Drugs List

Therapeutic Indications

Uses

Paget's disease of bone
Treatment of corticosteroid induced osteoporosis
Treatment of osteoporosis in men to prevent fractures
Treatment of osteoporosis in postmenopausal women to prevent fractures

Formulations linked to this monograph are indicated for:

Treatment of Paget's disease of bone.
Treatment of osteoporosis in men and postmenopausal women at increased risk of fracture, including those with recent low-trauma hip fracture.
Treatment of osteoporosis associated with long-term systemic glucocorticoid therapy in men and postmenopausal women at increased risk of fracture.

See separate information for formulations for other indications.

Administration

For intravenous infusion only.

Zoledronic acid (5 mg in 100 ml ready-to-infuse solution) is administered via a vented infusion line.

Contraindications

Children under 18 years
Breastfeeding
Hypocalcaemia
Pregnancy
Renal impairment - creatinine clearance below 35ml/minute

Precautions and Warnings

Dehydration
Renal impairment
Severe hepatic impairment

Avoid overhydration in patients at risk of cardiac failure
Advise ability to drive/operate machinery may be affected by side effects
Consider a dental exam & appropriate preventive dentistry before treatment
Maintain adequate hydration of patient prior / during treatment
Not all available brands are licensed for all indications
Treatment to be administered under the supervision of a specialist
Use calcium-free infusion solutions for dilution
Ensure patient's dietary intake of calcium and vitamin D is adequate
Monitor serum calcium levels
Monitor serum creatinine before each dose
Monitor serum magnesium regularly
Monitor serum phosphate levels
Advise patient to report any ear pain, discharge or infection
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, most cases have been in patients with advanced malignancies involving bone. In studies patients who developed ONJ had known risk factors, including a diagnosis of cancer with bone lesions, concomitant therapies (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 and an individual benefit-risk assessment is recommended prior to zoledronic acid therapy in patients with risk factors for ONJ. While on treatment, patients should avoid invasive dental procedures if possible, especially in close proximity to the start of treatment with zoledronic acid. The start of treatment or a new course of treatment should be delayed in patients with unhealed open soft tissue lesion in the mouth. Good oral hygiene practices and regular routine dental check-ups should be maintained during treatment with zoledronic acid.

For patients who develop ONJ during treatment, dental surgery may exacerbate the condition. If ONJ occurs during treatment with zoledronic acid, use clinical judgement and guide the management plan of each patient based on individual benefit/risk evaluation. The management plan for patients with ONJ should be set up in close collaboration between the treating physician and a dentist or oral surgeon with expertise in ONJ. Temporary interruption of treatment should be considered until the condition resolves and contributing risk factors are mitigated where possible.

Osteonecrosis of the external auditory canal has been reported very rarely with bisphosphonates, mainly in association with long term therapy (2 years or longer). Risk factors include steroid use and chemotherapy and/or local risk factors as infection or trauma. The possibility of osteonecrosis of the external auditory canal should be considered in patients receiving bisphosphonates who present with ear symptoms including chronic ear infections.

Atypical stress fractures of the proximal femoral shaft with poor healing have been reported for treatment with another bisphosphonate, alendronic acid. Limited data exists regarding a relationship for other bisphosphonates and atypical stress fractures. However, the possibility of atypical stress fractures cannot be excluded. Patients who develop atypical stress fractures should discontinue treatment and receive no further bisphosphonate treatment.

Pregnancy and Lactation

Pregnancy

Zoledronic acid is contraindicated during pregnancy.

Not recommended in women of childbearing potential.

Animal studies have shown reproduction toxicological effects and although the significance to humans is unknown, zoledronic acid should not be used in human pregnancy. If treatment has been discontinued before pregnancy, the very long elimination half life from bone indicates that women treated with zoledronic acid will have detectable concentrations of the drug for a prolonged interval. If exposure occurs during gestation, detailed ultrasound examination of the foetal skeleton appears to be warranted (Briggs, 2011) although Schaeffer (2007) states that accidental use of a single dose does not justify 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.

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

Acute phase reaction
Acute renal failure
Anaemia
Anaphylactic shock
Angioneurotic oedema
Anorexia
Anxiety
Arthralgia
Arthritis
Asthenia
Atrial fibrillation
Atypical femoral fracture
Blurred vision
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
Fever
Flushing
Gastritis
Gastroesophageal reflux disease
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
Iritis
Joint swelling
Lethargy
Leucopenia
Malaise
Muscle spasm
Muscle weakness
Muscular cramps
Myalgia
Nasopharyngitis
Nausea
Non-cardiac chest pain
Ocular hyperaemia
Oesophagitis
Orbital inflammation
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

Infusion containing 5mg anhydrous zoledronic acid per 100ml.

Drugs List

Therapeutic Indications

Uses

Paget's disease of bone
Treatment of corticosteroid induced osteoporosis
Treatment of osteoporosis in men to prevent fractures
Treatment of osteoporosis in postmenopausal women to prevent fractures

Formulations linked to this monograph are indicated for:

Treatment of Paget's disease of bone.
Treatment of osteoporosis in men and postmenopausal women at increased risk of fracture, including those with recent low-trauma hip fracture.
Treatment of osteoporosis associated with long-term systemic glucocorticoid therapy in men and postmenopausal women at increased risk of fracture.

See separate information for formulations for other indications.

Dosage

Adults

Elderly

Additional Dosage Information

Administration

For intravenous infusion only.

Zoledronic acid (5 mg in 100 ml ready-to-infuse solution) is administered via a vented infusion line.

Contraindications

Children under 18 years
Breastfeeding
Hypocalcaemia
Pregnancy
Renal impairment - creatinine clearance below 35ml/minute

Precautions and Warnings

Dehydration
Renal impairment
Severe hepatic impairment

Avoid overhydration in patients at risk of cardiac failure
Advise ability to drive/operate machinery may be affected by side effects
Consider a dental exam & appropriate preventive dentistry before treatment
Maintain adequate hydration of patient prior / during treatment
Not all available brands are licensed for all indications
Treatment to be administered under the supervision of a specialist
Use calcium-free infusion solutions for dilution
Ensure patient's dietary intake of calcium and vitamin D is adequate
Monitor serum calcium levels
Monitor serum creatinine before each dose
Monitor serum magnesium regularly
Monitor serum phosphate levels
Advise patient to report any ear pain, discharge or infection
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, most cases have been in patients with advanced malignancies involving bone. In studies patients who developed ONJ had known risk factors, including a diagnosis of cancer with bone lesions, concomitant therapies (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 and an individual benefit-risk assessment is recommended prior to zoledronic acid therapy in patients with risk factors for ONJ. While on treatment, patients should avoid invasive dental procedures if possible, especially in close proximity to the start of treatment with zoledronic acid. The start of treatment or a new course of treatment should be delayed in patients with unhealed open soft tissue lesion in the mouth. Good oral hygiene practices and regular routine dental check-ups should be maintained during treatment with zoledronic acid.

For patients who develop ONJ during treatment, dental surgery may exacerbate the condition. If ONJ occurs during treatment with zoledronic acid, use clinical judgement and guide the management plan of each patient based on individual benefit/risk evaluation. The management plan for patients with ONJ should be set up in close collaboration between the treating physician and a dentist or oral surgeon with expertise in ONJ. Temporary interruption of treatment should be considered until the condition resolves and contributing risk factors are mitigated where possible.

Osteonecrosis of the external auditory canal has been reported very rarely with bisphosphonates, mainly in association with long term therapy (2 years or longer). Risk factors include steroid use and chemotherapy and/or local risk factors as infection or trauma. The possibility of osteonecrosis of the external auditory canal should be considered in patients receiving bisphosphonates who present with ear symptoms including chronic ear infections.

Atypical stress fractures of the proximal femoral shaft with poor healing have been reported for treatment with another bisphosphonate, alendronic acid. Limited data exists regarding a relationship for other bisphosphonates and atypical stress fractures. However, the possibility of atypical stress fractures cannot be excluded. Patients who develop atypical stress fractures should discontinue treatment and receive no further bisphosphonate treatment.

Pregnancy and Lactation

Pregnancy

Zoledronic acid is contraindicated during pregnancy.

Not recommended in women of childbearing potential.

Animal studies have shown reproduction toxicological effects and although the significance to humans is unknown, zoledronic acid should not be used in human pregnancy. If treatment has been discontinued before pregnancy, the very long elimination half life from bone indicates that women treated with zoledronic acid will have detectable concentrations of the drug for a prolonged interval. If exposure occurs during gestation, detailed ultrasound examination of the foetal skeleton appears to be warranted (Briggs, 2011) although Schaeffer (2007) states that accidental use of a single dose does not justify 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.

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

Acute phase reaction
Acute renal failure
Anaemia
Anaphylactic shock
Angioneurotic oedema
Anorexia
Anxiety
Arthralgia
Arthritis
Asthenia
Atrial fibrillation
Atypical femoral fracture
Blurred vision
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
Fever
Flushing
Gastritis
Gastroesophageal reflux disease
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
Iritis
Joint swelling
Lethargy
Leucopenia
Malaise
Muscle spasm
Muscle weakness
Muscular cramps
Myalgia
Nasopharyngitis
Nausea
Non-cardiac chest pain
Ocular hyperaemia
Oesophagitis
Orbital inflammation
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: July 2013

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.

Summary of Product Characteristics: Aclasta 5mg Solution for Infusion. Novartis Pharmaceuticals UK Ltd. Revised December 2015.

Summary of Product Characteristics: Zoledronic acid 5mg/100ml Solution for Infusion. Dr Reddy's Laboratories Ltd. Revised February 2014.

Summary of Product Characteristics: Zoledronic acid 5mg/100ml Solution for Infusion. Hospira UK Ltd. Revised April 2014.

The Renal Drug Handbook. 3rd edition. (2009) ed. Ashley, C and Currie, Radcliffe Publishing Ltd, Abingdon.

MHRA Drug Safety Update: Bisphosphonates: atypical stress fractures. Dated: March 2009.
https://www.mhra.gov.uk/Publications/Safetyguidance/DrugSafetyUpdate/CON041211
Last accessed: July 12, 2013.

MHRA Drug Safety Update: Bisphosphonates-osteonecrosis of the jaw. Dated: November 2009.
https://www.mhra.gov.uk/Publications/Safetyguidance/DrugSafetyUpdate/CON062553
Last accessed: July 12, 2013.

MHRA Drug Safety Update: Intravenous zoledronic acid: adverse effects on renal function. Dated: April 2010.
https://www.mhra.gov.uk/Publications/Safetyguidance/DrugSafetyUpdate/CON076501
Last accessed: July 12, 2013.

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

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 12, 2013.

NICE Evidence Services Available at: www.nice.org.uk Last accessed: 23 August 2017