Zoltero 4

Zoledronic acid.

Each vial contains Zoledronic Acid Monohydrate 4.264 mg Equivalent to Zoledronic acid 4 mg.
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.
Zoledronic acid is a white crystalline powder. Its molecular formula is C₅H₁₀N₂O₇P₂ H₂O 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.
Zoledronic acid 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.
Excipients/Inactive Ingredients: Mannitol (Pearlitol PF), Ph.Eur, 220 mg, water for injection and trisodium citrate dehydrate, Ph. Eur to adjust pH.

Pharmacology: Pharmacodynamics: Mechanism of action: Zoledronic acid is a highly potent drug that belongs to the bisphosphonates 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 mineralised 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 anti-tumour 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 tumour cell growth, anti-angiogenic activity, anti-pain activity.
In vitro: inhibition of osteoblast proliferation, direct cytostatic and pro-apoptotic activity on tumour cells, synergistic cytostatic effect with other anti-cancer drugs, antiadhesion/invasion activity.
Clinical Studies: Clinical trial results in the treatment of osteolytic, osteoblastic and mixed bone metastases and osteolytic lesions of multiple myeloma, in conjunction with standard antineoplastic therapy: Zoledronic acid was compared to placebo for the prevention of skeletal related events (SREs) in adult prostate cancer patients with 214 men receiving Zoledronic acid 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. Zoledronic acid 4 mg demonstrated a significant advantage over placebo for the proportion of patients experiencing at least one skeletal related event (SRE) (38% for Zoledronic acid 4 mg versus 49% for placebo, p=0.028), delayed the median time to first SRE (488 days for Zoledronic acid 4 mg versus 321 daysfor placebo, p=0.009), and reduced the annual incidence of event per patient - skeletal morbidity rate (0.77 for Zoledronic acid 4 mg versus 1.47 for placebo, p=0.005). Multiple event analysis showed 36% risk reduction in developing skeletal related events in the Zoledronic acid group compared with placebo (p=0.002). Pain was measured at baseline and periodically throughout the trial. Patients receiving Zoledronic acid reported less increase in pain than those receiving placebo, and the differences reached significance at months 3, 9, 21 and 24. Fewer Zoledronic acid patients suffered pathological fractures. The treatment effects were less pronounced in patients with blastic lesions. Efficacy results are provided in Table 1.
In a second study, Zoledronic acid reduced the number of SREs and extended the median time to an SRE by over two months in the population of adult patients who had other solid tumors involving bone, which had a median survival of only six months (134 patients with non-small-cell lung cancer [NSCLC], 123 with other solid tumors treated with Zoledronic acid vs 130 patients with NSCLC, 120 with other solid tumors treated with placebo). After initial 9 months of treatment, 101 patients entered the 12 month extension study, and 26 completed the full 21 months. Zoledronic acid 4 mg reduced the proportion of patients with SREs (39% for Zoledronic acid 4 mg versus 48% for placebo, p=0.039), delayed the median time to first SRE (236 days for Zoledronic acid 4 mg versus 155 days for placebo, p=0.009), and reduced the annual incidence of events per patient - skeletal morbidity rate (1.74 for Zoledronic acid 4 mg versus 2.71 for placebo, p=0.012). Multiple event analysis showed 30.7% risk reduction in developing skeletal related events in the Zoledronic acid group compared with placebo (p=0.003). The treatment effect in non-small cell lung cancer patients appeared to be smaller than in patients with other solid tumors. Efficacy results are provided in Table 2. (See Tables 1 and 2.)

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In a third phase III randomized, double-blind trial comparing Zoledronic acid 4 mg to pamidronate 90 mg, 1,122 adult patients (564 Zoledronic acid 4 mg, 558 pamidronate 90 mg) with multiple myeloma or breast cancer with at least one bone lesion were treated with 4 mg Zoledronic acid or 90 mg pamidronate every 3 to 4 weeks. Eight patients were excluded from the efficacy analysis because of good clinical practice non-compliance. 606 patients entered the 12-month, double-blind extension phase. Total therapy lasted up to 24 months. The results demonstrated that Zoledronic acid 4 mg showed comparable efficacy to 90 mg pamidronate in the prevention of skeletal related events. The multiple event analyses revealed a significant risk reduction of 16% (p=0.030) in patients treated with Zoledronic acid 4 mg. Efficacy results are provided in 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.
Zoledronic acid 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 Zoledronic acid on the skeletal related event (SRE) rate ratio, calculated as the total number of SRE events (excluding hypercalcaemia and adjusted for prior fracture), divided by the total risk period. Patients received either 4 mg Zoledronic acid or placebo every four weeks for one year. Patients were evenly distributed between Zoledronic acid-treated and placebo groups.
The SRE rate ratio at one year was 0.61, indicating that treatment with Zoledronic acid reduced the rate of occurrence of SREs by 39% compared with placebo (p=0.027). The proportion of patients with at least one SRE (excluding hypercalcaemia) was 29.8% in the Zoledronic acid-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 Zoledronic acid-treated arm at the end of the study and was significantly prolonged compared to placebo (p=0.007). Zoledronic acid reduced the risk of SREs by 41% in a multiple event analysis (risk ratio=0.59, p=0.019) compared with placebo.
In the Zoledronic acid-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 (figure). Zoledronic acid inhibited the worsening of the analgesic score more than placebo. In addition, 71.8% of Zoledronic acid-treated patients versus 63.1% of placebo patients showed improvement or no change in the ECOG performance score at the final observation. (See figure.)

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

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Median time to normocalcaemia was 4 days. By day 10 the response rate was 87 to 88 % for the Zoledronic acid 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 to 40 days for patients treated with Zoledronic acid versus 17 days for those treated with pamidronate 90 mg. The results showed that both Zoledronic acid doses were statistically superior to pamidronate 90 mg for time to relapse. There were no statistically significant differences between the two Zoledronic acid doses.In clinical trials performed in adult patients with hypercalcaemia of malignancy (HCM), the overall safety profile amongst all three 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-minute infusions of 2, 4, 8 and 16 mg zoledronic acid 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 hours and < 1% of peak after 24 hours, with a subsequent prolonged period of very low concentrations not exceeding 0.1% of peak prior to the second infusion of drug on day 28.
Distribution: Zoledronic acid shows low affinity for the cellular components of human blood, with a mean blood to plasma concentration ratio of 0.59 in a concentration range of 30 ng/mL to 5000 ng/mL The plasma protein binding is low, with the unbound fraction ranging from 60% at 2 ng/mL to 77% at 2000 ng/mL of zoledronic acid.
Biotransformation/Metabolism: Zoledronic acid is not metabolised and is excreted unchanged via the kidney. Zoledronic acid does not inhibit human P450 enzymes in vitro.
Elimination: Intravenously administered zoledronic acid is eliminated via a triphasic process: rapid biphasic disappearance from the systemic circulation, with half-lives of t_½ alpha 0.24 and t_½ beta 1.87 hours, followed by a long elimination phase with a terminal elimination half-life of t_½ gamma 146 hours. There was no accumulation of drug in plasma after multiple doses of the drug given every 28 days. Over the first 24 hours, 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 thekidney. The total body clearance is 5.04 ± 2.5 L/h, independent of dose, and unaffected by gender, age, race, and body weight.
Linearity/Non-linearity: The zoledronic acid pharmacokinetics were found to be dose independent. Increasing the infusion time from 5 to 15 minutes 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 P450 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 correlated with creatinine clearance, renal clearance representing 75 ± 33% of the creatinine clearance, which showed a mean of 84 ± 29 mL/min (range 22 to 143 mL/min) in the 64 cancer patients studied. Population analysis showed that for a patient with creatinine clearance of 50 mL/min (moderate impairment), the corresponding predicted clearance of zoledronic acid would be 72% of that of a patient showing creatinine clearance of 84 mL/min. Only limited pharmacokinetic data are available in patients with severe renal insufficiency (creatinine clearance <30 mL/min). The use of Zoledronic acid is not recommended in patients with severe renal impairment (see Precautions).
Effect of gender, age and race: The three pharmacokinetic studies conducted in cancer patients with bone metastases reveal no effect by gender, race, age (range 38 to 84 years), and body weight on zoledronic acid total clearance.
Toxicology: Non-Clinical Safety Data: Toxicity studies: In the bolus parenteral studies, Zoledronic acid was well tolerated when administered subcutaneously to rats and intravenously to dogs at doses up to 0.02 mg/kg daily for 4 weeks. Administration of 0.001 mg/kg/day subcutaneously in rats and 0.005 mg/kg intravenously once every 2 to 3 days in dogs for up to 52 weeks was also well tolerated.
The most frequent finding in the repeat-dose studies consisted of increased primary spongiosa in the metaphysis of long bones in growing animals at nearly all doses, a finding that reflected the compound's pharmacological antiresorptive activity.
The kidney was identified as a major target organ for toxicity in parenteral studies with zoledronic acid. In the intravenous infusion studies, renal tolerability was observed in rats given six infusions at doses of up to 0.6 mg/kg at 3-day intervals, while five infusions of 0.25 mg/kg administered at 3-week intervals were well tolerated in dogs.
Reproduction toxicity: Teratogenicity studies were performed in two species, both via subcutaneous administration of zoledronic acid. Teratogenicity was observed in the rat at doses ≥0.2 mg/kg/day and was manifested by external, visceral and skeletal malformations. Dystocia was observed at the lowest dose (0.01 mg/kg/day) tested in rats.
No teratogenic or embryo/fetal effects were observed in the rabbit, although maternal toxicity was marked at 0.1 mg/kg/day. Adverse maternal effects were associated with, and may have been caused by, drug-induced hypocalcaemia.
Mutagenicity: Zoledronic acid was not mutagenic in vitro and in vivo in the mutagenicity tests performed.
Carcinogenicity: In oral carcinogenicity studies in rodents, zoledronic acid revealed no carcinogenic potential.

Treatment of osteolytic, osteoblastic, and mixed bone metastases of solid tumours and osteolytic lesions of multiple myeloma, in conjunction with standard antineoplastic therapy.
Treatment of hypercalcaemia of malignancy (HCM).

The Zoledronic acid 4 mg/5 mL concentrate should be further diluted with 100 mL 0.9% w/v sodium chloride or 5% w/v glucose solution before infusion (see Instructions for Use and Handling under Cautions for Usage). The final Zoledronic acid solution for infusion, should be given as an intravenous infusion of no less than 15 minutes.
The Zoledronic acid 4 mg/100 mL solution for infusion is a "ready to use" presentation 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 intravenous solution in a separate infusion line in no less than 15 minutes.
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Treatment of bone metastases and treatment of osteolytic lesions, in conjunction with standard antineoplastic therapy: In adults and elderly patients, the recommended Zoledronic acid dose is a 4 mg infusion given every 3 to 4 weeks.
Patients should also be administered an oral calcium supplement of 500 mg and 400 IU vitamin D daily.
Treatment of hypercalcemia of malignancy (HCM): In adult and elderly patients, the recommended Zoledronic acid dose in hypercalcaemia (albumin-corrected serum calcium ≥ 12.0 mg/dL or 3.0 mmol/L) is a single 4 mg infusion. Patients must be maintained well hydrated prior to and following administration of Zoledronic acid.
Treatment of patients with renal impairment: Patients with hypercalcemia with malignancy (HCM): Zoledronic acid treatment in adult patients with hypercalcaemia of malignancy (HCM) who also have severe renal impairment should be considered only after evaluating the risks and benefit 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).
Treatment of bone metastases and treatment of osteolytic lesions, in conjunction with standard antineoplastic therapy: When initiating treatment with Zoledronic acid, serum creatinine levels and creatinine clearance (CL_cr) should be determined. CL_cr is calculated from serum creatinine levels using the Cockcroft-Gault formula. Zoledronic acid is not recommended for patients presenting with severe renal impairment prior to initiation of therapy, which is defined for this population as CL_cr < 30 mL/min. In clinical trials with Zoledronic acid, patients with serum creatinine > 265 micromol/L or > 3.0 mg/dL were excluded.
In patients with bone metastases presenting with mild to moderate renal impairment prior to initiation of therapy, which is defined for this population as CrCl 30 to 60 mL/min, the following Zoledronic acid dose is recommended (see also Precautions): (See Table 5.)

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Following initiation of therapy, serum creatinine should be measured prior to each dose of Zoledronic acid 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 ≥ 1.0 mg/dL.
In the clinical studies, Zoledronic acid treatment was resumed only when the creatinine level returned to within 10% of the baseline value (see Precautions). Zoledronic acid should be resumed at the same dose as that prior to treatment interruption.
Method of administration: Zoledronic acid must only be administered to patients by healthcare professionals experienced in the administration of intravenous bisphosphonates.
Zoledronic acid 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 in no less than 15 minutes.
Patients must be maintained in a well hydrated state prior to and following administration of Zoledronic acid.
Preparation of reduced Zoledronic acid doses: In patients with mild to moderate renal impairment, which is defined as CLcr 30 to 60 mL/min, reduced Zoledronic acid dosages are recommended, except in patients with HCM (see Dosage & Administration as previously mentioned).
To prepare reduced doses of Zoledronic acid 4 mg/5 mL concentrate withdraw an appropriate volume of the liquid concentrate needed, as follows: 4.4 mL for 3.5 mg dose; 4.1 mL for 3.3 mg dose; 3.8 mL for 3.0 mg dose.
For information on the reconstitution and dilution of Zoledronic acid (see Instructions for Use and Handling under Cautions for Usage). The withdrawn amount of the concentrate must be 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 intravenous infusion of no less than 15 minutes.
To prepare reduced doses of Zoledronic acid 4 mg/100 mL solution for infusion remove the corresponding volume of Zoledronic acid 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 Zoledronic acid 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 hypocalcaemia, calcium gluconate infusions should be administered as clinically indicated.

Hypersensitivity to zoledronic acid or other bisphosphonates or any of the excipients in the formulation of Zoledronic acid.
Pregnancy and breast-feeding women (see Use in Pregnancy & Lactation).

General: All patients, including patients with mild to moderate renal impairment, must be assessed prior to administration of Zoledronic acid to assure that they are adequately hydrated.
Overhydration should be avoided in patients at risk of cardiac failure.
Standard hypercalcaemia-related metabolic parameters, such as albumin-corrected serum levels of calcium, phosphate and magnesium as well as serum creatinine should be carefully monitored after initiating Zoledronic acid therapy. If hypocalcaemia, hypophosphataemia, or hypomagnesaemia occur, short-term supplemental therapy may be necessary. Untreated hypercalcaemia patients generally have some degree of renal function impairment, therefore careful renal function monitoring should be considered.
Zoltero contains the same active ingredient as in Aclasta (zoledronic acid). Patients being treated with Zoledronic acid should not be treated with Aclasta concomitantly. Zoledronic acid 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 Zoledronic acid, there have been reports of bronchoconstriction in acetylsalicylic acid sensitive asthmatic patients receiving bisphosphonates.
Renal impairment: Adult patients with HCM and evidence of deterioration in renal function should be appropriately evaluated with consideration given as to whether the potential benefit of continued treatment with Zoledronic acid outweighs the possible risk (see Dosage & Administration).
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 to 3 months.
Bisphosphonates 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 Zoledronic acid 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 Zoledronic acid 4 mg administered over no less than 15 minutes, 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 Zoledronic acid. Increases in serum creatinine also occur in some patients with chronic administration of Zoledronic acid at recommended doses for prevention of skeletal related events, although less frequently.
Serum creatinine levels should be measured before each Zoledronic acid dose. In patients with mild to moderate renal impairment at the initiation of Zoledronic acid treatment, lower doses are recommended in all adult patients except patients with HCM. In patients who show evidence of renal deterioration during treatment, Zoledronic acid should only be resumed when creatinine level returns to within 10% of baseline value (see Dosage & Administration).
The use of Zoledronic acid 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 Zoledronic acid. 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 ≥ 3.0 mg/dL for all other patients, respectively.
In pharmacokinetic studies, patients with severe renal impairment were defined as those with baseline creatinine clearance <30 mL/min (see Pharmacology: Pharmacokinetics under Actions and Dosage & Administration).
Hepatic impairment: As only limited clinical data are available in patients with severe hepatic insufficiency, no specific recommendations can be given for this patient population.
Osteonecrosis of the jaw: Osteonecrosis of the jaw (ONJ) has been reported predominantly in adult cancer patients treated with bisphosphonates, including Zoledronic acid. Many of these patients were also receiving chemotherapy and corticosteroids. 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, these patients should avoid invasive dental procedures if possible. For patients who develop osteonecrosis of the jaw 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.
Osteonecrosis of other anatomical sites: Cases of osteonecrosis of other anatomical sites including the hip, femur and external auditory canal have been reported predominantly in adult cancer patients treated with bisphosphonates, including Zoltero.
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 Zoledronic acid-treated patients, who have sustained a femoral shaft fracture. Poor healing of these fractures has also been reported. Discontinuation of Zoledronic acid 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 Zoledronic acid; however causality with Zoledronic acid therapy has not been established.
During Zoledronic acid 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 Zoledronic acid (see Adverse Reactions). 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.
Hypocalcaemia: Hypocalcaemia has been reported in patients treated with Zoledronic acid. Cardiac arrhythmias and neurologic adverse events (seizures, tetany, and numbness) have been reported secondary to cases of severe hypocalcaemia. In some instances, the hypocalcaemia may be life- threatening. Caution is advised when Zoledronic acid is administered with other hypocalcaemia causing drugs, as they may have synergistic effect resulting in severe hypocalcaemia (see Inetractions). Serum calcium should be measured and hypocalcaemia must be corrected before initiating Zoledronic acid therapy. Patients should be adequately supplemented with calcium and vitamin D.

Women of child-bearing potential: Women of child-bearing potential should be advised to avoid becoming pregnant and advised of the potential hazard to the fetus while receiving Zoledronic acid. There may be a risk of fetal harm (e.g. skeletal and other abnormalities) if a woman becomes pregnant (see Contraindications) while receiving bisphosphonate therapy. The impact of variables such as time between cessation of bisphosphonate therapy to conception, the particular bisphosphonate used, and the route of administration on this risk has not been established.
Pregnancy: Studies in rats have shown reproductive toxicological effects (see Pharmacology: Toxicology: Non-Clinical Safety Data under Actions). The potential risk in humans is unknown. Zoledronic acid should not be used during pregnancy (see Contraindications).
Breast-feeding: It is not known whether zoledronic acid is excreted into human milk. Zoledronic acid should not be used by breast-feeding women (see Contraindications).
Fertility: The fertility was decreased in rats dosed subcutaneously with 0.01 mg/kg/day of zoledronic acid with systemic exposures of 0.12 times the human systemic exposure following an intravenous dose of 4 mg (based on AUC). The effects observed included an increase in pre-implantation losses and a decrease in the number of implantations and live fetuses. There are no data available in humans.

Summary of the safety profile: The most serious adverse drug reactions reported in patients receiving Zoledronic acid in the approved indications are: anaphylactic reaction, ocular adverse events, osteonecrosis of the jaw, atypical femoral fracture, atrial fibrillation, renal function impairment, acute phase reaction, and hypocalcaemia. The frequencies of these adverse reactions are shown in Table 7 or shown as adverse reactions from 'Spontaneous reports and literature cases' with 'not known' frequency.
Frequencies of adverse reactions for Zoledronic acid 4 mg are mainly based on data collected from chronic treatment. Adverse reactions to Zoledronic acid are usually mild and transient and similar to those reported for other bisphosphonates. Those reactions can be expected to occur in approximately one third of patients treated with Zoledronic acid.
Within three days after Zoledronic acid administration, an acute phase reaction has commonly been reported, with symptoms including pyrexia, fatigue, bone pain, chills, influenza-like illness, arthritis with subsequent joint swelling; these symptoms usually resolve within a few days (see Description of selected adverse reaction as follows). Cases of arthralgia and myalgia have 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. Commonly, the serum calcium may fall to asymptomatic hypocalcaemic levels.
Gastrointestinal reactions, such as nausea and vomiting have been commonly reported following intravenous infusion of Zoledronic acid. Uncommonly, local reactions at the infusion site such as redness or swelling and/or pain were also observed.
Anorexia was commonly reported in patients treated with Zoledronic acid 4 mg. Rash or pruritus has been uncommonly observed.
As with other bisphosphonates, cases of conjunctivitis have been commonly reported.
Based on pooled analysis of placebo controlled studies, severe anaemia (Hb < 8.0 g/dL) was commonly reported in patients receiving Zoledronic acid 4 mg.
Adverse reactions (Table 7) are listed by MedDRA system organ class. 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 for each adverse drug reaction is based on the following convention (CIOMS III): Very common (≥1/10),common (≥1/100, <1/10), uncommon (≥1/1,000, <1/100), rare (≥1/10,000, <1/1,000), very rare (<1/10,000). (See Table 7.)

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Adverse drug reactions from spontaneous reports and literature cases (frequency not known): The following adverse reactions have been reported during post-marketing experience with Zoledronic acid 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: 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: bronchospasm.
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 Zoledronic acid).
Description of selected adverse reactions: Renal function impairment: Zoledronic acid has been associated with reports of renal function impairment. In a pooled analysis of safety data from Zoledronic acid registration trials for the prevention of skeletalrelated events in patients with advanced malignancy involving bone, the frequency of renal function impairment adverse events suspected to be related to Zoledronic acid (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, pre-existing renal impairment, multiple cycles of Zoledronic acid 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 Zoledronic acid (see Precautions and Interactions).
Osteonecrosis of the jaw: Cases of osteonecrosis (primarily of the jaws) have been reported predominantly in cancer patients treated with bisphosphonates, including Zoledronic acid (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 jaws has multiple well documented risk factors including a diagnosis of cancer, concomitant therapies (e.g. chemotherapy, radiotherapy, corticosteroids) and co-morbid conditions (e.g. anaemia, coagulopathies, infection, pre-existing 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 tumour 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-Zoledronic acid 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 vs placebo in the treatment of postmenopausal osteoporosis (PMO), the overall incidence of atrial fibrillation was 2.5% (96 out of 3,862) and 1.9% (75 out of 3,852) in patients receiving zoledronic acid 5 mg and placebo, respectively. The rate of atrial fibrillation serious adverse events was 1.3% (51 out of 3,862) and 0.6% (22 out of 3,852) 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 Zoledronic acid (zoledronic acid) 4 mg every 3 to 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 Zoledronic acid are administered with aminoglycosides or calcitonin or loop diuretics, since these agents may have an additive effect, resulting in a lower serum calcium level for longer periods than required (see Precautions).
Caution is indicated when Zoledronic acid is used with other potentially nephrotoxic drugs (see Adverse Reactions).
Observed interactions to be considered: Caution is advised when Zoledronic acid is administered with anti-angiogenic drugs as an increase in incidence of ONJ have been observed in patients treated concomitantly with these drugs.
Absence of interactions: In clinical studies, Zoledronic acid has been administered concomitantly with commonly used anticancer agents, diuretics (except for loop diuretics, see Anticipated interactions to be considered as previously mentioned), antibiotics and analgesics without clinically apparent interactions occurring.
No dose adjustment for Zoledronic acid 4 mg is needed when coadministered with thalidomide. In a pharmacokinetic study of 24 patients with multiple myeloma, Zoledronic acid 4 mg given as a 15- minute infusion was administered either alone or with thalidomide (100 mg once daily on days 1-14 and 200 mg once daily on days 15-28).
Coadministration of thalidomide with Zoledronic acid did not significantly change the pharmacokinetics of zoledronic acid or creatinine clearance.
Zoledronic acid shows no appreciable binding to plasma proteins and does not inhibit human P450 enzymes in vitro (see Pharmacology: Pharmacokinetics under Actions), but no formal clinical interaction studies have been performed.

Instructions for Use and Handling: Zoledronic acid 4 mg/5 mL concentrate for solution for infusion and Zoledronic acid 4mg/100mL solution for infusion are for intravenous use only.
The 4mg/5mL concentrate from one 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 reconstitution and dilution (or for reduced doses of the 'ready-to-use' presentation), it is preferable to use the reconstituted and diluted product immediately. If not used immediately, the reconstituted solution should be stored at 2 to 8°C. The duration and conditions of storage prior to use are under the healthcare provider's responsibility. The total time between reconstitution, dilution, storage in a refrigerator at 2 to 8°C and end of administration must not exceed 24 hours. If refrigerated, the solutions must be allowed to reach room temperature before administration. (See also Dosage & Administration).
Any unused solution should be discarded. Only clear solution free from particles and discoloration should be used.
Incompatibilities: 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% w/v sodium chloride solution or 5% w/v glucose solution), showed no incompatibility with Zoledronic acid.
To avoid potential incompatibilities, Zoledronic acid concentrate is to be diluted with 0.9% w/v sodium chloride solution or 5% w/v glucose solution.
Zoledronic acid concentrate and Zoledronic acid "ready-to-use" solution for infusion must not be mixed or come into contact 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.
Zoledronic acid should not be used after the date marked "EXP" on the pack.

Store below 30°C and protect from moisture.

Agents Affecting Bone Metabolism

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