XGEVA^® 120 mg solution for injection

Each vial contains 120 mg of denosumab in 1.7 ml of solution (70 mg/ml).

Denosumab is a human monoclonal IgG2 antibody produced in a mammalian cell line (CHO) by recombinant DNA technology.

Excipients with known effects:

Each 1.7 ml of solution contains 78 mg sorbitol (E420).

For a full list of excipients, see section 6.1.

Solution for injection (injection).

Clear, colourless to slightly yellow solution and may contain trace amounts of translucent to white proteinaceous particles.

Prevention of skeletal related events (pathological fracture, radiation to bone, spinal cord compression or surgery to bone) in adults with bone metastases from solid tumours.

Posology

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

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

Patients with renal impairment

No dose adjustment is required in patients with renal impairment (see section 5.2). Experience in patients on dialysis or with severe renal impairment (creatinine clearance < 30 ml/min) is limited.

Patients with 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

XGEVA is not recommended in paediatric patients (age < 18) as the safety and efficacy of XGEVA in these patients have not been established. 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.

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

The instructions for use, handling and disposal are given in section 6.6.

Hypersensitivity to the active substance or to any of the excipients.

Severe, untreated hypocalcaemia (see section 4.4).

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 XGEVA.

Patients with severe renal impairment (creatinine clearance < 30 ml/min) or receiving dialysis are at greater risk of developing hypocalcaemia. Monitoring of calcium levels in these patients is recommended. If hypocalcaemia occurs while receiving XGEVA, additional short term calcium supplementation may be necessary.

Osteonecrosis of the jaw

Osteonecrosis of the jaw (ONJ) was reported in patients treated with denosumab, predominantly in patients with advanced malignancies involving bone (see section 4.8).

Patients who developed ONJ in clinical studies generally had known risk factors for ONJ, including invasive dental procedures (e.g., tooth extraction, dental implants, oral surgery), poor oral hygiene or other pre-existing dental disease, advanced malignancies, infections, or concomitant therapies (e.g., chemotherapy, corticosteroids, angiogenesis inhibitors, radiotherapy to the head and neck). A dental examination with appropriate preventive dentistry should be considered prior to treatment with XGEVA in patients with active dental and jaw conditions (as listed above). While on treatment, patients should avoid invasive dental procedures if possible.

Good oral hygiene practices should be maintained during treatment with XGEVA. Patients who are suspected of having or who develop ONJ while on XGEVA therapy should receive care by a dentist or oral surgeon. In these patients, extensive dental surgery to treat ONJ may exacerbate the condition.

An individual risk/benefit eva luation should be done for each patient before prescribing XGEVA in patients with unavoidable risk factors for ONJ; and in patients who have developed ONJ during treatment with XGEVA.

Skin infections leading to hospitalisation (predominantly cellulitis)

In clinical trials in patients with advanced malignancies involving bone, skin infections leading to hospitalisation (predominantly cellulitis) were reported (see section 4.8). Patients should be advised to seek prompt medical attention if they develop signs or symptoms of cellulitis.

Others

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

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

Warnings for excipients

Patients with rare hereditary problems of fructose intolerance should not use XGEVA.

No interaction studies have been performed.

In clinical trials, XGEVA 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.

Pregnancy

There are no adequate data from the use of XGEVA in pregnant women. Animal studies are insufficient with respect to reproductive toxicity (see section 5.3). In genetically engineered mice in which RANKL has been turned off by gene removal (a “knockout mouse”), studies suggest absence of RANKL (the target of denosumab – see section 5.1) could interfere with the development of lymph nodes in the foetus and could lead to postnatal impairment of dentition and bone growth (see section 5.3). XGEVA is not recommended for use in pregnant women and women of childbearing potential not using contraception.

Breast-feeding

It is unknown whether denosumab is excreted in human milk. 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 on whether to abstain from breast-feeding or to abstain from therapy with XGEVA should be made, taking into account the benefit of breast-feeding to the newborn/infant and the benefit of XGEVA therapy to 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).

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

Summary of the safety profile

The safety of XGEVA was eva luated in 5,931 patients with advanced malignancies involving bone and is derived from active-controlled, clinical trials examining the efficacy and safety of XGEVA versus zoledronic acid in preventing the occurrence of skeletal related events. The adverse reactions are presented in table 1.

Tabulated list of adverse reactions

The following convention has been used for the classification of the adverse reactions reported in three phase III and one phase II clinical studies (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) and very rare (< 1/10,000). Within each frequency grouping and system organ class, adverse reactions are presented in order of decreasing seriousness.

Table 1 Adverse reactions reported in three phase III and one phase II active-controlled clinical studies in patients with advanced malignancies involving bone

¹ See section Description of selected adverse reactions

Description of selected adverse reactions

Hypocalcaemia

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 XGEVA 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 XGEVA 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 XGEVA and 0.2% of patients treated with zoledronic acid (see section 4.4).

Osteonecrosis of the jaw (ONJ)

In three phase III active-controlled clinical trials in patients with advanced malignancies involving bone, ONJ was confirmed in 1.8% of patients treated with XGEVA 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. In addition most subjects were receiving or had received chemotherapy (see section 4.4). Patients with certain identified risk factors for ONJ were excluded from participation in the pivotal studies (see section 5.1).

Skin infections (predominantly cellulitis) leading to hospitalisation

In three phase III active-controlled clinical trials in patients with advanced malignancies involving bone, skin infections leading to hospitalisation (predominantly cellulitis) were reported more frequently in patients receiving XGEVA (0.9%) compared with zoledronic acid (0.7%).

In postmenopausal women with osteoporosis, skin infections leading to hospitalisation were reported for 0.4% women receiving Prolia® (denosumab 60 mg every 6 months) and for 0.1% women receiving placebo (see section 4.4).

Other special populations

In a clinical study 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.

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

Pharmacotherapeutic group: Drugs for the treatment of bone diseases – other drugs affecting bone structure and mineralisation, ATC code: M05BX04

Mechanism of action

RANKL exists as a transmembrane or soluble protein. RANKL is essential for the formation, function and survival of osteoclasts, the sole cell type responsible for bone resorption. Increased osteoclast activity, stimulated by RANKL, is a key mediator 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 RANKL/RANK interaction from occurring and resulting in reduced osteoclast numbers and function, thereby decreasing bone resorption and cancer-induced bone destruction.

Pharmacodynamic effects

In phase II clinical studies of patients with advanced malignancies involving bone, subcutaneous (SC) dosing of XGEVA administered either every 4 weeks or every 12 weeks resulted in a rapid reduction in markers of bone resorption (uNTx/Cr, serum CTx), with median reductions of approximately 80% for uNTx/Cr occurring within 1 week regardless of prior bisphosphonate therapy or baseline uNTx/Cr level. In the phase III clinical trials, median reductions of approximately 80% were maintained in uNTx/Cr after 3 months of treatment in 2075 XGEVA-treated advanced cancer patients naïve to IV-bisphosphonate.

Immunogenicity

In clinical studies, neutralising antibodies have not been observed for XGEVA. Using a sensitive immunoassay < 1% of patients treated with denosumab for up to 3 years tested positive for non neutralising binding antibodies with no evidence of altered pharmacokinetics, toxicity, or clinical response.

Clinical efficacy in patients with bone metastases from solid tumours

Efficacy and safety of 120 mg XGEVA SC every 4 weeks or 4 mg zoledronic acid (dose-adjusted for reduced renal function) IV every 4 weeks were compared in three randomised, double blind, active controlled studies, in IV-bisphosphonate naïve patients with advanced malignancies involving bone: adults with breast cancer (study 1), other solid tumours or multiple myeloma (study 2), and castrate-resistant prostate cancer (study 3). 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 not eligible for inclusion in these studies. The primary and secondary endpoints eva luated the occurrence of one or more skeletal related events (SREs).

XGEVA reduced the risk of developing a SRE, and developing multiple SREs (first and subsequent) in patients with bone metastases from solid tumours (see table 2).

Table 2: Efficacy results in patients with advanced malignancies involving bone

NR = not reached; NA = not available; HCM = hypercalcaemia of malignancy; SMR = skeletal morbidity rate; HR = Hazard Ratio; RRR = Relative Risk Reduction †Adjusted p-values are presented for Studies 1, 2 and 3 (first SRE and first and subsequent SRE endpoints); *Accounts for all skeletal events over time; only events occurring 21 days after the previous event are counted.

** Including NSCLC, renal cell cancer, colorectal cancer, small cell lung cancer, bladder cancer, head and neck cancer, GI/genitourinary cancer and others, excluding breast and prostate cancer

Figure 1. Kaplan-Meier plots of time to first on-study SRE

Disease progression and overall survival

Disease progression was similar between XGEVA and zoledronic acid in all three studies and in the pre-specified analysis of all three-studies combined.

In all three studies overall survival was balanced between XGEVA and zoledronic acid in patients with advanced malignancies involving bone: patients with breast cancer (hazard ratio and 95% CI was 0.95 [0.81, 1.11]), patients with prostate cancer (hazard ratio and 95% CI was 1.03 [0.91, 1.17]), and patients with other solid tumours or multiple myeloma (hazard ratio and 95% CI was 0.95 [0.83, 1.08]). A post-hoc analysis in study 2 (patients with other solid tumours or multiple myeloma) examined overall survival for the 3 tumour types used for stratification (non-small cell lung cancer, multiple myeloma, and other). Overall survival was longer for XGEVA in non-small cell lung cancer (hazard ratio [95% CI] of 0.79 [0.65, 0.95]; n = 702) and longer for zoledronic acid in multiple myeloma (hazard ratio [95% CI] of 2.26 [1.13, 4.50]; n = 180) and similar between XGEVA and zoledronic acid in other tumour types (hazard ratio [95% CI] of 1.08 (0.90, 1.30); n = 894). This study did not control for prognostic factors and anti-neoplastic treatments. In a combined pre-specified analysis from studies 1, 2 and 3, overall survival was similar between XGEVA and zoledronic acid (hazard ratio and 95% CI 0.99 [0.91, 1.07]) (see section 4.4).

Effect on pain

The time to pain improvement (i.e., 2 point decrease from baseline in BPI-SF worst pain score) was similar for denosumab and zoledronic acid in each study and the integrated analyses. In a post-hoc analysis of the combined dataset, the median time to worsening pain (> 4-point worst pain score) in patients with mild or no pain at baseline was delayed for XGEVA compared to zoledronic acid (198 versus 143 days) (p = 0.0002).

Paediatric population

The European Medicines Agency has deferred the obligation to submit the results of studies with XGEVA in one or more subsets of the paediatric population in bone metastases (see section 4.2 for information on paediatric use).

Following SC administration, bioavailability was 62% and denosumab displayed non-linear pharmacokinetics with dose over a wide dose range, but approximately dose-proportional increases in exposure for doses of 60 mg (or 1 mg/kg) and higher. The non-linearity is likely due to a saturable target-mediated elimination pathway of importance at low concentrations.

With multiple doses of 120 mg every 4 weeks an approximate 2-fold accumulation in serum denosumab concentrations was observed and steady-state was achieved by 6 months, consistent with time-independent pharmacokinetics. In subjects who discontinued 120 mg every 4 weeks, the mean half-life was 28 days (range 14 to 55 days).

A population pharmacokinetic analysis did not indicate clinically significant changes in the systemic exposure of denosumab at steady state with respect to age (18 to 87 years), race/ethnicity (Blacks, Hispanics, Asians and Caucasians explored), gender or solid tumour types. Increasing body weight was associated with decreases in systemic exposure, and vice versa. The alterations were not considered clinically relevant, since pharmacodynamic effects based on bone turnover markers were consistent across a wide range of body weight.

Denosumab is composed solely of amino acids and carbohydrates as native immunoglobulin and is unlikely to be eliminated via hepatic metabolic mechanisms. Its metabolism and elimination are expected to follow the immunoglobulin clearance pathways, resulting in degradation to small peptides and individual amino acids.

Special populations

No overall differences in safety or efficacy were observed between geriatric patients and younger patients. Controlled clinical studies of XGEVA in patients with advanced malignancies involving bone over age 65 revealed similar efficacy and safety in older and younger patients. No dose adjustment is required in elderly patients.

In a study of 55 patients without advanced cancer but with varying degrees of renal function, including patients on dialysis, the degree of renal impairment had no effect on the pharmacokinetics of denosumab. There is no need for renal monitoring when receiving XGEVA.

No specific study in patients with hepatic impairment was performed. In general, monoclonal antibodies are not eliminated via hepatic metabolic mechanisms. The pharmacokinetics of denosumab is not expected to be affected by hepatic impairment.

The pharmacokinetic profile in paediatric populations has not been assessed.

Since the biological activity of denosumab in animals is specific to nonhuman primates, eva luation of genetically engineered (knockout) mice or use of other biological inhibitors of the RANK/RANKL pathway, such as OPG-Fc and RANK-Fc, were used to eva luate the pharmacodynamic properties of denosumab in rodent models.

In mouse bone metastasis models of oestrogen receptor positive and negative human breast cancer, prostate cancer and non small cell lung cancer, OPG-Fc reduced osteolytic, osteoblastic, and osteolytic/osteoblastic lesions, delayed formation of de novo bone metastases, and reduced skeletal tumour growth. When OPG-Fc was combined with hormonal therapy (tamoxifen) or chemotherapy (docetaxel) in these models, there was additive inhibition of skeletal tumour growth in breast, and prostate or lung cancer respectively. In a mouse model of mammary tumour induction, RANK-Fc reduced hormone-induced proliferation in mammary epithelium and delayed tumour formation.

Standard tests to investigate the genotoxicity potential of denosumab have not been eva luated, since such tests are not relevant for this molecule. However, due to its character it is unlikely that denosumab has any potential for genotoxicity.

The carcinogenic potential of denosumab has not been eva luated in long-term animal studies.

In single and repeated dose toxicity studies in cynomolgus monkeys, denosumab doses resulting in 2.7 to 15 times greater systemic exposure than the recommended human dose had no impact on cardiovascular physiology, male or female fertility, or produced specific target organ toxicity. In an embryofoetal developmental study in cynomolgus monkeys, denosumab doses resulting in 9 times greater systemic exposure than the recommended human dose did not induce maternal toxicity or foetal harm during a period equivalent to the first trimester, although foetal lymph nodes were not examined (see section 4.6). During the second and third trimesters, when denosumab is expected to cross the placenta, potential maternal and foetal toxicity have not been assessed.

In preclinical bone quality studies in monkeys on long-term denosumab treatment, decreases in bone turnover were associated with improvement in bone strength and normal bone histology.

In male mice genetically engineered to express huRANKL (knock-in mice), which were subjected to a transcortical fracture, denosumab delayed the removal of cartilage and remodelling of the fracture callus compared to control, but biomechanical strength was not adversely affected.

In preclinical studies knockout mice lacking RANK or RANKL had an absence of lactation due to inhibition of mammary gland maturation (lobulo-alveolar gland development during pregnancy) and exhibited impairment of lymph node formation. Neonatal RANK/RANKL knockout mice exhibited decreased body weight, reduced bone growth, altered growth plates and lack of tooth eruption. Reduced bone growth, altered growth plates and impaired tooth eruption were also seen in studies of neonatal rats administered RANKL inhibitors, and these changes were partially reversible when dosing of RANKL inhibitor was discontinued. Adolescent primates dosed with denosumab at 2.7 and 15 times (10 and 50 mg/kg dose) the clinical exposure had abnormal growth plates. Therefore, treatment with denosumab may impair bone growth in children with open growth plates and may inhibit eruption of dentition.

Acetic acid, glacial*

Sodium hydroxide (for pH adjustment)*

Sorbitol (E420)

Water for injections

* Acetate buffer is formed by mixing acetic acid with sodium hydroxide

In the absence of compatibility studies, this medicinal product must not be mixed with other medicinal products.

3 years.

XGEVA may be stored at room temperature (up to 25°C) for up to 30 days in the original container. Once removed from the refrigerator, XGEVA must be used within this 30 day period.

Store in a refrigerator (2°C – 8°C).

Do not freeze.

Keep the vial in the outer carton in order to protect from light.

1.7 ml solution in a single use vial (type I glass) with stopper (fluoropolymer coated elastomeric) and seal (aluminium) with flip-off cap.

Pack size of one or four.

Not all pack sizes may be marketed.

Before administration, the XGEVA solution should be inspected visually. The solution may contain trace amounts of translucent to white proteinaceous particles. Do not inject the solution if it is cloudy or discoloured. Do not shake excessively. To avoid discomfort at the site of injection, allow the vial to reach room temperature (up to 25ºC) before injecting and inject slowly. Inject the entire contents of the vial. A 27 gauge needle is recommended for the administration of denosumab. Do not re-enter the vial.

Any unused product or waste material should be disposed of in accordance with local requirements.

Amgen Europe B.V.

Minervum 7061

NL-4817 ZK Breda

The Netherlands

EU/1/11/703/001

EU/1/11/703/002

13 July 2011

XGEVA is a registered trademark of Amgen Inc.

Detailed information on this medicinal product is available on the website of the European Medicines Agency http://www.ema.europa.eu/.