Alendronate:

MEDICATION SAFETY ISSUES
Sound-alike/look-alike issues:
Alendronate may be confused with risedronate
Fosamax® may be confused with Flomax®, Fosamax Plus D™ , fosinopril, Zithromax®

International issues:
Fosamax® may be confused with Fisamox® which is a brand name for amoxicillin in Australia

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®

PHARMACOLOGIC CATEGORY
Bisphosphonate Derivative

DOSING: ADULTS — Note: Patients treated with glucocorticoids and those with Paget's disease should receive adequate amounts of calcium and vitamin D.

Osteoporosis in postmenopausal females: Oral:
Prophylaxis: 5 mg once daily or 35 mg once weekly
Treatment: 10 mg once daily or 70 mg once weekly

Osteoporosis in males: Oral: 10 mg once daily or 70 mg once weekly

Osteoporosis secondary to glucocorticoids in males and females: Oral: Treatment: 5 mg once daily; a dose of 10 mg once daily should be used in postmenopausal females who are not receiving estrogen.

Paget's disease of bone in males and females: Oral: 40 mg once daily for 6 months
Retreatment: Relapses during the 12 months following therapy occurred in 9% of patients who responded to treatment. Specific retreatment data are not available. Following a 6-month post-treatment evaluation period, treatment with alendronate may be considered in patients who have relapsed based on increases in serum alkaline phosphatase, which should be measured periodically. Retreatment may also be considered in those who failed to normalize their serum alkaline phosphatase.

DOSING: ELDERLY — Refer to adult dosing.

DOSING: RENAL IMPAIRMENT
Clcr 35-60 mL/minute: None necessary.

Clcr <35 mL/minute: Alendronate is not recommended due to lack of experience.

DOSING: HEPATIC IMPAIRMENT — No adjustment necessary.

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

Solution, oral:
Fosamax®: 70 mg/75 mL [contains parabens; raspberry flavor]

Tablet: 5 mg, 10 mg, 35 mg, 40 mg, 70 mg
Fosamax®: 5 mg, 10 mg, 35 mg, 40 mg, 70 mg

DOSAGE FORMS: CONCISE
Solution, oral:
Fosamax®: 70 mg/75 mL

Tablet: 5 mg, 10 mg, 35 mg, 40 mg, 70 mg
Fosamax®: 5 mg, 10 mg, 35 mg, 40 mg, 70 mg

GENERIC EQUIVALENT AVAILABLE — Yes: Tablet

ADMINISTRATION — Alendronate must be taken with plain water (tablets 6-8 oz; oral solution follow with 2 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. Patients 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). Patients should receive supplemental calcium and vitamin D if dietary intake is inadequate.

USE — Treatment and prevention of osteoporosis in postmenopausal females; treatment of osteoporosis in males; Paget's disease of the bone in patients who are symptomatic, at risk for future complications, or with alkaline phosphatase ≥ 2 times the upper limit of normal; treatment of glucocorticoid-induced osteoporosis in males and females with low bone mineral density who are receiving a daily dosage ≥ 7.5 mg of prednisone (or equivalent)

ADVERSE REACTIONS SIGNIFICANT — Note: Incidence of adverse effects (mostly GI) increases significantly in patients treated for Paget's disease at 40 mg/day.

>10%: Endocrine & metabolic: Hypocalcemia (transient, mild, 18%); hypophosphatemia (transient, mild, 10%)

1% to 10%:
Cardiovascular: Atrial fibrillation (1% to 2%)
Central nervous system: Headache (up to 3%)
Gastrointestinal: Abdominal pain (1% to 7%), acid reflux (1% to 4%), dyspepsia (1% to 4%), nausea (1% to 4%), flatulence (up to 4%), diarrhea (1% to 3%), gastroesophageal reflux disease (1% to 3%), constipation (up to 3%), esophageal ulcer (up to 2%), abdominal distension (up to 1%), gastritis (up to 1%), vomiting (up to 1%), dysphagia (up to 1%), gastric ulcer (1%), melena (1%)
Neuromuscular & skeletal: Musculoskeletal pain (up to 6%), muscle cramps (up to 1%)

<1% (Limited to important or life-threatening): Alopecia, anastomotic ulcer, angioedema; bone, muscle, or joint pain (occasionally severe, considered incapacitating in rare cases); dizziness, duodenal ulcer, episcleritis, erythema, esophageal cancer, esophageal erosions, esophageal perforation, esophageal stricture, esophagitis, fever, flu-like syndrome, hypersensitivity reactions, hypocalcemia (symptomatic), joint swelling, lymphocytopenia, malaise, myalgia, oropharyngeal ulceration, osteonecrosis (jaw), peripheral edema, photosensitivity (rare), pruritus, rash, scleritis (rare), Stevens-Johnson syndrome, taste perversion, toxic epidermal necrolysis, urticaria, uveitis (rare), vertigo, weakness

CONTRAINDICATIONS — Hypersensitivity to alendronate, other bisphosphonates, 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; oral solution should not be used in patients at risk of aspiration

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. Hypocalcemia: Hypocalcemia has been reported with the use of bisphosphonates. Prior to therapy initiation, hypocalcemia must be corrected; ensure adequate calcium and vitamin D intake. 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: 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
Ethanol: Avoid ethanol (may increase risk of osteoporosis and gastric irritation).

Food: All food and beverages interfere with absorption. Coadministration with caffeine may reduce alendronate efficacy. Coadministration with dairy products may decrease alendronate absorption. Beverages (especially orange juice and coffee) and food may reduce the absorption of alendronate as much as 60%.

PREGNANCY RISK FACTOR — C (show table)

PREGNANCY IMPLICATIONS — Safety and efficacy have not been established in pregnant women. 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. Based on limited case reports with pamidronate, serum calcium levels in the newborn may be altered if administered during pregnancy.

LACTATION — Excretion in breast milk unknown/use caution

DIETARY CONSIDERATIONS — Ensure adequate calcium and vitamin D intake; women >50 years of age should consume 1200-1500 mg/day of elemental calcium and 800-1000 int. units/day of vitamin D. Wait at least 30 minutes after taking alendronate before taking any supplement. Alendronate must be taken with plain water first thing in the morning and at least 30 minutes before the first food or beverage of the day.

PRICING — (data from drugstore.com)
Solution (Fosamax)
70 mg/75 mL (75): $33.13

Tablets (Alendronate Sodium)
5 mg (100): $255.98
10 mg (100): $234.99
35 mg (4): $49.99
40 mg (30): $179.99
70 mg (4): $32.99

Tablets (Fosamax)
5 mg (30): $91.92
10 mg (30): $95.12
35 mg (4): $87.65
70 mg (4): $93.00

MONITORING PARAMETERS — Alkaline phosphatase should be periodically measured; serum calcium and phosphorus; 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)

CANADIAN BRAND NAMES — Apo-Alendronate®; CO Alendronate; Dom-Alendronate; Fosamax®; Gen-Alendronate; Novo-Alendronate; PHL-Alendronate; PHL-Alendronate-FC; PMS-Alendronate; PMS-Alendronate-FC; ratio-Alendronate; Riva-Alendronate; Sandoz Alendronate

INTERNATIONAL BRAND NAMES — Aldrox (CN); Alenato (AR); Alend (KP); Alendro (AU); Alendros (KP); Alenmax (KP); Alnax (PY); Alond (KP); Alovell (ID); Arendal (PE); Armol (CO); Bifemelan (CO); Bifosa (IN); Bisbon (KP); Bonapex (EG); Endronax (BR); Eucalen (CO); Fixopan (EC); Fosalan (IL); Fosamax (AR, AT, AU, BB, BE, BG, BM, BR, BS, BZ, CH, CL, CN, CR, CZ, DE, DK, EC, EE, EG, ES, FI, FR, GB, GR, GT, GY, HK, HN, ID, IE, IT, JM, MX, MY, NI, NL, NO, PA, PE, PH, PK, PT, SE, SG, SR, SV, TH, TT, TW, VE); Fosaqueen (KP); Fosmin (PE); Fosval (PY); Gendarin (SE); Marvil (PE, UY); MaxiBone (IL); MaxiBone 70 (IL); Neobon (CO); Nichospor (ID); Oseotenk (AR); Osficar (CO); Osteofar (ID); Osteofos (HK, IN); Osteopor (UY); Osteosan (CN); Osteovan (CR); Porosal (VE); Tevanate (BG); Voroste (ID)

MECHANISM OF ACTION — A bisphosphonate which inhibits bone resorption via actions on osteoclasts or on osteoclast precursors; decreases the rate of bone resorption, leading to an indirect increase in bone mineral density. In Paget's disease, characterized by disordered resorption and formation of bone, inhibition of resorption leads to an indirect decrease in bone formation; but the newly-formed bone has a more normal architecture.

PHARMACODYNAMICS / KINETICS
Distribution: 28 L (exclusive of bone)

Protein binding: ~78%

Metabolism: None

Bioavailability: Fasting: 0.6%; reduced 60% with food or drink

Half-life elimination: Exceeds 10 years

Excretion: Urine; feces (as unabsorbed drug)

PATIENT INFORMATION — Take as directed, with a full glass of water first thing in the morning and at least 30 minutes before the first food or beverage of the day. Wait at least 30 minutes after taking alendronate before taking anything else. Stay in sitting or standing position for 30 minutes following administration and until after the first food of the day to reduce potential for esophageal irritation. Consult prescriber to determine necessity of lifestyle changes (eg, decreased smoking, decreased alcohol intake, dietary supplements of calcium, or increased dietary vitamin D