Zinvel

Each vial contains zoledronic acid monohydrate 4.264 mg equivalent to zoledronic acid 4 mg on an anhydrous basis. It also contains the following inactive ingredients: Mannitol, sodium citrate, water for injection.
Zoledronic acid is a bisphosphonic acid which is an inhibitor of osteoclastic bone resorption. Zoledronic acid is designated chemically as (1-hydroxy-2-imidazol-1-ylphosphonoethyl) phosphonic acid monohydrate. It is a white crystalline powder. Its molecular formula is C₅H₁₀N₂O₇P₂·H2O and its molar mass is 290.1 g/mol. Zoledronic acid is highly soluble in sodium hydroxide solution 0.1 N, sparingly soluble in water and hydrochloric acid 0.1 N, and practically insoluble in organic solvents. The pH of a 0.7% solution of zoledronic acid in water is approximately 2.

Pharmacology: Pharmacodynamics: Zoledronic acid inhibits bone resorption by altering osteoclast activity and by inhibiting normal endogenous, as well as tumor induced, mediators of bone degradation. Like other bisphosphonates, zoledronic acid binds to hydroxyapatite crystals in mineralized bone matrix. The binding to calcium phosphates slows the dissolution of hydroxyapatite crystals, as well as inhibits the formation and aggregation of these crystals. Zoledronic acid is incorporated into osteoclastic bone surfaces, where it inhibits bone resorption by inhibiting osteoclastic activity and inducing osteoclastic apoptosis. The presence of bisphosphonates in the bone structure appears to prevent acid extrusion, an important step stimulated by osteoclasts during the bone resorption process.
Following subsequent resorption, bone tissue surrounding the bisphosphonate containing bone tends to lack ruffled borders and has fewer vacuoles, which are changes consistent with lower resorptive capacity, therefore osteoclasts may be inhibited not only when bisphosphonates are directly incorporated into the bone matrix, but after they engulf bisphosphonate containing mineral during active resorption as well.
Zoledronic acid affects chemical and hormonal mediators of bone degradation. Zoledronic acid inhibits the increased osteoclastic activity and skeletal calcium release induced by various stimulatory factors released by tumors. This may be due to mediation of release of interleukin (IL-1β, IL-6) and tumor necrosis factor (TNF) by monocytes. These cytokines are involved in osteoclast recruitment and activation. Zoledronic acid appears to have direct antitumor effects in specific types of cancer cells. Although the exact mechanism is not known. Zoledronic acid has been demonstrated to inhibit cell growth and induce apoptosis in human myeloma, breast cancer and prostate cancer cell lines.
Pharmacokinetics: Zoledronic acid is administered by IV infusion. Human oral absorption data for zoledronic acid are unavailable. Other bisphosphonates are poorly absorbed (eg, <5% of a dose for alendronate, tiludronate, etidronate) and absorption is further retarded by administration with food or calcium or other divalent cations. After IV infusion, zoledronic acid distributes primarily to bone in a triphasic process. It does not inhibit P-450 enzymes in vitro. Zoledronic acid plasma concentrations are dose proportional. Plasma protein-binding is approximately 22% and independent of zoledronic acid concentrations. More than 95% of zoledronic acid is excreted unchanged, via the kidney. The elimination is triphasic with and α early distribution half-life (t_½) of 0.23 hrs, a β t_½ of 1.75 hrs and terminal elimination t_½ of 167 hrs with low plasma concentrations observed up to 28 days post-dose.

Hypercalcemia of Malignancy (HCM): Treatment of moderate to severe hypercalcemia of malignancy [albumin-corrected calcium (cCa) of ≥12 mg/dL (≥3 mmol/L)] using the formula: cCa in mg/dL=Ca in mg/dL + 0.8 (mid-range of measured albumin in mg/dL).
Multiple Myeloma and Bone Metastases of Solid Tumors: Treatment of osteolytic, osteoblastic, and mixed bone metastases of solid tumors and osteolytic lesion of multiple myeloma, in conjunction with standard antineoplastic therapy. In patients with bone metastases associated with prostate cancer, zoledronic acid should be used as 2nd-line therapy and is reserved for those with disease progression following ≥1 hormonal therapies.
Reduction of bone damage in patients with advanced malignancies involving bone.
Important Limitation of Use: The safety and efficacy of zoledronic acid in the treatment of hypercalcemia associated with hyperparathyroidism or with other non-tumor related conditions has not been established.

Treatment of Hypercalcemia of Malignancy: The maximum recommended dose of zoledronic acid in hypercalcemia of malignancy (albumin-corrected serum calcium ≥12 mg/dL (≥3 mmol/L) is 4 mg, The 4-mg dose must be given as a single-dose IV infusion over no less than 15 mins. Patients who receive zoledronic acid should have serum creatinine assessed prior to each treatment.
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 micromol/L or <4.5 mg/dL). Patients should be adequately rehydrated prior to administration of zoledronic acid. 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 (ie, saline hydration, with or without loop diuretics). Patients should be hydrated adequately throughout the treatment, but overhydration, especially in those patients who have cardiac failure, must be avoided. Diuretic therapy should not be employed prior to correction of hypovolemia. Re-treatment with zoledronic acid may be considered if serum calcium does not return to normal or remain normal after initial treatment. It is recommended that a minimum of 7 days elapse before re-treatment, to allow for full response to the initial dose. Renal function must be carefully monitored in all patients receiving zoledronic acid and serum creatinine must be assessed prior to re-treatment with zoledronic acid.
Treatment of Bone Metastases and Treatment of Osteolytic Lesions in Conjunction with Standard Antineoplastic Therapy and Reduction of Bone Damage in Patients with Advanced Malignancy Involving Bone: The recommended dose of zoledronic acid in patients with multiple myeloma and metastatic bone lesions from solid tumors for patients with creatinine clearance (CrCl) >60 mL/min is 4 mg infused over no less than 15 mins 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 (see Table 1). These doses are calculated to achieve the same AUC as that achieved in patients with CrCl of 75 mL/min. Creatinine clearance (CrCl) is calculated using the Cockroft-Gault formula.

Click on icon to see table/diagram/image

During treatment, serum creatinine should be measured before each zoledronic acid dose and treatment should be withheld for renal deterioration. In the clinical studies, renal deterioration was defined as follows: For patients with normal baseline creatinine, increase of 0.5 mg/dL.
For patients with abnormal baseline creatinine, increase of 1 mg/dL.
In the clinical studies, zoledronic acid treatment was resumed only when the creatinine returned to within 10% of the baseline value. Zoledronic acid should be reinitiated at the same dose as that prior to treatment interruption.
Patients should also be administered an oral calcium supplement of 500 mg and a multiple vitamin containing 400 IU of vitamin D daily.
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 zoledronic acid 4 mg). This concentrate should immediately be diluted in 100 mL of sterile sodium chloride 0.9% USP or dextrose injection 5% 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).

Click on icon to see table/diagram/image

The withdrawn concentrate must be diluted in 100 mL of sterile sodium chloride 0.9% USP or dextrose injection 5% USP.
For All Prepared Doses: If not used immediately after dilution with infusion media, for microbiological integrity, the solution should be refrigerated at 2-8°C (36-46°F). The refrigerated solution should then be equilibrated to room temperature prior to administration. The total time between dilution, storage in the refrigerator, and end of administration must not exceed 24 hrs.
Zoledronic acid 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.
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 mins.
Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit.

Clinical experience with acute overdose 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 hypocalcemia, calcium gluconate infusions should be administered as clinically indicated.

Hypersensitivity to Zoledronic Acid, Bisphosphonates or Any Components of Zoledronic Acid: Hypersensitivity reactions including rare cases of urticaria and angioedema, and very rare cases of anaphylactic reaction/shock have been reported.
Patients with bone metastasis and severe renal impairment, serum creatinine >3 mg/dL.
Use in pregnancy: Zoledronic acid should not be used during pregnancy. There are no studies in pregnant women using zoledronic acid. In reproductive studies, zoledronic acid was teratogenic in the rat at SC doses ≥0.2 mg/kg. If the patient becomes pregnant while taking Zinvel, the patient should be apprised of the potential harm to the fetus. Women of childbearing potential should be advised to avoid becoming pregnant.

Hydration and Electrolyte Monitoring: Patients with hypercalcemia of malignancy must be adequately rehydrated prior to administration ot zoledronic acid.
Loop diuretics should not be used until the patient is adequately rehydrated and should be used with caution in combination with zoledronic acid in order to avoid hypocalcemia.
Zoledronic acid should be used with caution with other nephrotoxic drugs.
Standard hypercalcemia-related metabolic parameters eg, serum levels of calcium, phosphate, and magnesium, as well as serum creatinine, should be carefully monitored following initiation of therapy with Zinvel. If hypocalcemia, hypophosphatemia or hypomagnesemia occur, short-term supplemental therapy may be necessary.
Osteonecrosis of the Jaw: Osteonecrosis of the jaw (ONJ) has been reported predominantly in cancer patients treated with IV bisphosphonates, including zoledronic acid. Many of these patients were also receiving chemotherapy and corticosteroids which may be risk factors for ONJ. Cancer patients should maintain good oral hygiene and should have a dental examination with preventive dentistry prior to treatment with bisphosphonates.
While on treatment, these 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 ONJ. Clinical judgment of the treating physician should guide the management plan of each patient based on individual benefit/risk assessment.
Musculoskeletal Pain: Discontinue use if severe bone, joint and/or muscle pain develop.
Patients with Asthma: While not observed in clinical trials with zoledronic acid, there have been reports of bronchoconstriction in aspirin-sensitive patients receiving bisphosphonates.
Renal Impairment: Zoledronic acid is excreted intact primarily via the kidney, and the risk of adverse reactions, in particular renal adverse reactions, may be greater in patients with impaired renal function.
Safety and pharmacokinetic data are limited in patients with severe renal impairment and the risk of renal deterioration is increased.
Preexisting renal insufficiency and multiple cycles of zoledronic acid and other bisphosphonates are risk factors for subsequent renal deterioration with Zinvel. Factors predisposing to renal deterioration eg, dehydration or the use of other nephrotoxic drugs, should be identified and managed, if possible.
Zoledronic acid treatment in patients with hypercalcemia of malignancy with 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.
Zoledronic acid treatment is not recommended in patients with bone metastases with severe renal impairment. In the clinical studies, patients with serum creatinine >265 micromol/L or >3 mg/dL were excluded and there were only 8 of 564 patients treated with zoledronic acid 4 mg by 15-min infusion with a baseline creatinine >2 mg/dL. Limited pharmacokinetic data exists in patients with CrCl <30 mL/min.
Hepatic Impairment: Only limited clinical data are available for use of zoledronic acid 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.
Effects on the Ability to Drive or Operate Machinery: No studies on the effects on the ability to drive and use machines have been performed.
Use in lactation: It is not known whether zoledronic acid is excreted in human milk. Because many drugs are excreted in human milk, and because zoledronic acid binds to bone long term, zoledronic acid should not be administered to a nursing woman.
Use in children: Zoledronic acid is not indicated for use in children.
Use in the elderly: Clinical studies of zoledronic acid in hypercalcemia of malignancy included 34 patients who were ≥65 years. No significant differences in response rate or adverse reactions were seen in geriatric patients receiving zoledronic acid as compared to younger patients.
Controlled clinical studies of zoledronic acid in the treatment of multiple myeloma and bone metastases of solid tumors in patients >65 years revealed similar efficacy and safety in older and younger patients. Because decreased renal function occurs more commonly in the elderly, special care should be taken to monitor renal function.

Use in pregnancy: Zoledronic acid should not be used during pregnancy. There are no studies in pregnant women using zoledronic acid. In reproductive studies, zoledronic acid was teratogenic in the rat at SC doses ≥0.2 mg/kg. If the patient becomes pregnant while taking Zinvel, the patient should be apprised of the potential harm to the fetus. Women of childbearing potential should be advised to avoid becoming pregnant.
Use in lactation: It is not known whether zoledronic acid is excreted in human milk. Because many drugs are excreted in human milk, and because zoledronic acid binds to bone long term, zoledronic acid should not be administered to a nursing woman.

Side effects include nausea, constipation, fatigue, confusion, hallucination, anemia, leucopenia, thrombocytopenia, muscle pain, vomiting, weakness, anorexia, fever, dyspnea, eye irritation, hypocalcemia, headache, diarrhea, bone pain and hypophosphatemia.
Administration is mostly associated with fever. Occasionally, patients experience a flu-like syndrome consisting of fever, chills, bone pain and/or arthralgia and myalgia.
Gastrointestinal reactions eg, nausea/vomiting and anorexia, have been reported following administration. Injection site reactions eg, erythema, redness or swelling were observed infrequently and resolved in most cases without treatment within 24-48 hrs.
Azotemia has been reported during therapy with zoledronic acid; serum creatinine should be monitored. Electrolyte imbalances may occur during treatment with zoledronic acid.
Hypocalcemia, hypomagnesemia and hypophosphatemia have been reported. Monitor serum calcium, phosphate and magnesium during therapy; short-term supplementation of these electrolytes may be necessary.

In vitro studies indicate that zoledronic acid is approximately 22% bound to plasma proteins. In vitro studies also indicate that zoledronic acid does not inhibit microsomal CYP-450 enzymes. In vivo studies showed that zoledronic acid is not metabolized, and is excreted into the urine as the intact drug. However, no in vivo drug interaction studies have been performed.
Aminoglycosides: Caution is advised when bisphosphonates are administered with aminoglycosides, since these agents may have an additive effect to lower serum-calcium level for prolonged periods. This effect has not been reported in zoledronic acid clinical trials.
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 is indicated when zoledronic acid is used with other potentially nephrotoxic drugs.
Thalidomide: In multiple myeloma patients, the risk of renal dysfunction may be increased when zoledronic acid is used in combination with thalidomide.

Store below 30°C. Do not freeze.
Reconstituted Solution: After preparation, infusion solution should preferably be used immediately. If the solution is not used immediately, it should be refrigerated at 2-8°C.
The total time between dilution, storage in the refrigerator and end of administration must not exceed 24 hrs.
Shelf-Life: 24 months.

Agents Affecting Bone Metabolism

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

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