Summary of medicine characteristics - Zoledronic acid medac
Zoledronic acid medac 4 mg/100 ml solution for infusion
2. QUALITATIVE AND QUANTITATIVE COMPOSITION
One bottle with 100 ml solution contains 4 mg zoledronic acid (as monohydrate).
One ml solution contains 0.04 mg zoledronic acid (as monohydrate).
For the full list of excipients, see section 6.1.
3. PHARMACEUTICAL FORM
Solution for infusion
Clear, colourless solution.
4. CLINICAL PARTICULARS4.1 Therapeutic indications
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– 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.
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– Treatment of adult patients with tumour-induced hypercalcaemia (TIH).
4.2 Posology and method of administration
Zoledronic acid medac must only be prescribed and administered to patients by healthcare professionals experienced in the administration of intravenous bisphosphonates. Patients treated with Zoledronic acid medac 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 elderly 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 elderly people
The recommended dose in hypercalcaemia (albumin-corrected serum calcium > 12.0 mg/dl or
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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 |jmol/l or > 4.5 mg/dl were excluded. No dose adjustment is necessary in TIH patients with serum creatinine < 400 |jmol/l or < 4.5 mg/dl (see section 4.4).
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 |jmol/l or > 3.0 mg/dl were excluded.
For patients with normal renal function (defined as CLcr > 60 ml/min), zoledronic acid 4 mg/100 ml 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, the following zoledronic acid dose is recommended (see also section 4.4):
Baseline creatinine clearance (ml/min)__________Zoledronic acid recommended dose*__________
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> 60 4.0 mg
50 – 60 3.5 mg*
40 – 49 3.3 mg*
30 – 39_______________________________________3.0 mg*_____________________________________
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* Doses have been calculated assuming target AUC of 0.66 (mgdir/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:
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– For patients with normal baseline serum creatinine (< 1.4 mg/dl or < 124 |jmol/l), an increase of 0.5 mg/dl or 44 |jmol/l;
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– For patients with abnormal baseline creatinine (> 1.4 mg/dl or > 124 |jmol/l), an increase of 1.0 mg/dl or 88 |jmol/l.
In the clinical studies, zoledronic acid treatment was resumed only when the creatinine level returned to within 10% of the baseline value (see section 4.4). Zoledronic acid treatment should be resumed at the same dose as that 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. Currently available data are described in section 5.1 but no recommendation on a posology can be made.
Method of administration
Intravenous use.
Zoledronic acid medac 4 mg/100 ml solution for infusion should be given as a single intravenous infusion in no less than 15 minutes.
In patients with normal renal function, defined as CLcr > 60 ml/min, zoledronic acid 4 mg/100 ml solution for infusion must not be further diluted.
In patients with mild to moderate renal impairment, reduced Zoledronic acid medac 4 mg/100 ml solution for infusion doses are recommended (see section “Posology” above and section 4.4).
To prepare reduced doses for patients with baseline CLcr < 60 ml/min, refer to Table 1 below.
Remove the volume of Zoledronic acid medac 4 mg/100 ml solution indicated from the bottle and replace with an equal volume of sterile sodium chloride 9 mg/ml (0.9%) solution for injection, or 5% glucose solution for injection.
Table 1: Preparation of reduced doses of Zoledronic acid medac 4 mg/100 ml solution for infusion
| Baseline creatinine clearance (ml/min) | Remove the following amount of Zoledronic acid medac solution for infusion (ml) | Replace with the following volume of sterile sodium chloride 9 mg/ml (0.9%), or 5% glucose solution for injection (ml) | Adjusted dose (mg zoledronic acid in 100 ml) |
| 50–60 | 12.0 | 12.0 | 3.5 |
| 40–49 | 18.0 | 18.0 | 3.3 |
| 30–39 | 25.0 | 25.0 | 3.0 |
Zoledronic acid medac 4 mg/100 ml solution for infusion must not be mixed with other infusion solutions 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.
4.3 Contraindications
- • Hypersensitivity to the active substance, to other bisphosphonates or to any of the excipients listed in section 6.1.
- • Breast-feeding (see section 4.6).
4.4 Special warnings and precautions for use
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.
Other medicinal 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 medac should not be treated with such medicinal products concomitantly or any other bisphosphonate, 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 medac 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 ^mol/l or > 4.5 mg/dl for patients with TIH and > 265 ^mol/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 postmarketing setting 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 (see section 5.1).
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 (see section 4.5), 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 medac. 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 medac.
Musculoskeletal pain
In post-marketing experience, severe and occasionally incapacitating bone, joint, and/or muscle pain have been reported in patients taking bisphosphonates, including 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 (see section 4.8). 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 (see section 4.5). 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.
Sodium
Zoledronic acid medac contains less than 1 mmol (23 mg) sodium per dose, i.e. essentially ‘sodium-free’.
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4.5 Interactions with other medicinal products and other forms of interaction
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 (see section 5.2), 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 (see section 4.4).
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.
4.6 Fertility, pregnancy and lactation
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 (see section 5.3). 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 (see section 4.3).
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.
4.7 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.
4.8 Undesirable effects
Summary of the safety profile
Within three days after zoledronic acid administration, an acute phase reaction has 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 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).
| Blood and lymphatic system disorders Common: Uncommon: Rare: | Anaemia Thrombocytopenia, leukocytopenia Pancytopenia |
| Immune system disorders Uncommon: Rare: | Hypersensitivity reaction Angioneurotic oedema |
| Psychiatric disorders Uncommon: Rare: | Anxiety, sleep disturbance Confusion |
| Nervous system disorders Common: Uncommon: Very rare: | Headache Dizziness, paraesthesia, dysgeusia, hypoaesthesia, hyperaesthesia, tremor, somnolence Convulsions, hypoaesthesia and tetany (secondary to hypocalcaemia) |
| Eye disorders Common: Uncommon: Rare: Very rare: | Conjunctivitis Blurred vision, scleritis and orbital inflammation Uveitis Episcleritis |
| Cardiac disorders Uncommon: Rare: | Hypertension, hypotension, atrial fibrillation, hypotension leading to syncope or circulatory collapse Bradycardia, cardiac arrhythmia (secondary to hypocalcaemia) |
| Respiratory, thoracic and mediastinal disorders Uncommon: Rare: | Dyspnoea, cough, bronchoconstriction Interstitial lung disease |
| Gastrointestinal disorders Common: | Nausea, vomiting, decreased appetite |
| Uncommon: | Diarrhoea, constipation, abdominal pain, dyspepsia, stomatitis, dry mouth |
| Skin and subcutaneous tissue disorders Uncommon: | Pruritus, rash (including erythematous and macular rash), increased sweating |
| Musculoskeletal and connective tissue disorders Common: Uncommon: Very rare: | Bone pain, myalgia, arthralgia, generalised pain Muscle spasms, osteonecrosis of the jaw Osteonecrosis of the external auditory canal (bisphosphonate class adverse reaction) and other anatomical sites including femur and hip |
| Renal and urinary disorders Common: Uncommon: Rare: | Renal impairment Acute renal failure, haematuria, proteinuria Acquired Fanconi syndrome |
| General disorders and administration site conditions Common: Uncommon: Rare: | Fever, flu-like syndrome (including fatigue, rigors, malaise and flushing) Asthenia, peripheral oedema, injection site reactions (including pain, irritation, swelling, induration), chest pain, weight increase, anaphylactic reaction/shock, urticaria Arthritis and joint swelling as a symptom of acute phase reaction |
| Investigations Very common: Common: Uncommon: Rare: | Hypophosphataemia Blood creatinine and blood urea increased, hypocalcaemia Hypomagnesaemia, hypokalaemia Hyperkalaemia, hypernatraemia |
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 (see section 4.4).
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 medac (see section 4.4). 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 (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 (see section 4.4).
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. Healthcare professionals are asked to report any suspected adverse reactions via the national reporting system listed in
4.9 Overdose
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 (see section 4.2) 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.
5. PHARMACOLOGICAL PROPERTIES5.1 Pharmacodynamic properties
Pharmacotherapeutic group: Drugs for treatment of bone diseases, bisphosphonates, ATC code: M05BA08
Mechanism of action
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, mineralisation 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:
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- 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.
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- In vitro: Inhibition of osteoblast proliferation, direct cytostatic and pro-apoptotic activity on tumour cells, synergistic cytostatic effect with other anti-cancer medicinal products, anti-adhesion/invasion activity.
5.2 Pharmacokinetic properties
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.
Distribution
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.
Elimination
Intravenously administered zoledronic acid is eliminated by a triphasic process: rapid biphasic disappearance from the systemic circulation, with half-lives of t./2(a 0.24 and t/2p 1.87 hours, followed by a long elimination phase with a terminal elimination half-life of t./2Y146 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.
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 5,000 ng/ml. The plasma protein binding is low, with the unbound fraction ranging from 60% at 2 ng/ml to 77% at 2,000 ng/ml of zoledronic acid.
Special populations
Hepatic impairment
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.
Renal impairment
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).
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.
5.3 Preclinical safety data
Acute toxicity
The highest non-lethal single intravenous dose was 10 mg/kg bodyweight in mice and 0.6 mg/kg in rats.
Subchronic and chronic toxicity
Zoledronic acid was well tolerated when administered subcutaneously to rats and intravenously to dogs at doses up to 0.02 mg/kg daily for 4 weeks. Administration of 0.001 mg/kg/day subcutaneously in rats and 0.005 mg/kg intravenously once every 2 – 3 days in dogs for up to 52 weeks was also well tolerated.
The most frequent finding in repeat-dose studies consisted of increased primary spongiosa in the metaphyses of long bones in growing animals at nearly all doses, a finding that reflected the compound’s pharmacological antiresorptive activity.
The safety margins relative to renal effects were narrow in the long-term repeat-dose parenteral animal studies but the cumulative no adverse event levels (NOAELs) in the single dose (1.6 mg/kg) and multiple dose studies of up to one month (0.06 – 0.6 mg/kg/day) did not indicate renal effects at doses equivalent to or exceeding the highest intended human therapeutic dose. Longer-term repeat administration at doses bracketing the highest intended human therapeutic dose of zoledronic acid produced toxicological effects in other organs, including the gastrointestinal tract, liver, spleen and lungs, and at intravenous injection sites.
Reproduction toxicity
Zoledronic acid was teratogenic in the rat at subcutaneous doses > 0.2 mg/kg. Although no teratogenicity or foetotoxicity was observed in the rabbit, maternal toxicity was found. Dystocia was observed at the lowest dose (0.01 mg/kg bodyweight) tested in the rat.
Mutagenicity and carcinogenic potential
Zoledronic acid was not mutagenic in the mutagenicity tests performed and carcinogenicity testing did not provide any evidence of carcinogenic potential.
6. PHARMACEUTICAL PARTICULARS6.1 List of excipients
Mannitol
Sodium citrate
Water for injections
6.2 Incompatibilities
This medicinal product must not be allowed to come into contact with any calcium-containing solutions and it must not be mixed or given intravenously with any other medicinal product in the same infusion line.
6.3 Shelf life
Unopened bottle: 3 years.
After first opening: Chemical and physical in-use stability has been demonstrated for 4 days at 2 – 8°C and 25°C.
Chemical and physical in-use stability has been demonstrated for glass bottles, polyethylene, polyvinylchloride and polypropylene infusion lines and infusion bags (prefilled with sodium chloride 9 mg/ml (0.9 %) solution for injection or 5 % w/v glucose solution) for 96 hours at 2–8°C and 25°C.
After first opening and dilution: From a microbiological point of view the medicinal product 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 2–8°C unless dilution has taken place in controlled and validated aseptic conditions.
6.4 Special precautions for storage
Do not freeze.
For storage conditions after first opening of the medicinal product, see section 6.3.
6.5 Nature and contents of container
Colourless glass bottle type I with fluoropolymer coated halobutyl rubber stopper and aluminium flip-off cap.
Each vial contains 100 ml of solution
Zoledronic acid medac is supplied as packs containing 1 bottle or multipacks of 4 cartons each containing 1 bottle. Not all pack sizes may be marketed.
6.6 Special precautions for disposal and other handling
Additional information on handling of Zoledronic acid medac 4 mg/100 ml solution for infusion, including guidance on the preparation of reduced doses using the Zoledronic acid medac ready-to-use bottle, is provided in section 4.2.
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 medac via the domestic sewage system.
Any unused medicinal product or waste material should be disposed of in accordance with local requirements.
7. MARKETING AUTHORISATION HOLDER
medac
Gesellschaft für klinische
Spezialpräparate mbH
Theaterstr. 6
22880 Wedel
Germany
8. MARKETING AUTHORISATION NUMBER
EU/1/12/779/004
EU/1/12/779/005
9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION
Date of first authorisation: 03 August 2012.
Date of latest renewal: 28 April 2017.