ACID ZOLEDRONIC ACCORD 4mg / 5ml perfusive solution concentrate medication leaflet

Zoledronic Acid Accord 4 mg/5 ml concentrate for solution for infusion

One vial with 5 ml concentrate contains 4 mg zoledronic acid (as monohydrate)

One ml concentrate contains 0.8 mg zoledronic acid (as monohydrate).

For the full list of excipients, see section 6.1.

Concentrate for solution for infusion (sterile concentrate)

Clear and colourless solution.

- Prevention of skeletal related events (pathological fractures, spinal compression, radiation orsurgery to bone, or tumour-induced hypercalcaemia) in adult patients with advancedmalignancies involving bone.

- Treatment of adult patients with tumour-induced hypercalcaemia (TIH).

Zoledronic Acid Accord must only be prescribed and administered to patients by healthcareprofessionals experienced in the administration of intravenous bisphosphonates. Patients treated with

Zoledronic Acid Accord should be given the package leaflet and the patient reminder card.

Prevention of skeletal related events in patients with advanced malignancies involving bone

Adults and older people

The recommended dose in the prevention of skeletal related events in patients with advancedmalignancies 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 Ddaily.

The decision to treat patients with bone metastases for the prevention of skeletal related events shouldconsider that the onset of treatment effect is 2-3 months.

Treatment of TIH

Adults and older people

The recommended dose in hypercalcaemia (albumin-corrected serum calcium ≥12.0 mg/dl or3.0 mmol/l) is a single dose of 4 mg zoledronic acid.

TIH:

Zoledronic Acid Accord treatment in TIH patients who also have severe renal impairment should beconsidered only after evaluating the risks and benefits of treatment. In the clinical studies, patientswith serum creatinine > 400 µmol/l or > 4.5 mg/dl were excluded. No dose adjustment is necessary in

TIH patients with serum creatinine < 400 µmol/l or < 4.5 mg/dl (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 bonelesions 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 notrecommended for patients presenting with severe renal impairment prior to initiation of therapy, whichis defined for this population as CLcr < 30 ml/min. In clinical trials with zoledronic acid, patients withserum creatinine > 265 µmol/l or > 3.0 mg/dl were excluded.

In patients with bone metastases presenting with mild to moderate renal impairment prior to initiationof therapy, which is defined for this population as CLcr 30-60 ml/min, the following zoledronic aciddose is recommended (see also section 4.4):

Baseline creatinine clearance (ml/min) Zoledronic acid recommended dose*> 60 4.0 mg zoledronic acid50-60 3.5 mg* zoledronic acid40-49 3.3 mg* zoledronic acid30-39 3.0 mg* zoledronic acid

* Doses have been calculated assuming target AUC of 0.66 (mg-hr/l) (CLcr = 75 ml/min). Thereduced doses for patients with renal impairment are expected to achieve the same AUC as that seen inpatients with creatinine clearance of 75 ml/min.

Following initiation of therapy, serum creatinine should be measured prior to each dose of zoledronicacid and treatment should be withheld if renal function has deteriorated. In the clinical trials, renaldeterioration was defined as follows:

- For patients with normal baseline serum creatinine (< 1.4 mg/dl or < 124 µmol/l), an increase of0.5 mg/dl or 44 µmol/l;

- For patients with abnormal baseline creatinine (> 1.4 mg/dl or > 124 µmol/l), an increase of1.0 mg/dl or 88 µmol/l.

In the clinical studies, zoledronic acid treatment was resumed only when the creatinine level returnedto within 10% of the baseline value (see section 4.4). Zoledronic acid treatment should be resumed atthe same dose as that given prior to treatment interruption.

The safety and efficacy of zoledronic acid in children aged 1 year to 17 years have not beenestablished. Currently available data are described in section 5.1 but no recommendation on aposology can be made.

Zoledronic Acid Accord 4 mg concentrate for solution for infusion, further diluted in 100 ml (seesection 6.6), should be given as a single intravenous infusion in no less than 15 minutes.

In patients with mild to moderate renal impairment, reduced zoledronic acid doses are recommended(see section “Posology” above and section 4.4).

Instructions for preparing reduced doses of Zoledronic Acid Accord

Withdraw an appropriate volume of the concentrate needed, as follows:

- 4.4 ml for 3.5 mg dose

- 4.1 ml for 3.3 mg dose

- 3.8 ml for 3.0 mg dose

For instructions on the dilution of zoledronic acid before administration, see section 6.6. Thewithdrawn amount of concentrate must be further diluted in 100 ml of sterile 0.9% w/v sodiumchloride solution or 5% w/v glucose solution. The dose must be given as a single intravenous infusionover no less than 15 minutes.

Zoledronic Acid Accord concentrate must not be mixed with calcium or other divalentcation-containing infusion solutions such as lactated Ringer’s solution, and should be administered asa single intravenous solution in a separate infusion line.

Patients must be maintained well hydrated prior to and following administration of zoledronic acid.

- Hypersensitivity to the active substance, to other bisphosphonates or to any of the excipientslisted in section 6.1- Breast-feeding (see section 4.6)

Patients must be assessed prior to administration of zoledronic acid to ensure that they are adequatelyhydrated.

Overhydration should be avoided in patients at risk of cardiac failure.

Standard hypercalcaemia-related metabolic parameters, such as serum levels of calcium, phosphateand magnesium, should be carefully monitored after initiating zoledronic acid therapy. Ifhypocalcaemia, hypophosphataemia, or hypomagnesaemia occurs, short-term supplemental therapymay be necessary. Untreated hypercalcaemia patients generally have some degree of renal functionimpairment, therefore careful renal function monitoring should be considered.

Zoledronic Acid Accord contains the same active substance as found in Aclasta (zoledronic acid).

Patients being treated with Zoledronic Acid Accord should not be treated with Aclasta or any otherbisphosphonate concomitantly, since the combined effects of these agents are unknown.

Patients with TIH and evidence of deterioration in renal function should be appropriately evaluatedwith consideration given as to whether the potential benefit of treatment with zoledronic acidoutweighs the possible risk.

The decision to treat patients with bone metastases for the prevention of skeletal related events shouldconsider that the onset of treatment effect is 2-3 months.

Zoledronic acid has been associated with reports of renal dysfunction. Factors that may increase thepotential for deterioration in renal function include dehydration, pre-existing renal impairment,multiple cycles of zoledronic acid and other bisphosphonates as well as use of other nephrotoxicmedicinal products. While the risk is reduced with a dose of 4 mg zoledronic acid administered over15 minutes, deterioration in renal function may still occur. Renal deterioration, progression to renalfailure and dialysis have been reported in patients after the initial dose or a single dose of 4 mgzoledronic acid. Increases in serum creatinine also occur in some patients with chronic administrationof zoledronic acid at recommended doses for prevention of skeletal related events, although lessfrequently.

Patients should have their serum creatinine levels assessed prior to each dose of zoledronic acid. Uponinitiation of treatment in patients with bone metastases with mild to moderate renal impairment, lowerdoses of zoledronic acid are recommended. In patients who show evidence of renal deteriorationduring treatment, zoledronic acid should be withheld. Zoledronic acid should only be resumed whenserum creatinine returns to within 10% of baseline. Zoledronic acid treatment should be resumed at thesame 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 inpatients with severe renal impairment (in clinical trials defined as serum creatinine ≥ 400 µmol/l or≥ 4.5 mg/dl for patients with TIH and ≥ 265 µmol/l or ≥ 3.0 mg/dl for patients with cancer and bonemetastases, respectively) at baseline and only limited pharmacokinetic data in patients with severerenal impairment at baseline (creatinine clearance < 30 ml/min), the use of zoledronic acid is notrecommended in patients with severe renal impairment.

As only limited clinical data are available in patients with severe hepatic insufficiency, no specificrecommendations can be given for this patient population.

Osteonecrosis of the jaw (ONJ) has been reported uncommonly in clinical trials in patients receiving

Zoledronic Acid Accord. Post-marketing experience and the literature suggest a greater frequency ofreports of ONJ based on tumour type (advanced breast cancer, multiple myeloma). A study showedthat 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 unhealedopen soft tissue lesions in the mouth, except in medical emergency situations. A dental examinationwith appropriate preventive dentistry and an individual benefit-risk assessment is recommended priorto 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 ofadministration (higher risk for parenteral administration) and cumulative dose ofbisphosphonate.

- Cancer, co-morbid conditions (e.g. anaemia, coagulopathies, infection), smoking.

- Concomitant therapies: chemotherapy, angiogenesis inhibitors (see section 4.5), radiotherapy toneck 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-upsand immediately report any oral symptoms such as dental mobility, pain or swelling, or non-healing ofsores or discharge during treatment with Zoledronic Acid Accord.

While on treatment, invasive dental procedures should be performed only after careful considerationand be avoided in close proximity to zoledronic acid administration. For patients who developosteonecrosis of the jaw while on bisphosphonate therapy, dental surgery may exacerbate thecondition. For patients requiring dental procedures, there are no data available to suggest whetherdiscontinuation 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 betweenthe treating physician and a dentist or oral surgeon with expertise in ONJ. Temporary interruption ofzoledronic acid treatment should be considered until the condition resolves and contributing riskfactors are mitigated where possible.

Osteonecrosis of other anatomical sites

Osteonecrosis of the external auditory canal has been reported with bisphosphonates, mainly inassociation with long-term therapy. Possible risk factors for osteonecrosis of the external auditorycanal include steroid use and chemotherapy and/or local risk factors such as infection or trauma. Thepossibility of osteonecrosis of the external auditory canal should be considered in patients receivingbisphosphonates who present with ear symptoms including chronic ear infections.

Additionally, there have been sporadic reports of osteonecrosis of other sites, including the hip andfemur, reported predominantly in adult cancer patients treated with Zoledronic Acid .

Musculoskeletal pain

In post-marketing experience, severe and occasionally incapacitating bone, joint, and/or muscle painhave been reported in patients taking zoledronic acid. However, such reports have been infrequent.

The time to onset of symptoms varied from one day to several months after starting treatment. Mostpatients had relief of symptoms after stopping treatment. A subset had recurrence of symptoms whenrechallenged with zoledronic acid or another bisphosphonate.

Atypical fractures of the femur

Atypical subtrochanteric and diaphyseal femoral fractures have been reported with bisphosphonatetherapy, primarily in patients receiving long-term treatment for osteoporosis. These transverse or shortoblique fractures can occur anywhere along the femur from just below the lesser trochanter to justabove the supracondylar flare. These fractures occur after minimal or no trauma and some patientsexperience thigh or groin pain, often associated with imaging features of stress fractures, weeks tomonths before presenting with a completed femoral fracture. Fractures are often bilateral; therefore thecontralateral femur should be examined in bisphosphonate-treated patients who have sustained afemoral shaft fracture. Poor healing of these fractures has also been reported. Discontinuation ofbisphosphonate therapy in patients suspected to have an atypical femur fracture should be consideredpending 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 andany patient presenting with such symptoms should be evaluated for an incomplete femur fracture.

Hypocalcaemia has been reported in patients treated with zoledronic acid. Cardiac arrhythmias andneurologic adverse events (including convulsions, hypoasthesia and tetany) have been reportedsecondary to cases of severe hypocalcaemia. Cases of severe hypocalcaemia requiring hospitalisationhave been reported. In some instances, the hypocalcaemia may be life-threatening (see section 4.8).

Caution is advised when Zolendronc Acid Accord is administered with medicinal products known tocause hypocalcaemia, as they may have a synergistic effect resulting in severe hypocalcaemia (seesection 4.5). Serum calcium should be measured and hypocalcaemia must be corrected beforeinitiating Zoledronic Acid Accord therapy. Patients should be adequately supplemented with calciumand vitamin D.

Zoledronic Acid Accord contains sodium

This medicine contains less than 1 mmol sodium (23 mg) per vial, that is to say essentially‘sodium-free’. However, if a solution of common salt (0.9% w/v sodium chloride solution) is used forthe dilution of Zoledronic Acid Accord prior to administration then the dose of sodium received wouldbe higher.

In clinical studies, zoledronic acid has been administered concomitantly with commonly usedanticancer agents, diuretics, antibiotics and analgesics without clinically apparent interactionsoccurring. Zoledronic acid shows no appreciable binding to plasma proteins and does not inhibithuman P450 enzymes in vitro (see section 5.2), but no formal clinical interaction studies have beenperformed.

Caution is advised when bisphosphonates are administered with aminoglycosides, calcitonin or loopdiuretics, since these agents may have an additive effect, resulting in a lower serum calcium level forlonger periods than required (see section 4.4).

Caution is indicated when zoledronic acid is used with other potentially nephrotoxic medicinalproducts. Attention should also be paid to the possibility of hypomagnesaemia developing duringtreatment.

In multiple myeloma patients, the risk of renal dysfunction may be increased when zoledronic acid isused in combination with thalidomide.

Caution is advised when zoledronic acid is administered with anti-angiogenic medicinal products, asan increase in the incidence of ONJ has been observed in patients treated concomitantly with thesemedicinal products.

There are no adequate data on the use of zoledronic acid in pregnant women. Animal reproductionstudies with zoledronic acid have shown reproductive toxicity (see section 5.3). The potential risk forhumans is unknown. Zoledronic acid should not be used during pregnancy. Women of child-bearingpotential should be advised to avoid becoming pregnant.

It is not known whether zoledronic acid is excreted into human milk. Zoledronic acid iscontraindicated in breast-feeding women (see section 4.3).

Zoledronic acid was evaluated in rats for potential adverse effects on fertility of the parental and F1generation. This resulted in exaggerated pharmacological effects considered to be related to thecompound’s inhibition of skeletal calcium metabolisation, resulting in periparturient hypocalcaemia, abisphosphonate class effect, dystocia and early termination of the study. Thus these results precludeddetermining a definitive effect of zoledronic acid on fertility in humans.

Adverse reactions, such as dizziness and somnolence, may have influence on the ability to drive or usemachines, therefore caution should be exercised with the use of Zoledronic Acid Accord along withdriving and operating of machinery.

Within three days after zoledronic acid administration, an acute phase reaction has commonly beenreported, with symptoms including bone pain, fever, fatigue, arthralgia, myalgia, rigors and arthritiswith subsequent joint swelling; these symptoms usually resolve within a few days (see description ofselected 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, atrialfibrillation, anaphylaxis, interstitial lung disease. The frequencies for each of these identified risks areshown in Table 1.

The following adverse reactions, listed in Table 1, have been accumulated from clinical studies andpost-marketing reports following predominantly chronic treatment with 4 mg zoledronic acid:

Table 1

Adverse reactions are ranked under headings of frequency, the most frequent first, using the followingconvention:

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).

Common: Anaemia

Uncommon: Thrombocytopenia, leukopenia

Rare: Pancytopenia

Uncommon: Hypersensitivity reaction

Rare: Angioneurotic oedema

Uncommon: Anxiety, sleep disturbance

Rare: Confusion

Common: Headache

Uncommon: Dizziness, paraesthesia, dysgeusia,hypoaesthesia, hyperaesthesia, tremor,somnolence

Very rare: Convulsions, hypoaesthesia and tetany(secondary to hypocalcaemia)

Common: Conjunctivitis

Uncommon: Blurred vision, scleritis and orbital inflammation

Rare: Uveitis

Very rare: Episcleritis

Uncommon: Hypertension, hypotension, atrial fibrillation,hypotension leading to syncope or circulatorycollapse

Rare: Bradycardia, cardiac arrhythmia (secondary tohypocalcaemia)

Uncommon: Dyspnoea, cough, bronchoconstriction

Rare: Interstitial lung disease

Common: Nausea, vomiting, decreased appetite

Uncommon: Diarrhoea, constipation, abdominal pain,dyspepsia, stomatitis, dry mouth

Uncommon: Pruritus, rash (including erythematous andmacular rash), increased sweating

Common: Bone pain, myalgia, arthralgia, generalised pain

Uncommon: Muscle spasms, osteonecrosis of the jaw

Very rare: Osteonecrosis of the external auditory canal(bisphosphonate class adverse reaction) andother anatomical sites including femur and hip

Common: Renal impairment

Uncommon: Acute renal failure, haematuria, proteinuria

Rare: Acquired Fanconi syndrome

Not Known: Tubulointerstitial nephritis

Common: Fever, flu-like syndrome (including fatigue,rigors, malaise and flushing)

Uncommon: Asthenia, peripheral oedema, injection sitereactions (including pain, irritation, swelling,induration), chest pain, weight increase,anaphylactic reaction/shock, urticaria

Rare: Arthritis and joint swelling as a symptom ofacute phase reaction

Very common: Hypophosphataemia

Common: Blood creatinine and blood urea increased,hypocalcaemia

Uncommon: Hypomagnesaemia, hypokalaemia

Rare: Hyperkalaemia, hypernatraemia

Zoledronic acid has been associated with reports of renal dysfunction. In a pooled analysis of safetydata from zoledronic acid registration trials for the prevention of skeletal-related events in patientswith advanced malignancies involving bone, the frequency of renal impairment adverse eventssuspected 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 thatmay increase the potential for deterioration in renal function include dehydration, pre-existing renalimpairment, multiple cycles of zoledronic acid or other bisphosphonates, as well as concomitant use ofnephrotoxic medicinal products or using a shorter infusion time than currently recommended. Renaldeterioration, progression to renal failure and dialysis have been reported in patients after the initialdose or a single dose of 4 mg zoledronic acid (see section 4.4).

Cases of osteonecrosis of the jaw have been reported, predominantly in cancer patients treated withmedicinal products that inhibit bone resorption, such as zoledronic acid (see section 4.4). Many ofthese patients were also receiving chemotherapy and corticosteroids and had signs of local infectionincluding osteomyelitis. The majority of the reports refer to cancer patients following tooth extractionsor other dental surgeries.

Atrial fibrillation

In one 3-year, randomised, double-blind controlled trial that evaluated the efficacy and safety ofzoledronic 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) inpatients receiving zoledronic acid 5 mg and placebo, respectively. The rate of atrial fibrillation seriousadverse events was 1.3% (51 out of 3,862) and 0.6% (22 out of 3,852) in patients receiving zoledronicacid 5 mg and placebo, respectively. The imbalance observed in this trial has not been observed inother trials with zoledronic acid, including those with zoledronic acid 4 mg every 3-4 weeks inoncology patients. The mechanism behind the increased incidence of atrial fibrillation in this singleclinical 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 jointswelling. The onset time is ≤ 3 days post-zoledronic acid infusion, and the reaction is also referred tousing the terms “flu-like” or “post-dose” symptoms.

Atypical fractures of the femur

During post-marketing experience the following reactions have been reported (frequency rare):

Atypical subtrochanteric and diaphyseal femoral fractures (bisphosphonate class adverse reaction).

Hypocalcaemia-related ADRs

Hypocalcaemia is an important identified risk with zoledronic acid in the approved indications. Basedon the review of both clinical trial and post-marketing cases, there is sufficient evidence to support anassociation between zoledronic acid therapy, the reported event of hypocalcaemia, and the secondarydevelopment of cardiac arrhythmia. Furthermore, there is evidence of an association betweenhypocalcaemia and secondary neurological events reported in these cases including; convulsions,hypoaesthesia and tetany (see section 4.4).

Reporting suspected adverse reactions after authorisation of the medicinal product is important. Itallows continued monitoring of the benefit/risk balance of the medicinal product. Healthcareprofessionals are asked to report any suspected adverse reactions via the national reporting systemlisted in Appendix V.

Clinical experience with acute overdose of zoledronic acid is limited. The administration of doses upto 48 mg of zoledronic acid in error has been reported. Patients who have received doses higher thanthose 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 shouldbe administered as clinically indicated.

Pharmacotherapeutic group: Drugs for treatment of bone diseases, bisphosphonates,

ATC code: M05BA08

Zoledronic acid belongs to the class of bisphosphonates and acts primarily on bone. It is an inhibitor ofosteoclastic 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. Inlong-term animal studies, zoledronic acid inhibits bone resorption without adversely affecting theformation, mineralization or mechanical properties of bone.

In addition to being a potent inhibitor of bone resorption, zoledronic acid also possesses severalanti-tumour properties that could contribute to its overall efficacy in the treatment of metastatic bonedisease. The following properties have been demonstrated in preclinical studies:

- In-vivo: Inhibition of osteoclastic bone resorption, which alters the bone marrowmicroenvironment, making it less conducive to tumour cell growth, anti-angiogenic activity andanti-pain activity.

- In-vitro: Inhibition of osteoblast proliferation, direct cytostatic and pro-apoptotic activity ontumour cells, synergistic cytostatic effect with other anti-cancer drugs, anti-adhesion/invasionactivity.

Clinical trial results in the prevention of skeletal related events in patients with advanced malignanciesinvolving bone

The first randomised, double-blind, placebo-controlled study compared zoledronic acid 4 mg toplacebo for the prevention of skeletal related events (SREs) in prostate cancer patients. Zoledronicacid 4 mg significantly reduced the proportion of patients experiencing at least one skeletal relatedevent (SRE), delayed the median time to first SRE by > 5 months, and reduced the annual incidence ofevents per patient-skeletal morbidity rate. Multiple event analysis showed a 36% risk reduction indeveloping SREs in the zoledronic acid 4 mg group compared with placebo. Patients receivingzoledronic acid 4 mg reported less increase in pain than those receiving placebo, and the differencereached significance at months 3, 9, 21 and 24. Fewer zoledronic acid 4 mg patients sufferedpathological fractures. The treatment effects were less pronounced in patients with blastic lesions.

Efficacy results are provided in Table 2.

In a second study including solid tumours other than breast or prostate cancer, zoledronic acid 4 mgsignificantly reduced the proportion of patients with an SRE, delayed the median time to first SRE by> 2 months, and reduced the skeletal morbidity rate. Multiple event analysis showed 30.7% riskreduction in developing SREs in the zoledronic acid 4 mg group compared with placebo. Efficacyresults are provided in Table 3.

Table 2: Efficacy results (prostate cancer patients receiving hormonal therapy)

Any SRE (+TIH) Fractures* Radiation therapy tobonezoledronic Placebo zoledronic Placebo zoledronic Placeboacid 4 mg acid 4 mg acid 4 mg

N 214 208 214 208 214 208

Proportion of patients with 38 49 17 25 26 33

SREs (%)p-value 0.028 0.052 0.119

Median time to SRE (days) 488 321 NR NR NR 640p-value 0.009 0.020 0.055

Skeletal morbidity rate 0.77 1.47 0.20 0.45 0.42 0.89p-value 0.005 0.023 0.060

Risk reduction of suffering from 36 - NA NA NA NAmultiple events** (%)p-value 0.002 NA NA

* Includes vertebral and non-vertebral fractures

** Accounts for all skeletal events, the total number as well as time to each event during the trial

NR-Not Reached

NA-Not Applicable

Table 3: Efficacy results (solid tumours other than breast or prostate cancer)

Any SRE (+TIH) Fractures* Radiation therapy tobonezoledronic Placebo zoledronic Placebo zoledronic Placeboacid 4 mg acid 4 mg acid 4 mg

N 257 250 257 250 257 250

Proportion of patients with 39 48 16 22 29 34

SREs (%)p-value 0.039 0.064 0.173

Median time to SRE (days) 236 155 NR NR 424 307p-value 0.009 0.020 0.079

Skeletal morbidity rate 1.74 2.71 0.39 0.63 1.24 1.89p-value 0.012 0.066 0.099

Risk reduction of suffering from 30.7 - NA NA NA NAmultiple events** (%)p-value 0.003 NA NA

* Includes vertebral and non-vertebral fractures

** Accounts for all skeletal events, the total number as well as time to each event during the trial

NR-Not Reached

NA-Not Applicable

In a third phase III randomised, double-blind trial, zoledronic acid 4 mg or 90 mg pamidronate every3 to 4 weeks were compared in patients with multiple myeloma or breast cancer with at least one bonelesion. The results demonstrated that zoledronic acid 4 mg showed comparable efficacy to 90 mgpamidronate in the prevention of SREs. The multiple event analysis revealed a significant riskreduction of 16% in patients treated with zoledronic acid 4 mg in comparison with patients receivingpamidronate. Efficacy results are provided in Table 4.

Table 4: Efficacy results (breast cancer and multiple myeloma patients)

Any SRE (+TIH) Fractures* Radiation therapy tobonezoledronic Pam zoledronic Pam zoledronic Pamacid 4 mg 90 mg acid 4 mg 90 mg acid 4 mg 90 mg

N 561 555 561 555 561 555

Proportion of patients with SREs 48 52 37 39 19 24(%)p-value 0.198 0.653 0.037

Median time to SRE (days) 376 356 NR 714 NR NRp-value 0.151 0.672 0.026

Skeletal morbidity rate 1.04 1.39 0.53 0.60 0.47 0.71p-value 0.084 0.614 0.015

Risk reduction of suffering from 16 - NA NA NA NAmultiple events** (%)p-value 0.030 NA NA

* Includes vertebral and non-vertebral fractures

** Accounts for all skeletal events, the total number as well as time to each event during the trial

NR-Not Reached

NA-Not Applicable

Zoledronic acid 4 mg was also studied in a double-blind, randomised, placebo-controlled trial in228 patients with documented bone metastases from breast cancer to evaluate the effect of 4 mgzoledronic acid on the skeletal related event (SRE) rate ratio, calculated as the total number of SREevents (excluding hypercalcaemia and adjusted for prior fracture), divided by the total risk period.

Patients received either 4 mg zoledronic acid or placebo every four weeks for one year. Patients wereevenly distributed between zoledronic acid-treated and placebo groups.

The SRE rate (events/person year) was 0.628 for zoledronic acid and 1.096 for placebo. Theproportion of patients with at least one SRE (excluding hypercalcaemia) was 29.8% in the zoledronicacid-treated group versus 49.6% in the placebo group (p=0.003). Median time to onset of the first SREwas not reached in the zoledronic acid-treated arm at the end of the study and was significantlyprolonged compared to placebo (p=0.007). Zoledronic acid 4 mg reduced the risk of SREs by 41% in amultiple event analysis (risk ratio=0.59, p=0.019) compared with placebo.

In the zoledronic acid-treated group, statistically significant improvement in pain scores (using the

Brief Pain Inventory, BPI) was seen at 4 weeks and at every subsequent time point during the study,when compared to placebo (Figure 1). The pain score for zoledronic acid was consistently belowbaseline and pain reduction was accompanied by a trend in reduced analgesics score.

Figure 1. Mean changes from baseline in BPI scores. Statistically significant differences aremarked (*p< 0.05) for between treatment comparisons (4 mg zoledronic acid vs. Placebo)

CZOL446EUS122/SWOG study

The primary objective of this observational study was to estimate the cumulative incidence ofosteonecrosis of the jaw (ONJ) at 3 years in cancer patients with bone metastasis receiving zoledronicacid. The osteoclast inhibition therapy, other cancer therapy, and dental care was performed asclinically indicated in order to best represent academic and community-based care. A baseline dentalexamination was recommended but was not mandatory.

Among the 3491 evaluable patients, 87 cases of ONJ diagnosis were confirmed. The overall estimatedcumulative incidence of confirmed ONJ at 3 years was 2.8% (95% CI: 2.3-3.5%). The rates were 0.8%at year 1 and 2.0% at year 2. Rates of 3-year confirmed ONJ were highest in myeloma patients (4.3%)and lowest in breast cancer patients (2.4%). Cases of confirmed ONJ were statistically significantlyhigher in patients with multiple myeloma (p=0.03) than other cancers combined.

Clinical trial results in the treatment of TIH

Clinical studies in tumour-induced hypercalcaemia (TIH) demonstrated that the effect of zoledronicacid is characterised by decreases in serum calcium and urinary calcium excretion. In Phase I dosefinding studies in patients with mild to moderate tumour-induced hypercalcaemia (TIH), effectivedoses tested were in the range of approximately 1.2-2.5 mg.

To assess the effects of 4 mg zoledronic acid versus pamidronate 90 mg, the results of two pivotalmulticentre studies in patients with TIH were combined in a pre-planned analysis. There was fasternormalisation of corrected serum calcium at day 4 for 8 mg zoledronic acid and at day 7 for 4 mg and8 mg zoledronic acid. The following response rates were observed:

Table 5: Proportion of complete responders by day in the combined TIH studies

Day 4 Day 7 Day 10

Zoledronic acid 4 mg (N=86) 45.3% (p=0.104) 82.6% (p=0.005)* 88.4% (p=0.002)*

Zoledronic acid 8 mg (N=90) 55.6% (p=0.021)* 83.3% (p=0.010)* 86.7% (p=0.015)*

Pamidronate 90 mg (N=99) 33.3% 63.6% 69.7%

*p-values compared to pamidronate.

Median time to normocalcaemia was 4 days. Median time to relapse (re-increase of albumin-correctedserum calcium ≥ 2.9 mmol/l) was 30 to 40 days for patients treated with zoledronic acid versus17 days for those treated with pamidronate 90 mg (p-values: 0.001 for 4 mg and 0.007 for 8 mgzoledronic acid). There were no statistically significant differences between the two zoledronic aciddoses.

In clinical trials 69 patients who relapsed or were refractory to initial treatment (zoledronic acid 4 mg,8 mg or pamidronate 90 mg) were retreated with 8 mg zoledronic acid. The response rate in thesepatients was about 52%. Since those patients were retreated with the 8 mg dose only, there are no dataavailable allowing comparison with the 4 mg zoledronic acid dose.

In clinical trials performed in patients with tumour-induced hypercalcaemia (TIH), the overall safetyprofile amongst all three treatment groups (zoledronic acid 4 and 8 mg and pamidronate 90 mg) wassimilar in types and severity.

Clinical trial results in the treatment of severe osteogenesis imperfecta in paediatric patients aged 1 to17 years

The effects of intravenous zoledronic acid in the treatment of paediatric patients (age 1 to 17 years)with severe osteogenesis imperfecta (types I, III and IV) were compared to intravenous pamidronate inone international, multicentre, randomised, open-label study with 74 and 76 patients in each treatmentgroup, respectively. The study treatment period was 12 months preceded by a 4- to 9-week screeningperiod during which vitamin D and elemental calcium supplements were taken for at least 2-weeks. Inthe clinical programme patients aged 1 to < 3 years received 0.025 mg/kg zoledronic acid (up to amaximum single dose of 0.35 mg) every 3 months and patients aged 3 to 17 years received 0.05 mg/kgzoledronic acid (up to a maximum single dose of 0.83 mg) every 3 months. An extension study wasconducted in order to examine the long-term general and renal safety of once yearly or twice yearlyzoledronic acid over the 12-month extension treatment period in children who had completed one yearof treatment with either zoledronic acid or pamidronate in the core study.

The primary endpoint of the study was the percent change from baseline in lumbar spine bone mineraldensity (BMD) after 12 months of treatment. Estimated treatment effects on BMD were similar, butthe trial design was not sufficiently robust to establish non-inferior efficacy for zoledronic acid. Inparticular there was no clear evidence of efficacy on incidence of fracture or on pain. Fracture adverseevents of long bones in the lower extremities were reported in approximately 24% (femur) and 14%(tibia) of zoledronic acid-treated patients vs 12% and 5% of pamidronate-treated patients with severeosteogenesis imperfecta, regardless of disease type and causality but overall incidence of fractures wascomparable for the zoledronic acid and pamidronate-treated patients: 43% (32/74) vs 41% (31/76).

Interpretation of the risk of fracture is confounded by the fact that fractures are common events inpatients with severe osteogenesis imperfecta as part of the disease process.

The type of adverse reactions observed in this population were similar to those previously seen inadults with advanced malignancies involving the bone (see section 4.8). The adverse reactions rankedunder headings of frequency, are presented in Table 6.

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).

Table 6: Adverse reactions observed in paediatric patients with severe osteogenesis imperfecta1

Common: Headache

Common Tachycardia

Common: Nasopharyngitis

Very common Vomiting, nausea

Common Abdominal pain

Common Pain in extremities, arthralgia, musculoskeletal pain

Very common Pyrexia, fatigue

Common Acute phase reaction, pain

Very common Hypocalcaemia

Common: Hypophosphataemia1 Adverse events occurring with frequencies < 5% were medically assessed and it was shown thatthese cases are consistent with the well established safety profile of zoledronic acid (see section 4.8)

In paediatric patients with severe osteogenesis imperfecta, zoledronic acid seems to be associated withmore pronounced risks for acute phase reaction, hypocalcaemia and unexplained tachycardia, incomparison to pamidronate, but this difference declined after subsequent infusions.

The European Medicines Agency has waived the obligation to submit the results of studies with thereference product containing zoledronic acid in all subsets of the paediatric population in the treatmentof tumour-induced hypercalcaemia and prevention of skeletal-related events in patients with advancedmalignancies involving bone (see section 4.2 for information on paediatric use).

Single and multiple 5- and 15-minute infusions of 2, 4, 8 and 16 mg zoledronic acid in 64 patientswith bone metastases yielded the following pharmacokinetic data, which were found to be doseindependent.

After initiating the infusion of zoledronic acid, the plasma concentrations of zoledronic acid rapidlyincreased, 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 lowconcentrations not exceeding 0.1% of peak prior to the second infusion of zoledronic acid on day 28.

Intravenously administered zoledronic acid is eliminated by a triphasic process: rapid biphasicdisappearance from the systemic circulation, with half-lives of t½α 0.24 and t½β 1.87 hours, followed bya long elimination phase with a terminal elimination half-life of t½γ 146 hours. There was noaccumulation of zoledronic acid in plasma after multiple doses given every 28 days. Zoledronic acid isnot metabolised and is excreted unchanged via the kidney. Over the first 24 hours, 39 ± 16% of theadministered 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 viathe 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% decreasein zoledronic acid concentration at the end of the infusion, but had no effect on the area under theplasma concentration versus time curve.

The interpatient variability in pharmacokinetic parameters for zoledronic acid was high, as seen withother bisphosphonates.

No pharmacokinetic data for zoledronic acid are available in patients with hypercalcaemia or inpatients 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 thefaeces, suggesting no relevant role of liver function in the pharmacokinetics of zoledronic acid.

The renal clearance of zoledronic acid was correlated with creatinine clearance, renal clearancerepresenting 75 ± 33% of the creatinine clearance, which showed a mean of 84 ± 29 ml/min (range22 to 143 ml/min) in the 64 cancer patients studied. Population analysis showed that for a patient withcreatinine clearance of 20 ml/min (severe renal impairment), or 50 ml/min (moderate impairment), thecorresponding predicted clearance of zoledronic acid would be 37% or 72%, respectively, of that of apatient showing creatinine clearance of 84 ml/min. Only limited pharmacokinetic data are available inpatients with severe renal insufficiency (creatinine clearance < 30 ml/min).

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 to5000 ng/ml. The plasma protein binding is low, with the unbound fraction ranging from 60% at2 ng/ml to 77% at 2000 ng/ml of zoledronic acid

Limited pharmacokinetic data in children with severe osteogenesis imperfecta suggest that zoledronicacid pharmacokinetics in children aged 3 to 17 years are similar to those in adults at a similar mg/kgdose level. Age, body weight, gender and creatinine clearance appear to have no effect on zoledronicacid systemic exposure.

Acute toxicity

The highest non-lethal single intravenous dose was 10 mg/kg bodyweight in mice and 0.6 mg/kg inrats.

Subchronic and chronic toxicity

Zoledronic acid was well tolerated when administered subcutaneously to rats and intravenously todogs at doses up to 0.02 mg/kg daily for 4 weeks. Administration of 0.001 mg/kg/day subcutaneouslyin rats and 0.005 mg/kg intravenously once every 2-3 days in dogs for up to 52 weeks was also welltolerated.

The most frequent finding in repeat-dose studies consisted of increased primary spongiosa in themetaphyses of long bones in growing animals at nearly all doses, a finding that reflected thecompound’s pharmacological antiresorptive activity.

The safety margins relative to renal effects were narrow in the long-term repeat-dose parenteral animalstudies but the cumulative no adverse event levels (NOAELs) in the single dose (1.6 mg/kg) andmultiple dose studies of up to one month (0.06-0.6 mg/kg/day) did not indicate renal effects at dosesequivalent to or exceeding the highest intended human therapeutic dose. Longer-term repeatadministration at doses bracketing the highest intended human therapeutic dose of zoledronic acidproduced toxicological effects in other organs, including the gastrointestinal tract, liver, spleen andlungs, and at intravenous injection sites.

Reproduction toxicity

Zoledronic acid was teratogenic in the rat at subcutaneous doses  0.2 mg/kg. Although noteratogenicity or foetotoxicity was observed in the rabbit, maternal toxicity was found. Dystocia wasobserved 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 didnot provide any evidence of carcinogenic potential.

6 PHARMACEUTICAL PARTICULARS

Mannitol (E421)

Sodium citrate

Water for injections

To avoid potential incompatibilities, Zoledronic Acid Accord concentrate is to be diluted with0.9% w/v sodium chloride solution for Injection or 5% w/v glucose solution.

This medicinal product must not be mixed with calcium or other divalent cation-containing infusionsolutions such as lactated Ringer’s solution, and should be administered as a single intravenoussolution in a separate infusion line.

30 months.

Chemical and physical in-use stability has been demonstrated for 36 hours at 2 - 8 °C.

After dilution: From a microbiological point of view, the product should be used immediately. If notused immediately, in-use storage times and conditions prior to use are the responsibility of the userand would normally not be longer than 24 hours at 2°C to 8°C, unless dilution has taken place incontrolled and validated aseptic conditions.

This medicinal product does not require any special storage condition.

For storage conditions of the reconstituted solution for infusion, see section 6.3.

5-ml plastic vial made of clear, cycloolefine copolymer with chlorobutyl rubber stopper andaluminium cap with flip-off component.

Packs containing 1, 4 or 10 vials.

Not all pack sizes may be marketed.

Prior to administration, 5ml concentrate from one vial or the volume of the concentrate withdrawn asrequired must be further diluted with 100 ml of calcium-free infusion solution (0.9% w/v sodiumchloride solution for Injection or 5% w/v glucose solution).

Additional information on handling of Zoledronic Acid Accord, including guidance on preparation ofreduced doses, 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 Accord via thedomestic sewage system.

Any unused medicinal product or waste material should be disposed of in accordance with localrequirements.

Accord Healthcare S.L.U.

World Trade Center, Moll de Barcelona, s/n,

Edifici Est 6ª planta,08039 Barcelona,

Spain

EU/1/13/834/001

EU/1/13/834/002

EU/1/13/834/003

Date of first authorisation: 16.01.2014

Date of latest renewal: 20th November 2018

Detailed information on this medicinal product is available on the website of the European Medicines

Agency http://www.ema.europa.eu.