Zometa Information
Zometa (Zoledronic) dosage And Administration
Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit
The maximum recommended dose of Zometa (Zoledronic) in hypercalcemia of malignancy (albumin-corrected serum calcium greater than or equal to 12 mg/dL [3.0 mmol/L]) is 4 mg. The 4-mg dose must be given as a single-dose intravenous infusion over . Patients who receive Zometa (Zoledronic) should have serum creatinine assessed prior to each treatment.
Dose adjustments of Zometa (Zoledronic) are not necessary in treating patients for hypercalcemia of malignancy presenting with mild-to-moderate renal impairment prior to initiation of therapy (serum creatinine less than 400 µmol/L or less than 4.5 mg/dL).
Patients should be adequately rehydrated prior to administration of Zometa (Zoledronic) [].
Consideration should be given to the severity of, as well as the symptoms of, tumor-induced hypercalcemia when considering use of Zometa (Zoledronic) . Vigorous saline hydration, an integral part of hypercalcemia therapy, should be initiated promptly and an attempt should be made to restore the urine output to about 2 L/day throughout treatment. Mild or asymptomatic hypercalcemia may be treated with conservative measures (i.e., saline hydration, with or without loop diuretics). Patients should be hydrated adequately throughout the treatment, but overhydration, especially in those patients who have cardiac failure, must be avoided. Diuretic therapy should not be employed prior to correction of hypovolemia.
Retreatment with Zometa (Zoledronic) 4 mg may be considered if serum calcium does not return to normal or remain normal after initial treatment. It is recommended that a minimum of 7 days elapse before retreatment, to allow for full response to the initial dose. Renal function must be carefully monitored in all patients receiving Zometa (Zoledronic) and serum creatinine must be assessed prior to retreatment with Zometa (Zoledronic) [].
The recommended dose of Zometa (Zoledronic) in patients with multiple myeloma and metastatic bone lesions from solid tumors for patients with creatinine clearance greater than 60 mL/min is 4 mg infused over every 3-4 weeks. The optimal duration of therapy is not known.
Upon treatment initiation, the recommended Zometa (Zoledronic) doses for patients with reduced renal function (mild and moderate renal impairment) are listed in Table 1. These doses are calculated to achieve the same AUC as that achieved in patients with creatinine clearance of 75 mL/min. Creatinine clearance (CrCl) is calculated using the Cockcroft-Gault formula [].
During treatment, serum creatinine should be measured before each Zometa (Zoledronic) dose and treatment should be withheld for renal deterioration. In the clinical studies, renal deterioration was defined as follows: For patients with normal baseline creatinine, increase of 0.5 mg/dL For patients with abnormal baseline creatinine, increase of 1.0 mg/dL
In the clinical studies, Zometa (Zoledronic) treatment was resumed only when the creatinine returned to within 10% of the baseline value. Zometa (Zoledronic) should be reinitiated at the same dose as that prior to treatment interruption.
Patients should also be administered an oral calcium supplement of 500 mg and a multiple vitamin containing 400 IU of Vitamin D daily.
Zometa (Zoledronic) must not be mixed with calcium or other divalent cation-containing infusion solutions, such as Lactated Ringer’s solution, and should be administered as a single intravenous solution in a line separate from all other drugs.
Bottles of Zometa (Zoledronic) ready-to-use solution for infusion contain overfill allowing for the administration of 100 mL of solution (equivalent to 4 mg zoledronic acid). This solution is ready-to-use and may be administered directly to the patient without further preparation. For single use only
To prepare reduced doses for patients with baseline CrCl less than or equal to 60 mL/min, withdraw the specified volume of the Zometa (Zoledronic) solution from the bottle (see Table 2) and replace with an equal volume of sterile 0.9% Sodium Chloride, USP, or 5% Dextrose Injection, USP. Administer the newly-prepared dose-adjusted solution to the patient by infusion. Follow proper aseptic technique. Properly discard previously withdrawn volume of ready-to-use solution - do not store or reuse.
If not used immediately after dilution with infusion media, for microbiological integrity, the solution should be refrigerated at 2°C - 8°C (36°F 46°F). The refrigerated solution should then be equilibrated to room temperature prior to administration. The total time between dilution, storage in the refrigerator, and end of administration must not exceed 24 hours.
Vials of Zometa (Zoledronic) concentrate for infusion contain overfill allowing for the withdrawal of 5 mL of concentrate (equivalent to 4 mg zoledronic acid). This concentrate should immediately be diluted in 100 mL of sterile 0.9% Sodium Chloride, USP, or 5% Dextrose Injection, USP, following proper aseptic technique, and administered to the patient by infusion. Do not store undiluted concentrate in a syringe, to avoid inadvertent injection.
To prepare reduced doses for patients with baseline CrCl less than or equal to 60 mL/min, withdraw the specified volume of the Zometa (Zoledronic) concentrate from the vial for the dose required (see Table 3).
The withdrawn concentrate must be diluted in 100 mL of sterile 0.9% Sodium Chloride, USP, or 5% Dextrose Injection, USP.
If not used immediately after dilution with infusion media, for microbiological integrity, the solution should be refrigerated at 2°C-8°C (36°F-46°F). The refrigerated solution should then be equilibrated to room temperature prior to administration. The total time between dilution, storage in the refrigerator, and end of administration must not exceed 24 hours.
Zometa (Zoledronic)
Zometa (Zoledronic)
Zometa (Zoledronic) adverse Reactions
Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.
Hypercalcemia of Malignancy
The safety of Zometa (Zoledronic) was studied in 185 patients with hypercalcemia of malignancy (HCM) who received either Zometa (Zoledronic) 4 mg given as a 5-minute intravenous infusion (n=86) or pamidronate 90 mg given as a 2-hour intravenous infusion (n=103). The population was aged 33-84 years, 60% male and 81% Caucasian, with breast, lung, head and neck, and renal cancer as the most common forms of malignancy. NOTE: pamidronate 90 mg was given as a 2-hour intravenous infusion. The relative safety of pamidronate 90 mg given as a 2-hour intravenous infusion compared to the same dose given as a 24-hour intravenous infusion has not been adequately studied in controlled clinical trials.
Renal Toxicity
Administration of Zometa (Zoledronic) 4 mg given as a 5-minute intravenous infusion has been shown to result in an increased risk of renal toxicity, as measured by increases in serum creatinine, which can progress to renal failure. The incidence of renal toxicity and renal failure has been shown to be reduced when Zometa (Zoledronic) 4 mg is given as a 15-minute intravenous infusion. Zometa (Zoledronic) should be administered by intravenous infusion over no less than 15 minutes [].
The most frequently observed adverse events were fever, nausea, constipation, anemia, and dyspnea (see Table 4).
Table 4 provides adverse events that were reported by 10% or more of the 189 patients treated with Zometa (Zoledronic) 4 mg or Pamidronate 90 mg from the two HCM trials. Adverse events are listed regardless of presumed causality to study drug.
The following adverse events from the two controlled multicenter HCM trials (n=189) were reported by a greater percentage of patients treated with Zometa (Zoledronic) 4 mg than with pamidronate 90 mg and occurred with a frequency of greater than or equal to 5% but less than 10%. Adverse events are listed regardless of presumed causality to study drug: Asthenia, chest pain, leg edema, mucositis, dysphagia, granulocytopenia, thrombocytopenia, pancytopenia, nonspecific infection, hypocalcemia, dehydration, arthralgias, headache and somnolence.
Rare cases of rash, pruritus, and chest pain have been reported following treatment with Zometa (Zoledronic) .
Symptoms consistent with acute phase reaction (APR) can occur with intravenous bisphosphonate use. Fever has been the most commonly associated symptom, occurring in 44% of patients treated with Zometa (Zoledronic) 4 mg and 33% of patients treated with Pamidronate 90 mg. Occasionally, patients experience a flu-like syndrome consisting of fever, chills, flushing, bone pain and/or arthralgias, and myalgias.
Mineral and Electrolyte Abnormalities
Electrolyte abnormalities, most commonly hypocalcemia, hypophosphatemia and hypomagnesemia, can occur with bisphosphonate use.
Grade 3 and Grade 4 laboratory abnormalities for serum creatinine, serum calcium, serum phosphorus, and serum magnesium observed in two clinical trials of Zometa (Zoledronic) in patients with HCM are shown in Table 5 and 6.
Injection Site Reactions
Local reactions at the infusion site, such as redness or swelling, were observed infrequently. In most cases, no specific treatment is required and the symptoms subside after 24-48 hours.
Ocular Adverse Events
Ocular inflammation such as uveitis and scleritis can occur with bisphosphonate use, including Zometa (Zoledronic) . No cases of iritis, scleritis or uveitis were reported during these clinical trials. However, cases have been seen in postmarketing use [
Multiple Myeloma and Bone Metastases of Solid Tumors
The safety analysis includes patients treated in the core and extension phases of the trials. The analysis includes the 2,042 patients treated with Zometa (Zoledronic) 4 mg, pamidronate 90 mg, or placebo in the three controlled multicenter bone metastases trials, including 969 patients completing the efficacy phase of the trial, and 619 patients that continued in the safety extension phase. Only 347 patients completed the extension phases and were followed for 2 years (or 21 months for the other solid tumor patients). The median duration of exposure for safety analysis for Zometa (Zoledronic) 4 mg (core plus extension phases) was 12.8 months for breast cancer and multiple myeloma, 10.8 months for prostate cancer, and 4.0 months for other solid tumors.
Table 7 describes adverse events that were reported by 10% or more of patients. Adverse events are listed regardless of presumed causality to study drug.
Grade 3 and Grade 4 laboratory abnormalities for serum creatinine, serum calcium, serum phosphorus, and serum magnesium observed in three clinical trials of Zometa (Zoledronic) in patients with bone metastases are shown in Tables 8 and 9.
Among the less frequently occurring adverse events (less than 15% of patients), rigors, hypokalemia, influenza-like illness, and hypocalcemia showed a trend for more events with bisphosphonate administration (Zometa (Zoledronic) 4 mg and pamidronate groups) compared to the placebo group.
Less common adverse events reported more often with Zometa (Zoledronic) 4 mg than pamidronate included decreased weight, which was reported in 16% of patients in the Zometa (Zoledronic) 4 mg group compared with 9% in the pamidronate group. Decreased appetite was reported in slightly more patients in the Zometa (Zoledronic) 4 mg group (13%) compared with the pamidronate (9%) and placebo (10%) groups, but the clinical significance of these small differences is not clear.
Renal Toxicity
In the bone metastases trials, renal deterioration was defined as an increase of 0.5 mg/dL for patients with normal baseline creatinine (less than 1.4 mg/dL) or an increase of 1.0 mg/dL for patients with an abnormal baseline creatinine (greater than or equal to1.4 mg/dL). The following are data on the incidence of renal deterioration in patients receiving Zometa (Zoledronic) 4 mg over 15 minutes in these trials (see Table 10).
The risk of deterioration in renal function appeared to be related to time on study, whether patients were receiving Zometa (Zoledronic) (4 mg over 15 minutes), placebo, or pamidronate.
In the trials and in postmarketing experience, renal deterioration, progression to renal failure and dialysis have occurred in patients with normal and abnormal baseline renal function, including patients treated with 4 mg infused over a 15-minute period. There have been instances of this occurring after the initial Zometa (Zoledronic) dose.
The following adverse reactions have been reported during postapproval use of Zometa (Zoledronic) . Because these reports are from a population of uncertain size and are subject to confounding factors, it is not possible to reliably estimate their frequency or establish a causal relationship to drug exposure.
Osteonecrosis of the Jaw
Cases of osteonecrosis (primarily involving the jaws) have been reported predominantly in cancer patients treated with intravenous bisphosphonates including Zometa (Zoledronic) . Many of these patients were also receiving chemotherapy and corticosteroids which may be a risk factor for ONJ. Data suggests a greater frequency of reports of ONJ in certain cancers, such as advanced breast cancer and multiple myeloma. The majority of the reported cases are in cancer patients following invasive dental procedures, such as tooth extraction. It is therefore prudent to avoid invasive dental procedures as recovery may be prolonged [].
Musculoskeletal Pain
Severe and occasionally incapacitating bone, joint, and/or muscle pain has been reported with bisphosphonate use [)].
Ocular Adverse Events
Cases of uveitis, scleritis, episcleritis, conjunctivitis, iritis, and orbital inflammation including orbital edema have been reported during postmarketing use. In some cases, symptoms resolved with topical steroids.
Hypersensitivity Reactions
There have been rare reports of allergic reaction with intravenous zoledronic acid including angioedema, and bronchoconstriction. Very rare cases of anaphylactic reaction/shock have also been reported.
Additional adverse reactions reported in postmarketing use include:
Zometa (Zoledronic) drug Interactions
Zometa (Zoledronic)
Zometa (Zoledronic) overdosage
Clinical experience with acute overdosage of Zometa (Zoledronic) is limited. Two patients received Zometa (Zoledronic) 32 mg over 5 minutes in clinical trials. Neither patient experienced any clinical or laboratory toxicity. Overdosage may cause clinically significant hypocalcemia, hypophosphatemia, and hypomagnesemia. Clinically relevant reductions in serum levels of calcium, phosphorus, and magnesium should be corrected by intravenous administration of calcium gluconate, potassium or sodium phosphate, and magnesium sulfate, respectively.
In an open-label study of zoledronic acid 4 mg in breast cancer patients, a female patient received a single 48-mg dose of zoledronic acid in error. Two days after the overdose, the patient experienced a single episode of hyperthermia (38°C), which resolved after treatment. All other evaluations were normal, and the patient was discharged seven days after the overdose.
A patient with non-Hodgkin’s lymphoma received zoledronic acid 4 mg daily on four successive days for a total dose of 16 mg. The patient developed paresthesia and abnormal liver function tests with increased GGT (nearly 100U/L, each value unknown). The outcome of this case is not known.
In controlled clinical trials, administration of Zometa (Zoledronic) 4 mg as an intravenous infusion over 5 minutes has been shown to increase the risk of renal toxicity compared to the same dose administered as a 15-minute intravenous infusion. In controlled clinical trials, Zometa (Zoledronic) 8 mg has been shown to be associated with an increased risk of renal toxicity compared to Zometa (Zoledronic) 4 mg, even when given as a 15-minute intravenous infusion, and was not associated with added benefit in patients with hypercalcemia of malignancy [].
Zometa (Zoledronic) description
Zometa (Zoledronic) contains zoledronic acid, a bisphosphonic acid which is an inhibitor of osteoclastic bone resorption. Zoledronic acid is designated chemically as (1-Hydroxy-2-imidazol-1-yl-phosphonoethyl) phosphonic acid monohydrate and its structural formula is
Zoledronic acid is a white crystalline powder. Its molecular formula is CHNOP • HO and its molar mass is 290.1g/Mol. Zoledronic acid is highly soluble in 0.1N sodium hydroxide solution, sparingly soluble in water and 0.1N hydrochloric acid, and practically insoluble in organic solvents. The pH of a 0.7% solution of zoledronic acid in water is approximately 2.0.
Zometa (Zoledronic) is available in 100-mL bottles as a sterile liquid ready-to-use solution for intravenous infusion and in 5-mL vials as a sterile liquid concentrate solution for intravenous infusion.
Zometa (Zoledronic) clinical Pharmacology
Clinical studies in patients with hypercalcemia of malignancy (HCM) showed that single-dose infusions of Zometa (Zoledronic) are associated with decreases in serum calcium and phosphorus and increases in urinary calcium and phosphorus excretion.
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 []
Pharmacokinetic data in patients with hypercalcemia are not available.
Distribution
Single or multiple (q 28 days) 5-minute or 15-minute infusions of 2, 4, 8 or 16 mg Zometa (Zoledronic) were given to 64 patients with cancer and bone metastases. The postinfusion decline of zoledronic acid concentrations in plasma was consistent with a triphasic process showing a rapid decrease from peak concentrations at end of infusion to less than 1% of C 24 hours postinfusion with population half-lives of t0.24 hours and t 1.87 hours for the early disposition phases of the drug. The terminal elimination phase of zoledronic acid was prolonged, with very low concentrations in plasma between Days 2 and 28 postinfusion, and a terminal elimination half-life t of 146 hours. The area under the plasma concentration versus time curve (AUC) of zoledronic acid was dose proportional from 2-16 mg. The accumulation of zoledronic acid measured over three cycles was low, with mean AUCratios for cycles 2 and 3 versus 1 of 1.13 ± 0.30 and 1.16 ± 0.36, respectively.
Metabolism
Zoledronic acid does not inhibit human P450 enzymes . Zoledronic acid does not undergo biotransformation . In animal studies, less than 3% of the administered intravenous dose was found in the feces, with the balance either recovered in the urine or taken up by bone, indicating that the drug is eliminated intact via the kidney. Following an intravenous dose of 20 nCi C-zoledronic acid in a patient with cancer and bone metastases, only a single radioactive species with chromatographic properties identical to those of parent drug was recovered in urine, which suggests that zoledronic acid is not metabolized.
Excretion
In 64 patients with cancer and bone metastases, on average (± s.d.) 39 ± 16% of the administered zoledronic acid dose was recovered in the urine within 24 hours, with only trace amounts of drug found in urine post-Day 2. The cumulative percent of drug excreted in the urine over 0-24 hours was independent of dose. The balance of drug not recovered in urine over 0-24 hours, representing drug presumably bound to bone, is slowly released back into the systemic circulation, giving rise to the observed prolonged low plasma concentrations. The 0-24 hour renal clearance of zoledronic acid was 3.7 ± 2.0 L/h.
Zoledronic acid clearance was independent of dose but dependent upon the patient’s creatinine clearance. In a study in patients with cancer and bone metastases, increasing the infusion time of a 4-mg dose of zoledronic acid from 5 minutes (n=5) to 15 minutes (n=7) resulted in a 34% decrease in the zoledronic acid concentration at the end of the infusion ([mean ± SD] 403 ± 118 ng/mL versus 264 ± 86 ng/mL) and a 10% increase in the total AUC (378 ± 116 ng x h/mL versus 420 ± 218 ng x h/mL). The difference between the AUC means was not statistically significant.
Special Populations
Pediatrics
Zometa (Zoledronic) is not indicated for use in children [].
Geriatrics
The pharmacokinetics of zoledronic acid were not affected by age in patients with cancer and bone metastases who ranged in age from 38 years to 84 years.
Race
Population pharmacokinetic analyses did not indicate any differences in pharmacokinetics among Japanese and North American (Caucasian and African American) patients with cancer and bone metastases.
Hepatic Insufficiency
No clinical studies were conducted to evaluate the effect of hepatic impairment on the pharmacokinetics of zoledronic acid.
Renal Insufficiency
The pharmacokinetic studies conducted in 64 cancer patients represented typical clinical populations with normal to moderately impaired renal function. Compared to patients with normal renal function (N=37), patients with mild renal impairment (N=15) showed an average increase in plasma AUC of 15%, whereas patients with moderate renal impairment (N=11) showed an average increase in plasma AUC of 43%. Limited pharmacokinetic data are available for Zometa (Zoledronic) in patients with severe renal impairment (creatinine clearance less than 30 mL/min). Based on population PK/PD modeling, the risk of renal deterioration appears to increase with AUC, which is doubled at a creatinine clearance of 10 mL/min. Creatinine clearance is calculated by the Cockcroft-Gault formula: CrCl = {x 0.85 for female patients} [72 x serum creatinine (mg/dL)]
Zometa (Zoledronic) systemic clearance in individual patients can be calculated from the population clearance of Zometa (Zoledronic) , CL (L/h)=6.5(CL/90). These formulae can be used to predict the Zometa (Zoledronic) AUC in patients, where CL = Dose/AUC. The average AUC in patients with normal renal function was 0.42 mg•h/L and the calculated AUC for a patient with creatinine clearance of 75 mL/min was 0.66 mg•h/L following a 4-mg dose of Zometa (Zoledronic) . However, efficacy and safety of adjusted dosing based on these formulae have not been prospectively assessed [].
Zometa (Zoledronic) clinical Studies
Two identical multicenter, randomized, double-blind, double-dummy studies of Zometa (Zoledronic) 4 mg given as a 5-minute intravenous infusion or pamidronate 90 mg given as a 2-hour intravenous infusion were conducted in 185 patients with hypercalcemia of malignancy (HCM). NOTE: Administration of Zometa (Zoledronic) 4 mg given as a 5-minute intravenous infusion has been shown to result in an increased risk of renal toxicity, as measured by increases in serum creatinine, which can progress to renal failure. The incidence of renal toxicity and renal failure has been shown to be reduced when Zometa (Zoledronic) 4 mg is given as a 15-minute intravenous infusion. Zometa (Zoledronic) should be administered by intravenous infusion over no less than 15 minutes [].The treatment groups in the clinical studies were generally well balanced with regards to age, sex, race, and tumor types. The mean age of the study population was 59 years; 81% were Caucasian, 15% were Black, and 4% were of other races. 60% of the patients were male. The most common tumor types were lung, breast, head and neck, and renal.
In these studies, HCM was defined as a corrected serum calcium (CSC) concentration of greater than or equal to 12.0 mg/dL (3.00 mmol/L). The primary efficacy variable was the proportion of patients having a complete response, defined as the lowering of the CSC to less than or equal to 10.8 mg/dL (2.70 mmol/L) within 10 days after drug infusion.
To assess the effects of Zometa (Zoledronic) versus those of pamidronate, the two multicenter HCM studies were combined in a preplanned analysis. The results of the primary analysis revealed that the proportion of patients that had normalization of corrected serum calcium by Day 10 were 88% and 70% for Zometa (Zoledronic) 4 mg and pamidronate 90 mg, respectively (P=0.002) (see Figure 1). In these studies, no additional benefit was seen for Zometa (Zoledronic) 8 mg over Zometa (Zoledronic) 4 mg; however, the risk of renal toxicity of Zometa (Zoledronic) 8 mg was significantly greater than that seen with Zometa (Zoledronic) 4 mg.
Secondary efficacy variables from the pooled HCM studies included the proportion of patients who had normalization of corrected serum calcium (CSC) by Day 4; the proportion of patients who had normalization of CSC by Day 7; time to relapse of HCM; and duration of complete response. Time to relapse of HCM was defined as the duration (in days) of normalization of serum calcium from study drug infusion until the last CSC value less than 11.6 mg/dL (less than 2.90 mmol/L). Patients who did not have a complete response were assigned a time to relapse of 0 days. Duration of complete response was defined as the duration (in days) from the occurrence of a complete response until the last CSC ≤10.8 mg/dL (2.70 mmol/L). The results of these secondary analyses for Zometa (Zoledronic) 4 mg and pamidronate 90 mg are shown in Table 11.
Table 12 describes an overview of the efficacy population in three randomized Zometa (Zoledronic) trials in patients with multiple myeloma and bone metastases of solid tumors. These trials included a pamidronate-controlled study in breast cancer and multiple myeloma, a placebo-controlled study in prostate cancer, and a placebo-controlled study in other solid tumors. The prostate cancer study required documentation of previous bone metastases and 3 consecutive rising PSAs while on hormonal therapy. The other placebo-controlled solid tumor study included patients with bone metastases from malignancies other than breast cancer and prostate cancer, including NSCLC, renal cell cancer, small cell lung cancer, colorectal cancer, bladder cancer, GI/genitourinary cancer, head and neck cancer, and others. These trials were comprised of a core phase and an extension phase. In the solid tumor, breast cancer and multiple myeloma trials, only the core phase was evaluated for efficacy as a high percentage of patients did not choose to participate in the extension phase. In the prostate cancer trials, both the core and extension phases were evaluated for efficacy showing the Zometa (Zoledronic) effect during the first 15 months was maintained without decrement or improvement for another 9 months. The design of these clinical trials does not permit assessment of whether more than one-year administration of Zometa (Zoledronic) is beneficial. The optimal duration of Zometa (Zoledronic) administration is not known.
The studies were amended twice because of renal toxicity. The Zometa (Zoledronic) infusion duration was increased from 5 minutes to 15 minutes. After all patients had been accrued, but while dosing and follow-up continued, patients in the 8 mg Zometa (Zoledronic) treatment arm were switched to 4 mg due to toxicity. Patients who were randomized to the Zometa (Zoledronic) 8 mg group are not included in these analyses.
Each study evaluated skeletal-related events (SREs), defined as any of the following: pathologic fracture, radiation therapy to bone, surgery to bone, or spinal cord compression. Change in antineoplastic therapy due to increased pain was a SRE in the prostate cancer study only. Planned analyses included the proportion of patients with a SRE during the study and time to the first SRE. Results for the two Zometa (Zoledronic) placebo-controlled studies are given in Table 13.
In the breast cancer and myeloma trial, efficacy was determined by a noninferiority analysis comparing Zometa (Zoledronic) to pamidronate 90 mg for the proportion of patients with a SRE. This analysis required an estimation of pamidronate efficacy. Historical data from 1,128 patients in three pamidronate placebo-controlled trials demonstrated that pamidronate decreased the proportion of patients with a SRE by 13.1% (95% CI = 7.3%, 18.9%). Results of the comparison of treatment with Zometa (Zoledronic) compared to pamidronate are given in Table 14.
Zometa (Zoledronic) how Supplied/storage And Handling
Carton of 1 bottle……………………………………………………………………………...NDC 0078-0590-61
Store at 25°C (77°F); excursions permitted to 15-30°C (59-86°F) [see USP Controlled Room Temperature].
Carton of 1 vial……………………………………………………………………………..NDC 0078-0387-25
Store at 25°C (77°F); excursions permitted to 15-30°C (59-86°F) [see USP Controlled Room Temperature].
Zometa (Zoledronic) patient Counseling Information
Manufactured byNovartis Pharma Stein AGStein, Switzerland forNovartis Pharmaceuticals CorporationEast Hanover, New Jersey 07936
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T2011-90
Zometa (Zoledronic)
Zometa (Zoledronic)
