 mg/dL (2.05-2.54 mmol/L), may slightly decrease with aging

Phosphorus: 2.5-4.5 mg/dL (0.81-1.45 mmol/L)

25-hydroxyvitamin D: 10-80 ng/mL (higher during summer)

CANADIAN BRAND NAMES — Fosavance

INTERNATIONAL BRAND NAMES — Adrovance (FR); Fosamax Plus (AR, CN, CO, CR, EC, GT, HK, HN, ID, KP, MX, MY, NI, NZ, PA, SG, SV, TH, TW); Fosavance (AT, BE, BG, CH, CZ, DE, DK, ES, FI, FR, GB, GR, HN, IE, IT, NL, NO, PH, PT, RU, SE, TR); Maximus (PE)

MECHANISM OF ACTION — See individual agents.

PATIENT INFORMATION — Do not take more than the recommended amount. While taking this medication, your prescriber may want you to follow a special diet or take a calcium supplement. Follow this diet closely. Avoid taking magnesium supplements or magnesium-containing antacids. Early symptoms of hypercalcemia include weakness, fatigue, somnolence, headache, anorexia, dry mouth, metallic taste, nausea, vomiting, cramps, diarrhea, muscle pain, bone pain, and irritability.