Zoledronic Acid Fresenius Kabi

Zoledronic acid monohydrate.

One vial with 5 mL concentrate contains 4 mg of zoledronic acid (as monohydrate).
One mL concentrate contains 0.8 mg of zoledronic acid (as monohydrate).
Excipients/Inactive Ingredients: Mannitol, sodium citrate and water for injections.

Pharmacotherapeutic group: Drugs for treatment of bone diseases, bisphosphonate, ATC code: M05BA08.
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 mineralized 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 antitumour 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 t½α 0.24 and t½β 1.87 hours, followed by a long elimination phase with a terminal elimination half-life of t½γ 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. An infusion time 20 minutes provides acceptable peak plasma concentrations without increased risk for renal toxicity.
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).
Zoledronic acid shows on affinity for the cellular components of blood and plasma protein binding is low (approximately 56%) and independent of the concentration of zoledronic acid.
Special Populations: Paediatric patients: Limited pharmacokinetic data in children with severe osteogenesis imperfect 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.

Reduction 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 (TH).

Zoledronic acid Fresenius Kabi must only be prescribed and administered to patients by healthcare professionals experienced in the administration of intravenous bisphosphonates.
Mode of Administration: Intravenous use.
Zoledronic acid Fresenius Kabi concentrate for solution for infusion contains overfill, allowing for the withdrawal of 5 ml of concentrate (equivalent to zoledronic acid 4 mg). Dilute this concentrate immediately in 100 ml of sterile sodium chloride 0.9% or glucose 5% injection. To avoid inadvertent injection, do not store undiluted concentrate in a syringe. (see Special Precautions for Disposal and Other Handling under Cautions for Usage) Diluted solution should be given as a single intravenous infusion in no less than 20 minutes.
In patients with mild to moderate renal impairment, reduced Zoledronic acid Fresenius Kabi doses are recommended (see Recommended Dose as follows and Precautions).
Instructions for preparing reduced doses of Zoledronic acid Fresenius Kabi: 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.
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 on less than 20 minutes.
Zoledronic acid Fresenius Kabi 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 Fresenius Kabi.
Recommended Dose: Reduction of skeletal related events in patients with advanced malignancies involving bone: Adults and Elderly: The recommended dose in the reduction 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 reduction of skeletal related events should consider that the onset of treatment effect is 2-3 months.
Treatment of TIH: Adults and Elderly: 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: Treatment of TIH: Zoledronic acid Fresenius Kabi 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 (see Precautions).
Reduction of skeletal related events in patients with advanced malignancies involving bone: When initiating treatment with Zoledronic acid Fresenius Kabi 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 Fresenius Kabi is not recommended for patients presenting with severe renal impairment prior to initiation of therapy, which is defined for the 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 Fresenius Kabi dose is recommended (see Precautions): see Table 1.

Click on icon to see table/diagram/image

The reduced doses for patients with renal impairment are expected to achieve the same AUC as that seen in patients with creatinine clearance of 75 ml/min.
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 an abnormal baseline 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 (see Precautions). Zoledronic acid Fresenius Kabi 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. From currently available data no recommendation on a posology can be made.

Patients who have received doses higher than recommended should be carefully monitored. Overdosage may cause clinically significant hypocalcemia, hypophosphatemia, and hypomagnesemia. Clinically relevant reductions in serum levels of calcium, phosphorus, and magnesium should be corrected by IV administration of calcium gluconate, potassium or sodium phosphate, and magnesium sulfate, respectively.

Hypersensitivity to the active substance, to other bisphosphonates or to any of the excipients listed in Description.
Breast-feeding (see Use in Pregnancy & Lactation).

General: Patients must be assessed prior to administration of Zoledronic acid Fresenius Kabi 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 Fresenius Kabi 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.
Other products containing zoledronic acid as active substances are available for osteoporosis indications and treatment of Paget's disease of the bone. Patients being treated with Zoledronic acid Fresenius Kabi should not be treated with any other medicines containing zoledronic acid or any other bisphosphonate concomitantly, since the combined effects of these agents are unknown.
Renal Insufficiency: Patients with TIH with evidence of deterioration in renal function should be appropriately evaluated with consideration given as to whether the potential benefit of treatment with Zoledronic acid Fresenius Kabi outweighs the possible risk.
The decision to treat patients with bone metastases for the reduction of skeletal related events should consider that the onset of treatment effect is 2-3 months.
Zoledronic acid, used as indicated in Indications and Recommended dose and Mode of administration under Dosage & Administration 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 Fresenius Kabi and other bisphosphonates as well as use of other nephrotoxic medicinal products or using a shorter infusion time than currently recommended. Development of kidney injury associated with zoledronic acid is potentially related to high peak plasma concentration increasing the intracellular concentration of zoledronic acid and the risk for cellular damage. While the risk is reduced with a dose of 4 mg zoledronic acid administered over 20 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 reduction of skeletal related events, although less frequently.
Patients should have their serum creatinine levels assessed prior to each dose of Zoledronic acid Fresenius Kabi. Upon initiation of treatment in patients with bone metastases with mild to moderate renal impairment, lower doses of Zoledronic acid Fresenius Kabi are recommended. In patients who show evidence of renal deterioration during treatment, Zoledronic acid Fresenius Kabi should be withheld. Zoledronic acid Fresenius Kabi should only be resumed when serum creatinine returns to within 10% of baseline.
Zoledronic acid Fresenius Kabi 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 Fresenius Kabi 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 of the jaw: Osteonecrosis of the jaw (ONJ) has been reported in patients, predominantly those with cancer, receiving treatment with medicinal products that inhibit bone resorption, such as zoledronic acid. Many of these patients were also receiving chemotherapy and corticosteroids. The majority of reported cases have been associated with dental procedures such as tooth extraction or other dental surgeries. Many had sings of local infection including osteomyelitis.
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.
Cancer, chemotherapy (see section Interactions with other medicaments), radiotherapy, corticosteroids, smoking and co-morbid conditions (e.g. anaemia, coagulopathies, infection).
History of dental disease, poor oral hygiene, periodontal disease, invasive dental procedures and poorly fitting dentures.
A dental examination with appropriate preventive dentistry should be considered prior to treatment with bisphosphonates in patients with concomitant risk factors.
While on treatment. These patients should avoid invasive dental procedures if possible. 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. Clinical judgement of the treating physician should guide the management plan of each patient based on individual benefit/risk assessment.
Musculoskeletal Pain: In post-marketing experience, severe and occasionally incapacitating bone, joint, and/or muscle pain have been reported in patients that were given zoledronic acid as indicated in section Indications and Recommended dose and Mode of administration. 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 re-challenged with the 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.
This medicinal product contains less than 1 mmol sodium (23 mg) per dose, i.e. it is essentially "sodium-free".
Hypocalcaemia: Hypocalcaemia has been reported in patients treated with zoledronic acid. Cardiac arrhythmias and neurologic adverse events (including seizures, numbness and tetany) have been reported secondary to cases of severe hypocalcaemia. Cases of severe hypocalcaemia requiring hospitalization have been reported. In some instances, the hypocalcaemia may be life-threatening (see Adverse Reactions).
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 Fresenius Kabi along with driving and operating of machinery.

Pregnancy: Category: D.
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 Fresenius Kabi should not be used during pregnancy.
Breast-feeding: It is not known whether zoledronic acid is excreted into human milk. Zoledronic acid Fresenius Kabi is contraindicated in breads-feeding women (see Contraindications).
Fertility: Zoledronic acid was evaluated in rats for potential adverse effects on fertility of the parental and F1generation. 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, used as indicated in section Indications and Recommended dose and Mode of administration, an acute phase reaction has commonly been reported, with symptoms including bone pain, fever, fatigue, arthralgia, myalgia and rigors; these symptoms usually resolve within a few days (see Description of Selected Adverse Reactions).
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, ocular adverse events, atrial fibrillation, anaphylaxis. The frequencies for each of these identified risks are shown in table as follows.
Tabulated List of Adverse Reactions: (See Table 2.)

Click on icon to see table/diagram/image

Description of Selected Adverse Reactions: Renal Function Impairment: Zoledronic acid, used as indicated in sections indications and Recommended dose and Mode of administration, has been associated with reports of renal dysfunction. (see Precautions).
Osteonecrosis of the jaw: Although causality has not been determined, it is recommended to avoid dental surgery as recovery may be prolonged (see Precautions).
Atrial Fibrillation: In one 3-year, randomized, 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 trails 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 and arthralgia. The onset time is ≤3 days post- zoledronic acid infusion, (used as indicated in section Recommended dose and Mode of administration), 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 ADR's: There is evidence of an association between hypocalcaemia and secondary neurological events reported in these cases including; seizures, numbness and tetany (see Precautions).
Reporting of Suspected Adverse Reactions: Reporting suspected adverse reactions after authorization of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the national reporting system.

In clinical studies, zoledronic acid, used as indicated in section indications and Recommended dose and Mode of administration, 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, since both agents may have an additive effect, resulting in a lower serum calcium level for longer periods than required.
Caution is indicated when Zoledronic acid Fresenius Kabi 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 Fresenius Kabi 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.

Special precautions for disposal and other handling: Prior to administration, 5.0 ml concentrate from one vial or the volume of the concentrate withdrawn as required must be immediately further diluted with 100 ml of calcium-free infusion solution (0.9% w/v sodium chloride solution or 5% w/v glucose solution).
Studies with glass bottles, as well as several containers types made from polyvinylchloride, polyethylene and polypropylene (prefilled with 0.9% w/v sodium chloride solution or 5% w/v glucose solution), showed no incompatibility with Zoledronic acid Fresenius Kabi.
Additional information on handling of Zoledronic acid Fresenius kabi, including guidance on preparation of reduced doses, is provided in section Recommended dose 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 Fresenius Kabi via the domestic sewage system.
Any unused medicinal product or waste material should be disposed in accordance with local requirements.
Incompatibilities: To avoid potential incompatibilities, Zoledronic acid concentrate is to be diluted with 0.9% w/v sodium chloride solution or 5% w/v glucose solution.
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.

Store below 30°C.
This medicinal product does not require any special storage condition.
After dilution: Chemical and physical in-use stability has been demonstrated for 24 hours at 2°C-8°C. From a microbiological point of view, the diluted solution for infusion should be used immediately. If not used immediately, in-use storage times and conditions prior to use are the responsibility of the user and would normally not be longer than 24 hours at 2°C-8°C. The refrigerated solution 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.

Agents Affecting Bone Metabolism

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

D