Xgeva

Included as part of the "PRECAUTIONS" Section

Medications can interact with certain foods. In some cases, this may be harmful and your doctor may advise you to avoid certain foods. In the case of Xgeva, there are no specific foods you must exclude from your diet when receiving this medication.

Tell your doctor if you are pregnant or plan to become pregnant.

The FDA categorizes medications based on safety for use during pregnancy. Five categories - A, B, C, D, and X, are used to classify possible risks of an unborn baby when a medication is taken during pregnancy.

Xgeva falls into category X. It has been shown that women taking Xgeva during pregnancy may have babies born with problems. There are no situations in which the benefits of the medication to the mother outweigh the risks of harm to the baby. These medications should never be used by pregnant women.

This medication guide provides information about the Xgeva brand of denosumab. Prolia is another brand of denosumab used to treat osteoporosis in postmenopausal women who have high risk of bone fracture.

You should not receive denosumab if you have low levels of calcium in your blood (hypocalcemia).

Xgeva can harm an unborn baby or cause birth defects. Do not use if you are pregnant.

Call your doctor for instructions if you miss an appointment for your Xgeva injection.

Denosumab injection is used to treat osteoporosis (thinning of the bones) in women who have an increased risk for fractures after menopause, and osteoporosis in men. It is given when other medicines cannot be used or after other medicines did not work well.

Denosumab injection is also used to treat bone loss in men with prostate cancer and women with breast cancer who are receiving cancer treatment. It is used to prevent bone problems in patients with bone metastases (cancer that has spread) from tumors. Denosumab is used to treat giant cell tumor of the bone that cannot be removed by surgery. This medicine is also used to treat hypercalcemia of malignancy that has been treated with bisphosphonates (eg, alendronate, ibandronate, risedronate, Fosamax®) but did not work well.

This medicine is to be given only by or under the supervision of your doctor.

• It is used when treating some cancers.
• It is used to treat high calcium levels in patients with cancer.
• It may be given to you for other reasons. Talk with the doctor.

If you think there has been an overdose, call your poison control center or get medical care right away. Be ready to tell or show what was taken, how much, and when it happened.

No formal drug-drug interaction trials have been conducted with Xgeva.

There was no evidence that various anticancer treatments affected denosumab systemic exposure and pharmacodynamic effect.  Serum denosumab concentrations at 1 and 3 months and reductions in the bone turnover marker uNTx/Cr (urinary N-terminal telopeptide corrected for creatinine) at 3 months were similar in patients with and without prior intravenous bisphosphonate therapy and were not altered by concomitant chemotherapy and/or hormone therapy.

8.1       Pregnancy

Risk Summary
Based on findings in animals and its mechanism of action, Xgeva can cause fetal harm when administered to a pregnant woman [see Clinical Pharmacology (12.1)]. 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 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).  

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 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 Use in Specific Populations (8.3) and Nonclinical Toxicology (13.2)].

8.2       Lactation

Risk Summary
There is no information regarding the presence of Xgeva (denosumab) in human milk, the effects on the breastfed infant, 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 Use in Specific Populations (8.1) and Nonclinical Toxicology (13.2)].  Consider the developmental and health benefits of breastfeeding along with the mother’s clinical need for Xgeva treatment and any potential adverse effects on the breastfed child from Xgeva or from the underlying maternal condition.

8.3       Females and Males of Reproductive Potential

Based on findings in animals and its mechanism of action, Xgeva can cause fetal harm when administered to a pregnant woman [see Use in Specific Populations (8.1)].

Pregnancy Testing
Verify the pregnancy status of females of reproductive potential prior to initiating 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 Xgeva.

8.4       Pediatric Use

The safety and efficacy of Xgeva have not been established in pediatric patients except in skeletally mature adolescents with giant cell tumor of bone. Xgeva is recommended only for treatment of skeletally mature adolescents with giant cell tumor of bone [see Indications and Usage (1.2)].

Xgeva was studied in an open-label trial that enrolled a subset of 10 adolescent patients (aged 13-17 years) with giant cell tumor of bone who had reached skeletal maturity, defined by at least 1 mature long bone (e.g., closed epiphyseal growth plate of the humerus), and had a body weight ≥ 45 kg [see Indications and Usage (1.2) and Clinical Trials (14.2)].  A total of two of six (33%) evaluable adolescent patients had an objective response by retrospective independent assessment of radiographic response according to modified Response Evaluation Criteria in Solid Tumors (RECIST 1.1) criteria. The adverse reaction profile and efficacy results appeared to be similar in skeletally mature adolescents and adults [see Adverse Reactions (6.1) and Clinical Trials (14.2)].

Treatment with Xgeva may impair bone growth in children with open growth plates and may inhibit eruption of dentition. In neonatal rats, inhibition of RANKL (the target of Xgeva therapy) with a construct of osteoprotegerin bound to Fc (OPG-Fc) at doses ≤ 10 mg/kg was associated with inhibition of bone growth and tooth eruption. Adolescent primates treated with denosumab at doses 5 and 25 times (10 and 50 mg/kg dose) higher than the recommended human dose of 120 mg administered once every 4 weeks, based on body weight (mg/kg), had abnormal growth plates, considered to be consistent with the pharmacological activity of denosumab.

Cynomolgus monkeys exposed in utero to denosumab exhibited bone abnormalities, reduced hematopoiesis, tooth malalignment, decreased neonatal growth, and an absence of axillary, inguinal, mandibular, and mesenteric lymph nodes. Some bone abnormalities recovered once exposure was ceased following birth; however, axillary and inguinal lymph nodes remained absent 6 months post-birth [see Use in Specific Populations (8.1)].

8.5       Geriatric Use

Of patients who received Xgeva in Trials 1, 2, and 3, 1260 (44%) were 65 years of age or older. No overall differences in safety or efficacy were observed between these patients and younger patients.

8.6       Renal Impairment

Two clinical trials were conducted in patients without cancer and with varying degrees of renal function.

In one study, patients (N=55) with varying degrees of renal function (ranging from normal through end-stage renal disease requiring dialysis) received a single 60 mg subcutaneous dose of denosumab.  In a second study, patients (N=32) with severe renal dysfunction (creatinine clearance less than 30 mL/minute and/or on dialysis) were given two 120 mg subcutaneous doses of denosumab.  In both studies, greater risk of developing hypocalcemia was observed with increasing renal impairment, and with inadequate/no calcium supplementation.  Hypocalcemia was mild to moderate in severity in 96% of patients.  Monitor calcium levels and calcium and vitamin D intake [see Warnings and Precautions (5.3), Adverse Reactions (6.1), and Clinical Pharmacology (12.3)].

There is no experience with overdosage of Xgeva.