ZOLEDRONIC ACID ACTAVIS zoledronic acid 4 mg/5 mL concentrated solution for injection vial

Main information

  • Trade name:
  • ZOLEDRONIC ACID ACTAVIS zoledronic acid 4 mg/5 mL concentrated solution for injection vial
  • Medicine domain:
  • Humans
  • Medicine type:
  • Allopathic drug

Documents

Localization

  • Available in:
  • ZOLEDRONIC ACID ACTAVIS zoledronic acid 4 mg/5 mL concentrated solution for injection vial
    Australia
  • Language:
  • English

Status

  • Source:
  • Dept. of Health,Therapeutic Goods Administration - Australia
  • Authorization status:
  • Registered
  • Authorization number:
  • 186529
  • Last update:
  • 22-05-2019

Public Assessment Report

Public Summary

Summary for ARTG Entry:

186529

ZOLEDRONIC ACID ACTAVIS zoledronic acid 4 mg/5 mL concentrated solution for injection vial

ARTG entry for

Medicine Registered

Sponsor

Medis Pharma Pty Ltd

Postal Address

PO Box 6127,North Sydney, NSW, 2059

Australia

ARTG Start Date

26/07/2012

Product category

Medicine

Status

Active

Approval area

Drug Safety Evaluation Branch

Conditions

Conditions applicable to all therapeutic goods as specified in the document "Standard Conditions Applying to Registered or Listed Therapeutic Goods

Under Section 28 of the Therapeutic Goods Act 1989" effective 1 July 1995.

Conditions applicable to the relevant category and class of therapeutic goods as specified in the document "Standard Conditions Applying to Registered

or Listed Therapeutic Goods Under Section 28 of the Therapeutic Goods Act 1989" effective 1 July 1995.

Products

1. ZOLEDRONIC ACID ACTAVIS zoledronic acid 4 mg/5 mL concentrated solution for injection vial

Product Type

Single Medicine Product

Effective date

8/10/2013

Warnings

See Product Information and Consumer Medicine Information for this product

Standard Indications

Specific Indications

Prevention of skeletal-related events (pathological fracture, spinal cord compression, radiation to bone or surgery to bone) in patients with advanced

malignancies involving bone.,Treatment of tumour induced hypercalcaemia.

Additional Product information

Container information

Type

Material

Life Time

Temperature

Closure

Conditions

Vial

Plastic

18 Months

Store below 30

degrees Celsius

Neither child resistant

closure nor restricted

flow insert

Store in Original

Container

Pack Size/Poison information

Pack Size

Poison Schedule

1 vial

(S4) Prescription Only Medicine

Components

1. ZOLEDRONIC ACID ACTAVIS zoledronic acid 4 mg/5 mL concentrated solution for injection vial

Dosage Form

Injection, concentrated

Route of Administration

Intravenous

Visual Identification

clear, colourless solution

Active Ingredients

zoledronic acid monohydrate

4.264 mg

© Commonwealth of Australia.This work is copyright.You are not permitted to re-transmit, distribute or commercialise the material without obtaining prior

written approval from the Commonwealth.Further details can be found at http://www.tga.gov.au/about/website-copyright.htm.

Public Summary

Page 1 of

Produced at 29.11.2017 at 02:43:09 AEDT

This is not an ARTG Certificate document.

The onus is on the reader to verify the current accuracy of the information on the document subsequent to the date shown.

Visit www.tga.gov.au for contact information

Summary of Product characteristics: dosage, interactions, side effects

Zoledronic acid Actavis – Product information

Page 1 of 1

Zoledronic acid Actavis PI/05/12/2018/5

AUSTRALIAN PRODUCT INFORMATION - ZOLEDRONIC ACID ACTAVIS

1.

NAME OF THE MEDICINE

Zoledronic Acid.

2 & 3. QUALITATIVE AND QUANTITATIVE COMPOSITION AND

PHARMACEUTICAL FORM

ZOLEDRONIC ACID ACTAVIS concentrated solution for injection is a sterile concentrated

solution for intravenous infusion after dilution and is supplied in a 5 mL vial containing 4

mg of Zoledronic acid (as monohydrate). The solution also contains: Mannitol, sodium

citrate and water for injections.

Zoledronic acid monohydrate is a white, crystalline powder. It is soluble in water, most

soluble at neutral pH (> 290 mg/mL; pH = 6.8) and practically insoluble in organic

solvents.

4. CLINICAL PARTICULARS

THERAPEUTIC INDICATIONS

Prevention of skeletal-related events (pathological fracture, spinal cord compression,

radiation to bone or surgery to bone) in patients with advanced malignancies involving

bone.

Treatment of tumour induced hypercalcaemia

DOSE AND METHOD OF ADMINISTRATION

For information on the reconstitution and dilution of ZOLEDRONIC ACID ACTAVIS, see

Instructions for use and handling, below.

Prevention of skeletel related events in patients with advanced malignancies involving

bone. Dosage regimen for adults (including elderly patients)

recommended

dose

prevention

SREs

patients

with

advanced

malignancies involving bone is 4 mg reconstituted and further diluted zoledronic acid

solution for infusion (diluted with 100 mL sodium chloride 0.9% w/v or glucose solution 5%

w/v), given as an IV infusion lasting no less than 15 minutes every three to four weeks.

Patients should also be administered an oral calcium supplement of 500 mg and a

multiple vitamin containing vitamin D 400 IU daily.

Treatment

tumour

induced

hypercalcaemia

(TIH).

Dosage

regimen

adults

(including elderly patients)

The recommended dose in hypercalcaemia (albumin corrected serum calcium ≥ 3.0

mmol/L) is 4 mg reconstituted and further diluted zoledronic acid solution for infusion

(diluted with 100 mL sodium chloride 0.9% w/v or glucose 5% w/v solution), given as a

single IV infusion of no less than 15 minutes (see Instructions for use and handling,

below). The hydration status of patients must be assessed prior to administration of

ZOLEDRONIC ACID ACTAVIS to assure that patients are adequately hydrated prior to and

following administration of ZOLEDRONIC ACID ACTAVIS. Following an initial dose of 4 mg,

Zoledronic acid Actavis – Product information

Page 2 of 2

Zoledronic acid Actavis PI/05/12/2018/5

the median time to relapse is 30 days.

Patients with impaired renal function

The use of zoledronic acid is not recommended in patients with severe renal impairment

(calculated creatinine clearance by Cockcroft-Gault formula of < 30 mL/minute) ((see 4.4

Special

Warnings

Precautions

use, 5.1 Pharmacological

properties and

Pharmacokinetics).

Dose adjustments are not recommended in patients with TIH presenting with mild to

moderate renal impairment prior to initiation of therapy (serum creatinine < 400

micromol/L or calculated creatinine clearance by Cockcroft-Gault formula of ≥ 30

mL/minute) as there are insufficient data to support the efficacy of doses less than 4 mg.

When initiating treatment with ZOLEDRONIC ACID ACTAVIS in patients with advanced

malignancies involving bone, serum creatinine levels and creatinine clearance (CrCl)

should

determined.

CrCl

calculated

from

serum

creatinine

levels

using

Cockcroft-Gault formula.

In patients with bone metastases presenting with mild to moderate renal impairment

prior to initiation of therapy, which is defined for this population as CrCl 30 to 60

mL/minute, the recommended zoledronic acid dose is shown in Table 1 (also see 4.4

Special warnings and Precautions for use).

Table 1 Dosage recommendations in patients with bone metastases presenting with mild

to moderate renal impairment prior to initiation of therapy (CrCl 30 to 60 mL/minute)

Baseline creatinine clearance

(mL/min)

Zoledronic acid

recommended dose

> 60

50 – 60

40 – 49

30 – 39

4.0 mg

3.5 mg*

3.3 mg*

3.0 mg*

* Doses have been calculated assuming target AUC of 0.66 (mg.hr/L) (CICr = 75 mL/min)

The reduced doses for patients with renal impairment are expected to achieve the same

AUC as that seen in patients with creatinine clearance of 75 mL/min

Following initiation of therapy, patients who receive zoledronic acid should have serum

creatinine assessed prior to each dose (see 4.4 Special warnings and Precautions for use).

Patients being treated for TIH who have evidence of deterioration in renal function

should be appropriately evaluated, with consideration given as to whether the potential

benefit of continued treatment with zoledronic acid outweighs the possible risk. Patients

being treated for bone metastases should have the dose of zoledronic acid withheld if

renal function has deteriorated. In the clinical studies, deterioration in renal function

was defined as follows. For patients with normal baseline creatinine (< 125 μmol/L),

increase of > 44 μmol/L.

For patients with abnormal baseline creatinine (> 125 μmol/L), increase of > 88 μmol/L.

In the clinical studies, zoledronic acid treatment was resumed only when the creatinine

returned to within 10% of the baseline value. Zoledronic acid should be resumed at the

same dose administered prior to treatment interruption.

Monitoring advice

Zoledronic acid Actavis – Product information

Page 3 of 3

Zoledronic acid Actavis PI/05/12/2018/5

Standard hypercalcaemia related metabolic parameters, such as serum levels of calcium,

phosphate, magnesium and potassium, as well as serum creatinine, should be carefully

monitored after initiating zoledronic acid therapy.

Instructions for use and handling

ZOLEDRONIC ACID ACTAVIS solution concentrate for injection contains no antimicrobial

agent. ZOLEDRONIC ACID ACTAVIS is for single use in one patient only. Discard any

remaining residue.

Liquid concentrate for intravenous injection

ZOLEDRONIC ACID ACTAVIS solution concentrate for injection contains an overfill of 6% to

permit the withdrawal of the labelled amount of zoledronic acid from the vial. Prior to

administration, the required amount of concentrate from one vial must be further diluted

with 100 mL of calcium free infusion solution (sodium chloride 0.9% w/v solution or

glucose 5% w/v solution). If refrigerated, the solution must be allowed to reach room

temperature before administration.

Instructions on preparing reduced doses of ZOLEDRONIC ACID ACTAVIS

Withdraw an appropriate volume of the concentrated solution (4 mg/5 mL) as needed:

4.4 mL for 3.5 mg dose, 4.1 mL for 3.3 mg dose and 3.8 mL for 3.0 mg dose.

In patients with mild to moderate renal impairment, which is defined as ClCr 30 to 60

mL/min, reduced zoledronic acid dosages are recommended, except in patients with TIH

(see 4.4 Special Warnings and Precautions for use).

Stability after dilution

After addition of the solution to the infusion media, the infusion solution should be used

as soon as practicable to reduce the risk of microbiological hazard. If storage of the

infusion solution is necessary, hold at 2 to 8°C for not more than 24 hours.

CONTRAINDICATIONS

Clinically significant hypersensitivity to zoledronic acid, other bisphosphonates or any of

the excipients in the formulation of ZOLEDRONIC ACID ACTAVIS.

Pregnancy; lactation.

SPECIAL WARNINGS AND PRECAUTIONS FOR USE

Administration of ZOLEDRONIC ACID ACTAVIS

ZOLEDRONIC ACID ACTAVIS should be administered as a single intravenous solution in a

line separate from all other drugs and should be administered over a period of no less

than 15 minutes.

Rehydration

Patients

must

maintained

well

hydrated

state

prior

following

administration of

ZOLEDRONIC ACID ACTAVIS. Patients must be assessed prior to

Zoledronic acid Actavis – Product information

Page 4 of 4

Zoledronic acid Actavis PI/05/12/2018/5

administration

ZOLEDRONIC

ACID

ACTAVIS

ensure

that

they

adequately

hydrated. It is essential in the initial treatment of tumour induced hypercalcaemia that

intravenous rehydration be instituted to restore urine output. Patients should be

hydrated adequately throughout treatment but overhydration must be avoided. In

patients with cardiac disease, especially in the elderly, additional saline overload may

precipitate cardiac failure (left ventricular failure or congestive heart failure). Fever

(influenza-like symptoms) may also contribute to this deterioration.

Monitoring of metabolic parameters

Standard hypercalcaemia related metabolic parameters, such as serum levels of calcium,

phosphate, magnesium and potassium, as well as serum creatinine, should be carefully

monitored

after

initiating

ZOLEDRONIC

ACID

ACTAVIS

therapy.

hypocalcaemia,

hypophosphataemia or hypomagnesaemia occur, short-term supplemental therapy may be

necessary. Untreated hypercalcaemia patients generally have some degree of renal

function impairment, therefore careful renal function monitoring should be considered.

Zoledronic acid is also marketed in 5 mg/100 mL for indications related to decreased

bone mineral density (e.g. osteoporosis in post-menopausal women, osteoporosis in men,

treatment and prevention of osteoporosis caused by long-term glucocorticoid use) and for

Paget’s disease. Patients being treated with zoledronic acid for these conditions should

not be treated with other strengths of zoledronic acid nor any other bisphosphonate

concomitantly.

While not observed in clinical trials with zoledronic acid, there have been reports of

bronchoconstriction

acetylsalicylic

acid

sensitive

asthmatic

patients

receiving

bisphosphonates.

Occasional cases of mild, transient hypocalaemia, usually asymptomatic, have been

reported. Symptomatic hypocalcaemia occurs rarely and can be reversed with calcium

gluconate. Patients who have undergone thyroid surgery may be particularly susceptible

to develop hypocalcaemia due to relative hypoparathyroidism.

Monitoring of renal function

Zoledronic acid, in common with other bisphosphonates, has been associated with the

development of renal impairment in some subjects, sometimes progressing to renal

failure. Factors that may increase the potential for deterioration in renal function include

dehydration, pre-existing renal impairment, multiple cycles of zoledronic acid or other

bisphosphonates, as well as the use of nephrotoxic drugs, or using a shorter infusion time

than 15 minutes. Impairment of renal function may occur in patients with bone

metastases receiving zoledronic acid for the prevention of SREs, as well as those with

TIH. Renal deterioration, progression to renal failure and dialysis have been reported in

patients after the initial dose or a single dose of zoledronic acid.

Patients who receive ZOLEDRONIC ACID ACTAVIS should have serum creatinine assessed

prior to each dose. Patients being treated for TIH who have a deterioration in renal

function should be appropriately evaluated, with consideration given as to whether the

potential benefit of continued treatment outweighs the possible risk. Patients being

treated for bone metastases who have a deterioration in renal function should have the

dose withheld, and have treatment resumed only when the creatinine level returns to

within 10% of baseline.

Upon initiation of treatment of bone metastases in patients with mild to moderate renal

Zoledronic acid Actavis – Product information

Page 5 of 5

Zoledronic acid Actavis PI/05/12/2018/5

impairment at baseline, dosage reductions are recommended (see 4.2 Dose and method

of administration). The use of ZOLEDRONIC ACID ACTAVIS is not recommended in patients

with severe renal impairment (creatinine clearance < 30 mL/minute).

Osteonecrosis of the jaw

Osteonecrosis of the jaw (ONJ) has been reported predominately in patients treated with

bisphosphonates, including zoledronic acid. Many of these patients were also receiving

chemotherapy

corticosteroids.

Many

signs

local

infection

including

osteomyelitis. Presentation may include jaw pain, toothache, exposed bone, altered

sensation and local infection, including osteomyletitis. The condition may result in

chronic pain, may be resistant to treatment and, in serious cases, may result in

disfigurement.

Postmarketing experience and the literature suggest a greater frequency of reports of

ONJ based on tumour type (advanced breast cancer, multiple myeloma) and dental status

(dental extraction, periodontal disease, local trauma including poorly fitting dentures).

Cancer patients should maintain good oral hygiene and should have a dental examination

with preventive dentistry prior to treatment with bisphosphonates. Patients and their

dentists should be advised of the reports of ONJ so that dental symptoms developing

during treatment can be fully assessed before commencing dental procedures.

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

developing ONJ:

Potency of the bisphosphonate (higher risk for highly potent compounds), route of

administration (higher risk for parenteral administration) and cumulative dose

Cancer, chemotherapy, radiotherapy, corticosteroids, smoking

History

dental

disease,

poor

oral

hygiene,

periodontal

disease,

invasive

dental

procedures and poorly fitting dentures

While on treatment, these patients should avoid invasive dental procedures if possible.

For patients who develop ONJ while on bisphosphonate therapy, dental surgery may

exacerbate the condition. For patients requiring dental procedures, there are no data

available to suggest whether discontinuation of bisphosphonate treatment reduces the

risk of ONJ. Clinical judgment of the treating doctor should guide the management plan

of each patient based on individual benefit/ risk assessment.

Atypical fractures of the femur

Atypical subtrochanteric and diaphyseal femoral fractures have been reported with

bisphosphonate

therapy,

primarily

patients

receiving

long-term

treatment

osteoporosis. These transverse or short oblique fractures can occur anywhere along the

femur from just below the lesser trochanter to just above the supracondylar flare. These

fractures occur after minimal or no trauma and some patients experience thigh or groin

pain, often associated with imaging features of stress fractures, weeks to months before

presenting with a completed femoral fracture. Fractures are often bilateral; therefore

the contralateral femur should be examined in zoledronic acid-treated patients, who

have sustained a femoral shaft fracture. Poor healing of these fractures has also been

reported. Discontinuation of zoledronic acid therapy in patients suspected to have an

atypical femur fracture should be considered pending evaluation of the patient, based on

an individual benefit risk assessment. Reports of atypical femoral fracture have been

received in patients treated with zoledronic acid; however, causality with zoledronic acid

therapy has not been established.

Zoledronic acid Actavis – Product information

Page 6 of 6

Zoledronic acid Actavis PI/05/12/2018/5

During zoledronic acid treatment patients should be advised to report any thigh, hip or

groin pain and any patient presenting with such symptoms should be evaluated for an

incomplete femur fracture.

Hypocalcemia

Hypocalcemia has been reported in patients treated with zoledronic acid. Cardiac

arrhymias and neurologic adverse events (seizures, tetany, and numbness) have been

reported

secondary

cases

severe

hypocalcemia.

some

instances,

hypocalcemia may be life-threatening.

Onset of effect

The decision to treat patients with bone metastases for the prevention of SREs should

consider that the onset of treatment effect is two to three months.

Severe musculoskeletal pain

In postmarketing experience, severe and occasionally incapacitating bone, joint and/or

muscle pain have been reported in patients taking bisphosphonates. However, such

reports have been infrequent. This category of drugs includes zoledronic acid. The time

to onset of symptoms varied from one day to several months after starting treatment.

Most patients had relief of symptoms after stopping treatment. A subset had recurrence

of symptoms when rechallenged with the same drug or another bisphosphonate.

Use in hepatic impairment

As only limited clinical data are available in patients with severe hepatic insufficiency, no

specific recommendations can be given for this patient population.

Use in renal impairment

Limited clinical data are available in patients with pre-existing renal impairment.

Zoledronic acid is excreted exclusively via the kidney and the risk of adverse reactions

may be greater in patients with pre-existing impairment of renal function. Patients with

severe renal impairment (creatinine levels > 400 μmol/L for patients with TIH and > 265

μmol/L for patients with bone metastases) were excluded from the pivotal clinical

studies. In view of the potential impact of bisphosphonates, including zoledronic acid, on

renal function, the lack of extensive clinical safety data in patients with severe renal

impairment (serum creatinine > 400 μmol/L) and only limited pharmacokinetic data in

patients with severe renal impairment at baseline (creatinine clearance < 30 mL/minute,

see 5. Pharmacological properties and 5.2 Pharmacokinetics), the use of ZOLEDRONIC

ACID ACTAVIS is not recommended in this patient population.

Use in the elderly

Please see section 4.2 Dose and method of administration

Paediatric use

safety

efficacy

zoledronic

acid

paediatric

patients

have

been

established.

Effect on laboratory tests

The following changes in laboratory results were seen with zoledronic acid treatment:

Very common (≥ 1/10): hypophosphataemia.

Common (≥ 1/100, < 1/10): blood creatinine and blood urea increased, hypocalcaemia.

Zoledronic acid Actavis – Product information

Page 7 of 7

Zoledronic acid Actavis PI/05/12/2018/5

Uncommon (≥ 1/1,000, < 1/100): hypomagnesaemia, hypokalaemia.

Rare(≥ 1/10,000, < 1/1,000): hyperkalaemia, hypernatraemia.

INTERACTIONS WITH OTHER MEDICINES AND OTHER FORMS OF INTERACTIONS

In clinical studies, zoledronic acid has been administered concomitantly with commonly

used anticancer agents, diuretics, antibiotics and analgesics without clinically apparent

interactions occurring. Zoledronic acid shows moderate binding to plasma proteins and

human

P450

enzymes

vitro

(see

Pharmacodynamic

properties

Pharmacokinetics), but no formal clinical interaction studies have been performed.

Caution is indicated when zoledronic acid is used in combination with other potentially

nephrotoxic drugs.

In multiple myeloma patients, the risk of renal dysfunction may be increased when

intravenous bisphosphonates are used in combination with thalidomide.

Caution is advised when bisphosphonates are administered with aminoglycosides and loop

diuretics, since both agents may have an additive effect, resulting in a lower serum

calcium level for longer periods than required. Attention should also be paid to the

possibility of hypomagnesaemia developing during treatment.

Caution is advised when zoledronic acid is administered with anti-angiogenic drugs as

cases of ONJ have been observed in patients treated concomitantly with these drugs.

FERTILITY, PREGNANCY AND LACTATION

Effects on fertility

The fertility was decreased in rats dosed subcutaneously (SC) with zoledronic acid 0.1

mg/kg/day (0.1 times the maximum human exposure of 8 mg, based on body surface area

(BSA)), and preimplantation loss was increased at 0.01 mg/kg/day. Reversible testicular

atrophy occurred in rats at 0.003 mg/kg/day SC for 12 months (0.004 times the maximum

human exposure of 8 mg, based on BSA). In dogs, testicular and prostatic atrophy and

oligospermia were observed at 0.2 mg/kg/day IV for three months (0.6 times the

maximum human exposure of 8 mg, based on BSA), and testicular atrophy and/or

mineralisation at 0.03 mg/kg IV dosed every two to three days for six months (0.1 times

the maximum human exposure of 8 mg, based on BSA). Female dogs had decreased

weights of ovaries and uterus, correlated with anoestrus and, in some animals, with

vaginal epithelial degeneration at 0.01 mg/kg/day IV (0.03 times the maximum human

exposure of 8 mg, based on BSA).

Use in pregnancy. (Category B3)

Zoledronic acid was administered subcutaneously to rats and rabbits during the foetal

organogenesis period. In rats, increased malformations were seen at 0.2 mg/kg/day (1.5

times

expected

human

exposure

based

AUC),

increased

postimplantation loss occurred at 0.4 mg/kg/day (three times the human exposure). No

embryofoetal effects were observed at 0.1 mg/kg/day (0.7 times the human exposure).

In rabbits, zoledronic acid increased late resorptions at 0.03 mg/kg/day and above (0.07

times the highest clinical dose, based on BSA). Maternal toxicity was apparent in rabbits

Zoledronic acid Actavis – Product information

Page 8 of 8

Zoledronic acid Actavis PI/05/12/2018/5

at these doses.

In the absence of adequate available experience in human pregnancy, ZOLEDRONIC ACID

ACTAVIS should not be used during pregnancy.

Use in lactation

Studies have not been performed in lactating animals, and the transfer of zoledronic acid

into milk is unknown. Because many drugs are excreted in human milk, breastfeeding

should be discontinued before ZOLEDRONIC ACID ACTAVIS administration.

EFFECTS ON ABILITY TO DRIVE AND USE MACHINES

No studies on the effects on the ability to drive and use machines have been performed.

ADVERSE EFFECTS (UNDESIRABLE EFFECTS)

Overview of clinical trial data

Frequencies of adverse reactions to zoledronic acid 4 mg are mainly based on data

collected from chronic treatment. Adverse reactions to zoledronic acid are usually mild

and transient and similar to those reported for other bisphosphonates. These reactions

can be expected to occur in approximately one-third of patients who receive either

zoledronic acid 4 mg or pamidronate 90 mg. IV administration has been most commonly

associated with a flu-like syndrome in approximately 9% of patients, consisting of bone

pain,

fever,

fatigue

rigors.

Arthralgia

myalgia

have

been

reported

approximately 3% of patients. In most cases no specific treatment is required and the

symptoms subside after a couple of hours/days.

Frequently, the reduction in renal calcium excretion is accompanied by a fall in serum

phosphate levels in approximately 20% of patients, which is asymptomatic and does not

require treatment. The serum calcium may fall to asymptomatic hypocalcaemic levels in

approximately 3% of patients.

Gastrointestinal reactions such as nausea (5.8%) and vomiting (2.6%) have been reported

following intravenous infusion of zoledronic acid. Anorexia was reported in 1.5% of

patients treated with zoledronic acid 4 mg.

Local reactions at the infusion site such as redness or swelling and/or pain were also

observed in less than 1% of patients.

Some cases of rash, pruritus and chest pain have been observed.

As with other bisphosphonates, cases of conjunctivitis in approximately 1% of patients

and cases of hypomagnesaemia have been reported.

There

have

been

some

reports

impaired

renal

function

(2.3%)

with

chronic

administration of zoledronic acid 4 mg. However, other risk factors in this severely ill

patient population may have contributed as well.

In clinical trials of patients with tumour induced hypercalcaemia, grade 3 (NCI Common

Toxicity Criteria (CTC)) elevations of serum creatinine were seen in 2.3, 3.1 and 3.0% of

patients receiving zoledronic acid 4 mg, zoledronic acid 8 mg and pamidronate 90 mg,

respectively, as expected in this disease state and with this class of compounds.

However, other risk factors in this severely ill patient population may have contributed as

Zoledronic acid Actavis – Product information

Page 9 of 9

Zoledronic acid Actavis PI/05/12/2018/5

well.

While not observed with zoledronic acid, administration of other bisphosphonates has

been

associated

with

bronchoconstriction

aspirin

(acetylsalicylic

acid)

sensitive

asthmatic patients.

The following adverse drug reactions have been accumulated from clinical studies

following predominately chronic treatment with zoledronic acid.

Adverse

reactions

ranked

under

headings

frequency,

using

following

convention: very common (≥ 1/10), common (≥ 1/100, < 1/10), uncommon (≥ 1/1,000, <

1/100), rare (≥ 1/10,000, < 1/1,000), very rare (< 1/10,000), including isolated reports.

Blood and lymphatic system

Common: anaemia.

Uncommon: thrombocytopenia, leucopenia.

Rare: pancytopenia.

Cardiovascular

Common: hypertension

Uncommon: hypotension.

Rare: bradycardia.

Common: conjunctivitis.

Uncommon: blurred vision.

Very rare: uveitis, episcleritis.

Gastrointestinal

Common: nausea, vomiting, anorexia, constipation.

Uncommon: diarrhoea, abdominal pain, dyspepsia, stomatitis, dry mouth.

General disorders and administration site conditions

Common: acute phase reaction, asthenia, peripheral oedema, fever, flu-like syndrome

(including fatigue, rigors, malaise and flushing).

Uncommon:,

injection

site

reactions

(including

pain,

irritation,

redness,

swelling,

induration), chest pain, weight increase.

Immune system

Uncommon: hypersensitivity reaction.

Rare: angioneurotic oedema.

Musculoskeletal, connective tissue and bone

Common: bone pain, myalgia, arthralgia, joint stiffness, generalised pain.

Uncommon: osteonecrosis of the jaw (ONJ), muscle cramps.

Nervous system

Common: paraesthesia, headache.

Uncommon: dizziness, taste disturbance, hypoaesthesia, hyperaesthesia, tremor.

Psychiatric disorders

Common: sleep disturbance

Zoledronic acid Actavis – Product information

Page 10 of 10

Zoledronic acid Actavis PI/05/12/2018/5

Uncommon: anxiety,.

Rare: confusion.

Renal and urinary

Common: renal impairment.

Uncommon: acute renal failure, haematuria, proteinuria.

Respiratory, thoracic and mediastinal disorders

Uncommon: dyspnoea, cough.

Rare: dyspnoea, cough.

Skin and subcutaneous tissue

Common: hyperhidrosis

Uncommon: pruritus, rash (including erythematous and macular rash).

Post marketing Experience

The following adverse reactions have been reported during postapproval use of zoledronic

acid. Because these reports are from a population of uncertain size and are subject to

confounding factors, it is not possible to reliably estimate their frequency or establish a

causal relationship to drug exposure.

Cases of osteonecrosis (primarily of the jaws) have been reported predominately in

cancer patients treated with bisphosphonates, including zoledronic acid (uncommon).

Many of these patients had signs of local infection including osteomyelitis and the

majority of the reports refer to cancer patients following tooth extractions or other

dental surgeries. ONJ has multiple well documented risk factors including a diagnosis of

cancer, concomitant therapies (e.g. chemotherapy, radiotherapy, corticosteroids) and

comorbid conditions (e.g. anaemia, coagulopathies, infection, pre-existing oral disease).

Although causality has not been determined, it is prudent to avoid dental surgery as

recovery may be prolonged (see 4.4 Special warnings and Precautions for use). Data

suggest a greater frequency of reports of ONJ based on tumour type (advanced breast

cancer, multiple myeloma).

The following events have also been reported: hypotension leading to syncope or

circulatory collapse, primarily in patients with underlying risk factors, atrial fibrillation,

somnolence, bronchoconstriction, bronchospasm, interstitial lung disease, anaphylactic

reaction/shock, urticaria, uvetis, episcleritis, scleritis and orbital inflammation, severe

and occasionally incapacitating bone, joint, and/or muscle pain, atypical subtrochanteric

diaphyseal

femoral

fractures

(bisphosphonate

class

adverse

reaction,

including

zoledronic acid).

Acute phase reaction: This adverse drug reaction consists of a constellation of symptoms

that includes pyrexia, fatigue, bone pain, chills, and influenza-like illness. The onset time

is ≤ 3 days post zoledronic acid infusion, and the reaction is also referred to using the

terms “flu-like” or “post-dose” symptoms; these symptoms usually resolve within a few

days.

Reporting suspected adverse effects

Reporting suspected adverse reactions after registration of the medicinal product is

important. It allows continued monitoring of the benefit-risk balance of the medicinal

product. Healthcare professionals are asked to report any suspected adverse reactions at

http://www.tga.gov.au/reporting-problems

Zoledronic acid Actavis – Product information

Page 11 of 11

Zoledronic acid Actavis PI/05/12/2018/5

OVERDOSE

Clinical experience with acute overdosage of zoledronic acid is limited. Patients who

have received doses higher than those recommended should be carefully monitored, since

renal function impairment (including renal failure) and serum electrolyte (including

calcium, phosphorus and magnesium) abnormalities have been observed. In the event of

hypocalcaemia,

calcium

gluconate

infusions

should

administered

clinically

indicated.

For information on the management of overdose, contact the Poison Information Centre

on 131126 (Australia).

5. PHARMACOLOGICAL PROPERTIES

5.1

PHARMACODYNAMIC PROPERTIES

Mechanism of action

Zoledronic acid is a bisphosphonate, potently inhibiting osteoclastic bone resorption.

Bisphosphonates have a high affinity for mineralised bone, but the precise molecular

mechanism leading to the inhibition of osteoclastic activity is still unclear. In long-term

studies in adult animals, zoledronic acid inhibits bone resorption and increases bone

mineralisation without adversely affecting the formation or mechanical properties of

bone.

Clinical studies in tumour induced hypercalcaemia demonstrated that the effect of

zoledronic acid is characterised by decreases in serum calcium and urinary calcium

excretion.

Preclinical studies demonstrate that, in addition to its inhibitory activity against bone

resorption, zoledronic acid possesses the following properties that could contribute to its

overall efficacy in the treatment of metastatic bone disease:

In vivo: antitumour activity in some animal models, antiangiogenic activity, antipain

activity.

In vitro: inhibition of osteoclast proliferation, cytostatic and proapoptotic activity on

tumour cells at concentrations greater than the clinical Cmax, synergistic cytostatic

effect with other anticancer drugs.

Clinical Trials

Prevention of skeletal related events in patients with advanced malignancies involving

bone Three randomised, double blind studies (039, 010, 011) were conducted to assess

the efficacy of zoledronic acid in preventing skeletal related events (SREs) in patients

with advanced malignancies involving bone. The primary efficacy variable was the

proportion of patients experiencing at least one SRE, defined as radiation therapy to

bone, surgery to bone, pathological bone fracture or spinal cord compression.

In study 039, zoledronic acid was compared to placebo for the prevention of SREs in

prostate cancer patients with 214 men receiving zoledronic acid 4 mg intravenous (IV)

infusion every three weeks versus 208 receiving placebo (IV infusion of saline). After the

initial 15 months of treatment, 186 patients continued for up to an additional nine

months, giving a total duration of double blind therapy up to 24 months. Zoledronic acid

Zoledronic acid Actavis – Product information

Page 12 of 12

Zoledronic acid Actavis PI/05/12/2018/5

4 mg significantly reduced the proportion of patients with SRE (p = 0.028) and delayed

the time to first SRE (p = 0.009). Multiple event analysis showed 36% relative risk

reduction in developing SREs in the zoledronic acid group compared with placebo (p =

0.002). Pain was measured at baseline and periodically throughout the trial. Patients

receiving zoledronic acid reported less increase in pain than those receiving placebo, and

the differences reached significance at months 21 (p = 0.014) and 24 (p = 0.024). The

treatment effects were less pronounced in patients with blastic lesions. Efficacy results

are summarised in Table 2.

Table 2. Efficacy results (prostate cancer patients with biochemical progression of

disease while receiving first-line hormonal therapy)

Any SRE (-TIH)*

Fractures**

Radiation therapy to

bone

Zoledroni

4 mg

Placebo

Zoledroni

4 mg

Placebo

Zoledroni

4 mg

Placebo

Number of patients

214

214

Proportion

patients with SREs

38

26

Difference

(95%

CI)1

-10.7

(-20.2, -1.3)

-7.7

(-15.4, 0.0)

-7.0

(-15.7, 1.7)

Median time to SRE

(days)

488

NR***

NR

Hazard

ratio

time

(95%

CI)2

0.68

(0.51, 0.91)

0.60

(0.39, 0.92)

0.71

(0.50, 1.01)

Hazard

ratio

multiple

event

analysis (95% CI)3

0.64

(0.49, 0.85)

NA

confidence

intervals

differences

based

normal

approximation of the differences

The 95% confidence intervals for the hazard ratios are derived from the estimates

of Cox regression analysis

The 95% confidence intervals for the hazard ratios are derived from estimates of

robust variances

*

SRE (-TIH) = skeletal related event excluding tumour induced hypercalcaemia

includes vertebral and nonvertebral fractures

NR = not reached

In a second phase III randomised, double blind trial (study 010) comparing zoledronic acid

4 mg to pamidronate 90 mg, 1,116 patients (561 zoledronic acid 4 mg, 555 pamidronate

90 mg) with multiple myeloma or breast cancer with at least one bone lesion were

treated with zoledronic acid 4 mg IV infusion every three to four weeks or pamidronate

90 mg IV infusion every three to four weeks. 606 patients entered the 12 month, double

blind extension phase. Total therapy lasted up to 24 months. The results demonstrated

that zoledronic acid 4 mg showed comparable efficacy to pamidronate 90 mg in the

prevention of SREs The multiple event analysis did not reveal a significant difference

between the two treatments (p = 0.059). Efficacy results are provided in Table 3.

Table 3. Efficacy results (breast cancer and multiple myeloma patients)

Zoledronic acid Actavis – Product information

Page 13 of 13

Zoledronic acid Actavis PI/05/12/2018/5

Any SRE (-TIH)*

Fractures**

Radiation therapy to

bone

Zoledroni

4 mg

90 mg

Zoledroni

4 mg

90 mg

Zoledroni

4 mg

90 mg

Number of patients

561

561

Proportion

patients with SREs

47

19

Difference

(95%

CI)1

-3.4

(-9.3, 2.5)

-1.1

(-6.8, 4.6)

-5.2

(-10.1, -0.4)

Median time to SRE

(days)

377

NR***

NR

Hazard

ratio

time

(95%

CI)2

0.89

(0.75, 1.06)

0.96

(0.79, 1.16)

0.75

(0.58, 0.97)

Hazard

ratio

multiple

event

analysis (95% CI)3

0.86

(0.74, 1.01)

NA

confidence

intervals

differences

based

normal

approximation of the differences

The 95% confidence intervals for the hazard ratios are derived from the estimates

of Cox regression analysis

The 95% confidence intervals for the hazard ratios are derived from estimates of

robust variances

SRE (-TIH) = skeletal related event excluding tumour induced hypercalcaemia

includes vertebral and nonvertebral fractures

NR = not reached

= pamidronate

In the third trial (study 011), zoledronic acid 4 mg IV infusion every three weeks (n = 257)

was compared with placebo (IV infusion of saline; n = 250) in patients with other solid

tumours involving bone. The tumours included non-small cell lung cancer (approximately

50% of subjects), renal cell cancer, thyroid cancer, head and neck cancer and other solid

tumours. These patients had a median survival of only six months. After initial nine

months of treatment, 101 patients entered the 12 month double blind extension study,

and 26 completed the full 21 months. Zoledronic acid 4 mg showed a trend to reduce the

proportion of patients with SRE (p = 0.127) and significantly delayed the time to first SRE

(p = 0.03). Multiple event analysis showed 28% relative risk reduction in developing

skeletal related events in the zoledronic acid group compared with placebo (p = 0.01).

The treatment effect in non-small cell lung cancer patients appeared to be smaller than

in patients with other solid tumours. Efficacy results are provided in Table 4.

Table 4 Efficacy results (non-small cell lung cancer and other tumours)

Any SRE (-TIH)*

Fractures**

Radiation therapy to

bone

Zoledroni

4 mg

Placebo

Zoledroni

4 mg

Placebo

Zoledroni

4 mg

Placebo

Number of patients

257

257

Proportion

patients with SREs

39

29

Zoledronic acid Actavis – Product information

Page 14 of 14

Zoledronic acid Actavis PI/05/12/2018/5

Difference

(95%

CI)1

-6.7

(-15.3, 1.9)

-6.4

(-13.2, 0.4)

-5.6

(-13.7, 2.5)

Median time to SRE

(days)

236

NR***

424

Hazard

ratio

time

(95%

CI)2

0.74

(0.56, 0.97)

0.62

(0.41, 0.93)

0.76

(0.55, 1.03)

Hazard

ratio

multiple

event

analysis (95% CI)3

0.72

(0.56, 0.92)

confidence

intervals

differences

based

normal

approximation of the differences

The 95% confidence intervals for the hazard ratios are derived from the estimates

of Cox regression analysis

The 95% confidence intervals for the hazard ratios are derived from estimates of

robust variances

SRE (-TIH) = skeletal related event excluding tumour induced hypercalcaemia

includes vertebral and nonvertebral fractures

NR = not reached

Zoledronic acid was also studied in a double blind, randomised, placebo controlled trial in

228 Japanese patients with documented bone metastases from breast cancer. This study

evaluated the effect of zoledronic acid on the SRE rate ratio, calculated as the total

number of SRE events (adjusted for the presence of prior pathological fracture), divided

by the total risk period. Patients received either zoledronic acid 4 mg or placebo every

four weeks for one year. Patients were evenly distributed between Zoledronic acid

treated and placebo groups.

The SRE rate ratio at one year was 0.61, indicating that treatment with zoledronic acid

reduced the rate of occurrence of SREs by 39% compared with placebo (p = 0.027). The

proportion of patients with at least one SRE (excluding hypercalcaemia) was 29.8% in the

zoledronic acid treated group versus 49.6% in the placebo group (p = 0.003). Zoledronic

acid significantly delayed the time of onset of the first SRE compared with placebo

(median not reached versus 364 days; p = 0.007). Zoledronic acid reduced the risk of

SREs by 41% in a multiple event analysis (risk ratio = 0.59, p = 0.019) compared with

placebo. In the zoledronic acid treated group, statistically significant improvement (p <

0.05) in pain scores, a complication of bone metastases, (using the Brief Pain Inventory,

BPI) was seen at four weeks and at every subsequent time point during the study, when

compared to placebo. The pain score for zoledronic acid was consistently below

baseline.

Tumour induced hypercalcaemia

identical

multicentre,

randomised,

double

blind,

double

dummy

studies

zoledronic acid 4 or 8 mg given as a five minute infusion or pamidronate 90 mg given as a

two hour infusion were conducted in patients with tumour induced hypercalcaemia (TIH).

TIH was defined as corrected serum calcium (CSC) concentration of ≥ 3.00 mmol/L. The

primary efficacy variable was the proportion of patients having a complete response,

defined as the lowering of the CSC to ≤ 2.70 mmol/L within ten days after drug infusion.

Each

treatment

group

considered

efficacious

lower

bound

confidence interval for the proportion of complete responders was > 70%. This was

achieved for the zoledronic acid 4 and 8 mg groups in each study, but not for the

pamidronate 90 mg group. To assess the effects of zoledronic acid versus those of

Zoledronic acid Actavis – Product information

Page 15 of 15

Zoledronic acid Actavis PI/05/12/2018/5

pamidronate, the two multicentre TIH studies were combined in a preplanned analysis.

The results showed that zoledronic acid 4 and 8 mg were statistically superior to

pamidronate 90 mg for the proportion of complete responders at day 7 and 10. The

results also demonstrated a faster normalisation of CSC by day 4 for zoledronic acid 8 mg

and by day 7 for zoledronic acid 4 and 8 mg doses.

The response rates shown in Table 5 were observed.

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

Treatment

Day 4

Day 7

Day 10

Zoledronic acid 4 mg (n

= 86)

Zoledronic acid 8 mg (n

= 90)

Pamidronate 90 mg (n =

99)

45.3%

0.104)

55.6%

0.021)

33.3%

82.6%

0.005)*

83.3%

0.010)*

63.36%

88.4% (p = 0.002)*

86.7% (p = 0.015)

69.7%

P-values versus pamidronate 90 mg based on Cochran-Mantel Haenszel adjusting for

baseline CSC

*P-values denote statistical superiority over pamidronate

There were no statistically significant differences between the two zoledronic acid doses.

Secondary efficacy variables, time to relapse and duration of complete response were

also assessed (see Table 5). Time to relapse was defined as the duration (in days) from

study infusion until the last CSC value ≤ 2.90 mmol/L. Patients who did not have a

complete response were assigned a time to relapse of 0 days. Duration of complete

response was defined as the duration (in days) from the occurrence of a complete

response until the last CSC ≤ 2.70 mmol/L. The results showed that both zoledronic acid

doses had a statistically longer time to relapse than pamidronate. There was no

statistically significant difference between the zoledronic acid doses.

Table 6 Results for secondary efficacy variables in the combined TIH studies

Zoledronic acid 4 mg

Zoledronic acid 8 mg

Pamidronate

90 mg

Media

(days)

value

Media

(days)

Median

(days)

Media

(days)

Time to relapse

Duration

complete

response

86

76

30

32

0.001*

NA

90

78

40

43

0.007*

NA

99

69

17

18

P-values versus pamidronate 90 mg based on Cox regression adjusted for baseline CSC

NA: Duration of complete response was not analysed in the subset of complete responders

*P-values denote statistical superiority over pamidronate

Retreatment with zoledronic acid 8 mg was allowed for patients in any of the treatment

arms whose serum calcium did not return to normal or remain normal after initial

treatment. A minimum of seven days was allowed to elapse before retreatment to allow

for full response to the initial dose. In clinical studies, 69 patients have received a

second infusion of zoledronic acid 8 mg for hypercalcaemia. The complete response rate

Zoledronic acid Actavis – Product information

Page 16 of 16

Zoledronic acid Actavis PI/05/12/2018/5

observed in these retreated patients was 52%. Although these studies used doses of 8 mg

and an infusion time of five minutes, subsequent safety data have indicated that such

dosage regimens are associated with an increased risk of renal impairment. Therefore,

doses of zoledronic acid should not exceed 4 mg and should not be administered over less

than 15 minutes (see 4.4 Special warnings and Precautions for use).

5.2

PHARMACOKINETIC PROPERTIES

Single 5 and 15 minute infusions of zoledronic acid 2, 4, 8 and 16 mg in 32 patients with

bone metastases yielded the following pharmacokinetic data, which were found to be

dose independent.

Absorption

Zoledronic acid is administered by IV infusion. By definition, absorption is complete at

the end of the infusion.

Distribution

Zoledronic acid shows no affinity for the cellular components of blood. Protein binding is

dependent on calcium ions and possibly other cations present in plasma. Plasma protein

binding in heparinised plasma from healthy subjects is moderate (approximately 60%) and

independent of the concentration of zoledronic acid.

Excretion

Intravenously administered zoledronic acid is eliminated by a triphasic process: rapid

biphasic disappearance from the systemic circulation, with half-lives of 0.23 and 1.75

hours, followed by a long elimination phase with a terminal elimination half-life of 167

hours. Zoledronic acid is not metabolised and is excreted unchanged via the kidney.

Over the first 24 hours, 39 to 46% of the administered dose is recovered in the urine,

while the remainder is principally bound to bone tissue. From the bone tissue it is

released slowly back into the systemic circulation and eliminated via the kidney with a

half-life of at least 167 hours. The total body clearance is 3.7 to 4.7 L/hour, independent

of dose, and unaffected by gender, age, race and bodyweight. Increasing the infusion

time from 5 to 15 minutes caused a 30% decrease in zoledronic acid concentration at the

end of the infusion, but had no effect on the area under the plasma concentration versus

time curve.

Special Populations

pharmacokinetic

data

zoledronic

acid

available

patients

with

hypercalcaemia or in patients with hepatic insufficiency. Zoledronic acid does not inhibit

human P450 enzymes in vitro, shows no biotransformation and, in animal studies, < 3% of

the administered dose was recovered in the faeces, suggesting no relevant role of liver

function in the pharmacokinetics of zoledronic acid.

Renal insufficiency

The renal clearance of zoledronic acid was significantly positively correlated with

creatinine clearance, renal clearance representing 75 ± 33% of the creatinine clearance,

which showed a mean of 84 ± 29 mL/min (range 22 to 143 mL/min) in the 64 cancer

patients

studied.

Population

analysis

showed

that,

patient

with

creatinine

clearance

mL/minute

(severe

renal

impairment)

mL/min

(moderate

impairment), the corresponding predicted clearance of zoledronic acid would be 37 or

72%, respectively, of that of a patient showing creatinine clearance of 84 mL/min. Only

limited pharmacokinetic data are available in patients with severe renal insufficiency

(creatinine clearance < 30 mL/min) (see 4.4 Special warnings and Precautions for use).

Zoledronic acid Actavis – Product information

Page 17 of 17

Zoledronic acid Actavis PI/05/12/2018/5

5.3

PRECLINICAL SAFETY DATA

Genotoxicity

Zoledronic acid was not mutagenic in bacterial reverse mutation tests in Salmonella

typhimurium

Escherichia

coli

cultured

Chinese

hamster

lung

cells.

Zoledronic acid did not induce chromosome aberrations in an in vitro test in Chinese

hamster ovary cells or in an in vivo micronucleus test in rats.

Carcinogenicity

In carcinogenicity studies, zoledronic acid was administered orally by gavage to rats and

mice at daily doses of 0.1, 0.5 and 2.0 mg/kg and 0.1, 0.3 and 1.0 mg/kg, respectively,

for at least 104 weeks without evidence of carcinogenic potential. Chronic parenteral

administration was not feasible given the potential of the compound to cause severe local

irritation. The pharmacological bone changes typically observed following long-term

bisphosphonate administration to young

animals with growing skeletons gave clear

evidence of systemic exposure to zoledronic acid in both species at all doses.

6. PHARMACEUTICAL PARTICULARS

6.1

LIST OF EXCIPIENTS

Refer to section 2 & 3– Qualitative and Quantitative Composition & Pharmaceutical form

6.2

INCOMPATIBILITIES

Studies with glass bottles, as well as several types of infusion bags and infusion lines

made from polyvinylchloride, polyethylene and polypropylene (prefilled with sodium

chloride 0.9% solution or glucose 5% solution), showed no incompatibility with zoledronic

acid.

To avoid potential incompatibilities, ZOLEDRONIC ACID ACTAVIS concentrated solution is

to be diluted with sodium chloride 0.9% solution or glucose 5% solution.

ZOLEDRONIC ACID ACTAVIS must not be mixed with calcium or other divalent cation

containing

infusion

solutions,

such

lactated

Ringer's

solution,

should

administered as a single IV solution in a line separate from all other drugs

6.3

SHELF LIFE

In Australia, information on the shelf life can be found on the public summary of the

Australian Register of Therapeutic Goods (ARTG). The expiry date can be found on the

packaging

6.4

SPECIAL PRECAUTIONS FOR STORAGE

Store below 30°C.

6.5

NATURE AND CONTENTS OF CONTAINER

4 mg/5 mL zoledronic acid concentrated solution for injection (sterile concentrate for

appropriate dilution for IV infusion), 4 mg (

zoledronic acid monohydrate 4.264

Zoledronic

Zoledronic

mg):

Plastic Vi

Pack Size

1 vial

6.6

SPEC

In Australi

with local

6.7

PHYS

Chemical s

The che

diphospho

Molecular

CAS Num

CAS No.: 1

7. MED

PRESCRIPT

8. SPON

Medis Pha

Suite 100

North Sydn

Australia

c acid Acta

acid Actav

1's.Conta

CIAL PRECA

ia, any un

requireme

SICOCHEM

structure

mical name

onic acid m

weight: 2

165800-06

ICINE S

TION ONLY

NSOR

rma Pty Lt

2, 53 Walke

ney, NSW 2

avis

– Prod

is PI/05/12/

iner type

AUTIONS F

used medi

ents.

MICAL PROP

e for zole

monohydrat

∙H2O

90.11

6-6

SCHEDU

Y MEDICINE

td

er Street

2060,

duct informa

/2018/5

FOR DISPO

icine or wa

PERTIES

edronic aci

te. Its stru

ULE (PO

ES - S4

ation

OSAL

aste mater

id is 1-hy

uctural for

OISON S

rial should

ydroxy-2- (

rmula is:

STANDA

d be dispos

(1H-imidaz

ARD)

sed of in a

zol-1-yl)et

ge 18 of 18

accordance

hane- 1,1

Zoledronic acid Actavis – Product information

Page 19 of 19

Zoledronic acid Actavis PI/05/12/2018/5

9. DATE OF FIRST APPROVAL

26 July 2012

10. DATE OF REVISION

8 February 2019

Summary table of cha

nges

Section changed

Summary of new information

---

PI reformatting as per new TGO 91

8

Sponsor address updated as per current ARTG