Wyost

/ Sandoz Pharmaceuticals Israel Ltd

Supplementation of at least 500 mg calcium and 400 IU vitamin D daily is required in all patients, unless hypercalcemia is present.
Prevention of skeletal related events in adults with multiple myeloma and in adults with bone metastases from solid tumors: The recommended dose is 120 mg administered as a single subcutaneous injection once every 4 weeks into the thigh, abdomen or upper arm.
Giant cell tumor of bone: The recommended dose is 120 mg administered as a single subcutaneous injection once every 4 weeks into the thigh, abdomen or upper arm with additional 120 mg doses on days 8 and 15 of treatment of the first month of therapy.
Patients with giant cell tumor of bone should be evaluated at regular intervals to determine whether they continue to benefit from treatment. In patients whose disease is controlled by this drug, the effect of interruption or cessation of treatment has not been evaluated, however limited data in these patients does not indicate a rebound effect upon cessation of treatment.
Please refer to the license holder for further details.

Prevention of skeletal related events (pathological fracture, radiation to bone, spinal cord compression or surgery to bone) in adults with multiple myeloma and in adults with bone metastases from solid tumours. Treatment of adult and skeletally mature adolescents with giant cell tumor of bone that is unresectable or where surgical resection is likely to result in severe morbidity.

* Hypersensitivity to the active substance or to any of the excipients.
* Severe, untreated hypocalcemia.
* Unhealed lesions from dental or oral surgery.

Calcium and vitamin D supplementation: Supplementation with calcium and vitamin D is required in all patients unless hypercalcemia is present.
Hypocalcemia: Pre-existing hypocalcemia must be corrected prior to initiating therapy. Hypocalcemia can occur at any time during therapy with denosumab. Monitoring of calcium levels should be conducted (i) prior to the initial dose of denosumab, (ii) within two weeks after the initial dose, (iii) if suspected symptoms of hypocalcemia occur. Additional monitoring of calcium level should be considered during therapy in patients with risk factors for hypocalcemia, or if otherwise indicated based on the clinical condition of the patient.
Patients should be encouraged to report symptoms indicative of hypocalcemia. If hypocalcemia occurs while receiving denosumab, additional calcium supplementation and additional monitoring may be necessary.
Renal impairment: Patients with severe renal impairment (creatinine clearance < 30 mL/min) or receiving dialysis are at greater risk of developing hypocalcemia. The risk of developing hypocalcemia and accompanying elevations in parathyroid hormone increases with increasing degree of renal impairment. Regular monitoring of calcium levels is especially important in these patients.
Osteonecrosis of the jaw (ONJ): ONJ has been reported commonly in patients receiving denosumab.The start of treatment/new treatment course 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 denosumab.
The following risk factors 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., anemia, coagulopathies, infection), smoking.
• concomitant therapies: corticosteroids, chemotherapy, angiogenesis inhibitors, radiotherapy to head and neck.
• poor oral hygiene, periodontal disease, poorly fitting dentures, pre-existing dental disease, invasive dental procedures (e.g., tooth extractions).
All patients should be encouraged to maintain good oral hygiene, receive routine dental check-ups, and immediately report any oral symptoms such as dental mobility, pain or swelling, or non-healing of sores or discharge during treatment with denosumab. While on treatment, invasive dental procedures should be performed only after careful consideration and be avoided in close proximity to denosumab administration.
The management plan of the 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 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 denosumab. 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 denosumab who present with ear symptoms including chronic ear infections.
Atypical fractures of the femur: Atypical femoral fractures have been reported in patients receiving denosumab. Atypical femoral fractures may occur with little or no trauma in the subtrochanteric and diaphyseal regions of the femur. Specific
radiographic findings characterize these events. Atypical femoral fractures have also been reported in patients with certain co-morbid conditions (e.g., vitamin D deficiency, rheumatoid arthritis, hypophosphatasia) and with use of certain pharmaceutical agents (e.g., bisphosphonates, glucocorticoids, proton pump inhibitors). These events have also occurred without antiresorptive therapy. Similar fractures reported in association with bisphosphonates are often bilateral; therefore, the contralateral femur should be examined in denosumab-treated patients who have sustained a femoral shaft fracture. Discontinuation of 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 denosumab treatment, patients should be advised to report new or unusual thigh, hip, or groin pain. Patients presenting with such symptoms should be evaluated for an incomplete femoral fracture.
Hypercalcemia following treatment discontinuation in patients with giant cell tumor of bone and in patients with growing skeletons: Clinically significant hypercalcemia requiring hospitalization and complicated by acute renal injury has been reported in denosumab -treated patients with giant cell tumor of bone weeks to months following treatment discontinuation.
After treatment is discontinued, monitor patients for signs and symptoms of hypercalcemia, consider periodic assessment of serum calcium and re-evaluate the patient’s calcium and vitamin D supplementation requirements.
Denosumab is not recommended in patients with growing skeletons. Clinically significant hypercalcemia has also been reported in this patient group weeks to months following treatment discontinuation.
Multiple vertebral fractures (MVF) following treatment discontinuation:
Cases of multiple vertebral fractures (MVF) have occurred rarely following discontinuation of denosumab in patients participating in ongoing clinical trials. These fractures were not due to bone metastases and occurred approximately 1 year following discontinuation of treatment with denosumab, particularly in post-menopausal women with malignancies with risk factors such as osteoporosis or prior (non-vertebral or vertebral) fractures.
Consistent with the pharmacological properties of denosumab, effects on bone are known to be reversible and bone turnover increases after denosumab is discontinued.
Advise patients not to interrupt denosumab therapy without their physician’s advice.
When denosumab treatment is discontinued, evaluate the individual patient’s risk for vertebral fractures.
Others: Patients being treated with denosumab should not be treated concomitantly with other denosumab containing medicinal products (for osteoporosis indications).
Patients being treated with denosumab should not be treated concomitantly with bisphosphonates.
Malignancy in giant cell tumor of bone or progression to metastatic disease is an infrequent event and a known risk in patients with giant cell tumor of bone. Patients should be monitored for radiological signs of malignancy, new radiolucency or osteolysis. Available clinical data does not suggest an increased risk of malignancy in giant cell tumor of bone patients treated with denosumab.
See prescribing information for full details.

Very common: Hypocalcemia, dyspnea, diarrhea, musculoskeletal pain.
Common: New primary malignancy, hypophosphatemia, tooth extraction, hyperhidrosis, osteonecrosis of the jaw.
See prescribing information for full details.

No interaction studies have been performed.
In clinical trials, denosumab has been administered in combination with standard anti-cancer treatment and in subjects previously receiving bisphosphonates. There were no clinically-relevant alterations in trough serum concentration and pharmacodynamics of denosumab by concomitant chemotherapy and/or hormone therapy or by previous intravenous bisphosphonate exposure.

Pregnancy: There are no or limited amount of data from the use of denosumab in pregnant women. Studies in animals have shown reproductive toxicity.
This medicinal product is not recommended during pregnancy and women of child-bearing potential not using contraception. Women should be advised not to become pregnant during and for at least 5 months after treatment. Any effects of denosumab are likely to be greater during the second and third trimesters of pregnancy since monoclonal antibodies are transported across the placenta in a linear fashion as pregnancy progresses, with the largest amount transferred during the third trimester.
Lactation: It is unknown whether denosumab is excreted in human milk. A risk to the newborns/infants cannot be excluded. Knockout mouse studies suggest absence of RANKL during pregnancy may interfere with maturation of the mammary gland leading to impaired lactation post-partum. A decision must be made on whether to abstain from breast-feeding or to abstain from denosumab therapy, taking into account the benefit of breast-feeding to the newborn/infant and the benefit of therapy for the woman.                     

There is no experience with overdose in clinical studies. denosumab has been administered in clinical studies using doses up to 180 mg every 4 weeks and 120 mg weekly for 3 weeks.

• Do not shake.
• To avoid discomfort at the site of injection, allow the vial to reach room temperature (up to 25°C) before injecting and inject slowly.
• The entire contents of the vial should be injected.
• A 27-gauge needle is recommended for the administration of denosumab.
• The vial should not be re-entered.