Jubbonti

/ Sandoz Pharmaceuticals Israel Ltd

The recommended dose is 60 mg denosumab administered as a single subcutaneous injection once every 6 months into the thigh, abdomen or upper arm.

Patients must be adequately supplemented with calcium and vitamin D.

The optimal total duration of antiresorptive treatment for osteoporosis (including both denosumab and bisphosphonates) has not been established. The need for continued treatment should be re-evaluated periodically based on the benefits and potential risks of denosumab on an individual patient basis, particularly after 5 or more years of use.

* Treatment of osteoporosis in postmenopausal women and in men at increased risk of fractures. In postmenopausal women denosumab significantly reduces the risk of vertebral, non-vertebral and hip fractures.
* Treatment of bone loss associated with hormone ablation in men with prostate cancer at increased risk of fractures. In men with prostate cancer receiving hormone ablation, denosumab significantly reduces the risk of vertebral fractures.
* Treatment of bone loss associated with long-term systemic glucocorticoid therapy of a daily dosage equivalent to 7.5 mg or greater of prednisone and expected to remain on glucocorticoids for at least 3 months, in adult patients at high risk of fracture.

* Hypersensitivity to the active substance or to any of the excipients
* Hypocalcemia

Calcium and vitamin D supplementation
Adequate intake of calcium and vitamin D is important in all patients.
Hypocalcemia
It is important to identify patients at risk for hypocalcemia. Hypocalcemia must be corrected by adequate intake of calcium and vitamin D before initiating therapy. Clinical monitoring of calcium levels is recommended before each dose and, in patients predisposed to hypocalcemia within two weeks after the initial dose. If any patient presents with suspected symptoms of hypocalcemia during treatment calcium levels should be measured.
Concomitant glucocorticoid treatment is an additional risk factor for hypocalcemia.
Renal impairment
Patients with severe renal impairment (creatinine clearance < 30 mL/min) or receiving dialysis are at greater risk of developing hypocalcemia. The risks of developing hypocalcemia and accompanying parathyroid hormone elevations increase with increasing degree of renal impairment. Severe and fatal cases have been reported. Adequate intake of calcium, vitamin D and regular monitoring of calcium is especially important in these patients.
Skin infections
Patients receiving denosumab may develop skin infections (predominantly cellulitis) leading to hospitalization.
Osteonecrosis of the jaw (ONJ)
ONJ has been reported rarely in patients receiving denosumab for osteoporosis.
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 in patients with concomitant risk factors.
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, history of 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.
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 medicinal products (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 denosumab 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.
Long-term antiresorptive treatment
Long-term antiresorptive treatment (including both denosumab and bisphosphonates) may contribute to an increased risk for adverse outcomes such as osteonecrosis of the jaw and atypical femur fractures due to significant suppression of bone remodeling.
Treatment discontinuation
Following denosumab discontinuation, decrease in bone mineral density (BMD) is expected, leading to an increased risk for fractures. Monitoring of BMD is recommended, and alternative treatment should be considered according to clinical guidelines.
Concomitant treatment with other denosumab-containing medicinal products
Patients being treated with denosumab should not be treated concomitantly with other denosumab-containing medicinal products (for prevention of skeletal related events in adults with bone metastases from solid tumors).
Hypercalcemia in pediatric patients
This medical product should not be used in pediatric patients (age < 18). Serious hypercalcemia has been reported. Some clinical trial cases were complicated by acute renal injury.
Multiple vertebral fractures (MVF) following discontinuation
MVF may occur following discontinuation of treatment, particularly in patients with a history of vertebral fracture.
See prescribing information for full details

Very common: Pain in extremity, Musculoskeletal pain
Common: Urinary tract infection, Upper respiratory tract infection, Sciatica, Constipation, Abdominal discomfort, Rash, Eczema, Alopecia.
See prescribing information for full details

In an interaction study, denosumab did not affect the pharmacokinetics of midazolam, which is metabolized by cytochrome P450 3A4 (CYP3A4). This indicates that denosumab should not alter the pharmacokinetics of medicinal products metabolized by CYP3A4.
There are no clinical data on the co-administration of denosumab and hormone replacement therapy (estrogen), however the potential for a pharmacodynamic interaction is considered to be low.
See prescribing information for full details.

Pregnancy: There are no or limited amount of data from the use of denosumab in pregnant women. Women should be advised not to become pregnant during and for at least 5 months after treatment. Any effects 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.