Special Warning : אזהרת שימוש

4.4   Special warnings and precautions for use

Renal function
The use of Aclasta in patients with severe renal impairment (creatinine clearance < 35 ml/min) is contraindicated due to an increased risk of renal failure in this population.


ACL API MAY21 V13                              Page 2 of 17                   EU SmPC Mar2021, NZ DS AUG 2020 Renal impairment has been observed following the administration of Aclasta (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 Aclasta 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-Gault formula before each Aclasta 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.
•   Aclasta 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 Aclasta.
•   A single dose of Aclasta 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 Aclasta (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 Aclasta (see section 4.8).
Adequate calcium and vitamin D intake are recommended in association with Aclasta 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 Aclasta 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 Aclasta 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 Aclasta (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 Aclasta 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.
ACL API MAY21 V13                              Page 3 of 17                    EU SmPC Mar2021, NZ DS AUG 2020 -     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 other bones
Cases of osteonecrosis of other bones (including femur, hip, knee and humerus) have also been reported; however, causality has not been determined in the population treated with Aclasta.
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 Aclasta 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 Aclasta 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 Aclasta 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 Aclasta, i.e. essentially “sodium free” (see also section 6.1).
ACL API MAY21 V13                              Page 4 of 17                    EU SmPC Mar2021, NZ DS AUG 2020 

Effects on Driving

4.7   Effects on ability to drive and use machines

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