Zometa

Zoledronic acid.

Each vial contains anhydrous zoledronic acid 4 mg corresponding to zoledronic acid monohydrate 4.264 mg. Zometa also contains the following excipients: Mannitol, sodium citrate, water for injection.

Pharmacology: Pharmacodynamics: Mechanism of Action: Hypercalcemia of Malignancy and Bone Metastases from Solid Tumors: Zoledronic acid is a highly potent drug that belongs to the bisphosphonate class of drugs which act primarily on bone. It is one of the most potent inhibitors of osteoclastic bone resorption known to date.
The selective action of bisphosphonates on bone is based on their high affinity for mineralized bone, but the precise molecular mechanism leading to the inhibition of osteoclastic activity is still unclear. In long-term animal studies, zoledronic acid inhibits bone resorption without adversely affecting the formation, mineralization or mechanical properties of bone.
In addition to being a very potent inhibitor of bone resorption, zoledronic acid also possesses several antitumor properties that could contribute to its overall efficacy in the treatment of metastatic bone disease. The following properties have been demonstrated in preclinical studies: In Vivo: Inhibition of osteoclastic bone resorption, which alters the bone marrow microenvironment making it less conducive to tumor cell growth, antiangiogenic activity, anti-pain activity.
In Vitro: Inhibition of osteoblast proliferation, direct cytostatic and pro-apoptotic activity on tumor cells, synergistic cytostatic effect with other anticancer drugs, anti-adhesion/invasion activity.
Clinical Studies: Clinical Trial Results in the Treatment of Osteolytic, Osteoblastic and Mixed Bone Metastases of Solid Tumors and Osteolytic Lesions of Multiple Myeloma, in Conjunction with Standard Antineoplastic Therapy and Reduction of Bone Damage in Patients with Advanced Malignancies Involving Bone: Zometa was compared to placebo for the prevention of skeletal-related events (SREs) in adult prostate cancer patients with 214 men receiving Zometa 4 mg versus 208 receiving placebo. After the initial 15 months of treatment, 186 patients continued for up to an additional 9 months, giving a total duration of double-blind therapy up to 24 months. Zometa 4 mg demonstrated a significant advantage over placebo for the proportion of patients experiencing at least 1 SRE (38% for Zometa 4 mg vs 49% for placebo, p=0.028), delayed the median time to 1st SRE (488 days for Zometa 4 mg vs 321 days for placebo, p=0.009), and reduced the annual incidence of event per patient, skeletal morbidity rate (0.77 for Zometa 4 mg vs 1.47 for placebo, p=0.005). Multiple event analysis showed 36% risk reduction in developing SREs in the Zometa group compared with placebo (p=0.002). Pain was measured at baseline and periodically throughout the trial. Patients receiving Zometa reported less increase in pain than those receiving placebo, and the differences reached significance at months 3, 9, 21 and 24. Fewer Zometa patients suffered pathological fractures. The treatment effects were less pronounced in patients with blastic lesions. Efficacy results are provided in Table 1. (See Table 1.)

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In a 2nd study, Zometa reduced the number of SREs and extended the median time to an SRE by over 2 months in the population of adult patients who had other solid tumors involving bone, which had a median survival of only 6 months [134 patients with non-small cell lung cancer (NSCLC), 123 with other solid tumors treated with Zometa vs 130 patients with NSCLC, 120 with other solid tumors treated with placebo]. After 9 months of initial treatment, 101 patients entered the 12-month extension study and 26 completed the full 21 months. Zometa 4 mg reduced the proportion of patients with SREs (39% for Zometa 4 mg vs 48% for placebo, p=0.039), delayed the median time to 1st SRE (236 days for Zometa 4 mg vs 155 days for placebo, p=0.009) and reduced the annual incidence of events per patient-skeletal morbidity rate (1.74 for Zometa 4 mg vs 2.71 for placebo, p=0.012). Multiple event analysis showed 30.7% risk reduction in developing SREs in the Zometa group compared with placebo (p=0.003). The treatment effect in NSCLC patients appeared to be smaller than in patients with other solid tumors. Efficacy results are provided in Table 2. (See Table 2.)

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In a 3rd phase III randomized, double-blind trial comparing Zometa 4 mg to pamidronate 90 mg, 1122 adult patients (564 Zometa 4 mg, 558 pamidronate 90 mg) with multiple myeloma or breast cancer with at least 1 bone lesion were treated with Zometa 4 mg or pamidronate 90 mg every 3-4 weeks. Eight patients were excluded from the efficacy analysis because of good clinical practice noncompliance. Six hundred six (606) patients entered the 12-month, double-blind extension phase. Total therapy lasted up to 24 months. The results demonstrated that Zometa 4 mg showed comparable efficacy to pamidronate 90 mg in the prevention of SREs. The multiple event analyses revealed a significant risk reduction of 16% (p=0.03) in patients treated with Zometa 4 mg. Efficacy results are provided in Table 3. (See Table 3.)

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In clinical trials performed in adult patients with bone metastases or osteolytic lesions, the overall safety profile amongst all treatment groups (zoledronic acid 4 mg and pamidronate 90 mg and placebo) was similar in types and severity.
Zometa was also studied in a double-blind, randomized, placebo-controlled trial in 228 adult patients with documented bone metastases from breast cancer to evaluate the effect of Zometa on the SRE rate ratio, calculated as the total number of SRE events (excluding hypercalcemia and adjusted for prior fracture), divided by the total risk period. Patients received either Zometa 4 mg or placebo every 4 weeks for 1 year. Patients were evenly distributed between Zometa-treated and placebo groups.
The SRE rate ratio at 1 year was 0.61, indicating that treatment with Zometa reduced the rate of occurrence of SREs by 39% compared with placebo (p=0.027). The proportion of patients with at least 1 SRE (excluding hypercalcemia) was 29.8% in the Zometa-treated group versus 49.6% in the placebo group (p=0.003). Median time to onset of the first SRE was not reached in the Zometa-treated arm at the end of the study and was significantly prolonged compared to placebo (p=0.007). Zometa reduced the risk of SREs by 41% in a multiple event analysis (risk ratio=0.59, p=0.019) compared with placebo.
In the Zometa-treated group, decreases in pain scores from baseline [using the brief pain inventory (BPI)] occurred from 4 weeks onwards and at every subsequent time point during the study, while the pain score in the placebo group remained unchanged or increased from baseline (see figure). Zometa inhibited the worsening of the analgesic score more than placebo. In addition, 71.8% of Zometa-treated patients versus 63.1% of placebo patients showed improvement or no change in the ECOG performance score at the final observation.

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Clinical Trial Results in the Treatment of Hypercalcemia of Malignancy (HCM): Clinical studies in HCM demonstrated that the effect of zoledronic acid is characterized by decreases in serum calcium and urinary calcium excretion.
To assess the effects of Zometa versus pamidronate 90 mg, the results of 2 pivotal multicentre studies in adult patients with HCM were combined in a pre-planned analysis. The results showed that Zometa 4 and 8 mg were statistically superior to pamidronate 90 mg for the proportion of complete responders at days 7 and 10. There was faster normalization of corrected serum calcium at day 4 for Zometa 8 mg and at day 7 for Zometa 4 and 8 mg. The following response rates were observed: See Table 4.

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Median time to normocalcemia was 4 days. By day 10, the response rate was 87-88% for the Zometa treatment groups versus 70% for pamidronate 90 mg. Median time to relapse (re-increase of albumin-corrected serum calcium ≥2.9 mmol/L) was 30-40 days for patients treated with Zometa versus 17 days for those treated with pamidronate 90 mg. The results showed that both Zometa doses were statistically superior to pamidronate 90 mg for time to relapse. There were no statistically significant differences between the 2 Zometa doses.
In clinical trials performed in adult patients with HCM, the overall safety profile amongst all 3 treatment groups (zoledronic acid 4 and 8 mg and pamidronate 90 mg) was similar in types and severity.
Pharmacokinetics: Single and multiple 5- and 15-min infusions of zoledronic acid 2, 4, 8 and 16 mg in 64 patients with bone metastases yielded the following pharmacokinetic data.
No pharmacokinetic data for zoledronic acid are available in patients with hypercalcemia.
After initiating the infusion of zoledronic acid, the plasma concentrations of drug rapidly increased, achieving their peak at the end of the infusion period, followed by a rapid decline to <10% of peak after 4 hrs and <1% of peak after 24 hrs, with a subsequent prolonged period of very low concentrations not exceeding 0.1% of peak prior to the 2nd infusion of drug on day 28.
Distribution: Zoledronic acid shows no affinity for the cellular components of blood and plasma protein binding is low (60-77%) and slightly dependent on the concentration of zoledronic acid.
Biotransformation/Metabolism: Zoledronic acid is not metabolized and is excreted unchanged via the kidney. Zoledronic acid does not inhibit human P-450 enzymes in vitro.
Elimination: Intravenously administered zoledronic acid is eliminated via a triphasic process: Rapid biphasic disappearance from the systemic circulation, with half-lives (t_½) of t_½α 0.24 and t_½β 1.87 hrs, followed by a long elimination phase with a terminal elimination t_½ of t_½γ 146 hrs. There was no accumulation of drug in plasma after multiple doses of Zometa given every 28 days. Over the first 24 hrs, 39±16% of the administered dose is recovered in the urine, while the remainder is principally bound to bone tissue. From the bone tissue, it is released very slowly back into the systemic circulation and eliminated via the kidney. The total body clearance is 5.04±2.5 L/hr, independent of dose.
Linearity/Non-linearity: The zoledronic acid pharmacokinetics were found to be dose dependent. Increasing the infusion time from 5-15 min caused a 30% decrease in zoledronic acid concentration at the end of the infusion, but had no effect on the area under the plasma concentration versus time curve.
Special Populations: Hepatic Impairment: No pharmacokinetic data for zoledronic acid are available in patients with hepatic impairment. Zoledronic acid does not inhibit human P-450 enzymes in vitro, shows no biotransformation and in animal studies <3 % of the administered dose was recovered in the feces, suggesting no relevant role of liver function in the pharmacokinetics of zoledronic acid.
Renal Impairment: The renal clearance of zoledronic acid was significantly positively correlated with creatinine clearance, renal clearance representing 75±33% of the CrCl, which showed a mean of 84±29 mL/min (range 22-143 mL/min) in the 64 cancer patients studied. Population analysis showed that for a patient with CrCl of 50 mL/min (moderate impairment), the corresponding predicted clearance of zoledronic acid would be 72% of that of a patient showing CrCl of 84 mL/min. Only limited pharmacokinetic data are available in patients with severe renal impairment (CrCl <30 mL/min). The use of Zometa is not recommended in patients with severe renal impairment (see Precautions).
Effect of Gender, Age and Race: The 3 pharmacokinetic studies conducted in cancer patients with bone metastases reveal no effect by gender, race, age (range 38-84 years), and body weight on zoledronic acid total clearance.
Toxicology: Nonclinical Safety Data: Acute Toxicity: The highest nonlethal single IV dose was 10 mg/kg body weight in mice and 0.6 mg/kg in rats.
Subchronic and Chronic Toxicity: Zoledronic acid was well tolerated when administered SC to rats and IV to dogs at doses up to 0.02 mg/kg daily for 4 weeks. Administration of 0.001 mg/kg/day SC in rats and 0.005 mg/kg/day IV in dogs for up to 52 weeks was also well tolerated.
Reproduction Toxicity: Zoledronic acid was teratogenic in the rat at SC doses ≥0.2 mg/kg. Although no teratogenicity or fetotoxicity was observed in the rabbit, maternal toxicity was found.
Mutagenicity and Carcinogenic Potential: Zoledronic acid was not mutagenic in the mutagenicity tests performed and carcinogenicity testing did not provide any evidence of carcinogenic potential.
Local Tolerance: Local tolerance testing in rabbits showed that IV administration was well tolerated.

Treatment of osteolytic, osteoblastic and mixed bone metastases of solid tumors and osteolytic lesions of multiple myeloma, in conjunction with standard antineoplastic therapy.
Reduction of bone damage in patients with advanced malignancies involving bone.
Treatment of hypercalcemia of malignancy (HCM) defined as albumin-corrected serum calcium (cCa) ≥12 mg/dL (3 mmol/L).

Treatment of Bone Metastases and Osteolytic Lesions in Conjunction with Standard Antineoplastic Therapy and Reduction of Bone Damage in Patients with Advanced Malignancies Involving Bone: Adults and Elderly: Recommended Dose: 4 mg. The Zometa 4 mg/5 mL concentrate must be further diluted with 0.9% w/v sodium chloride 100 mL or 5% w/v glucose solution and given as an IV infusion lasting no less than 15 min every 3-4 weeks.
The Zometa 4 mg/100 mL solution for infusion is ready to use and must not be further diluted or mixed with other infusion solutions except for patients with renal impairment. It should be administered as a single IV solution in a separate infusion line in no less than 15 min.
Patients should also be administered an oral calcium supplement of 500 mg and vitamin D 400 IU daily.
Treatment of Hypercalcemia of Malignancy (HCM): Adults and Elderly: The recommended dose is 4 mg single infusion. Patients must be maintained well hydrated prior to and following administration of Zometa.
Renal Impairment: Zometa treatment in adult patients with HCM who also have severe renal impairment should be considered only after evaluating the risks and benefits of treatment. In the clinical studies, patients with serum creatinine >400 micromol/L or >4.5 mg/dL were excluded. No dose adjustment is necessary in HCM patients with serum creatinine <400 micromol/L or <4.5 mg/dL (see Precautions).
When initiating treatment with Zometa, serum creatinine levels and CrCl should be determined. Creatinine clearance is calculated from serum creatinine levels using the Cockcroft-Gault formula. Zometa is not recommended for patients presenting with severe renal impairment prior to initiation of therapy, which is defined for this population as CrCl <30 mL/min. In clinical trials with Zometa, patients with serum creatinine ≥265 micromol/L or ≥3 mg/dL were excluded.
In all patients except patients with HCM presenting with mild to moderate renal impairment prior to initiation of therapy, which is defined for these populations as CrCl 30-60 mL/min, the following Zometa dose is recommended (see Table 5 and Precautions).

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Following initiation of therapy, serum creatinine should be measured prior to each dose of Zometa and treatment should be withheld if renal function has deteriorated. In the clinical trials, renal deterioration was defined as follows: For patients with normal baseline serum creatinine (<1.4 mg/dL), an increase of ≥0.5 mg/dL; for patients with an abnormal baseline creatinine (>1.4 mg/dL), an increase of ≥1 mg/dL.
In the clinical studies, Zometa treatment was resumed only when the creatinine level returned to within 10% of the baseline value (see Precautions). Zometa should be resumed at the same dose as that prior to treatment interruption.
Administration: Zometa must only be administered to patients by healthcare professionals experienced in the administration of IV bisphosphonates.
Zometa must not be mixed with calcium or other divalent cation-containing infusion solutions eg, Lactated Ringer's solution and should be administered as a single IV solution in a line separate from all other drugs in no less than 15 min.
Patients must be maintained in a well-hydrated state prior to and following administration of Zometa.
Preparation of Reduced Zometa Doses: In patients with mild to moderate renal impairment, which is defined as CrCl 30-60 mL/min, reduced Zometa dosages are recommended, except in patients with HCM.
To prepare reduced doses of Zometa 4 mg/5 mL concentrate, withdraw an appropriate volume of the liquid concentrate needed as follows: 4.4 mL, 4.1 mL and 3.8 mL for 3.5-mg, 3.3-mg and 3-mg doses, respectively.
The withdrawn amount of liquid concentrate must be further diluted in 100 mL of sterile 0.9% w/v sodium chloride solution or 5% w/v glucose solution. The dose must be given as a single IV infusion of no less than 15 min.
To prepare reduced doses of Zometa 4 mg/100 mL solution for infusion, remove the corresponding volume of Zometa solution as indicated as follows and replace it with an equal volume of sterile 0.9% w/v sodium chloride solution or 5% w/v glucose solution. (See Table 6.)

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Clinical experience with acute overdosage of Zometa is limited. Patients who have received doses higher than those recommended should be carefully monitored, since renal function impairment (including renal failure) and serum electrolyte (including calcium, phosphorus and magnesium) abnormalities have been observed. In the event of hypocalcemia, calcium gluconate infusions should be administered as clinically indicated.

Hypersensitivity to zoledronic acid, other bisphosphonates or any of the excipients in the formulation of Zometa.
Use in pregnancy & lactation: In animal reproduction studies, zoledronic acid was administered SC to rats and rabbits. It was found to be teratogenic at doses ≥0.2 mg/kg body weight in rats. In rabbits, there was no teratogenicity or fetotoxicity but maternotoxicity was found. Zometa should not be used during pregnancy.
It is not known whether zoledronic acid is excreted into human milk. Zometa should not be used by breastfeeding women.

General: All patients, including patients with mild to moderate renal impairment, must be assessed prior to administration of Zometa to assure that they are adequately hydrated.
Overhydration should be avoided in patients at risk of cardiac failure.
Standard hypercalcemia-related metabolic parameters eg, albumin-corrected serum levels of calcium, phosphate and magnesium as well as serum creatinine should be carefully monitored after initiating Zometa therapy. If hypocalcemia, hypophosphatemia or hypomagnesemia occur, short-term supplemental therapy may be necessary. Untreated hypercalcemia patients generally have some degree of renal function impairment, therefore careful renal function monitoring should be considered.
Zometa contains the same active ingredient as found in Aclasta (zoledronic acid). Patients being treated with Zometa should not be treated with Aclasta concomitantly. Zometa should also not be given together with other bisphosphonates since the combined effects of these agents are unknown.
While not observed in clinical trials with Zometa, there have been reports of bronchoconstriction in acetylsalicylic acid sensitive asthmatic patients receiving bisphosphonates.
Renal Impairment: Adult patients with HCM with evidence of impairment in renal function should be appropriately evaluated with consideration given as to whether the potential benefit of treatment with Zometa outweighs the possible risk.
The decision to treat patients with bone metastases for the prevention of skeletal-related events should consider that the onset of treatment effect is 2-3 months.
Bisphosphonates have been associated with reports of renal function deterioration. Factors that may increase the potential for deterioration in renal function include dehydration, preexisting renal impairment, multiple cycles of Zometa or other bisphosphonates as well as use of nephrotoxic drugs or using a shorter infusion time than currently recommended. While the risk is reduced with a dose of Zometa 4 mg administered over no less than 15 min, deterioration in renal function may still occur. Renal deterioration, progression to renal failure and dialysis have been reported in patients after the initial dose or a single dose of Zometa. Increases in serum creatinine also occur in some patients with chronic administration of Zometa at recommended doses for prevention of skeletal-related events, although less frequently.
Serum creatinine levels should be measured before each Zometa dose. In patients with mild to moderate renal impairment at the initiation of Zometa treatment, lower doses are recommended in all adult patients except patients with HCM. In patients who show evidence of renal deterioration during treatment, Zometa should only be resumed when creatinine level returns to within 10% of baseline value (see Dosage & Administration).
The use of Zometa is not recommended in patients with severe renal impairment because there are limited clinical safety and pharmacokinetic data in this population, and there is a risk of renal function deterioration in patients treated with bisphosphonates, including Zometa. In clinical trials, patients with severe renal impairment were defined as those with baseline serum creatinine ≥400 micromol/L or ≥4.5 mg/dL for patients with HCM and ≥265 micromol/L or ≥3 mg/dL for all other patients, respectively. In pharmacokinetic studies, patients with severe renal impairment were defined as those with baseline CrCl <30 mL/min (see Pharmacology: Pharmacokinetics under Actions).
Hepatic Impairment: As only limited clinical data are available in patients with severe hepatic impairment, no specific recommendations can be given for this patient population.
Osteonecrosis of the Jaw (ONJ): ONJ has been reported predominantly in adult cancer patients treated with bisphosphonates, including Zometa. Many of these patients were also receiving chemotherapy and corticosteroids. The majority of reported cases have been associated with dental procedures eg, tooth extraction. Many had signs of local infection, including osteomyelitis.
Post-marketing experience and the literature suggest a greater frequency of reports of ONJ based on tumor type (advanced breast cancer, multiple myeloma) and dental status (dental extraction, periodontal disease, local trauma including poorly fitting dentures).
Patients should maintain good oral hygiene and should have a dental examination with preventive dentistry prior to treatment with bisphosphonates.
While on treatment with bisphosphonates, patients should avoid invasive dental procedures if possible. For patients who develop ONJ while on bisphosphonate therapy, dental surgery may exacerbate the condition. For patients requiring dental procedures, there are no data available to suggest whether discontinuation of bisphosphonate treatment reduces the risk of osteonecrosis of the jaw. Clinical judgment of the treating physician should guide the management plan of each patient based on individual benefit/risk assessment.
Atypical Fractures of the Femur: Atypical subtrochanteric and diaphyseal femoral fractures have been reported in patients receiving bisphosphonate therapy, primarily in patients receiving long-term treatment for osteoporosis. These transverse or short oblique fractures can occur anywhere along the femur from just below the lesser trochanter to just above the supracondylar flare. These fractures occur after minimal or no trauma and some patients experience thigh or groin pain, often associated with imaging features of stress fractures, weeks to months before presenting with a completed femoral fracture. Fractures are often bilateral; therefore, the contralateral femur should be examined in Zometa-treated patients, who have sustained a femoral shaft fracture. Poor healing of these fractures has also been reported. Discontinuation of Zometa therapy in patients suspected to have an atypical femur fracture should be considered pending evaluation of the patient, based on an individual benefit risk assessment. Reports of atypical femoral fracture have been received in patients treated with Zometa; however, causality with Zometa therapy has not been established.
During Zometa treatment, patients should be advised to report any thigh, hip or groin pain and any patient presenting with such symptoms should be evaluated for an incomplete femur fracture.
Musculoskeletal Pain: In post-marketing experience, severe and occasionally incapacitating bone, joint and/or muscle pain have been reported in patients taking bisphosphonates, including Zometa (see Adverse Reactions). The time to onset of symptoms varied from 1 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.
Hypocalcemia: Hypocalcemia has been reported in patients treated with Zometa. Cardiac arrhythmias and neurologic adverse events (seizures, tetany and numbness) have been reported secondary to cases of severe hypocalcemia. In some instances, the hypocalcemia may be life-threatening.

In animal reproduction studies, zoledronic acid was administered SC to rats and rabbits. It was found to be teratogenic at doses ≥0.2 mg/kg body weight in rats. In rabbits, there was no teratogenicity or fetotoxicity but maternotoxicity was found. Zometa should not be used during pregnancy.
It is not known whether zoledronic acid is excreted into human milk. Zometa should not be used by breastfeeding women.

Summary of the Safety Profile: The most serious adverse drug reactions reported in patients receiving Zometa in the approved indications are: Anaphylactic reaction, ocular adverse events, ONJ, atypical femoral fracture, atrial fibrillation, renal function impairment, acute phase reaction and hypocalcemia. The frequencies for each of these adverse reactions are shown as follows or in Adverse Drug Reactions from Spontaneous Reports and Literature Cases.
Frequencies of adverse reactions for Zometa 4 mg are mainly based on data collected from chronic treatment. Adverse reactions to Zometa are usually mild and transient and similar to those reported for other bisphosphonates. Those reactions can be expected to occur in approximately ¹/₃ of patients treated with Zometa.
Within 3 days after Zometa administration, an acute phase reaction has commonly been reported, with symptoms including pyrexia, fatigue, bone pain, chills and influenza-like illness, arthritis with subsequent joint swelling; these symptoms usually resolve within a few days (see Description of Selected Adverse Reactions). Cases of arthralgia and myalgia have commonly been reported.
Very commonly, the reduction in renal calcium excretion is accompanied by a fall in serum phosphate levels, which is asymptomatic not requiring treatment. The serum calcium may fall to asymptomatic hypocalcemic levels.
Gastrointestinal reactions eg, nausea and vomiting have been commonly reported following IV infusion of Zometa. Uncommonly local reactions at the infusion site eg, redness or swelling and/or pain were also observed.
Anorexia was commonly reported in patients treated with Zometa 4 mg.
Rash or pruritus has been uncommonly observed. As with other bisphosphonates, cases of conjunctivitis have been reported.
Based on pooled analysis of placebo-controlled studies, severe anemia (Hb <8 g/dL) was commonly reported in patients receiving Zometa 4 mg.
Adverse drug reactions from clinical trials are listed according to system organ classes in MedDRA. Within each system organ class, the adverse drug reactions are ranked by frequency, with the most frequent reactions first. Within each frequency grouping, adverse drug reactions are presented in order of decreasing seriousness. In addition, the corresponding frequency category using the following convention (CIOMS III) is also provided for each adverse drug reaction: Very common (≥1/10), common (≥1/100, <1/10), uncommon (≥1/1000, <1/100), rare (≥1/10,000, <1/1000), very rare (<1/10,000), including isolated reports.
Blood and Lymphatic System Disorders: Common: Anemia. Uncommon: Thrombocytopenia, leucopenia. Rare: Pancytopenia.
Immune System Disorders: Uncommon: Hypersensitivity reaction. Rare: Angioedema.
Nervous System Disorders: Common: Headache, paresthesia. Uncommon: Dizziness, taste disturbance, hypoesthesia, hyperesthesia, tremor.
Psychiatric Disorders: Common: Sleep disorder. Uncommon: Anxiety. Rare: Confusion.
Eye Disorders: Common: Conjunctivitis. Uncommon: Blurred vision.
Gastrointestinal Disorders: Common: Nausea, vomiting, anorexia, constipation. Uncommon: Diarrhea, abdominal pain, dyspepsia, stomatitis, dry mouth.
Respiratory, Thoracic and Mediastinal Disorders: Uncommon: Dyspnea, cough.
Skin and Subcutaneous Tissue Disorders: Common: Hyperhidrosis. Uncommon: Pruritus, rash (including erythematous and macular rash).
Musculoskeletal and Connective Tissue Disorders: Common: Bone pain, myalgia, arthralgia, generalized pain. Uncommon: Osteonecrosis of the jaw (ONJ), muscle cramps.
Cardiovascular Disorders: Rare: Bradycardia.
Vascular Disorders: Common: Hypertension. Uncommon: Hypotension.
Renal and Urinary Disorders: Common: Renal impairment. Uncommon: Acute renal failure, hematuria, proteinuria.
General Disorders and Administration Site Conditions: Common: Acute phase reaction, pyrexia, influenza-like illness (including fatigue, chills, malaise and flushing), peripheral edema, asthenia. Uncommon: Injection site reactions (including pain, irritation, swelling, induration, redness), chest pain, increased weight. Rare: Arthritis and joint swelling as a symptom of acute phase reaction.
Investigations: Very Common: Hypophosphatemia. Common: Increased blood creatinine and blood urea, hypocalcemia. Uncommon: Hypomagnesemia, hypokalemia. Rare: Hyperkalemia, hypernatremia.
Adverse Drug Reactions from Spontaneous Reports and Literature Cases (Frequency Not Known): The following adverse reactions have been reported during post-marketing experience with Zometa via spontaneous case reports and literature cases. Because these reactions are reported voluntarily from a population of uncertain size and are subject to confounding factors, it is not possible to reliably estimate their frequency (which is therefore categorized as not known) or establish a causal relationship to drug exposure.
Immune System Disorders: Anaphylactic reaction/shock.
Nervous System Disorders: Somnolence.
Eye Disorders: Uveitis, episcleritis, scleritis and orbital inflammation.
Cardiac Disorders: Atrial fibrillation.
Vascular Disorders: Hypotension leading to syncope or circulatory collapse, primarily in patients with underlying risk factors.
Respiratory, Thoracic and Mediastinal Disorders: Bronchospasms, interstitial lung disease (ILD).
Skin and Subcutaneous Tissue Disorders: Urticaria.
Musculoskeletal and Connective Tissue Disorders: Severe and occasionally incapacitating bone, joint, and/or muscle pain, atypical subtrochanteric and diaphyseal femoral fractures (bisphosphonate class adverse reaction, including Zometa).
Description of Selected Adverse Reactions: Renal Function Impairment: Zometa has been associated with reports of renal function impairment. In a pooled analysis of safety data from Zometa registration trials for the prevention of skeletal-related events in patients with advanced malignancy involving bone, the frequency of renal function impairment adverse events suspected to be related to Zometa (adverse reactions) was as follows: Multiple myeloma (3.2%), prostate cancer (3.1%), breast cancer (4.3%), lung and other solid tumors (3.2%). Factors that may increase the potential for deterioration in renal function include dehydration, preexisting renal impairment, multiple cycles of Zometa or other bisphosphonates, as well as concomitant use of nephrotoxic medicinal products or using a shorter infusion time than currently recommended. Renal deterioration, progression to renal failure and dialysis have been reported in patients after the initial dose or a single dose of Zometa (see Precautions).
Osteonecrosis of the Jaw (ONJ): Cases of osteonecrosis (primarily of the jaws) have been reported predominantly in cancer patients treated with bisphosphonates, including Zometa (uncommon). Many of these patients had signs of local infection including osteomyelitis, and the majority of the reports refer to cancer patients following tooth extractions or other dental surgeries. Osteonecrosis of the jaw has multiple well documented risk factors including a diagnosis of cancer, concomitant therapies (eg, chemotherapy, radiotherapy, corticosteroids) and co-morbid conditions (eg, anemia, coagulopathies, infection, preexisting oral disease). Although causality has not been determined, it is prudent to avoid dental surgery as recovery may be prolonged (see Precautions). Data suggests a greater frequency of reports of ONJ based on tumor type (advanced breast cancer, multiple myeloma).
Acute Phase Reaction: This adverse drug reaction consists of a constellation of symptoms that includes pyrexia, fatigue, bone pain, chills, influenza-like illness, arthritis with subsequent joint swelling. The onset time is ≤3 days post-Zometa infusion and the reaction is also referred to using the terms "flu-like" or "post-dose" symptoms; these symptoms usually resolve within a few days.
Atrial Fibrillation: In one 3-year, randomized, double-blind controlled trial that evaluated the efficacy and safety of zoledronic acid 5 mg once yearly versus placebo in the treatment of postmenopausal osteoporosis (PMO), the overall incidence of atrial fibrillation was 2.5% (96 out of 3862) and 1.9% (75 out of 3852) in patients receiving zoledronic acid 5 mg 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 zoledronic acid 5 mg and placebo, respectively. The imbalance observed in this trial has not been observed in other trials with zoledronic acid, including those with Zometa (zoledronic acid) 4 mg every 3-4 weeks in oncology patients. The mechanism behind the increased incidence of atrial fibrillation in this single clinical trial is unknown.

Anticipated Interactions to be Considered: Caution is advised when bisphosphonates like Zometa are administered with aminoglycosides and loop diuretics, since both agents may have an additive effect, resulting in a lower serum calcium level for longer periods than required.
Caution is indicated when Zometa is used with other potentially nephrotoxic drugs.
Caution is advised when Zometa is administered with antiangiogenic drugs as cases of ONJ have been observed in patients treated concomitantly with these drugs.
Absence of Interactions: In clinical studies, Zometa has been administered concomitantly with commonly used anticancer agents, diuretics (except for loop diuretics), antibiotics and analgesics without clinically apparent interactions occurring.
No dose adjustment for Zometa is needed when co-administered with thalidomide, except in patients with mild to moderate renal impairment at baseline (see Dosage & Administration). Co-administration of thalidomide (100 or 200 mg once daily) with Zometa (4 mg given as a 15-min infusion) did not significantly change the pharmacokinetics of zoledronic acid and the CrCl of patients with multiple myeloma.
Incompatibilities: Studies with glass bottles, as well as several types of infusion bags and lines made from polyvinylchloride, polyethylene and polypropylene (pre-filled with 0.9% w/v sodium chloride solution or 5% w/v glucose solution), showed no incompatibility with Zometa.
To avoid potential incompatibilities, Zometa concentrate is to be diluted with 0.9% w/v sodium chloride solution or 5% w/v glucose solution.
Zometa concentrate and Zometa "ready-to-use" solution for infusion must not be mixed or come into contact with calcium- or other divalent cation-containing infusion solutions eg, lactated Ringer's solution, and should be administered as a single IV solution in a line separate from all other drugs.

Instructions for Use and Handling: Zometa 4 mg/5 mL concentrate for solution and Zometa 4 mg/100 mL solution for infusion is for IV use only.
The 4 mg/5 mL concentrate from 1 vial (or the volume of the concentrate withdrawn as required) must be further diluted with 100 mL of calcium-free infusion solution (0.9% w/v sodium chloride solution or 5% w/v glucose solution).
The 4 mg/100 mL solution is a "ready-to-use" presentation which must not be further diluted or mixed with other infusion solutions except for patients with renal impairment. For reduced doses of this presentation in patients with mild and moderate renal impairment (see Dosage & Administration).
After aseptic dilution (or for reduced doses of the "ready-to-use" presentation), it is preferable to use the diluted product immediately. If not used immediately, the duration and conditions of storage prior to use are under the healthcare provider’s responsibility. The total time between dilution, storage in a refrigerator at 2-8°C and end of administration must not exceed 24 hrs. If refrigerated, the solutions must be allowed to reach room temperature before administration. (See Dosage & Administration).
Any unused solution should be discarded. Only clear solution free from particles and discoloration should be used.

Do not store above 30°C.

Agents Affecting Bone Metabolism

M05BA08 - zoledronic acid ; Belongs to the class of bisphosphonates. Used in the treatment of bone diseases.

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