4.1. Therapeutic indications

Treatment of osteoporosis

• in post-menopausal women

• in adult men

at increased risk of fracture, including those with a recent low-trauma hip fracture.

Treatment of osteoporosis associated with long-term systemic glucocorticoid therapy

• in post-menopausal women

• in adult men

at increased risk of fracture.

Treatment of Paget's disease of the bone in adults.

4.2. Posology and method of administration

Posology

Patients must be appropriately hydrated prior to administration of Zoledronic Acid. This is especially important for the elderly (≥65 years) and for patients receiving diuretic therapy.

Adequate calcium and vitamin D intake are recommended in association with Zoledronic Acid administration.

Osteoporosis

For the treatment of post-menopausal osteoporosis, osteoporosis in men and the treatment of osteoporosis associated with long-term systemic glucocorticoid therapy, the recommended 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 established. The need for continued treatment should be re-evaluated periodically based on the benefits and potential risks 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 (see section 5.1). In patients with a recent low-trauma 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 physicians 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 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 (see section 4.4).

Re-treatment of Paget's disease: After initial treatment with Zoledronic Acid in Paget's disease, an extended remission period is observed in responding patients. Re-treatment consists of an additional intravenous 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 (see section 5.1).

Special populations

Patients with renal impairment

Zoledronic Acid is contraindicated in patients with creatinine clearance < 35 ml/min (see sections 4.3 and 4.4).

No dose adjustment is necessary in patients with creatinine clearance ≥ 35 ml/min.

Patients with hepatic impairment

No dose adjustment is required (see section 5.2).

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. Currently available data for children aged 5 to 17 years are described in section 5.1.

Method of administration

Intravenous use.

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 information on the infusion of Zoledronic Acid, see section 6.6.

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

4.3. Contraindications

• Hypersensitivity to the active substance, to any bisphosphonates or to any of the excipients listed in section 6.1.

• Patients with hypocalcaemia (see section 4.4).

• Severe renal impairment with creatinine clearance < 35 ml/min (see section 4.4)

• Pregnancy and breast-feeding (see section 4.6).

4.4. Special warnings and precautions for use

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 (see section 4.8), especially in patients with pre-existing renal dysfunction or other risks including advanced age, concomitant nephrotoxic medicinal products, concomitant diuretic therapy (see section 4.5), 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 adverse reactions:

• Creatinine clearance should be calculated based on actual body weight using the Cockcroft-Grault formula before each Zoledronic Acid dose.

• Transient increase in serum creatinine may be greater in patients with underlying impaired renal function.

• Monitoring of serum creatinine should be considered in at-risk patients.

• Zoledronic Acid should be used with caution when concomitantly used with other medicinal products that could impact renal function (see section 4.5).

• Patients, especially elderly patients and those receiving diuretic therapy, should be appropriately hydrated prior to administration of Zoledronic Acid.

• A single dose of Zoledronic Acid should not exceed 5 mg and the duration of infusion should be at least 15 minutes (see section 4.2).

Hypocalcaemia

Pre-existing hypocalcaemia must be treated by adequate intake of calcium and vitamin D before initiating therapy with Zoledronic Acid (see section 4.3). 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 (see section 4.8).

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 (see section 4.2).

Patients should be informed about symptoms of hypocalcaemia and receive adequate clinical 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 infrequently reported in patients taking bisphosphonates, including Zoledronic Acid (see section 4.8).

Osteonecrosis of the jaw (ONJ)

ONJ has been reported in the post-marketing setting in patients receiving Zoledronic Acid for osteoporosis (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 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 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, 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 collaboration 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 including chronic ear infections.

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.

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 problematic (see section 4.8).

General

Other products containing zoledronic acid as an active substance are available for oncology 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 Zoledronic acid, i.e. essentially “sodium free”.

4.5. Interaction with other medicinal products and other forms of interaction

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 (see section 5.2). 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) (see section 4.4).

In patients with renal impairment, the systemic exposure to concomitant medicinal products that are primarily excreted via the kidney may increase.

4.6. Fertility, pregnancy and lactation

Women of childbearing potential

Zoledronic Acid is not recommended in women of childbearing potential.

Pregnancy

Zoledronic Acid is contraindicated during pregnancy (see section 4.3). 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 (see section 5.3). The potential risk for humans is unknown.

Breast-feeding

Zoledronic Acid is contraindicated during breast-feeding (see section 4.3). 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 related 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.

4.7. Effects on ability to drive and use machines

Adverse reactions, such as dizziness, may affect the ability to drive or use machines.

4.8. Undesirable effects

Summary of the safety profile

The overall percentage of patients who experienced adverse reactions were 44.7%, 16.7% and 10.2% after the first, second and third infusion, respectively. Incidence of individual adverse reactions following the first infusion was: fever (17.1%), myalgia (7.8%), influenza-like illness (6.7%), arthralgia (4.8%) and headache (5.1%), see “acute phase reactions” below.

Tabulated list of adverse reactions

Adverse reactions in Table 1 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.

Table 1

Infections and infestations

Uncommon

Influenza, nasopharyngitis

Blood and lymphatic system disorders

Uncommon

Anaemia

Immune system disorders

Not known**

Hypersensitivity reactions including rare cases of bronchospasm, urticaria and angioedema, and very rare cases of anaphylactic reaction/shock

Metabolism and nutrition disorders

Common

Uncommon

Rare

Hypocalcaemia*

Decreased appetite

Hypophosphataemia

Psychiatric disorders

Uncommon

Insomnia

Nervous system disorders

Common

Uncommon

Headache, dizziness

Lethargy, paraesthesia, somnolence, tremor, syncope, dysgeusia

Eye disorders

Common

Uncommon

Rare

Not known**

Ocular hyperaemia

Conjunctivitis, eye pain

Uveitis, episcleritis, iritis

Scleritis and parophthalmia

Ear and labyrinth disorders

Uncommon

Vertigo

Cardiac disorders

Common

Uncommon

Atrial fibrillation

Palpitations

Vascular disorders

Uncommon

Not known**

Hypertension, flushing

Hypotension (some of the patients had underlying risk factors)

Respiratory, thoracic and mediastinal disorders

Uncommon

Cough, dyspnoea

Gastrointestinal disorders

Common

Uncommon

Nausea, vomiting, diarrhoea

Dyspepsia, abdominal pain upper, abdominal pain, gastro-oesophageal reflux disease, constipation, dry mouth, oesophagitis, toothache, gastritis#

Skin and subcutaneous tissue disorders

Uncommon

Rash, hyperhydrosis, pruritus, erythema

Musculoskeletal and connective tissue disorders

Common

Uncommon

Rare

Very rare

Not known**

Myalgia, arthralgia, bone pain, back pain, pain in extremity

Neck pain, musculoskeletal stiffness, joint swelling, muscle spasms, , musculoskeletal chest pain, musculoskeletal pain, joint stiffness, arthritis, muscular weakness

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

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

Osteonecrosis of the jaw (see sections 4.4 and 4.8 Class effects)

Renal and urinary disorders

Uncommon

Not known**

Blood creatinine increased, pollakiuria, proteinuria

Renal impairment. Rare cases of renal failure 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 (see sections 4.4 and 4.8 Class effects)

General disorders and administration site conditions

Very common

Common

Uncommon

Not known**

Pyrexia

Influenza-like illness, chills, fatigue, asthenia, pain, malaise, infusion site reaction

Peripheral oedema, thirst, acute phase reaction, non-cardiac chest pain

Dehydration secondary to acute phase reactions (post-dose symptoms such as pyrexia, vomiting and diarrhoea)

Investigations

Common

Uncommon

C-reactive protein increased

Blood calcium decreased

#Observed in patients taking concomitant glucocorticosteroids.

*Common in Paget's disease only.

**Based on post-marketing reports. Frequency cannot be estimated from available data.

+Identified in post-marketing experience

Description of selected adverse reactions

Atrial fibrillation

In the HORIZON – Pivotal Fracture Trial [PFT] (see section 5.1), the overall incidence of atrial fibrillation was 2.5% (96 out of 3,862) and 1.9% (75 out of 3,852) in patients receiving Zoledronic acid and placebo, respectively. The rate of atrial fibrillation serious adverse events was increased in patients receiving Zoledronic acid (1.3%) (51 out of 3,862) compared with patients receiving placebo (0.6%) (22 out of 3,852). The mechanism behind the increased incidence of atrial fibrillation is unknown. In the osteoporosis trials (PFT, HORIZON - Recurrent Fracture Trial [RFT]) the pooled atrial fibrillation incidences were comparable between Zoledronic acid (2.6%) and placebo (2.1%). For atrial fibrillation serious adverse events the pooled incidences were 1.3% for Zoledronic acid and 0.8% for placebo.

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, concomitant 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 versus 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 normal 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 subsequent 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 (see also section 4.2). In the trial for the prevention of clinical fractures following 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 (see section 4.2).

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 (see section 4.4). In a large clinical trial in 7,736 patients, osteonecrosis of the 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 symptoms (including serious cases) after Aclasta administration is as follows (frequencies 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 which occurred within the first 3 days following Aclasta administration. 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 Aclasta. 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 (see section 4.4).

Reporting of suspected adverse reactions

Reporting 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 Yellow Card Scheme. Website: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.

4.9. Overdose

Clinical experience with acute overdose is limited. Patients who have received doses higher than those recommended should be carefully monitored. In the event of overdose leading to clinically significant hypocalcaemia, reversal may be achieved with supplemental oral calcium and/or an intravenous infusion of calcium gluconate.