Zometa 4mg/5mL

Dose reduction in patients with tumor-induced hypercalcemia with mild to moderate renal impairment is not recommended.

The recommended dose of ZOMETA (zoledronic acid for injection) in hypercalcemia (albumin-corrected serum calcium ≥3.0 mmol/L (12 mg/dL)) is 4 mg. The 4 mg dose is given as a single-dose intravenous infusion over no less than 15 minutes following standard rehydration procedures.

Albumin-corrected serum calcium (cCa, mmol/L)=tCa+0.02 (mid-range albumin-measured albumin).

Prior to treatment with ZOMETA (zoledronic acid for injection) renal excretion of excess calcium should be promoted by restoring and maintaining adequate fluid balance and urine output.

Patients who show complete or partial response initially may be retreated with ZOMETA 4 mg if serum calcium does not return to normal or does not remain normal after initial treatment although retreatment with ZOMETA 4 mg in TIH patients has not been assessed for efficacy and safety in prospective studies. It is recommended that at least one week must elapse before retreatment to allow for a full response to the initial dose. In addition, retreatment should be given to only those patients who can tolerate the standard rehydration procedures (i.e., 3 to 5 litres of fluids per day and more than 400 meq of sodium chloride per day). In any patient requiring repeated administration, serum BUN and creatinine must be evaluated and possible deterioration in renal function must be assessed prior to each re-administration (see Warnings and Precautions).

If not used immediately after dilution with infusion media, for microbiological integrity, the solution should be refrigerated at 2-8°C. 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.

Strict adherence to the intravenous route is recommended for the parenteral administration of ZOMETA.

Note: Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit.

Store ZOMETA concentrate at 15-30°C.

As only limited clinical data are available for patients with hepatic insufficiency, dosage recommendations cannot be given for this group.

ZOMETA must not be mixed with calcium-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.

Studies with glass bottles, as well as several types of infusion bags and infusion lines made from polyvinylchloride, polyethylene and polypropylene (prefilled with 0.9 % sodium chloride solution or 5 % glucose solution), showed no incompatibility with ZOMETA.

Monitoring of renal function is recommended in all patients prior to the administration of each dose of ZOMETA.

Vials of ZOMETA concentrate contain overfill allowing for the withdrawal of 5 mL of concentrate (equivalent to 4 mg zoledronic acid for injection). The content of the vials is withdrawn using a sterile syringe. This concentrate should immediately be diluted in 100 mL of sterile 0.9% Sodium Chloride Injection, USP, or 5% Dextrose Injection, USP. Do not store undiluted concentrate in a syringe, to avoid inadvertent injection. Any unused portion of ZOMETA concentrate should be discarded.

Reduced Doses for Patients with Baseline CrCl ≤60 mL/min: Withdraw an appropriate volume of the 5 mL—ZOMETA concentrate as needed:

4.4 mL for 3.5 mg dose

4.1 mL for 3.3 mg dose

3.8 mL for 3.0 mg dose

The withdrawn concentrate must be diluted in 100 mL of sterile 0.9% Sodium Chloride Injection, USP, or 5% Dextrose Injection, USP. The dose must be given as a single intravenous injection over no less than 15 minutes.

The recommended dose of ZOMETA in patients with documented metastatic bone lesions from solid tumors and patients with osteolytic lesions of multiple myeloma for patients with creatinine clearance >60 mL/min is 4 mg, given as a single dose intravenous infusion over no less than 15 minutes every 3 to 4 weeks. In patients requiring antineoplastic therapy, ZOMETA should be administered either prior to or after this treatment. Patients will be required to take an oral calcium supplement of 500 mg and a multivitamin containing at least 400 IU of Vitamin D daily. If a patient has a prior history of hypercalcemia or develops hypercalcemia during treatment with calcium and Vitamin D supplementation, the patient is advised to discontinue taking calcium and Vitamin D.

ZOMETA has been used with cyclophosphamide, doxorubicin, paclitaxel, anastrozole, melphalan and tamoxifen. It has been given less frequently with docetaxel, dexamethasone, prednisone, carboplatin, letrozole, vinorelbine, cisplatin and gemcitabine.

ZOMETA is excreted exclusively via the kidney and the risk of adverse reactions may be greater in patients with impaired renal function.

ZOMETA has not been tested in patients with severe renal impairment (serum creatinine >400 μmol/L or >4.5 mg/dL in patients with tumor-induced hypercalcemia; and serum creatinine >265 μmol/L or >3.0 mg/dL in patients with bone metastases of solid tumors and osteolytic lesions of multiple myeloma). Therefore, its use is not recommended in this patient population.

During treatment, serum creatinine should be measured before each ZOMETA 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 (<123 µmol/L or <1.4 mg/dL), an increase of 44 µmol/L or 0.5 mg/dL

  
  

• For patients with abnormal baseline creatinine (>123 µmol/L or >1.4 mg/dL), an increase of 88 µmol/L or 1.0 mg/dL

  
  

In the clinical studies, ZOMETA treatment was resumed only when the creatinine returned to within 10% of the baseline value. ZOMETA should be re-initiated at the same dose as that prior to treatment interruption.

Renal function should be monitored appropriately during therapy with ZOMETA. Patients with evidence of renal function deterioration should be appropriately evaluated and consideration should be given as to whether the potential benefit outweighs the possible risk.

Cases of ONJ are uncommon, although data suggests a higher number of reported cases in certain cancers, such as advanced breast cancer and multiple myeloma. The majority of reported cases of ONJ are associated with invasive dental procedures (such as tooth extraction or dental surgery) or periodontal disease. Many patients had signs of local infection including osteomyelitis.

Spontaneously reported adverse drug reactions are presented below. Because these events are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or clearly establish a causal relationship to ZOMETA exposure.

Atrial fibrillation, bronchoconstriction, episcleritis, hypotension leading to syncope or circulatory collapse (primarily in patients with underlying risk factors), somnolence, and uveitis have been reported.

Based on the clinical trial experience, the frequency of nonserious hypotensive events is uncommon (between 0.1% and 1.0%).

Adverse reactions to ZOMETA (zoledronic acid for injection) are usually mild and transient and similar to those reported for other bisphosphonates. Intravenous administration has been most commonly associated with fever. Occasionally, patients experience a flu-like syndrome consisting of fever, chills, bone pain and/or arthralgias and myalgias. In most cases, no specific treatment is required and the symptoms subside after 24-48 hours.

Gastrointestinal reactions such as nausea and vomiting have been reported following intravenous infusion of ZOMETA. Local reactions at the infusion site, such as redness or swelling, were observed infrequently.

Rare cases of rash, pruritus, and chest pain have been reported following treatment with ZOMETA.

As with other bisphosphonates, isolated cases of hypomagnesemia have been reported. Isolated cases of uveitis, episcleritis, and conjunctivitis have also been reported.

While not observed in clinical trials with ZOMETA, administration of other bisphosphonates has been associated with bronchoconstriction in acetylsalicylic acid-sensitive asthmatic patients.

The adverse events occurring during the studies were generally of a type and frequency expected in patients with cancer and bone metastases, many of whom were undergoing antineoplastic therapy. Except for pyrexia, the absolute difference in the proportions of patients in the ZOMETA 4 mg group compared with the placebo group for any of the common adverse events did not exceed 10%. Pyrexia, or fever, may occur as part of an acute phase reaction with bisphosphonate administration.

Among less commonly occurring adverse events (<15% of patients in any group), hypocalcemia was reported in 4.7%, 2.5%, and 0.7% of patients in the ZOMETA 4 mg, AREDIA, and placebo groups, respectively. Hypokalemia was reported in 9.7%, 9.0%, and 4.8% of patients in the ZOMETA 4 mg, AREDIA, and placebo groups, respectively.

ZOMETA (zoledronic acid for injection) is indicated for the treatment of Tumor-Induced Hypercalcemia following adequate saline rehydration. Prior to treatment with ZOMETA, renal excretion of excess calcium should be promoted by restoring and maintaining adequate fluid balance and urine output.

ZOMETA is indicated for the treatment of patients with documented bone metastases from solid tumors (including prostate cancer, breast cancer, lung cancer, renal cell carcinoma and other solid tumors) and patients with osteolytic lesions of multiple myeloma in conjunction with standard care in order to prevent or delay potential complications from the bone lesions (see Warnings and Precautions, Renal Dysfunction).

Monitoring of renal function is recommended in all patients prior to the administration of each dose of ZOMETA.

In rare cases, somnolence and/or dizziness may occur, in which case the patient should not drive, operate potentially dangerous machinery or engage in other activities that may be hazardous.

Specific drug-drug interaction studies have not been conducted with ZOMETA. Zoledronic acid is not systemically metabolized and does not affect human cytochrome P450 enzymes in vitro. Zoledronic acid is not highly bound to plasma proteins (approximately 55%) and therefore, interactions resulting from displacement of highly protein-bound drugs are unlikely.

ZOMETA is eliminated by renal excretion. Caution is indicated when zoledronic acid is administered in conjunction with drugs that are potentially nephrotoxic (e.g. aminoglycosides, other antineoplastic agents, ASA, NSAIDs), or that can significantly impact renal function (e.g. diuretics, ACE inhibitors, leading to dehydration).

ZOMETA should be used with extreme caution in conjunction with other antineoplastic agents that are either known to produce renal dysfunction (it is advised that renal function be monitored); or where the dose depends upon renal function (for example platinum-containing agents).

In multiple myeloma patients, the risk of renal dysfunction may be increased when ZOMETA is used in combination with thalidomide.

While not observed in clinical trials with ZOMETA, administration of other bisphosphonates has been associated with bronchoconstriction in aspirin-sensitive asthmatic patients. ZOMETA should be used with caution in patients with aspirin-sensitive asthma.

In carcinogenicity studies, zoledronic acid was administered orally (gavage) to rats and mice for at least 104 weeks without evidence of carcinogenic potential. Chronic parenteral administration was not feasible given the potential of the compound to cause severe local irritation. The pharmacological bone changes (nonproliferative hyperostosis) typically observed following long term bisphosphonate administration to young animals with growing skeletons gave clear evidence of systemic exposure to zoledronic acid in both species at all doses.

Six mutagenicity studies were conducted with zoledronic acid: three Ames Assays (using E. coli and/or S. typhimurium), a gene mutation assay using V79 hamster cells, a cytogenetics test with Chinese hamster cells and an in vivo micronucleus assay in rats. There was no evidence of mutagenic potential.

In post-marketing experience, severe and occasionally incapacitating bone, joint, and/or muscle pain have been reported in patients taking bisphosphonates. However, such reports have been infrequent. This category of drugs includes ZOMETA (zoledronic acid). The time to onset of symptoms varied from one day to several months after starting treatment. Most patients had relief of symptoms after stopping treatment. A subset had recurrence of symptoms when rechallenged with the same drug or another bisphosphonate.

As only limited clinical data are available for patients with hepatic insufficiency, dosage recommendations cannot be given for this group.

Due to the risk of clinically significant deterioration in renal function, which may progress to renal failure, single doses of ZOMETA should not exceed 4 mg and the duration of the infusion should be no less than 15 minutes.

Bisphosphonates, including ZOMETA have been associated with reports of renal dysfunction. Factors that may increase the potential for deterioration in renal function include dehydration, pre-existing renal impairment, multiple cycles of ZOMETA or other bisphosphonates or using an infusion time shorter than currently recommended (the 4 mg dose is given as a single-dose intravenous infusion over not less than 15 minutes in not less than 100 mL diluent). Concomitant use of potentially nephrotoxic drugs (i.e. ASA, NSAIDS, diuretics, ACE inhibitors etc.) may also increase the potential for renal impairment. Renal function should be monitored appropriately during therapy with ZOMETA. Renal deterioration, progression to renal failure (some with fatal outcome) and dialysis have been reported very rarely in cancer patients (e.g., those with hypercalcemia of malignancy and/or pre-existing renal disease) after the initial dose or a single dose of ZOMETA. Increases in serum creatinine may occur in some patients with chronic administration of ZOMETA at recommended doses. Patients with evidence of deterioration in renal function should be appropriately evaluated with consideration given as to whether the potential benefit of continued treatment with ZOMETA outweighs the possible risk.

The use of ZOMETA is not recommended in patients with severe renal impairment. This recommendation is made in view of the potential impact of bisphosphonates including ZOMETA on renal function, the lack of extensive clinical safety data in patients with severe renal impairment at baseline (serum creatinine >400 μmol/L or >4.5 mg/dL in patients with tumor-induced hypercalcemia; and serum creatinine >265 μmol/L or >3.0 mg/dL in patients with bone metastases of solid tumors and osteolytic lesions of multiple myeloma) and only limited pharmacokinetic data in patients with severe renal impairment at baseline (creatinine clearance <30 mL/min).

ZOMETA should not be given together with other bisphosphonates to treat hypercalcemia since the combined effects of these agents are unknown.

ZOMETA should not be mixed with calcium-containing intravenous infusions.

ZOMETA should be used with extreme caution in conjunction with other antineoplastic agents that are either known to produce renal dysfunction (it is advised that renal function be monitored); or where the dose depends upon renal function (for example platinum-containing agents).

The safety and efficacy of ZOMETA in children have not been established. Until further experience is gained, ZOMETA can only be recommended for use in adult patients.

ZOMETA should not be administered during pregnancy (see Contraindications). There is no clinical evidence to support the use of ZOMETA in pregnant women, and animal studies suggest ZOMETA may cause fetal harm when administered to a pregnant woman.

In animal reproduction studies zoledronic acid was administered subcutaneously to rats and rabbits. Teratogenicity manifested by external, visceral and skeletal malformations was observed in the rat at doses ≥0.2 mg/kg. There was also evidence of maternal toxicity at ≥0.2 mg/kg as well as fetal toxicity at 0.4 mg/kg. No teratological or embryo/fetal effects were observed in the rabbit. However, maternal toxicity was marked at ≥0.1 mg/kg due to decreased serum calcium. Bisphosphonates readily cross the placental barrier and are taken up into the developing fetal skeleton; thus, the teratogenicity observed in the rat was attributed to the compound's potency in lowering serum calcium and binding to fetal bone.

Limited clinical data are available for patients with renal impairment and monitoring of renal function is recommended in these patients. ZOMETA is excreted exclusively via the kidney and the risk of adverse reactions may be greater in patients with impaired renal function. ZOMETA has not been tested in patients with severe renal impairment (serum creatinine >400 μmol/L or >4.5 mg/dL in patients with tumor-induced hypercalcemia; and serum creatinine >265 μmol/L or >3.0 mg/dL in patients with bone metastases of solid tumors and osteolytic lesions of multiple myeloma). Therefore, its use is not recommended in this patient population. Close monitoring of renal function is necessary in patients who are receiving concomitant drugs with nephrotoxic potential.

Patients should have their serum creatinine levels assessed prior to each dose of ZOMETA.

Upon initiation of treatment in patients with bone metastases of solid tumors and osteolytic lesions of multiple myeloma, with mild-to-moderate renal impairment, lower doses of ZOMETA are recommended. In patients who show evidence of renal deterioration during treatment, appropriate evaluation should be carried out and consideration should be given as to whether the potential benefit outweighs the possible risk. If ZOMETA treatment is to be continued in these patients, ZOMETA should only be resumed when serum creatinine returns to within 10% of baseline (see Dosage and Administration).

Controlled clinical studies of ZOMETA in TIH do not provide a sufficient number of geriatric subjects to determine whether patients 65 years and older respond differently. The median age in the two controlled clinical trials in patients with tumor-induced hypercalcemia was 61 years old (range: 21-87 years old).

Controlled clinical studies of ZOMETA in the treatment of bone metastases of solid tumors and osteolytic lesions of multiple myeloma in patients over age 65 revealed similar efficacy and safety compared to younger patients. The proportion of patients experiencing SREs is lower in the ZOMETA treatment group when compared to placebo and similar to AREDIA (pamidronate) 90 mg. Older patients generally had adverse events similar to those of the overall population. However, because of the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy in elderly patients, ZOMETA should be administered with caution in this patient population.

Japanese female subjects had substantially higher systemic exposure, i.e., 47% higher AUC_0-24h and 39% higher C_max than the North American population (see Action and Clinical Pharmacology, Special Populations and Conditions, Race).

It is essential in the initial treatment of tumor-induced hypercalcemia that intravenous rehydration be instituted to restore urine output. Patients should be hydrated adequately throughout treatment but overhydration must be avoided.

In patients with cardiac disease, especially in the elderly, additional saline overload may precipitate cardiac failure (left ventricular failure or congestive heart failure). Fever (influenza-like symptoms) may also contribute to this deterioration.

Serum electrolytes, calcium, phosphate and serum creatinine should be carefully monitored following initiation of therapy with ZOMETA (zoledronic acid for injection). Patients with anemia, leukopenia or thrombocytopenia should have regular hematology assessments. Occasional cases of mild, transient hypocalcemia, usually asymptomatic, have been reported. Symptomatic hypocalcemia occurs rarely and can be reversed with calcium gluconate. Patients who have undergone thyroid surgery may be particularly susceptible to develop hypocalcemia due to relative hypoparathyroidism.

In tumor-induced hypercalcemia, either ionized calcium or total serum calcium corrected (adjusted) for albumin should be monitored during treatment with ZOMETA. Serum calcium levels in patients who have hypercalcemia of malignancy may not reflect the severity of hypercalcemia, since hypoalbuminemia is commonly present. Corrected serum calcium values should be calculated using established algorithms, such as: Albumin-corrected serum calcium (cCa, mmol/L)=tCa+0.02 (mid-range albumin-measured albumin).

ZOMETA contains the same active ingredient that is found in ACLASTA (zoledronic acid). Patients being treated with ZOMETA should not be treated with ACLASTA or other bisphosphonates concomitantly.

Osteonecrosis of the jaw (ONJ), has been reported in cancer patients treated with bisphosphonates, including ZOMETA. Although no causal relationship has been established, there is an association between bisphosphonate use and the development of ONJ. Tumor type (advanced breast cancer, multiple myeloma) and dental status (dental extractions, periodontal disease) are associated with a greater risk of developing ONJ. Cancer patients also receive other treatments that may play a role in the development of ONJ, such as chemotherapy and corticosteroids.

The majority of reported ONJ cases have been associated with dental procedures such as tooth extraction or periodontal disease. Many patients had signs of local infection including osteomyelitis. Presentation may include altered local sensation (hyperaesthesia or numbness), maxillofacial pain, “toothaches”, denture sore spots, loose teeth, exposed bone in the oral cavity, impaired healing, recurrent or persistent soft tissue infection in the oral cavity and marked oral odour. The onset can be from months to years after commencing bisphosphonate therapy. It is recommended that advanced cancer patients be encouraged to have an oral examination of both hard and soft tissues, with preventive dentistry prior to treatment with bisphosphonates, and that such assessments continue at regularly scheduled intervals after bisphosphonate therapy is initiated. While on bisphosphonate treatment, these patients should avoid invasive dental procedures if possible. Biopsies are not recommended unless metastasis to the jaw is suspected. For patients who develop ONJ while on bisphosphonate therapy, dental surgery may exacerbate the condition. For patients requiring dental procedures, there is no data available to suggest whether discontinuation of bisphosphonate treatment reduces the risk of ONJ. Clinical judgment of the treating physician should guide the management plan of each patient based on individual benefit/risk assessment.

Serum calcium, electrolytes, phosphate, magnesium and creatinine, and CBC, differential, and hematocrit/hemoglobin must be closely monitored in patients treated with ZOMETA.

ZOMETA should not be administered to breast-feeding women (see Contraindications). There is no clinical experience with ZOMETA in lactating women and it is not known whether ZOMETA passes into breast milk. A study in lactating rats has shown that another bisphosphonate AREDIA (pamidronate) passes into the milk. Mothers treated with ZOMETA should therefore not breast feed their infants.

Overall incidence of atrial fibrillation in a 3-year trial using ACLASTA (zoledronic acid) 5 mg dose yearly, was 2.5% (96 out of 3862) and 1.9% (75 out of 3852) in patients receiving ACLASTA (zoledronic acid) and placebo, respectively. The rate of atrial fibrillation serious adverse events was 1.3% (51 out of 3862) and 0.6% (22 out of 3852) in patients receiving ACLASTA (zoledronic acid) and placebo, respectively. The increased incidence observed in this trial has not been observed in other clinical trials with zoledronic acid, including those with ZOMETA (zoledronic acid) 4 mg administered every 3-4 weeks in oncology patients. The mechanism behind the increased incidence of atrial fibrillation is unknown.

There are no pharmacokinetic data in patients with impaired liver function. ZOMETA is not cleared by the liver, therefore impaired liver function may not affect the pharmacokinetics of ZOMETA.

The pharmacokinetics of ZOMETA were not affected by age in cancer patients with bone metastases aged 38 years to 84 years.

Single or multiple (q 28 days) 5-minute or 15-minute infusions of 2, 4, 8 or 16 mg ZOMETA were given to 64 cancer patients with bone metastases. The post infusion 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 <1% of C_max after 24 hours post infusion with population half-lives of t _½α 0.24 hours and t_½β 1.87 hours for the early disposition phases of the drug, followed by a prolonged period of very low concentrations in plasma between days 2 and 28 post infusion, with a terminal elimination half-life t_½γ of 146 hours. The area under the plasma concentration versus time curve (AUC_0-24h) of zoledronic acid was linearly related to dose. The accumulation of zoledronic acid following a 28-day dosing schedule over 3 cycles was low, with mean AUC_0-24h ratios cycles 2 and 3 versus 1 of 1.13±0.30 and 1.16±0.36, respectively.

In vitro and ex vivo studies showed low affinity of zoledronic acid for the cellular components of human blood. Binding to human plasma proteins was approximately 56% and independent of the concentration of zoledronic acid.

Zoledronic acid does not inhibit human P-450 enzymes in vitro. Zoledronic acid does not experience biotransformation. In animal studies <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 ¹⁴C-zoledronic acid in a cancer patient with bone metastases, the radioactivity excreted in the urine consisted solely of intact drug.

In 64 cancer patients with bone metastases on average (±s.d.) 39±16% of the administered 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 tissue is slowly released back into the systemic circulation, giving rise to the observed prolonged low plasma concentrations days 2 to 28 post dose. The 0-24 h renal clearance of zoledronic acid was on average (±s.d.) 3.7±2.0 L/h.

Zoledronic acid clearance was reasonably independent of dose and demographic variables, with effects of body weight, gender, and race on clearance being within the bounds of the inter-patient variability of clearance, which was 36%.

Increasing the infusion time from 5 minutes to 15 minutes caused a 30% decrease in the zoledronic acid concentration at the end of the infusion, but had no effect on the area under the plasma concentration versus time curve.

There are no pharmacokinetic data in patients with hypercalcemia.

The principal pharmacologic action of ZOMETA (zoledronic acid for injection) is inhibition of bone resorption. Although the antiresorptive mechanism is not completely understood, several factors are thought to contribute to this action. Zoledronic acid accumulates in bone, where it blocks the resorption of mineralized bone and cartilage. In vitro, zoledronic acid inhibits osteoclastic activity and induces apoptosis in osteoclasts, as well as reducing the formation and recruitment of osteoclasts into bone. In vitro, zoledronic acid has a very large ratio between the desired inhibition of bone resorption and the adverse effects on bone mineralization. Zoledronic acid inhibits the osteoclastic hyperactivity and accelerated bone resorption induced by various stimulatory factors released by tumors. In long-term animal studies, doses of zoledronic acid similar to those recommended for the treatment of hypercalcemia inhibit bone resorption without adversely affecting the formation, mineralization, or mechanical properties of bone.

In addition to inhibiting osteoclastic bone resorption, zoledronic acid exerts direct anti-tumor effects on cultured human myeloma and breast cancer cells, inhibiting their proliferation and inducing apoptosis. Zoledronic acid also inhibits the proliferation of human endothelial cells in vitro and is anti-angiogenic in animal tumor models. In vitro zoledronic acid reduces the invasion of human breast cancer cells into the extracellular matrix.

Preclinical data suggest that low micromolar concentrations of zoledronic acid are cytostatic and pro-apoptotic in vitro to a range of human cancer cell lines (breast, prostate, lung, bladder, myeloma). This anti-tumor efficacy may be enhanced when used in combination with other anti-cancer drugs. Preclinical data suggest that zoledronic acid is also anti-proliferative for human fetal osteoblasts and promotes their differentiation, a property that may be potentially relevant for the treatment of bone metastases in prostate cancer. Zoledronic acid has been shown to inhibit the proliferation of human endothelial cells in vitro and is anti-angiogenic in vivo. Zoledronic acid at picomolar concentrations has been shown to inhibit tumor cell invasion through extracellular matrix in preclinical cancer models.

Osteoclastic hyperactivity resulting in excessive bone resorption is the underlying pathophysiologic derangement in tumor-induced hypercalcemia (TIH, hypercalcemia of malignancy) 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 results in increased renal resorption of calcium, setting up a cycle of worsening systemic hypercalcemia. Correction of excessive bone resorption and adequate fluid administration to correct volume deficits are, therefore, essential to the management of hypercalcemia.

Most cases of hypercalcemia associated with malignancy occur in patients who have breast cancer, squamous-cell tumors of the lung or head and neck, renal cell carcinoma, and certain hematologic malignancies, such as multiple myeloma and some types of lymphomas. A few less common malignancies, including vasoactive intestinal-peptide-producing tumors and cholangiocarcinoma, have a high incidence of hypercalcemia as a metabolic complication. Patients who have tumor-induced hypercalcemia can generally be divided into two groups according to the pathophysiologic mechanism involved.

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 tumor-induced hypercalcemia 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 is often used in place of measurement of ionized calcium; several nomograms are in use for this type of calculation (see Dosage and Administration).

Limited pharmacokinetic data are available for ZOMETA in patients with severe renal impairment (creatinine clearance <30 mL/min). The pharmacokinetic studies were conducted in cancer patients (n=64) typical of the target clinical population, showing renal function mainly in the range of normal to moderately impaired [mean (±s.d.) creatinine clearance 84±29 mL/min, range 22-143 mL/min]. In these 64 patients the renal clearance of zoledronic acid was found to closely correlate with creatinine clearance, representing in the mean (±s.d.) 75±33% of the creatinine clearance. Creatinine clearance is calculated by the Cockcroft-Gault formula (see Dosage and Administration):

Patients with mild to moderate renal impairment (creatinine clearance 50-80 mL/min) showed increases in plasma AUC of 26% to 36%, whereas patients with moderate to severe renal impairment (creatinine clearance 30-50 mL/min) showed increases in plasma AUC of 27-41%, compared to patients with normal renal function (creatinine clearance >80 mL/min). However, there were no further increases in the systemic exposure after multiple doses in patients with impaired renal function (see Warnings and Precautions).

The population-derived relationship of ZOMETA clearance with creatinine clearance offers an algorithm for dose reduction in renal impairment. ZOMETA systemic clearance (CL) in individual patients can be calculated from the population clearance of ZOMETA and that individual’s creatinine clearance, as CL (L/h)=6.5×(CLcr/90)^0.4. This formula can be used to predict ZOMETA AUC in patients, where CL=Dose/AUC_0-∞. The average AUC_0-24 in patients with normal renal function was 0.42 mg·h/L and the calculated AUC_0-∞ for a patient with creatinine clearance of 75 mL/min was 0.66 mg·h/L following a 4 mg dose of ZOMETA.

Clinical studies in TIH demonstrated that the effect of ZOMETA is characterized by decreases in serum calcium and urinary calcium excretion. Normalization of serum calcium by day 4 was greater for the ZOMETA 4 mg and 8 mg doses (45% and 56%, respectively) compared with AREDIA (pamidronate) 90 mg (33%).

Osteolytic bone lesions and metastases commonly occur in patients with multiple myeloma, breast cancer, non-small cell lung cancer, renal cell carcinoma and a variety of other solid tumors. Bone lesions associated with bone metastases from prostate carcinoma classically are osteoblastic in contrast to those from other carcinomas, which are usually osteolytic or mixed osteolytic/osteoblastic. Adenocarcinoma of the prostate spreads most commonly to the well vascularized areas of the skeleton such as the vertebral column, ribs, skull, and the proximal ends of the long bones. Prostate carcinoma cells have long been believed to gain access to the vertebral column and ribs via the Batson venous plexus, which is a low pressure, high volume plexus of vertebral veins that join the intercostal veins.

These bone changes in patients with evidence of osteolytic and osteoblastic skeletal destruction may cause severe bone pain that requires either radiation therapy or narcotic analgesics (or both) for symptomatic relief. These changes also cause pathologic fractures of bone in both the axial and appendicular skeleton. Axial skeletal fractures of the vertebral bodies may lead to spinal cord compression or vertebral body collapse with significant neurologic complications. Patients may also experience episode(s) of hypercalcemia.

There are no pharmacokinetic data in pediatric patients (see Warnings and Precautions).