Zoledronic acid is indicated for:
-in post-menopausal women
-in adult men
at increased risk of fracture, including those with a recent low-trauma hip fracture.
– in post-menopausal women
– in adult men
at increased risk of fracture.
Treatment of Paget’s disease of the bone in adults
Renal function
The use of Zoledronic Acid in patients with severe renal impairment (creatinine clearance < 35 ml/min) is contraindicated due to an increased risk of renal failure in this population. Renal impairment has been observed following the administration of Zoledronic Acid, espe-cially in patients with pre-existing renal dysfunction or other risks including advanced age, concomitant nephrotoxic medicinal products, concomitant diuretic therapy, or dehydration occurring after Zoledronic Acid administration. Renal impairment has been observed in patients after a single administration. Renal failure requiring dialysis or with a fatal outcome has rarely occurred in patients with underlying renal impairment or with any of the risk factors described above.
The following precautions should be taken into account to minimise the risk of renal ad-verse reactions:
Hypocalcaemia
Pre-existing hypocalcaemia must be treated by adequate intake of calcium and vitamin D
before initiating therapy with Zoledronic Acid. Other disturbances of mineral metabolism must also be
effectively treated (e.g. diminished parathyroid reserve, intestinal calcium malabsorption). Physicians should consider clinical monitoring for these patients.
Elevated bone turnover is a characteristic of Paget’s disease of the bone. Due to the rapid onset of effect of zoledronic acid on bone turnover, transient hypocalcaemia, sometimes symptomatic, may develop and is usually maximal within the first 10 days after infusion of Zoledronic Acid.
Adequate calcium and vitamin D intake are recommended in association with Zoledronic Acid administration. In addition, in patients with Paget’s disease, it is strongly advised that adequate supplemental calcium corresponding to at least 500 mg elemental calcium twice daily is ensured for at least 10 days following Zoledronic Acid administration.
Patients should be informed about symptoms of hypocalcaemia and receive adequate clin-ical monitoring during the period of risk. Measurement of serum calcium before infusion of Zoledronic Acid is recommended for patients with Paget´s disease.
Severe and occasionally incapacitating bone, joint and/or muscle pain have been infre-quently reported in patients taking bisphosphonates, including Zoledronic Acid.
Osteonecrosis of the jaw (ONJ)
ONJ has been reported in the post-marketing setting in patients receiving Zoledronic Acid for osteoporosis.
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 den-tistry and an individual benefit-risk assessment is recommended prior to treatment with Zoledronic Acid in patients with concomitant risk factors.
The following should be considered when evaluating a patient’s risk of developing ONJ:
– Potency of the medicinal product that inhibits bone resorption (higher risk for highly potent compounds), route of administration (higher risk for parenteral administration) and cumula-tive dose of bone resorption therapy.
– Cancer, co-morbid conditions (e.g. anaemia, coagulopathies, infection), smoking.
– Concomitant therapies: corticosteroids, chemotherapy, angiogenesis inhibitors, radiother-apy 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, non-healing of sores or discharge during treatment with zoledronic acid. While on treatment, invasive dental procedures should be performed with caution and avoided in close proximity to zoledronic acid treatment.
The management plan for patients who develop ONJ should be set up in close collabo-ration between the treating physician and a dentist or oral surgeon with expertise in ONJ. Temporary
interruption of zoledronic acid treatment should be considered until the condition resolves and contributing risk factors are mitigated where possible.
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 in-cluding chronic ear infections.
Atypical fractures of the femur
Atypical subtrochanteric and diaphyseal femoral fractures have been reported with bis-phosphonate 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 asso-ciated 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.
Acute phase reactions
Acute phase reactions (APRs) or post-dose symptoms such as fever , myalgia , flu-like symptoms, arthralgia and headache have been observed, the majority of which occurred within three days following Zoledronic acid administration.
APRs may sometimes be serious or prolonged in duration. The incidence of post-dose symptoms can be reduced with the administration of paracetamol or ibuprofen shortly following Zoledronic acid administration. It is also advisable to postpone treatment if the patient is clinically unstable due to an acute medical condition and an APR could be prob-lematic.
General
Other products containing zoledronic acid as an active substance are available for oncolo-gy indications. Patients being treated with Zoledronic acid should not be treated with such products or any other bisphosphonate concomitantly, since the combined effects of these agents are unknown.
This medicinal product contains less than 1 mmol sodium (23 mg) per 100 ml vial of Zole-dronic acid, i.e. essentially “sodium free”.
Osteoporosis:
For the treatment of post-menopausal osteoporosis, osteoporosis in men and the treatment of osteoporosis associated with long-term systemic glucocorticoid therapy, the rec-ommended dose is a single intravenous infusion of 5 mg Zoledronic Acid administered once a year.
The optimal duration of bisphosphonate treatment for osteoporosis has not been estab-lished. The need for continued treatment should be re-evaluated periodically based on the benefits and potential risk of Zoledronic Acid on an individual patient basis , particularly after 5 or more years of use.
In patients with a recent low-trauma hip fracture, it is recommended to give the Zoledronic Acid infusion at least two weeks after hip fracture repair. In patients with a recent low-trau-ma hip fracture, a loading dose of 50 000 to 125 000 IU of vitamin D given orally or via the intramuscular route is recommended prior to the first Zoledronic Acid infusion.
Paget’s disease:
For the treatment of Paget’s disease, Zoledronic Acid should be prescribed only by physi-cians with experience in the treatment of Paget’s disease of the bone. The recommended dose is a single intravenous infusion of 5 mg Zoledronic Acid. In patients with Paget’s dis-ease, it is strongly advised that adequate supplemental calcium corresponding to at least 500 mg elemental calcium twice daily is ensured for at least 10 days following Zoledronic Acid administration.
Re-treatment of Paget’s disease:
After initial treatment with Zoledronic Acid in Paget’s disease, an extended remission pe-riod is observed in responding patients. Re-treatment consists of an additional intrave-nous infusion of 5 mg Zoledronic Acid after an interval of one year or longer from initial treatment in patients who have relapsed. Limited data on re-treatment of Paget’s disease are available
Special populations
Patients with renal impairment
Zoledronic Acid is contraindicated in patients with creatinine clearance < 35 ml/min
no dose adjustment is necessary in patients with creatinine clearance ³ 35 ml/min.
Patients with hepatic impairment
No dose adjustment is required
Elderly (≥ 65 years )
No dose adjustment is necessary since bioavailability, distribution and elimination were similar in elderly patients and younger subjects.
Paediatric population
Zoledronic Acid should not be used in children and adolescents below 18 years of age. There are no data available for children under 5 years of age.
Method of administration
Zoledronic Acid (5 mg in 100 ml ready-to-infuse solution) is administered via a vented infusion line and given slowly at a constant infusion rate. The infusion time must not be less than 15 minutes.
For single use only:
Only clear solution free from particles and discoloration should be used.
If refrigerated, allow the refrigerated solution to reach room temperature before administra-tion. Aseptic techniques must be followed during the preparation of the infusion.
Any unused medicinal product or waste material should be disposed of in accordance with local requirements.
The following adverse reactions, listed below, have been accumulated from clinical studies and post-marketing reports following predominantly chronic treatment with 4 mg zoledronic acid:
Very common (≥ 1/10 ) : Pyrexia
Common (≥ 1/100 to < 1/10 ) : Hypocalcaemia, Headache, dizziness, Ocular hyperaemia, Atrial fibrillation, Nausea, vomiting, diarrhoea, Myalgia, arthralgia, bone pain, back pain, pain in
Extremely , Influenza-like illness, chills, fatigue, asthenia, C-reactive protein increased. AD-verse reactions in Table 1 are listed
Uncommon (≥1/1000 to < 1/100 ) : Influenza, naspharyngitis, Anaemia, decreased appetite, Lethargy, paraesthesia, somnolence, tremor, syncope, dysgeusia, Conjunctivitis, eye pain, Vertigo, Palpitations, hypertension, flushing, Cough, dyspnoea, Dyspepsia, abdominal pain upper, abdominal pain, gastre-oesophageal reflux disease, constipation, dry mouth, oesophagitis, toothache, gastritis (Observed in patients taking concomitant glu-cocorticosteroids), Rash, hyperhydrosis, pruritus, erythema, Neck pain, musculoskeletal stiffness, joint swelling, muscle spasms, , musculoskeletal chest pain, musculoskeletal pain, joint stiffness, arthritis, muscular weakness, Blood creatinine increased, pollakiuria, proteinuria, Peripheral oedema, thirst, acute phase reaction, non-cardiac chest pain, Blood calcium decreased
Rare (≥ 1/10000 to < 1/1000 ) : Hypophosphataemia, Uveitis, episcleritis, iritis, Atypical sub-trochanteric and diaphyseal femoral fractures (bisphosphonate class adverse reaction and identified in post-marketing experience).
Very rare (<1/10,000): Osteonecrosis of the external auditory canal (bisphosphonate class adverse reaction).
Not known (cannot be estimated from the available data):Hypersensitivity reactions includ-ing rare cases of bronchospasm, urticaria and angioedema, and very rare cases of anaphy-lactic reaction/shock, Scleritis and parophthalmia, Hypotension (some of the patients had underlying risk factors), Osteonecrosis of the jaw, Renal impairment(Rare cases of renal ailure requiring dialysis and rare cases with a fatal outcome have been reported in patients with pre-existing renal dysfunction or other risk factors such as advanced age, concomitant nephrotoxic medicinal products, concomitant diuretic therapy, or dehydration in the post infusion period), Dehydration secondary to acute phase reactions (post-dose symptoms such as pyrexia, vomiting and diarrhoea).
Description of selected adverse reactions.
Atrial fibrillation
The mechanism behind the increased incidence of atrial is unknown
Class effects:
Renal impairment
Zoledronic acid has been associated with renal impairment manifested as deterioration in renal function (i.e. increased serum creatinine) and in rare cases acute renal failure. Renal impairment has been observed following the administration of zoledronic acid, especially in patients with pre-existing renal dysfunction or additional risk factors (e.g advanced age, oncology patients with chemotherapy, concomitant nephrotoxic medicinal products, con-comitant diuretic therapy, severe dehydration), with the majority of them receiving a 4 mg dose every 3–4 weeks, but it has been observed in patients after a single administration. In clinical trials in osteoporosis, the change in creatinine clearance (measured annually prior to dosing) and the incidence of renal failure and impairment was comparable for both the Zoledronic Acid and placebo treatment groups over three years. There was a transient increase in
serum creatinine observed within 10 days in 1.8% of Zoledronic Acid-treated patients ver-sus 0.8% of placebo-treated patients.
Hypocalcaemia
In clinical trials in osteoporosis, approximately 0.2% of patients had notable declines of serum calcium levels (less than 1.87 mmol/l) following Zoledronic Acid administration. No symptomatic cases of hypocalcaemia were observed.
In the Paget’s disease trials, symptomatic hypocalcaemia was observed in approximately 1% of patients, in all of whom it resolved.
Based on laboratory assessment, transient asymptomatic calcium levels below the nor-mal reference range (less than 2.10 mmol/l) occurred in 2.3% of Zoledronic Acid-treated patients in a large clinical trial compared to 21% of Zoledronic Acid-treated patients in the Paget’s disease trials. The frequency of hypocalcaemia was much lower following sub-sequent infusions.
All patients received adequate supplementation with vitamin D and calcium in the post-menopausal osteoporosis trial, the prevention of clinical fractures after hip fracture trial, and the Paget’s disease trials. In the trial for the prevention of clinical fractures fol-lowing a recent hip fracture, vitamin D levels were not routinely measured but the majority of patients received a loading dose of vitamin D prior to Zoledronic Acid administration. Local reactions
In a large clinical trial, local reactions at the infusion site, such as redness, swelling and/or pain, were reported (0.7%) following the administration of zoledronic acid.
Osteonecrosis of the jaw
Cases of osteonecrosis of the jaw have been reported, predominantly in cancer patients treated with medicinal products that inhibit bone resorption, including zoledronic acid. In a large clinical trial in 7736 patients, osteonecrosis of jaw has been reported in one patient treated with zoledronic acid and one patient treated with placebo. Cases of ONJ have been reported in the post-marketing setting for zoledronic acid.
Acute phase reactions
The overall percentage of patients who reported acute phase reactions or post-dose symp-toms (including serious cases) after Zoledronic acid administration is as follows (frequen-cies derived from the study in treatment of post-menopausal osteoporosis): fever (18.1%), myalgia (9.4%) , flu-like symptoms (7.8%) , arthralgia (6.8%) and headache (6.5%), the majority of these symptoms were mild to moderate in nature and resolved within 3 days of the event onset. The incidence of these symptoms decreased with subsequent annual doses of Zoledronic acid. The percentage of patients who experienced adverse reactions was lower in a smaller study (19.5%, 10.4%, 10.7% after the first, second and third infusion, respectively), where prophylaxis against adverse reactions was used.
Reporting of suspected adverse reactions
Reporting suspected adverse reactions after authorisation of the medicinal product is im- portant. It allows continued monitoring of the benefit/risk balance of the medicinal product. Please report
any adverse drug reactions via contacting Cedal Nano.(1)
No interaction studies with other medicinal products have been performed. Zoledronic acid is not systemically metabolised and does not affect human cytochrome P450 enzymes in vitro. Zoledronic acid is not highly bound to plasma proteins (approximately 43-55% bound) and interactions resulting from displacement of highly protein-bound medicinal products are therefore unlikely.
Zoledronic acid is eliminated by renal excretion. Caution is indicated when zoledronic acid is administered in conjunction with medicinal products that can significantly impact renal function (e.g. aminoglycosides or diuretics that may cause dehydration)
In patients with renal impairment, the systemic exposure to concomitant medicinal products that are primarily excreted via the kidney may increase.
Women of childbearing potential
Zoledronic Acid is not recommended in women of childbearing potential.
Pregnancy
Zoledronic Acid is contraindicated during pregnancy. There are no adequate data on the use of zoledronic acid in pregnant women. Studies in animals with zoledronic acid have shown reproductive toxicological effects including malformations. The potential risk for humans is unknown.
Breast-feeding
Zoledronic Acid is contraindicated during breast-feeding. It is unknown whether zoledronic acid is excreted into human milk.
Fertility
Zoledronic acid was evaluated in rats for potential adverse effects on fertility of the parental and F1 generation. This resulted in exaggerated pharmacological effects considered relat-ed to the compound’s inhibition of skeletal calcium mobilisation, resulting in periparturient hypocalcaemia, a bisphosphonate class effect, dystocia and early termination of the study. Thus, these results precluded determining a definitive effect of Zoledronic Acid on fertility in humans.
Storage
–Store below 30°C.Protect from freezing.
– Store in original package in order to protect from light.
– The shelf life of Unopened bottle is 2 years.
– The shelf life after opening: From a microbiological point of view, the solution for infusion should be used immediately. If not used immediately, in-use storage times and conditions prior to use are the responsibility of the user and would normally not be longer than 24 hours at 2°C-8°C. The refrigerated solution should then be equilibrated to room temperature prior to administration.
– Keep the product out of the sight and reach of children.
Disposal and handling
For single use only.
Only clear solution free from particles and discoloration should be used.
If refrigerated, allow the refrigerated solution to reach room temperature before administra-tion. Aseptic techniques must be followed during the preparation of the infusion.
Any unused medicinal product or waste material should be disposed of in accordance with local requirements.