HealthSpring Coverage Determination
Health Services - Medical Policy Number: HSCD-GM045
Subject: Zoledronic Acid: (Zometa, Reclast)
Issue Date: 05/2008
Zoledronic acid inhibits osteoclastic activity and induces osteoclast apoptosis. Zoledronic acid also blocks the osteoclastic resorption of mineralized bone and cartilage through its binding to bone. Zoledronic acid inhibits the increased osteoclastic activity and skeletal calcium release induced by various stimulatory factors released by tumors. Zoledronic acid (Zometa®) for the treatment of hypercalcemia of malignancy (HCM) is considered medically appropriate if the individual is being vigorously hydrated with saline. Zoledronic acid (Zometa®) for the treatment of prostate cancer is considered medically appropriate if the prostate cancer has progressed after treatment with at least one hormonal therapy. Zoledronic (Zometa®) acid for the treatment of objectively documented osteopenia is considered medically appropriate if the osteopenia is secondary to androgen-deprivation therapy in prostate cancer. Zoledronic acid (Zometa®) for the treatment of multiple myeloma is considered medically appropriate if zoledronic acid is being used in conjunction with standard antineoplastic therapy. Zoledronic acid (Zometa®) for the treatment of bone metastases is considered medically appropriate if all of the following criteria are met: • • If the bone metastases are the result of solid tumors; and Zoledronic acid is being used in conjunction with standard antineoplastic therapy.
Zoledronic acid (Reclast®) for the treatment of osteoporosis in postmenopausal women is considered medically appropriate. Zoledronic acid (Reclast®) for the treatment of Paget’s disease of the bone to induce remission (normalization) of serum alkaline phosphatase is considered medically appropriate if any of the following criteria are met: • The men or women have elevations of serum alkaline phosphatase two times or higher than the upper limit of the age-specific normal reference range; or • Are symptomatic, or at risk for complications from their disease.
Zoledronic Acid (Reclast, Zometa): HSCD-GM045
Zoledronic acid is a bisphosphonic acid. It is a white crystalline powder, and the principal pharmacologic action of zoledronic acid is inhibition of bone resorption. Zoledronic acid is designated chemically as (1-Hydroxy-2-imidazol-1-yl-phosphonoethyl) phosphonic acid monohydrate.
The bisphosphonates are highly effective inhibitors of osteoclast-mediated bone resorption and the resultant calcium release from bone. Intravenous bisphosphonates (i.e. Zometa and Reclast) are the current standard of care for the treatment of hypercalcemia of malignancy (HCM), the management of skeletal morbidity in cancer patients with bone involvement, and osteoporosis in postmenopausal women. Osteoclastic hyperactivity resulting in excessive bone resorption is the underlying pathophysiologic derangement in hypercalcemia of malignancy (HCM, tumor-induced hypercalcemia) and metastatic bone disease. Excessive release of calcium into the blood as bone is resorbed results in polyuria and gastrointestinal disturbances, with progressive dehydration and decreasing glomerular filtration rate. This, in turn, results in increased renal resorption of calcium, setting up a cycle of worsening systemic hypercalcemia. Reducing excessive bone resorption and maintaining adequate fluid administration are, therefore, essential to the management of hypercalcemia of malignancy. Patients who have hypercalcemia of malignancy can generally be divided into two groups according to the pathophysiologic mechanism involved: humoral hypercalcemia and hypercalcemia due to tumor invasion of bone. In humoral hypercalcemia, osteoclasts are activated and bone resorption is stimulated by factors such as parathyroid-hormone-related protein, which are elaborated by the tumor and circulate systemically. Humoral hypercalcemia usually occurs in squamous-cell malignancies of the lung or head and neck or in genitourinary tumors such as renal-cell carcinoma or ovarian cancer. Skeletal metastases may be absent or minimal in these patients. Extensive invasion of bone by tumor cells can also result in hypercalcemia due to local tumor products that stimulate bone resorption by osteoclasts. Tumors commonly associated with locally mediated hypercalcemia include breast cancer and multiple myeloma. Total serum calcium levels in patients who have hypercalcemia of malignancy may not reflect the severity of hypercalcemia, since concomitant hypoalbuminemia is commonly present. Ideally, ionized calcium levels should be used to diagnose and follow hypercalcemic conditions; however, these are not commonly or rapidly available in many clinical situations. Therefore, adjustment of the total serum calcium value for differences in albumin levels (corrected serum calcium, CSC) is often used in place of measurement of ionized calcium; several nomograms are in use for this type of calculation (see DOSAGE AND ADMINISTRATION). Reclast is indicated for treatment of osteoporosis in postmenopausal women. In postmenopausal women with osteoporosis, Reclast reduces the incidence of fractures (hip, vertebral and nonvertebral osteoporosis-related fractures). Reclast is also indicated for treatment of Paget's disease of bone in men and women. Treatment is indicated in patients with Paget’s disease of bone with elevations in serum alkaline phosphatase of two times or higher than the upper limit of the age-specific normal reference range, or those who are symptomatic, or those at risk for complications from their disease.
Zolderonic Acid (Reclast, Zometa): HSCD-GM045
This guideline’s purpose is to provide guidance for making medical necessity coverage determinations when requests are received for safe and effective treatment using Zoledronic Acid. This assesses the efficacy of therapy in patients being treated, as well as monitoring patients for recurrence following curative measures. This guidance is based upon available systematic reviews and meta-analyses of published studies. It is important to emphasize that the guidelines and technology assessments cannot always account for individual variation among patients. They are not intended to supplant physician judgment with respect to particular patients or special clinical situations, and cannot be considered inclusive of all proper methods of care or exclusive of other treatments reasonably directed at obtaining the same result. In addition, this guideline describes the use of procedures and therapies in clinical practice; it cannot be assumed to apply to the use of these interventions performed in the context of clinical trials, given that clinical studies are designed to evaluate or validate innovative approaches in a disease for which improved staging and treatment is needed. In that guideline development involves a review and synthesis of the latest literature, a practice guideline also serves to identify important questions and settings for further research.
Criteria and Procedure:
DOSAGE AND ADMINISTRATION Consideration should be given to the severity of, as well as the symptoms of, tumor-induced hypercalcemia when considering use of Zometa® (zoledronic acid for injection). Vigorous saline hydration alone may be sufficient to treat mild, asymptomatic hypercalcemia. The maximum recommended dose of Zometa in hypercalcemia of malignancy (albumin-corrected serum calcium* >12 mg/dL (3.0 mmol/L)) is 4 mg. The 4-mg dose must be given as a single-dose intravenous infusion over no less than 15 minutes every 3-4 weeks for patients with creatinine clearance of >60 mL/min. • Reduce the dose for patients with renal impairment • Coadminister oral calcium supplements of 500 mg and a multiple vitamin containing 400 IU of Vitamin D daily Dosage with Renal Impairment: For patients with Tumor induced hypercalcemia (TIH), the dose of zoledronic acid does not need to be reduced for mild to moderate renal failure. For other patients, reduce the dose of Zoledronic Acid doses as shown below: Creatinine Clearance (mL/min) > 60 50 - 60 40 - 49 30 - 39 Zoledronic Acid Recommended Dose 4.0 mg 3.5 mg 3.3 mg 3.0 mg
Dosage with Hepatic Impairment: There are no pharmacokinetic data in patients with impaired liver function. Zoledronic acid is not cleared by the liver; therefore impaired liver function may not affect the pharmacokinetics of zoledronic acid. Zolderonic Acid (Reclast, Zometa): HSCD-GM045 Page 3
Treatment of Osteoporosis in Postmenopausal Women The recommended regimen is a single 5 mg infusion once a year given intravenously over no less than 15 minutes. For osteoporosis treatment, and t o reduce the risk of hypocalcemia, patients must be adequately supplemented with calcium and vitamin D if dietary intake is not sufficient. Postmenopausal women require an average of 1200 mg calcium and 400 – 800 IU vitamin D daily. Treatment of Paget’s Disease of Bone The recommended dose is a 5 mg infusion. The infusion time must not be less than 15 minutes given over a constant infusion rate. To reduce the risk of hypocalcemia, all patients with Paget’s disease should receive 1500 mg elemental calcium daily in divided doses (750 mg two times a day, or 500 mg three times a day) and 800 IU vitamin D daily, particularly in the 2 weeks following Reclast administration. All patients should be instructed on the importance of calcium and vitamin D supplementation in maintaining serum calcium levels, and on the symptoms of hypocalcemia. Re-treatment of Paget’s Disease After a single treatment with Reclast in Paget’s disease an extended remission period is observed. Specific re-treatment data are not available. However, re-treatment with Reclast may be considered in patients who have relapsed, based on increases in serum alkaline phosphatase, or in those patients who failed to achieve normalization of their serum alkaline phosphatase, or in those patients with symptoms, as dictated by medical practice. WARNINGS: Due to the risk of clinically significant deterioration in renal function, which may progress to renal failure, single doses of Zometa® (zoledronic acid) should not exceed 4 mg and the duration of infusion should be no less than 15 minutes. In the trials and in post-marketing experience, renal deterioration, progression to renal failure and dialysis, have occurred in patients, including those treated with the approved dose of 4 mg infused over 15 minutes. There have been instances of this occurring after the initial Zometa dose. Safety and pharmacokinetic data are limited in patients with severe renal impairment and the risk of renal deterioration is increased. Zometa treatment is not recommended in patients with bone metastases with severe renal impairment. In the clinical studies, patients with serum creatinine >265 μmol/L or >3.0 mg/dL were excluded and there were only eight of 564 patients treated with Zometa 4 mg by 15-minute infusion with a baseline creatinine >2 mg/dL. Limited pharmacokinetic data exists in patients with creatinine clearance <30 mL/min. • Pre-existing renal insufficiency and multiple cycles of Zometa and other bisphosphonates are risk factors for subsequent renal deterioration with Zometa. factors predisposing to renal deterioration, such as dehydration or the use of other nephrotoxic drugs, should be identified and managed if possible.
Zolderonic Acid (Reclast, Zometa): HSCD-GM045
• Zometa treatment in patients with hypercalcemia of malignancy with severe renal impairment should be considered only after evaluating the risks and benefits of treatment. In the clinical studies, patients with serum creatinine >400 μmol/L or >4.5 mg/dL were excluded. Patients who receive Zometa should have serum creatinine assessed prior to each treatment. Patients treated with Zometa for multiple myeloma and bone metastases of solid tumors should have the dose withheld if renal function has deteriorated. (See DOSAGE AND ADMINISTRATION.) Patients with hypercalcemia of malignancy with evidence of deterioration in renal function should be appropriately evaluated as to whether the potential benefit of continued treatment with Zometa outweighs the possible risk.
Attachments: FDA Alert Notice: [01/07/2008] FDA informed healthcare professionals and patients of the
possibility of severe and sometimes incapacitating bone, joint, and/or muscle (musculoskeletal) pain in patients taking bisphosphonates. Although severe musculoskeletal pain is included in the prescribing information for all bisphosphonates, the association between bisphosphonates and severe musculoskeletal pain may be overlooked by healthcare professionals, delaying diagnosis, prolonging pain and/or impairment, and necessitating the use of analgesics. The severe musculoskeletal pain may occur within days, months, or years after starting a bisphosphonates. Some patients have reported complete relief of symptoms after discontinuing the bisphosphonate, whereas others have reported slow or incomplete resolution. The risk factors for and incidence of severe musculoskeletal pain associated with bisphosphonates are unknown. Healthcare professionals should consider whether bisphosphonate use might be responsible for severe musculoskeletal pain in patients who present with these symptoms and consider temporary or permanent discontinuation of the drug. For more information visit the FDA website at: http://www.fda.gov/medwatch/safety/2008/safety08.htm#Bisphosphonates and http://www.fda.gov/cder/drug/infopage/bisphosphonates/default.htm. APPLICABLE TENNESSEE STATE MANDATE REQUIREMENTS Tennessee State law requires coverage of off-label indications of Food and Drug Administration (FDA) approved drugs when the off-label use is relative to life-threatening illnesses, such as cancer, AIDS, and coronary heart disease and recognized in one of the standard reference compendia (As defined in the statute: The United States Pharmacopoeia Drug Information, The American Medical Association Drug Evaluations, & The American Hospital Formulary Service Drug Information) or in the medical literature. This law is applicable to all fully insured members. The law is not applicable to self-funded accounts.
References: 1. http://www.fda.gov/cder/foi/label/2001/21223lbl.pdf 2. http://www.fda.gov/medwatch/SAFETY/2004/feb_PI/Zometa_PI.pdf 3. http://www.cancercare.on.ca/pdfdrugs/zoledronic-acid.pdf 4. http://www.us.zometa.com/hcp/landing.jsp 5. Novartis Pharmaceuticals Corporation. (2007, August). Highlights of Prescribing Information. Reclast® (zoledronic acid) injection. Retrieved September 19, 2007 from http://www.pharma.us.novartis.com/product/pi/pdf/reclast.pdf.
Zolderonic Acid (Reclast, Zometa): HSCD-GM045
6. J. Berenson, R. Hirschberg; Safety and Convenience of a 15-Minute Infusion of Zoledronic Acid; The Oncologist, Vol. 9, No. 3, 319–329, June 2004 7. http://patient.cancerconsultants.com/druginserts/Zoledronic_acid.pdf 8. U. S. Food and Drug Administration. (2006, May). Center for Drug Evaluation and Research. Drugs@FDA. Label and Approval History. (2006, May). Zometa®. Retrieved September 13, 2006 from http://www.fda.gov/cder/foi/label/2006/021223s012lbl.pdf. 9. U. S. Food and Drug Administration. (2007, April). Center for Drug Evaluation and Research. Drugs@FDA. Label and Approval History. (2006, May). Reclast® (zoledronic acid) injection. Retrieved September 25, 2007 from http://www.fda.gov/cder/foi/label/2007/021817lbl.pdf. 10. D.M. Black, P.D. Delmas, R. Eastell, MD., Once-Yearly Zoledronic Acid for Treatment of Postmenapausal Osteoporesis; New England Journal of Medicine; Vol. 356: 1809-1822; May 3, 2007; Number 18.
Approved by: ____________________________________________________________________ Date: Chairperson Corporate Clinical Guideline Committee
History: Created: 04/2008 Original approval date: Disclaimer Notes: It is important to emphasize that these guidelines and technology assessments cannot always account for individual variation among patients. They are not intended to supplant physician judgment with respect to particular patients or special clinical situations, and cannot be considered inclusive of all proper methods of care or exclusive of other treatments reasonably directed at obtaining the same result. Accordingly, adherence to this technology assessment is considered to be voluntary, with the ultimate determination regarding its application to be made by the physician in light of each patient's individual circumstances. In addition, this technology assessment describes the use of procedures and therapies in clinical practice; it cannot be assumed to apply to the use of these interventions performed in the context of clinical trials, given that clinical studies are designed to evaluate or validate innovative approaches in a disease for which improved staging and treatment is needed. In that guideline and technology assessment development involve a review and synthesis of the latest literature, a practice guideline or technology assessment also serves to identify important questions and settings for further research. HealthSpring may request medical records for determination of medical necessity. When medical records are requested, letters of support and/or explanation are often useful, but are not sufficient documentation unless all specific information needed to make a medical necessity determination is included. Medical policy is not an authorization, certification, explanation of benefits or a contract. Benefits and eligibility are determined before medical guidelines and payment guidelines are applied. Benefits are determined by the group contract and subscriber certificate that is in effect at the time services are rendered. This document is solely provided for informational purposes only and is based on research of current medical literature and review of common medical practices in the treatment and diagnosis of disease. Medical practices and knowledge are constantly changing and HealthSpring reserves the right to review and revise its medical policies periodically.
Zolderonic Acid (Reclast, Zometa): HSCD-GM045