Denosumab

Denosumab is a human IgG2 monoclonal antibody produced in Chinese hamster ovary cells. It targets RANKL, the main signal that drives the formation, function and survival of osteoclasts, the cells that break down bone. The 60 mg product (Prolia) is used to slow bone loss in osteoporosis and related conditions; the 120 mg product (Xgeva) is used to limit cancer-related bone destruction. Biosimilar denosumab products follow the dose and indications of the reference product they copy, Prolia or Xgeva.

Mechanism of Action

• RANKL binding: denosumab binds RANKL with high affinity and specificity, preventing RANKL from activating its receptor RANK on osteoclast precursors and osteoclasts. This inhibits osteoclast formation, function and survival and so reduces bone resorption in cortical and trabecular bone.
• Cancer-related bone disease (Xgeva): increased osteoclast activity, stimulated by RANKL, is a key driver of bone destruction in metastatic bone disease and multiple myeloma. Denosumab reduces osteoclast numbers and function and so cancer-induced bone destruction.
• Giant cell tumour of bone: these tumours contain neoplastic stromal cells that express RANKL and osteoclast-like giant cells that express RANK. Denosumab binds RANKL, markedly reducing or eliminating the giant cells; osteolysis is reduced and the proliferating tumour stroma is replaced by non-proliferating, differentiated, densely woven new bone.
• Bone turnover markers with Prolia: the bone resorption marker serum CTX fell by 85% within 3 days. By the end of each 6-month interval the reduction was partly lost (from at least 87% to about 45% or more), which shows the effect is reversible; markers generally returned to pre-treatment levels within 9 months of the last dose, and re-starting produced a similar response to first-time treatment.
• Bone turnover markers with Xgeva: urinary NTX/creatinine fell by about 80% within the first week and stayed down through 49 weeks of 120 mg every 4 weeks.
• Immunogenicity: no neutralising antibodies were seen in clinical studies. Fewer than 1% of patients treated for up to 5 years (Prolia) or 3 years (Xgeva) had non-neutralising binding antibodies, with no sign of altered pharmacokinetics, toxicity or response.

Pharmacokinetics

• Absorption: after subcutaneous injection of about 60 mg, exposure (AUC) was 78% of that after the same dose given intravenously. The peak serum level was about 6 µg/mL (range 1–17), reached after about 10 days (range 2–28). With Xgeva, bioavailability was 62%.
• Distribution and metabolism: denosumab is made only of amino acids and carbohydrates, like natural immunoglobulin, and is unlikely to be cleared by the liver. It is expected to be broken down along the immunoglobulin clearance pathway into small peptides and amino acids.
• Elimination with Prolia: after the peak, serum levels fell with a half-life of 26 days (range 6–52) over about 3 months, and 53% of patients had no measurable denosumab at 6 months. There was no accumulation with 60 mg every 6 months.
• Elimination with Xgeva: serum levels about doubled with 120 mg every 4 weeks, with steady state by 6 months; in giant cell tumour of bone, with extra doses on days 8 and 15, steady state was reached within the first month. After stopping, the mean half-life was 28 days (range 14–55).
• Non-linearity: pharmacokinetics are non-linear, with lower clearance at higher doses (saturable, target-mediated elimination) but roughly dose-proportional increases in exposure from 60 mg upwards.
• Special populations: pharmacokinetics were similar in men and women and were not meaningfully changed by age, race or disease state. Higher body weight lowered exposure, but not to a clinically important degree because bone-turnover effects were consistent across weights. Renal impairment, including dialysis, had no effect on pharmacokinetics. Hepatic impairment was not studied and is not expected to matter. In skeletally mature adolescents (12–17 years) with giant cell tumour of bone, pharmacokinetics resembled those in adults.

Prolia and Xgeva are different medicines with different indications and doses.

Prolia (60 mg)

• Osteoporosis in postmenopausal women and in men at increased risk of fractures. In postmenopausal women Prolia significantly reduces the risk of vertebral, non-vertebral and hip fractures.
• Bone loss associated with hormone ablation in men with prostate cancer at increased risk of fractures. In these men Prolia significantly reduces the risk of vertebral fractures.
• Bone loss associated with long-term systemic glucocorticoid therapy in adult patients at increased risk of fracture.

Xgeva (120 mg)

• Prevention of skeletal-related events (pathological fracture, radiation to bone, spinal cord compression or surgery to bone) in adults with advanced malignancies involving bone.
• Giant cell tumour of bone that is unresectable, or where surgical resection is likely to result in severe morbidity, in adults and skeletally mature adolescents.

Biosimilars

Biosimilar denosumab products are authorised separately and follow the strength, dose and indications of the reference product they copy (Prolia or Xgeva). The strength on the pack and the SmPC of the individual product show which regimen applies.

• Prolia: hypersensitivity to denosumab or to any excipient; hypocalcaemia.
• Xgeva: hypersensitivity to denosumab or to any excipient; severe, untreated hypocalcaemia; unhealed lesions from dental or oral surgery.

With Prolia, the most common reactions (more than 1 patient in 10) are musculoskeletal pain and pain in the extremities; cellulitis is uncommon, and hypocalcaemia, hypersensitivity, osteonecrosis of the jaw and atypical femoral fractures are rare. With Xgeva, hypocalcaemia is very common, mostly within the first 2 weeks, and can be severe and symptomatic; musculoskeletal pain is the most common other reaction, and osteonecrosis of the jaw is common. The groups below show each product separately.

Very common (≥1/10): Prolia — pain in the extremities, musculoskeletal pain. Xgeva — hypocalcaemia, dyspnoea, diarrhoea, musculoskeletal pain.

Common (≥1/100 to <1/10): Prolia — urinary tract infection, upper respiratory tract infection, sciatica, constipation, abdominal discomfort, rash, eczema, alopecia. Xgeva — new primary malignancy, hypophosphataemia, tooth extraction, hyperhidrosis, osteonecrosis of the jaw.

Uncommon (≥1/1,000 to <1/100): Prolia — diverticulitis, cellulitis, ear infection, lichenoid drug eruptions. Xgeva — hypercalcaemia after stopping treatment in giant cell tumour of bone, lichenoid drug eruptions, atypical femoral fracture, injection site reactions.

Rare (≥1/10,000 to <1/1,000): Prolia — drug hypersensitivity, anaphylactic reaction, hypocalcaemia, osteonecrosis of the jaw, atypical femoral fractures. Xgeva — drug hypersensitivity, anaphylactic reaction.

Very rare (<1/10,000): Prolia — hypersensitivity vasculitis.

Not known: osteonecrosis of the external auditory canal (both products).

Important serious reactions:

• Hypocalcaemia: severe symptomatic hypocalcaemia, including fatal cases, has been reported after marketing, mostly in the first weeks of treatment; QT prolongation, tetany, seizures and altered mental state have occurred. Symptoms in studies included tingling, muscle stiffness, twitching, spasms and cramps. In active-controlled trials in advanced cancer, hypocalcaemia was reported in 9.6% of patients on Xgeva and 5.0% on zoledronic acid (16.9% against 12.4% in a multiple myeloma trial), and in 5.7% of patients with giant cell tumour of bone.
• Osteonecrosis of the jaw: with Prolia it was rare (16 patients among 23,148 in trials; incidence 0.04% at 3 years, 0.06% at 5 years and 0.44% at 10 years of treatment, rising with exposure). With Xgeva it was confirmed in 1.8% of patients in three active-controlled trials (1.3% with zoledronic acid), in 5.9% in the multiple myeloma trial, and in 6.8% in a long-term giant cell tumour of bone trial; the risk rises with treatment duration, and cases have appeared after stopping.
• Skin infections (Prolia): infections leading to hospitalisation, mainly cellulitis, occurred in 0.4% of women on Prolia against 0.1% on placebo.
• Atypical femoral fractures: rare with Prolia, uncommon with Xgeva overall and more frequent (0.95%) in giant cell tumour of bone.
• New primary malignancy (Xgeva): 1.5% of patients on Xgeva against 0.9% on zoledronic acid in the advanced cancer trials, with no pattern by cancer type.

• Prolia: denosumab did not change the pharmacokinetics of midazolam (a CYP3A4 substrate), so it should not alter medicines cleared by CYP3A4. There are no clinical data on combining denosumab with hormone replacement therapy (oestrogen), but a pharmacodynamic interaction is considered unlikely. Previous alendronate treatment did not alter denosumab’s pharmacokinetics or effects.
• Xgeva: no interaction studies have been performed. In clinical trials it was given with standard anticancer treatment and to patients previously given bisphosphonates, with no clinically relevant change in trough levels or effects on bone turnover.
• Other denosumab products and bisphosphonates: patients on Prolia should not receive another denosumab-containing medicine (such as Xgeva), and patients on Xgeva should not receive one for osteoporosis (such as Prolia) or a bisphosphonate at the same time.
• Glucocorticoids: concomitant glucocorticoid treatment is an additional risk factor for hypocalcaemia with Prolia.
• Calcium and vitamin D: supplements are part of the treatment and are used to prevent hypocalcaemia.

Prolia and Xgeva are both injected under the skin, but they differ in dose, schedule and indication; one is never a substitute for the other. Patients receive the package leaflet and the patient reminder card with either product.

Prolia: 60 mg Every 6 Months

• Dose: 60 mg as a single subcutaneous injection once every 6 months into the thigh, abdomen or upper arm.
• Supplements: patients must be adequately supplemented with calcium and vitamin D.
• Duration: the best total duration of antiresorptive treatment (denosumab and bisphosphonates together) has not been established. The need for continued treatment should be re-evaluated periodically, especially after 5 years or more.
• Who injects: an individual adequately trained in injection technique.

Xgeva: 120 mg Every 4 Weeks

• Prevention of skeletal-related events: 120 mg as a single subcutaneous injection once every 4 weeks into the thigh, abdomen or upper arm.
• Giant cell tumour of bone: 120 mg every 4 weeks, with additional 120 mg doses on days 8 and 15 of the first month. Patients are re-evaluated at regular intervals to see whether they continue to benefit. In patients whose disease was controlled, the effect of stopping has not been evaluated, but limited data do not suggest a rebound.
• Supplements: at least 500 mg calcium and 400 IU vitamin D daily in all patients, unless hypercalcaemia is present.
• Who injects: the 120 mg/1.7 mL vial only by a healthcare professional. The 120 mg/1.0 mL pre-filled syringe may be used by a patient or caregiver trained by a healthcare professional, with the first self-injection supervised.

The Two Regimens Side by Side

• Prolia: 60 mg, every 6 months, for osteoporosis and bone loss from hormone ablation or glucocorticoids.
• Xgeva: 120 mg, every 4 weeks (with extra doses in the first month for giant cell tumour of bone), for bone metastases and giant cell tumour of bone.
• The two are never given together.

Special Populations

• Elderly (65 years and over): no dose adjustment for either product.
• Renal impairment: no dose adjustment for either product, but calcium must be monitored, especially in severe impairment or dialysis. For Prolia there are no data in patients on long-term glucocorticoids with severe renal impairment (GFR below 30 mL/min).
• Hepatic impairment: safety and efficacy have not been studied.
• Children and adolescents: Prolia must not be used under 18 years because of safety concerns (serious hypercalcaemia, possible inhibition of bone growth and lack of tooth eruption). Xgeva is not recommended under 18 years, except in skeletally mature adolescents (12–17 years) with giant cell tumour of bone, who receive the adult dose.

Missed Dose

The dosing section of the SmPC does not set a rule for a missed injection. The prescriber decides when the next dose is due.

Calcium and Vitamin D

Adequate intake of calcium and vitamin D matters in all patients. Xgeva requires at least 500 mg calcium and 400 IU vitamin D daily unless hypercalcaemia is present.

Hypocalcaemia

Existing hypocalcaemia must be corrected before treatment. With Prolia, calcium is monitored before each dose and, in patients predisposed to hypocalcaemia, within two weeks after the first dose. With Xgeva, it is monitored before the first dose, within two weeks afterwards, and if symptoms appear, with more checks when risk factors exist. Patients should report symptoms of low calcium. Severe symptomatic hypocalcaemia, including fatal cases, has occurred, mostly in the first weeks but also later. Patients with severe renal impairment (creatinine clearance below 30 mL/min) or on dialysis are at greater risk, as are patients taking glucocorticoids.

Osteonecrosis of the Jaw

Osteonecrosis of the jaw is rare with Prolia and common with Xgeva. Starting or restarting treatment 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 are recommended before treatment (with Prolia, in patients with risk factors). Risk factors include potent, parenteral and high cumulative doses of bone-resorption therapy; cancer, anaemia, coagulopathies, infection and smoking; corticosteroids, chemotherapy, angiogenesis inhibitors and head and neck radiotherapy; and poor oral hygiene, periodontal disease, poorly fitting dentures, dental disease and invasive dental procedures such as extractions. Patients should keep good oral hygiene, have routine dental check-ups and report oral symptoms (loose teeth, pain, swelling, non-healing sores, discharge) at once. Invasive dental procedures should follow careful consideration and be avoided close to an injection. If osteonecrosis of the jaw develops, a dentist or oral surgeon with expertise in it should be involved and temporary interruption considered.

Osteonecrosis of the External Auditory Canal

This has been reported. Possible risk factors are steroid use, chemotherapy and local factors such as infection or trauma. It should be considered in patients with ear symptoms, including chronic ear infections.

Atypical Femoral Fractures

These can occur with little or no trauma in the thigh bone below the hip and along the shaft, and have also been reported in patients with certain conditions (such as vitamin D deficiency, rheumatoid arthritis, hypophosphatasia) and medicines (bisphosphonates, glucocorticoids, proton pump inhibitors), and without antiresorptive therapy. The other thigh bone should be examined after a femoral shaft fracture, and stopping denosumab considered pending evaluation if one is suspected. Patients should report new or unusual thigh, hip or groin pain.

Long-Term Antiresorptive Treatment

Long-term treatment with denosumab or bisphosphonates may add to the risk of osteonecrosis of the jaw and atypical femoral fractures because bone remodelling is strongly suppressed.

Stopping Treatment

• Prolia: bone mineral density is expected to fall after stopping, with a higher risk of fracture. Bone density should be monitored and alternative treatment considered according to clinical guidelines.
• Xgeva: clinically significant hypercalcaemia needing hospital treatment and complicated by acute kidney injury has been reported weeks to months after stopping in giant cell tumour of bone, and also in patients with growing skeletons. After stopping, patients are monitored for signs and symptoms of hypercalcaemia, calcium may be checked periodically, and calcium and vitamin D needs are re-evaluated. Xgeva is not recommended in patients with growing skeletons.

Skin Infections (Prolia)

Skin infections, mainly cellulitis, can lead to hospitalisation. Patients should seek prompt medical attention for signs of cellulitis.

Giant Cell Tumour of Bone

Malignancy or progression to metastatic disease is infrequent but a known risk. Patients should be monitored for radiological signs of malignancy, new radiolucency or osteolysis. Available data do not suggest a higher risk of malignancy with Xgeva.

Pregnancy, Breastfeeding and Fertility

• Pregnancy: neither product is recommended in pregnancy or in women of childbearing potential not using contraception. Women should not become pregnant during treatment and for at least 5 months afterwards. Animal studies showed reproductive toxicity, and effects are likely to be greater in the second and third trimesters because antibodies cross the placenta more as pregnancy advances.
• Breastfeeding: it is unknown whether denosumab passes into human milk. Studies in mice lacking RANKL suggest it may interfere with mammary gland maturation and lactation, so a decision is made to abstain from breastfeeding or from therapy.
• Fertility: no human data; animal studies do not indicate harmful effects on fertility.

Excipients, Traceability and Driving

• Sorbitol: both products contain sorbitol (47 mg per mL in Prolia; 78 mg per Xgeva vial and 37 mg per Xgeva pre-filled syringe); the combined intake from other sorbitol or fructose sources should be taken into account.
• Phenylalanine: the Xgeva pre-filled syringe contains 6.1 mg of L-phenylalanine, which may be harmful in phenylketonuria; these patients should use the Xgeva vial, which contains none.
• Polysorbate 20 and sodium: polysorbates may cause allergic reactions, and each dose contains less than 1 mmol of sodium.
• Traceability: the product name and batch number should be clearly recorded.
• Driving: no or negligible influence on the ability to drive and use machines.

Store in a refrigerator (2–8 °C). Do not freeze. Keep the vial or pre-filled syringe in the outer carton to protect from light. Once removed from the refrigerator, Prolia may be kept at room temperature (up to 25 °C) in the original carton for up to 30 days and must be used within that period. Xgeva may likewise be kept at room temperature (up to 25 °C) in the original container for up to 30 days, must not be put back in the refrigerator, and must be used within that period. Both are cold-chain products: they should be held at 2–8 °C until shortly before use. Allow the vial or syringe to reach room temperature before injecting, and do not shake it.

• Prolia: 4 years.
• Xgeva: 4 years (vial) and 3 years (pre-filled syringe).
• After removal from the refrigerator, up to 30 days at room temperature (up to 25 °C), as described under Storage Conditions.

Prescription only (Rx). Prolia is subject to medical prescription. Xgeva is subject to restricted medical prescription (Annex II B) and is used under the responsibility of a healthcare professional. The Xgeva vial is given only by a healthcare professional, so it is supplied to the hospital or clinic that administers it. Prolia, and the Xgeva pre-filled syringe when a trained patient or caregiver injects it, are supplied to the patient or the treating clinic on prescription; for all presentations, cold-chain delivery at 2–8 °C is needed.