Denosis60 mg/ml

Denosis is a human monoclonal antibody (RANK ligand inhibitor) marketed under different brand names and dosing schedules depending on indication. Approved uses include:

Established / FDA-approved uses

• Osteoporosis: Treatment of postmenopausal women with osteoporosis at high risk for fracture; treatment to increase bone mass in men with osteoporosis at high risk for fracture; treatment of glucocorticoid-induced osteoporosis in men and women at high risk for fracture.
• Cancer treatment-induced bone loss: To increase bone mass in patients at high risk for fracture receiving androgen deprivation therapy for non-metastatic prostate cancer, or adjuvant aromatase inhibitor therapy for breast cancer.
• Skeletal-related events (SRE) in cancer: Prevention of SREs (pathologic fracture, radiation to bone, spinal cord compression, or surgery to bone) in patients with multiple myeloma and in patients with bone metastases from solid tumors.
• Giant cell tumor of bone: Treatment in adults and skeletally mature adolescents when the tumor is unresectable or surgical resection is likely to result in severe morbidity.
• Hypercalcemia of malignancy: Treatment of hypercalcemia of malignancy refractory to bisphosphonate therapy.

The osteoporosis-dose formulation of Denosis and the higher oncology-dose formulation of Denosis are not interchangeable; the correct brand/strength depends on the indication.

Each pre-filled syringe/vial of Denosumab contains Denosumab (a fully human IgG2 monoclonal antibody produced in a mammalian cell line by recombinant DNA technology) as the active ingredient, formulated as an aqueous solution with excipients such as acetate buffer, sorbitol, polysorbate 20, and water for injection.

Denosis is a fully human monoclonal antibody that binds to and inhibits RANK ligand (RANKL), a key mediator of osteoclast formation, function, and survival. By inhibiting RANKL, Denosis reduces bone resorption and increases bone mineral density. Denosis is given as a subcutaneous injection, with the dose and frequency differing between the osteoporosis/bone-loss indications (lower dose, every 6 months) and the oncology skeletal-related-event/giant cell tumor/hypercalcemia indications (higher dose, every 4 weeks, with extra loading doses for some uses).

Monoclonal antibody; RANK ligand (RANKL) inhibitor; bone resorption inhibitor (antiresorptive agent).

Mechanism of Action

Denosumab is a monoclonal antibody that specifically binds RANK ligand (RANKL), a protein essential for the formation, function, and survival of osteoclasts, the cells responsible for bone resorption. By binding RANKL, Denosumab prevents RANKL from activating its receptor, RANK, on osteoclasts and their precursors, thereby inhibiting osteoclast-mediated bone resorption and increasing bone mass and strength in both cortical and trabecular bone.

Pharmacokinetics

• Absorption: After subcutaneous injection, bioavailability of Denosumab is approximately 62%; peak serum concentrations are reached in about 10 days.
• Metabolism/Elimination: Denosumab is not metabolized by the liver; it is cleared via the reticuloendothelial system, similar to endogenous immunoglobulins, with an effective half-life of approximately 25-28 days at the osteoporosis dose.
• Duration of effect: Bone turnover markers are suppressed rapidly after dosing with Denosumab, and the effect is reversible upon discontinuation.

Denosis is for subcutaneous injection only, administered by a qualified healthcare professional into the upper arm, upper thigh, or abdomen. Denosis must not be given intravenously or intramuscularly, and must not be mixed with other medicinal products. Allow the Denosis pre-filled syringe/vial to reach room temperature before injection (do not warm by hot water or microwave). Visually inspect Denosis for particulate matter or discoloration before use; discard if present. Patients should take calcium and vitamin D supplements as directed, and a dental evaluation is recommended before starting oncology-dose Denosis therapy.

No formal drug-drug interaction studies have identified clinically significant interactions between Denosis and other medicines, including chemotherapy agents. Denosis is not metabolized by cytochrome P450 enzymes and is not expected to interact with drugs cleared via that pathway. Clinically relevant considerations include:

• Other RANKL inhibitors / bisphosphonates: Concomitant use with Denosis is not recommended, as combined use is not established and osteonecrosis of the jaw risk may increase.
• Corticosteroids and other immunosuppressive agents: May increase the risk of serious infections when used together with Denosis (see Precautions and Warnings).
• Calcium/vitamin D supplements: Not a drug interaction, but necessary co-administration to reduce the hypocalcemia risk of Denosis.

Common

• Back pain, pain in extremities, musculoskeletal pain
• Hypercholesterolemia
• Urinary tract infection
• Fatigue, asthenia
• Hypophosphatemia, nausea, diarrhea, anemia (more common with oncology-dose Denosis)
• Skin reactions: rash, eczema, dermatitis

Serious (see Precautions and Warnings)

• Severe hypocalcemia
• Serious infections (including skin infections, endocarditis)
• Osteonecrosis of the jaw
• Atypical femoral fractures
• Multiple vertebral fractures after discontinuation of Denosis

Pregnancy: Denosis is contraindicated in pregnancy. Animal studies have shown that RANKL inhibition by Denosis is associated with fetal harm, including increased fetal loss, stillbirth, and postnatal mortality. Females of reproductive potential should use effective contraception during Denosis treatment and for at least 5 months after the final dose. If pregnancy occurs, Denosis should be discontinued and the patient counseled on potential risk to the fetus.

Lactation: It is unknown whether Denosis is excreted in human milk. Because of the potential for serious adverse effects in a breastfed infant, use Denosis only if clearly needed and if the potential benefit justifies the potential risk, and only under medical supervision; a decision should be made whether to discontinue breastfeeding or discontinue Denosis.

Hypocalcemia

Denosis can cause severe, symptomatic hypocalcemia, which may be life-threatening, particularly in patients with advanced chronic kidney disease. Pre-existing hypocalcemia must be corrected before starting Denosis, and adequate calcium and vitamin D intake is required in all patients. Monitor serum calcium closely, especially within the first weeks of Denosis therapy and in patients at risk (renal impairment, malabsorption).

Osteonecrosis of the Jaw (ONJ)

ONJ has been reported with Denosis, more frequently at higher/more frequent oncology dosing and in patients with poor oral hygiene, invasive dental procedures, or dental appliances. A dental examination is recommended before starting Denosis, particularly at oncology doses. Good oral hygiene should be maintained, and invasive dental procedures should be avoided during treatment when possible.

Atypical Femoral Fractures

Atypical, low-energy, or low-trauma fractures of the femoral shaft have been reported with long-term Denosis use. Patients should be advised to report new or unusual thigh, hip, or groin pain, and any patient with a suspected atypical fracture should be evaluated.

Serious Infections

Because Denosis inhibits RANKL, which plays a role in immune function, serious infections (including skin infections, endocarditis, and abdominal, urinary tract, and ear infections) have occurred more frequently with Denosis than with placebo. Advise patients to seek prompt medical attention for signs of infection.

Multiple Vertebral Fractures After Discontinuation

Discontinuing Denosis therapy, particularly when used for osteoporosis, can result in rebound bone loss and increased risk of multiple vertebral fractures. Patients discontinuing Denosis should be evaluated for transition to another antiresorptive agent, and the risks and benefits of stopping should be discussed with a physician.

Hypercalcemia After Discontinuation

Clinically significant hypercalcemia has been reported after discontinuation of Denosis in patients with growing skeletons and in some giant cell tumor patients; monitor calcium after stopping Denosis in these populations.

There is limited clinical experience with Denosis overdose, and no specific antidote exists. In case of suspected overdose of Denosis, patients should be monitored closely for signs and symptoms of hypocalcemia (such as muscle cramps, numbness or tingling, or cardiac rhythm disturbances) and other adverse effects. Seek immediate medical attention or contact emergency services or a poison control center for appropriate supportive care and monitoring.

Store Denosis refrigerated at 2°C to 8°C (36°F to 46°F) in the original carton, protected from light. Do not freeze Denosis. If needed, it may be kept at room temperature (up to 25°C) for a limited period as specified by the manufacturer before use; once removed from the carton, protect from direct light and use within the specified time, and do not shake vigorously. Keep out of reach of children.

Renal Impairment

No dosage adjustment of Denosis is required based on renal function; however, patients with advanced chronic kidney disease (including those on dialysis) are at greater risk of severe hypocalcemia with Denosis and require close monitoring of calcium levels and adequate calcium/vitamin D supplementation.

Hepatic Impairment

No specific studies of Denosis have been conducted in hepatic impairment; no dosage adjustment is considered necessary, as Denosis is not hepatically metabolized.

Elderly

No overall differences in the safety or efficacy of Denosis have been observed between elderly and younger patients; no dosage adjustment is required.

Pediatric

See Pediatric Uses.

Duration of Denosis therapy is individualized by indication and determined by the treating physician based on ongoing risk-benefit assessment. For osteoporosis, Denosis is typically continued long-term (multiple years) with periodic reassessment of fracture risk; if discontinuation is considered, transition to another antiresorptive therapy is generally recommended to prevent rebound bone loss. For oncology indications (skeletal-related event prevention, giant cell tumor, hypercalcemia of malignancy), Denosis is generally continued as long as clinically indicated and tolerated.

Monoclonal antibodies; RANK ligand (RANKL) inhibitors; bone-modifying agents / antiresorptive agents. Denosumab is the representative agent of this class.

Denosumab binds with high affinity and specificity to RANK ligand (RANKL), preventing the RANKL-RANK interaction on osteoclasts and their precursors. This action of Denosumab inhibits osteoclast formation, function, and survival, thereby decreasing bone resorption and increasing bone mineral density in both cortical and trabecular bone. In cancer settings, this same mechanism allows Denosumab to reduce tumor-induced osteolysis, decreasing skeletal-related events, and, in giant cell tumor of bone, to reduce osteoclast-like giant cells within the tumor stroma.

Denosis (osteoporosis-dose formulation) is not approved for use in pediatric patients; safety and efficacy in patients under 18 years have not been established for this dose/indication, and use of Denosis may impair bone growth in patients with open growth plates.

Denosis (oncology-dose formulation) is approved for giant cell tumor of bone in skeletally mature adolescents aged 12 years and older (defined as having at least one mature long bone with a closed epiphyseal growth plate), at the same dose and schedule used in adults. Denosis is not approved for other pediatric indications, and safety and efficacy in skeletally immature pediatric patients have not been established; use in growing children can impair bone growth and tooth eruption.