Bonazoll 5 mg Solution

u2022 Treatment of osteoporosis in postmenopausal women to reduce the incidence of hip, vertebral and non-vertebral fractures and to increase bone mineral density.

u2022 In patients with a recent low trauma hip fracture, BONAZOLL 5 reduces the incidence of new clinical fractures.

u2022 Treatment of osteoporosis in men.

u2022 Treatment of glucocorticoid-induced osteoporosis.

u2022 Treatment of Paget's disease of bone.

Posology

The incidence of post-dose symptoms occurring within the first three days after administration of BONAZOLL 5 can be reduced with the administration of paracetamol or ibuprofen shortly following BONAZOLL 5 administration. Patients must be appropriately hydrated prior to administration of zoledronic acid. This is especially important for the elderly (u2265 65 years) and for patients receiving diuretic therapy (see section 4.4).

Treatment of postmenopausal osteoporosis, osteoporosis in men and glucocorticoid-induced osteoporosis: The recommended dose is a single intravenous infusion of 5 mg infusion of BONAZOLL 5 administered once a year. Adequate supplemental calcium and vitamin D intake is important in patients with osteoporosis if dietary intake is inadequate.

Treatment of Paget's disease of bone: For the treatment of Pagetu2019s disease BONAZOLL 5 should be prescribed only by medical practitioners with experience in treatment of Pagetu2019s disease of the bone. The recommended dose is one intravenous infusion of 5 mg BONAZOLL 5 (anhydrous) in 100 mL aqueous solution administered intravenously via a vented infusion line, given at a constant infusion rate. Re-treatment of Paget's disease: Specific re-treatment data are not available.

After a single treatment with BONAZOLL 5 in Paget's disease, an extended remission period is observed in responding patients (see section 5.1). However, re-treatment with BONAZOLL 5 may be considered in patients who have relapsed, based on increases in serum alkaline phosphatase, in patients who failed to achieve normalisation of serum alkaline phosphatase, or in patients with symptoms, as dictated by medical Practice 12 months after the initial dose. In patients with Paget's disease, adequate vitamin D intake is recommended in association with BONAZOLL 5 administration. In addition, it is strongly advised that adequate supplemental calcium corresponding to at least 500 mg elemental calcium twice daily is ensured in patients with Paget's disease for at least 10 days following BONAZOLL 5 administration (see section 4.4).

Special populations

Elderly population: No dose adjustment is necessary since bioavailability, distribution and elimination were similar in elderly patients and younger patients.

Renal Impairment: The use of BONAZOLL 5 in patients with creatinine clearance < 35 mL /min is not recommended due to limited clinical safety data in such patients (see sections 4.3 and 4.4). No dose adjustment is necessary in patients with creatinine clearance u2265 35 mL /min.

Hepatic Impairment: No dose adjustment is required (see section 5.2).

Paediatric population: BONAZOLL 5 is not recommended for use in children and adolescents below 18 years of age due to lack of data on safety and efficacy.

Method of administration: Intravenous use. BONAZOLL 5 (5 mg in 100 mL ready-to-infuse solution) is administered via a vented infusion line and given at a constant infusion rate. The infusion time must not be less than 15 minutes. For further information on the handling of zoledronic acid solution for infusion, see section 6.6.

u2022 Hypersensitivity to the active substance or to any of the excipients listed in section 6.1 or to any bisphosphonates.

u2022 Hypocalcaemia (see section 4.4)

u2022 Pregnancy and lactation (see section 4.6).

u2022 Severe impairment of renal function (creatinine clearance of < 35 mL /min): the safety and efficacy in patients with severe renal impairment have not been established.

Renal function

The use of BONAZOLL 5 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 medicines, 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:

• Patients should have serum creatinine measured before receiving each BONAZOLL 5 dose.
• Creatinine clearance should be calculated based on actual body weight using the Cockcroft-Gault formula before each BONAZOLL 5 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.
• BONAZOLL 5 should be used with caution when concomitantly used with other medicines 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 BONAZOLL 5 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 BONAZOLL 5 (see section 4.3). Other disturbances of mineral metabolism must also be effectively treated (e.g. diminished parathyroid reserve, intestinal calcium malabsorption). Medical Practitioners 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 as in BONAZOLL 5 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 BONAZOLL 5 administration, in patients with osteoporosis if dietary intake is inadequate and to prevent clinical fractures after a hip fracture. 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 BONAZOLL 5 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 BONAZOLL 5 is recommended for patients with Pagetu00b4s disease.

Musculoskeletal pain

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)

Osteonecrosis of the jaw has been reported in the post-marketing setting in patients receiving zoledronic acid as in BONAZOLL 5 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 BONAZOLL 5 in patients with concomitant risk factors.

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

• Potency of the medicine 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.

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 BONAZOLL 5 treatment. The management plan for patients who develop ONJ should be set up in close collaboration between the treating doctor and a dentist or oral surgeon with expertise in ONJ. Temporary interruption of BONAZOLL 5 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 BONAZOLL 5 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).

No interaction studies with other medicines have been performed. Zoledronic acid is not systemically metabolized 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 medicines are therefore unlikely. Zoledronic acid is eliminated by renal excretion. Caution is indicated when BONAZOLL 5 is administered in conjunction with medicines 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 medicines that are primarily excreted via the kidney may increase. BONAZOLL 5 solution for infusion must not be allowed to come into contact with any calcium containing solutions.

Women of childbearing potential: BONAZOLL 5 is not recommended in women of childbearing potential.

Pregnancy: BONAZOLL 5 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. The potential risk for humans is unknown.

Breastfeeding: BONAZOLL 5 is contraindicated during breast-feeding (see section 4.3). It is unknown whether BONAZOLL 5 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 BONAZOLL 5 on fertility in humans.

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

Summary of the safety profile: The most frequently reported side effects within 3 days of zoledronic acid dosing were pyrexia, myalgia, influenza-like illness, arthralgia and headache, (see u201cacute phase reactionsu201d below and section 4.4.)

Adverse Effects

Infections and infestations: Less frequent: influenza, nasopharyngitis

Blood and lymphatic system disorders: Less frequent: anaemia

Immune system disorders: Frequency unknown: hypersensitivity reactions including rare cases of bronchospasm, urticaria and angioedema, and very rare cases of anaphylactic reaction/shock.

Metabolism and nutrition disorders: Frequent: hypocalcaemia (common in Pagetu2019s disease) Less frequent: decreased appetite, hypophosphataemia

Psychiatric disorders: Less frequent: insomnia

Nervous system disorders: Frequent: headache, dizziness Less frequent: lethargy, paraesthesia, somnolence, tremor, syncope, dysgeusia

Eye disorders: Frequent: ocular hyperaemia Less frequent: conjunctivitis, eye pain, uveitis, episcleritis, iritis Frequency unknown: scleritis and parophthalmia

Ear and labyrinth disorders: Less frequent: Vertigo

Cardiac disorders: Frequent: atrial fibrillation Less frequent: palpitations

Vascular disorders: Less frequent: hypertension, flushing Frequency unknown: hypotension (some of the patients had underlying risk factors)

Respiratory, thoracic and mediastinal disorders: Less frequent: dyspnoea, cough

Gastrointestinal disorders: Frequent: nausea, vomiting, diarrhoea Less frequent: dyspepsia, abdominal pain upper, abdominal pain, gastro-oesophageal reflux disease, constipation, dry mouth, oesophagitis, toothache, gastritis (observed in patients taking concomitant glucocorticoids)

Skin and subcutaneous tissue disorders: Less Frequent: rash, hyperhidrosis, pruritus, erythema

Musculoskeletal and connective tissue disorders: Frequent: myalgia, arthralgia, bone pain, back pain, pain in extremity Less frequent: neck pain, musculoskeletal stiffness, joint swelling, shoulder pain, muscle spasms, musculoskeletal chest pain, musculoskeletal pain, joint stiffness, arthritis, muscular weakness, osteonecrosis of the external auditory canal (bisphosphonate class adverse reaction). Frequency unknown: osteonecrosis of the jaw (see sections 4.4 and 4.8 Class effects), atypical subtrochanteric and diaphyseal femoral fractures (bisphosphonate class adverse reaction).

Renal and urinary disorders: Less frequent: blood creatinine increased, pollakiuria, proteinuria Frequency unknown: 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 medicines, 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: Frequent: pyrexia, influenza-like illness, chills, fatigue, asthenia, pain, malaise, infusion site reaction Less frequent: peripheral oedema, thirst, acute phase reaction, non-cardiac chest pain Frequency unknown: dehydration secondary to acute phase reactions (post-dose symptoms such as pyrexia, vomiting and diarrhoea)

Investigations: Frequent: C-reactive protein increased Less frequent: blood calcium decreased

Class effects: Description of selected adverse reactions

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 medicines, concomitant diuretic therapy, severe dehydration), the majority of whom received 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 of zoledronic acid-treated and 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: Local reactions at the infusion site, such as redness, swelling and/or pain, were reported following the administration of zoledronic acid in clinical trials.

Osteonecrosis of the jaw: Cases of osteonecrosis of the jaw have been reported, predominantly in cancer patients treated with medicines that inhibit bone resorption, including zoledronic acid, as in BONAZOLL 5 (see section 4.4). Cases of ONJ have been reported in the post-marketing setting for zoledronic acid.

Acute phase reactions: In a study on the treatment of post-menopausal osteoporosis the most frequently reported side effects were: fever, myalgia, flu-like symptoms, arthralgia and headache, the majority of which occurred within the first 3 days following zoledronic acid 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 zoledronic acid. The percentage of patients who experienced adverse reactions was lower where prophylaxis against adverse reactions was used (see section 4.4).

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.