Zinvel

Zoledronic acid.

Each vial contains: Zoledronic acid Monohydrate equivalent to Zoledronic acid 4 mg, Water for injection USP q.s.
Zinvel 4 mg/5ml solution for Intravenous infusion contains 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 290.1 g/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.
It is available in vials as a sterile liquid concentrate solution for intravenous infusion. Each 5-mL vial contains 4.264 mg of zoledronic acid monohydrate, corresponding to 4 mg zoledronic acid as an anhydrous basis.
Excipients/Inactive Ingredients: Mannitol USP, Sodium citrate USP, Water for injection USP.

Pharmacology: Mechanism of Action: 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-1 beta, IL-6 and tumour necrosis factor (TNF)) by monocytes. These cytokines are involved in osteoclast recruitment and activation. Zoledronic Acid appears to have direct antitumour 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 intravenous infusion. Human oral absorption data for Zoledronic Acid are unavailable. Other bisphosphonates are poorly absorbed (e.g. less than 5% of a dose for alendronate, tiludronate, etidronate) and absorption is further retarded by administration with food or calcium or other divalent cations. After intravenous infusion, zoledronic acid distributes primarily to bone in a triphasic process. It does not inhibit P450 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 alpha early distribution half life of 0.23 hrs, a beta half life of 1.75 hrs and terminal elimination half life of 167 hrs with low plasma concentrations observed up to 28 days post dose.

Zoledronic acid is a bisphosphonate indicated for the treatment of: Hypercalcemia of Malignancy: Zoledronic acid is indicated for the treatment of hypercalcemia of malignancy defined as an albumin-corrected calcium (cCa) of ≥12 mg/dL [3.0 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: Zoledronic acid is indicated for the treatment of patients with multiple myeloma and patients with documented bone metastases from solid tumors, in conjunction with standard antineoplastic therapy. Prostate cancer should have progressed after treatment with at least one hormonal therapy.
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.

Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit.
Hypercalcemia of Malignancy: The maximum recommended dose of Zoledronic acid in hypercalcemia of malignancy (albumin-corrected serum calcium ≥ 12 mg/dl [3.0 mmol/L]) is 4 mg. The 4-mg dose must be given as a single-dose intravenous infusion over no less than 15 minutes. 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 μmol/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 (i.e., 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. Retreatment with Zoledronic acid 4 mg 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 retreatment, 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 retreatment with Zoledronic acid.
Multiple Myeloma and Metastatic Bone Lesions of Solid Tumors: The recommended dose of Zoledronic acid in patients with multiple myeloma and metastatic bone lesions from solid tumors for patients with creatinine clearance >60 mL/min is 4 mg 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) is calculated using the Cockcroft-Gault formula. (See Table 1.)

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 1.0 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 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).

Click on icon to see table/diagram/image

The withdrawn concentrate must be diluted in 100 mL of sterile 0.9% Sodium Chloride, USP, or 5% Dextrose Injection, USP.
For All Prepared Doses: If not used immediately after dilution with infusion media, for microbiological integrity, the solution should be refrigerated at 2°C-8°C (36°F-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 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.
Method of 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.

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 hypocalcaemia, calcium gluconate infusions should be administered as clinically indicated.

Hypersensitivity to Zoledronic Acid 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.

Hydration and Electrolyte Monitoring: Patients with hypercalcemia of malignancy must be adequately rehydrated prior to administration of 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, such as 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.
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, such as 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 μmol/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 μmol/L or >3.0 mg/dL were excluded and there were only 8 of 564 patients treated with Zoledronic acid 4 mg by 15-minute infusion with a baseline creatinine >2 mg/dL. 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. 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 judgement of the treating physician should guide the management plan of each patient based on individual benefit/risk assessment.
Musculoskeletal Pain: Discontinue use if severe symptoms 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.
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 ability to drive and use machines: No studies on the effects on the ability to drive and use machines have been performed.
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 of age or older. 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 over age 65 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.

Pregnancy: ZOLEDRONIC ACID SHOULD NOT BE USED DURING PREGNANCY. There are no studies in pregnant women using Zoledronic acid. If the patient becomes pregnant while taking this drug, the patient should be apprised of the potential harm to the fetus. Women of childbearing potential should be advised to avoid becoming pregnant.
Nursing Mothers: 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 bone pain, nausea, constipation, fatigue, confusion, hallucination, anemia, muscle pain, vomiting, weakness, anorexia, fever, dyspnea, eye irritation, hypocalcemia, headache, diarrhea, bone pain and hypophosphatemia.
Administration is mostly associated with fever (44.2%). Occasionally patients experience a flu like syndrome consisting of fever, chills, bone pain and/or arthralgia (10%) and myalgia.
Gastrointestinal reactions such as nausea/vomiting (29%/14%) and anorexia (9%) have been reported following administration. Injection site reactions such as erythema, redness or swelling were observed infrequently and resolved in most cases without treatment within 24-48 hrs.
Azotemia (2%) has been reported during therapy with zoledronic acid, serum creatinine should be monitored.
Electrolyte imbalances may occur during treatment with zoledronic acid. Hypocalcaemia (1.2%), hypomagnesemia (10%) and hypophosphatemia (52%) 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 CYP450 enzymes. ln-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.

Protect from light and moisture.
Store below 30°C.
Do not freeze.
Shelf-Life: 24 months.

Agents Affecting Bone Metabolism

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

POM

Inj (vial) 4 mg/5 mL x 1's.