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EUROPEAN MEDICINES AGENCY

SCIENCE MEDICINES HEALTH

EMA/333043/2015

EMEA/H/C/002173

EPAR summary for the public

Xgeva

denosumab

This is a summary of the European public assessment report (EPAR) for Xgeva. It explains how the Committee for Medicinal Products for Human Use (CHMP) assessed the medicine to reach its opinion in favour of granting a marketing authorisation and its recommendations on the conditions of use for Xgeva.

What is Xgeva?

Xgeva is a solution for injection that contains the active substance denosumab. It is available in singleuse vials containing 120 mg denosumab.

What is Xgeva used for?

Xgeva is used to prevent bone complications in adults with a solid tumour that has spread to the bone. These complications include fractures (breaks in the bone), spinal compression (when the spinal cord is compressed by the bone), or complications requiring radiotherapy (treatment with radiation) or surgery.

Xgeva is also used to treat a type of bone cancer called giant cell tumour of bone in adults and adolescents whose bones have fully developed. It is used in patients who cannot be treated by surgery or in whom surgery would cause severe problems.

The medicine can only be obtained with a prescription.

How is Xgeva used?

To prevent bone complications in cancer that has spread to the bone, Xgeva is given once every four weeks as a single injection under the skin (120 mg) in the thigh, abdomen or upper arm.

In patients with giant cell tumour of bone, an injection of 120 mg under the skin is given on days 1, 8 and 15 of a four week cycle, and then once every four weeks.

Patients should take calcium and vitamin D supplements while being treated with Xgeva.

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How does Xgeva work?

The active substance in Xgeva, denosumab, is a monoclonal antibody. This is an antibody (a type of protein) that has been designed to recognise and attach to a specific structure (called an antigen) that is found in the body. Denosumab has been designed to attach to an antigen called RANKL, which is involved in activating osteoclasts, the cells in the body that are involved in breaking down bone tissue. By attaching to and blocking RANKL, denosumab reduces the formation and activity of the osteoclasts. This reduces the loss of bone, making fractures and other serious bone complications less likely to happen. The cells in giant cell tumour of bone are also activated via RANKL, and treatment with denosumab prevents them from growing and breaking down bone, allowing normal bone to replace the tumour.

How has Xgeva been studied?

Xgeva was compared with zoledronic acid (another medicine used to prevent bone complications) in three main studies in patients with different types of cancer which had spread to the bone. The first study involved 2,046 patients with breast cancer. The second study involved 1,901 men with prostate cancer which did not respond to hormonal treatment. The third study involved 1,776 patients with advanced solid tumours in various parts of the body, excluding the breast or the prostate, or with multiple myeloma (a cancer of the bone marrow).

All the studies looked at the risk of patients having a first 'skeletal-related event' (such as a fracture, pressure on the spinal cord or the need to receive radiotherapy or surgery) during the study period by measuring how long it took for this event to happen.

Two more main studies looked at the action of Xgeva in adults or full-grown adolescents with giant cell tumour of bone that was unsuitable for surgery or in whom surgery would have resulted in severe complications like amputation of a limb. The first study involved 37 patients and response to treatment was defined as elimination of at least 90% of the giant cells or no progression of the condition after 25 weeks of treatment. The second study involved 507 patients and measured effectiveness by how many patients had disease that got worse during treatment.

What benefit has Xgeva shown during the studies?

In patients at risk of bone complications due to spread of cancer to the bone, Xgeva was shown to be effective in delaying the patients' first skeletal-related event. In the first and second studies, Xgeva reduced the risk of developing a first skeletal-related event by 18% compared with zoledronic acid. In the third study, Xgeva reduced the risk of developing a first skeletal-related event by 16% compared with zoledronic acid.

In patients with giant cell tumour of bone, Xgeva was effective in controlling the disease. In the first study 86% of the patients had a response to treatment. In the second study, only 31 patients had disease that got worse during treatment; overall, about half (109 of 225) of the group in whom surgery would have resulted in complications did not have surgery, and of the remainder, 84 were able to have less extensive surgery than previously planned. About 20% of patients were able to have complete surgical removal of the cancer.

What is the risk associated with Xgeva?

The most common side effects with Xgeva (seen in more than 1 patient in 10) are dyspnoea (difficulty breathing), diarrhoea and pain in the muscles and bones. Other common side effects (seen in up to 1 patient in 10) are hypocalcaemia and hypophosphataemia (low levels of calcium or phosphate in the blood), excessive sweating, tooth loss and osteonecrosis in the jaw (damage to the bones of the jaw, which could lead to pain, sores in the mouth or loosening of teeth).

Xgeva must not be used in patients whose wounds from dental or mouth surgery have not yet healed completely, or in people with severe, untreated hypocalcaemia (low blood calcium levels).

For the full list of all side effects and restrictions with Xgeva, see the package leaflet.

Why has Xgeva been approved?

The CHMP decided that Xgeva's benefits are greater than its risks for patients with cancers involving solid tumours, and recommended that it be given marketing authorisation. The CHMP noted that there is a need for a new effective treatment for bone disease in advanced cancer, particularly for patients with kidney problems since currently available treatments can be toxic for the kidneys. The Committee considered that Xgeva was shown to be effective in preventing bone-related events and was less toxic to the kidneys and easier to administer than existing treatments. However, in multiple myeloma the rates of overall survival and disease progression (the length of time until the disease gets worse) were worse in patients treated with Xgeva than patients treated with zoledronic acid, and the Committee decided that thebenefits did not outweigh the risks for these patients.

With respect to patients with giant cell tumour of bone the possibility of complete surgical removal of the tumour after treatment and the reduction in extent of the surgery needed in some patients were considered clinically important. As treatment was likely to be long-term, further follow-up will be important in ensuring that the balance of risk to benefit does not change with continued use of the medicine, especially in adolescents, but the CHMP considered that the benefits of treatment in giant cell tumour of bone outweighed the known risks of treatment with denosumab, and recommended that it be given marketing authorisation.

What measures are being taken to ensure the safe and effective use of Xgeva?

A risk management plan has been developed to ensure that Xgeva is used as safely as possible. Based on this plan, safety information has been included in the summary of product characteristics and the package leaflet for Xgeva, including the appropriate precautions to be followed by healthcare professionals and patients.

In addition, the company that markets Xgeva will provide a card to inform patients about the risk of osteonecrosis of the jaw and to instruct them to contact their doctor if they experience symptoms.

Other information about Xgeva

The European Commission granted a marketing authorisation valid throughout the European Union for Xgeva on 13 July 2011.

The full EPAR for Xgeva can be found on the Agency's website: ema.europa.eu/Find medicine/Human medicines/European Public Assessment Reports. For more information about treatment with Xgeva, read the package leaflet (also part of the EPAR) or contact your doctor or pharmacist.

This summary was last updated in 05-2015.

Xgeva

EMA/333043/2015

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