SUMMARY OF PRODUCT CHARACTERISTICS

1 NAME OF THE MEDICINAL PRODUCT

Zoledronic acid Fair-Med 5 mg/100ml solution for infusion

2 QUALITATIVE AND QUANTITATIVE COMPOSITION

Each vial 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 (23 mg) per infusion, i.e. essentially ‘sodium free’.

For the full list of excipients, see section 6.1.

3 PHARMACEUTICAL FORM

Solution for infusion Clear and colourless solution. pH: 5.50-7.00

Osmolality (Osmol / kg): 0.23-0.33

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

Paget’s disease

For the treatment of Paget’s disease, Zoledronic acid Fair-Med 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 Fair-Med.

Re-treatment of Paget’s disease: After initial treatment with Zoledronic acid Fair-Med in Paget’s disease, an extended remission period is observed in responding patients. Re-treatment consists of an additional intravenous infusion of 5 mg Zoledronic acid Fair-Medafter 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 Fair-Med. This is especially important for the elderly and for patients receiving diuretic therapy.

Adequate calcium and vitamin D intake are recommended in association with Zoledronic acid Fair-Med administration. 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 Zoledronic acid Fair-Med administration (see section 4.4).

Special populations Patients with renal impairment

Zoledronic acid Fair-Med 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 Fair-Med in children and adolescents below 18 years of age have not been established.

Method of administration

Intravenous use.

Zoledronic acid Fair-Med (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 Fair-Med, see section 6.6.

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 Fair-Med 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 the administration of Zoledronic acid Fair-Med (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 Zoledronic acid Fair-Med administration. 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-Grault formula before each Zoledronic acid Fair-Med dose.

•    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 Fair-Med 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 Fair-Med.

•    A single dose of Zoledronic acid Fair-Med 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 Fair-Med (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 Fair-Med (see section 4.8).

Adequate calcium and vitamin D intake are recommended in association with Zoledronic acid Fair-Med administration. 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 Zoledronic acid Fair-Med administration (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 Fair-Med 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 Fair-Med (see section 4.8).

Osteonecrosis of the jaw (ONJ)

Osteonecrosis of the jaw has been reported predominantly in patients with cancer receiving treatment regimens including bisphosphonates, including 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. Many had signs of local infection including osteomyelitis. A dental examination with appropriate preventive dentistry should be considered prior to treatment with bisphosphonates in patients with concomitant risk factors (e.g. cancer, chemotherapy, corticosteroids, poor oral hygiene). 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. The clinical judgement of the treating physician should guide the management plan of each patient based on individual benefit/risk assessment.

Atypical fractures of the femur

Atypical subtrochanteric and diaphyseal femoral fractures have been reported with bisphosphonate therapy. 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 Fair-Med can be reduced with the administration of paracetamol or ibuprofen shortly following Zoledronic acid Fair-Med administration.

Zoledronic acid Fair-Med contains the same active substance found in zoledronic acid 4mg/100ml solution for infusion or zoledronic acid 4mg/5ml concentrate for solution for infusion, used for oncology indications, and a patient being treated with zoledronic acid 4mg/100ml solution for infusion or zoledronic acid 4mg/5ml concentrate for solution for infusion should not be treated with Zoledronic acid Fair-Med.

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 Fair-Med 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 Fair-Med 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 Fair-Med 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 Fair-Med 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 Fair-Med on fertility in humans.

4.7 Effects on ability to drive and use machines

Zoledronic acid Fair-Med 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 Fair-Med 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 Fair-Med. The majority of these reactions occur within the first three days following Zoledronic acid Fair-Med 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.

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials may not reflect the rates observed in practice.

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.

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 Uncommon	Hypocalcaemia* Anorexia, decreased appetite
Psychiatric disorders	Uncommon	Insomnia
Nervous system disorders	Common Uncommon	Headache, dizziness Lethargy, paraesthesia, somnolence, tremor, syncope, dysgeusia
Eye disorders	Common Uncommon Rare Not known**	Ocular hyperaemia Conjunctivitis, eye pain Uveitis, episcleritis, iritis Scleritis and orbital inflammation
Ear and labyrinth disorders	Uncommon	Vertigo
Cardiac disorders	Common Uncommon	Atrial fibrillation Palpitations
Vascular disorders	Uncommon Not known**	Hypertension, flushing Hypotension (some of the patients had underlying risk factors)
Respiratory, thoracic and mediastinal disorders	Uncommon	Cough, dyspnoea
Gastrointestinal disorders	Common Uncommon	Nausea, vomiting, diarrhoea 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 Uncommon	Myalgia, arthralgia, bone pain, back pain, pain in extremity Neck pain, musculoskeletal stiffness,

	Rare Not known**	joint swelling, muscle spasms, shoulder pain, musculoskeletal chest pain, musculoskeletal pain, joint stiffness, arthritis, muscular weakness Atypical subtrochanteric and diaphyseal femoral fractures+ (bisphosphonate class adverse reaction) Osteonecrosis of the jaw (see sections 4.4 and 4.8 Class effects)
Renal and urinary disorders	Uncommon Not known**	Blood creatinine increased, pollakiuria, proteinuria 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 Common Uncommon Not known**	Fever Flu-like symptoms, chills, fatigue, asthenia, pain, malaise, infusion site reaction Peripheral oedema, thirst, acute phase reaction, non-cardiac chest pain Dehydration secondary to post-dose symptoms such as fever, vomiting and diarrhoea
Investigations	Common Uncommon	C-reactive protein increased 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.

+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).

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 Zoledronic acid Fair-Med-treated patients in a large clinical trial compared to 21% of Zoledronic acid Fair-Med-treated patients 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

Uncommonly, cases of osteonecrosis (primarily of the jaw) have been reported, predominantly in cancer patients treated with bisphosphonates, including zoledronic acid. Many of these patients had signs of local infection including osteomyelitis, and the majority of the reports refer to cancer patients following tooth extractions or other dental surgeries. Osteonecrosis of the jaw has multiple well documented risk factors including a diagnosis of cancer, concomitant therapies (e.g. chemotherapy, radiotherapy, corticosteroids) and co-morbid conditions (e.g. anaemia, coagulopathies, infection, pre-existing dental disease). Although causality has not been determined, it is prudent to avoid dental surgery as recovery may be prolonged (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 Fair-Med and one patient treated with placebo. Both cases resolved.

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 to:

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.

Clinical efficacy in the treatment of Paget’s disease of the bone

Zoledronic acid Fair-Med 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 Fair-Med 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 Fair-Med 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 the reference medicinal product containing zoledronic acid in all subsets of the paediatric population in Paget's disease of the bone, osteoporosis in postmenopausal women at an increased risk of fracture, osteoporosis in men at increased risk of fracture and prevention of clinical fractures after a hip fracture in men and women (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.

Intravenously administered zoledronic acid is eliminated by a triphasic process: rapid biphasic disappearance from the systemic circulation, with half-lives of t./_2a 0.24 and t_/b 1.87 hours, followed by a long elimination phase with a terminal elimination halflife of t_/Y 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/pharmacodynamics 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 (Cl_cr = 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 Fair-Med 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 (E331) Water for injections

6.2 Incompatibilities

This medicinal product must not be allowed to come into contact with any calcium-containing solutions. Zoledronic acid Fair-Med must not be mixed or given intravenously with any other medicinal products.

6.3 Shelf life

Unopened vials: 3 years

After opening:

Chemical and physical in-use stability has been demonstrated for 24 hours at 2°C -8°C and at 25^oC.

From a microbiological point of view, the product should be used immediately. If not used immediately, in-use storage times and conditions prior to use are the responsibility of the user. The refrigerated solution should then be equilibrated to room temperature prior to administration.

6.4    Special precautions for storage

This medicinal product does not require any special storage conditions. For storage conditions after first opening of the medicinal product, see section 6.3.

6.5    Nature and contents of container

100 ml solution is packed in clear Type I silicon dioxide inner coated glass vials, capped with Type I bromobutyl rubber stoppers and sealed with aluminum polypropylene flip off seals.

Zoledronic acid Fair-Med 5mg/100ml solution for infusions is supplied in: 1 vial 4 vials 10vials

Not all pack sizes may be marketed.

6.6 Special precautions for disposal

For single use only.

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.

If refrigerated, allow the refrigerated solution to reach room temperature before administration.

Aseptic techniques must be followed during the preparation of the infusion.

7    MARKETING AUTHORISATION HOLDER

Fair-Med Healthcare GmbH Planckstrasse 13 Hamburg, 22765 Germany

8    MARKETING AUTHORISATION NUMBER(S)

PL 20242/0024

9 DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

16/05/2014

10 DATE OF REVISION OF THE TEXT

16/05/2014