4.1. Therapeutic indications

Prevention of skeletal related events (pathological fracture, radiation to bone, spinal cord compression or surgery to bone) in adults with advanced malignancies involving bone (see section 5.1).

Treatment of adults and skeletally mature adolescents with giant cell tumour of bone that is unresectable or where surgical resection is likely to result in severe morbidity.

4.2. Posology and method of administration

Bomyntra should be administered under the responsibility of a healthcare professional.

Posology

Supplementation of at least 500 mg calcium and 400 IU vitamin D daily is required in all patients, unless hypercalcaemia is present (see section 4.4).

Patients treated with denosumab should be given the package leaflet and the patient reminder card.

Prevention of skeletal related events in adults with advanced malignancies involving bone

The recommended dose is 120 mg administered as a single subcutaneous injection once every 4 weeks into the thigh, abdomen or upper arm.

Giant cell tumour of bone

The recommended dose of denosumab is 120 mg administered as a single subcutaneous injection once every 4 weeks into the thigh, abdomen or upper arm with additional 120 mg doses on days 8 and 15 of treatment of the first month of therapy. Patients in the phase II study who underwent complete resection of giant cell tumour of bone did receive an additional 6 months of treatment following the surgery as per study protocol.

Patients with giant cell tumour of bone should be evaluated at regular intervals to determine whether they continue to benefit from treatment. In patients whose disease is controlled by denosumab, the effect of interruption or cessation of treatment has not been evaluated, however limited data in these patients does not indicate a rebound effect upon cessation of treatment.

Renal impairment

No dose adjustment is required in patients with renal impairment (see section 4.4 for recommendations relating to monitoring of calcium, 4.8 and 5.2).

Hepatic impairment

The safety and efficacy of denosumab have not been studied in patients with hepatic impairment (see section 5.2).

Elderly patients (age ≥ 65)

No dose adjustment is required in elderly patients (see section 5.2).

Paediatric population

The safety and efficacy of denosumab have not been established in paediatric patients (age < 18) other than skeletally mature adolescents (aged 12-17 years) with giant cell tumour of bone.

Denosumab is not recommended in paediatric patients (age < 18) other than skeletally mature adolescents (aged 12-17 years) with giant cell tumour of bone (see section 4.4).

Treatment of skeletally mature adolescents with giant cell tumour of bone that is unresectable or where surgical resection is likely to result in severe morbidity: the posology is the same as in adults.

Inhibition of RANK/RANK ligand (RANKL) in animal studies has been coupled to inhibition of bone growth and lack of tooth eruption, and these changes were partially reversible upon cessation of RANKL inhibition (see section 5.3).

Method of administration

For subcutaneous use.

Bomyntra 120 mg solution in a pre-filled syringe: The administration using the 120 mg pre-filled syringe can be administered by a patient or caregiver who has been trained in injection techniques by a healthcare professional. The first self-administration with the Bomyntra pre-filled syringe should be supervised by a healthcare professional.

For instructions for use, handling and disposal see section 6.6.

4.3. Contraindications

Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.

Severe, untreated hypocalcaemia (see section 4.4).

Unhealed lesions from dental or oral surgery.

4.4. Special warnings and precautions for use

Traceability

In order to improve the traceability of biological medicinal products, the name and the batch number of the administered product should be clearly recorded.

Calcium and Vitamin D supplementation

Supplementation with calcium and vitamin D is required in all patients unless hypercalcaemia is present (see section 4.2).

Hypocalcaemia

Pre-existing hypocalcaemia must be corrected prior to initiating therapy with denosumab. Hypocalcaemia can occur at any time during therapy with denosumab. Monitoring of calcium levels should be conducted (i) prior to the initial dose of denosumab, (ii) within two weeks after the initial dose, (iii) if suspected symptoms of hypocalcaemia occur (see section 4.8 for symptoms). Additional monitoring of calcium level should be considered during therapy in patients with risk factors for hypocalcaemia, or if otherwise indicated based on the clinical condition of the patient.

Patients should be encouraged to report symptoms indicative of hypocalcaemia. If hypocalcaemia occurs while receiving denosumab, additional calcium supplementation and additional monitoring may be necessary.

In the post-marketing setting, severe symptomatic hypocalcaemia (including fatal cases) has been reported (see section 4.8), with most cases occurring in the first weeks of initiating therapy, but can occur later.

Renal impairment

Patients with severe renal impairment (creatinine clearance < 30 mL/min) or receiving dialysis are at greater risk of developing hypocalcaemia. The risk of developing hypocalcaemia and accompanying elevations in parathyroid hormone increases with increasing degree of renal impairment. Regular monitoring of calcium levels is especially important in these patients.

Osteonecrosis of the jaw (ONJ)

ONJ has been reported commonly in patients receiving denosumab (see section 4.8).

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.

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. anaemia, coagulopathies, infection), smoking.

• concomitant therapies: corticosteroids, chemotherapy, angiogenesis inhibitors, radiotherapy to head and neck.

• poor oral hygiene, periodontal disease, poorly fitting dentures, pre-existing 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.

The management plan of the patients who develop ONJ should be set up in close collaboration between the treating physician and a dentist or oral surgeon with expertise in ONJ. Temporary interruption of denosumab treatment should be considered until the condition resolves and contributing risk factors are mitigated where possible.

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 (see section 4.8). Atypical femoral fractures may occur with little or no trauma in the subtrochanteric and diaphyseal regions of the femur. Specific radiographic findings characterise 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 pharmaceutical agents (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.

Hypercalcaemia following treatment discontinuation in patients with giant cell tumour of bone and in patients with growing skeletons

Clinically significant hypercalcaemia requiring hospitalisation and complicated by acute renal injury has been reported in denosumab-treated patients with giant cell tumour of bone weeks to months following treatment discontinuation.

After treatment is discontinued, monitor patients for signs and symptoms of hypercalcaemia, consider periodic assessment of serum calcium and re-evaluate the patient's calcium and vitamin D supplementation requirements (see section 4.8).

Denosumab is not recommended in patients with growing skeletons (see section 4.2). Clinically significant hypercalcaemia has also been reported in this patient group weeks to months following treatment discontinuation.

Others

Patients being treated with denosumab should not be treated concomitantly with other denosumab containing medicinal products (for osteoporosis indications).

Patients being treated with denosumab should not be treated concomitantly with bisphosphonates.

Malignancy in giant cell tumour of bone or progression to metastatic disease is an infrequent event and a known risk in patients with giant cell tumour of bone. Patients should be monitored for radiological signs of malignancy, new radiolucency or osteolysis. Available clinical data does not suggest an increased risk of malignancy in giant cell tumour of bone patients treated with denosumab.

Warnings for excipients

This medicinal product contains sorbitol. The additive effect of concomitantly administered products containing sorbitol (or fructose) and dietary intake of sorbitol (or fructose) should be taken into account.

This medicine contains 0.17 mg of polysorbate 20 in each prefilled syringe which is equivalent to 0.10 mg/mL. Polysorbates may cause allergic reactions. Tell your doctor if you have any known allergies.

This medicinal product contains less than 1 mmol sodium (23 mg) per 120 mg dose, that is to say essentially 'sodium-free'.

4.5. Interaction with other medicinal products and other forms of interaction

No interaction studies have been performed.

In clinical trials, denosumab has been administered in combination with standard anti-cancer treatment and in subjects previously receiving bisphosphonates. There were no clinically-relevant alterations in trough serum concentration and pharmacodynamics of denosumab (creatinine adjusted urinary N-telopeptide, uNTx/Cr) by concomitant chemotherapy and/or hormone therapy or by previous intravenous bisphosphonate exposure.

4.6. Fertility, pregnancy and lactation

Pregnancy

There are no or limited amount of data from the use of denosumab in pregnant women. Studies in animals have shown reproductive toxicity (see section 5.3).

Denosumab is not recommended for use in pregnant women and women of child-bearing potential not using contraception. Women should be advised not to become pregnant during and for at least 5 months after treatment with denosumab. Any effects of denosumab 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.

Breast-feeding

It is unknown whether denosumab is excreted in human milk. A risk to the newborns/infants cannot be excluded. Knockout mouse studies suggest absence of RANKL during pregnancy may interfere with maturation of the mammary gland leading to impaired lactation post-partum (see section 5.3). A decision must be made on whether to abstain from breast-feeding or to abstain from denosumab therapy taking into account the benefit of breast-feeding to the newborn/infant and the benefit of therapy for the woman.

Fertility

No data are available on the effect of denosumab on human fertility. Animal studies do not indicate direct or indirect harmful effects with respect to fertility (see section 5.3).

4.7. Effects on ability to drive and use machines

Denosumab has no or negligible influence on the ability to drive and use machines.

4.8. Undesirable effects

Summary of the safety profile

Overall safety profile is consistent in all approved indications for denosumab.

Hypocalcaemia has very commonly been reported following denosumab administration, mostly within the first 2 weeks. Hypocalcaemia can be severe and symptomatic (see section 4.8 - description of selected adverse reactions). The decreases in serum calcium were generally appropriately managed by calcium and vitamin D supplementation. The most common adverse reactions with denosumab are musculoskeletal pain. Cases of osteonecrosis of the jaw (see sections 4.4 and section 4.8 - description of selected adverse reactions) have been commonly observed in patients taking denosumab.

Tabulated list of adverse reactions

The following convention has been used for the classification of the adverse reactions based on incidence rates in four phase III, two phase II clinical studies and post-marketing experience (see Table 1): very common (? 1/10), common (? 1/100 to < 1/10), uncommon (? 1/1 000 to < 1/100), rare (? 1/10 000 to < 1/1 000), very rare (< 1/10 000) and not known (cannot be estimated from the available data. Within each frequency grouping and system organ class, adverse reactions are presented in order of decreasing seriousness.

Table 1. Adverse reactions reported in patients with advanced malignancies involving bone, multiple myeloma, or with giant cell tumour of bone

MedDRA system organ class

Frequency category

Adverse reactions

Neoplasms benign, malignant and unspecified (including cysts and polyps)

Common

New primary malignancy1

Immune system disorders

Rare

Drug hypersensitivity1

Rare

Anaphylactic reaction1

Metabolism and nutrition disorders

Very common

Hypocalcaemia1, 2

Common

Hypophosphataemia

Uncommon

Hypercalcaemia following treatment discontinuation in patients with giant cell tumour of bone3

Respiratory, thoracic and mediastinal disorders

Very common

Dyspnoea

Gastrointestinal disorders

Very common

Diarrhoea

Common

Tooth extraction

Skin and subcutaneous tissue disorders

Common

Hyperhidrosis

Uncommon

Lichenoid drug eruptions1

Musculoskeletal and connective tissue disorders

Very common

Musculoskeletal pain1

Common

Osteonecrosis of the jaw1

Uncommon

Atypical femoral fracture1

Not known

Osteonecrosis of the external auditory canal3,4

1 See section Description of selected adverse reactions

2 See section Other special populations

3 See section 4.4

4 Class effect

Description of selected adverse reactions

Hypocalcaemia

A higher incidence of hypocalcaemia among subjects treated with denosumab compared to zoledronic acid has been observed in SRE prevention clinical trials.

The highest incidence of hypocalcaemia was observed in a phase III trial in patients with multiple myeloma. Hypocalcaemia was reported in 16.9% of patients treated with denosumab and 12.4% of patients treated with zoledronic acid. A grade 3 decrease in serum calcium levels was experienced in 1.4% of patients treated with denosumab and 0.6% of patients treated with zoledronic acid. A grade 4 decrease in serum calcium levels was experienced in 0.4% of patients treated with denosumab and 0.1% of patients treated with zoledronic acid.

In three phase III active-controlled clinical trials in patients with advanced malignancies involving bone, hypocalcaemia was reported in 9.6% of patients treated with denosumab and 5.0% of patients treated with zoledronic acid.

A grade 3 decrease in serum calcium levels was experienced in 2.5% of patients treated with denosumab and 1.2% of patients treated with zoledronic acid. A grade 4 decrease in serum calcium levels was experienced in 0.6% of patients treated with denosumab and 0.2% of patients treated with zoledronic acid (see section 4.4).

In two phase II single-arm clinical trials in patients with giant cell tumour of bone, hypocalcaemia was reported in 5.7% of patients. None of the adverse events was considered serious.

In the post-marketing setting, severe symptomatic hypocalcaemia (including fatal cases) has been reported, with most cases occurring in the first weeks of initiating therapy. Examples of clinical manifestations of severe symptomatic hypocalcaemia have included QT interval prolongation, tetany, seizures and altered mental status (including coma) (see section 4.4). Symptoms of hypocalcaemia in clinical studies included paraesthesias or muscle stiffness, twitching, spasms and muscle cramps.

Osteonecrosis of the jaw (ONJ)

In clinical trials, the incidence of ONJ was higher with longer duration of exposure; ONJ has also been diagnosed after stopping treatment with denosumab with the majority of cases occurring within 5 months after the last dose. Patients with prior history of ONJ or osteomyelitis of the jaw, an active dental or jaw condition requiring oral surgery, non-healed dental/oral surgery, or any planned invasive dental procedure were excluded from the clinical trials.

A higher incidence of ONJ among subjects treated with denosumab compared to zoledronic acid has been observed in SRE prevention clinical trials. The highest incidence of ONJ was observed in a phase III trial in patients with multiple myeloma. In the double-blind treatment phase of this trial, ONJ was confirmed in 5.9% of patients treated with denosumab (median exposure of 19.4 months; range 1 - 52) and in 3.2% of patients treated with zoledronic acid. At the completion of the double-blind treatment phase of this trial, the patient-year adjusted incidence of confirmed ONJ in the denosumab group (median exposure of 19.4 months; range 1 - 52), was 2.0 per 100 patient-years during the first year of treatment, 5.0 in the second year, and 4.5 thereafter. The median time to ONJ was 18.7 months (range: 1 - 44).

In the primary treatment phases of three phase III active-controlled clinical trials in patients with advanced malignancies involving bone, ONJ was confirmed in 1.8% of patients treated with denosumab (median exposure of 12.0 months; range: 0.1 – 40.5) and 1.3% of patients treated with zoledronic acid. Clinical characteristics of these cases were similar between treatment groups. Among subjects with confirmed ONJ, most (81% in both treatment groups) had a history of tooth extraction, poor oral hygiene, and/or use of a dental appliance. Most subjects were receiving or had received chemotherapy.

The trials in patients with breast or prostate cancer included an denosumab extension treatment phase (median overall exposure of 14.9 months; range: 0.1 – 67.2). ONJ was confirmed in 6.9% of patients with breast cancer and prostate cancer during the extension treatment phase.

The patient-year adjusted overall incidence of confirmed ONJ was 1.1 per 100 patient-years during the first year of treatment, 3.7 in the second year and 4.6 thereafter. The median time to ONJ was 20.6 months (range: 4 - 53).

A non-randomised, retrospective, observational study in 2,877 patients with cancer treated with denosumab or zoledronic acid in Sweden, Denmark, and Norway showed that 5-year incidence proportions of medically confirmed ONJ were 5.7% (95% CI: 4.4, 7.3; median follow up time of 20 months [range 0.2-60]) in a cohort of patients receiving denosumab and 1.4% (95% CI: 0.8, 2.3; median follow up time of 13 months [range 0.1-60]) in a separate cohort of patients receiving zoledronic acid. Five-year incidence proportion of ONJ in patients switching from zoledronic acid to denosumab was 6.6% (95% CI: 4.2, 10.0; median follow up time of 13 months [range 0.2-60]).

In a phase III trial in patients with non-metastatic prostate cancer (a patient population for which denosumab is not indicated), with longer treatment exposure of up to 7 years, the patient-year adjusted incidence of confirmed ONJ was 1.1 per 100 patient-years during the first year of treatment, 3.0 in the second year, and 7.1 thereafter.

In a long-term phase II open-label clinical trial in patients with giant cell tumour of bone (Study 6, see section 5.1), ONJ was confirmed in 6.8% of patients, including one adolescent (median number of 34 doses; range 4 – 116). At the completion of the trial, median time on trial including safety follow- up phase was 60.9 months (range: 0 – 112.6). The patient-year adjusted incidence of confirmed ONJ was 1.5 per 100 patient-years overall (0.2 per 100 patient-years during the first year of treatment, 1.5 in the second year, 1.8 in the third year, 2.1 in the fourth year, 1.4 in the fifth year, and 2.2 thereafter). The median time to ONJ was 41 months (range: 11 - 96).

Drug related hypersensitivity reactions

In the post-marketing setting, events of hypersensitivity, including rare events of anaphylactic reactions, have been reported in patients receiving denosumab.

Atypical fractures of the femur

In the clinical trial programme, atypical femoral fractures have been reported uncommonly in patients treated with denosumab and the risk increased with longer duration of treatment. Events have occurred during treatment and up to 9 months after treatment was discontinued (see section 4.4).

Musculoskeletal pain

In the post-marketing setting, musculoskeletal pain, including severe cases, has been reported in patients receiving denosumab. In clinical trials, musculoskeletal pain was very common in both the denosumab and zoledronic acid treatment groups. Musculoskeletal pain leading to discontinuation of study treatment was uncommon.

New primary malignancy

In the primary double blind treatment phases of four phase III active-controlled clinical trials in patients with advanced malignancies involving bone, new primary malignancy was reported in 54/3691 (1.5%) of patients treated with denosumab (median exposure of 13.8 months; range: 1.0 – 51.7) and 33/3688 (0.9%) of patients treated with zoledronic acid (median exposure of 12.9 months; range: 1.0-50.8).

The cumulative incidence at one year was 1.1 % for denosumab and 0.6 % for zoledronic acid, respectively.

No treatment-related pattern in individual cancers or cancer groupings was apparent.

Lichenoid drug eruptions

Lichenoid drug eruptions (e.g., lichen planus-like reactions), have been reported in patients in the post- marketing setting.

Paediatric population

Denosumab was studied in an open-label trial that enrolled 28 skeletally mature adolescents with giant cell tumour of bone. Based on these limited data, the adverse event profile appeared to be similar to adults.

Clinically significant hypercalcaemia after treatment discontinuation has been reported in the post-marketing setting in paediatric patients (see section 4.4).

Other special populations

Renal impairment

In a clinical trial of patients without advanced cancer with severe renal impairment (creatinine clearance < 30 mL/min) or receiving dialysis, there was a greater risk of developing hypocalcaemia in the absence of calcium supplementation. The risk of developing hypocalcaemia during denosumab treatment is greater with increasing degree of renal impairment. In a clinical trial in patients without advanced cancer, 19% of patients with severe renal impairment (creatinine clearance < 30 mL/min) and 63% of patients receiving dialysis developed hypocalcaemia despite calcium supplementation.

The overall incidence of clinically significant hypocalcaemia was 9%.

Accompanying increases in parathyroid hormone have also been observed in patients receiving denosumab with severe renal impairment or receiving dialysis. Monitoring of calcium levels and adequate intake of calcium and vitamin D is especially important in patients with renal impairment (see section 4.4).

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via Yellow Card Scheme Website: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.

4.9. Overdose

There is no experience with overdose in clinical studies. denosumab has been administered in clinical studies using doses up to 180 mg every 4 weeks and 120 mg weekly for 3 weeks.