Zoledronic acid is indicated for:
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.
– Patients being treated with Zoledronic Acid should not be treated with zoledronic acid 5mg/100ml 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 4 mg 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 in patients receiving Zoledronic Acid. Post-marketing experience and the literature suggest a greater frequency of reports of ONJ based on tumour type (advanced breast cancer, multiple myeloma). A study showed that ONJ was higher in myeloma patients when compared to other cancers.
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, hypoaesthesia 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 medicinal product contains less than 1 mmol sodium (23 mg) per infusion, that is to say essentially “sodium-free”. However, if a solution of common salt (0.9% w/v sodium chloride solution) is used for the dilution of Zoledronic acid prior to administration then the dose of sodium received would be higher.
Zoledronic Acid must only be prescribed and administered to patients by healthcare professionals experienced in the administration of intravenous bisphosphonates.
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.
For patients with normal renal function (defined as CLcr > 60 ml/min), zoledronic acid 4mg/5ml concentrate solution for infusion may be administered directly without any further preparation. 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, reduced Zoledronic Acid doses are recommended.
Baseline Creatinine Clearance (ml/min) | Zoledronic acid Recommended Dose* |
> 60 | 4.0 mg zoledronic acid |
50–60 | 3.5 mg* zoledronic acid |
40–49 | 3.3 mg* zoledronic acid |
30–39 | 3.0 mg* zoledronic acid |
* Doses have been calculated assuming target AUC of 0.66 (mg•hr/l) (CLcr = 75 ml/min). 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 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. 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.
Instructions for preparing reduced doses of Zoledronic Acid Concentrate
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 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 Concentrate
Method of administration
Intravenous use.
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 (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, atrial fibrillation, anaphylaxis, interstitial lung disease. The frequencies for each of these.
List of adverse reactions
The following adverse reactions, listed below, have been accumulated from clinical studies and post-marketing reports following predominantly chronic treatment with 4 mg zoledronic acid:
Very common (≥ 1/10): Hypophosphataemia|
Common (≥1/100 to <1/10): Anaemia, headache, conjunctivitis, nausea, vomiting, decrease appetite, bone pain, myalgia, arthralgia, generalised pain, renal impairment, fever, flu-like syndrome (including fatigue, rigors, malaise and flushing), blood creatinine and blood urea increased, hypocalcaemia.
uncommon (≥1/1,000 to <1/100): Thrombocytopenia, leukopenia, hypersensitivity reaction, anxiety, sleep disturbance, dizziness, paraesthesia, dysgeusia, hypoaesthesia, hyperaesthesia, tremor, somnolence, blurred vision, scleritis and orbital inflammation, hypertension, hypotension, atrial fibrillation, hypotension leading to syncope or circulatory collapse, dyspnoea, cough, bronchoconstriction, diarrhoea, constipation, abdominal pain, dyspepsia, stomatitis, dry mouth, pruritus, rash (including erythematous and macular rash), increased sweating, muscle cramps, osteonecrosis of the jaw, acute renal failure, haematuria, proteinuria, asthenia, peripheral oedema, injection site reactions (including pain, irritation, swelling, induration), chest pain, weight increase, anaphylactic reaction/shock, urticaria, hypomagnesaemia, hypokalaemia
Rare (≥1/10,000 to <1/1,000): Pancytopenia, angioneurotic oedema, confusion, uveitis, bradycardia, cardiac arrhythmia (secondary to hypocalcaemia), interstitial lung disease, acquired Fanconi syndrome, arthritis and joint swelling as a symptom of acute phase reaction, hyperkalaemia, hypernatraemia
Very rare (<1/10,000): Convulsions, hypoaesthesia and tetany (secondary to hypocalcaemia), episcleritis, osteonecrosis of the external auditory canal (bisphosphonate class adverse reaction) and other anatomical sites including femur and hip,
Description of selected adverse reactions
Renal function impairment
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 (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 (bisphopsphonate 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.
Reporting of suspected adverse reactions
Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Please report any adverse drug reactions via contacting Cedal Nano.
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.
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.
Breast-feeding
It is not known whether zoledronic acid is excreted into human milk. Zoledronic acid is contraindicated in breast-feeding 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.
– Store below 30°C.Protect from freezing.
-Store in original package in order to protect from light.
-The shelf life of Unopened bottle is 2 years.
-The shelf life after first opening: From a microbiological point of view, the 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 should then be equilibrated to room temperature prior to administration.
-Keep the product out of the sight and reach of children.