4.3 Contraindications

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

Severe, untreated hypocalcaemia (see section 4.4).

4.4 Special warnings and precautions for use

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.

4.5 Interaction with other medicinal products and other forms of interaction

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