Drugs List

Therapeutic Indications

Uses

Hypercalcaemia due to malignant disease
Prevention of skeletal related events in advanced malignancy involving bone

Administration

For intravenous infusion only.

Preparation prior to administration is not consistent for all available preparations of zoledronic acid. Consult individual product information for details.

Contraindications

Children under 18 years
Breastfeeding
Pregnancy
Renal impairment - creatinine clearance below 30 ml/minute

Precautions and Warnings

Dehydration
Renal impairment - creatinine clearance 30-60ml/minute
Unhealed lesions from dental or oral surgery

Avoid overhydration in patients at risk of cardiac failure
Sodium content of formulation may be significant
Advise ability to drive/operate machinery may be affected by side effects
Consider a dental exam & appropriate preventive dentistry before treatment
Correct serum calcium levels before commencing treatment
Maintain adequate hydration of patient prior / during treatment
Not all available brands are licensed for all indications
Not all available strengths are licensed for all indications
Prevention of skeletal events:Give 500mg calcium + 400units vitamin D daily
Treatment to be administered under the supervision of a specialist
Consider short term supplementation of Ca, Mg or phosphate if necessary
Ensure patient's dietary intake of calcium and vitamin D is adequate
Monitor serum calcium levels regularly from starting treatment
Monitor serum creatinine before each dose
Monitor serum magnesium regularly
Monitor serum phosphate levels
Advise patient to report any ear pain, discharge or infection
Advise patient to report any new thigh, hip or groin pain
Consider osteonecrosis of external auditory canal if ear symptoms occur
Withdraw if renal function deteriorates: reinstate when within 10% baseline
Consider withholding treatment if osteonecrosis of the jaw occurs
Discontinue bisphosphonates permanently if atypical stress fracture occurs
Female: Ensure adequate contraception during treatment
Advise patient of need for high oral hygiene standards
Advise patient to report any dental mobility, pain or swelling
Give patient package leaflet and patient reminder card
Patient to inform dentist of bisphosphonate use: avoid invasive procedures
Prevention of skeletal related events - onset of effect is 2-3 months

Osteonecrosis of the jaw (ONJ) has been reported in patients treated with bisphosphonates. Risk factors include cancer with bone lesions, concomitant therapy (e.g. chemotherapy, antiangiogenic biologics, corticosteroids, radiotherapy to head and neck), poor oral hygiene, invasive dental procedures including extractions and dental implants, co-morbid disorders (e.g. pre-existing dental disease, anaemia, coagulopathy, infection) and previous treatment with bisphosphonates.

Dental examination (with appropriate preventative procedures) prior to initiating treatment is recommended, particularly in patients with risk factors for ONJ. Patients should maintain good oral hygiene throughout treatment and attend regular routine dental check-ups. Invasive dental procedures should be avoided where possible, particularly during the initial stages of treatment. In patients that have unhealed, open soft tissue lesions within the mouth, treatment should be delayed. Should ONJ occur, treatment should be withheld and a dentist or oral surgeon with expertise in ONJ consulted regarding ongoing management.

Osteonecrosis has also been reported at other sites including the external auditory canal, hip and femur. Osteonecrosis of the external auditory canal should be considered if patients report ear symptoms including chronic ear infections. Risk factors include infection or trauma in the ear and/or use of concomitant steroids and chemotherapy. Cases are more frequent in long term treatment.

Atypical stress fractures of the proximal femoral shaft with poor healing have been reported during treatment with another bisphosphonate, alendronic acid. Evidence to support a relationship with zoledronic acid is limited however a causal link cannot be excluded. Should a patient develop an atypical stress fracture, treatment with all bisphosphonates should be permanently discontinued.

Pregnancy and Lactation

Pregnancy

Zoledronic acid is contraindicated in pregnancy.

There are no adequate data on the use of zoledronic acid in pregnant women. Animal reproduction studies with zoledronic acid have shown reproductive toxicity. Dystocia was observed at the lowest dose (0.01 mg/kg bodyweight) tested in the rat. The potential risk for humans is unknown.

Schaefer (2007) states that accidental use of individual doses of bisphosphonates in the first trimester do not justify either interruption of the pregnancy or additional diagnostic procedures.

The use of all medication in pregnancy should be avoided whenever possible; particularly in the first trimester. Non-drug treatments should also be considered. When essential, a medication with the best safety record over time should be chosen, employing the lowest effective dose for the shortest possible time. Polypharmacy should be avoided. Teratogens taken in the pre-embryonic period, often quoted as lasting until 14 to 17 days post-conception, are believed to have an all-or-nothing effect. Where drugs have a short half-life, and when the date of conception is certain, this may allow women to be reassured where drug exposure has occurred within this time frame. Further advice may be available from the UK National Teratology Information Service (NTIS) and through ToxBase, available via password on the internet ( www.toxbase.org ) or if this is unavailable at the backup site ( www.toxbasebackup.org ).

Lactation

Zoledronic acid is contraindicated during breastfeeding.

Briggs (2011) states that it is not known whether zoledronic acid is excreted into human milk. The molecular weight (about 290 for the hydrated form), lack of metabolism, low plasma protein binding, plasma half life and the prolonged terminal elimination half life suggest that the drug will be excreted into breast milk. Detectable amounts of the drug are measured in adult plasma for less than 28 days post dose. Although the low lipid solubility of zoledronic acid may limit the amount present in milk, and maternal treatment may be compatible with nursing, until data are available the best course is not to breastfeed.

Neonates, infants born prematurely, those with low birth weight, those with an unstable gastrointestinal function or who have serious illnesses may require special consideration. For any infant, if a drug is prescribed to the nursing mother, it should be at the lowest practical dose and for the shortest time. When drug administration is unavoidable and breastfeeding is to continue, minimisation of exposure of the infant to the drug may sometimes be achieved by timing the maternal doses to just after a feeding episode. Infants exposed to drugs via breast milk should be monitored for unusual signs or symptoms. Interactions between the drug received by the infant from the mother's milk and medication prescribed for the infant should also be considered, for example, when the drug given to the infant may prevent metabolism of the drug received via breast milk.
Specialist advice is available from the UK Drugs in Lactation Advisory Service at https://www.midlandsmedicines.nhs.uk/content.asp?section=6&subsection=17&pageIdx=1

Side Effects

Abdominal pain
Acute phase reaction
Acute renal failure
Anaemia
Anaphylactic shock
Angioneurotic oedema
Anorexia
Anxiety
Arthralgia
Arthritis
Asthenia
Atrial fibrillation
Atypical femoral fracture
Blurred vision
Bone pain
Bradycardia
Bronchoconstriction
Circulatory collapse
Confusion
Conjunctivitis
Constipation
Cough
Decreased appetite
Dehydration
Deterioration of renal function in pre-existing renal disease
Diarrhoea
Dizziness
Dry mouth
Dysgeusia
Dyspepsia
Dyspnoea
Episcleritis
Erythema
Fatigue
Flushing
Haematuria
Headache
Hyperaesthesia
Hyperhidrosis
Hyperkalaemia
Hypernatraemia
Hypersensitivity reactions
Hypertension
Hypoaesthesia
Hypocalcaemia
Hypokalaemia
Hypomagnesaemia
Hypophosphataemia
Hypotension
Increase in blood urea or creatinine
Influenza-like syndrome
Injection site reactions
Interstitial lung disease
Iritis
Joint swelling
Lethargy
Leucopenia
Malaise
Muscle spasm
Muscular cramps
Myalgia
Nasopharyngitis
Nausea
Non-cardiac chest pain
Ocular hyperaemia
Orbital inflammation
Osteomyelitis
Osteonecrosis (primarily of the jaw)
Osteonecrosis of the external auditory canal
Pain
Palpitations
Pancytopenia
Paraesthesia
Peripheral oedema
Pollakiuria
Proteinuria
Pruritus
Pyrexia
Raised C-reactive protein
Rash
Renal impairment
Rigors
Scleritis
Sleep disturbances
Somnolence
Stiffness
Stomatitis
Syncope
Taste disturbances
Thirst
Thrombocytopenia
Tooth ache
Tremor
Urticaria
Uveitis
Vertigo
Vomiting
Weight gain

Presentation

Infusions of zoledronic acid.

Drugs List

Therapeutic Indications

Uses

Hypercalcaemia due to malignant disease
Prevention of skeletal related events in advanced malignancy involving bone

Dosage

Adults

Patients with Renal Impairment

Administration

For intravenous infusion only.

Preparation prior to administration is not consistent for all available preparations of zoledronic acid. Consult individual product information for details.

Contraindications

Children under 18 years
Breastfeeding
Pregnancy
Renal impairment - creatinine clearance below 30 ml/minute

Precautions and Warnings

Dehydration
Renal impairment - creatinine clearance 30-60ml/minute
Unhealed lesions from dental or oral surgery

Avoid overhydration in patients at risk of cardiac failure
Sodium content of formulation may be significant
Advise ability to drive/operate machinery may be affected by side effects
Consider a dental exam & appropriate preventive dentistry before treatment
Correct serum calcium levels before commencing treatment
Maintain adequate hydration of patient prior / during treatment
Not all available brands are licensed for all indications
Not all available strengths are licensed for all indications
Prevention of skeletal events:Give 500mg calcium + 400units vitamin D daily
Treatment to be administered under the supervision of a specialist
Consider short term supplementation of Ca, Mg or phosphate if necessary
Ensure patient's dietary intake of calcium and vitamin D is adequate
Monitor serum calcium levels regularly from starting treatment
Monitor serum creatinine before each dose
Monitor serum magnesium regularly
Monitor serum phosphate levels
Advise patient to report any ear pain, discharge or infection
Advise patient to report any new thigh, hip or groin pain
Consider osteonecrosis of external auditory canal if ear symptoms occur
Withdraw if renal function deteriorates: reinstate when within 10% baseline
Consider withholding treatment if osteonecrosis of the jaw occurs
Discontinue bisphosphonates permanently if atypical stress fracture occurs
Female: Ensure adequate contraception during treatment
Advise patient of need for high oral hygiene standards
Advise patient to report any dental mobility, pain or swelling
Give patient package leaflet and patient reminder card
Patient to inform dentist of bisphosphonate use: avoid invasive procedures
Prevention of skeletal related events - onset of effect is 2-3 months

Osteonecrosis of the jaw (ONJ) has been reported in patients treated with bisphosphonates. Risk factors include cancer with bone lesions, concomitant therapy (e.g. chemotherapy, antiangiogenic biologics, corticosteroids, radiotherapy to head and neck), poor oral hygiene, invasive dental procedures including extractions and dental implants, co-morbid disorders (e.g. pre-existing dental disease, anaemia, coagulopathy, infection) and previous treatment with bisphosphonates.

Dental examination (with appropriate preventative procedures) prior to initiating treatment is recommended, particularly in patients with risk factors for ONJ. Patients should maintain good oral hygiene throughout treatment and attend regular routine dental check-ups. Invasive dental procedures should be avoided where possible, particularly during the initial stages of treatment. In patients that have unhealed, open soft tissue lesions within the mouth, treatment should be delayed. Should ONJ occur, treatment should be withheld and a dentist or oral surgeon with expertise in ONJ consulted regarding ongoing management.

Osteonecrosis has also been reported at other sites including the external auditory canal, hip and femur. Osteonecrosis of the external auditory canal should be considered if patients report ear symptoms including chronic ear infections. Risk factors include infection or trauma in the ear and/or use of concomitant steroids and chemotherapy. Cases are more frequent in long term treatment.

Atypical stress fractures of the proximal femoral shaft with poor healing have been reported during treatment with another bisphosphonate, alendronic acid. Evidence to support a relationship with zoledronic acid is limited however a causal link cannot be excluded. Should a patient develop an atypical stress fracture, treatment with all bisphosphonates should be permanently discontinued.

Pregnancy and Lactation

Pregnancy

Zoledronic acid is contraindicated in pregnancy.

There are no adequate data on the use of zoledronic acid in pregnant women. Animal reproduction studies with zoledronic acid have shown reproductive toxicity. Dystocia was observed at the lowest dose (0.01 mg/kg bodyweight) tested in the rat. The potential risk for humans is unknown.

Schaefer (2007) states that accidental use of individual doses of bisphosphonates in the first trimester do not justify either interruption of the pregnancy or additional diagnostic procedures.

The use of all medication in pregnancy should be avoided whenever possible; particularly in the first trimester. Non-drug treatments should also be considered. When essential, a medication with the best safety record over time should be chosen, employing the lowest effective dose for the shortest possible time. Polypharmacy should be avoided. Teratogens taken in the pre-embryonic period, often quoted as lasting until 14 to 17 days post-conception, are believed to have an all-or-nothing effect. Where drugs have a short half-life, and when the date of conception is certain, this may allow women to be reassured where drug exposure has occurred within this time frame. Further advice may be available from the UK National Teratology Information Service (NTIS) and through ToxBase, available via password on the internet ( www.toxbase.org ) or if this is unavailable at the backup site ( www.toxbasebackup.org ).

Lactation

Zoledronic acid is contraindicated during breastfeeding.

Briggs (2011) states that it is not known whether zoledronic acid is excreted into human milk. The molecular weight (about 290 for the hydrated form), lack of metabolism, low plasma protein binding, plasma half life and the prolonged terminal elimination half life suggest that the drug will be excreted into breast milk. Detectable amounts of the drug are measured in adult plasma for less than 28 days post dose. Although the low lipid solubility of zoledronic acid may limit the amount present in milk, and maternal treatment may be compatible with nursing, until data are available the best course is not to breastfeed.

Neonates, infants born prematurely, those with low birth weight, those with an unstable gastrointestinal function or who have serious illnesses may require special consideration. For any infant, if a drug is prescribed to the nursing mother, it should be at the lowest practical dose and for the shortest time. When drug administration is unavoidable and breastfeeding is to continue, minimisation of exposure of the infant to the drug may sometimes be achieved by timing the maternal doses to just after a feeding episode. Infants exposed to drugs via breast milk should be monitored for unusual signs or symptoms. Interactions between the drug received by the infant from the mother's milk and medication prescribed for the infant should also be considered, for example, when the drug given to the infant may prevent metabolism of the drug received via breast milk.
Specialist advice is available from the UK Drugs in Lactation Advisory Service at https://www.midlandsmedicines.nhs.uk/content.asp?section=6&subsection=17&pageIdx=1

Side Effects

Abdominal pain
Acute phase reaction
Acute renal failure
Anaemia
Anaphylactic shock
Angioneurotic oedema
Anorexia
Anxiety
Arthralgia
Arthritis
Asthenia
Atrial fibrillation
Atypical femoral fracture
Blurred vision
Bone pain
Bradycardia
Bronchoconstriction
Circulatory collapse
Confusion
Conjunctivitis
Constipation
Cough
Decreased appetite
Dehydration
Deterioration of renal function in pre-existing renal disease
Diarrhoea
Dizziness
Dry mouth
Dysgeusia
Dyspepsia
Dyspnoea
Episcleritis
Erythema
Fatigue
Flushing
Haematuria
Headache
Hyperaesthesia
Hyperhidrosis
Hyperkalaemia
Hypernatraemia
Hypersensitivity reactions
Hypertension
Hypoaesthesia
Hypocalcaemia
Hypokalaemia
Hypomagnesaemia
Hypophosphataemia
Hypotension
Increase in blood urea or creatinine
Influenza-like syndrome
Injection site reactions
Interstitial lung disease
Iritis
Joint swelling
Lethargy
Leucopenia
Malaise
Muscle spasm
Muscular cramps
Myalgia
Nasopharyngitis
Nausea
Non-cardiac chest pain
Ocular hyperaemia
Orbital inflammation
Osteomyelitis
Osteonecrosis (primarily of the jaw)
Osteonecrosis of the external auditory canal
Pain
Palpitations
Pancytopenia
Paraesthesia
Peripheral oedema
Pollakiuria
Proteinuria
Pruritus
Pyrexia
Raised C-reactive protein
Rash
Renal impairment
Rigors
Scleritis
Sleep disturbances
Somnolence
Stiffness
Stomatitis
Syncope
Taste disturbances
Thirst
Thrombocytopenia
Tooth ache
Tremor
Urticaria
Uveitis
Vertigo
Vomiting
Weight gain

Overdosage

It is strongly recommended that the UK National Poisons Information Service be consulted on cases of suspected or actual overdose where there is doubt over the degree of risk or about appropriate management.

The following number will direct the caller to the relevant local centre (0844) 892 0111

Information may be obtained if you have access to ToxBase the primary clinical toxicology database of the National Poisons Information Service. This is available via password on the internet ( www.toxbase.org ) or if this is unavailable at the backup site ( www.toxbasebackup.org ).

Further Information

Last Full Review Date: November 2014

Reference Sources

Drugs During Pregnancy and Lactation: Treatment Options and Risk Assessment, 2nd edition (2007) ed. Schaefer, C., Peters, P. and Miller, R. Elsevier, London.

Drugs in Pregnancy and Lactation: A Reference Guide to Fetal and Neonatal Risk, 9th edition (2011) ed. Briggs, G., Freeman, R. and Yaffe, S. Lippincott Williams & Wilkins, Philadelphia.

Martindale: The Complete Drug Reference, 37th edition (2011) ed. Sweetman, S. Pharmaceutical Press, London.

Summary of Product Characteristics: Zoledronic acid 4mg/5ml concentrate for solution for infusion. Accord Healthcare Ltd. Revised August 2017.

Summary of Product Characteristics: Zerlinda 4mg/100ml solution for infusion. Actavis UK Ltd. Revised February 2014.

Summary of Product Characteristics: Zoledronic acid 4mg/5ml concentrate for solution for infusion. Dr Reddy's Laboratories Ltd. Revised December 2012.
Summary of Product Characteristics: Zoledronic acid 4mg/100ml solution for infusion. Dr Reddy's Laboratories Ltd. Revised June 2014.

Summary of Product Characteristics: Zoledronic acid 4mg/5ml concentrate for solution for infusion. Hospira UK Ltd. Revised July 2015.
Summary of Product Characteristics: Zoledronic acid 4mg/100ml solution for infusion. Hospira UK Ltd. Revised July 2015.

Summary of Product Characteristics: Zoledronic acid medac 4mg/100ml solution for infusion. Medac GmbH. Revised July 2013.
Summary of Product Characteristics: Zoledronic acid medac 4mg/5ml concentration for solution for infusion. Medac GmbH. Revised July 2013.

Summary of Product Characteristics: Zoledronic acid 4mg/5ml concentration for solution for infusion. Sandoz Ltd. Revised March 2014.
Summary of Product Characteristics: Zoledronic acid 4mg/100ml solution for infusion. Sandoz Ltd. Revised April 2014.

Summary of Product Characteristics: Zometa 4mg/5ml concentrate for solution for infusion. Novartis Pharmaceuticals UK Ltd. Revised July 2017.
Summary of Product Characteristics: Zometa 4mg/100ml concentrate for solution for infusion. Novartis Pharmaceuticals UK Ltd. Revised July 2017.

The Renal Drug Handbook. Fourth Edition (2014) ed. Ashley, C and Dunleavy, A, Radcliffe Publishing Ltd, London.

MHRA Drug Safety Update November 2009
Available at: https://www.mhra.gov.uk
Last accessed: 23 October 2015

MHRA Drug Safety Update April 2010
Available at: https://www.mhra.gov.uk
Last accessed: 23 October 2015

MHRA Drug Safety Update July 2015
Available at: https://www.mhra.gov.uk
Last accessed: 23 October 2015

MHRA Drug Safety Update December 2015
Available at: https://www.mhra.gov.uk
Last accessed: 13 January 2016

NICE Evidence Services Available at: www.nice.org.uk Last accessed: 06 November 2014

US National Library of Medicine. Toxicology Data Network. Drugs and Lactation Database (LactMed).
Available at: https://toxnet.nlm.nih.gov/cgi-bin/sis/htmlgen?LACT
Zoledronic Acid
Last revised: January 4, 2011.
Last accessed: July 8, 2013.