SYNTHESIS |
VIDAL pharmacotherapeutic classification:Rheumatology : Paget's disease : Bisphosphonates : Zoledronic acid - Osteoporosis : Bisphosphonates ( Zoledronic acid )
ATC classification:MUSCLE AND SKELETON : DRUGS FOR THE TREATMENT OF BONE DISORDERS - DRUGS ACTING ON BONE STRUCTURE AND MINERALIZATION : BISPHOSPHONATES ( ZOLEDRONIC ACID )
Excipients:
mannitol , sodium citrate , ppi water
SHAPES AND PRESENTATIONS |
COMPOSITION |
| per vial | |
| Zoledronic acid (INN) | 5mg |
Each ml of the solution contains 0.05 mg of zoledronic acid, corresponding to 0.0533 mg of zoledronic acid monohydrate.
| DC | DIRECTIONS |
- Treatment of :
- postmenopausal osteoporosis,
- male osteoporosis in adults,
- postmenopausal osteoporosis,
- Treatment of osteoporosis associated with long-term systemic corticosteroid therapy:
- in postmenopausal women,
- in adult men,
- in postmenopausal women,
- Treatment of Paget's disease in adults.
| DC | DOSAGE AND METHOD OF ADMINISTRATION |
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| DC | CONTRAINDICATIONS |
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| DC | WARNINGS AND PRECAUTIONS FOR USE |
- Kidney function:
- The use of Aclasta in patients with severe renal impairment (creatinine clearance < 35 ml/min) is contraindicated, due to a higher risk of renal failure in this population.
- Impaired renal function has been observed after administration of Aclasta ( see Adverse Effects ), particularly in patients with pre-existing renal impairment or other risk factors such as advanced age, concomitant use of nephrotoxic drugs or diuretics ( see Interactions ) or in the event of dehydration occurring after administration of Aclasta. Impaired renal function has been observed in patients after 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 below.
- The following precautions should be considered to minimize the risk of renal side effects:
- Creatinine clearance should be calculated on the basis of actual body weight using the Cockcroft-Gault formula before each administration of Aclasta.
- Aclasta should not be used in patients whose creatinine clearance is < 35 ml/min ( see Pharmacokinetics ).
- The transient elevation of serum creatinine may be greater in patients with pre-existing impaired renal function.
- Monitoring of serum creatinine should be considered in patients at risk.
- Aclasta should be used with caution when used concomitantly with drugs that may impair kidney function ( see Interactions ).
- Patients, especially elderly patients and those receiving diuretic therapy, should be adequately hydrated prior to administration of Aclasta.
- The single dose of Aclasta must not exceed 5 mg and the duration of the infusion must be at least 15 minutes ( see Posology and Method of administration ).
- Hypocalcemia:
- Pre-existing hypocalcaemia must be treated with appropriate calcium and vitamin D intakes before initiating treatment with Aclasta ( see Contraindications ). Other disorders of mineral metabolism should also be treated effectively (eg hypoparathyroidism, intestinal calcium malabsorption). Clinical monitoring of these patients should be considered by the prescriber.
- High bone turnover is one of the hallmarks of Paget's disease. Due to the rapid onset of action of zoledronic acid on bone remodeling, transient hypocalcaemia, sometimes symptomatic, may occur and generally reaches a maximum value within the first 10 days following administration of Aclasta ( see Adverse Reactions ).
- An adequate intake of calcium and vitamin D is recommended simultaneously with the administration of Aclasta. In addition, in patients with Paget's disease, it is strongly advised to administer appropriate calcium supplements corresponding to an elemental calcium intake of at least 500 mg twice daily for at least 10 days following treatment. administration of Aclasta ( see Dosage and Method of administration ).
- Patients should be informed about the symptoms characterizing hypocalcaemia and be subject to appropriate clinical monitoring during the risk period. It is recommended to measure serum calcium before Aclasta infusion in patients with Paget's disease of bone.
- Severe and sometimes disabling bone, joint and/or muscle pain has been reported rarely in patients treated with bisphosphonates, including zoledronic acid ( see Adverse Reactions ).
- Osteonecrosis of the jaw:
- Osteonecrosis of the jaw has been reported post-marketing in patients receiving Aclasta (zoledronic acid) for the treatment of osteoporosis ( see Adverse effects ).
- The start of treatment or a new cycle of treatment should be delayed in patients with open, unhealed lesions of the soft tissues of the mouth. A dental check-up accompanied by preventive dental care and an individual risk-benefit assessment is recommended before treatment with Aclasta in patients with risk factors.
- The following should be considered when assessing a patient's risk factors for developing osteonecrosis of the jaw:
- Potency of action of the bone resorption inhibitor drug (higher risk for very potent molecules), route of administration (higher risk for parenteral administration) and cumulative dose of the bone resorption inhibitor treatment.
- Cancer, comorbid situations (such as anemia, coagulopathies, infection), smoking.
- Concomitant treatments: corticosteroids, chemotherapy, angiogenesis inhibitors, radiotherapy of the head and neck.
- Poor oral hygiene, periodontal disease, ill-fitting dentures, history of dental disease, invasive dental procedures such as tooth extractions.
- All patients should be encouraged to maintain good oral hygiene, have regular dental check-ups, and report any oral symptoms such as loose teeth, pain or swelling, non-healing wounds or discharge immediately. during treatment with zoledronic acid. During treatment, invasive dental procedures should be performed with caution and away from zoledronic acid injections.
- Management of patients who develop osteonecrosis of the jaw must be implemented in close collaboration between the attending physician and a dentist or oral surgeon with expertise in osteonecrosis of the jaw. A temporary interruption of zoledronic acid treatment should be considered until the problem is resolved and if possible until the contributing risk factors have subsided.
- Osteonecrosis of the external auditory canal:
- Osteonecrosis of the external auditory canal has been reported with bisphosphonates, especially 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 experience auditory symptoms, including chronic ear infections.
- Atypical fractures of the femur:
- Atypical subtrochanteric and diaphyseal femoral fractures have been reported under bisphosphonates, mainly in patients undergoing long-term treatment for osteoporosis. These transverse or short oblique fractures can occur on any part of the femur from below the lesser trochanter to above the supracondylar area. These fractures occur after minimal or no trauma, and some patients present with pain in the thigh or groin, often associated with radiological evidence of stress fractures, weeks or months before the femoral fracture. Fractures are often bilateral; therefore, the contralateral femur should be examined in bisphosphonate-treated patients who have had a diaphyseal femoral fracture. Poor healing of these fractures has also been reported. Discontinuation of bisphosphonate therapy in patients in whom an atypical femoral fracture is suspected should be considered on the basis of the patient benefit/risk assessment.
- During bisphosphonate treatment, patients should be advised that any pain in the thigh, hip or groin should be reported and all patients presenting with such symptoms should be evaluated for an atypical femoral fracture.
- Acute phase reactions:
- Acute phase reactions (APRs) or post-administration symptoms such as fever, myalgia, flu-like symptoms, arthralgia and headache have been observed, the majority of them occurring within three days of Aclasta administration.
- RPAs can sometimes be serious or of prolonged duration. The incidence of post-administration symptoms can be reduced by administering paracetamol or ibuprofen shortly after administration of Aclasta. It is also recommended to postpone the treatment if the patient is clinically unstable due to an acute pathology and an APR could be problematic ( cf Undesirable effects ).
- General :
- Other medicinal products containing the active substance zoledronic acid are available for indications in oncology. Patients treated with Aclasta should not be treated concomitantly with these medicinal products or any other bisphosphonate, since the cumulative effects of these medicinal products are not known.
- This medicinal product contains less than 1 mmol sodium (23 mg) per 100 ml vial of Aclasta, i.e. essentially 'sodium free'.
| DC | FERTILITY / PREGNANCY / BREASTFEEDING |
Aclasta is not recommended for women of childbearing age.
Pregnancy :
Aclasta is contraindicated during pregnancy ( see Contraindications ). There are no adequate data from the use of zoledronic acid in pregnant women. Animal studies with zoledronic acid have shown reproductive toxicity, including malformations ( see Preclinical Safety ). The potential risk to humans is not known.
Feeding with milk :
Aclasta is contraindicated during breast-feeding ( see Contraindications ). Excretion of zoledronic acid in breast milk is unknown.
Fertility:Zoledronic acid has been studied in rats for potential adverse effects on fertility of the parents and the F1 generation. This gave rise to exacerbated pharmacological effects which were thought to be related to inhibition of the compound responsible for calcium mobilization from the skeleton, inducing hypocalcemia during or around the period of parturition, a class effect of bisphosphonates , dystocia and early termination of the study. Thus, these results preclude the determination of a definitive effect of Aclasta on fertility in humans.
| DC | OVERDOSAGE |
Clinical experience in acute poisoning is limited. Patients who have received more than the recommended dose should be carefully monitored. In the event of an overdose resulting in clinically significant hypocalcaemia, reversibility may be achieved by administration of an oral calcium supplement and/or intravenous infusion of calcium gluconate.
| PP | PRECLINICAL SAFETY |
- Acute toxicity :
- The highest non-lethal single intravenous dose was 10 mg/kg body weight in mice and 0.6 mg/kg in rats. In single infusion studies in dogs, the dose of 1.0 mg/kg (6 times the recommended human therapeutic exposure based on AUC) administered over 15 minutes was well tolerated with no renal effects.
- Subchronic and chronic toxicity:
- In intravenous infusion studies, renal tolerance of zoledronic acid has been established in rats given 6 x 15-minute infusions of 0.6 mg/kg administered 3 days apart (for a cumulative dose corresponding to AUC levels approximately 6 times the human therapeutic exposure), while 5 x 15-minute intravenous infusions of 0.25 mg/kg given at 2-3 week intervals (for a cumulative dose equivalent to 7 times the human therapeutic exposure) were well tolerated in dogs. In intravenous bolus studies, dose tolerance decreased with increasing study duration: doses of 0.2 and 0.02 mg/kg per day were well tolerated for 4 weeks respectively in rats and dogs, but doses of 0.01 mg/kg and 0.
- Longer-term repeated administration for cumulative exposures significantly exceeding the maximum expected exposure in humans has produced toxicological effects in other organs, including the gastrointestinal tract and liver, and at the site of administration. The clinical relevance of these observations is not known. The most common finding in repeat dose studies was an increase in primary cancellous tissue in the metaphyses of long bones in growing animals at nearly all doses, a finding reflecting the anti-resorptive pharmacological activity of product.
- Reproductive toxicity:
- Teratology studies have been performed in two species, each time by subcutaneous administration. Teratogenicity was observed in rats at doses ≥ 0.2 mg/kg and manifested as external, visceral and skeletal malformations. Dystocia was observed at the lowest dose tested in rats (0.01 mg/kg body weight). No teratogenic or embryofoetal effects were observed in rabbits, although pronounced maternal toxicity was observed at the 0.1 mg/kg dose due to decreased serum calcium levels.
- Mutagenicity and carcinogenic potential:
- Zoledronic acid was not mutagenic in mutagenicity tests and carcinogenicity studies showed no evidence of carcinogenic potential.
| DP | INCOMPATIBILITIES |
This medication should not come into contact with solutions containing calcium. Aclasta should not be mixed or given intravenously with other medicines.
| DP | STORAGE CONDITIONS |
- Shelf life before opening:
- 3 years.
This medicinal product does not require any special storage precautions.
- After first opening the bottle:
- 24 hours at 2°C to 8°C. From a microbiological point of view, the product 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 to 8°C.
| DP | HANDLING/DISPOSAL PROCEDURES |
For single use only.
Only a clear solution, free of particles and staining should be used.
If the solution has been refrigerated, it should be allowed to return to room temperature before administration. Aseptic conditions must be observed when preparing the infusion.
Any unused medication or waste should be disposed of in accordance with applicable regulations.
PRESCRIPTION/ISSUE/CARE |
| Medicine subject to special monitoring during treatment. | |
| MA | EU/1/05/308/001; CIP 3400936587113 (RCP rev 26.03.2020). |
| Price : | 189.26 euros (100 ml bottle). |
| Remb Séc soc at 65% on the basis of the TFR: 129.63 euros (100 ml bottle) and Collect approved in the following indications: | |
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Marketing Authorization Holder: Novartis Europharm Limited, Vista Building, Elm Park, Merrion Road, Dublin 4, Ireland.
