Zoledronic Acid 5mg/100ml Solution For Infusion
SUMMARY OF PRODUCT CHARACTERISTICS
1 NAME OF THE MEDICINAL PRODUCT
Zoledronic Acid 5mg/100ml Solution for Infusion
2 QUALITATIVE AND QUANTITATIVE COMPOSITION
Each bottle with 100 ml of solution contains 5 mg zoledronic acid (as monohydrate).
Each ml of the solution contains 0.05 mg zoledronic acid anhydrous (as monohydrate).
This medicinal product contains less than 1 mmol sodium (23mg) per dose.
For the full list of excipients, see section 6.1.
3 PHARMACEUTICAL FORM
Solution for infusion
Clear, colourless solution; free from visible foreign matter.
The pH of the solution is 6.0 - 7.0 and the osmolarity is 260 - 340 mOsm.
4 CLINICAL PARTICULARS
4.1 Therapeutic indications
Treatment of Paget's disease of the bone in adults.
4.2 Posology and method of administration
Posology
For the treatment of Paget's disease, zoledronic acid infusion should be prescribed only by physicians with experience in the treatment of Paget's disease of the bone. The recommended dose is a single intravenous infusion of 5 mg zoledronic acid.
Re-treatment of Paget's disease: After initial treatment with zoledronic acid infusion in Paget's disease an extended remission period is observed in responding patients. Re-treatment consists of an additional intravenous infusion of 5mg zoledronic acid after an interval of one year or longer from initial treatment in patients who have relapsed. Limited data on re-treatment of Paget’s disease are available (see section 5.1).
Patients must be appropriately hydrated prior to administration of zoledronic acid infusion. This is especially important for the elderly and for patients receiving diuretic therapy.
Adequate calcium and vitamin D intake are recommended in association with administration of zoledronic acid infusion. In addition, in patients with Paget's disease, it is strongly advised that adequate supplemental calcium corresponding to at least 500 mg elemental calcium twice daily is ensured for at least 10 days following administration of zoledronic acid infusion (see section 4.4).
Special populations Patients with renal impairment
Zoledronic acid infusion is contraindicated in patients with creatinine clearance < 35 ml/min (see sections 4.3 and 4.4).
No dose adjustment is necessary in patients with creatinine clearance ^35 ml/min.
Patients with hepatic impairment
No dose adjustment is required (see section 5.2).
Older people 65 years)
No dose adjustment is necessary since bioavailability, distribution and elimination were similar in elderly patients and younger subjects.
Paediatric population
The safety and efficacy of zoledronic acid infusion in children and adolescents below 18 years of age have not been established. No data are available.
Method of administration Intravenous use.
Zoledronic acid infusion (5 mg in 100 ml ready-to-infuse solution) is administered via a vented infusion line and given at a constant infusion rate. The infusion time must not be less than 15 minutes. For information on the infusion of zoledronic acid, see section 6.6.
Patients treated with zoledronic acid should be given the package leaflet and the patient reminder card.
4.3 Contraindications
• Hypersensitivity to the active substance, to any bisphosphonates or to any of the excipients listed in section 6.1.
• Patients with hypocalcaemia (see section 4.4).
• Severe renal impairment with creatinine clearance < 35 ml/min (see section 4.4).
• Pregnancy and breast-feeding (see section 4.6).
4.4 Special warnings and precautions for use
Renal function
The use of zoledronic acid infusion in patients with severe renal impairment (creatinine clearance < 35 ml/min) is contraindicated due to an increased risk of renal failure in this population.
Renal impairment has been observed following administration of zoledronic acid infusion (see section 4.8), especially in patients with pre-existing renal dysfunction or other risks including advanced age, concomitant nephrotoxic medicinal products, concomitant diuretic therapy (see section 4.5), or dehydration occurring after administration of zoledronic acid infusion. Renal impairment has been observed in patients after a single administration. Renal failure requiring dialysis or with a fatal outcome has rarely occurred in patients with underlying renal impairment or with any of the risk factors described above.
The following precautions should be taken into account to minimise the risk of renal adverse reactions:
• Creatinine clearance should be calculated based on actual body weight using the Cockcroft-Gault formula before each dose of zoledronic acid infusion.
• Transient increase in serum creatinine may be greater in patients with underlying impaired renal function.
• Monitoring of serum creatinine should be considered in at-risk patients.
• Zoledronic acid infusion should be used with caution when concomitantly used with other medicinal products that could impact renal function (see section 4.5).
• Patients, especially elderly patients and those receiving diuretic therapy, should be appropriately hydrated prior to administration of zoledronic acid infusion.
• A single dose of zoledronic acid infusion should not exceed 5 mg and the duration of infusion should be at least 15 minutes (see section 4.2).
Hypocalcaemia
Pre-existing hypocalcaemia must be treated by adequate intake of calcium and vitamin D before initiating therapy with zoledronic acid infusion (see section 4.3). Other disturbances of mineral metabolism must also be effectively treated (e.g. diminished parathyroid reserve, intestinal calcium malabsorption). Physicians should consider clinical monitoring for these patients.
Elevated bone turnover is a characteristic of Paget's disease of the bone. Due to the rapid onset of effect of zoledronic acid on bone turnover, transient hypocalcaemia, sometimes symptomatic, may develop and is usually maximal within the first 10 days after infusion of zoledronic acid (see section 4.8).
Adequate calcium and vitamin D intake are recommended in association with administration of zoledronic acid infusion. In addition, in patients with Paget's disease, it is strongly advised that adequate supplemental calcium corresponding to at least 500 mg elemental calcium twice daily is ensured for at least 10 days following administration of zoledronic acid infusion (see section 4.2). Patients should be informed about symptoms of hypocalcaemia and receive adequate clinical monitoring during the period of risk. Measurement of serum calcium before infusion of zoledronic acid is recommended for patients with Paget's disease.
Severe and occasionally incapacitating bone, joint and/or muscle pain have been infrequently reported in patients taking bisphosphonates, including zoledronic acid infusion (see section 4.8).
Osteonecrosis of the jaw (ONJ)
ONJ has been reported in the post-marketing setting in patients receiving zoledronic acid for osteoporosis (see section 4.8).
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. A dental examination with preventive dentistry and an individual benefit-risk assessment is recommended prior to treatment with zoledronic acid in patients with concomitant risk factors.
The following should be considered when evaluating a patient’s risk of developing ONJ:
• Potency of the medicinal product that inhibits bone resorption (higher risk for highly potent compounds), route of administration (higher risk for parenteral administration) and cumulative dose of bone resorption therapy.
• Cancer, co-morbid conditions (e.g. anaemia, coagulopathies, infection), smoking.
• Concomitant therapies: corticosteroids, chemotherapy, angiogenesis inhibitors, radiotherapy to head and neck.
• Poor oral hygiene, periodontal disease, poorly fitting dentures, history of dental disease, invasive dental procedures, e.g. tooth extractions.
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, non-healing of sores or discharge during treatment with zoledronic acid. While on treatment, invasive dental procedures should be performed with caution and avoided in close proximity to zoledronic acid treatment.
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 the external auditory canal 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.
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.
General
The incidence of post-dose symptoms occurring within the first three days after administration of zoledronic acid can be reduced with the administration of paracetamol or ibuprofen shortly following zoledronic acid administration.
Zoledronic acid solution for infusion contains the same active substance found in zoledronic acid products used for oncology indications, and a patient being treated with zoledronic acid solution for infusion should not be treated with other zoledronic acid products.
This medicinal product contains less than 1 mmol sodium (23mg) per dose, i.e. essentially ‘sodium-free’.
4.5 Interaction with other medicinal products and other forms of interaction
No interaction studies with other medicinal products have been performed.
Zoledronic acid is not systemically metabolised and does not affect human cytochrome P450 enzymes in vitro (see section 5.2). Zoledronic acid is not highly bound to plasma proteins (approximately 43 _ 55% bound) and interactions resulting from displacement of highly protein-bound drugs are therefore unlikely.
Zoledronic acid is eliminated by renal excretion. Caution is indicated when zoledronic acid infusion is administered in conjunction with medicinal products that can significantly impact renal function (e.g. aminoglycosides or diuretics that may cause dehydration) (see section 4.4).
In patients with renal impairment, the systemic exposure to concomitant medicinal products that are primarily excreted via the kidney may increase.
4.6 Fertility, pregnancy and lactation
Pregnancy
Zoledronic acid infusion is contraindicated during pregnancy (see section 4.3). There are no adequate data on the use of zoledronic acid in pregnant women. Studies in animals with zoledronic acid have shown reproductive toxicological effects including malformations (see section 5.3). The potential risk for humans is unknown.
Breast-feeding
Zoledronic acid infusion is contraindicated during breast-feeding (see section 4.3). It is unknown whether zoledronic acid is excreted into human milk.
Women of childbearing potential
Zoledronic acid infusion is not recommended in women of childbearing potential. 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 related to the compound's inhibition of skeletal calcium mobilisation, 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 infusion on fertility in humans.
4.7 Effects on ability to drive and use machines
Zoledronic acid infusion has no or negligible influence on the ability to drive and use machines. Adverse reactions, such as dizziness, may affect the ability to drive or use machines, though no studies on this effect with zoledronic acid infusion have been performed.
4.8 Undesirable effects
Summary of the safety profile
The overall percentage of patients who experienced adverse reactions were 44.7%, 16.7% and 10.2% after the first, second and third infusion, respectively. Incidence of individual adverse reactions following the first infusion was: fever (17.1%), myalgia (7.8%), flu-like symptoms (6.7%), arthralgia (4.8%) and headache (5.1%). The incidence of these reactions decreased markedly with subsequent annual doses of zoledronic acid infusion. The majority of these reactions occur within the first three days following administration. The majority of these reactions were mild to moderate and resolved within three days of the event onset. The percentage of patients who experienced adverse reactions was lower in a smaller study (19.5%, 10.4%, 10.7% after the first, second and third infusion, respectively), where prophylaxis against adverse reactions was used as described below.
Tabulated list of adverse reactions
Adverse reactions in Table 1 are listed according to MedDRA system organ class and frequency category. Frequency categories are defined 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). Within each frequency grouping, adverse reactions are presented in order of decreasing seriousness.
Table 1
|
Infections and infestations |
Uncommon |
Influenza, nasopharyngitis |
|
Blood and lymphatic system disorders |
Uncommon |
Anaemia |
|
Immune system disorders |
Not known** |
Hypersensitivity reactions including rare cases of bronchoconstriction, urticaria and angioedema, and very rare cases of anaphylactic reaction/shock |
|
Metabolism and nutrition disorders |
Common |
Hypocalcaemia* |
|
Uncommon |
Anorexia, decreased appetite | |
|
Psychiatric disorders |
Uncommon |
Insomnia |
|
Nervous system disorders |
Common |
Headache, dizziness |
|
Uncommon |
Lethargy, paraesthesia, somnolence, tremor, syncope, dysgeusia | |
|
Eye disorders |
Common |
Ocular hyperaemia |
|
Uncommon |
Conjunctivitis, eye pain | |
|
Rare |
Uveitis, episcleritis, iritis | |
|
Not known** |
Scleritis and orbital inflammation | |
|
Ear and labyrinth disorders |
Uncommon |
Vertigo |
|
Cardiac disorders |
Common |
Atrial fibrillation |
|
Uncommon |
Palpitations | |
|
Vascular disorders |
Uncommon |
Hypertension, flushing |
|
Not known** |
Hypotension (some of the patients had underlying risk factors) | |
|
Respiratory, thoracic and mediastinal disorders |
Uncommon |
Cough, dyspnoea |
|
Gastrointestinal disorders |
Common |
Nausea, vomiting, diarrhoea |
|
Uncommon |
Dyspepsia, abdominal pain upper, abdominal pain, gastroesophageal reflux disease, constipation, dry mouth, oesophagitis, toothache, gastritis# | |
|
Skin and subcutaneous tissue disorders |
Uncommon |
Rash, hyperhydrosis, pruritus, erythema |
|
Musculoskeletal and connective tissue disorders |
Common |
Myalgia, arthralgia, bone pain, back pain, pain in extremity |
|
Uncommon |
Neck pain, musculoskeletal stiffness, joint swelling, muscle spasms, shoulder pain, musculoskeletal chest pain, musculoskeletal pain, joint stiffness, arthritis, muscular weakness | |
|
Rare |
Atypical subtrochanteric and diaphyseal femoral fractures! (bisphosphonate class adverse reaction) | |
|
Very Rare: |
Osteonecrosis of the external auditory canal | |
|
Not known** |
Osteonecrosis of the jaw (see sections 4.4 and 4.8 Class effects) | |
|
Renal and urinary disorders |
Uncommon |
Blood creatinine increased, |
|
pollakiuria, proteinuria | ||
|
Not known** |
Renal impairment. Rare cases of renal failure requiring dialysis and rare cases with a fatal outcome have been reported in patients with pre-existing renal dysfunction or other risk factors such as advanced age, concomitant nephrotoxic medicinal products, concomitant diuretic therapy, or dehydration in the post infusion period (see sections 4.4 and 4.8 Class effects) | |
|
General disorders and administration site conditions |
Very common |
Fever |
|
Common |
Flu-like symptoms, chills, fatigue, asthenia, pain, malaise, infusion site reaction | |
|
Uncommon |
Peripheral oedema, thirst, acute phase reaction, non-cardiac chest pain | |
|
Not known** |
Dehydration secondary to postdose symptoms such as fever, vomiting and diarrhoea | |
|
Investigations |
Common |
C-reactive protein increased |
|
Uncommon |
Blood calcium decreased |
# Observed in patients taking concomitant glucocorticosteroids.
* Common in Paget's disease only.
** Based on post-marketing reports. Frequency cannot be estimated from available data.
f Identified in post-marketing experience.
Description of selected adverse reactions Class effects:
Renal impairment
Zoledronic acid has been associated with renal impairment manifested as deterioration in renal function (i.e. increased serum creatinine) and in rare cases acute renal failure. Renal impairment has been observed following the administration of zoledronic acid, especially in patients with pre-existing renal dysfunction or additional risk factors (e.g advanced age, oncology patients with chemotherapy, concomitant nephrotoxic medicinal products, concomitant diuretic therapy, severe dehydration), the majority of whom received a 4 mg dose every 3-4 weeks, but it has been observed in patients after a single administration.
Hypocalcaemia
In the Paget's disease trials, symptomatic hypocalcaemia was observed in approximately 1% of patients, in all of whom it resolved.
Based on laboratory assessment, transient asymptomatic calcium levels below the normal reference range (less than 2.10 mmol/l) occurred in 2.3% of patients treated with zoledronic acid infusion in a large clinical trial compared to 21% of patients treated with zoledronic acid infusion in the Paget's disease trials. The frequency of hypocalcaemia was much lower following subsequent infusions.
All patients received adequate supplementation with vitamin D and calcium in the Paget's disease trials (see also section 4.2).
Local reactions
In a large clinical trial, local reactions at the infusion site, such as redness, swelling and/or pain, were reported (0.7%) following the administration of 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, including zoledronic acid (see section 4.4). In a large clinical trial in 7,736 patients, osteonecrosis of the jaw has been reported in one patient treated with zoledronic acid infusion and one patient treated with placebo. Cases of ONJ have been reported in the post-marketing setting for zoledronic acid.
Osteonecrosis of the external auditory canal
During post-marketing experience the following reaction has been reported (frequency very rare):
Osteonecrosis of the external auditory canal (bisphosphonate class adverse reaction)
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 Yellow Card Scheme Website: www.mhra.gov.uk/yellowcard.
4.9 Overdose
Clinical experience with acute overdose is limited. Patients who have received doses higher than those recommended should be carefully monitored. In the event of overdose leading to clinically significant hypocalcaemia, reversal may be achieved with supplemental oral calcium and/or an intravenous infusion of calcium gluconate.
5 PHARMACOLOGICAL PROPERTIES
5.1 Pharmacodynamic properties
Pharmacotherapeutic group: Drugs for treatment of bone diseases, bisphosphonates, ATC code: M05BA08
Mechanism of action
Zoledronic acid belongs to the class of nitrogen-containing bisphosphonates and acts primarily on bone. It is an inhibitor of osteoclast-mediated bone resorption.
Pharmacodynamic effects
The selective action of bisphosphonates on bone is based on their high affinity for mineralised bone.
The main molecular target of zoledronic acid in the osteoclast is the enzyme farnesyl pyrophosphate synthase. The long duration of action of zoledronic acid is attributable to its high binding affinity for the active site of farnesyl pyrophosphate (FPP) synthase and its strong binding affinity to bone mineral.
Zoledronic acid infusion treatment rapidly reduced the rate of bone turnover from elevated post-menopausal levels with the nadir for resorption markers observed at 7 days, and for formation markers at 12 weeks. Thereafter bone markers stabilised within the pre-menopausal range. There was no progressive reduction of bone turnover markers with repeated annual dosing.
Clinical efficacy in the treatment of Paget's disease of the bone Zoledronic acid infusion was studied in male and female patients aged above 30 years with primarily mild to moderate Paget's disease of the bone (median serum alkaline phosphatase level 2.6-3.0 times the upper limit of the age-specific normal reference range at the time of study entry) confirmed by radiographic evidence.
The efficacy of one infusion of 5 mg zoledronic acid versus daily doses of 30 mg risedronate for 2 months was demonstrated in two 6-month comparative trials. After 6 months, zoledronic acid infusion showed 96% (169/176) and 89% (156/176) response and serum alkaline phosphatase (SAP) normalisation rates compared to 74% (127/171) and 58% (99/171) for risedronate (all p<0.001).
In the pooled results, a similar decrease in pain severity and pain interference scores relative to baseline were observed over 6 months for zoledronic acid infusion and risedronate.
Patients who were classified as responders at the end of the 6 month core study were eligible to enter an extended follow-up period. Of the 153 zoledronic acid-treated patients and 115 risedronate-treated patients who entered an extended observation study, after a mean duration of follow-up of 3.8 years from time of dosing, the proportion of patients ending the Extended Observation Period due to the need for retreatment (clinical judgment) was higher for risedronate (48 patients, or 41.7%) compared with zoledronic acid (11 patients, or 7.2%). The mean time of ending the Extended Observation Period due to the need for Paget’s re-treatment from the initial dose was longer for zoledronic acid (7.7 years) than for risedronate (5.1 years).
Six patients who achieved therapeutic response 6 months after treatment with zoledronic acid and later experienced disease relapse during the extended follow-up period were re-treated with zoledronic acid after a mean time of 6.5 years from initial treatment to re-treatment. Five of the 6 patients had SAP within the normal range at month 6 (Last Observation Carried Forward, LOCF).
Bone histology was evaluated in 7 patients with Paget's disease 6 months after treatment with 5 mg zoledronic acid. Bone biopsy results showed bone of normal quality with no evidence of impaired bone remodelling and no evidence of mineralisation defects. These results were consistent with biochemical marker evidence of normalisation of bone turnover.
The European Medicines Agency has waived the obligation to submit the results of studies with zoledronic acid infusion in all subsets of the paediatric population in Paget’s disease of the bone (see section 4.2 for information on paediatric use).
5.2 Pharmacokinetic properties
Single and multiple 5 and 15-minute infusions of 2, 4, 8 and 16 mg zoledronic acid in 64 patients yielded the following pharmacokinetic data, which were found to be dose independent.
Distribution
After initiation of the zoledronic acid infusion, plasma concentrations of the active substance increased rapidly, 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 levels.
Elimination
Intravenously administered zoledronic acid is eliminated by a triphasic process: rapid biphasic disappearance from the systemic circulation, with half-lives of t/a 0.24 and t./2p 1.87 hours, followed by a long elimination phase with a terminal elimination halflife of t/2y 146 hours. There was no accumulation of the active substance in plasma after multiple doses given every 28 days. The early disposition phases (a and P, with t/ values above) presumably represent rapid uptake into bone and excretion via the kidneys.
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. This uptake into bone is common for all bisphosphonates and is presumably a consequence of the structural analogy to pyrophosphate. As with other bisphosphonates, the retention time of zoledronic acid in bones is very long. 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 or body weight. The inter- and intra-subject variation for plasma clearance of zoledronic acid was shown to be 36% and 34%, respectively. 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.
Pharmacokinetic/pharmacodynamic relationships
No interaction studies with other medicinal products have been performed with zoledronic acid. Since zoledronic acid is not metabolised in humans and the substance was found to have little or no capacity as a direct-acting and/or irreversible metabolism-dependent inhibitor of P450 enzymes, zoledronic acid is unlikely to reduce the metabolic clearance of substances which are metabolised via the cytochrome P450 enzyme systems. Zoledronic acid is not highly bound to plasma proteins (approximately 43 _ 55% bound) and binding is concentration independent. Therefore, interactions resulting from displacement of highly protein-bound drugs are unlikely.
Special populations (see section 4.2)
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 patients studied. Small observed increases in AUC(0-24hr), by about 30% to 40% in mild to moderate renal impairment, compared to a patient with normal renal function, and lack of accumulation of drug with multiple doses irrespective of renal function, suggest that dose adjustments of zoledronic acid in mild (Clcr= 50-80 ml/min) and moderate renal impairment down to a creatinine clearance of 35 ml/min are not necessary. The use of zoledronic acid infusion in patients with severe renal impairment (creatinine clearance < 35 ml/min) is contraindicated due to an increased risk of renal failure in this population.
5.3 Preclinical safety data
Acute toxicity
The highest non-lethal single intravenous dose was 10 mg/kg body weight in mice and 0.6 mg/kg in rats. In the single-dose dog infusion studies, 1.0 mg/kg (6 fold the recommended human therapeutic exposure based on AUC) administered over 15 minutes was well tolerated with no renal effects.
Subchronic and chronic toxicity
In the intravenous infusion studies, renal tolerability of zoledronic acid was established in rats when given 0.6 mg/kg as 15-minute infusions at 3-day intervals, six times in total (for a cumulative dose that corresponded to AUC levels about 6 times the human therapeutic exposure) while five 15-minute infusions of 0.25 mg/kg administered at 2-3-week intervals (a cumulative dose that corresponded to 7 times the human therapeutic exposure) were well tolerated in dogs. In the intravenous bolus studies, the doses that were well-tolerated decreased with increasing study duration: 0.2 and 0.02 mg/kg daily was well tolerated for 4 weeks in rats and dogs, respectively but only 0.01 mg/kg and 0.005 mg/kg in rats and dogs, respectively, when given for 52 weeks.
Longer-term repeat administration at cumulative exposures sufficiently exceeding the maximum intended human exposure produced toxicological effects in other organs, including the gastrointestinal tract and liver, and at the site of intravenous administration. The clinical relevance of these findings is unknown. The most frequent finding in the 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.
Reproduction toxicity
Teratology studies were performed in two species, both via subcutaneous administration. Teratogenicity was observed in rats at doses ^0.2 mg/kg and was manifested by external, visceral and skeletal malformations. Dystocia was observed at the lowest dose (0.01 mg/kg body weight) tested in rats. No teratological or embryo/foetal effects were observed in rabbits, although maternal toxicity was marked at 0.1 mg/kg due to decreased serum calcium levels.
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 PARTICULARS
6.1 List of excipients
Mannitol (E421)
Sodium citrate Water for injection
6.2 Incompatibilities
This medicinal product must not be allowed to come into contact with any calcium-containing solutions. Zoledronic acid infusion must not be mixed or given intravenously with any other medicinal products.
6.3 Shelf life
Unopened bottle: 2 years
6.4 Special precautions for storage
This medicinal product does not require any special storage conditions.
6.5 Nature and contents of container
100 ml clear plastic (cycloolefinic polymer) bottle fitted with a 32mm fluorotech coated rubber stopper and a 32mm aluminium flip-off seal.
Zoledronic acid infusion is supplied in packs containing one bottle.
6.6 Special precautions for disposal
Any unused medicinal product or waste material should be disposed of in accordance with local requirements. Only clear solution free from particles and discoloration should be used.
7 MARKETING AUTHORISATION HOLDER
Wockhardt UK Ltd Ash Road North Wrexham LL13 9UF UK
8 MARKETING AUTHORISATION NUMBER(S)
PL 29831/0480
9 DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION
30/11/2012
10 DATE OF REVISION OF THE TEXT
15/02/2016