Denosumab Instructions

(Xgeva) Instructions

Generic name: denosumab

Product name: Xgeva

Full names: denosumab, denosumab, denosumab, Xgeva, Denosumab

Indications: (1) Bone metastasis from solid tumors: It is suitable for preventing bone-related events in patients with bone metastases from solid tumors. (2) Important limitations of use: Not suitable for prevention of bone-related events in patients with multiple myeloma. 

Usage and Dosage: Inject 120 mg subcutaneously into the upper arm, upper thigh, or abdomen, once every 4 weeks. When treatment or prevention of hypocalcemia is required, give calcium and vitamin D. 

Adverse Reactions: The most common adverse reactions (incidence greater than or equal to 25% per patient) in patients receiving Xgeva were fatigue/asthenia, hypophosphatemia, and nausea. 

Contraindications: allergies; hypocalcemia.

Precautions: Hypocalcemia must be corrected before denosumab therapy can be initiated. For patients who are prone to hypocalcemia and mineral metabolism imbalance (such as those with a history of hypoparathyroidism, thyroid surgery, parathyroid surgery, malnutrition, small bowel resection, severe renal insufficiency), clinical monitoring of creatinine and mineral levels is required, and such patients should be instructed to pay attention to the symptoms of hypocalcemia and to supplement adequate amounts of calcium and vitamin D. Patients who are concurrently taking immunosuppressants or have compromised immune systems may be at increased risk of serious infections, and physicians need to fully consider the benefit-risk ratio before prescribing denosumab to such patients. Physicians should evaluate the need to continue denosumab therapy in patients who develop serious infections while taking denosumab. Osteonecrosis of the jaw often occurs with tooth extraction and local infection that delays healing. A routine oral examination should be performed before starting denosumab treatment, and good oral hygiene should be maintained after treatment is started. If a patient develops osteonecrosis of the jaw, treatment for osteonecrosis of the jaw may worsen the condition, and discontinuation of the medication should be considered at this time. 

Storage: Refrigerate at 2-8°C (36-46°F); do not freeze; must be used within 14 days after removal from the refrigerator and do not expose to temperatures above 25°C (77°F); avoid direct light and heat. 

Mechanism of action: Denosumab is the first approved monoclonal antibody that specifically targets RANK ligand. RANK ligand is a transmembrane or soluble protein that is necessary for osteoclasts to maintain their structure, function, and survival. Human RANKL mRNA is mainly found in bones, bone marrow and lymphoid tissues. Its main function in bones is to stimulate the differentiation and activity of osteoclasts and inhibit the apoptosis of osteoclasts. Osteoclasts are responsible for bone resorption, and osteoclast precursors must have low levels of macrophage colony-stimulating factor and RANKL during their differentiation into mature osteoclasts. Denosumab has a high affinity with RANKL, preventing RANK ligand from activating RANK on the surface of osteoclasts, inhibiting osteoclast activation and development, reducing bone resorption, increasing bone density and bone strength of both cortical bone and trabecular bone, promoting bone reconstruction, and reducing the incidence of vertebral, non-vertebral and hip fractures in postmenopausal osteoporotic women. The effect of denosumab on bone reconstruction can be evaluated by measuring some bone renewal markers, such as the bone resorption marker N-telopeptide, the bone formation marker bone-specific alkaline phosphatase, etc. A phase I clinical study conducted in healthy postmenopausal women showed that a dose-dependent decrease in morning urine NTX levels was observed on day 2 after administration. This decrease lasted for 6 months, with the maximum decrease reaching 84% compared with baseline. This effect is reversible. When serum denosumab levels disappear, NTX levels can be seen to rise again, which reflects the reversibility of its effect on bone reconstruction. As treatment continues, these effects will persist for a new cycle. 

Efficacy and safety: A study showed that when healthy volunteers were fasted for at least 12 hours and given a single subcutaneous injection of 60 mg denosumab, the average maximum plasma concentration Cmax was 6.75 ± 1.89 μg/mL, the median peak time Tmax was 10 d (range 3-21 d), the average elimination half-life t1 /2 was 25.4 ± 8.5 d, and the average area under the drug-time curve AUC at 16 weeks was 316 ± 101 μg/d/mL. Denosumab plasma concentrations can be maintained for 4 to 5 months. In addition, there is no accumulation in the body after multiple subcutaneous injections of 60 mg of denosumab every 6 months, and the pharmacokinetic parameters do not change over time. The pharmacokinetic parameters of denosumab are not affected by gender and age. Similar to other human monoclonal antibodies, the pharmacokinetics of denosumab are non-linearly related to dose. When a single subcutaneous injection of denosumab 0.01 to 3.0 mg/kg was given to healthy postmenopausal women, three phases of metabolism were observed: ① A prolonged absorption process, with Cmax appearing 5 to 21 days after administration, and the concentration increased as the dose increased. ② The elimination half-life of the drug is as long as 32 days. ③ There is a rapid elimination period after the blood drug concentration drops below 1 000 ng/mL. The bioavailability, distribution and elimination process in the body are currently unknown.