4.6 Pregnancy and lactation

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).

4.7 Effects on ability to drive and use machines

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

4.8 Undesirable effects

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

MedDRA system organ class

Frequency category

Adverse reactions

Infections and infestations

Uncommon

Cellulitis1

Immune system disorder

Uncommon

Drug hypersensitivity

Metabolism and nutrition disorders

Common

Hypocalcaemia1

Common

Hypophosphataemia

Respiratory, thoracic and mediastinal disorders

Very common

Dyspnoea

Gastrointestinal disorders

Very common

Diarrhoea

Common

Tooth extraction

Skin and subcutaneous tissues disorders

Common

Hyperhidrosis

Musculoskeletal and connective tissue disorders

Common

Osteonecrosis of the jaw1

1 See section Description of selected adverse reactions

Description of selected adverse reactions

Hypocalcaemia

In three