Drug Criteria & Outcomes: Actonel and Fosamax Formulary Evaluation
February 1, 2002 10 minutes read
Drug Criteria & Outcomes: Actonel and Fosamax Formulary Evaluation
By Travis Ball, PharmD
Written as a PharmD candidate at Auburn
University School of Pharmacy, Auburn, AL
Description
Alendronate (Fosamax) and risedronate (Actonel) are bisphosphonates used to increase bone mineral density (BMD) in patients with osteoporosis and glucocorticoid-induced osteoporosis. In addition, both drugs are used to treat Paget’s disease.1,2
Mechanism of action1,2
Bisphosphonates are synthetic analogs of pyrophosphate that bind to bone hydroxyapatite and become a permanent part of the bone structure. Once bound, they act as a specific inhibitor of osteoclast-mediated bone resorption. When osteoclasts bind to the bisphosphonate-contained bone surface, their structure and function are altered, preventing adherence and resorption.
Alendronate differs from other bisphosphonate compounds by its side chain amino group. This side chain imparts greater potency and specificity by preferentially localizing resorption sites of active bone turnover. Normal doses have been shown to inhibit bone resorption, but have minimal or no effect on bone mineralization.
Risedronate is a pyridinyl bisphosphonate that is more potent and specific than other
bisphosphonates, including alendronate. Risedronate has been shown to decrease bone resorption without impairing mineralization or interfering with bone formation.
Pharmacokinetics1,2
The timing of bisphosphonate administration in relation to food intake influences both the extent and rate of absorption. Alendronate’s bioavailability is almost negligible if administered within two hours following a meal. Administration with coffee or orange juice can decrease the amount of drug absorbed by 60%. Approximately 20-50% of the bisphosphonate in blood binds to bone surfaces, and the remainder of the drug is excreted unchanged in the urine. The circulating serum half-life is relatively short, but the terminal half-life, bound to bone surface, involves extended time periods. See Table 1, for more pharmacokinetic information.
Indications and dosage
Both alendronate and risedronate are indicated for treatment and prevention of osteoporosis in postmenopausal women, glucocorticoid-induced osteoporosis, and Paget’s disease.1,2 Alendronate, however, is additionally indicated for osteoporosis in men and also can be dosed once weekly for osteoporosis in postmenopausal women. The risedronate dosage regimen specifies only two months of treatment for Paget’s disease; the alendronate dosage regimen recommends six months.
Both alendronate and risedronate should be taken with 6-8 ounces of water 30 minutes prior to food. In addition, the patient should remain in an upright position for 30 minutes after taking medication to reduce the chances of experiencing upper GI irritations. Currently, studies are in progress to investigate the safety and efficacy of risedronate, 35 mg once weekly, for treatment of osteoporosis; Food and Drug Administration approval of this regimen is expected in 2002.
Risedronate
Treatment and prevention of osteoporosis in postmenopausal women: 5 mg once daily. Treatment and prevention of glucocorticoid-induced osteoporosis: 5 mg once daily. Treatment of Paget’s disease: 30 mg once daily for two months; retreatment may be necessary.
Alendronate
Treatment of osteoporosis in postmenopausal women: 10 mg once daily or 70 mg once weekly.
Prevention of osteoporosis in postmenopausal women: 5 mg once daily or 35 mg once weekly.
Treatment to increase bone mass in men with osteoporosis: 10 mg once daily (70 mg once weekly currently is being studied).
Treatment and prevention of glucocorticoid-induced osteoporosis: 5 mg once daily.
Treatment of Paget’s disease: 40 mg once daily for six months; retreatment may be necessary
Contraindications
Alendronate and risedronate have similar contraindications. However, since some studies show that risedronate may not be as irritating to the GI tract, the manufacturer did not include esophageal abnormalities as a contraindication for that drug. In addition, patients who are unable to stand up for 30 minutes after taking their dose are not contraindicated to receive risedronate.1,2
Alendronate
- Hypersensitivity to alendronate or any component of the product;
- Hypocalcemia;
- Esophageal abnormalities that delay esophageal emptying;
- Patients unable to stand or sit upright for 30 minutes after dose.
Risedronate
- Hypersensitivity to risedronate or other bisphosphonates;
- Hypocalcemia.
Precautions1,2
Caution should be exercised in patients with a CrCl < 35 mL/min or with GI disorders. In addition, vitamin D and mineral deficiencies should be corrected before initiating therapy.
Clinical studies
To date, there are no head-to-head clinical trials comparing the efficacy of alendronate to risedronate. However, there are numerous trials that examine the effects of each drug in different indicated disease states. Tables 2-9 (see chart 2, 3, 4, 5, 6, 7, 8, 9) show the abbreviated results of the major studies with each drug.
All of the clinical trials reviewed were reliable. The sample size in a few trials was small, but overall there were not any apparent major credibility problems. The doses used in each trial and the criteria used to evaluate the results were appropriate for each disease state. According to the results of the studies, both risedronate and alendronate are effective for their indicated disease states. However, because there were no comparative efficacy trials between the two drugs, and endpoints differed in many trials (e.g., BMD vs. fracture risk), it would be difficult to conclude which drug is more effective.
Adverse effects1,2
Some studies show that the degree of GI irritation may differ among the bisphosphonates, particularly with risedronate. Risedronate is a pyridinyl bisphosphonate, whereas alendronate is a primary amino bisphosphonate. The primary amino structure of alendronate is thought to be more irritating to the GI tract due to interference with the hydrophobic phospholipid barrier of the gastric tissue. This interference may lead to damage of the esophageal and gastric lining. Due to the nitrogen found in the pyridinyl ring structure in risedronate, phospholipid interference may not be as significant as that seen with alendronate.
The data from the head-to-head comparison showed that there was a statistically significant difference in the incidence of gastric ulcers between alendronate and risedronate (to see Table 10, click here). In addition, patients in the alendronate group had higher average gastric endoscopy scores. However, there was neither a significant difference in the incidence of esophageal or duodenal ulcers, nor in the average esophageal or duodenal endoscopy scores. The results of this trial are not consistent with previous reports of gastric ulcers caused by bisphosphonates. Prior to this trial, reports of gastric ulcers caused by alendronate or risedronate were rare. Because this trial was not placebo-controlled, it is difficult to evaluate the reliability of these results.
Lanza et al conducted both of these studies and had conflicting findings. In the study comparing alendronate to aspirin and placebo (to see Table 11, click here), the results were similar to other reports of gastric ulcers. In this study, the incidence was shown to be low in a small sample size. However, in the study comparing alendronate to risedronate (to see Table 10, click here), the reported incidence of gastric ulcers increased greatly (~ 13.2%). Unlike the first study, there was no placebo group to compare the results to in the alendronate vs. risedronate study. Therefore, it is difficult to base a conclusion as to which bisphosphonate is safer. The results of the alendronate vs. risedronate study differ from any other literature currently available, including a study by the same author. Due to this discrepancy, a conclusion cannot be based on its results.
The following adverse events also have been reported with alendronate: hypocalcemia (13%), acid regurgitation (2%), esophagitis (1.5%), rash (< 1%), and headache (2.6%). Adverse events reported with the use of risedronate include (vs. placebo if available): diarrhea (10.6% vs. 9.6%), arthralgia (23.7% vs. 21.1%), epgasric discomfort (2%), rash (7.7% vs. 7.2%), and headache (2.9%).
Drug interactions
Alendronate1
- Products containing antacids and calcium may decrease the bioavailability of alendronate if they are taken at the same time as the dose.
- Drugs that are known to cause GI damage (salicylates and NSAIDs) may potentiate the GI effects of alendronate.
- IV ranitidine has been shown to increase the bioavailability of alendronate; however, the clinical significance of this reaction has yet to be determined.
Risedronate2
- Products containing antacids and calcium may decrease the bioavailability of risedronate if they are taken at the same time as the dose.
- Due to a lower incidence of GI irritation, salicylates and NSAIDs are not documented drug interactions with risedronate.
Administration
To reduce the potential for gastrointestinal reactions and to maximize oral absorption, a special administration procedure with bisphosphonates is recommended. They should be taken with 6-8 ounces of plain water at least 30 minutes prior to the first food, drink, or medication of the day. The patient then should avoid lying down for at least 30 minutes and until after the first food of the day. Patients should be instructed not to take either drug at bedtime or before rising for the day. The tablets should also not be sucked or chewed. These administration recommendations are the same for both the once-daily and once-weekly dosages. Within an institution, development of a standard bisphosphonate administration protocol may prove valuable. Cost information is available in Table 12 (to see table 12, click here).
Summary
Due of the lack of head-to-head trials comparing the efficacy of alendronate and risedronate, it is difficult to conclude which drug is more effective or safe. One study demonstrated that risedronate might have an advantage over alendronate with the incidence of gastric erosions and ulcers; however, the results may not be reliable because the study lacked a placebo group and the results differed from all other previous reports of gastric ulcers caused by alendronate.
Alendronate is available in a once-weekly tablet that may increase patient compliance compared to once-daily dosing. However, since the average stay in the hospital is now five days or less, once-weekly alendronate may not be cost-effective for the hospital since the cost of one 70 mg tablet is equal to the price of seven 10 mg tablets. Therefore, once-weekly alendronate may actually increase drug cost in patients who will be admitted to the hospital for a short period of time. However, for patients who are admitted for more than two weeks (i.e., rehabilitation hospital), once-weekly dosing generally would not appreciably increase drug costs.
Additionally, due to the higher risk of esophageal erosions in acutely ill bedridden patients receiving bisphosphonates, it is reasonable for acute care hospitals to remove these two drugs from the formulary and not administer them to patients for prevention or treatment of osteoporosis. Because of the long terminal half-life of these agents, temporary discontinuation during a hospital stay should have no significant clinical impact on long-term outcomes with osteoporosis. If appropriate, either drug could be continued during hospitalization for the infrequent cases of Paget’s disease. At Huntsville (AL) Hospital, a 900-bed acute care hospital, annual drug expenditures could be reduced by approximately $12,000-$15,000 if alendronate and risedronate were recognized as non-formulary drugs and inpatient therapy was deferred.
Currently, daily alendronate is less expensive and offers more dosing options than daily risedronate. Additional studies should be conducted, directly comparing both the safety and efficacy of these two bisphosphonates.
Recommendation
Alendronate and risedronate could be deleted from most acute-care hospital formularies, based on safety, efficacy, and economic considerations. Alternatively, either drug could represent the other on the formulary.
For example, if alendronate is the formulary agent, patients who are admitted to the hospital on alendronate for the treatment or prevention of osteoporosis or Paget’s disease could be continued on alendronate. If a patient is admitted to the hospital on alendronate 70 mg/wk, then the patient could be continued on the once-weekly dose or placed on once-daily dosing, depending on the predicted length of stay, or bisphosphonate therapy could be held during hospitalization. If a patient presents to the hospital on risedronate for the treatment or prevention of osteoporosis or Paget’s disease, then the drug could be changed to the equivalent dose of alendronate. If a patient needs to be started on a bisphosphonate for treatment or prevention of postmenopausal osteoporosis, glucocorticoid osteoporosis, or Paget’s disease, then alendronate could be started, either in the hospital or at discharge.
References
1. Merck & Co. Fosamax package insert. Whitehouse Station, NJ; 2000.
2. Proctor & Gamble Pharmaceuticals. Actonel prescribing information. Cincinnati; 2000.
3. Harris ST, et al. Effects of risedronate treatment on vertebral and nonvertebral fractures in women with postmenopausal osteoporosis: A randomized controlled trial. JAMA 1999; 282:1344-1352.
4. Reginster J, et al. Randomized trial of the effects or risedronate on vertebral fractures in women with established postmenopausal osteoporosis. Osteoporos Int 2000; 11:83-91.
5. Cohen S, et al. Risedronate therapy prevents corticosteroid-induced bone loss. Arthritis Rheum 1999; 42:2309-2318.
6. Reid DM, et al. Efficacy and safety of daily risedronate in the treatment of corticosteroid-induced osteoporosis in men and women: A randomized trial. J Bone Miner Res 2000; 15:1006-1013.
7. Miller PD, et al. A randomized, double-blind comparison of risedronate and etidronate in the treatment of Paget’s disease of bone. Am J Med 1999; 106:513-520.
8. Singer FR, et al. Risedronate, a highly effective oral agent in the treatment of patients with severe Paget’s disease. J Clin Endocrinol Metab 1998; 83:1906-1910.
9. McClung M, et al. Alendronate prevents postmenopausal bone loss in women without osteoporosis. A double-blind, randomized, controlled trial. Ann Intern Med 1998; 128:253-261.
10. Saag KG, et al. Alendronate for the prevention and treatment of glucocorticoid-induced osteoporosis. N Engl J Med 1998; 339:292-299.
11. Reid IR, et al. Biochemical and radiologic improvement in Paget’s disease of bone treated with alendronate: A randomized, placebo-controlled trial. Am J Med 1996; 101:341-348.
12. Orwoll E, et al. Alendronate for the treatment of osteoporosis in men. JAMA 2000; 343:604-610.
13. Schnitzer T, et al. Therapeutic equivalence of alendronate 70 mg once-weekly and aldendronate10 mg daily in the treatment of osteoporosis. Aging (Milano) 2000; 12:1-12.
14. Lanza FL, et al. Endoscopic comparison of esophageal and gastroduodenal effects of risedronate and alendronate in postmenopausal women. Gastroenterology 2000; 119:631-638.
15. Lanza FL, et al. Effects of alendronate on gastric and duodenal mucosa. Am J Gastroenterol 1998; 93:753-757.
16. Personal communication. Cindy Hall, Huntsville Hospital Pharmacy Buyer. November 2000.
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