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.

6. PHARMACEUTICAL PARTICULARS

6.1 List of excipients

Acetic acid, glacial*

Sodium hydroxide (for pH adjustment)*

Sorbitol (E420)

Water for injections

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

6.2 Incompatibilities

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

6.3 Shelf life

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.

6.4 Special precautions for storage

Store in a refrigerator (2°C – 8°C).

Do not freeze.

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

6.5 Nature and contents of container

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 mar