Xgeva Use In Pregnancy & Lactation

Pregnancy: Risk Summary: Based on findings in animals and its mechanism of action, denosumab (XGEVA) can cause fetal harm when administered to a pregnant woman [see Pharmacology: Mechanism of Action under Actions]. There are insufficient data with denosumab use in pregnant women to inform any drug associated risks for adverse developmental outcomes. In utero denosumab exposure from cynomolgus monkeys dosed monthly with denosumab throughout pregnancy at a dose 25-fold higher than the recommended human dose of denosumab (XGEVA) based on body weight resulted in increased fetal loss, stillbirths, and postnatal mortality; and absent lymph nodes, abnormal bone growth, and decreased neonatal growth [see Data as follows].
Apprise pregnant women of the potential risk to the fetus.
The background rate of major birth defects and miscarriage is unknown for the indicated population. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively.
Data: Animal Data: The effects of denosumab on prenatal development have been studied in both cynomolgus monkeys and genetically engineered mice in which RANK ligand (RANKL) expression was turned off by gene removal (a "knockout mouse"). In cynomolgus monkeys dosed subcutaneously with denosumab throughout pregnancy starting at gestational day 20 and at a pharmacologically active dose 25-fold higher than the recommended human dose of denosumab (XGEVA) based on body weight, there was increased fetal loss during gestation, stillbirths, and postnatal mortality. Other findings in offspring included absence of axillary, inguinal, mandibular, and mesenteric lymph nodes; abnormal bone growth, reduced bone strength, reduced hematopoiesis, dental dysplasia, and tooth malalignment; and decreased neonatal growth. At birth out to one month of age, infants had measurable blood levels of denosumab (22-621% of maternal levels).
Following a recovery period from birth out to 6 months of age, the effects on bone quality and strength returned to normal; there were no adverse effects on tooth eruption, though dental dysplasia was still apparent; axillary and inguinal lymph nodes remained absent, while mandibular and mesenteric lymph nodes were present, though small; and minimal to moderate mineralization in multiple tissues was seen in one recovery animal. There was no evidence of maternal harm prior to labor; adverse maternal effects occurred infrequently during labor. Maternal mammary gland development was normal. There was no fetal NOAEL (no observable adverse effect level) established for this study because only one dose of 50 mg/kg was evaluated. Mammary gland histopathology at 6 months of age was normal in female offspring exposed to denosumab in utero; however, development and lactation have not been fully evaluated.
In RANKL knockout mice, absence of RANKL (the target of denosumab) also caused fetal lymph node agenesis and led to postnatal impairment of dentition and bone growth. Pregnant RANKL knockout mice showed altered maturation of the maternal mammary gland, leading to impaired lactation [see Females and Males of Reproductive Potential as follows and Pharmacology: Nonclinical Toxicology: Animal Toxicology and/or Pharmacology under Actions].
Lactation: Risk Summary: There is no information regarding the presence of denosumab (XGEVA) in human milk, the effects on the breastfed child, or the effects on milk production. Denosumab was detected in the maternal milk of cynomolgus monkeys up to 1 month after the last dose of denosumab (≤0.5% milk:serum ratio) and maternal mammary gland development was normal, with no impaired lactation. However, pregnant RANKL knockout mice showed altered maturation of the maternal mammary gland, leading to impaired lactation [see Pregnancy previously and Pharmacology: Nonclinical Toxicology: Animal Toxicology and/or Pharmacology under Actions]. Consider the developmental and health benefits of breastfeeding along with the mother's clinical need for denosumab (XGEVA) treatment and any potential adverse effects on the breastfed child from denosumab (XGEVA) or from the underlying maternal condition.
Females and Males of Reproductive Potential: Based on findings in animals and its mechanism of action, denosumab (XGEVA) can cause fetal harm when administered to a pregnant woman [see Pregnancy previously].
Pregnancy Testing: Verify the pregnancy status of females of reproductive potential prior to initiating denosumab (XGEVA) treatment.
Contraception: Females: Advise females of reproductive potential to use effective contraception during therapy, and for at least 5 months after the last dose of denosumab (XGEVA).