Last Updated on eMC 06-05-2016 View medicine  | Roche Products Limited Contact details

When a pharmaceutical company changes an SPC or PIL, a new version is published on the eMC.  For each version, we show the dates it was published on the eMC and the reasons for change.

Reasons for adding or updating:

  • Change to section 4.2 - Posology and method of administration
  • Change to section 4.4 - Special warnings and precautions for use
  • Change to section 4.8 - Undesirable effects
  • Change to section 10 - Date of revision of the text

Date of revision of text on the SPC:25-04-2016

Legal Category:POM

Black Triangle (CHM): NO

Free-text change information supplied by the pharmaceutical company:



Underline text = new text

Strike through text = deleted text

 

4.2     Posology and method of administration

 

Patients treated with Bondronat should be given the package leaflet and the patient reminder card.

 

Bondronat therapy should only be initiated by physicians experienced in the treatment of cancer.

 

[ … ]

 

 

4.4     Special warnings and precautions for use

 

[ … ]

 

Osteonecrosis of the jaw

Osteonecrosis of the jaw (ONJ) has been reported very rarely in the post marketing setting in patients receiving Bondronat for oncology indications (see section 4.8).

 

The start of treatment or of a new course of treatment should be delayed in patients with unhealed open soft tissue lesions in the mouth.

 

A dental examination with preventive dentistry and an individual benefit-risk assessment is recommended prior to treatment with Bondronat in patients with concomitant risk factors.

 

The following risk factors should be considered when evaluating a patient’s risk of developing ONJ:

-        Potency of the medicinal product that inhibit bone resorption (higher risk for highly potent compounds), route of administration (higher risk for parenteral administration) and cumulative dose of bone resorption therapy

-        Cancer, co-morbid conditions (e.g. anaemia, coagulopathies, infection), smoking

-        Concomitant therapies: corticosteroids, chemotherapy, angiogenesis inhibitors, radiotherapy to head and neck

-        Poor oral hygiene, periodontal disease, poorly fitting dentures, history of dental disease, invasive dental procedures e.g. tooth extractions

 

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

 

The management plan of the patients who develop 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 Bondronat treatment should be considered until the condition resolves and contributing risk factors are mitigated where possible.

Osteonecrosis of the jaw, generally associated with tooth extraction and/or local infection (including osteomyelitis) has been reported in patients with cancer receiving treatment regimens including primarily intravenously administered bisphosphonates. Many of these patients were also receiving chemotherapy and corticosteroids. Osteonecrosis of the jaw has also been reported in patients with osteoporosis receiving oral bisphosphonates.

 

A dental examination with appropriate preventive dentistry should be considered prior to treatment with bisphosphonates in patients with concomitant risk factors (e.g. cancer, chemotherapy, radiotherapy, corticosteroids, poor oral hygiene).

 

While on treatment, these patients should avoid invasive dental procedures if possible. For patients who develop osteonecrosis of the jaw 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 osteonecrosis of the jaw. Clinical judgement of the treating physician should guide the management plan of each patient based on individual benefit/risk assessment.

 

Osteonecrosis of the external auditory canal

Osteonecrosis of the external auditory canal has been reported with bisphosphonates, mainly in association with long-term therapy. Possible risk factors for osteonecrosis of the external auditory canal include steroid use and chemotherapy and/or local risk factors such 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.

 

[ … ]

 

4.8     Undesirable effects

 

[ … ]

Table 1 Adverse Reactions Reported for Intravenous Administration of Bondronat

 

System Organ Class

Common

Uncommon

Rare

Very rare

Not known

 

[ … ]

 

 

 

 

 

 

Musculoskeletal and connective tissue disorders

Osteoarthritis, myalgia, arthralgia, joint disorder,

bone pain

 

Atypical subtrochanteric and diaphyseal femoral fractures

Osteonecrosis
of jaw
†**  

Osteonecrosis of the external auditory canal (bisphosphonate class adverse reaction)†

 

 

[ … ]

 

 

 

 

 

 

**See further information below

†Identified in post-marketing experience.

 

[ … ]

 

Osteonecrosis of jaw

Cases of osteonecrosis of the jaw have been reported, predominantly in cancer patients treated with medicinal products that inhibit bone resorption, such as ibandronic acid (see section 4.4.) Cases of ONJ have been reported in the post marketing setting for ibandronic acid.Osteonecrosis of the jaw has been reported in patients treated by bisphosphonates. The majority of the reports refer to cancer patients, but such cases have also been reported in patients treated for osteoporosis. Osteonecrosis of the jaw is generally associated with tooth extraction and/or local infection (including osteomyelitis). Diagnosis of cancer, chemotherapy, radiotherapy, corticosteroids and poor oral hygiene are also deemed as risk factors (see section 4.4).

 

[ … ]

 

 

 

10.       DATE OF REVISION OF THE TEXT

 

25 April 2016

 

Reasons for adding or updating:

  • Change to section 4.2 - Posology and method of administration
  • Change to section 4.8 - Undesirable effects
  • Change to section 10 - Date of revision of the text

Date of revision of text on the SPC:28-05-2015

Legal Category:POM

Black Triangle (CHM): NO

Free-text change information supplied by the pharmaceutical company:



Underlined text has been added, text with strike-through deleted:

 

4.2       Posology and method of administration

[…]

Patients with renal impairment

For patients with mild renal impairment (CLcr 50 and <80 mL/min) no dose adjustment is necessary. For patients with moderate renal impairment (CLcr ≥30 and <50 mL/min) or severe renal impairment (CLcr <30 mL/min) being treated for the prevention of skeletal events in patients with breast cancer and metastatic bone disease the following dosing recommendations should be followed (see section 5.2):

 

Creatinine Clearance (ml/min)

Dosage / Infusion time 1

Infusion Volume 2

50 CLcr <80

6 mg / 15 minutes

100 ml

30 CLcr <50

4 mg / 1 hour

500 ml

<30

2 mg / 1 hour

500 ml

1  Administration every 3 to 4 week

2  0.9% sodium chloride solution or 5% glucose solution

 

Creatinine Clearance (ml/min)

Dosage

Infusion Volume 1 and Time 2

50 CLcr<80

6 mg      (6 ml of concentrate for solution for infusion)

100 ml over 15 minutes

30 CLcr <50

4 mg      (4 ml of concentrate for solution for infusion)

500 ml over 1 hour

<30

2 mg      (2 ml of concentrate for solution for infusion)

500 ml over 1 hour

1  0.9% sodium chloride solution or 5% glucose solution

2  Administration every 3 to 4 week

[…]

4.8       Undesirable effects

[…]

Stevens-Johnson Syndrome, Erythema Multiforme, Dermatitis Bullous added as very rare under Skin and subcutaneous tissue disorders

[…]

10.          DATE OF REVISION OF THE TEXT

 

28 May 2015

 

Reasons for adding or updating:

  • Change to section 4.2 - Posology and method of administration
  • Change to section 4.4 - Special warnings and precautions for use
  • Change to section 4.6 - Fertility, pregnancy and lactation
  • Change to section 4.8 - Undesirable effects
  • Change to section 4.8 - Undesirable effects - how to report a side effect
  • Change to section 5.1 - Pharmacodynamic properties
  • Change to section 10 - Date of revision of the text
  • Change from joint to individual SPC

Date of revision of text on the SPC:20-03-2014

Legal Category:POM

Black Triangle (CHM): NO

Free-text change information supplied by the pharmaceutical company:

Underlined Text = new text$0Struck Through Text = deleted text$0$0$04.2     Posology and method of administration$0$0 $0$0[ … ]$0$0 $0$0Special populations$0$0Patients with hepatic impairment$0$0No dose adjustment is required (see section 5.2).$0$0 $0$0[ … ]$0$0 $0$0Paediatric population$0$0The safety and efficacy of Bondronat in children and adolescents below the age of 18 years have not been established. No data are available. (see section 5.1 and section 5.2).$0$0 $0$0[ … ]$0$0 $0$0For single use only. Only clear solution without particles should be used.$0$0Bondronat concentrate for solution for infusion should be administered as an intravenous infusion. $0$0As the inadvertent intra-arterial administration of preparations not expressly recommended for this purpose as well as paravenous administration can lead to tissue damage, cCare must be taken not to ensure that administer Bondronat concentrate for solution for infusion via intra-arterial or paravenous administration, as this could lead to tissue damage.is administered intravenously.$0$0 $0$04.4     Special warnings and precautions for use $0$0 $0$0[ … ]$0$0 $0$0Osteonecrosis of the jaw (ONJ)$0$0Osteonecrosis of the jaw, generally associated with tooth extraction and/or local infection (including osteomyelitis) has been reported in patients with cancer receiving treatment regimens including primarily intravenously administered bisphosphonates. Many of these patients were also receiving chemotherapy and corticosteroids. Osteonecrosis of the jaw has also been reported in patients with osteoporosis receiving oral bisphosphonates. $0$0 $0$0[ … ]$0$0 $0$0Excipients with known effect $0$0 $0$0Bondronat is essentially sodium free.$0$0 $0$04.6     Fertility, pregnancy and lactation$0$0 $0$0[ … ]$0$0 $0$0Fertility$0$0There are no data on the effects of ibandronic acid from in humans. In reproductive studies in rats by the oral route, ibandronic acid decreased fertility. In studies in rats using the intravenous route, ibandronic acid decreased fertility at high daily doses (see section 5.3).$0$0 $0$04.8     Undesirable effects$0$0 $0$0Summary of the Ssafety Pprofile$0$0The safety profile for Bondronat is derived from controlled clinical trials in the respective indications after the intravenous administration of Bondronat at the recommended doses, and from post-marketing experience.$0$0The most serious reported adverse reactions are anaphylactic reaction/shock, atypical fractures of the femur, osteonecrosis for the jaw, and ocular inflammation (see paragraph “description of selected adverse reactions” and section 4.4).$0$0 $0$0In the tTreatment of tumour induced hypercalcaemia treatment was is most frequently associated with a rise in body temperature. Less frequently, a decrease in serum calcium below normal range (hypocalcaemia) was is reported. In most cases no specific treatment was is required and the symptoms subsided after a couple of hours/days.$0$0In the prevention of skeletal events in patients with breast cancer and bone metastases, treatment was is most frequently associated with asthenia followed by rise in body temperature and headache.$0$0 $0$0[ … ]$0$0 $0$0Adverse reactions are listed according to MedDRA system organ class and frequency category. Frequency categories are defined using the following convention: very common (>1/10), common (≥ 1/100 to < 1/10), uncommon (≥ 1/1,000 to < 1/100), rare (≥ 1/10,000 to < 1/1,000), very rare (<1/10,000), not known (cannot be estimated from the available data). Within each frequency grouping, adverse reactions are presented in order of decreasing seriousness.$0$0 $0$0Table 1 Adverse Reactions Reported for Intravenous Administration of Bondronat$0$0 $0$0$0$0$0$0Adverse reactions are listed according to MedRA system organ class and frequency category. Frequency categories are defined using the following convention: very common (>1/10), common (≥ 1/100 to < 1/10), uncommon (≥ 1/1,000 to < 1/100), rare (≥ 1/10,000 to < 1/1,000), very rare (<1/10,000), not known (cannot be estimated from the available data). Within each frequency grouping, adverse reactions are presented in order of decreasing seriousness.$0$0$0$0$0$0System Organ Class$0$0$0$0Common$0$0$0$0Uncommon$0$0$0$0Rare$0$0$0$0Very rare$0$0$0$0Not known$0$0$0$0$0$0$0$0 $0$0[ … ]$0$0 $0$0$0$0 $0$0$0$0 $0$0$0$0 $0$0$0$0 $0$0$0$0 $0$0$0$0$0$0Immune system disorders$0$0$0$0 $0$0$0$0 $0$0$0$0 $0$0$0$0Hypersensitivity†,$0$0bronchospasm†,$0$0angioedema†,$0$0anaphylactic reaction/shock†**$0$0$0$0Asthma exacerbation$0$0$0$0$0$0 $0$0[ … ]$0$0 $0$0$0$0 $0$0$0$0 $0$0$0$0 $0$0$0$0 $0$0$0$0 $0$0$0$0$0$0Nervous system disorders$0$0$0$0Headache, dizziness, dysgeusia (taste perversion)$0$0$0$0Cerebrovascular disorder, nerve root lesion, amnesia, migraine, neuralgia, hypertonia, hyperaestesia, paraesthesia circumoral, parosmia$0$0$0$0 $0$0$0$0 $0$0$0$0 $0$0$0$0$0$0 $0$0[ … ]$0$0 $0$0$0$0 $0$0$0$0 $0$0$0$0 $0$0$0$0 $0$0$0$0 $0$0$0$0$0$0**See further information below$0$0†Identified in post-marketing experience.$0$0 $0$0[ … ]$0$0 $0$0Reporting of suspected adverse reactions$0$0Reporting suspected adverse reactions after authorisation 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 via the national reporting system listed in Appendix V(see details below).$0$0 $0$0Ireland$0$0IMB Pharmacovigilance$0$0Earlsfort Terrace $0$0IRL - Dublin 2$0$0Tel: +353 1 6764971$0$0Fax: +353 1 6762517$0$0Website: www.imb.ie$0$0e-mail: imbpharmacovigilance@imb.ie$0$0 $0$0Malta$0$0ADR Reporting$0$0The Medicines Authority $0$0Post-Licensing Directorate$0$0203 Level 3, Rue D'Argens$0$0GŻR-1368 Gżira$0$0Website: www.medicinesauthority.gov.mt$0$0e-mail: postlicensing.medicinesauthority@gov.mt$0$0 $0$0United Kingdom$0$0Yellow Card Scheme$0$0Website: www.mhra.gov.uk/yellowcard$0$0 $0$0 $0$05.1     Pharmacodynamic properties$0$0 $0$0[ … ]$0$0 $0$0Paediatric population (see section 4.2 and section 5.2)$0$0The safety and efficacy of Bondronat in children and adolescents below the age of 18 years have not been established. No data are available.$0$0 $0$010.       DATE OF REVISION OF THE TEXT$0$0 $0$020 March 2014$0$0 $0$0[ … ]$0$0 $0

Reasons for adding or updating:

  • Change to section 2 - Qualitative and quantitative composition
  • Change to section 4.2 - Posology and method of administration
  • Change to section 4.3 - Contraindications
  • Change to section 4.4 - Special warnings and precautions for use
  • Change to section 4.5 - Interaction with other medicinal products and other forms of interaction
  • Change to section 4.6 - Fertility, pregnancy and lactation
  • Change to section 4.7 - Effects on ability to drive and use machines
  • Change to section 4.8 - Undesirable effects
  • Change to section 5.1 - Pharmacodynamic properties
  • Change to section 5.2 - Pharmacokinetic properties
  • Change to section 6.4 - Special precautions for storage
  • Change to section 6.5 - Nature and contents of container
  • Change to section 6.6 - Special precautions for disposal and other handling
  • Change to section 9 - Date of first authorisation/renewal of the authorisation
  • Change to section 10 - Date of revision of the text

Date of revision of text on the SPC:15-11-2012

Legal Category:POM

Black Triangle (CHM): NO

Free-text change information supplied by the pharmaceutical company:



Underlined text = new text

Strike-through text = deleted text

 

 

2.       QUALITATIVE AND QUANTITATIVE COMPOSITION

 

One vial with 2 ml concentrate for solution for infusion contains 2 mg ibandronic acid (as 2.25 mg ibandronic acid, monosodium salt,sodium monohydrate).

One vial with 6 ml concentrate for solution for infusion contains 6  mg ibandronic acid, (as 6.75 mg ibandronic acid, monosodium salt,sodium monohydrate).

 

Excipients: Sodium (less than 1 mmol per dose).

 

For athe full list of excipients, see section 6.1.

 

 

4.2     Posology and method of administration

 

Bondronat therapy should only be initiated by physicians experienced in the treatment of cancer.

 

Posology

Prevention of skeletal events in patients with breast cancer and bone metastases

 

The recommended dose for prevention of skeletal events in patients with breast cancer and bone metastases is 6 mg intravenous injection given every 3-4 weeks. The dose should be infused over at least 15 minutes. For infusion, the contents of the vial(s) should only be added to 100 ml isotonic sodium chloride solution or 100 ml 5% glucose solution.

 

[…]

 

Treatment of tumour-induced hypercalcaemia

 

Prior to treatment with Bondronat the patient should be adequately rehydrated with 9 mg/ml (0.9%) sodium chloride solution. Consideration should be given to the severity of the hypercalcaemia as well as the tumour type. In general patients with osteolytic bone metastases require lower doses than patients with the humoral type of hypercalcaemia. In most patients with severe hypercalcaemia (albumin-corrected serum calcium* ³3 mmol/l or ³12 mg/dl) 4 mg is an adequate single dosage.dose. In patients with moderate hypercalcaemia (albumin-corrected serum calcium <3 mmol/l or <12 mg/dl) 2 mg is an effective dose. The highest dose used in clinical trials was 6 mg but this dose does not add any further benefit in terms of efficacy.

 

[…]

 

Bondronat concentrate for solution for infusion should be administered as an intravenous infusion over 2 hours.

 

Patients with hepatic impairment

No dosagedose adjustment is required (see section 5.2).

 

Patients with renal impairment

For patients with mild renal impairment (CLcr 50 and <80 mL/min) no dosagedose adjustment is necessary. For patients with moderate renal impairment (CLcr ≥30 and <50 mL/min) or severe renal impairment (CLcr <30 mL/min) being treated for the prevention of skeletal events in patients with breast cancer and metastatic bone disease the following dosing recommendations should be followed (see Sectionsection 5.2):

 

[…]

 

Elderly population (> 65 years)

No dose adjustment is required. (see section 5.2).

 

Paediatric population

The safety and efficacy of Bondronat in children and adolescents below age 18 years have not been established. No data are available. (see section 5.1 and section 5.2).

 

Method of administration

For intravenous administration.

 

 

 

The content of the vial is to be used as follows:

 

·    Prevention of Skeletal Events - added to 100 ml isotonic sodium chloride solution or 100 ml 5% dextrose solution and infused over at least 15 minutes. See also dose section above for patients with renal impairment.

 

·    Treatment of tumour-induced hypercalcaemia - added to 500 ml isotonic sodium chloride solution or 500 ml 5% dextrose solution and infused over 2 hours.

 

For single use only. Only clear solution without particles should be used.

Bondronat concentrate for solution for infusion should be administered as an intravenous infusion. For this purpose, the contents of the vials are to be added to 500 ml isotonic sodium chloride solution (or 500 ml 5% dextrose solution) and infused over two hours.

 

[…]

 

4.3     Contraindications

 

-        Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.

-        Caution is to be taken in patients with known hypersensitivity to other bisphosphonates.

-        Hypocalcaemia.

 

4.4     Special warnings and precautions for use

 

[…]

 

Anaphylactic reaction/shock

Cases of anaphylactic reaction/shock, including fatal events, have been reported in patients treated with intravenous ibandronic acid.

Appropriate medical support and monitoring measures should be readily available when Bondronat intravenous injection is administered. If anaphylactic or other severe hypersensitivity/allergic reactions occur, immediately discontinue the injection and initiate appropriate treatment.

 

[…]

 

Patients with renal impairment

Clinical studies have not shown any evidence of deterioration in renal function with long term Bondronat therapy. Nevertheless, according to clinical assessment of the individual patient, it is recommended that renal function, serum calcium, phosphate and magnesium should be monitored in patients treated with Bondronat. (see section 4.2).

 

Patients with hepatic impairment

As no clinical data are available, dosagedose recommendations cannot be given for patients with severe hepatic insufficiency. (see section 4.2).

 

[…]

 

Patients with known hypersensitivity to other bisphosphonates

Caution is to be taken in patients with known hypersensitivity to other bisphosphonates.

 

Bondronat is essentially sodium free.

 

4.5     Interaction with other medicinal products and other forms of interaction

 

Interaction studies have only been performed in adults.

 

No interaction was observed when co-administered with melphalan/prednisolone in patients with multiple myeloma.

 

Other interaction studies in postmenopausal women have demonstrated the absence of any interaction potential with tamoxifen or hormone replacement therapy (oestrogen).

 

In relation to disposition, no drugMetabolic interactions of clinical significance are not considered likely. Ibandronic acid is eliminated by renal secretion only and does not undergo any biotransformation. The secretory pathway does not appear to include known acidic or basic transport systems involved in the excretion of otheractive substances. In addition,, since ibandronic acid does not inhibit the major human hepatic P450 isoenzymes and doeshas been shown not to induce the hepatic cytochrome P450 system in rats. Plasma protein binding is low at therapeutic concentrations and ibandronic acid is therefore unlikely to displace other active substances (see section 5.2). Ibandronic acid is eliminated by renal excretion only and does not undergo any biotransformation.

 

Caution is advised when bisphosphonates are administered with aminoglycosides, since both substances can lower serum calcium levels for prolonged periods. Attention should also be paid to the possible existence of simultaneous hypomagnesaemia.

 

In clinical studies, Bondronat has been administered concomitantly with commonly used antineoplastics, diuretics, antibiotics and analgesics without clinically apparent interactions occurring.

 

4.6     Fertility, pregnancy and lactation

 

[…]

 

Breast-feeding

It is not known whether ibandronic acid is excreted in human milk. Studies in lactating rats have demonstrated the presence of low levels of ibandronic acid in the milk following intravenous administration. Bondronat should not be used during lactationbreast-feeding.

 

[…]

 

4.7     Effects on ability to drive and use machines

 

No studies onOn the effectsbasis of the pharmacodynamic and pharmacokinetic profile and reported adverse reactions, it is expected that Bondronat has no or negligible influence on the ability to drive and use machines have been performed..

 

4.8     Undesirable effects

 

Adverse reactions are ranked under heading of frequency, the most frequent first, using the following convention: very common ( ³1/10), common ( ³1/100 and <1/10), uncommon ( ³1/1,000 and <1/100), rare ( ³1/10,000 and <1/1,000), and very rare (<1/10,000).

 

Treatment of tumour induced hypercalcaemia

Summary of Safety Profile

The safety profile for Bondronat in tumour-induced hypercalcaemia is derived from controlled clinical trials in this indication andthe respective indications after the intravenous administration of Bondronat at the recommended doses. Treatment, and from post-marketing experience.

In the treatment of tumour induced hypercalcaemia treatment was most commonlyfrequently associated with a rise in body temperature. OccasionallyLess frequently, a flu-like syndrome consisting of fever, chills, bone and/or muscle ache-like paindecrease in serum calcium below normal range (hypocalcaemia) was reported. In most cases no specific treatment was required and the symptoms subsided after a couple of hours/days.

 

Table 1       Adverse Events in Controlled Clinical Trials in Tumour-Induced Hypercalcaemia after Treatment with Bondronat

System Organ Class

Very common

Common

Uncommon

Rare

Very rare

Immune system disorders

 

 

 

 

Hypersensitivity

Metabolism and nutritional disorders

 

Hypo-calcaemia**

 

 

 

Respiratory, thoracic, and mediastinal disorders

 

 

 

 

Bronchospasm

Skin and subcutaneous tissue disorders

 

 

 

 

Angioneurotic oedema

Musculo-skeletal and connective tissue disorders

 

Bone pain

Myalgia

 

 

General disorders and administration site conditions

Pyrexia

 

Influenza-like illness**, rigors

 

 

Note: Data for both the 2 mg and 4 mg doses of ibandronic acid are pooled.

**See further information below

 

Hypocalcaemia

Decreased renal calcium excretion may be accompanied by a fall in serum phosphate levels not requiring therapeutic measures. The serum calcium level may fall to hypocalcaemic values.

 

Influenza-like illness

A flu-like syndrome consisting of fever, chills, bone and/or muscle ache-like pain has occurred. In most cases no specific treatment was required and the symptoms subsided after a couple of hours/days.

 

In the prevention of skeletal events in patients with breast cancer and bone metastases, treatment was most frequently associated with asthenia followed by rise in body temperature and headache.

 

Tabulated list of adverse reactions

Table 1 lists adverse drug reactions from the pivotal phase III studies (Treatment of tumour induced hypercalcaemia: 311 patients treated with Bondronat 2 mg or 4 mg; Prevention of skeletal events in patients with breast cancer and bone metastases

The safety profile of intravenous Bondronat in patients with breast cancer and bone metastases is derived from a controlled clinical trial in this indication and after the intravenous administration of Bondronat at the recommended dose. 

 

Table 2 lists adverse drug reactions from the pivotal phase III study (: 152 patients treated with  Bondronat 6 mg), i.e. adverse events with a remote, possible, or probable relationship to study medication, and from post-marketing experience.

 

Table 2            1 Adverse Drug Reactions Occurring in Patients with Metastatic Bone Disease due to Breast Cancer Treated with Bondronat 6 mg administered intravenouslyReported for Intravenous Administration of Bondronat

 

Adverse reactions are listed according to MedRA system organ class and frequency category. Frequency categories are defined using the following convention: very common (>1/10), common (≥ 1/100 to < 1/10), uncommon (≥ 1/1,000 to < 1/100), rare (≥ 1/10,000 to < 1/1,000), very rare (<1/10,000), not known (cannot be estimated from the available data). Within each frequency grouping, adverse reactions are presented in order of decreasing seriousness.

System Organ Class

Very common

Common

Uncommon

Rare

Very rare

Infections and infestations

 

Infection

Cystitis, vaginitis, oral candidiasis

 

 

Neoplasms benign, malignant, and unspecified

 

 

Benign skin neoplasm

 

 

Blood and lymphatic system disorders

 

 

Anaemia, blood dyscrasia

 

 

Immune system disorders

 

 

 

 

Hypersensitivity†,

bronchospasm†,

angioedema†

anaphylactic reaction/shock†**

Endocrine disorders

 

Parathyroid disorder

 

 

 

Metabolism and nutrition disorders

 

Hypocalcaemia**

 

Hypophosphataemia

 

 

Psychiatric disorders

 

 

Sleep disorder, anxiety, affection lability

 

 

Nervous system disorders

 

Headache, dizziness, dysgeusia (taste perversion)

Cerbrovascular disorder, nerve root lesion , amnesia, migraine, neuralgia, hypertonia, hyperaestesia, paraesthesia circumoral, parosmia

 

 

Eye disorders

 

Cataract

 

Ocular inflammation†**

 

Ear and labyrinth disorders

 

 

Deafness

 

 

Cardiac disorders

 

Bundle branch block

Myocardial ischaemia, cardiovascular disorder, palpitations

 

 

Respiratory, thoracic, and mediastinal disorders

 

Pharyngitis

Lung oedema, stridor

 

 

Gastrointestinal disorders

 

Diarrhoea, vomiting, dyspepsia, gastrointestinal pain, tooth disorder

Gastroenteritis, gastritis, mouth ulceration, dysphagia, cheilitis

 

 

Hepatobiliary disorders

 

 

Cholelithiasis

 

 

Skin and subcutatneoussubcutaneous tissue disorders

 

Skin disorder, ecchymosis

Rash, alopecia

 

 

Musculoskeletal and connective tissue disorders

 

Osteoarthritis, myalgia, arthralgia, joint disorder,

bone pain

 

Atypical subtrochanteric and diaphyseal femoral fractures (bisphosphonate class adverse reaction)

Osteonecrosis of jaw†**

Renal and urinary disorders

 

 

Urinary retention, renal cyst

 

 

Reproductive system and breast disorders

 

 

Pelvic pain

 

 

General disorders and administration site conditions

 

Pyrexia,

influenza-like illness**, oedema peripheral, asthenia, thirst

Hypothermia

 

 

Investigations

 

Gamma-GT increased, Creatinine increased

Blood alkaline phosphatase increase, weight decrease

 

 

Injury, poisoning and procedural complications

 

 

Injury, injection site pain

 

 

**See further information below

†Identified in post-marketing experience.

 

Description of selected adverse reactions

 

Hypocalcaemia

Decreased renal calcium excretion may be accompanied by a fall in serum phosphate levels not requiring therapeutic measures. The serum calcium level may fall to hypocalcaemic values.

 

Influenza-like illness

A flu-like syndrome consisting of fever, chills, bone and/or muscle ache-like pain has occurred. In most cases no specific treatment was required and the symptoms subsided after a couple of hours/days.

 

[…]

 

Anaphylactic reaction/shock

Cases of anaphylactic reaction/shock, including fatal events, have been reported in patients treated with intravenous intraveneous ibandronic acid.

 

 

5.       PHARMACOLOGICAL PROPERTIES

 

5.1     Pharmacodynamic properties

 

Pharmaco-therapeutic group: DrugsMedicinal products for treatment of bone diseases, bisphosphonate, ATC Code: M05BA06

 

[…]

 

 

Ibandronic acid dose

% of Patients with Response

90% Confidence Interval

2 mg

54

44-63

4 mg

76

62-86

6 mg

78

64-88

 

[…]

 

The analysis of the SMPR was time-adjusted and considered that one or more events occurring in a single 12 week period could be potentially related. Multiple events were therefore counted only once for the purposes of the analysis. Data from this study demonstrated a significant advantage for intravenous Bondronat 6 mg over placebo in the reduction in SREs measured by the time-adjusted SMPR (p=0.004). The number of SREs was also significantly reduced with Bondronat 6 mg and there was a 40% reduction in the risk of a SRE over placebo (relative risk 0.6, p = 0.003). Efficacy results are summarised in Table 3.

 

2.

 

Table 32     Efficacy Results (Breast Cancer Patients with Metastatic Bone Disease)

 

 

All Skeletal Related Events (SREs)

Placebo

n=158

Bondronat 6 mg

n=154

 

p-value

SMPR (per patient year)

 

1.48

1.19

p=0.004

Number of events (per patient)

 

3.64

2.65

p=0.025

SRE relative risk

 

-

0.60

p=0.003

 

Secondary efficacy endpoints

A statistically significant improvement in bone pain score was shown for intravenous Bondronat 6 mg compared to placebo. The pain reduction was consistently below baseline throughout the entire study and accompanied by a significantly reduced use of analgesics. The deterioration in Quality of Life was significantly less in Bondronat treated patients compared with placebo. A tabular summary of these secondary efficacy results is presented in Table 43.

 

Table 43     Secondary Efficacy Results (Breast cancer Patients with Metastatic Bone Disease)

 

 

Placebo

n=158

Bondronat 6 mg

n=154

 p-value

Bone pain *

 

0.21

-0.28

p<0.001

Analgesic use *

 

0.90

0.51

p=0.083

Quality of Life *

 

-45.4

-10.3

p=0.004

* Mean change from baseline to last assessment.

 

[…]

 

Paediatric population (see section 4.2 and section 5.2)

The safety and efficacy of Bondronat in children and adolescents below age 18 years have not been established. No data are available.

 

5.2     Pharmacokinetic properties

 

[…]

 

Distribution

After initial systemic exposure, ibandronic acid rapidly binds to bone or is excreted into urine. In humans, the apparent terminal volume of distribution is at least 90 l and the amount of dose reaching the bone is estimated to be 40-50% of the circulating dose. Protein binding in human plasma is approximately 87% at therapeutic concentrations, and thus drug-drug  interaction with other medicinal products, due to displacement is unlikely.

 

[…]

 

The secretory pathway of renal elimination does not appear to include known acidic or basic transport systems involved in the excretion of other active substances. In addition, ibandronic acid does not inhibit the major human hepatic P450 isoenzymes and does not induce the hepatic cytochrome P450 system in rats.

 

[…]

 

Patients with hepatic impairment (see section 4.2)

There are no pharmacokinetic data for ibandronic acid in patients who have hepatic impairment. The liver has no significant role in the clearance of ibandronic acid since it is not metabolized but is cleared by renal excretion and by uptake into bone.  Therefore dosage adjustment is not necessary in patients with hepatic impairment. Further, as protein binding of ibandronic acid is approximately 87% at therapeutic concentrations, hypoproteinaemia in severe liver disease is unlikely to lead to clinically significant increases in free plasma concentration.

 

Elderly (see section 4.2)

In a multivariate analysis, age was not found to be an independent factor of any of the pharmacokinetic parameters studied. As renal function decreases with age, this is the only factor that should be considered (see renal impairment section).

 

Paediatric population  (see section 4.2 and section 5.1)

 

There are no data on the use of Bondronat in patients less than 18 years old.

 

 

6.4     Special precautions for storage

 

No special precautions for storage prior to reconstitution.This medicinal product does not require any special storage conditions prior to reconstitution.

After reconstitution: Store at 2 °C – 8 °C (in a refrigerator).

 

[…]

 

 

6.5     Nature and contents of container

 

Bondronat is supplied as packs containing 1 vial (2 ml type I glass vial with a bromobutyl rubber stopper).

 

Bondronat  is supplied as packs containing 1, 5 and 10 vials (6 ml type I glass vial). The vials are closed with a bromobutyl rubber stoppers complying with Ph.Eur.stopper). Not all pack sizes may be marketed.

 

6.6     Special precautions for disposal

 

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

The release of pharmaceuticals in the environment should be minimized.

 

 

9.       DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

 

Date of first Aauthorisation: 25 June 1996

 

Date of last latest renewal: 25 June 2006

 

 

10.       DATE OF REVISION OF THE TEXT

 

15 November 2012

 

 

Reasons for adding or updating:

  • Change to section 4.3 - Contraindications
  • Change to section 5.3 - Preclinical Safety Data

Date of revision of text on the SPC:26-07-2011

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4.6      Fertility, Ppregnancy and lactation

 

Pregnancy

There are no adequate data from the use of ibandronic acid in pregnant women. Studies in rats have shown reproductive toxicity (see section 5.3). The potential risk for humans is unknown. Therefore, Bondronat should not be used during pregnancy.

 

Breast-feeding

It is not known whether ibandronic acid is excreted in human milk. Studies in lactating rats have demonstrated the presence of low levels of ibandronic acid in the milk following intravenous administration. Bondronat should not be used during lactation.

 

Fertility

There are no data on the effects of ibandronic acid from humans. In reproductive studies in rats by the oral route, ibandronic acid decreased fertility. In studies in rats using the intravenous route, ibandronic acid decreased fertility at high daily doses (see section 5.3).

5.3      Preclinical safety data

 

Effects in non-clinical studies were observed only at exposures sufficiently in excess of the maximum human exposure indicating little relevance to clinical use. As with other bisphosphonates, the kidney was identified to be the primary target organ of systemic toxicity.

 

Mutagenicity/Carcinogenicity:

No indication of carcinogenic potential was observed. Tests for genotoxicity revealed no evidence of effects on genetic activity for ibandronic acid.

 

Reproductive toxicity:

No evidence of direct foetal toxicity or teratogenic effects were observed for ibandronic acid in intravenously treated rats and rabbits. In reproductive studies in rats by the oral route effects on fertility consisted of increased preimplantation losses at dose levels of 1 mg/kg/day and higher. In reproductive studies in rats by the intravenous route, ibandronic acid decreased sperm counts at doses of 0.3 and 1 mg/kg/day and decreased fertility in males at 1 mg/kg/day and in females at 1.2 mg/kg/day. Adverse effects of ibandronic acid in reproductive toxicity studies in the rat were those expected for this class of drug (bisphosphonates). They include a decreased number of implantation sites, interference with natural delivery (dystocia), an increase in visceral variations (renal pelvis ureter syndrome) and teeth abnormalities in F1 offspring in rats.

 

Reasons for adding or updating:

  • Change to section 4.4 - Special warnings and precautions for Use
  • Change to section 4.8 - Undesirable Effects

Date of revision of text on the SPC:29-06-2011

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Underlined text has been added

 

4.4      Special warnings and  precautions for use

 

Patients with disturbances of bone and mineral metabolism

Hypocalcaemia and other disturbances of bone and mineral metabolism should be effectively treated before starting Bondronat therapy for metastatic bone disease.

 

Adequate intake of calcium and vitamin D is important in all patients. Patients should receive supplemental calcium and/or vitamin D if dietary intake is inadequate

 

Osteonecrosis of the jaw (ONJ)

Osteonecrosis of the jaw, generally associated with tooth extraction and/or local infection (including osteomyelitis) has been reported in patients with cancer receiving treatment regimens including primarily intravenously administered bisphosphonates. Many of these patients were also receiving chemotherapy and corticosteroids. Osteonecrosis of the jaw has also been reported in patients with osteoporosis receiving oral bisphosphonates.

 

A dental examination with appropriate preventive dentistry should be considered prior to treatment with bisphosphonates in patients with concomitant risk factors (e.g. cancer, chemotherapy, radiotherapy, corticosteroids, poor oral hygiene).

 

While on treatment, these patients should avoid invasive dental procedures if possible. For patients who develop osteonecrosis of the jaw 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 osteonecrosis of the jaw. Clinical judgement of the treating physician 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 in patients receiving long-term treatment for 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 bisphosphonate-treated patients who have sustained a femoral shaft fracture. Poor healing of these fractures has also been reported. Discontinuation of bisphosphonate 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.

During bisphosphonate 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.

 

Patients with renal impairment

Clinical studies have not shown any evidence of deterioration in renal function with long term Bondronat therapy. Nevertheless, according to clinical assessment of the individual patient, it is recommended that renal function, serum calcium, phosphate and magnesium should be monitored in patients treated with Bondronat.

 

Patients with hepatic impairment

As no clinical data are available, dosage recommendations cannot be given for patients with severe hepatic insufficiency.

 

Patients with cardiac impairment

Overhydration should be avoided in patients at risk of cardiac failure.

4.8      Undesirable effects

 

Adverse reactions are ranked under heading of frequency, the most frequent first, using the following convention: very common ( ³1/10), common ( ³1/100 and <1/10), uncommon ( ³1/1,000 and <1/100), rare ( ³1/10,000 and <1/1,000), and very rare ( <1/10,000).

 

Treatment of tumour induced hypercalcaemia

The safety profile for Bondronat in tumour-induced hypercalcaemia is derived from controlled clinical trials in this indication and after the intravenous administration of Bondronat at the recommended doses. Treatment was most commonly associated with a rise in body temperature. Occasionally, a flu-like syndrome consisting of fever, chills, bone and/or muscle ache-like pain was reported. In most cases no specific treatment was required and the symptoms subsided after a couple of hours/days.

 

Table 1          Adverse  Events in Controlled Clinical Trials in Tumour-Induced Hypercalcaemia  after Treatment with Bondronat

 

System Organ Class

Very common

Common

Uncommon

Rare

Very rare

Immune system disorders

 

 

 

 

Hypersensitivity

Metabolism and nutritional disorders

 

Hypo-calcaemia**

 

 

 

Respiratory, thoracic, and mediastinal disorders

 

 

 

 

Bronchospasm

Skin and subcutaneous tissue disorders

 

 

 

 

Angioneurotic oedema

Musculo-skeletal and connective tissue disorders

 

Bone pain

Myalgia

 

 

General disorders and administration site conditions

Pyrexia

 

Influenza-like illness**, rigors

 

 

Note: Data for both the 2 mg and 4 mg doses of ibandronic acid are pooled.

**See further information below

 

Hypocalcaemia

Decreased renal calcium excretion may be accompanied by a fall in serum phosphate levels not requiring therapeutic measures. The serum calcium level may fall to hypocalcaemic values.

 

Influenza-like illness

A flu-like syndrome consisting of fever, chills, bone and/or muscle ache-like pain has occurred. In most cases no specific treatment was required and the symptoms subsided after a couple of hours/days.

 

Prevention of skeletal events in patients with breast cancer and bone metastases

The safety profile of intravenous Bondronat in patients with breast cancer and bone metastases is derived from a controlled clinical trial in this indication and after the intravenous administration of Bondronat at the recommended dose.

 

Table 2 lists adverse drug reactions from the pivotal phase III study (152 patients treated with  Bondronat 6 mg), i.e. adverse events with a remote, possible, or probable relationship to study medication, and from postmarketing experience.

 

Table 2          Adverse Drug Reactions Occurring in Patients with Metastatic Bone Disease due to Breast Cancer Treated with Bondronat 6 mg administered intravenously

 

System Organ Class

Very common

Common

Uncommon

Rare

Very rare

Infections and infestations

 

Infection

Cystitis, vaginitis, oral candidiasis

 

 

Neoplasms benign, malignant, and unspecified

 

 

Benign skin neoplasm

 

 

Blood and lymphatic system disorders

 

 

Anaemia, blood dyscrasia

 

 

Endocrine disorders

 

Parathyroid disorder

 

 

 

Metabolism and nutrition disorders

 

 

Hypophosphataemia

 

 

Psychiatric disorders

 

 

Sleep disorder, anxiety, affection lability

 

 

Nervous system disorders

 

Headache, dizziness, dysgeusia (taste perversion)

Cerbrovascular disorder, nerve root lesion , amnesia, migraine, neuralgia, hypertonia, hyperaestesia, paraesthesia circumoral, parosmia

 

 

Eye disorders

 

Cataract

 

Ocular inflammation†**

 

Ear and labyrinth disorders

 

 

Deafness

 

 

Cardiac disorders

 

Bundle branch block

Myocardial ischaemia, cardiovascular disorder, palpitations

 

 

Respiratory, thoracic, and mediastinal disorders

 

Pharyngitis

Lung oedema, stridor

 

 

Gastrointestinal disorders

 

Diarrhoea, vomiting, dyspepsia, gastrointestinal pain, tooth disorder

Gastroenteritis, gastritis, mouth ulceration, dysphagia, cheilitis

 

 

Hepatobiliary disorders

 

 

Cholelithiasis

 

 

Skin and subcutatneous tissue disorders

 

Skin disorder, ecchymosis

Rash, alopecia

 

 

Musculoskeletal and connective tissue disorders

 

Osteoarthritis, myalgia, arthralgia, joint disorder

 

Atypical subtrochanteric and diaphyseal femoral fractures (bisphosphonate class adverse reaction)

Osteonecrosis of jaw†**

Renal and urinary disorders

 

 

Urinary retention, renal cyst

 

 

Reproductive system and breast disorders

 

 

Pelvic pain

 

 

General disorders and administration site conditions

 

Influenza-like illness, oedema peripheral, asthenia, thirst

Hypothermia

 

 

Investigations

 

Gamma-GT increased, creatinine increased

Blood alkaline phosphatase increase, weight decrease

 

 

Injury, poisoning and procedural complications

 

 

Injury, injection site pain

 

 

**See further information below.

†Identified in postmarketing experience.

 

Osteonecrosis of jaw

Osteonecrosis of the jaw has been reported in patients treated by bisphosphonates. The majority of the reports refer to cancer patients, but such cases have also been reported in patients treated for osteoporosis. Osteonecrosis of the jaw is generally associated with tooth extraction and / or local infection (including osteomyelitis). Diagnosis of cancer, chemotherapy, radiotherapy, corticosteroids and poor oral hygiene are also deemed as risk factors (see section 4.4).

 

Ocular inflammation

Ocular inflammation events such as uveitis, episcleritis and scleritis have been reported with ibandronic acid. In some cases, these events did not resolve until the ibandronic acid was discontinued.

 

Reasons for adding or updating:

  • Change to section 4.8 - Undesirable Effects
  • Change to section 5.1 - Pharmacodynamic Properties
  • Change to section 6. 6 - Instructions for use, handling and disposal
  • Change to section 2 - Qualitative and quantitative composition
  • Change to section 4.1 - Therapeutic indications
  • Change to section 4.2 - Posology and method of administration
  • Change to section 4.3 - Contraindications
  • Change to section 4.4 - Special warnings and precautions for Use
  • Change to section 4.5 - Interaction with other medicinal products and other forms of interaction

Date of revision of text on the SPC:14-04-2011

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2.       QUALITATIVE AND QUANTITATIVE COMPOSITION

 

Bondronat 2 mg

One vial with 2 ml concentrate for solution for infusion contains 2 mg ibandronic acid (as 2.25 mg ibandronic acid, monosodium salt, monohydrate).

 

Bondronat 6 mg

One vial with 6 ml concentrate for solution for infusion contains 6 mg ibandronic acid (as 6.75 mg ibandronic acid, monosodium salt, monohydrate).

 

Excipients: Sodium (less than 1 mmol per dose).

 

For a full list of excipients, see section 6.1.

 

4.1     Therapeutic indications

 

Bondronat is indicated in adults for

 

-        Prevention of skeletal events (pathological fractures, bone complications requiring radiotherapy or surgery) in patients with breast cancer and bone metastases.

 

-        Treatment of tumour-induced hypercalcaemia with or without metastases.

 

 

4.2     Posology and method of administration

 

Bondronat therapy should only be initiated by physicians experienced in the treatment of cancer.

 

For intravenous administration.

 

For single use only. Only clear solution without particles should be used.

 

Posology

Prevention of Sskeletal eEvents in pPatients with Bbreast Ccancer and bBone Mmetastases

 

The recommended dose for prevention of skeletal events in patients with breast cancer and bone metastases is 6 mg intravenous injection given every 3-4 weeks. The dose should be infused over at least 15 minutes. For infusion, the contents of the vials(s) should only be added to 100 ml isotonic sodium chloride solution or 100 ml 5% glucose solution.

 

A shorter (i.e. 15 min) infusion time should only be used for patients with normal renal function or mild renal impairment. There are no data available characterizing the use of a shorter infusion time in patients with creatinine clearance below 50 ml/min. Prescribers should consult the section Patients with Renal Impairment (see sSection 4.2) for recommendations on dosing and administration in this patient group.

 

Treatment of Ttumour-Iinduced hHypercalcaemia

 

Prior to treatment with Bondronat the patient should be adequately rehydrated with 9 mg/ml (0.9%) sodium chloride. Consideration should be given to the severity of the hypercalcaemia as well as the tumour type. In general patients with osteolytic bone metastases require lower doses than patients with the humoral type of hypercalcaemia. In most patients with severe hypercalcaemia (albumin-corrected serum calcium* ³3 mmol/l or ³12 mg/dl) 4 mg is an adequate single dosage. In patients with moderate hypercalcaemia (albumin-corrected serum calcium <3 mmol/l or <12 mg/dl) 2 mg is an effective dose. The highest dose used in clinical trials was 6 mg but this dose does not add any further benefit in terms of efficacy.

 

* Note albumin-corrected serum calcium concentrations are calculated as follows:

Albumin-corrected

Sserum calcium (mmol/l)

=

serum calcium (mmol/l) - [0.02 x albumin (g/l)] + 0.8

Or

Albumin-corrected

Sserum calcium (mg/dl)

=

serum calcium (mg/dl)  + 0.8 x [4 - albumin (g/dl)]

 

 

 

To convert the albumin-corrected serum calcium in mmol/l value to mg/dl, multiply by 4.

 

 

In most cases a raised serum calcium level can be reduced to the normal range within 7 days. The median time to relapse (return of albumin-corrected serum calcium to levels above 3 mmol/l) was 18 ‑ 19 days for the 2 mg and 4 mg doses. The median time to relapse was 26 days with a dose of 6 mg.

 

A limited number of patients (50 patients) have received a second infusion for hypercalcaemia. Repeated treatment may be considered in case of recurrent hypercalcaemia or insufficient efficacy.

 

Bondronat concentrate for solution for infusion should be administered as an intravenous infusion. For this purpose, the contents of the vials are to be added to 500 ml isotonic sodium chloride solution (or 500 ml 5% dextrose solution) and infused over two hours.

 

As the inadvertent intra-arterial administration of preparations not expressly recommended for this purpose as well as paravenous administration can lead to tissue damage, care must be taken to ensure that Bondronat concentrate for solution for infusion is administered intravenously.

 

Patients with hepatic impairment

No dosage adjustment is required (see section 5.2).

 

Patients with renal impairment

For patients with mild renal impairment (CLcr 50 and <80 mL/min) no dosage adjustment is necessary. For patients with moderate renal impairment (CLcr ≥30 and <50 mL/min) or severe renal impairment (CLcr <30 mL/min) being treated for the prevention of skeletal events in patients with breast cancer and metastatic bone disease the following dosing recommendations should be followed (see Section 5.2):

 

Creatinine Clearance (ml/min)

Dosage / Infusion time 1

Infusion Volume 2

50 CLcr <80

6 mg / 15 minutes

100 ml

30 CLcr <50

4 mg / 1 hour

500 ml

<30

2 mg / 1 hour

500 ml

1  Administration every 3 to 4 week

2  0.9% sodium chloride solution or 5% glucose solution

 

A 15 minute infusion time has not been studied in cancer patients with CLCr <50 mL/min.

 

Elderly

No dose adjustment is required.

 

Children and adolescentsPaediatric population

The safety and efficacy of Bondronat is not recommended for patients in children and adolescents below age 18 years have not been established. due to insufficient data on safety and efficacy No data are available.

 

Method of administration

For intravenous administration.

 

For single use only. Only clear solution without particles should be used.

Bondronat concentrate for solution for infusion should be administered as an intravenous infusion. For this purpose, the contents of the vials are to be added to 500 ml isotonic sodium chloride solution (or 500 ml 5% dextrose solution) and infused over two hours.

 

As the inadvertent intra-arterial administration of preparations not expressly recommended for this purpose as well as paravenous administration can lead to tissue damage, care must be taken to ensure that Bondronat concentrate for solution for infusion is administered intravenously.

 

 

4.3     Contraindications

 

Hypocalcaemia (see section 4.4).

 

-        Hypersensitivity to the active substance or to any of the excipients.

-        Caution is to be taken in patients with known hypersensitivity to other bisphosphonates.

 

Bondronat should not be used in children.

 

-        Hypocalcaemia

 

 

4.4     Special warnings and  precautions for use

 

Clinical studies have not shown any evidence of deterioration in renal function with long term Bondronat therapy. Nevertheless, according to clinical assessment of the individual patient, it is recommended that renal function, serum calcium, phosphate and magnesium should be monitored in patients treated with Bondronat.Patients with disturbances of bone and mineral metabolism

 

As no clinical data are available, dosage recommendations cannot be given for patients with severe hepatic insufficiency.

 

Overhydration should be avoided in patients at risk of cardiac failure.

 

Hypocalcaemia and other disturbances of bone and mineral metabolism should be effectively treated before starting Bondronat therapy for metastatic bone disease.

 

Adequate intake of calcium and vitamin D is important in all patients. Patients should receive supplemental calcium and/or vitamin D if dietary intake is inadequate.

 

Osteonecrosis of the jaw (ONJ)

Osteonecrosis of the jaw, generally associated with tooth extraction and/or local infection (including osteomyelitis) has been reported in patients with cancer receiving treatment regimens including primarily intravenously administered bisphosphonates. Many of these patients were also receiving chemotherapy and corticosteroids. Osteonecrosis of the jaw has also been reported in patients with osteoporosis receiving oral bisphosphonates.

 

A dental examination with appropriate preventive dentistry should be considered prior to treatment with bisphosphonates in patients with concomitant risk factors (e.g. cancer, chemotherapy, radiotherapy, corticosteroids, poor oral hygiene).

 

While on treatment, these patients should avoid invasive dental procedures if possible. For patients who develop osteonecrosis of the jaw 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 osteonecrosis of the jaw. Clinical judgement of the treating physician should guide the management plan of each patient based on individual benefit/risk assessment.

 

Patients with renal impairment

Clinical studies have not shown any evidence of deterioration in renal function with long term Bondronat therapy. Nevertheless, according to clinical assessment of the individual patient, it is recommended that renal function, serum calcium, phosphate and magnesium should be monitored in patients treated with Bondronat.

 

Patients with hepatic impairment

As no clinical data are available, dosage recommendations cannot be given for patients with severe hepatic insufficiency.

 

Patients with cardiac impairment

Overhydration should be avoided in patients at risk of cardiac failure.

 

 

4.5     Interaction with other medicinal products and other forms of interaction

 

Bondronat should not be mixed with calcium containing solutions

 

Interaction studies have only been performed in adults.

 

No interaction was observed when co-administered with melphalan/prednisolone in patients with multiple myeloma.

 

Other interaction studies in postmenopausal women have demonstrated the absence of any interaction potential with tamoxifen or hormone replacement therapy (oestrogen).

 

In relation to disposition, no drug interactions of clinical significance are likely. Ibandronic acid is eliminated by renal secretion only and does not undergo any biotransformation. The secretory pathway does not appear to include known acidic or basic transport systems involved in the excretion of other active substances. In addition, ibandronic acid does not inhibit the major human hepatic P450 isoenzymes and does not induce the hepatic cytochrome P450 system in rats. Plasma protein binding is low at therapeutic concentrations and ibandronic acid is therefore unlikely to displace other active substances.

 

Caution is advised when bisphosphonates are administered with aminoglycosides, since both agentssubstances can lower serum calcium levels for prolonged periods. Attention should also be paid to the possible existence of simultaneous hypomagnesaemia.

 

In clinical studies, Bondronat has been administered concomitantly with commonly used anticancer agentsantineoplastics, diuretics, antibiotics and analgesics without clinically apparent interactions occurring.

 

 

Interaction studies have only been performed in adults.

 

4.8     Undesirable effects

 

Adverse reactions are ranked under heading of frequency, the most frequent first, using the following convention: very common ( ³1/10%), common ( ³1%/100 and <1/10%), uncommon ( ³0.1%/1,000 and <1%/100), rare ( ³0.01%1/10,000 and <0.1%/1,000), and very rare ( £0.01%<1/10,000).

 

Treatment of tTumour iInduced Hhypercalcaemia

The safety profile for Bondronat in tumour-induced hypercalcaemia is derived from controlled clinical trials in this indication and after the intravenous administration of Bondronat at the recommended doses. Treatment was most commonly associated with a rise in body temperature. Occasionally, a flu-like syndrome consisting of fever, chills, bone and/or muscle ache-like pain was reported. In most cases no specific treatment was required and the symptoms subsided after a couple of hours/days.

 

Table 1 lists adverse reactions recorded in the trials (events were recorded irrespective of a determination of causality).

 

Table 1       Number (percentage) of Patients Reporting     Adverse Reactions  Events in Controlled Clinical Trials in Tumour-Induced Hypercalcaemia  after Treatment with Bondronat

 

System Organ Class / Adverse reaction

Frequency

Number (%)

(n=352)

Metabolism and nutrition disorders

Common:         Hypocalcaemia

 

 

10 (2.8)

Musculoskeletal and connective tissue disorders:

Common:         Bone Pain

Uncommon:      Myalgia

 

 

6 (1.7)

1 (0.3)

General disorders and administration site conditions:

Very common: Pyrexia

Uncommon:      Influenza-like illness

                        Rigors

 

39 (11.1)

2 (0.6)

1 (0.3)

 

System Organ Class

Very common

Common

Uncommon

Rare

Very rare

Immune system disorders

 

 

 

 

Hypersensitivity

Metabolism and nutritional disorders

 

Hypo-calcaemia**

 

 

 

Respiratory, thoracic, and mediastinal disorders

 

 

 

 

Bronchospasm

Skin and subcutaneous tissue disorders

 

 

 

 

Angioneurotic oedema

Musculo-skeletal and connective tissue disorders

 

Bone pain

Myalgia

 

 

General disorders and administration site conditions

Pyrexia

 

Influenza-like illness**, rigors

 

 

Note: Data for both the 2 mg and 4 mg doses of ibandronic acid are pooled. Events were recorded irrespective of a determination of causality.

 

Frequently, decreased**See further information below

 

Hypocalcaemia

Decreased renal calcium excretion ismay be accompanied by a fall in serum phosphate levels not requiring therapeutic measures. The serum calcium level may fall to hypocalcaemic values.

 

Other reactions reported at lower frequency are as follows:Influenza-like illness

 

Immune system disorders:

Very rare:         Hypersensitivity

 

Skin and subcutaneous tissue disorders:

Very rare:         Angioneurotic oedema

 

Respiratory, thoracic and mediastinal disorders:

Very rare:         Bronchospasm

 

Administration of other bisphosphonates has been associated with broncho-constriction in

acetylsalicylic acid-sensitive asthmatic patients.

 

Prevention of Skeletal Events in Patients with Breast Cancer and Bone Metastases

A flu-like syndrome consisting of fever, chills, bone and/or muscle ache-like pain has occurred. In most cases no specific treatment was required and the symptoms subsided after a couple of hours/days.

 

Prevention of skeletal events in patients with breast cancer and bone metastases

The safety profile of intravenous Bondronat in patients with breast cancer and bone metastases is derived from a controlled clinical trial in this indication and after the intravenous administration of Bondronat at the recommended dose. 

 

Table 2 lists adverse drug reactions from the pivotal phase III study (152 patients treated with  Bondronat 6 mg), i.e. adverse events with a remote, possible, or probable relationship to study medication, occurring commonly and more frequently in the active treatment group than in placeboand from postmarketing experience.

 

Table 2       Adverse Drug Reactions Occurring Commonly and Greater than Placebo in Patients with Metastatic Bone Disease due to Breast Cancer Treated with Bondronat 6 mg administered intravenously

 

Adverse Reaction

Placebo

(n = 157)

No. (%)

Bondronat 6mg

(n = 152)

No. (%)

Infections and Infestations:

            Infection

 

1 (0.6)

 

2 (1.3)

Endocrine disorders:

            Parathyroid disorder

 

1 (0.6)

 

2 (1.3)

Nervous System disorders:

            Headache

            Dizziness

            Dysgeusia (taste perversion)

 

4 (2.5)

2 (1.3)

0 (0.0)

 

9 (5.9)

4 (2.6)

2 (1.3)

Eye disorders:

            Cataract

 

1 (0.6)

 

2 (1.3)

Cardiac disorders:

            Bundle branch block

 

1 (0.6)

 

2 (1.3)

Respiratory, thoracic and mediastinal disorders:

            Pharyngitis

 

 

0 (0.0)

 

 

3 (2.0)

Gastrointestinal disorders:

            Diarrhoea

            Dyspepsia

            Vomiting

            Gastrointestinal pain

            Tooth disorder

 

1 (0.6)

5 (3.2)

2 (1.3)

2 (1.3)

0 (0.0)

 

8 (5.3)

6 (3.9)

5 (3.3)

4 (2.6)

3 (2.0)

Skin and subcutaneous tissue disorders:

            Skin disorder

            Ecchymosis

 

 

0 (0.0)

0 (0.0)

 

 

2 (1.3)

2 (1.3)

Musculoskeletal and connective tissue disorders:

            Myalgia

            Arthralgia

            Joint disorder

            Osteoarthritis

 

 

6 (3.8)

1 (0.6)

0 (0.0)

0 (0.0)

 

 

8 (5.3)

2 (1.3)

2 (1.3)

2 (1.3)

General disorders:

            Asthenia

            Influenza-like illness

            Oedema peripheral

            Thirst

 

8 (5.1)

2 (1.3)

2 (1.3)

0 (0.0)

 

10 (6.6)

8 (5.3)

3 (2.0)

2 (1.3)

Investigations:

            Gamma-GT increased

            Creatinine increased

 

1 (0.6)

1 (0.6)

 

4 (2.6)

3 (2.0)

 

Other adverse reactions reported  at a lower frequency are as follows:

 

Uncommon:

Infection and infestation: cystitis, vaginitis, oral candidiasis

Neoplasms benign and malignant (including cysts and polyps): benign skin neoplasm        

Blood and lymphatic system: anaemia, blood dyscrasia

Metabolism and nutrition disorders: hypophosphataemia

Psychiatric disorders: sleep disorder, anxiety, affection lability

Nervous system disorders: cerbrovascular disorder, nerve root lesion , amnesia, migraine, neuralgia, hypertonia, hyperaesthesia, paraesthesia circumoral, parosmia.

Ear and labyrinth disorders: deafness

Cardiac disorders: myocardial ischaemia, cardiovascular disorder, palpitations

Vascular disorders: hypertension, lymphoedema, varicose veins

Respiratory, thoracic and mediastinal disorders: lung oedema, stridor

Gastrointestinal disorders: gastroenteritis, dysphagia, gastritis, mouth ulceration, cheilitis

Hepato-biliary disorders: cholelithiasis

Skin and subcutaneous tissue disorders: rash, alopecia

Renal and urinary disorders: urinary retention, renal cyst

Reproductive system and breast disorders: pelvic pain

General disorders and administration site conditions: hypothermia

Investigations: blood alkaline phosphatase increase, weight decrease

Injury, poisoning and procedural complications: injury, injection site pain

 

System Organ Class

Very common

Common

Uncommon

Rare

Very rare

Infections and infestations

 

Infection

Cystitis, vaginitis, oral candidiasis

 

 

Neoplasms benign, malignant, and unspecified

 

 

Benign skin neoplasm

 

 

Blood and lymphatic system disorders

 

 

Anaemia, blood dyscrasia

 

 

Endocrine disorders

 

Parathyroid disorder

 

 

 

Metabolism and nutrition disorders

 

 

Hypophosphataemia

 

 

Psychiatric disorders

 

 

Sleep disorder, anxiety, affection lability

 

 

Nervous system disorders

 

Headache, dizziness, dysgeusia (taste perversion)

Cerbrovascular disorder, nerve root lesion , amnesia, migraine, neuralgia, hypertonia, hyperaestesia, paraesthesia circumoral, parosmia

 

 

Eye disorders

 

Cataract

 

Ocular inflammation†**

 

Ear and labyrinth disorders

 

 

Deafness

 

 

Cardiac disorders

 

Bundle branch block

Myocardial ischaemia, cardiovascular disorder, palpitations

 

 

Respiratory, thoracic, and mediastinal disorders

 

Pharyngitis

Lung oedema, stridor

 

 

Gastrointestinal disorders

 

Diarrhoea, vomiting, dyspepsia, gastrointestinal pain, tooth disorder

Gastroenteritis, gastritis, mouth ulceration, dysphagia, cheilitis

 

 

Hepatobiliary disorders

 

 

Cholelithiasis

 

 

Skin and subcutatneous tissue disorders

 

Skin disorder, ecchymosis

Rash, alopecia

 

 

Musculoskeletal and connective tissue disorders

 

Osteoarthritis, myalgia, arthralgia, joint disorder

 

 

Osteonecrosis of jaw†**

Renal and urinary disorders

 

 

Urinary retention, renal cyst

 

 

Reproductive system and breast disorders

 

 

Pelvic pain

 

 

General disorders and administration site conditions

 

Influenza-like illness, oedema peripheral, asthenia, thirst

Hypothermia

 

 

Investigations

 

Gamma-GT increased, creatinine increased

Blood alkaline phosphatase increase, weight decrease

 

 

Injury, poisoning and procedural complications

 

 

Injury, injection site pain

 

 

**See further information below.

†Identified in postmarketing experience.

 

Osteonecrosis of jaw

Osteonecrosis of the jaw has been reported in patients treated by bisphosphonates. The majority of the reports refer to cancer patients, but such cases have also been reported in patients treated for osteoporosis. Osteonecrosis of the jaw is generally associated with tooth extraction and / or local infection (including osteomyelitis). Diagnosis of cancer, chemotherapy, radiotherapy, corticosteroids and poor oral hygiene are also deemed as risk factors (see section 4.4).

 

Ocular inflammation

Ocular inflammation events such as uveitis, episcleritis and scleritis have been reported with

ibandronic acid. In some cases, these events did not resolve until the ibandronic acid was

discontinued.

 

5.1     Pharmacodynamic properties

 

Pharmaco-therapeutic group: Drugs for treatment of bone diseases, bBisphosphonate, ATC Code: M05B A 06

 

[…]

 

Paediatric population

The safety and efficacy of Bondronat in children and adolescents below age 18 years have not been established. No data are available.

 

6.6     Special precautions for disposal and other handling

 

Any unused product or waste material should be disposed of in accordance with local requirements. The release of pharmaceuticals in the environment should be minimized.

 

Reasons for adding or updating:

  • Change to section 4.2 - Posology and method of administration
  • Change to section 4.3 - Contraindications
  • Change to section 5.2 - Pharmacokinetic Properties

Date of revision of text on the SPC:25-01-2010

Legal Category:POM

Black Triangle (CHM): NO

Free-text change information supplied by the pharmaceutical company:



Underlined text has been added, text with strike through deleted:

 

4.2     Posology and method of administration

There is no evidence of a reduction in tolerability associated with an increase in exposure to ibandronate in patients with various degrees of renal impairment. However, for the prevention of skeletal events in patients with breast cancer and bone metastases the following recommendations should be followed:

For patients with mild renal impairment (CLcr 50 and <80 mL/min) no dosage adjustment is necessary. For patients with moderate renal impairment (CLcr ≥30 and <50 mL/min) or severe renal impairment (CLcr <30 mL/min) being treated for the prevention of skeletal events in patients with breast cancer and metastatic bone disease the following dosing recommendations should be followed (see Section 5.2):

 

Creatinine Clearance (ml/min)

Dosage / Infusion time 1

Infusion Volume 2

50 CLcr <80

6 mg / 15 minutes

100 ml

30<  CLcr <50

4 mg / 1 hour

500 ml

<30

2 mg / 1 hour

500 ml

 

4.3     Contraindications

 

Hypocalcaemia (see section 4.4).

 

5.2     Pharmacokinetic properties

Pharmacokinetics in Special Populations

 

Gender

Bioavailability and pharmacokinetics of ibandronic acid are similar in both men and women.

 

Race

There is no evidence for clinically relevant interethnic differences between Asians and Caucasians in ibandronic acid disposition. There are only very few data available on patients with African origin.

 

Patients with renal impairment

Exposure to ibandronic acid in patients with various degrees of renal impairment is related to creatinine clearance (CLcr). In subjects with severe renal impairment (mean estimated CLcr = 21.2  mL/min), dose-adjusted mean AUC0-24h was increased by 110% compared to healthy volunteers. In clinical pharmacology trial WP18551, after a single dose intravenous administration of 6 mg (15 minutes infusion), mean AUC0-24 increased by 14% and 86%, respectively, in subjects with mild (mean estimated CLcr=68.1 mL/min) and moderate (mean estimated CLcr=41.2 mL/min) renal impairment compared to healthy volunteers (mean estimated CLcr=120 mL/min). Mean Cmax was not increased in patients with mild renal impairment and increased by 12% in patients with moderate renal impairment. There is no evidence of a reduction in tolerability associated with an increase in exposure. However, an adjustment in the dose or infusion time is recommended in patients being treated for the prevention of skeletal events in patients with breast cancer and bone metastases (see section 4.2).For patients with mild renal impairment (CLcr ≥50 and <80 mL/min) no dosage adjustment is necessary. For patients with moderate renal impairment (CLcr ≥30 and <50 mL/min) or severe renal impairment (CLcr <30 mL/min) being treated for the prevention of skeletal events in patients with breast cancer and metastatic bone disease an adjustment in the dose is recommended (see section 4.2).

 

Reasons for adding or updating:

  • Removal of Black Triangle

Date of revision of text on the SPC:06-03-2007

Legal Category:POM

Black Triangle (CHM): NO

Free-text change information supplied by the pharmaceutical company:

Removal of the black triangle

Reasons for adding or updating:

  • Change to section 4.2 - Posology and method of administration
  • Change to section 5.1 - Pharmacodynamic Properties
  • Change to section 5.2 - Pharmacokinetic Properties
  • Change to section 10 date of revision of the text

Date of revision of text on the SPC:01-03-2007

Legal Category:POM

Black Triangle (CHM): NO

Free-text change information supplied by the pharmaceutical company:

Underlined text has been added, text with strike though deleted:

 

4.2        Posology and method of administration

 

Prevention of Skeletal Events in Patients with Breast Cancer and Bone Metastases

 

The recommended dose for prevention of skeletal events in patients with breast cancer and bone metastases is 6 mg intravenous injection given every 3-4 weeks. The dose should be infused over 1 hourat least 15 minutes. For infusion, the contents of the vials(s) should only be added to 500100 ml isotonic sodium chloride solution or 500100 ml 5% glucose solution.

 

A shorter (i.e. 15 min) infusion time should only be used for patients with normal renal function or mild renal impairment. There are no data available characterising the use of a shorter infusion time in patients with creatinine clearance below 50 ml/min. Prescribers should consult the section Patients with Renal Impairment (Section 4.2) for recommendations on dosing and administration in this patient group.

 

Patients with renal impairment

There is no evidence of a reduction in tolerability associated with an increase in exposure to ibandronate in patients with various degrees of renal impairment. However, for the prevention of skeletal events in patients with breast cancer and bone metastases the following recommendations should be followed:

 

Creatinine Clearance (ml/min)

Dosage / Infusion time 1

Infusion Volume 2

¡Ã 50

6mg / 15 minutes

100ml

30 < CLcr < 50

6mg / 1 hour

500ml

<30

2mg / 1 hour

500ml

1  Administration every 3 to 4 week

2  0.9% sodium chloride solution or 5% glucose solution

 

A 15 minute infusion time has not been studied in cancer patients with CLCr < 50 mL/min.

 

No dosage adjustment is necessary for patients with mild or moderate renal impairment where creatinine clearance is equal to or greater than 30 ml/min.

 

Below 30 ml/min creatinine clearance, the dose for prevention of skeletal events in patients with breast cancer and bone metastases should be reduced to 2 mg every 3-4 weeks, infused over 1 hour.

 

5.1        Pharmacodynamic properties

 

In a study in 130 patients with metastatic breast cancer the safety of Bondronat infused over 1 hour or 15 minutes was compared. No difference was observed in the indicators of renal function. The overall adverse event profile of ibandronic acid following the 15 minute infusion was consistent with the known safety profile over longer infusion times and no new safety concerns were identified relating to the use of a 15 minute infusion time.

 

A 15 minute infusion time has not been studied in cancer patients with a creatinine clearance of          < 50ml/min.

 

5.2        Pharmacokinetic properties

 

Patients with renal impairment

Exposure to ibandronic acid in patients with various degrees of renal impairment is related to creatinine clearance (CLcr). In clinical pharmacology trial WP18551, after a single dose intravenous administration of 6 mg (15 minutes infusion), mean AUC0-24 increased by 14% and 86%, respectively, in subjects with mild (mean estimated CLcr=68.1 mL/min) and moderate (mean estimated CLcr=41.2 mL/min) renal impairment compared to healthy volunteers (mean estimated CLcr=120 mL/min). Mean Cmax was not increased in patients with mild renal impairment and increased by 12% in patients with moderate renal impairment. There is no evidence of a reduction in tolerability associated with an increase in exposure. However, an adjustment in the dose or infusion time is recommended in patients being treated for the prevention of skeletal events in patients with breast cancer and bone metastases (see section 4.2).

 

Renal clearance of ibandronic acid in patients with various degrees of renal impairment is linearly related to creatinine clearance (CLcr). No dosage adjustment is necessary for patients with mild or moderate renal impairment (CLcr  ©ø 30 ml/min).  After intravenous administration of 0.5 mg, total, renal, and non-renal clearances decreased by 67%, 77% and 50%, respectively, in subjects with severe renal impairment.  However, there was no reduction in tolerability associated with the increase in exposure. Reduction of the intravenous dose to 2 mg infused over 1 hour every 3 - 4 weeks is recommended in patients with severe renal impairment (CLcr < 30 ml/min) (see section 4.2).

 

9.         DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

 

Bondronat 2 mg

Date of First Authorisation: 25 June 1996

Date of Renewal: 12 September 2001Date of last renewal: 25 June 2006

 

 

Bondronat 6 mg

Date of first Authorisation: 25 June 1996

Date of last renewal: 25 June 2006

 

 

10.        DATE OF REVISION OF THE TEXT

June 2006March 2007

 

Reasons for adding or updating:

  • Change to section 2 - qualitative and quantitative composition
  • Change to section 3 - pharmaceutical form
  • Change to section 4.2 - Posology and Method of Administration
  • Change to section 4.3 - Contra-indications
  • Change to section 4.4 - Special Warnings and Precautions for Use
  • Change to section 4.5 - Interactions with other Medicaments and other forms of Interaction
  • Change to section 4.6 - Pregnancy and Lactation
  • Change to section 4.8 - Undesirable Effects
  • Change to section 5.3 - Preclinical Safety Data
  • Change to section 6.2 - Incompatibilities
  • Change to section 6. 4 - Special Precautions for Storage
  • Change to section 6. 5 - Nature and Contents of Container
  • Change to section 6. 6 - Instruction for Use/Handling
  • Change to section 8 - MA number
  • Change to section 9 - Date of Renewal of Authorisation
  • Change to section 10 (date of (partial) revision of the text

Date of revision of text on the SPC:01-06-2006

Legal Category:POM

Black Triangle (CHM): NO

Free-text change information supplied by the pharmaceutical company:

1.                                NAME OF THE MEDICINAL PRODUCT

Bondronat 2 mg/2ml

Bondronat 6 mg/6ml

Concentrate for solution for infusion

 

2.                                QUALITATIVE AND QUANTITATIVE COMPOSITION

Qualitative composition

Ibandronic acid, monosodium salt, monohydrate.

 

Quantitative composition

Bondronat 2 mg/2ml

One vial with 2 ml concentrate for solution for infusion (colourless, clear solution) contains 2 mg ibandronic acid (as 2.25 mg ibandronic acid, monosodium salt, monohydrate), corresponding to 2mg ibandronic acid.

 

1ml of solution contains 1.125mg ibandronic acid, monosodium salt, monohydrate, corresponding to 1mg ibandronic acid.

 

Bondronat 6 mg/6ml

One vial with 6 ml concentrate for solution for infusion (colourless, clear solution) contains 6 mg ibandronic acid (as 6.75 mg ibandronic acid, monosodium salt, monohydrate) corresponding to 6mg ibandronic acid.

1ml of solution contains 1.125mg ibandronic acid, monosodium salt, monohydrate, corresponding to 1mg ibandronic acid.

 

 

For excipients, see section 6.1.Excipients:

For a full list of excipients, see section 6.1.

 

 

 

3.                                PHARMACEUTICAL FORM

Concentrate for solution for infusion.

Clear, colourless solution

 

 

4.2             Posology and method of administration

For single use only.  Only clear solution without particles should be used.

                       

                         Albumin-corrected serum calcium (mmol/l)
                         = serum calcium (mmol/l) - [0.02 x albumin (g/l)] + 0.8
or
                        
Albumin-corrected serum calcium (mg/dl)
                         = serum calcium (mg/dl) + 0.8 x [4 - albumin (g/dl)]

 

                    To convert the albumin-corrected serum calcium in mmol/l value to mg/dl, multiply by 4.

 

Albumin-corrected

serum calcium (mmol/l)

=

serum calcium (mmol/l) - [0.02 x albumin (g/l)] + 0.8

Or

Albumin-corrected

serum calcium (mg/dl)

=

serum calcium (mg/dl)  + 0.8 x [4 - albumin (g/dl)]

 

 

 

To convert the albumin-corrected serum calcium in mmol/l value to mg/dl, multiply by 4.

 

Safety and efficacy have not been established in patients less than 18 years old.

Bondronat is not recommended for patients below age 18 years due to insufficient data on safety and efficacy.

 

4.3                   Contraindications

Bondronat concentrate for solution for infusion must not be used in known hHypersensitivity to the drug active substance or to any of the excipients.

 

Caution is indicated to be taken in patients with known hypersensitivity to other bisphosphonates.

 

Bondronat concentrate for solution for infusion should not be used in children because of lack of clinical experience.

 

4.4                   Special warnings and special precautions for use

Osteonecrosis of the jaw, generally associated with tooth extraction and/or local infection (including osteomyelitis) has been reported in patients with cancer receiving treatment regimens including primarily intravenously administered bisphosphonates.  Many of these patients were also receiving chemotherapy and corticosteroids.  Osteonecrosis of the jaw has also been reported in patients with osteoporosis receiving oral bisphosphonates.

 

A dental examination with appropriate preventive dentistry should be considered prior to treatment with bisphosphonates in patients with concomitant risk factors (e.g. cancer, chemotherapy, radiotherapy, corticosteroids, poor oral hygiene).

 

While on treatment, these patients should avoid invasive dental procedures if possible.  For patients who develop osteonecrosis of the jaw 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 osteonecrosis of the jaw.  Clinical judgement of the treating physician should guide the management plan of each patient based on individual benefit/risk assessment.

 

4.5                   Interaction with other medicinal products and other forms of interaction

 

Bondronat should not be mixed with calcium containing solutions.

 

No interaction was observed Wwhen co-administered with melphalan/prednisolone in patients with multiple myeloma, no interaction was observed.

 

Interaction studies have only been performed in adults.

 

 

4.6                   Pregnancy and lactation

 

It is not known whether ibandronic acid is excreted in human milk.  Studies in lactating rats have demonstrated the presence of low levels of ibandronic acid in the milk following intravenous administration.  Consequently, caution should be exercised when prescribing Bondronat to breast-feeding women. Bondronat should not be used during lactation.

 

 

4.8                   Undesirable effects

The following events occurred rarely (one patient in the Bondronat group): gastroenteritis NOS, oral candidiasis, vaginitis, benign skin neoplasm, anaemia NOS, blood dyscrasia NOS, hypophosphataemia, sleep disorder, anxiety, affect lability, amnesia, paraesthesia circumoral, hyperaesthesia, hypertonia, nerve root lesion NOS, neuralgia NOS, migraine, cerebrovascular disorder NOS, parosmia, deafness, cardiovascular disorder NOS, palpitations, myocardial ischaemia, hypertension, varicose veins NOS, lymphoedema, lung oedema, stridor, gastritis NOS, cheilitis, dysphagia, mouth ulceration, cholelithiasis, rash NOS, alopecia, cystitis NOS, renal cyst NOS, urinary retention, pelvic pain NOS, injection site pain, blood alkaline phosphatase increase, weight decreased, injury, hypothermia.

 

Other adverse reactions reported at a lower frequency are as follows:

 

Uncommon:

Infection and infestation: cystitis, vaginitis, oral candidiasis

Neoplasms benign and malignant (including cysts and polyps): benign skin neoplasm

Blood and lymphatic system: anaemia, blood dyscrasia

Metabolism and nutrition disorders: hypophosphataemia

Psychiatric disorders: sleep disorder, anxiety, affection lability

Nervous system disorders: cerbrovascular disorder, nerve root lesion, amnesia, migraine, neuralgia, hypertonia, hyperaestesia, paraesthesia circumoral, parosmia.

Ear and labyrinth disorders: deafness

Cardiac disorders: myocardial ischaemia, cardiovascular disorder, palpitations

Vascular disorders: hypertension, lymphoedema, varicose veins

Respiratory, thoracic and mediastinal disorders: lung oedema, stridor

Gastrointestinal disorders: gastroenteritis, dysphagia, gastritis, mouth ulceration, cheilitis

Hepato-biliary disorders: cholelithiasis

Skin and subcutaneous tissue disorders: rash, alopecia

Renal and urinary disorders: urinary retention, renal cyst

Reproductive system and breast disorders: pelvic pain

General disorders and administration site conditions: hypothermia

Investigations: blood alkaline phosphatase increase, weight decrease

Injury, poisoning and procedural complications: injury, injection site pain

 

Osteonecrosis of the jaw has been reported in patients treated by bisphosphonates.  The majority of the reports refer to cancer patients, but such cases have also been reported in patients treated for osteoporosis.  Osteonecrosis of the jaw is generally associated with tooth extraction and / or local infection (including osteomyelitis).  Diagnosis of cancer, chemotherapy, radiotherapy, corticosteroids and poor oral hygiene are also deemed as risk factors (see section 4.4).

 

 

5.3                   Preclinical safety data

 

Effects in non-clinical studies were observed only at exposures sufficiently in excess of the maximum human exposure indicating little relevance to clinical use.  As with other bisphosphonates, the kidney was identified to be the primary target organ of systemic toxicity.  in animal studies. Toxic effects in animals were observed only at exposures sufficiently in excess of the maximum human exposure indicating little relevance to clinical use.

 

 

6.2                   Incompatibilities

 

To avoid potential incompatibilities Bondronat concentrate for solution for infusion should only be diluted with isotonic sodium chloride solution or 5% dextroseglucose solution.

 

Bondronat should not be mixed with calcium containing solutions.

 

 

6.4                   Special precautions for storage

 

No special precautions for storage prior to reconstitution.

 

6.6                   Instructions for use and handling, andSpecial precautions for disposal

 

Any unused product or waste material should be disposed of in accordance with local requirements.

 

 

For single use only.  Only clear solution without particles should be used.

 

Strict adherence to the intravenous route is recommended on parenteral administration of Bondronat concentrate for solution for infusion.

 

Use only isotonic saline or 5% dextrose solution as infusion solution.

 

Bondronat concentrate for solution for infusion should not be mixed with calcium containing solutions.

 

Unused solution should be discarded.

 

8.                     MARKETING AUTHORISATION NUMBER(S)

 

Bondronat 2 mg/2ml

EU/1/96/012/004          -     Packs of 1 vial

 

Bondronat 6 mg/6ml

EU/1/96/012/012       -    Packs of 5 vials

EU/1/96/012/011       -    Packs of 1 vial

EU/1/96/012/012       -    Packs of 5 vials

EU/1/96/012/013       -    Packs of 10 vials

 

 

9.                     DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

 

Bondronat 2 mg/2ml

Date of First Authorisation: 25 June 1996

Date of Renewal: 12 September 2001

 

 

Bondronat 6 mg/6ml

Date of first Authorisation: 31 October 2003

 

 November 2003

 

 

10.                   DATE OF REVISION OF THE TEXT

 

November 2005April June 2006

 

 

 

Detailed information on this medicinal product is available on the website of the European Medicines Agency (EMEA) http://www.emea.eu.int/

Reasons for adding or updating:

  • Change to section 7 - Marketing Authorisation Holder
  • Change to section 10 (date of (partial) revision of the text

Reasons for adding or updating:

  • Change to section 10 (date of (partial) revision of the text

Reasons for adding or updating:

  • Change to section 2 - qualitative and quantitative composition
  • Change to section 6. 5 - Nature and Contents of Container
  • Change to section 8 - MA number
  • Change to section 10 (date of (partial) revision of the text

Reasons for adding or updating:

  • Change to section 2 - qualitative and quantitative composition
  • Change to section 4.2 - Posology and Method of Administration
  • Change to section 6. 5 - Nature and Contents of Container
  • Change to section 8 - MA number

Reasons for adding or updating:

  • Change to section 4.2 - Posology and Method of Administration
  • Change to section 4.4 - Special Warnings and Precautions for Use
  • Change to section 4.5 - Interactions with other Medicaments and other forms of Interaction
  • Change to section 4.6 - Pregnancy and Lactation
  • Change to section 4.8 - Undesirable Effects
  • Change to section 5.1 - Pharmacodynamic Properties
  • Change to section 5.2 - Pharmacokinetic Properties
  • Change to section 5.3 - Preclinical Safety Data
  • Change to section 6. 4 - Special Precautions for Storage
  • Change to section 6. 5 - Nature and Contents of Container
  • Change to section 8 - MA number
  • Change to section 9 - Date of Renewal of Authorisation
  • Change to section 2 - qualitative and quantitative composition
  • Change to section 4.1 - Therapeutic Indications
  • Change to section 4.3 - Contra-indications

Reasons for adding or updating:

  • Change to section 1 - trade name
  • Change to section 8 - MA number

Reasons for adding or updating:

  • Addition of Black Triangle

Reasons for adding or updating:

  • New SPC for eMC ie an SPC for an existing product, but one that is new for the eMC