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

Zoledronic acid medac 4 mg/100 ml solution for infusion

One bottle with 100 ml solution contains 4 mg zoledronic acid (as monohydrate).

One ml solution contains 0.04 mg zoledronic acid (as monohydrate).

For the full list of excipients, see section 6.1.

Solution for infusion

Clear, 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 medac must only be prescribed and administered to patients by healthcareprofessionals experienced in the administration of intravenous bisphosphonates. Patients treated with

Zoledronic acid medac 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 elderly 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 elderly 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 treatment in TIH patients who also have severe renal impairment should be consideredonly after evaluating the risks and benefits of treatment. In the clinical studies, patients with serumcreatinine > 400 µmol/l or > 4.5 mg/dl were excluded. No dose adjustment is necessary in TIHpatients 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.

For patients with normal renal function (defined as CLcr > 60 ml/min), zoledronic acid 4 mg/100 mlsolution for infusion may be administered directly without any further preparation. In patients withbone metastases presenting with mild to moderate renal impairment prior to initiation of therapy,which is defined for this population as CLcr 30 - 60 ml/min, the following zoledronic acid dose isrecommended (see also section 4.4):

Baseline creatinine clearance (ml/min) Zoledronic acid recommended dose*> 60 4.0 mg50 - 60 3.5 mg*40 - 49 3.3 mg*30 - 39 3.0 mg*

*Doses have been calculated assuming target AUC of 0.66 (mg*hr/l) (CLcr=75 ml/min). The reduceddoses for patients with renal impairment are expected to achieve the same AUC as that seen in patientswith 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 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 medac 4 mg/100 ml solution for infusion should be given as a single intravenousinfusion in no less than 15 minutes.

In patients with normal renal function, defined as CLcr > 60 ml/min, zoledronic acid 4 mg/100 mlsolution for infusion must not be further diluted.

In patients with mild to moderate renal impairment, reduced Zoledronic acid medac 4 mg/100 mlsolution for infusion doses are recommended (see section “Posology” above and section 4.4).

To prepare reduced doses for patients with baseline CLcr ≤ 60 ml/min, refer to Table 1 below.

Remove the volume of Zoledronic acid medac 4 mg/100 ml solution indicated from the bottle andreplace with an equal volume of sterile sodium chloride 9 mg/ml (0.9%) solution for injection, or 5%glucose solution for injection.

Table 1: Preparation of reduced doses of Zoledronic acid medac 4 mg/100 ml solution for infusion

Baseline creatinine Remove the following Replace with the Adjusted dose (mgclearance (ml/min) amount of Zoledronic following volume of zoledronic acid inacid medac solution for sterile sodium chloride 100 ml)infusion (ml) 9 mg/ml (0.9%), or 5%glucose solution forinjection (ml)50-60 12.0 12.0 3.540-49 18.0 18.0 3.330-39 25.0 25.0 3.0

Zoledronic acid medac 4 mg/100 ml solution for infusion must not be mixed with other infusionsolutions and should be administered as a single intravenous solution in a separate infusion line.

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

* 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.

Other medicinal products containing zoledronic acid as active substances are available forosteoporosis indications and treatment of Paget´s disease of the bone. Patients being treated with

Zoledronic acid medac should not be treated with such medicinal products concomitantly or any otherbisphosphonate, 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 4 mg 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 medac treatment should beresumed at the same dose as that given prior to treatment interruption.

In view of the potential impact of zoledronic acid on renal function, the lack of clinical safety data 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 and in the post-marketing setting in patients receiving zoledronic acid. Post-marketing experience and the literaturesuggest a greater frequency of reports of ONJ based on tumour type (advanced breast cancer, multiplemyeloma). A study showed that ONJ was higher in myeloma patients when compared to other cancers(see section 5.1).

The start of treatment or of a new course of treatment should be delayed in patients with unhealedopen soft tissue lesions in the mouth except in medical emergency situations.

A dental examination with appropriate preventive dentistry and an individual benefit-risk assessmentis recommended prior to treatment with bisphosphonates in patients with concomitant risk factors.

The following risk factors should be considered when evaluating an individual’s risk of developing

ONJ:

* Potency of the bisphosphonate (higher risk for highly potent compounds), route 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), radiotherapyto neck and head, corticosteroids.

* History of dental disease, poor oral hygiene, periodontal disease, invasive dental procedures(e.g. tooth extractions) and poorly fitting dentures.

All patients should be encouraged to maintain good oral hygiene, undergo routine dental check-ups,and immediately report any oral symptoms such as dental mobility, pain or swelling, or non-healing ofsores or discharge during treatment with Zoledronic acid medac. While on treatment, invasive dentalprocedures should be performed only after careful consideration and be avoided in close proximity tozoledronic acid administration.

For patients who develop osteonecrosis of the jaw while on bisphosphonate therapy, dental surgerymay exacerbate the condition. For patients requiring dental procedures, there are no data available tosuggest whether discontinuation of bisphosphonate treatment reduces the risk of osteonecrosis of thejaw.

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 medac.

Musculoskeletal pain

In post-marketing experience, severe and occasionally incapacitating bone, joint, and/or muscle painhave been reported in patients taking bisphosphonates, including zoledronic acid. However, suchreports have been infrequent. The time to onset of symptoms varied from one day to several monthsafter starting treatment. Most patients had relief of symptoms after stopping treatment. A subset hadrecurrence of symptoms when rechallenged with zoledronic acid or another bisphosphonate.

Atypical fractures of the femur

Atypical subtrochanteric and diaphyseal femoral fractures have been reported with 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, hypoaesthesia 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 zoledronic acid is administered with medicinal products known to causehypocalcaemia, as they may have a synergistic effect resulting in severe hypocalcaemia (see section4.5). Serum calcium should be measured and hypocalcaemia must be corrected before initiatingzoledronic acid therapy. Patients should be adequately supplemented with calcium and vitamin D.

Zoledronic acid medac contains less than 1 mmol (23 mg) sodium per dose, i.e. essentially‘sodium-free’.

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 along with driving andoperating of machinery.

Within three days after zoledronic acid administration, an acute phase reaction has been reported, withsymptoms including bone pain, fever, fatigue, arthralgia, myalgia, rigors and arthritis with subsequentjoint swelling; these symptoms usually resolve within a few days (see description of selected adversereactions).

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 2.

The following adverse reactions, listed in Table 2, have been accumulated from clinical studies andpost-marketing reports following predominantly chronic treatment with 4 mg zoledronic acid:

Table 2

Adverse reactions are ranked under headings of frequency, the most frequent first, using the 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 theavailable data).

Common: Anaemia

Uncommon: Thrombocytopenia, leukocytopenia

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 orbitalinflammation

Rare: Uveitis

Very rare: Episcleritis

Uncommon: Hypertension, hypotension, atrialfibrillation, hypotension leading to syncopeor circulatory collapse

Rare: Bradycardia, cardiac arrhythmia (secondaryto hypocalcaemia)

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, generalisedpain

Uncommon: Muscle spasms, osteonecrosis of the jaw

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

Common: Renal impairment

Uncommon: Acute renal failure, haematuria, proteinuria

Rare: Acquired Fanconi syndrome

General disorders and administration siteconditions Fever, flu-like syndrome (including fatigue,

Common: rigors, malaise and flushing)

Asthenia, peripheral oedema, injection site

Uncommon: reactions (including pain, irritation,swelling, induration), chest pain, weightincrease, anaphylactic reaction/shock,urticaria

Arthritis and joint swelling as a symptom of

Rare: acute 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 medac (see section 4.4). Manyof these 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 receivingzoledronic acid 5 mg and placebo, respectively. The imbalance observed in this trial has not beenobserved in other trials with zoledronic acid, including those with zoledronic acid 4 mg every 3 - 4weeks in oncology patients. The mechanism behind the increased incidence of atrial fibrillation in thissingle clinical trial is unknown.

Acute phase reaction

This adverse drug reaction consists of a constellation of symptoms that includes fever, myalgia,headache, extremity pain, nausea, vomiting, diarrhoea, arthralgia and arthritis with subsequent 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 (bisphopsphonate 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, mineralisation or mechanical properties of bone.

In addition to being a potent inhibitor of bone resorption, zoledronic acid also possesses several anti-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 medicinal products, anti-adhesion/invasion activity.

Clinical Efficacy and Safety

Clinical trial results in the prevention of skeletal related events in patients with advancedmalignancies involving 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 3.

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 4.

Table 3: Efficacy results (prostate cancer patients receiving hormonal therapy)

Any SRE (+TIH) Fractures* Radiation therapy tobone

Zoledronic Placebo Zoledronic Placebo Zoledronic Placeboacid 4 mg acid 4 mg acid 4 mg

N 214 208 214 208 214 208

Proportion of patients 38 49 17 25 26 33with SREs (%)p-value 0.028 0.052 0.119

Median time to SRE 488 321 NR NR NR 640(days)p-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 36 - NA NA NA NAsuffering from multipleevents** (%)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 4: Efficacy results (solid tumours other than breast or prostate cancer)

Any SRE (+TIH) Fractures* Radiation therapy tobone

Zoledronic Placebo Zoledronic Placebo Zoledronic Placeboacid 4 mg acid 4 mg acid 4 mg

N 257 250 257 250 257 250

Proportion of patients 39 48 16 22 29 34with SREs (%)p-value 0.039 0.064 0.173

Median time to SRE 236 155 NR NR 424 307(days)p-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 30.7 - NA NA NA NAsuffering from multipleevents** (%)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 every 3to 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 5.

Table 5: Efficacy results (breast cancer and multiple myeloma patients)

Any SRE (+TIH) Fractures* Radiation therapyto bone

Zoledronic Pamidronate Zoledronic Pamidronate Zoledronic Pamidronateacid 4 mg 90 mg acid 4 mg 90 mg acid 4 mg 90 mg

N 561 555 561 555 561 555

Proportion of 48 52 37 39 19 24patients with

SREs (%)p-value 0.198 0.653 0.037

Median time to 376 356 NR 714 NR NR

SRE (days)p-value 0.151 0.672 0.026

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

Risk reduction of 16 - NA NA NA NAsuffering frommultiple 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

SRE was 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 % ina multiple 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 are marked(*p< 0.05) for between treatment comparisons (4 mg zoledronic acid vs. placebo)

Placebo

Zoledronic acid 4 mg

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 6: 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 versus 17days 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 versus 12 % and 5 % of pamidronate-treated patients withsevere osteogenesis imperfecta, regardless of disease type and causality but overall incidence offractures was comparable for the zoledronic acid and pamidronate-treated patients: 43 % (32/74)versus 41 % (31/76). Interpretation of the risk of fracture is confounded by the fact that fractures arecommon events in patients 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 7. The following conventional classification isused: 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 availabledata).

Table 7: 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

General disorders and administration siteconditions

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 medicinal product containing zoledronic acid in all subsets of the paediatric population inthe treatment of tumour-induced hypercalcaemia and prevention of skeletal-related events in patientswith advanced malignancies 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 verylow concentrations not exceeding 0.1 % of peak prior to the second infusion of zoledronic acid onday 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.

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 to5,000 ng/ml. The plasma protein binding is low, with the unbound fraction ranging from 60% at2 ng/ml to 77% at 2,000 ng/ml of zoledronic acid.

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 (range 22to 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).

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.

Mannitol

Sodium citrate

Water for injections

This medicinal product must not be allowed to come into contact with any calcium-containingsolutions and it must not be mixed or given intravenously with any other medicinal product in thesame infusion line.

Unopened bottle: 3 years.

After first opening: Chemical and physical in-use stability has been demonstrated for 4 days at 2 - 8°Cand 25°C.

Chemical and physical in-use stability has been demonstrated for glass bottles, polyethylene,polyvinylchloride and polypropylene infusion lines and infusion bags (prefilled with sodium chloride9 mg/ml (0.9 %) solution for injection or 5 % w/v glucose solution) for 96 hours at 2-8°C and 25°C.

After first opening and dilution: From a microbiological point of view the medicinal product should beused immediately. If not used immediately, in use storage times and conditions prior to use are theresponsibility of the user and would normally not be longer than 24 hours at 2-8°C unless dilution hastaken place in controlled and validated aseptic conditions.

Do not freeze.

For storage conditions after first opening of the medicinal product, see section 6.3.

Colourless glass bottle type I with fluoropolymer coated halobutyl rubber stopper and aluminium flip-off cap.

Each vial contains 100 ml of solution

Zoledronic acid medac is supplied as packs containing 1 bottle or multipacks of 4 cartons eachcontaining 1 bottle. Not all pack sizes may be marketed.

Additional information on handling of Zoledronic acid medac 4 mg/100 ml solution for infusion,including guidance on the preparation of reduced doses using the Zoledronic acid medac ready-to-usebottle, is provided in section 4.2.

Aseptic techniques must be followed during the preparation of the infusion. For single use only.

Only clear solution free from particles and discolouration should be used.

Healthcare professionals are advised not to dispose of unused Zoledronic acid medac via the domesticsewage system.

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

medac

Gesellschaft für klinische

Spezialpräparate mbH

Theaterstr. 622880 Wedel

Germany

EU/1/12/779/004

EU/1/12/779/005

Date of first authorisation: 03 August 2012.

Date of latest renewal: 28 April 2017.

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

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