Zoldron-4

Zoldron-4

zoledronic acid

Manufacturer:

Getwell Pharma

Distributor:

Distriphil

Marketer:

Ambica
Full Prescribing Info
Contents
Zoledronic acid monohydrate.
Description
Each vial contains zoledronic acid monohydrate equivalent to zoledronic acid 4 mg.
Zoledronic acid belongs to the chemotherapy drug class of bisphosphonates. It is an inhibitor of osteoclastic bone resorption and is designated chemically as (1-Hydroxy-2-imidazol-1-yl-phosphonoethyl) phosphonic acid monohydrate. It is highly soluble in 0.1N sodium hydroxide solution, sparingly soluble in water and 0.1N hydrochloric acid and practically insoluble in organic solvents. 0.7% solution of zoledronic acid in water has a pH approximately 2.0. The molecular formula and molecular weight of Zoledronic acid is C5H10N2O7P2•H2O and 290.1 g/mol, respectively.
Action
Pharmacology: Pharmacodynamics: Clinical studies in patients with hypercalcemia of malignancy (HCM) show that single dose infusions of Zoledronic acid for injection are associated with decrease in serum calcium and phosphorus and increase in urinary calcium and phosphorus excretion.
Osteoclastic hyperactivity resulting in excessive bone resorption is the underlying pathophysiologic derangement in hypercalcemia of malignancy (HCM, tumor-induced hypercalcemia) and metastatic bone disease. Excessive release of calcium into the blood as bone is resorbed results in polyuria and gastrointestinal disturbances, with progressive dehydration and decreasing glomerular filtration rate. This, in turn, results in increased renal resorption of calcium, setting up a cycle of worsening systemic hypercalcemia. Reducing excessive bone resorption and maintaining adequate fluid administration are, therefore, essential to the management of hypercalcemia of malignancy.
Patients who have hypercalcemia of malignancy can generally be divided into two groups according to the pathophysiologic mechanism involved: Humoral hypercalcemia and hypercalcemia due to tumor invasion of bone. In humoral hypercalcemia, osteoclasts are activated and bone resorption is stimulated by factors such as parathyroid hormone-related protein, which are elaborated by the tumor and circulate systemically. Humoral hypercalcemia usually occurs in squamous cell malignancies of the lung or head and neck or in genitourinary tumors such as renal cell carcinoma or ovarian cancer. Skeletal metastases may be absent or minimal in these patients.
Extensive invasion of bone by tumor cells can also result in hypercalcemia due to local tumor products that stimulate bone resorption by osteoclasts. Tumors commonly associated with locally mediated hypercalcemia include breast cancer and multiple myeloma.
Total serum calcium levels in patients who have hypercalcemia of malignancy may not reflect the severity of hypercalcemia, since concomitant hypoalbuminemia is commonly present. Ideally, ionized calcium levels should be used to diagnose and follow hypercalcemic conditions; however, these are not commonly or rapidly available in many clinical situations. Therefore, adjustment of the total serum calcium value for differences in albumin levels (corrected serum calcium, CSC) is often used in place of measurement of ionized calcium; several nomograms are in use for this type of calculation.
Mechanism of Action:
Studies suggest that the principal pharmacologic action of zoledronic acid is the inhibition of bone resorption. Several factors are thought to contribute to the antiresorptive mechanism but the exact mechanism of action is not completely understood. In vitro, zoledronic acid inhibits osteoclastic activity and induces osteoclast apoptosis. Zoledronic acid also blocks the osteoclastic resorption of mineralized bone and cartilage through its binding to bone. Zoledronic acid inhibits the increased osteoclastic activity and skeletal calcium release induced by various stimulatory factors released by tumors.
Pharmacokinetics: Distribution: Reports from studies of single or multiple (q 28 days) 5 minute or 15 minute infusions of 2, 4, 8 or 16 mg Zoledronic acid for Injection administered to patients with cancer and bone metastases showed that 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 Cmax 24 hours post-infusion with population half lives of t½a 0.24 hours and t 1.87 hours for the early disposition phases of the drug. The terminal elimination phase of zoledronic acid was prolonged, with very low concentrations in plasma between days 2 and 28 post-infusion and a terminal elimination half-life t½g of 146 hours. The area under the plasma concentration versus time curve (AUC0-24h) of zoledronic acid was dose proportional from 2-16 mg. The accumulation of zoledronic acid measured over three cycles was low with mean AUC0-24h ratios for cycles 2 and 3 versus 1 of 1.13±0.30 and 1.16±0.36, respectively. In vitro and ex vivo studies show a low affinity of zoledronic acid for the cellular components of human blood. In vitro, mean zoledronic acid protein binding in human plasma ranged from 28% at 200 ng/mL to 53% at 50 ng/mL. Zoledronic acid has a high affinity for calcified tissues ie., bone. No information is available with regard to crossing over of Zoledronic acid across the blood brain barrier. Zoledronic acid shows as much as 56% binding to plasma proteins.
Metabolism: Zoledronic acid does not inhibit human P450 enzymes in vitro and does not undergo biotransformation in vivo. In animal studies, <3% of the administered intravenous dose can be 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 patients with cancer and bone metastases, only a single radioactive species with chromatographic properties identical to those of parent drug may be recovered in urine, which suggests that zoledronic acid is not metabolized. No active or inactive metabolites have been reported.
Excretion: Study reports suggest that in patients with cancer and bone metastases, on average (± s.d.) 39±16% of the administered zoledronic acid dose was recovered in the urine within 24 hours, with only trace amounts of drug found in urine post day 2. The cumulative percent of drug excreted in the urine over 0-24 hours was independent of dose. The balance of drug not recovered in urine over 0-24 hours, representing drug presumably bound to bone, is slowly released back into the systemic circulation, giving rise to the observed prolonged low plasma concentrations. The 0-24 hour renal clearance of zoledronic acid was 3.7±2.0 L/h. Zoledronic acid clearance is independent of dose but dependent upon the patient's creatinine clearance. Zoledronic acid is excreted renally as intact drug. The renal clearance correlates with creatinine clearance in patients with mild-moderate renal failure. The terminal t½ is reported to be around 146 hours.
Special Population: Pediatrics: Zoledronic acid is not indicated for use in children.
Geriatrics: The pharmacokinetics of zoledronic acid may not be affected by age in patients with cancer and bone metastases with the age ranging from 38-84 years.
Race: Reports suggest that pharmacokinetics of zoledronic acid is not affected by race in patients with cancer and bone metastases.
Renal Impairment: Pharmacokinetic studies indicate that patients with normal renal function (creatinine clearance >80 mL/min), patients with mild renal impairment (creatinine clearance = 50-80 mL/min) show an average increase in plasma AUC of 15%, whereas patients with moderate renal impairment (creatinine clearance = 30-50 mL/min) show an average increase in plasma AUC of 43%. No dosage adjustment is required in patients with a creatinine clearance of 35 mL/min. Zoledronic acid is not recommended for patients with severe renal impairment (creatinine clearance <30 mL/min) due to lack of clinical experience in this population.
Based on population pK/pD, modeling the risk of renal deterioration appears to increase with AUC and doubles at a creatinine clearance of 10 mL/min. Creatinine clearance is calculated by the Cockcroft-Gault formula:

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The systemic clearance of Zoledronic acid for injection in individual patients can be calculated from the population clearance of Zoledronic acid for injection, CL (L/h)=6.5 (CLcr/90) 0.4. This formulae can be used to predict the AUC of Zoledronic acid for injection in patients, where CL = Dose/AUC0-8. The average AUC0-24h in patients with normal renal function was 0.42 mgh/L and the calculated AUC0-8 for a patient with creatinine clearance of 75 mL/min was 0.66 mgh/L following a 4 mg dose of Zoledronic acid for injection. However, efficacy and safety of adjusted dosing based on these formulae have not been prospectively assessed.
Hepatic Insufficiency: No clinical studies have been conducted to evaluate the effect of hepatic impairment on the pharmacokinetics of zoledronic acid.
Toxicology: Non-Clinical Toxicology: Carcinogenesis: Standard lifetime carcinogenicity bioassays were conducted in mice and rats by administering oral doses of zoledronic acid of 0.1, 0.5, or 2.0 mg/kg/day. Reports suggest an increased incidence of Harderian gland adenomas in male and female mice in all treatment groups (at doses ≥0.002 times a human intravenous dose of 4 mg based on a comparison of relative body surface areas). No increased incidence of tumors was observed in rats (at doses ≤0.2 times the human intravenous dose of 4 mg based on a comparison of relative body surface areas).
Mutagenesis: Zoledronic acid is not shown to be genotoxic in the Ames bacterial mutagenicity assay, in the Chinese hamster ovary cell assay or in the Chinese hamster gene mutation assay with or without metabolic activation. Zoledronic acid is not reported to be genotoxic in the In vivo rat micronucleus assay.
Impairment of Fertility: Female rats when given subcutaneous doses of zoledronic acid of 0.01, 0.03, or 0.1 mg/kg/day beginning 15 days before mating and continuing through gestation showed the following effects in the high dose group (with systemic exposure of 1.2 times the human systemic exposure following an intravenous dose of 4 mg based on AUC comparison) that included inhibition of ovulation and a decrease in the number of pregnant rats. Effects observed in both the mid dose group (with systemic exposure of 0.2 times the human systemic exposure following an intravenous dose of 4 mg based on an AUC comparison) and high-dose group included an increase in pre-implantation loss and a decrease in the number of implantations and live fetuses.
Indications/Uses
Used for hypercalcemia of malignancy, for the prevention of skeletal events in patients with advanced bone malignancies, for the treatment of Paget's disease of bone, and for osteoporosis in postmenopausal women.
Dosage/Direction for Use
Hypercalcemia of Malignancy: 4 mg [albumin corrected serum calcium ≥12 mg/dL (3.0 mmol/L)] is the maximum recommended dose of Zoledronic Acid in hypercalcemia of malignancy. The 4 mg dose must be given as a single dose intravenous infusion over no less than 15 minutes. Prior to each treatment with Zoledronic Acid, patients must have serum creatinine assessed. Dose adjustments of Zoledronic Acid are not necessary in treating patients for hypercalcemia of malignancy presenting with mild-to-moderate renal impairment prior to initiation of therapy (serum creatinine <400 μmol/L or <4.5 mg/dL). Prior to administration of Zoledronic Acid, the patients should be adequately rehydrated.
Consideration should be given to the severity of, as well as the symptoms of, tumor-induced hypercalcemia when considering use of Zoledronic Acid. Vigorous saline hydration, an integral part of hypercalcemia therapy, should be initiated promptly and an attempt should be made to restore the urine output to about 2 L/day throughout treatment. Mild or asymptomatic hypercalcemia may be treated with conservative measures (i.e., saline hydration, with or without loop diuretics). Throughout the treatment with Zoledronic Acid, patients should be hydrated adequately. Overhydration must be avoided especially in those patients who have cardiac failure. Diuretic therapy should not be employed prior to correction of hypovolemia. If serum calcium does not return to normal or remain normal after initial treatment the retreatment with Zoledronic Acid 4 mg may be considered. It is recommended that a minimum of 7 days elapse before retreatment, to allow for full response to the initial dose. Renal function must be carefully monitored in all patients receiving Zoledronic Acid.
Multiple Myeloma and Metastatic Bone Lesions of Solid Tumors:
For patients with creatinine clearance >60 mL/min, 4 mg is the recommended dose of Zoledronic Acid in patients with multiple myeloma and metastatic bone lesions from solid tumors to be infused over no less than 15 minutes every 3-4 weeks. The optimal duration of therapy is not known. Upon treatment initiation, the recommended Zoledronic Acid doses for patients with reduced renal function (mild and moderate renal impairment) are listed in Table 1. These doses are calculated to achieve the same AUC as that achieved in patients with creatinine clearance of 75 mL/min. Creatinine clearance (CrCl) may be calculated using the Cockcroft-Gaul. (See Table 1.)

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During treatment, serum creatinine should be measured before each Zoledronic Acid dose and treatment should be withheld for renal deterioration.
Patients should also be administered an oral calcium supplement of 500 mg and a multiple vitamin containing 400 IU of Vitamin D daily.
Preparation of Solution: 4 mg dose: Vials of Zoledronic Acid concentrate for infusion contain overfill allowing for the withdrawal of 5 mL of concentrate (equivalent to 4 mg zoledronic acid). This concentrate should immediately be diluted in 100 mL of sterile 0.9% Sodium Chloride USP or 5% Dextrose Injection USP. Do not store undiluted concentrate in a syringe to avoid inadvertent injection.
Preparing Reduced Doses for Patients with Baseline CrCl ≤60 mL/min: Withdraw the appropriate volume of the Zoledronic Acid concentrate from the vial for the dose required (see Table 2).

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The withdrawn concentrate must be diluted in 100 mL of sterile 0.9% Sodium Chloride USP or 5% Dextrose Injection USP.
Administration: Due to the risk of clinically significant deterioration in renal function, which may progress to renal failure, single doses of Zoledronic Acid should not exceed 4 mg and the duration of infusion should be no less than 15 minutes. Studies showed that renal deterioration, progression to renal failure and dialysis, have occurred in patients, including those treated with the approved dose of 4 mg infused over 15 minutes. There have been instances of this occurring after the initial Zoledronic Acid dose.
Note: Not for direct injection, the dose must be diluted.
Overdosage
Acute overdosage with Zoledronic acid for injection may cause clinically significant hypocalcemia, hypophosphatemia and hypomagnesemia. By the intravenous administration of calcium gluconate, potassium or sodium phosphate and magnesium sulfate, clinically relevant reductions in serum levels of calcium, phosphorus, and magnesium respectively should be corrected. The other effects of overdosage include hyperthermia, paresthesia, abnormal liver functions and renal toxicity.
Warnings
Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit.
Hydration and Electrolyte Monitoring: Prior to administration of Zoledronic acid for Injection patients with hypercalcemia of malignancy must be adequately rehydrated. Loop diuretics in combination with Zoledronic acid for Injection should be used with caution in order to avoid hypocalcemia. Loop diuretics should not be used until the patient is adequately rehydrated. Zoledronic acid for Injection should be used with caution with other nephrotoxic drugs.
Standard hypercalcemia-related metabolic parameters such as serum levels of calcium, phosphate and magnesium as well as serum creatinine should be carefully monitored following initiation of therapy with Zoledronic acid for Injection. If hypocalcemia, hypophosphatemia or hypomagnesemia occur, short-term supplemental therapy may be necessary.
Renal Impairment: Zoledronic acid for Injection is excreted intact primarily via the kidney. The risk of renal adverse reactions may be greater in patients with impaired renal function. Preexisting renal insufficiency and multiple cycles of Zoledronic acid for Injection and other bisphosphonates are risk factors for subsequent renal deterioration. Factors predisposing to renal deterioration such as dehydration or the use of other nephrotoxic drugs should be identified and managed if possible. In patients who have hypercalcemia of malignancy with severe renal impairment, the treatment with Zoledronic acid for Injection should be considered only after evaluating the risks and benefits of treatment.
Zoledronic acid for Injection treatment is not recommended in patients with bone metastases with severe renal impairment. Limited pharmacokinetic data exists in patients with creatinine clearance <30 mL/min.
Osteonecrosis of the Jaw: Osteonecrosis of the jaw (ONJ) has been reported predominantly in cancer patients treated with intravenous bisphosphonates including Zoledronic acid for Injection. Many reports of ONJ involved patients with signs of local infection including osteomyelitis. Cancer patients prior to treatment with bisphosphonates may be required to have a dental examination with preventive dentistry and should maintain good oral hygiene. While on treatment, patients should avoid invasive dental procedures if possible. Dental surgery may exacerbate the condition in patients who develop ONJ while on ANTINEOPLASTIC therapy.
Musculoskeletal Pain: Severe and occasionally incapacitating bone, joint and/or muscle pain has been reported in patients taking bisphosphonates. This category of drugs includes Zoledronic acid for Injection. The time to onset of symptoms varied from one day to several months after starting the drug. Discontinue the use of the drug if it develops severe symptoms. Most patients had relief of symptoms after stopping. The recurrence of symptoms might be possible when rechallenged with the same drug or another ANTINEOPLASTIC.
Patients with Asthma: The patients receiving bisphosphonates may have bronchoconstriction in aspirin sensitive patients.
Hepatic Impairment: Only limited clinical data are available for use of Zoledronic acid for Injection to treat hypercalcemia of malignancy in patients with hepatic insufficiency, and these data are not adequate to provide guidance on dosage selection or how to safely use Zoledronic Acid in these patients.
Use in Pregnancy: Zoledronic acid for Injection may cause fetal harm when administered to a pregnant woman. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to a fetus.
Special Precautions
Patients must be adequately supplemented with calcium and vitamin D.
A single dose should not exceed 4 mg as a single dose intravenous infusion and the duration of infusion should be no less than 15 minutes.
Adequately rehydrate patients with hypercalcemia of malignancy prior to administration of Zoledronic Acid for Injection and monitor electrolytes during treatment.
Renal toxicity may be greater in patients with renal impairment. Do not use doses greater than 4 mg. Treatment in patients with severe renal impairment is not recommended. Monitor serum creatinine before each dose.
ZOLEDRONIC ACID SHOULD NOT BE USED DURING PREGNANCY. It can cause fetal harm. Women of childbearing potential should be advised of the potential hazard to the fetus and to avoid becoming pregnant.
Osteonecrosis of the jaw has been reported. Preventive dental exams should be performed before starting Zoledronic Acid. Avoid invasive dental procedures.
Severe incapacitating bone, joint, and/or muscle pain may occur. Withhold future doses of Zoledronic Acid if severe symptoms occur.
Do not mix with calcium-containing infusion solutions.
Use In Pregnancy & Lactation
Use in Pregnancy: Zoledronic acid for Injection may cause fetal harm when administered to a pregnant woman. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to a fetus.
ZOLEDRONIC ACID SHOULD NOT BE USED DURING PREGNANCY. It can cause fetal harm. Women of childbearing potential should be advised of the potential hazard to the fetus and to avoid becoming pregnant.
Adverse Reactions
General: The most common adverse events (>25%) were nausea, fatigue, anemia, bone pain, constipation, fever, vomiting and dyspnea.
Hypercalcemia of Malignancy: The safety of Zoledronic acid for injection was studied in patients with hypercalcemia of malignancy (HCM) who received either Zoledronic acid for injection 4 mg given as a 5 minute intravenous infusion (n=86) or pamidronate 90 mg given as a 2 hour intravenous infusion (n=103). The population aged between 33-84 years, 60% male and 81% Caucasian with breast, lung, head and neck and renal cancer as the most common forms of malignancy. Note: Pamidronate 90 mg was given as a 2 hour intravenous infusion. The relative safety of pamidronate 90 mg given as a 2 hour intravenous infusion compared to the same dose given as a 24 hour intravenous infusion has not been adequately studied in controlled clinical trials.
Renal Toxicity: 5 minute intravenous infusion of Zoledronic acid for Injection 4 mg has been shown to result in an increased risk of renal toxicity as measured by increase in serum creatinine which can lead to renal failure. 15 minute intravenous infusion of Zoledronic acid for Injection 4 mg reduced the incidence of renal toxicity and renal failure. Zoledronic acid for Injection should be administered by intravenous infusion over no less than 15 minutes.
Acute Phase Reaction Like Events: Symptoms consistent with acute phase reaction (APR) can occur with intravenous ANTINEOPLASTIC use. Fever has been the most commonly associated symptom. Occasionally, a flu like syndrome consisting of fever, chills, flushing, bone pain and/or arthralgias and myalgias can be experienced by patients.
Mineral and Electrolyte Abnormalities: Electrolyte abnormalities, most commonly hypocalcemia, hypophosphatemia and hypomagnesemia can occur with ANTINEOPLASTIC use.
Injection Site Reactions: Local reactions such as redness or swelling may be observed infrequently at the infusion site. In most cases, no specific treatment is required and the symptoms subside after 24-48 hours.
Ocular Adverse Events: Ocular inflammation such as uveitis and scleritis can occur with ANTINEOPLASTIC use including Zoledronic acid for Injection.
Drug Interactions
Drug interactions may be the result of the altered pharmacokinetics or pharmacodynamics due to one of the following drugs involved.
Aminoglycosides: The caution should be taken during the co-administration of bisphosphonates and aminoglycosides, since these agents may have an additive effect to lower serum calcium level for prolonged periods.
Loop Diuretics: Caution should also be exercised when Zoledronic Acid is used in combination with loop diuretics due to an increased risk of hypocalcemia.
Nephrotoxic Drugs: Caution should be taken when Zoledronic Acid is used with other potentially nephrotoxic drugs.
Thalidomide: The co-administration of Zoledronic Acid with thalidomide may increase the risk of renal dysfunction in multiple myeloma patients.
Caution For Usage
For All Prepared Doses: The solution should be refrigerated at 2-8°C (36-46°F) if not used immediately after dilution with infusion media, for microbiological integrity. 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.
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.
Handling and Disposal: Procedures for proper handling and disposal of anticancer drugs should be considered. Several guidelines on this subject have been published. There is no general agreement that all of the procedures recommended in the guidelines are necessary or appropriate.
Storage
Store at temperatures not exceeding 25°C. Protect from light.
ATC Classification
M05BA08 - zoledronic acid ; Belongs to the class of bisphosphonates. Used in the treatment of bone diseases.
Presentation/Packing
Lyophilized powd for infusion (vial) 4 mg (white crystalline powder) x 5 mL x 1's.
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