Drugs List

Therapeutic Indications

Uses

Bone complications: prevention in breast cancer + bone metastases
Hypercalcaemia due to malignant disease
Pathological fracture: prevention in breast cancer + bone metastases

Administration

For intravenous infusion after dilution.

Contraindications

Children under 18 years
Breastfeeding
Hypocalcaemia
Pregnancy

Precautions and Warnings

Predisposition to cardiac failure
Renal impairment - creatinine clearance below 50ml/minute
Severe hepatic impairment

Avoid overhydration in patients at risk of cardiac failure
Consider a dental exam & appropriate preventive dentistry before treatment
Maintain adequate hydration during therapy
Dilute and use as an infusion
Must be given as an intravenous infusion
Resuscitation facilities must be immediately available
Treatment to be administered under the supervision of a specialist
Correct disturbances of calcium and mineral metabolism before initiation
Ensure patient's dietary intake of calcium and vitamin D is adequate
Monitor renal function
Monitor serum calcium levels
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 discontinuation if atypical femoral fracture occurs
Discontinue if serious allergic or anaphylactic reaction occurs
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

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 bisphosphonate therapy in patients with risk factors for ONJ. While on treatment, patients should avoid invasive dental procedures if possible. Good oral hygiene practices and regular routine dental check-ups should be maintained during treatment with bisphosphonates.

For patients who develop ONJ during treatment, dental surgery may exacerbate the condition. If ONJ occurs during treatment with bisphosphonates, 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 femoral fractures have been reported in patients receiving bisphosphonates. Atypical femoral fractures may occur with little or no trauma in the subtrochanteric and diaphyseal regions of the femur. Consider discontinuation of bisphosphonate therapy in patients suspected to have an atypical femoral fracture pending an individual risk/benefit assessment. During bisphosphonate therapy, advise patients to report new or unusual thigh, hip or groin pain. Patients presenting with such symptoms should be evaluated for an incomplete femoral fracture.

Pregnancy and Lactation

Pregnancy

Ibandronic acid is contraindicated in pregnancy.

There are no adequate data from the use of ibandronic acid in pregnant women, therefore the potential risk to humans is unkown. Animal studies have shown reproduction toxicological effects on skeletal development. 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.

Briggs (2011) states that the amount of drug retained in the bone and eventually released back into systemic circulation is directly related to the dose and duration of treatment and that ibandronate probably crosses the placenta, treatment of the mother before conception could result in continuous exposure of the embryo and foetus to an unknown amount of the drug. Therefore treatment with ibandronic acid in women who may become pregnant or during pregnancy is not recommended.

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

Ibandronic acid is contraindicated in breastfeeding.

It is unknown if ibandronic acid is excreted in human breast milk, animal studies have shown the presence of low levels of ibandronic acid in rat milk following intravenous administration. However, Briggs (2011) suggests that with a molecular weight of around 318 (for the free acid), prolonged elimination half life and lack of metabolism that the active drug will be excreted in breast milk.

The low oral bioavailability of ibandronic acid (less than 1% fasting, lower with food) and the fact that it binds to calcium in milk make it likely that the amount absorbed by a nursing infant would be insignificant.

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

Alopecia
Amnesia
Anaemia
Anaphylactic reaction
Angioedema
Anxiety
Arthralgia
Asthenia
Atypical femoral fracture
Benign skin neoplasms
Blood dyscrasias
Bone pain
Bronchospasm
Bundle branch block
Candidiasis (mouth or throat)
Cardiovascular disturbances
Cataracts
Cerebrovascular disorders
Cheilitis
Chills
Cholelithiasis
Cystitis
Deafness
Diarrhoea
Dizziness
Dysgeusia
Dyspepsia
Dysphagia
Ecchymosis
Exacerbation of pre-existing asthma
Fever
Gamma glutamyl transferase (GGT) increased
Gastritis
Gastro-enteritis
Gastro-intestinal pain
Headache
Hyperaesthesia
Hypersensitivity reactions
Hypertension
Hypertonia
Hypocalcaemia
Hypophosphataemia
Hypothermia
Increase in alkaline phosphatase
Increase in creatinine
Infections
Influenza-like syndrome
Joint disorder
Lability of affect
Local pain (injection site)
Local reaction at injection site
Lymphoedema
Migraine
Myalgia
Myocardial ischaemia
Nerve damage
Neuralgia
Ocular inflammation
Oral paraesthesia
Oral ulceration
Osteoarthritis
Osteonecrosis (primarily of the jaw)
Osteonecrosis of the external auditory canal
Palpitations
Parosmia
Pelvic pain
Peripheral oedema
Pharyngitis
Possible alteration in tests for parathyroid function
Pulmonary oedema
Pyrexia
Rash
Renal cysts
Rigors
Skin disorder
Sleep disturbances
Stridor
Thirst
Tooth disorder
Urinary retention
Vaginitis
Varicose veins
Vomiting
Weight loss

Presentation

Infusions of ibandronic acid

Drugs List

Therapeutic Indications

Uses

Bone complications: prevention in breast cancer + bone metastases
Hypercalcaemia due to malignant disease
Pathological fracture: prevention in breast cancer + bone metastases

Dosage

Adults

Elderly

Patients with Renal Impairment

Additional Dosage Information

Administration

For intravenous infusion after dilution.

Contraindications

Children under 18 years
Breastfeeding
Hypocalcaemia
Pregnancy

Precautions and Warnings

Predisposition to cardiac failure
Renal impairment - creatinine clearance below 50ml/minute
Severe hepatic impairment

Avoid overhydration in patients at risk of cardiac failure
Consider a dental exam & appropriate preventive dentistry before treatment
Maintain adequate hydration during therapy
Dilute and use as an infusion
Must be given as an intravenous infusion
Resuscitation facilities must be immediately available
Treatment to be administered under the supervision of a specialist
Correct disturbances of calcium and mineral metabolism before initiation
Ensure patient's dietary intake of calcium and vitamin D is adequate
Monitor renal function
Monitor serum calcium levels
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 discontinuation if atypical femoral fracture occurs
Discontinue if serious allergic or anaphylactic reaction occurs
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

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 bisphosphonate therapy in patients with risk factors for ONJ. While on treatment, patients should avoid invasive dental procedures if possible. Good oral hygiene practices and regular routine dental check-ups should be maintained during treatment with bisphosphonates.

For patients who develop ONJ during treatment, dental surgery may exacerbate the condition. If ONJ occurs during treatment with bisphosphonates, 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 femoral fractures have been reported in patients receiving bisphosphonates. Atypical femoral fractures may occur with little or no trauma in the subtrochanteric and diaphyseal regions of the femur. Consider discontinuation of bisphosphonate therapy in patients suspected to have an atypical femoral fracture pending an individual risk/benefit assessment. During bisphosphonate therapy, advise patients to report new or unusual thigh, hip or groin pain. Patients presenting with such symptoms should be evaluated for an incomplete femoral fracture.

Pregnancy and Lactation

Pregnancy

Ibandronic acid is contraindicated in pregnancy.

There are no adequate data from the use of ibandronic acid in pregnant women, therefore the potential risk to humans is unkown. Animal studies have shown reproduction toxicological effects on skeletal development. 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.

Briggs (2011) states that the amount of drug retained in the bone and eventually released back into systemic circulation is directly related to the dose and duration of treatment and that ibandronate probably crosses the placenta, treatment of the mother before conception could result in continuous exposure of the embryo and foetus to an unknown amount of the drug. Therefore treatment with ibandronic acid in women who may become pregnant or during pregnancy is not recommended.

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

Ibandronic acid is contraindicated in breastfeeding.

It is unknown if ibandronic acid is excreted in human breast milk, animal studies have shown the presence of low levels of ibandronic acid in rat milk following intravenous administration. However, Briggs (2011) suggests that with a molecular weight of around 318 (for the free acid), prolonged elimination half life and lack of metabolism that the active drug will be excreted in breast milk.

The low oral bioavailability of ibandronic acid (less than 1% fasting, lower with food) and the fact that it binds to calcium in milk make it likely that the amount absorbed by a nursing infant would be insignificant.

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

Alopecia
Amnesia
Anaemia
Anaphylactic reaction
Angioedema
Anxiety
Arthralgia
Asthenia
Atypical femoral fracture
Benign skin neoplasms
Blood dyscrasias
Bone pain
Bronchospasm
Bundle branch block
Candidiasis (mouth or throat)
Cardiovascular disturbances
Cataracts
Cerebrovascular disorders
Cheilitis
Chills
Cholelithiasis
Cystitis
Deafness
Diarrhoea
Dizziness
Dysgeusia
Dyspepsia
Dysphagia
Ecchymosis
Exacerbation of pre-existing asthma
Fever
Gamma glutamyl transferase (GGT) increased
Gastritis
Gastro-enteritis
Gastro-intestinal pain
Headache
Hyperaesthesia
Hypersensitivity reactions
Hypertension
Hypertonia
Hypocalcaemia
Hypophosphataemia
Hypothermia
Increase in alkaline phosphatase
Increase in creatinine
Infections
Influenza-like syndrome
Joint disorder
Lability of affect
Local pain (injection site)
Local reaction at injection site
Lymphoedema
Migraine
Myalgia
Myocardial ischaemia
Nerve damage
Neuralgia
Ocular inflammation
Oral paraesthesia
Oral ulceration
Osteoarthritis
Osteonecrosis (primarily of the jaw)
Osteonecrosis of the external auditory canal
Palpitations
Parosmia
Pelvic pain
Peripheral oedema
Pharyngitis
Possible alteration in tests for parathyroid function
Pulmonary oedema
Pyrexia
Rash
Renal cysts
Rigors
Skin disorder
Sleep disturbances
Stridor
Thirst
Tooth disorder
Urinary retention
Vaginitis
Varicose veins
Vomiting
Weight loss

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: September 2015

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.

Joint Formulary Committee. British National Formulary (online) London: BMJ Group and Pharmaceutical Press. Accessed on 11 September 2015.

Summary of Product Characteristics: Bondronat 2mg Concentrate for solution for infusion. Roche Products Ltd. Revised May 2015.

Summary of Product Characteristics: Ibandronic acid Accord 2 mg Concentrate for solution for infusion. Accord Healthcare Ltd. Revised July 2014.
Summary of Product Characteristics: Ibandronic acid Accord 6 mg Concentrate for solution for infusion. Accord Healthcare Ltd. Revised July 2014.

Summary of Product Characteristics: Ibandronic acid 2mg/2ml Concentrate for solution for infusion. Teva UK Limited. Revised June 2012.
Summary of Product Characteristics: Ibandronic acid 6mg/6ml Concentrate for solution for infusion. Teva UK Limited. Revised June 2012.

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

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

MHRA Drug Safety Update July 2015
Available at: https://www.mhra.gov.uk
Last accessed: 11 September 2015

MHRA Drug Safety Update November 2009
Available at: https://www.mhra.gov.uk
Last accessed: 11 September 2015