Zondrax

Clear and colorless solution.
Each mL contains: Zoledronic acid 800 mcg (Equivalent to 853 mcg Zoledronic Acid Monohydrate).

Pharmacology: Pharmacodynamics: Zoledronic acid belongs to the class of bisphosphonates and acts primarily on bone. It is an inhibitor of osteoclastic bone resorption.
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 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 and 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, anti-adhesion/invasion activity.
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, which were found to be dose independent.
After initiating the infusion of zoledronic acid, the plasma concentrations of zoledronic acid 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 zoledronic acid on day 28.
Intravenously administered zoledronic acid is eliminated by a triphasic process: rapid biphasic disappearance from the systemic circulation, with half-lives of t_½α 0.24 and t_½β 1.87 hours, followed by a long elimination phase with a terminal elimination half-life of t_½γ 146 hours. There was no accumulation of zoledronic acid in plasma after multiple doses given every 28 days. Zoledronic acid is not metabolised and is excreted unchanged via the kidney. 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 the kidney. The total body clearance is 5.04 ± 2.5 L/h, independent of dose, and unaffected by gender, age, race, and body weight. 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.
The interpatient variability in pharmacokinetic parameters for zoledronic acid was high, as seen with other bisphosphonates.
No pharmacokinetic data for zoledronic acid are available in patients with hypercalcaemia or in patients with hepatic insufficiency. 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 faeces, suggesting no relevant role of liver function in the pharmacokinetics of zoledronic acid.
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 20 mL/min (severe renal impairment), or 50 mL/min (moderate impairment), the corresponding predicted clearance of zoledronic acid would be 37% or 72%, respectively, 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).
In an in vitro study, zoledronic acid showed 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.
Special populations: Paediatric patients: Limited pharmacokinetic data in children with severe osteogenesis imperfecta suggest that zoledronic acid pharmacokinetics in children aged 3 to 17 years are similar to those in adults at a similar mg/kg dose level. Age, body weight, gender and creatinine clearance appear to have no effect on zoledronic acid systemic exposure.

Prevention of skeletal related events (pathological fractures, spinal compression, radiation or surgery to bone, or tumour-induced hypercalcaemia) in adult patients with advanced malignancies involving bone.
Treatment of adult patients with tumour-induced hypercalcaemia (TIH).

Zoledronic Acid must only be prescribed and administered to patients by healthcare professionals experienced in the administration of intravenous bisphosphonates. Patients treated with Zoledronic Acid should be given the package leaflet and the patient reminder card.
Posology: Prevention of skeletal related events in patients with advanced malignancies involving bone: Adults and older people: The recommended dose in the prevention of skeletal related events in patients with advanced malignancies involving bone is 4 mg zoledronic acid every 3 to 4 weeks. Patients should also be administered an oral calcium supplement of 500 mg and 400 IU vitamin D daily.
The decision to treat patients with bone metastases for the prevention of skeletal related events should consider that the onset of treatment effect is 2-3 months.
Treatment of TIH: Adults and older people: The recommended dose in hypercalcaemia (albumin-corrected serum calcium ≥12.0 mg/dL or 3.0 mmol/L) is a single dose of 4 mg zoledronic acid.
Renal impairment: TIH: Zoledronic Acid treatment in TIH patients who also have 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. No dose adjustment is necessary in TIH patients with serum creatinine <400 μmol/L or <4.5 mg/dL.
Prevention of skeletal related events in patients with advanced malignancies involving bone: When initiating treatment with zoledronic acid in patients with multiple myeloma or metastatic bone lesions from solid tumours, serum creatinine and creatinine clearance (CLcr) should be determined. CLcr is calculated from serum creatinine 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 CLcr <30 mL/min. In clinical trials with zoledronic acid, patients with serum creatinine >265 μmol/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 CLcr 30-60 mL/min, the following zoledronic acid dose is recommended: See Table 1.

Click on icon to see table/diagram/image

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 or <124 μmol/L), an increase of 0.5 mg/dL or 44 μmol/L; For patients with abnormal baseline serum creatinine (>1.4 mg/dL or >124 μmol/L), an increase of 1.0 mg/dL or 88 μmol/L.
In the clinical studies, zoledronic acid treatment was resumed only when the creatinine level returned to within 10% of the baseline value. Zoledronic acid treatment should be resumed at the same dose as that given prior to treatment interruption.
Paediatric population: The safety and efficacy of zoledronic acid in children aged 1 year to 17 years have not been established. No recommended dose is currently available for this population.
Method of administration: Intravenous use: Zoledronic Acid 4 mg concentrate for solution for infusion, further diluted in 100 mL, should be given as a single intravenous infusion in no less than 15 minutes.
In patients with mild to moderate renal impairment, reduced zoledronic acid doses are recommended.
Instructions for preparing reduced doses of Zoledronic Acid: Withdraw an appropriate volume of the 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 instructions on the dilution of zoledronic acid before administration. The withdrawn amount of concentrate must be further 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 over no less than 15 minutes.
Zoledronic Acid concentrate 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 separate infusion line.
Patients must be maintained well hydrated prior to and following administration of zoledronic acid.

Clinical experience with acute overdose of zoledronic acid is limited. The administration of doses up to 48 mg of zoledronic acid in error has been reported. 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 the active substance, to other bisphosphonates or to any of the excipients; Breastfeeding.

General: Patients must be assessed prior to administration of zoledronic acid to ensure that they are adequately hydrated.
Overhydration should be avoided in patients at risk of cardiac failure.
Standard hypercalcaemia-related metabolic parameters, such as serum levels of calcium, phosphate and magnesium, should be carefully monitored after initiating zoledronic acid therapy. If hypocalcaemia, hypophosphataemia, or hypomagnesaemia occurs, 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. Zoledronic Acid contains the same active substance as found in Aclasta (zoledronic acid). Patients being treated with Zoledronic Acid should not be treated with Aclasta or any other bisphosphonate concomitantly, since the combined effects of these agents are unknown.
Renal insufficiency: Patients with TIH and evidence of deterioration in renal function should be appropriately evaluated with consideration given as to whether the potential benefit of treatment with zoledronic acid outweighs the possible risk.
The decision to treat patients with bone metastases for the prevention of skeletal related events should consider that the onset of treatment effect is 2-3 months. Zoledronic acid has 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 and other bisphosphonates as well as use of other nephrotoxic medicinal products. While the risk is reduced with a dose of 4 mg zoledronic acid administered over 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 4 mg 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. Patients should have their serum creatinine levels assessed prior to each dose of zoledronic acid. Upon initiation of treatment in patients with bone metastases with mild to moderate renal impairment, lower doses of zoledronic acid are recommended. In patients who show evidence of renal deterioration during treatment, zoledronic acid should be withheld. Zoledronic acid should only be resumed when serum creatinine returns to within 10% of baseline. Zoledronic acid treatment should be resumed at the same dose as that given prior to treatment interruption.
In view of the potential impact of zoledronic acid on renal function, the lack of clinical safety data in patients with severe renal impairment (in clinical trials defined as serum creatinine ≥400 μmol/L or ≥4.5 mg/dL for patients with TIH and ≥265 μmol/L or ≥3.0 mg/dL for patients with cancer and bone metastases, respectively) at baseline and only limited pharmacokinetic data in patients with severe renal impairment at baseline (creatinine clearance <30 mL/min), the use of zoledronic acid is not recommended in patients with severe renal impairment.
Hepatic insufficiency: As only limited clinical data are available in patients with severe hepatic insufficiency, no specific recommendations can be given for this patient population.
Osteonecrosis: Osteonecrosis of the jaw: Osteonecrosis of the jaw (ONJ) has been reported uncommonly in clinical trials and in the post-marketing setting in patients receiving Zoledronic Acid.
The start of treatment or of a new course of treatment should be delayed in patients with unhealed open soft tissue lesions in the mouth, except in medical emergency situations. A dental examination with appropriate preventive dentistry and an individual benefit-risk assessment is recommended prior to treatment with bisphosphonates in patients with concomitant risk factors.
The following risk factors should be considered when evaluating an individual's risk of developing ONJ: Potency of the bisphosphonate (higher risk for highly potent compounds), route of administration (higher risk for parenteral administration) and cumulative dose of bisphosphonate; Cancer, co-morbid conditions (e.g. anaemia, coagulopathies, infection), smoking; Concomitant therapies: chemotherapy, angiogenesis inhibitors, radiotherapy to neck and head, corticosteroids; History of dental disease, poor oral hygiene, periodontal disease, invasive dental procedures (e.g. tooth extractions) and poorly fitting dentures.
All patients should be encouraged to maintain good oral hygiene, undergo routine dental check-ups and immediately report any oral symptoms such as dental mobility, pain or swelling, or non-healing of sores or discharge during treatment with Zoledronic Acid.
While on treatment, invasive dental procedures should be performed only after careful consideration and be avoided in close proximity to zoledronic acid administration. 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.
The management plan for patients who develop ONJ should be set up in close collaboration between the treating physician and a dentist or oral surgeon with expertise in ONJ. Temporary interruption of zoledronic acid treatment should be considered until the condition resolves and contributing risk factors are mitigated where possible.
Osteonecrosis of other anatomical sites: Osteonecrosis of the external auditory canal has been reported with bisphosphonates, mainly in association with long-term therapy. Possible risk factors for osteonecrosis of the external auditory canal include steroid use and chemotherapy and/or local risk factors such as infection or trauma. The possibility of osteonecrosis of the external auditory canal should be considered in patients receiving bisphosphonates who present with ear symptoms including chronic ear infections.
Additionally, there have been sporadic reports of osteonecrosis of other sites, including the hip and femur, reported predominantly in adult cancer patients treated with Zoledronic Acid.
Musculoskeletal pain: In post-marketing experience, severe and occasionally incapacitating bone, joint, and/or muscle pain have been reported in patients taking zoledronic acid. However, such reports have been infrequent. 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 zoledronic acid or another bisphosphonate.
Atypical fractures of the femur: Atypical subtrochanteric and diaphyseal femoral fractures have been reported with 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 bisphosphonate-treated patients who have sustained a femoral shaft fracture. Poor healing of these fractures has also been reported. Discontinuation of bisphosphonate 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.
During bisphosphonate 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.
Hypocalcaemia: Hypocalcaemia has been reported in patients treated with zoledronic acid. Cardiac arrhythmias and neurologic adverse events (including convulsions, hypoasthesia and tetany) have been reported secondary to cases of severe hypocalcaemia. Cases of severe hypocalcaemia requiring hospitalisation have been reported. In some instances, the hypocalcaemia may be life-threatening. Caution is advised when Zoledronic Acid is administered with medicinal products known to cause hypocalcaemia, as they may have a synergistic effect resulting in severe hypocalcaemia. 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.
Zoledronic Acid contains sodium: This medicine contains less than 1 mmol sodium (23 mg) per vial, that is to say essentially 'sodium-free'.
Effects on ability to drive and use machines: Adverse reactions, such as dizziness and somnolence, may have influence on the ability to drive or use machines, therefore caution should be exercised with the use of Zoledronic Acid along with driving and operating of machinery.

Pregnancy: There are no adequate data on the use of zoledronic acid in pregnant women. Animal reproduction studies with zoledronic acid have shown reproductive toxicity. The potential risk for humans is unknown. Zoledronic acid should not be used during pregnancy. Women of child-bearing potential should be advised to avoid becoming pregnant.
Breastfeeding: It is not known whether zoledronic acid is excreted into human milk. Zoledronic acid is contraindicated in breastfeeding women.
Fertility: Zoledronic acid was evaluated in rats for potential adverse effects on fertility of the parental and F1 generation. This resulted in exaggerated pharmacological effects considered to be related to the compound's inhibition of skeletal calcium metabolisation, resulting in periparturient hypocalcaemia, a bisphosphonate class effect, dystocia and early termination of the study. Thus these results precluded determining a definitive effect of zoledronic acid on fertility in humans.

Summary of the safety profile: Within three days after zoledronic acid administration, an acute phase reaction has commonly been reported, with symptoms including bone pain, fever, fatigue, arthralgia, myalgia, rigors and arthritis with subsequent joint swelling; these symptoms usually resolve within a few days.
The following are the important identified risks with zoledronic acid in the approved indications: Renal function impairment, osteonecrosis of the jaw, acute phase reaction, hypocalcaemia, atrial fibrillation, anaphylaxis, interstitial lung disease. The frequencies for each of these identified risks are shown in Table 2.
Tabulated list of adverse reactions: The following adverse reactions, listed in Table 2, have been accumulated from clinical studies and post-marketing reports following predominantly chronic treatment with 4 mg zoledronic acid: Table 2: Adverse reactions are ranked under headings of frequency, the most frequent first, using the following convention: Very common (≥1/10); Common (≥1/100 to <1/10); Uncommon (≥1/1,000 to <1/100); Rare (≥1/10,000 to <1/1,000); Very rare (<1/10,000); Not known (cannot be estimated from the available data) (see Table 2).

Click on icon to see table/diagram/image

Description of selected adverse reactions: Renal function impairment: Zoledronic acid has been associated with reports of renal dysfunction. In a pooled analysis of safety data from zoledronic acid registration trials for the prevention of skeletal-related events in patients with advanced malignancies involving bone, the frequency of renal 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 tumours (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 4 mg zoledronic acid.
Osteonecrosis of the jaw: Cases of osteonecrosis of the jaw have been reported, predominantly in cancer patients treated with medicinal products that inhibit bone resorption, such as zoledronic acid. Many of these patients were also receiving chemotherapy and corticosteroids and had signs of local infection including osteomyelitis. The majority of the reports refer to cancer patients following tooth extractions or other dental surgeries.
Atrial fibrillation: In one 3-year, randomised, 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 4 mg every 3-4 weeks in oncology patients. The mechanism behind the increased incidence of atrial fibrillation in this single clinical trial is unknown.
Acute phase reaction: This adverse drug reaction consists of a constellation of symptoms that includes fever, myalgia, headache, extremity pain, nausea, vomiting, diarrhoea, arthralgia and 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.
Atypical fractures of the femur: During post-marketing experience the following reactions have been reported (frequency rare): Atypical subtrochanteric and diaphyseal femoral fractures (bisphosphonate class adverse reaction).
Hypocalcaemia-related ADRs: Hypocalcaemia is an important identified risk with zoledronic acid in the approved indications. Based on the review of both clinical trial and post-marketing cases, there is sufficient evidence to support an association between zoledronic acid therapy, the reported event of hypocalcaemia, and the secondary development of cardiac arrhythmia. Furthermore, there is evidence of an association between hypocalcaemia and secondary neurological events reported in these cases including; convulsions, hypoaesthesia and tetany.

In clinical studies, zoledronic acid has been administered concomitantly with commonly used anticancer agents, diuretics, antibiotics and analgesics without clinically apparent interactions occurring. Zoledronic acid shows no appreciable binding to plasma proteins and does not inhibit human P450 enzymes in vitro, but no formal clinical interaction studies have been performed.
Caution is advised when bisphosphonates are administered with aminoglycosides, calcitonin or loop diuretics, since these agents may have an additive effect, resulting in a lower serum calcium level for longer periods than required.
Caution is indicated when zoledronic acid is used with other potentially nephrotoxic medicinal products. Attention should also be paid to the possibility of hypomagnesaemia developing during treatment.
In multiple myeloma patients, the risk of renal dysfunction may be increased when zoledronic acid is used in combination with thalidomide.
Caution is advised when zoledronic acid is administered with anti-angiogenic medicinal products, as an increase in the incidence of ONJ has been observed in patients treated concomitantly with these medicinal products.

Instructions and Special Precautions for Handling and Disposal: Additional information on handling of zoledronic acid, including guidance on the preparation of reduced doses using the zoledronic acid ready-to-use vial, is provided in dosage and mode of administration.
Aseptic techniques must be followed during the preparation of the infusion.
For single use only.
Only clear solution free from particles and discolouration should be used.
Healthcare professionals are advised not to dispose of unused zoledronic acid via the domestic sewage system.
Any unused medicinal product or waste material should be disposed of in accordance with local requirements.

Store at temperatures not exceeding 30°C.

Agents Affecting Bone Metabolism

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

Rx