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Special Alerts
Bisphosphonates: Health Canada Issues Update Regarding Atypical Femur Fractures
December 2011
Health Canada has issued an update to Canadian healthcare professionals in regards to its review of bisphosphonate drugs and the risk for atypical femur fractures. The regulatory agency has determined that bisphosphonate use is associated with a slightly increased risk for these uncommon fractures, but considers the benefit of therapy to outweigh the extremely small risk. The Canadian product monographs for bisphosphonates are being updated accordingly.
Canadian healthcare professionals are being reminded to be aware of this possible risk for fracture and to evaluate and rule out femur fracture in patients reporting new hip, thigh, or groin pain. Patients receiving bisphosphonate therapy should not discontinue therapy without consulting a healthcare professional and should be encouraged to report new or unusual hip, thigh, or groin pain.
Further information may be found at http://www.hc-sc.gc.ca/ahc-asc/media/advisories-avis/_2011/2011_172-eng.php.
Reports of Kidney Failure
September 2011
The U.S. Food and Drug Administration (FDA) has announced that zoledronic acid, marketed as Reclast®, is contraindicated in patients with a creatinine clearance <35 mL/minute or with evidence of acute renal impairment. Cases of renal failure requiring dialysis or leading to death have occurred following zoledronic acid administration. Patients at greatest risk include those with underlying moderate-to-severe renal impairment, concurrent use of nephrotoxic or diuretic medications, or severe dehydration prior to or after zoledronic acid administration. Others with increased risk include patients with renal impairment or dehydration secondary to fever, sepsis, gastrointestinal losses, or diuretic use. The risk of renal failure also increases with age for those with underlying renal impairment. Appropriate screening to identify risk factors is recommended prior to administration of zoledronic acid. Additionally, renal function should be assessed before therapy in all patients and monitored intermittently after therapy in at-risk patients.
Further information may be found at http://www.fda.gov/Drugs/DrugSafety/ucm270199.htm.
Pronunciation
(zoe le DRON ik AS id)
Generic Available (U.S.)
No
Index Terms
Medication Guide
An FDA-approved patient medication guide, which is available with the product information and at http://www.fda.gov/downloads/Drugs/DrugSafety/UCM241522.pdf, must be dispensed with this medication.
REMS Components
Reclast®: Released from REMS requirement 8/15/2011
Brand Names: U.S.
Brand Names: Canada
Pharmacologic Category
Use: Labeled Indications
Oncology-related uses: Treatment of hypercalcemia of malignancy (albumin-corrected serum calcium >12 mg/dL); treatment of multiple myeloma; treatment of bone metastases of solid tumors
Nononcology uses: Treatment of Paget's disease of bone; treatment of osteoporosis in postmenopausal women (to reduce the incidence of fractures or to reduce the incidence of new clinical fractures in patients with low-trauma hip fracture); prevention of osteoporosis in postmenopausal women, treatment of osteoporosis in men (to increase bone mass); treatment and prevention of glucocorticoid-induced osteoporosis (in patients initiating or continuing prednisone ≥7.5 mg/day [or equivalent] and expected to remain on glucocorticoids for at least 12 months)
Use: Unlabeled
Prevention of bone loss associated with aromatase inhibitor therapy in postmenopausal women with breast cancer; prevention of bone loss associated with androgen deprivation therapy in prostate cancer
Pregnancy Risk Factor
D
Pregnancy Considerations
Animal studies resulted in embryotoxicity and losses. Zoledronic acid should not be used during pregnancy; may cause fetal harm if administered to a pregnant woman. 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/not recommended
Breast-Feeding Considerations
Because it binds to bone long term, zoledronic acid use is not recommended in nursing women.
Contraindications
Hypersensitivity to zoledronic acid or any component of the formulation; hypocalcemia (Reclast®); in patients with a creatinine clearance (Clcr) <35 mL/minute and in patients with evidence of acute renal impairment due to an increased risk of renal failure (Reclast®)
Canadian labeling: Hypersensitivity to other bisphosphonates. Aclasta® is also contraindicated with uncorrected hypocalcemia at the time of infusion and in pregnancy and breast-feeding.
Warnings/Precautions
Concerns related to adverse effects:
• Bone fractures: Atypical, low energy, or low trauma 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; atypical femur fractures have also been reported in patients not taking bisphosphonates, and in patients receiving glucocorticoids. Patients receiving long-term (>3-5 years) bisphosphonate therapy may be at an increased risk. Patients presenting with thigh or groin pain with a history of receiving bisphosphonates should be evaluated for femur fracture. Consider interrupting bisphosphonate therapy in patients who develop a femoral shaft fracture; assess for fracture in the contralateral limb.
• Hypersensitivity reactions: Rare cases of urticaria and angioedema and very rare cases of anaphylactic reactions/shock have been reported.
• Musculoskeletal pain: Infrequently, 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.
• Osteonecrosis of the jaw (ONJ): ONJ has been reported in patients receiving bisphosphonates. Risk factors include invasive dental procedures (eg, tooth extraction, dental implants, boney surgery); a diagnosis of cancer, with concomitant chemotherapy, radiotherapy, or corticosteroids; poor oral hygiene, ill-fitting dentures; and comorbid disorders (anemia, coagulopathy, infection, pre-existing dental disease). Most reported cases occurred after I.V. bisphosphonate therapy; however, cases have been reported following oral therapy. A dental exam and preventative dentistry should be performed prior to placing patients with risk factors on chronic bisphosphonate therapy. The manufacturer's labeling states that there are no data to suggest whether discontinuing bisphosphonates in patients requiring invasive dental procedures reduces the risk of ONJ. However, other experts suggest that there is no evidence that discontinuing therapy reduces the risk of developing ONJ (Assael, 2009). The benefit/risk must be assessed by the treating physician and/or dentist/surgeon prior to any invasive dental procedure. Patients developing ONJ while on bisphosphonates should receive care by an oral surgeon.
Disease-related concerns:
• Aspirin-sensitive asthma: Use with caution in patients with aspirin-sensitive asthma; may cause bronchoconstriction.
• Hepatic impairment: Has not been adequately studied in patients with hepatic impairment.
• Hypocalcemia: May cause a significant risk of hypocalcemia in patients with Paget's disease, in whom the pretreatment rate of bone turnover may be greatly elevated. Hypocalcemia must be corrected before initiation of therapy in patients with Paget's disease or osteoporosis. Ensure adequate calcium and vitamin D intake during therapy. Use caution in patients with disturbances of calcium and mineral metabolism (eg, hypoparathyroidism, thyroid/parathyroid surgery, malabsorption syndromes, excision of small intestine).
• Multiple myeloma: According to the American Society of Clinical Oncology (ASCO) guidelines for bisphosphonates in multiple myeloma, treatment with zoledronic acid is not recommended for asymptomatic (smoldering) or indolent myeloma or with solitary plasmacytoma (Kyle, 2007). The National Comprehensive Cancer Network® (NCCN) multiple myeloma guidelines (v.1.2011) also do not recommend the use of bisphosphonates in stage 1 or smoldering disease, unless part of a clinical trial.
• Renal impairment: Use with caution in mild-to-moderate renal impairment. Single and multiple infusions in patients with both normal and impaired renal function have been associated with renal deterioration, resulting in renal failure and dialysis (rare). Pre-existing renal compromise, severe dehydration, and concurrent use with diuretics or other nephrotoxic drugs may increase the risk for renal impairment. Adequate hydration is required during treatment (urine output ~2 L/day); avoid overhydration, especially in patients with heart failure.
Reclast®: Use is contraindicated in patients with Clcr <35 mL/minute and in patients with evidence of acute renal impairment. Patients with underlying moderate-to-severe renal impairment, increased age, concurrent use of nephrotoxic or diuretic medications, or severe dehydration prior to or after zoledronic acid administration may have an increased risk of acute renal impairment or renal failure. Others with increased risk include patients with renal impairment or dehydration secondary to fever, sepsis, gastrointestinal losses, or diuretic use. If history or physical exam suggests dehydration, treatment should not be given until the patient is normovolemic. Creatinine clearance (using actual body weight) should be calculated with the Cockcroft-Gault formula prior to each administration. Transient increases in serum creatinine may be more pronounced in patients with impaired renal function; monitoring creatinine clearance in at-risk patients taking other renally-eliminated drugs is recommended.
Zometa®: Dosage adjustment required with renal impairment. Use is not recommended in patients with severe renal impairment (serum creatinine >3 mg/dL or Clcr <30 mL/minute) and bone metastases (limited data); use in patients with hypercalcemia of malignancy and severe renal impairment (serum creatinine >4.5 mg/dL for hypercalcemia of malignancy) should only be done if the benefits outweigh the risks. In cancer patients, renal toxicity has been reported with doses >4 mg or infusions administered over 15 minutes. Risk factors for renal deterioration include pre-existing renal insufficiency and repeated doses and other bisphosphonates therapy. Dehydration and the use of other nephrotoxic drugs which may contribute to renal deterioration should be identified and managed. Diuretics should not be used before correcting hypovolemia. Renal function should be assessed prior to treatment; if decreased after treatment, additional treatments should be withheld until renal function returns to within 10% of baseline.
Aclasta® [CAN; not available in U.S.]: Use is not recommended in patients with Clcr <30 mL/minute.
Special populations:
• Elderly: Use with caution in the elderly due to the possibility for decreased renal function; monitor.
• Pediatrics: Not approved for use in children.
• Women of childbearing age: Advise women of childbearing age against becoming pregnant.
Other warnings/precautions:
• Duplicate therapy: Do not administer Zometa® and Reclast® to the same patient for different indications.
• Reclast®: Re-evaluate the need for continued therapy for the treatment of osteoporosis periodically; the optimal duration of treatment has not yet been determined.
Adverse Reactions
Note: An acute reaction (eg, arthralgia, fever, flu-like symptoms, myalgia) may occur within the first 3 days following infusion in up to 44% of patients; usually resolves within 3-4 days of onset, although may take up to 14 days to resolve. The incidence may be decreased with acetaminophen (prior to infusion and for 72 hours postinfusion).
Zometa®:
>10%:
Cardiovascular: Leg edema (5% to 21%), hypotension (11%)
Central nervous system: Fatigue (39%), fever (32% to 44%), headache (5% to 19%), dizziness (18%), insomnia (15% to 16%), anxiety (11% to 14%), depression (14%), agitation (13%), confusion (7% to 13%), hypoesthesia (12%)
Dermatologic: Alopecia (12%), dermatitis (11%)
Endocrine & metabolic: Dehydration (5% to 14%), hypophosphatemia (13%), hypokalemia (12%), hypomagnesemia (11%)
Gastrointestinal: Nausea (29% to 46%), vomiting (14% to 32%), constipation (27% to 31%), diarrhea (17% to 24%), anorexia (9% to 22%), abdominal pain (14% to 16%), weight loss (16%), appetite decreased (13%)
Genitourinary: Urinary tract infection (12% to 14%)
Hematologic: Anemia (22% to 33%), neutropenia (12%)
Neuromuscular & skeletal: Bone pain (55%), weakness (5% to 24%), myalgia (23%), arthralgia (5% to 21%), back pain (15%), paresthesia (15%), limb pain (14%), skeletal pain (12%), rigors (11%)
Renal: Renal deterioration (8% to 17%; up to 40% in patients with abnormal baseline creatinine)
Respiratory: Dyspnea (22% to 27%), cough (12% to 22%)
Miscellaneous: Cancer progression (16% to 20%), moniliasis (12%)
1% to 10%:
Cardiovascular: Chest pain (5% to 10%)
Central nervous system: Somnolence (5% to 10%)
Endocrine & metabolic: Hypocalcemia (5% to 10%; grades 3/4: ≤1%), hypermagnesemia (grade 3: 2%)
Gastrointestinal: Dysphagia (5% to 10%), dyspepsia (10%), mucositis (5% to 10%), stomatitis (8%), sore throat (8%)
Hematologic: Granulocytopenia (5% to 10%), pancytopenia (5% to 10%), thrombocytopenia (5% to 10%)
Renal: Serum creatinine increased (grades 3/4: ≤2%)
Respiratory: Upper respiratory tract infection (10%)
Miscellaneous: Infection (nonspecific; 5% to 10%)
Reclast®:
>10%:
Cardiovascular: Hypertension (5% to 13%)
Central nervous system: Pain (2% to 24%), fever (9% to 22%), headache (4% to 20%), chills (2% to 18%), fatigue (2% to 18%)
Endocrine & metabolic: Hypocalcemia (≤3%; Paget's disease 21%)
Gastrointestinal: Nausea (5% to 18%)
Neuromuscular & skeletal: Arthralgia (9% to 27%), myalgia (5% to 23%), back pain (4% to 18%), limb pain (3% to 16%), musculoskeletal pain (≤12%)
Miscellaneous: Acute phase reaction (4% to 25%), flu-like syndrome (1% to 11%)
1% to 10%:
Cardiovascular: Chest pain (1% to 8%), peripheral edema (3% to 6%), atrial fibrillation (1% to 3%), palpitation (≤3%)
Central nervous system: Dizziness (2% to 9%), malaise (1% to 7%), hypoesthesia (≤6%), lethargy (3% to 5%), vertigo (1% to 4%), hyperthermia (≤2%)
Dermatologic: Rash (2% to 3%), hyperhidrosis (≤3%)
Gastrointestinal: Abdominal pain (1% to 9%), diarrhea (5% to 8%), vomiting (2% to 8%), constipation (6% to 7%), dyspepsia (2% to 7%), abdominal discomfort/distension (1% to 2%), anorexia (1% to 2%)
Neuromuscular & skeletal: Bone pain (3% to 9%), arthritis (2% to 9%), rigors (8%), shoulder pain (≤7%), neck pain (1% to 7%), weakness (2% to 6%), muscle spasm (2% to 6%), stiffness (1% to 5%), jaw pain (2% to 4%), joint swelling (≤3%), paresthesia (2%)
Ocular: Eye pain (≤2%)
Renal: Serum creatinine increased (2%)
Respiratory: Dyspnea (5% to 7%)
Miscellaneous: C-reactive protein increased (≤5%)
Zometa® and/or Reclast®: <1%, postmarketing, and/or case reports: Acute renal failure (requiring hospitalization/dialysis), allergic reaction, anaphylactic reaction/shock, angioedema, arrhythmia, blurred vision, bradycardia, bronchoconstriction, conjunctivitis, diaphoresis, episcleritis, femur fracture (diaphyseal or subtrochanteric), flu-like syndrome (fever, chills, flushing, bone pain, arthralgia, myalgia, fatigue, weakness), hematuria, hyperesthesia, hyperkalemia, hypernatremia, hyperparathyroidism, hypersensitivity, hypertension, injection site reaction (eg, itching, pain, redness), iridocyclitis, iritis, joint and/or muscle pain (sometimes severe and/or incapacitating), muscle cramps, orbital edema, orbital inflammation, osteonecrosis (primarily of the jaws), proteinuria, pruritus, rash, renal failure, renal impairment, scleritis, taste perversion, toxic acute renal tubular necrosis, tremor, urticaria, uveitis, weight gain, xerostomia
Metabolism/Transport Effects
None known.
Drug Interactions
Aminoglycosides: May enhance the hypocalcemic effect of Bisphosphonate Derivatives. Risk C: 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. Risk C: Monitor therapy
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
Proton Pump Inhibitors: May diminish the therapeutic effect of Bisphosphonate Derivatives. Risk C: Monitor therapy
Thalidomide: May enhance the adverse/toxic effect of Zoledronic Acid. Risk C: Monitor therapy
Storage
Aclasta® [CAN]: Store at room temperature of 15°C to 30°C (59°F to 86°F).
Reclast®: Store at room temperature of 25°C (77°F); excursions permitted to 15°C to 30°C (59°F to 86°F). After opening, stable for 24 hours at 2°C to 8°C (36°F to 46°F).
Zometa®: Store concentrate vials and ready-to-use bottles at 25°C (77°F); excursions permitted to 15°C to 30°C (59°F to 86°F). Diluted solutions for infusion which are not used immediately after preparation should be refrigerated at 2°C to 8°C (36°F to 46°F). Infusion of solution must be completed within 24 hours of preparation. The ready-to-use bottles are for single use only; if any preparation is necessary (preparing reduced dosage for patients with renal impairment), the prepared, diluted solution may be refrigerated at 2°C to 8°C (36°F to 46°F) if not used immediately. Infusion of solution must be completed within 24 hours of preparation. The previously withdrawn volume from the ready-to-use solution should be discarded; do not store or reuse.
Reconstitution
Zometa® concentrate vials: Further dilute in 100 mL NS or D5W prior to administration.
Zometa® ready-to use bottles: No further preparation necessary. If reduced doses are necessary for patients with renal impairment, withdraw the appropriate volume of solution and replace with an equal amount of NS or D5W.
Compatibility
Incompatible with calcium or other divalent cation-containing solutions (eg, LR).
Mechanism of Action
A bisphosphonate which inhibits bone resorption via actions on osteoclasts or on osteoclast precursors; inhibits osteoclastic activity and skeletal calcium release induced by tumors. Decreases serum calcium and phosphorus, and increases their elimination. In osteoporosis, zoledronic acid inhibits osteoclast-mediated resorption, therefore reducing bone turnover.
Pharmacodynamics/Kinetics
Distribution: Binds to bone
Protein binding: 28% to 53%
Half-life elimination: Triphasic; Terminal: 146 hours
Excretion: Urine (39% ± 16% as unchanged drug) within 24 hours; feces (<3%)
Dosage
I.V.: Adults: Note: Acetaminophen administration after the infusion may reduce symptoms of acute-phase reactions. Patients treated for multiple myeloma, osteoporosis, and Paget's disease should receive a daily calcium supplement and multivitamin containing vitamin D (if dietary intake is inadequate).
Hypercalcemia of malignancy (albumin-corrected serum calcium ≥12 mg/dL) (Zometa®): 4 mg (maximum) given as a single dose. Wait at least 7 days before considering retreatment. Dosage adjustment may be needed in patients with decreased renal function following treatment.
Multiple myeloma or metastatic bone lesions from solid tumors (Zometa®): 4 mg every 3-4 weeks
Osteoporosis, glucocorticoid-induced, treatment and prevention (Reclast®, Aclasta® [CAN]): 5 mg infused over at least 15 minutes once a year
Osteoporosis, prevention (Reclast®): 5 mg infused over at least 15 minutes every 2 years
Osteoporosis, treatment (Reclast®, Aclasta® [CAN]): 5 mg infused over at least 15 minutes once a year
Paget's disease: 5 mg infused over at least 15 minutes. Note: Data concerning retreatment is not available; retreatment may be considered for relapse (increase in alkaline phosphatase) if appropriate, for inadequate response, or in patients who are symptomatic.
Prevention of aromatase inhibitor-induced bone loss in breast cancer (unlabeled use): 4 mg every 6 months (Brufsky, 2007)
Prevention of androgen deprivation-induced bone loss in nonmetastatic prostate cancer (unlabeled use): 4 mg every 3 months for 1 year (Smith, 2003) or 4 mg every 12 months (Michaelson, 2007)
Dosage adjustment in renal impairment (at treatment initiation):
Reclast®:
Clcr ≥35 mL/minute: No adjustment required
Clcr <35 mL/minute: Use is contraindicated
Zometa®: Multiple myeloma and bone metastases:
Clcr >60 mL/minute: 4 mg
Clcr 50-60 mL/minute: 3.5 mg
Clcr 40-49 mL/minute: 3.3 mg
Clcr 30-39 mL/minute: 3 mg
Clcr <30 mL/minute: Use is not recommended
Zometa®: Hypercalcemia of malignancy:
Mild-to-moderate impairment: No adjustment necessary
Severe impairment (serum creatinine >4.5 mg/dL): Evaluate risk versus benefit
Aclasta® [CAN]:
Clcr ≥30 mL/minute: No adjustment required
Clcr <30 mL/minute: Use is not recommended
Dosage adjustment for renal toxicity (during treatment):
Hypercalcemia of malignancy: Evidence of renal deterioration: Evaluate risk versus benefit.
Multiple myeloma and bone metastases: Evidence of renal deterioration: Withhold dose until renal function returns to within 10% of baseline: renal deterioration defined as follows:
Normal baseline creatinine: Increase of 0.5 mg/dL
Abnormal baseline creatinine: Increase of 1 mg/dL
Reinitiate dose at the same dose administered prior to treatment interruption.
Multiple myeloma: Albuminuria >500 mg/24 hours (unexplained): Withhold dose until return to baseline, then re-evaluate every 3-4 weeks; consider reinitiating with a longer infusion time of at least 30 minutes (Kyle, 2007).
Dosage adjustment in hepatic impairment: Specific guidelines are not available.
Administration: I.V.
Infuse over at least 15 minutes. Flush I.V. line with 10 mL NS flush following infusion. Infuse in a line separate from other medications. Patients should be appropriately hydrated prior to treatment.
Reclast®, Zometa®: If refrigerated, allow to reach room temperature prior to administration. Acetaminophen after administration may reduce the incidence of acute reaction (eg, arthralgia, fever, flu-like symptoms, myalgia).
Administration: I.V. Detail
Zometa®: pH: ~2
Reclast®, Aclasta® [CAN]: pH 6-7 (infusion)
Monitoring Parameters
Prior to initiation of therapy, dental exam and preventative dentistry for patients at risk for osteonecrosis, including all cancer patients
Aclasta® [CAN], Reclast®: Serum creatinine prior to each dose,especially in patients with risk factors, calculate creatinine clearance before each treatment (consider interim monitoring in patients at risk for acute renal failure), evaluate fluid status and adequately hydrate patients prior to and following administration.
Osteoporosis: Bone mineral density as measured by central dual-energy x-ray absorptiometry (DXA) of the hip or spine (prior to initiation of therapy and at least every 2 years; after 6-12 months of combined glucocorticoid and zoledronic acid treatment); annual measurements of height and weight, assessment of chronic back pain; serum calcium and 25(OH)D; phosphorus and magnesium; may consider monitoring biochemical markers of bone turnover
Paget's disease: Alkaline phosphatase; pain; serum calcium and 25(OH)D; phosphorus and magnesium
Zometa®: Serum creatinine prior to each dose; serum electrolytes, phosphate, magnesium, and hemoglobin/hematocrit should be evaluated regularly. Monitor serum calcium to assess response and avoid overtreatment. In patients with multiple myeloma, monitor urine every 3-6 months for albuminuria.
Test Interactions
Bisphosphonates may interfere with diagnostic imaging agents such as technetium-99m-diphosphonate in bone scans.
Dietary Considerations
Multiple myeloma or metastatic bone lesions from solid tumors: Take daily calcium supplement (500 mg) and daily multivitamin (with 400 int. units vitamin D).
Osteoporosis: Ensure adequate calcium and vitamin D supplementation; general requirements are calcium 1200 mg/day and vitamin D 800-1000 int. units/day.
Paget's disease: Take elemental calcium 1500 mg/day (750 mg twice daily or 500 mg 3 times/day) and vitamin D 800 units/day, particularly during the first 2 weeks after administration.
Patient Education
Patients should be aware that a dental exam and any needed dental work should be completed before starting this medication. Patients need to understand the importance of good oral hygiene throughout treatment, especially if they are receiving chemotherapy, radiation therapy, or both.
Geriatric Considerations
The elderly are frequently treated long-term for osteoporosis. Elderly patients should be advised to report any lower extremity, jaw (osteonecrosis), or muscle pain that cannot be explained or lasts longer than 2 weeks. Additionally, elderly often receive concomitant diuretic therapy and therefore their electrolyte status (eg, calcium, phosphate) should be periodically evaluated.
Additional Information
Oncology Comment:
Metastatic breast cancer: The American Society of Clinical Oncology (ASCO) guidelines on the role of bone-modifying agents (BMAs) in the prevention and treatment of skeletal-related events for metastatic breast cancer patients were updated (Van Poznak, 2011). The guidelines recommend initiating a BMA (denosumab, pamidronate, zoledronic acid) in patients with a diagnosis of metastatic breast cancer to the bone. There is currently no literature indicating the superiority of one particular BMA over another. The optimal duration has yet to be defined; however, the guidelines recommend continuing therapy until substantial decline in patient's performance status. In patients with normal creatinine clearance (>60 mL/minute), no dosage/interval/infusion rate changes for pamidronate or zoledronic acid are necessary. For patients with Clcr <30 mL/minute, pamidronate and zoledronic acid are not recommended. While no renal dose adjustments are recommended for denosumab, close monitoring is advised for risk of hypocalcemia in patients with Clcr <30 mL/minute or on dialysis. The ASCO guidelines are in alignment with package insert guidelines for dosing, renal dose adjustments, infusion times, prevention and management of osteonecrosis of the jaw, and monitoring of laboratory parameter recommendations. BMAs are not the first-line therapy for pain. BMAs are to be used as adjunctive therapy for cancer-related bone pain associated with bone metastasis, demonstrating a modest pain control benefit. BMAs should be used in conjunction with agents such as NSAIDS, opioid and nonopioid analgesics, corticosteroids, radiation/surgery, interventional procedures.
Multiple myeloma: The American Society of Clinical Oncology (ASCO) also has guidelines published on the use of bisphosphonates for prevention and treatment of bone disease in multiple myeloma (Kyle, 2007). Pamidronate or zoledronic acid use is recommended in multiple myeloma patients with lytic bone destruction or compression spine fracture from osteopenia. Clodronate (not available in the U.S.; available in Canada), administered orally or I.V., is an alternative treatment. The use of the bisphosphonates pamidronate and zoledronic acid may be considered in patients with pain secondary to osteolytic disease, adjunct therapy to stabilize fractures or impending fractures, and I.V. bisphosphonates for multiple myeloma patients with osteopenia but no radiographic evidence of lytic bone disease. Bisphosphonates are not recommended in patients with solitary plasmacytoma, smoldering (asymptomatic) or indolent myeloma, or monoclonal gammopathy of undetermined significance. The guidelines recommend monthly treatment for a period of 2 years. At that time, physicians need to consider discontinuing in responsive and stable patients, and reinitiate if new-onset skeletal-related event occurs. The ASCO guidelines are in alignment with package insert guidelines for dosing, renal dose adjustments, infusion times, prevention and management of osteonecrosis of the jaw, and monitoring of laboratory parameter recommendations. The guidelines also state in patients with a serum creatinine >3 mg/dL or Clcr <30 mL/minute or extensive bone disease, pamidronate at a dose of 90 mg over 4-6 hours is recommended (unless pre-existing renal disease at which a reduced dose should be considered). The ASCO committee also recommends monitoring for the presence of albuminuria every 3-6 months. In patients with albuminuria >500 mg/24 hours, withhold the dose until level returns to baseline, then recheck every 3-4 weeks. Pamidronate may be reinitiated at a dose not to exceed 90 mg every 4 weeks with a longer infusion time of at least 4 hours. The committee also recommends considering increasing the infusion time of zoledronic acid to at least 30 minutes. However, one study has demonstrated that extending the infusion to 30 minutes did not change the safety profile (Berenson, 2011).
Dental Health: Effects on Dental Treatment
Key adverse event(s) related to dental treatment: Mucositis, dysphagia, stomatitis, and sore throat.
Osteonecrosis of the jaw (ONJ), generally associated with local infection and/or tooth extraction and often with delayed healing, has been reported in patients taking bisphosphonates. Symptoms included nonhealing extraction socket or an exposed jawbone. Most reported cases of bisphosphonate-associated osteonecrosis have been in cancer patients treated with intravenous bisphosphonates. However, some have occurred in patients with postmenopausal osteoporosis taking oral bisphosphonates. Dental surgery, particularly tooth extraction, may increase the risk for ONJ. Patients who develop ONJ while on bisphosphonate therapy should receive care by an oral surgeon. See Dental Health Professional Considerations.
Dental Health: Vasoconstrictor/Local Anesthetic Precautions
No information available to require special precautions
Dental Comment
Zoledronic acid (Reclast®) is administered once annually for the treatment of osteoporosis. A single, large prospective, placebo-controlled study established its efficacy for this indication through 3 years of treatment (Black, 2007). Two cases of ONJ were reported, one each in the treatment and control groups, suggesting a low risk of ONJ with this treatment protocol through 3 years.
The American Association of Oral and Maxillofacial Surgeons position paper on bisphosphonate-related osteonecrosis of the jaws, 2009 update, stated that I.V. bisphosphonate exposure in the setting of managing malignancy remains the major risk factor for the development of ONJ. After reviewing case series, case-controlled studies, and cohort studies, the estimates of the cumulative incidence of I.V. bisphosphonate-associated ONJ ranges from 0.8% to 12%.
Two reports have attempted to assess more accurately the percent of cancer patients developing ONJ after bisphosphonate treatment. Maerevoet et al, reported that among 194 patients treated with Zometa® every 3-4 weeks, nine developed ONJ. Before receiving Zometa®, six had received Aredia® 90 mg every 3-4 weeks. The median duration of treatment with Aredia® was 39 months and for Zometa® 18 months. The incidence of ONJ in these patients was calculated to be 4.6%. Durie et al, described the results of a survey by the International Myeloma Foundation in 2004 to assess the risk factors of ONJ. Out of 1203 respondents, 904 had myeloma and 299 had breast cancer. Of the myeloma patients, 62 developed ONJ and 54 had suspicious findings. Of the breast cancer patients, 13 had ONJ and 23 had suspicious findings. The total number of cases of either ONJ or suspicious findings was 152. ONJ developed in 10% of 211 patients receiving Zometa® compared to 4% of 413 receiving Aredia®. The mean time to onset of ONJ among patients taking Zometa® was 18 months; the mean time to onset after Aredia® was 6 years. It should be noted that an early report by authors from Novartis Pharmaceuticals Corporation stressed that Aredia® and Zometa® had been used in 2.5 million patients world wide and reports of ONJ during their extensive use had been rare (Tarassoff, 2003). In addition, these authors stated that review of the reported cases revealed multiple risk factors for avascular necrosis. McMahon et al, followed up with a report that, along with other factors, bisphosphonates are additional stressors of bone health that can tip the balance to osteonecrosis. They suggested that the prevention of ONJ should be stressed such as the elimination of chronic dental infections prior to chemotherapy and bisphosphonate use in cancer patients.
Mental Health: Effects on Mental Status
Insomnia, anxiety, agitation, depression, and dizziness are common; may rarely cause confusion
Mental Health: Effects on Psychiatric Treatment
Bisphosphonates have been associated with renal toxicity manifested as deterioration of renal function and potential renal failure. Use caution in patients receiving lithium. GI side effects are common; concomitant use with SSRIs may produce additive effects. May cause neutropenia; use caution with clozapine and carbamazepine.
Nursing: Physical Assessment/Monitoring
Assess kidney function prior to administration. Decision to administer medication may change if patient has severe renal dysfunction. A thorough oral exam should be done prior to initiating any therapy. Patients need to be instructed on maintaining good oral hygiene throughout treatment. It is important to know that if a patient is undergoing chemotherapy, radiation therapy, or a combination of both, they are at a higher risk for osteonecrosis of the jaw.
Dosage Forms
Excipient information presented when available (limited, particularly for generics); consult specific product labeling.
Infusion, premixed:
Reclast®: 5 mg (100 mL)
Zometa®: 4 mg (100 mL)
Injection, solution [concentrate]:
Zometa®: 4 mg/5 mL (5 mL)
Pricing: U.S. (www.drugstore.com)
Solution (Reclast)
5 mg/100 mL (100): $1137.19
References
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Brufsky A, Harker WG, Beck JT, et al, “Zoledronic Acid Inhibits Adjuvant Letrozole-Induced Bone Loss in Postmenopausal Women With Early Breast Cancer,” J Clin Oncol 2007, 25(7):829-36.
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Hadji P, Aapro MS, Body JJ, et al, “Management of Aromatase Inhibitor-Associated Bone Loss in Postmenopausal Women With Breast Cancer: Practical Guidance for Prevention and Treatment,” Ann Oncol, 2011, 22(12):2546-55.
Hillner BE, Ingle JN, Chlebowski RT, et al, “American Society of Clinical Oncology 2003 Update on the Role of Bisphosphonates and Bone Health Issues in Women With Breast Cancer,” J Clin Oncol, 2003, 21(21):4042-57.
Kyle RA, Yee GC, Somerfield MR, et al, “American Society of Clinical Oncology 2007 Clinical Practice Guideline Update on the Role of Bisphosphonates in Multiple Myeloma,” J Clin Oncol, 2007, 25(17):2464-72.
Lyles KW, Colon-Emeric CS, Magaziner JS, et al, “Zoledronic Acid and Clinical Fractures and Mortality After Hip Fracture,” N Engl J Med, 2005, 357(18):1799-809.
Maerevoet M, Martin C, and Duck L, “Osteonecrosis of the Jaw and Bisphosphonates,” N Engl J Med, 2005, 353(1):99-102.
“Management of Osteoporosis in Postmenopausal Women: 2010 Position Statement of The North American Menopause Society,” Menopause, 2010, 17(1):25-54.
McClung M, Miller P, Recknor C, et al, “Zoledronic Acid for the Prevention of Bone Loss in Postmenopausal Women With Low Bone Mass: A Randomized Controlled Trial,” Obstet Gynecol, 2009, 114(5):999-1007.
McMahon RE, Bouquot JE, Glueck CJ, et al, “Osteonecrosis: A Multifactorial Etiology,” J Oral Maxillofac Surg, 2004, 62(7):904-5.
Michaelson MD, Kaufman DS, Lee H, et al, “Randomized Controlled Trial of Annual Zoledronic Acid to Prevent Gonadotropin-Releasing Hormone Agonist-Induced Bone Loss in Men With Prostate Cancer,” J Clin Oncol, 2007, 25(9):1038-42.
National Comprehensive Cancer Network® (NCCN), “Clinical Practice Guidelines in Oncology™: Multiple Myeloma,” Version 1.2011. Available at http://www.nccn.org/professionals/physician_gls/PDF/myeloma.pdf
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Ralston SH, “Pathogenesis of Paget's Disease of Bone,” Bone, 2008, 43(5):819-25.
Reid DM, Devogelaer JP, Saag K, et al, “Zoledronic Acid and Risedronate in the Prevention and Treatment of Glucocorticoid-Induced Osteoporosis (HORIZON): A Multicentre, Double-Blind, Double-Dummy, Randomised Controlled Trial,” Lancet, 2009, 373(9671):1253-63.
Reid IR, Miller P, Lyles K, et al, “Comparison of a Single Infusion of Zoledronic Acid With Risedronate for Paget's Disease,” N Engl J Med, 2005, 353(9):898-908.
Ruggiero SL, Dodson TB, Assael LA, et al, “American Association of Oral and Maxillofacial Surgeons Position Paper on Bisphosphonate-Related Osteonecrosis of the Jaws-2009 Update,” J Oral Maxillofac Surg, 2009, 67(5 Suppl):2-12.
Sayin M and Yazici G, “Hyperparathyroidism Secondary to Zoledronic Acid Infusion: Case Report,” Support Care Cancer, 2009, 17(5):469-70.
Sellmeyer DE, “Atypical Fractures as a Potential Complication of Long-term Bisphosphonate Therapy,” JAMA, 2010, 304(13):1480-4.
Shane E, Burr D, Ebeling PR, et al, “Atypical Subtrochanteric and Diaphyseal Femoral Fractures: Report of a Task Force of the American Society for Bone and Mineral Research,” J Bone Miner Res, 2010, 25(11):2267-94.
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Van Poznak CH, Temin S, Yee GC, et al, “American Society of Clinical Oncology Executive Summary of the Clinical Practice Guideline Update on the Role of Bone-Modifying Agents in Metastatic Breast Cancer,” J Clin Oncol, 2011, 29(9):1221-7.
International Brand Names
Lexi-Comp.com
Last full review/revision February 2012
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