Each vial contains Zoledronic acid monohydrate equivalent to anhydrous Zoledronic acid 4 mg. (See Table 1.)
Click on icon to see table/diagram/image
XOLNIC contains Zoledronic acid, a bisphosphonic acid which is an inhibitor of oseteoclastic 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 C
5H
10O
7P
2H
2O and its molecular weight is 290.1.
XOLNIC (Zoledronic acid) Injection is available in vials as a sterile lyophilized powder.
Excipients/Inactive Ingredients: Mannitol BP, Sodium Citrate BP, Water for injection BP.
Pharmacotherapeutic group: Bisphosphonate. ATC Code: M05B A08.
Pharmacology: Pharmacodynamics: The principal pharmacologic action of Zoledronic acid is inhibition of bone resorption. It is one of the most potent inhibitors of osteoclast bone resorption. Although the antiresorptive mechanism is not completely understood, several factors are thought to contribute to this action. 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 exerts direct antitumor effects on human myeloma and breast cancer cells inhibiting their proliferation and inducing apoptosis. Zoledronic acid is antiangiogenic in animal tumor model. This antitumor efficacy may be enhanced when used in combination with other anticancer drugs.
Clinical studies in patients with hypercalcaemia of malignancy (HCM) showed that single-dose infusions of Zoledronic acid are associated with decrease in serum calcium and phosphorus and increase in urinary calcium and phosphorus excretion. Normalisation of serum calcium by day 4 was greater for Zoledronic acid 4 mg and 8 mg doses than pamidronate.
Hypercalcaemia of Malignancy: Osteoclastic hyperactivity resulting in excessive bone resorption is the underlying pathophysiologic derangement in hypercalcaemia of malignancy (HCM), tumor-induced hypercalcaemia) 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 hypercalcaemia. Reducing excessive bone resorption and adequate fluid administration are, therefore, essential to the management of hypercalcaemia.
Pharmacokinetics: Single or multiple (q 28 days) 5-minute infusion or 2,4,8 or 16mg Zoledronic acid were given to patients with cancer and bone metastases. 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% Cmax 24 hours post infusion with population half-lives of t1/2alpha 0.24 hours and t1/2beta 1.87 hours for the early disposition phases of the drug. The terminal elimination phase of Zoledronic acid was 146 hours. The area under the plasma concentration versus time curve (AUC0-24h) of Zoledronic acid was dose proportional from 2 to 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 ± 0.36, respectively.
In vitro and ex vivo studies showed low affinity of Zoledronic acid for the cellular components of human blood. Binding to human plasma proteins was approximately 22% and was independent of the concentration of Zoledronic acid.
Metabolism: Zoledronic acid does not inhibit P450 enzymes in vitro. Zoledronic acid does not undergo biotransformation in vivo. In animal studies, <3% of the administered intravenous dose was found in the faces, with the balance either recovered in the urine or taken up by bone, indicating that the drug is eliminated intact via the kidney.
Excretion: In patients with cancer and bone metastases on average (± s.d.) 39 ± 16% of the administration Zoledronic acid was recovered in the urine within 24 hour, with only trace amounts of drug found in urine post day 2. In cumulative percentage 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 circulations, giving rise to the observed prolonged low plasma concentrations days 2 to 20 post dose. The 0-24 hour renal clearance of Zoledronic acid was on average 3.7 ± 2.0l/h.
Zoledronic acid clearance was reasonably independent of dose and demographic variables, with effects of bodyweight, gender and race, on clearance was dependent on creatinine clearance.
Special Populations: No pharmacokinetic data in patients with hypocalcaemia.
Pediatrics: No pharmacokinetics data in pediatric patients.
Geriatrics: The pharmacokinetics of Zoledronic acid were not affected by age in patients with cancer and bone metastases aged 38 years to 84 years.
Race: The pharmacokinetics of Zoledronic acid was not affected by race in patients with cancer and bone metastases.
Hepatic insufficiency: There are no pharmacokinetic data in patients with impaired liver functions. Zoledronic acid is not cleared by liver therefore impaired liver function may not affect the pharmacokinetic of Zoledronic acid.
Renal insufficiency: Patients with mild to moderate (creatinine 50-80ml/min) renal impairment showed an increase in plasma AUC of 26-27% whereas patients with moderate to severe renal impairment (creatinine clearance 30-50ml/min) showed an increase in plasma AUC of 27-41%. Limited pharmacokinetic data are available for Zoledronic acid in patients with severe renal impairment (creatinine clearance <30 ml/min). Based on population PK/PD modeling, the risk of renal deterioration appears to increase with AUC, which is doubled at a creatinine clearance of 10ml/min.
Toxicology: Carcinogenesis, Mutagenesis, Impairment of Fertility: Carcinogenesis: Zoledronic acid was administered orally (gavage) to rats and mice for at least 104 weeks without evidence of carcinogenic potential. Chronic parenteral administration was not feasible given the potential of the compound to cause severe local irritation.
Mutagenesis: Zoledronic acid was not 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 was genotoxic in the vivo rat micronucleus assay.
Impairment of Fertility: Female rats were 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. Effects observed in the high-dose group (with systemic exposure of 1.2 time the human systemic exposure following an intravenous dose of 4 mg, based on AUC comparison) included inhibition of ovulation and a decrease in the number of pregnant rats.
Hypercalcaemia of Malignancy: Xolnic (Zoledronic Acid) Injection is indicated for the treatment of hypercalcaemia of malignancy following adequate saline rehydration.
Vigorous saline hydration, an integral part of Hypercalcaemia therapy, should be initiated promptly and an attempt should be made to restore the urine output to about 2 L/day throughout treatment.
Multiple Myeloma and bone metastases of solid tumors: Also used in the treatment of multiple myeloma, bone metastases from solid tumors, in conjunction with standard antineoplastic therapy.
The safety and efficacy of Zoledronic acid in the treatment of Hypercalcaemia associated with hyperparathyroidism or with other non-tumor related conditions have not been established.
Hypercalcaemia of Malignancy: The recommended dose of Zoledronic acid in hypercalcaemia (albumin corrected serum calcium = 12 mg/dl) is 4 mg. The 4 mg is given as a single dose i.v. infusion over 15 minutes. Patients should be adequately rehydrated prior to administration of Zoledronic acid. Retreatment with Zoledronic acid is 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.
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 greater than 60mL/min is 4 mg infused over no less than 15 min every 3-4 weeks.
The recommended doses of Zoledronic acid for patients with reduced renal function are listed in following table: See Table 2.
Click on icon to see table/diagram/image
Co-administrater oral calcium supplements of 500 mg and a multiple vitamin containing 400 IU of Vitamin D daily.
Preparation of solution: Xolnic lyophilized powder for infusion is reconstituted by adding 5 ml of sterile water for injection to each vial. The resulting concentration allows for withdrawal. The content of the reconstituted vials are withdrawn and further diluted in 100 ml of sterile 0.9% sodium chloride or 5% Dextrose injection. Do not store undiluted concentrate in a syringe, to avoid inadvertent injection. The dose must be given as a single intravenous solution infusion over no less than 15 minutes.
If not used immediately after dilution with infusion media, for microbiological integrity, the solution should be refrigerated at 2ºC-8ºC (36ºF-46ºF).
Zoledronic acid must not be mixed with calcium-containing infusion solution, such as Lactated Ringer's solution, and should be administered as a single intravenous solution in a line separate from all other drugs.
There is no experience of acute overdose with Zoledronic acid. Two patients received Zoledronic acid 32 mg over 5 minutes in clinical trials. Neither patients experienced any clinical nor laboratory toxicity. Over dosage may cause clinically significant hypocalcaemia, hypophosphatemia, and hypomagnesaemia. Clinically relevant reduction in serum levels of calcium, phosphorus, and magnesium should be corrected by intravenous administration of calcium gluconate, potassium or sodium phosphate, and magnesium sulfate, respectively.
Zoledronic acid injection is contraindicated in patient with clinically significant hypersensitivity to Zoledronic acid or other bisphosphonates or any of the excipients.
Due to the risk of clinical significant deterioration in renal function, which may progress to renal failure, single doses of Zoledronic acid should not exceed 4mg and the duration of infusion should be no less than 15 minutes.
Because safety and pharmacokinetic data are limited in patients with severe renal impairment (Serum creatine > 4.5 mg/ml). Zoledronic acid treatment is not recommended in patients its bone metastases with severe renal impairment. Concomitant use of potentially nephrotoxic drugs (Aspirin, NSAIDs, diuretics, ACE inhibitors) may increase the potential for renal impairment. Zoledronic acid should not be mixed with calcium containing I.V. infusion.
General: Standard hypercalcaemia-related metabolic parameters, such as serum levels of calcium, phosphate and magnesium as well as serum creatinine should carefully monitored after initiating Zoledronic acid injection. If hypocalcaemia, hypophosphatemia, or hypomagnesemia occur, short-term supplemental therapy may be necessary.
Patient with hypercalcaemia 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 hypocalcaemia. Zoledronic acid should be used with caution with other nephrotoxic drugs.
Renal Insufficiency: Zoledronic acid is excreted intact primarily via kidney, and the risk of adverse reactions, in particular renal adverse reactions, may be greater in patients treated with impaired renal function. Serum creatinine should be monitored in all patients treated with Zoledronic acid prior to each dose.
Zoledronic acid has not been tested in patients with severe renal impairment (serum creatinine >4.5 mg/ml). Therefore, its use is not recommended in this patient population.
Hepatic Insufficiency: Only limited clinical data are available for use of Zoledronic acid to treat hypercalcaemia of malignancy in patients with hepatic insufficiency, therefore, dosage recommendation cannot be given for the group.
Patient with Asthma: While not observed in clinical trial with Zoledronic acid, administration of other bisphosphonates has been associated with bronchoconstriction in aspirin-sensitive asthma.
Laboratory Test: Serum creatinine should be monitored prior to each dose of Zoledronic acid. Serum calcium, electrolytes, Phosphate, magnesium, and hematocrit/hemoglobin must be monitored closely in patients treated with Zoledronic acid.
Effects on ability to drive and use machine: Not known.
Use in Children: The safety and effectiveness of Zoledronic acid in pediatric patients have not been established. Because of long-term retention in bone, Zoledronic acid should only be used in children if the potential risk.
Use in the Elderly: No significant differences in response rate or adverse reactions were seen in geriatric patients receiving Zoledronic acid as compared to younger patients.
Pregnancy: Category D. There is no clinical evidence to support the use of Zoledronic acid in pregnant women. Therefore, Zoledronic acid should not be administered during pregnancy except for life threating hypercalcaemia.
Zoledronic acid should not be used during pregnancy. Zoledronic acid may cause fetal harm when administered to a pregnant woman. Women of childbearing potential should be advised to avoid becoming pregnant during treatment with Zoledronic acid.
Nursing Mothers: It is not known whether Zoledronic acid is excreted into human milk. Because many drugs are excreted in human milk, and Zoledronic acid binds to bone, it should not be administered to a nursing woman.
Hypercalcaemia of malignancy: Adverse reactions to Zoledronic acid injection are usually mild and transient and similar to those reported for other bisphosphonates. Intravenous administration has been most commonly associated with fever. Occasionally, patients experience a flulike syndrome consisting of fever, chills and bone pain and / or arthralgias, and myalgias. Gastrointestinal reactions such as nausea and vomiting have been reported following intravenous infusion of Zoledronic acid. Local reactions at the infusion site, such as redness or swelling, were observed infrequently. In most cases, no specific treatment is required and the symptoms subside after 24-48 hours.
Rare cases of rash, pruritus, and chest pain have been reported following treatment with Zoledronic acid.
As with other bisphosphonates, cases of conjunctivitis and hypomagnesaemia have been reported following treatment with Zoledronic acid.
Body as a Whole: Asthenia, chest pain, leg edema, mucositis, metastases.
Digestive System: dysphagia.
Hemic and Lymphatic System: Granulocytopenia, thrombocytopenia, pancytopenia.
Infection: non-specific infection.
Laboratory Abnormalities: Hypocalcemia.
Metabolic and Nutritional: Dehydration.
Musculoskeletal: Arthralgias.
Nervous System: Headache, somnolence.
Respiratory System: Pleural effusion.
Adverse events are listed regardless of presumed causality to study drug. Among the less frequently occurring adverse events (< 15% of patients), rigors, hypokalemia, influenza like illness, and hypocalcaemia showed a trend for more events with bisphosphonate administration compared to placebo group.
Less common adverse events reported more often with Zoledronic Acid 4mg than pamidronate included decreased weight, which was reported in 16.0% of patients in the Zoledronic acid 4mg compared with 9% in the pamidronate group. The incidence of deceased weight, however, was similar for the placebo group (12.5%) and Zoledronic acid. Decreased appetite was reported in slightly more patients in the Zoledronic acid 4mg. (13%) compared with the pamidronate (9%) and placebo 10%) groups, but the clinical significance of these small differences are not clear.
Single doses of Zoledronic acid should not exceed 4mg and the duration of the intravenous infusion should be not less than 15 minutes.
No clinically apparent interactions occurred when Zoledronic acid was administered concomitantly with commonly used anticancer drugs, diuretics, antibiotics and analgesics. Zoledronic acid had shown no appreciable binding in vitro to plasma protein and to human P450 enzymes, indicating a low likelihood of pharmacokinetic drug interactions. However, no formal clinical interaction studies have been performed.
Caution is advised when bisphosphonates are administered with amino glycoside, since these agents may have an additive effect to lower serum calcium level for prolonged periods. This has not been reported in Zoledronic acid clinical trials. Caution is advised when Zoledronic acid is used with potentially nephrotoxic drugs. (Renal functions are monitored). In multiple myeloma patients, the risk of renal dysfunction may be increased when Zoledronic acid is used in combination with thalidomide.
Store in cool dry place.
Shelf life of the medicinal product as package for sale: 36 Months.
M05BA08 - zoledronic acid ; Belongs to the class of bisphosphonates. Used in the treatment of bone diseases.
Lyo powd for inj (vial) 4 mg x 1's.
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