Xgeva^® (Solution) Instructions for Use

Marketing Authorization Holder

Amgen Europe, B.V. (Netherlands)

Manufactured By

Amgen Manufacturing, Limited (Puerto Rico)

Packaging and Quality Control Release

AMGEN MANUFACTURING, Limited (Netherlands)

Or

AMGEN TECHNOLOGY (Ireland), Unlimited Company (Ireland)

Or

DOBROLEK, LLC (Russia)

ATC Code

M05BX04 (Denosumab)

Active Substance

Denosumab (Rec.INN registered by WHO)

Dosage Form

Xgeva®

Solution for subcutaneous administration 70 mg/1 ml: fl. 1.7 ml 1 or 4 pcs.

Dosage Form, Packaging, and Composition

Solution for subcutaneous administration clear or slightly opalescent, from colorless to light yellow, practically free of visible particles.

Excipients: sorbitol (E420), glacial acetic acid, polysorbate 20, sodium hydroxide, water for injections.

1.7 ml – glass vials with a volume of 3 ml (1) – cardboard packs^× with a fixator.
1.7 ml – glass vials with a volume of 3 ml (4) – cardboard packs^× with a fixator.
1.7 ml – glass vials with a volume of 3 ml (1) – contour cell packs (1) – cardboard packs^× with a fixator.
1.7 ml – glass vials with a volume of 3 ml (1) – contour cell packs (4) – cardboard packs^× with a fixator.

^× each pack has transparent protective labels – first opening control, with a longitudinal colored stripe.

Clinical-Pharmacological Group

Bone resorption inhibitor. Monoclonal antibody

Pharmacotherapeutic Group

Drugs for the treatment of bone diseases – other drugs affecting bone structure and mineralization. Monoclonal antibodies

Pharmacological Action

The RANK ligand is a protein present in both membrane-bound and soluble forms. RANKL is necessary for the formation, function, and survival of osteoclasts – the only cell type responsible for bone resorption. Increased osteoclast activity induced by RANKL is the main cause of bone destruction in metastatic bone disease and multiple myeloma. Denosumab is a human monoclonal antibody (IgG2) that targets and binds with high affinity and specificity to RANKL, preventing the interaction between RANKL and RANK, leading to a reduction in the number of osteoclasts and inhibition of their function, thereby reducing bone resorption and bone destruction caused by malignancies.

Giant cell tumors of bone are characterized by the presence of neoplastic stromal cells expressing RANK ligand and giant osteoclast-like cells expressing RANK. In patients with giant cell tumors of bone, Denosumab binds to RANK ligand and significantly reduces or completely eliminates the number of giant osteoclast-like cells. As a result, osteolysis is reduced, and the proliferative tumor stroma is replaced by non-proliferative, differentiated, and dense new bone tissue.

Denosumab reduces or prevents the risk of developing skeletal-related events and multiple skeletal complications (first and subsequent) in patients with bone metastases from solid tumors and in patients with multiple myeloma. It increases the rate of objective tumor response, reduces the risk of progression, and eliminates the need for surgery in adult patients and skeletally mature adolescents with giant cell tumor of bone.

Pharmacokinetics

After subcutaneous administration, the bioavailability was 62%. Denosumab consists of amino acids and carbohydrates, like natural immunoglobulin, so it is unlikely to be eliminated via hepatic metabolic pathways. The metabolism and excretion of denosumab are presumed to occur via the same mechanisms as for immunoglobulins, with degradation into small peptides and individual amino acids. In patients with advanced cancer who received multiple doses of 120 mg every 4 weeks, an approximately two-fold increase in serum concentrations of denosumab was observed, reaching steady state at approximately 6 months of treatment according to time-independent pharmacokinetics. In patients with multiple myeloma who received 120 mg every 4 weeks, the median trough concentration varied by less than 8% between 6 and 12 months. In patients with giant cell tumor of bone receiving 120 mg every 4 weeks with loading doses on days 8 and 15, steady state was achieved during the first month of treatment. Between 9 and 49 weeks, the median trough concentration changed by no more than 9%. In patients who discontinued 120 mg every 4 weeks, the mean T_1/2 was about 28 days (range: 14-55 days).

When administered subcutaneously, Denosumab exhibits nonlinear pharmacokinetics over a wide dose range, and an approximately dose-dependent increase in exposure for doses of 60 mg (or 1 mg/kg) and higher. The nonlinearity of pharmacokinetics is likely due to the saturation of target-mediated elimination pathways, which are important at low drug concentrations.

Indications

Prevention of skeletal-related events in patients with multiple myeloma and in patients with bone metastases from solid tumors.

Treatment of unresectable giant cell tumor of bone in adult patients or skeletally mature adolescents, as well as in cases where surgical intervention is associated with a high risk of severe complications.

Treatment of hypercalcemia of malignancy in adult patients resistant to intravenous bisphosphonate therapy.

ICD codes

Dosage Regimen

Administer subcutaneously in the thigh, abdomen, or upper arm.

The standard dose is 120 mg once every 4 weeks.

For patients with giant cell tumor of bone, administer a loading dose of 120 mg on days 8 and 15 of the first month of therapy.

Correct preexisting hypocalcemia prior to initiating therapy.

Supplement with calcium and vitamin D for all patients to mitigate the risk of hypocalcemia, unless hypercalcemia is present.

Monitor serum calcium levels prior to the initial dose, within 2 weeks after the first dose, and periodically thereafter, especially in patients with risk factors.

In patients with severe renal impairment (CrCl <30 mL/min) or on dialysis, monitor calcium levels more frequently due to a significantly increased risk of hypocalcemia.

Do not administer to patients with unhealed lesions from dental or oral surgery; delay initiation until soft tissue healing is complete.

Perform a preventive dental examination before starting treatment to assess the risk of osteonecrosis of the jaw.

Avoid invasive dental procedures during therapy; if necessary, perform them with caution and avoid scheduling near the denosumab injection date.

Advise patients to report new or unusual thigh, hip, or groin pain for evaluation of atypical femoral fracture.

After treatment discontinuation, monitor patients for rebound hypercalcemia, particularly adolescents and young adults with open growth plates.

Do not administer concurrently with bisphosphonates or other drugs containing denosumab.

Adverse Reactions

Benign, malignant and unspecified neoplasms (including cysts and polyps): common – newly diagnosed malignancies.

Immune system disorders rare – hypersensitivity reactions, including anaphylactic reaction.

Metabolism and nutrition disorders very common – hypocalcemia; common – hypophosphatemia; uncommon – hypercalcemia after treatment discontinuation in patients with giant cell tumor of bone.

Respiratory, thoracic and mediastinal disorders very common – dyspnea.

Gastrointestinal disorders very common – diarrhea; common – tooth extraction.

Skin and subcutaneous tissue disorders common – hyperhidrosis; uncommon – lichenoid drug eruption.

Musculoskeletal and connective tissue disorders very common – musculoskeletal pain; common – osteonecrosis of the jaw; uncommon – atypical femoral fracture; rare – multiple vertebral fractures observed after discontinuation of denosumab treatment; frequency not known – osteonecrosis of the external auditory canal.

Contraindications

Hypersensitivity to denosumab, severe untreated hypocalcemia, unhealed lesions from dental or maxillofacial surgery, pregnancy, breastfeeding period, children under 18 years of age (except for skeletally mature adolescents with giant cell tumor of bone).

Use in Pregnancy and Lactation

Contraindicated for use during pregnancy and breastfeeding.

Use in Hepatic Impairment

Efficacy and safety have not been studied.

Use in Renal Impairment

Based on available data on the efficacy and safety of the drug in this patient group, no dose adjustment is required.

Patients with severe renal impairment (CrCl<30 ml/min) or on dialysis are at greater risk of developing hypocalcemia. Such patients must additionally take calcium and vitamin D supplements.

Pediatric Use

Contraindication: children under 18 years of age (except for skeletally mature adolescents with giant cell tumor of bone).

Geriatric Use

Based on available data on the efficacy and safety of the drug in this age group, no dose adjustment is required.

Special Precautions

Supplemental calcium and vitamin D intake is required for all patients, except in cases of hypercalcemia.

Preexisting hypocalcemia must be corrected prior to initiating denosumab therapy. Hypocalcemia may occur at any time during denosumab treatment. Calcium levels should be monitored prior to the initial dose of denosumab, within 2 weeks after the initial dose, and if symptoms suggestive of possible hypocalcemia occur. In patients with risk factors for hypocalcemia, or if other clinical indications arise due to the patient’s condition, additional calcium monitoring should be considered.

Patients should be advised to report symptoms characteristic of hypocalcemia. If hypocalcemia develops during denosumab therapy, additional calcium supplementation and monitoring may be required.

During the post-marketing surveillance period, cases of severe hypocalcemia (including fatal cases) have been reported, with most cases occurring in the first weeks of therapy, but they could occur at any time during denosumab treatment.

Patients with severe renal impairment (CrCl < 30 ml/min) or on dialysis are at greater risk of developing hypocalcemia. The risk of developing hypocalcemia and concomitant increase in parathyroid hormone concentration is higher with increasing severity of renal impairment. Regular monitoring of calcium levels is particularly important for this patient group.

Initiation of treatment/a new course of treatment should be delayed in patients with open soft tissue lesions of the oral cavity. A preventive dental examination and an individual benefit-risk assessment of treatment are recommended before starting denosumab therapy.

When assessing the risk of developing osteonecrosis of the jaw, the following patient risk factors should be considered: the therapeutic potential of the bone resorption-inhibiting drug (higher risk for more potent compounds), route of administration (higher risk for parenteral administration) and cumulative dose of bone resorptive therapy; diabetes, cancer, comorbid conditions (e.g., anemia, coagulopathy, infection), smoking; concomitant therapy, including corticosteroids, chemotherapy, angiogenesis inhibitors, head and neck radiation; poor oral hygiene, periodontal disease, ill-fitting dentures, pre-existing dental disease, invasive dental procedures (e.g., tooth extraction).

All patients should be advised to maintain good oral hygiene, have regular dental check-ups, and immediately report any oral symptoms such as loose teeth, pain or swelling, non-healing sores, or discharge during denosumab treatment. During therapy, invasive dental procedures should be performed only after careful assessment of the clinical situation and should be avoided in close proximity to the denosumab administration date.

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. In patients receiving Denosumab who have ear symptoms, including chronic ear infections, the possibility of osteonecrosis of the external auditory canal should be considered.

Atypical femoral fractures – subtrochanteric or diaphyseal fractures of the proximal femur – can occur with minimal or no trauma. On imaging, these fractures usually have a characteristic appearance. Atypical femoral fractures have also been reported in patients with comorbidities and conditions (e.g., vitamin D deficiency, rheumatoid arthritis, hypophosphatasia), and in patients receiving certain therapies (e.g., bisphosphonates, corticosteroids, proton pump inhibitors). These cases have also been observed in the absence of antiresorptive therapy. During bisphosphonate therapy, such fractures are often bilateral; therefore, in patients with a confirmed femoral shaft fracture receiving Denosumab, the contralateral femur should be examined. The decision to discontinue denosumab therapy in patients with suspected atypical femoral fracture should be considered based on an individual risk assessment. During denosumab treatment, patients should be instructed to report the occurrence of new or unusual pain in the thigh, hip, or groin. Patients who develop such symptoms should be evaluated for an incomplete femoral fracture.

After treatment discontinuation, patients should be monitored for the development of hypercalcemia, periodic assessment of serum calcium should be performed, and the patient’s need for calcium and vitamin D supplementation should be reviewed.

Denosumab is not recommended for patients with ongoing skeletal growth. Cases of clinically significant hypercalcemia have also been observed in this patient group from several weeks to several months after treatment discontinuation.

Patients receiving Denosumab should not concurrently receive other drugs containing Denosumab (with indications for the treatment of osteoporosis).

Patients receiving Denosumab should not concurrently receive bisphosphonates.

Malignant transformation of giant cell tumor of bone or its progression to a metastatic phase is an infrequent event and is a known risk in patients with giant cell tumor of bone. Patients should be monitored for radiological signs of a malignant process (new radiolucent areas or osteolysis). Available clinical data do not indicate an increased risk of malignant transformation of giant cell tumor of bone in patients treated with Denosumab.

Drug Interactions

Studies to evaluate drug interactions have not been conducted.

Storage Conditions

Store at 2°C (36°F) to 8°C (46°F). Keep in original packaging, protected from light. Keep out of reach of children.

Dispensing Status

Rx Only

Important Safety Information

This information is for educational purposes only and does not replace professional medical advice. Always consult your doctor before use. Dosage and side effects may vary. Use only as prescribed.