ZOBONE Concentrate for solution for infusion Ref.[50459] Active ingredients: Zoledronic acid

General

Patients should be assessed prior to administration of ZOBONE SOLUTION FOR INFUSION to assure adequate hydration. Over-hydration should be avoided in patients at risk of cardiac failure.

Standard hypercalcaemia-related metabolic parameters, such as serum levels of calcium, phosphate, magnesium, as well as serum creatinine should be carefully monitored after initiating ZOBONE SOLUTION FOR INFUSION therapy. If hypocalcaemia, hypophosphataemia, or hypomagnesaemia occur, short-term supplemental therapy may be necessary.

Renal insufficiency

Bisphosphonates as a class, including zoledronic acid as in ZOBONE SOLUTION FOR INFUSION, have been associated with reports of renal dysfunction. Renal function should be monitored appropriately during therapy with ZOBONE SOLUTION FOR INFUSION considering individual risk factors, and patients with evidence of deterioration in renal dysfunction should be appropriately evaluated with consideration given as to whether the potential benefit of continued treatment with ZOBONE SOLUTION FOR INFUSION outweighs the possible risk. The decision to treat patients with bone metastases for the prevention of skeletal related events should consider that the onset of treatment effect is 2–3 months.

Zoledronic acid as in ZOBONE SOLUTION FOR INFUSION has been associated with reports of renal dysfuction. Factors that may increase the potential for deterioration in renal function include dehydration, pre-existing renal impairment, multiple cycles of Zoledronic acid as in ZOBONE SOLUTION FOR INFUSION, and other bisphosphonates as well as use of other nephrotoxic medicines. While the risk is reduced with a dose of 4 mg zoledronic acid (as in ZOBONE SOLUTION FOR INFUSION) administered over 15 minutes, deterioration in renal function may still occur.

Renal deterioration, progression to renal failure and dialysis have been reported in patients after the initial dose or a single dose of 4 mg ZOBONE SOLUTION FOR INFUSION. Increases in serum creatinine also occur in some patients with chronic administration of ZOBONE SOLUTION FOR INFUSION at recommended doses for prevention of skeletal related events, although less frequently.

Patients should have their serum creatinine levels assessed prior to each dose of ZOBONE SOLUTION FOR INFUSION. Upon initiation of treatment in patients with bone metastases with mild to moderate renal impairment, lower doses of ZOBONE SOLUTION FOR INFUSION are recommended. In patients who report renal deterioration during treatment, ZOBONE SOLUTION FOR INFUSION should be withheld. ZOBONE SOLUTION FOR INFUSION should only be resumed when serum creatinine returns to within 10 % of baseline. ZOBONE SOLUTION FOR INFUSION treatment should be resumed at the same dose as that given prior to treatment interruption.

In view of the potential impact of bisphosphonates, including ZOBONE SOLUTION FOR INFUSION, on renal function, the use of ZOBONE SOLUTION FOR INFUSION is not recommended in this population (see section 4.3).

Hepatic insufficiency

In patients with severe hepatic insufficiency, no specific recommendations can be given for this patient population. Increases in serum creatinine also occur in some patients with chronic administration of ZOBONE SOLUTION FOR INFUSION at recommended doses.

Osteonecrosis

Osteonecrosis of the jaw

Osteonecrosis of the jaw (ONJ) has been reported uncommonly in clinical studies with patients receiving zoledronic acid as in ZOBONE SOLUTION FOR INFUSION. Post-marketing reports and published literature suggest a greater frequency of reports of ONJ based on tumour type (advanced breast cancer, multiple myeloma). In the reported study, ONJ was higher in myeloma patients when compared to other cancers.

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, except in medical emergency situations. A dental examination with appropriate preventive dentistry and an individual benefit-risk assessment is recommended prior to treatment with bisphosphonates in patients with concomitant risk factors. The following risk factors should be considered when evaluating an individual’s risk of developing ONJ:

• Potency of the bisphosphonate (higher risk for highly potent compounds), route of administration (higher risk for parenteral administration) and cumulative dose of bisphosphonate.
• Cancer, co-morbid conditions (e.g. anaemia, coagulopathies, infection), smoking.
• Concomitant therapies: chemotherapy, angiogenesis inhibitors (see section 4.5), radiotherapy to neck and head, corticosteroids.

History of dental disease, poor oral hygiene, periodontal disease, invasive dental procedures (e.g. tooth extractions) and poorly fitting dentures.

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 ZOBONE SOLUTION FOR INFUSION. While on treatment, invasive dental procedures should be performed only after careful consideration and be avoided in close proximity to ZOBONE SOLUTION FOR INFUSION administration. 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 reported to suggest whether discontinuation of bisphosphonate treatment reduces the risk of osteonecrosis of the jaw.

The management plan for 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 ZOBONE SOLUTION FOR INFUSION treatment should be considered until the condition resolves and contributing risk factors are mitigated where possible.

Osteonecrosis of other anatomical sites

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. Additionally, there have been sporadic reports of osteonecrosis of other sites, including the hip and femur, reported predominantly in adult cancer patients treated with zoledronic acid as in ZOBONE SOLUTION FOR INFUSION.

Musculoskeletal pain

In post-marketing experience, severe and occasionally incapacitating bone, joint, and/or muscle pain have been reported in patients taking zoledronic acid as in ZOBONE SOLUTION FOR INFUSION. However, such reports have relief of symptoms after stopping treatment. A subset had recurrence of symptoms when rechallenged with zoleronic acid as in ZOBONE SOLUTION FOR INFUSION, or another bisphosphonate.

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.

Hypocalcaemia

Hypocalcaemia has been reported in patients treated with cardiac arrhythmias and neurologic adverse events (including convulsions, hypoaesthesia and tetany) have been reported secondary to cases of severe hypocalcaemia. Cases of severe hypocalcaemia requiring hospitalisation have been reported. In some instances, the hypocalcaemia may be life-threatening (see section 4.8).

Caution is advised when ZOBONE SOLUTION FOR INFUSION is administered with medicines known to cause hypocalcaemia, as they may have a synergistic effect resulting in severe hypocalcaemia (see section 4.5).

Serum calcium should be measured and hypocalcaemia must be corrected before initiating ZOBONE SOLUTION FOR INFUSION therapy. Patients should be adequately supplemented with calcium and vitamin D.

ZOBONE SOLUTION FOR INFUSION contains sodium

This medicine contains 24 mg sodium per vial equivalent to 1,2% of the WHO recommended maximum daily intake of 2 g sodium for an adult.

Paediatric population

The safety and efficacy of ZOBONE SOLUTION FOR INFUSION in paediatric patients have not been established.

ZOBONE SOLUTION FOR INFUSION can be administered concomitantly with commonly used anticancer medicines, diuretics, antibiotics and analgesics without apparent interactions occurring. Zoledronic acid shows no appreciable binding to plasma proteins and human P450 enzymes in vitro. Caution is advised when ZOBONE SOLUTION FOR INFUSION is administered with aminoglycosides, calcitonin or loop diuretics, since these medicines may have an additive effect, resulting in a lower serum calcium level for longer periods than required (see section 4.4). Caution is advised when ZOBONE SOLUTION FOR INFUSION is used with other potentially nephrotoxic medicines. Attention should also be paid to the possibility of hypomagnesaemia developing during treatment.

In multiple myeloma patients, the risk of renal dysfunction may be increased when ZOBONE SOLUTION FOR INFUSION is used in combination with thalidomide. Caution is advised when ZOBONE SOLUTION FOR INFUSION is administered with anti-angiogenic medicines, as an increase in the incidence of ONJ has been reported in patients treated concomitantly with these medicines.

In clinical studies, ZOBONE SOLUTION FOR INFUSION has been administered concomitantly with analgesics without clinically apparent interactions occurring. ZOBONE SOLUTION FOR INFUSION shows no appreciable binding to plasma proteins and does not inhibit human P450 enzymes in vitro (see section 5.2), but no formal clinical interaction studies have been performed. No dose adjustment for ZOBONE SOLUTION FOR INFUSION is needed when co-administered with thalidomide, except in patients with mild to moderate renal impairment at baseline (see section 4.2).

Co-administration of thalidomide (100 or 200 mg once daily) with ZOBONE SOLUTION FOR INFUSION (4 mg given as a 15 minute infusion) did not significantly change the pharmacokinetics of zoledronic acid and the creatinine clearance of patients with multiple myeloma.

The use of ZOBONE SOLUTION FOR INFUSION during pregnancy and lactation is not recommended as safety and efficacy have not been established. ZOBONE SOLUTION FOR INFUSION should not be used during pregnancy (see section 4.3).

Pregnancy

There are no adequate data that have been reported on the use of ZOBONE SOLUTION FOR INFUSION acid in pregnant women. Animal reproduction studies with zoledronic acid as in ZOBONE SOLUTION FOR INFUSION have shown reproductive toxicity (see section 5.3). The potential risk for humans is unknown. ZOBONE SOLUTION FOR INFUSION should not be used during pregnancy. Women of child-bearing potential should be advised to avoid becoming pregnant.

Breast-feeding

It is not reported whether zoledronic acid as in ZOBONE SOLUTION FOR INFUSION is excreted into human milk. ZOBONE SOLUTION FOR INFUSION is contraindicated in breast-feeding women (see section 4.3).

Fertility

Zoledronic acid as in ZOBONE SOLUTION FOR INFUSION was reported to be evaluated in rats for potential adverse effects on fertility of the parental and F1 generation. This resulted in exaggerated pharmacological effects considered to be related to the compound’s inhibition of skeletal calcium metabolisation, resulting in periparturient hypocalcaemia, a bisphosphonate class effect, dystocia and early termination of the reported study. Thus reported results precluded determining a definitive effect of zoledronic acid on fertility in humans.

Adverse reactions, such as dizziness, blurred vision and somnolence, may have influence on the ability to drive or use machines, therefore caution should be exercised with the use of ZOBONE SOLUTION FOR INFUSION along with driving and operating of machinery (see section 4.8).

a) Summary of the safety profile

Within three days after zoledronic acid (as in ZOBONE SOLUTION FOR INFUSION) administration, an acute phase reaction has commonly been reported, with symptoms including bone pain, fever, fatigue, arthralgia, myalgia, rigors and arthritis with subsequent joint swelling; these symptoms usually resolve within a few days.

The following are the important identified risks with ZOBONE SOLUTION FOR INFUSION in the approved indications:

Renal function impairment, osteonecrosis of the jaw, acute, phase reaction, hypocalcaemia, atrial fibrillation, anaphylaxis interstitial lung disease.

b) Tabulated list of adverse reactions

The following side-effects may occur with the use of ZOBONE SOLUTION FOR INFUSION:

Description of selected adverse reactions

Renal function impairment

Zoledronic acid has been reported to be associated with renal dysfunction. In a pooled analysis for the prevention of skeletal-related events in patients with advanced malignancies involving bone, the frequency of renal impairment adverse events suspected to be related to zoledronic acid (adverse reactions) was as follows: multiple myeloma (3,2%), prostate cancer (3,1%), breast cancer (4,3%), lung and other solid tumours (3,2%). Factors that may increase the potential for deterioration in renal function include dehydration, pre-existing renal impairment, multiple cycles of zoledronic acid or other bisphosphonates, as well as concomitant use of nephrotoxic medicines or using a shorter infusion time than currently recommended. Renal deterioration, progression to renal failure and dialysis have been reported in patients after the initial dose or a single dose of 4 mg zoledronic acid (see section 4.4).

Osteonecrosis of the jaw

Cases of osteonecrosis of the jaw have been reported, predominantly in cancer patients treated with medicines that inhibit bone resorption, such as zoledronic acid (see section 4.4). Many of these patients were also receiving chemotherapy and corticosteroids and had signs of local infection including osteomyelitis. The majority of the reports refer to cancer patients following tooth extractions or other dental surgeries.

Atrial fibrillation

In a reported 3-year study, zoledronic acid 5 mg once yearly for treatment of postmenopausal osteoporosis (PMO), resulted the overall incidence of atrial fibrillation 2,5% and 1,9% in patients receiving zoledronic acid 5 mg and placebo, respectively. The reported rate of atrial fibrillation serious adverse events was 1,3% and 0,6% in patients receiving zoledronic acid 5 mg and placebo, respectively. The reported imbalance in the study has not been reported in other studies with zoledronic acid, including those with zoledronic acid 4 mg every 3-4 weeks in oncology patients. The mechanism behind the increased incidence of atrial fibrillation in this clinical study is unknown.

Acute phase reaction

This adverse drug reaction consists of a constellation of symptoms that includes fever, myalgia, headache, extremity pain, nausea, vomiting, diarrhoea arthralgia and arthritis with subsequent joint swelling. The onset time is ≤3 days post-zoledronic acid infusion, and the reaction is also referred to using the terms “flu-like” or “post-dose” symptoms.

Atypical fractures of the femur

During post-marketing experience, the following reactions have been reported (frequency rare): Atypical subtrochanteric and diaphyseal femoral fractures (bisphopsphonate class adverse reaction).

Hypocalcaemia-related ADRs

Hypocalcaemia is an important identified risk with zoledronic acid in the approved indications. Based on the review of both clinical study and post-marketing cases, there is sufficient evidence reported to support an association between zoledronic acid therapy, the reported event of hypocalcaemia, and the secondary development of cardiac arrhythmia. Furthermore, there is evidence of an association between hypocalcaemia and secondary neurological events reported in these cases including; convulsions, hypoaesthesia and tetany.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicine is important. It allows continued monitoring of the benefit/risk balance of the medicine. Health care providers are asked to report any suspected adverse reactions to SAHPRA via the “6.04 Adverse Drug Reaction Reporting Form”, found online under SAHPRA’s publications: https://www.sahpra.org.za/Publications/Index/8.

To avoid potential incompatibilities, ZOBONE SOLUTION FOR INFUSION concentrate is to be diluted with 0,9% w/v sodium chloride solution or 5% w/v glucose solution.

This medicine must not be mixed with calcium or other divalent cation-containing infusion solutions such as lactated Ringer’s solution, and should be administered as a single intravenous solution in a separate infusion line.

This medicine must not be mixed with other medicines except those mentioned in section 6.6.