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Xgeva

Last reviewed on RxList: 8/30/2016
Drug Description

Xgeva®
(denosumab) Injection, USP

DESCRIPTION

Xgeva (denosumab) is a human IgG2 monoclonal antibody with affinity and specificity for human RANKL (receptor activator of nuclear factor kappa-B ligand). Denosumab has an approximate molecular weight of 147 kDa and is produced in genetically engineered mammalian (Chinese hamster ovary) cells.

Xgeva is a sterile, preservative-free, clear, colorless to pale yellow solution.

Each 1 mL single-use prefilled syringe of Xgeva contains 60 mg denosumab (60 mg/mL solution), 4.7% sorbitol, 17 mM acetate, 0.01% polysorbate 20, Water for Injection (USP), and sodium hydroxide to a pH of 5.2.

Each 1 mL single-use vial of Xgeva contains 60 mg denosumab (60 mg/mL solution), 4.7% sorbitol, 17 mM acetate, Water for Injection (USP), and sodium hydroxide to a pH of 5.2.

For Consumers

What are the possible side effects of Xgeva (Xgeva)?

Get emergency medical help if you have any of these signs of an allergic reaction: hives; difficulty breathing; swelling of your face, lips, tongue, or throat.

Call your doctor at once if you have a serious side effect such as:

  • numbness or tingly feeling around your mouth or in your fingers or toes, fast or slow heart rate, muscle cramps or contraction, overactive reflexes; or
  • trouble breathing.

Less serious side effects may include:

  • feeling weak or tired;
  • diarrhea, nausea; or
  • headache.

This is not a complete list of...

Indications & Dosage

INDICATIONS

Treatment Of Postmenopausal Women With Osteoporosis At High Risk For Fracture

Xgeva is indicated for the treatment of postmenopausal women with osteoporosis at high risk for fracture, defined as a history of osteoporotic fracture, or multiple risk factors for fracture; or patients who have failed or are intolerant to other available osteoporosis therapy. In postmenopausal women with osteoporosis, Xgeva reduces the incidence of vertebral, nonvertebral, and hip fractures [see Clinical Studies].

Treatment To Increase Bone Mass In Men With Osteoporosis

Xgeva is indicated for treatment to increase bone mass in men with osteoporosis at high risk for fracture, defined as a history of osteoporotic fracture, or multiple risk factors for fracture; or patients who have failed or are intolerant to other available osteoporosis therapy [see Clinical Studies].

Treatment Of Bone Loss In Men Receiving Androgen Deprivation Therapy For Prostate Cancer

Xgeva is indicated as a treatment to increase bone mass in men at high risk for fracture receiving androgen deprivation therapy for nonmetastatic prostate cancer. In these patients Xgeva also reduced the incidence of vertebral fractures [see Clinical Studies].

Treatment Of Bone Loss In Women Receiving Adjuvant Aromatase Inhibitor Therapy For Breast Cancer

Xgeva is indicated as a treatment to increase bone mass in women at high risk for fracture receiving adjuvant aromatase inhibitor therapy for breast cancer [see Clinical Studies].

DOSAGE AND ADMINISTRATION

Recommended Dosage

Xgeva should be administered by a healthcare professional.

The recommended dose of Xgeva is 60 mg administered as a single subcutaneous injection once every 6 months. Administer Xgeva via subcutaneous injection in the upper arm, the upper thigh, or the abdomen. All patients should receive calcium 1000 mg daily and at least 400 IU vitamin D daily [see WARNINGS AND PRECAUTIONS].

If a dose of Xgeva is missed, administer the injection as soon as the patient is available. Thereafter, schedule injections every 6 months from the date of the last injection.

Preparation And Administration

Visually inspect Xgeva for particulate matter and discoloration prior to administration whenever solution and container permit. Xgeva is a clear, colorless to pale yellow solution that may contain trace amounts of translucent to white proteinaceous particles. Do not use if the solution is discolored or cloudy or if the solution contains many particles or foreign particulate matter.

Latex Allergy

People sensitive to latex should not handle the grey needle cap on the single-use prefilled syringe, which contains dry natural rubber (a derivative of latex).

Prior to administration, Xgeva may be removed from the refrigerator and brought to room temperature (up to 25°C/77°F) by standing in the original container. This generally takes 15 to 30 minutes. Do not warm Xgeva in any other way [see HOW SUPPLIED/Storage and Handling].

Instructions For Prefilled Syringe With Needle Safety Guard

IMPORTANT: In order to minimize accidental needlesticks, the Xgeva single-use prefilled syringe will have a green safety guard; manually activate the safety guard after the injection is given.

DO NOT slide the green safety guard forward over the needle before administering the injection; it will lock in place and prevent injection.

Parts of Prefilled Syringe = Illustration

Activate the green safety guard (slide over the needle) after the injection.

The grey needle cap on the single-use prefilled syringe contains dry natural rubber (a derivative of latex); people sensitive to latex should not handle the cap.

Step 1: Remove Grey Needle Cap

Remove Grey Needle Cap - Illustration

Step 2: Administer Subcutaneous Injection

Choose an injection site. The recommended injection sites for Xgeva include: the upper arm OR the upper thigh OR the abdomen.

Recommended injection sites - Illustration

Insert needle and inject all the liquid subcutaneously.

Do not administer into muscle or blood vessel.

Insert needle and inject - Illustration

DO NOT put grey needle cap back on needle.

Step 3: Immediately Slide Green Safety Guard Over Needle

With the needle pointing away from you…

Hold the prefilled syringe by the clear plastic finger grip with one hand. Then, with the other hand, grasp the green safety guard by its base and gently slide it towards the needle until the green safety guard locks securely in place and/or you hear a “click.” DO NOT grip the green safety guard too firmly – it will move easily if you hold and slide it gently.

Hold clear finger grip.

Hold clear finger grip - Illustration

Gently slide green safety guard over needle and lock securely in place. Do not grip green safety guard too firmly when sliding over needle.

Gently slide green safety guard over needle - Illustration

Immediately dispose of the syringe and needle cap in the nearest sharps container. DO NOT put the needle cap back on the used syringe.

Instructions for Single-use Vial

For administration of Xgeva from the single-use vial, use a 27-gauge needle to withdraw and inject the 1 mL dose. Do not re-enter the vial. Discard vial and any liquid remaining in the vial.

HOW SUPPLIED

Dosage Forms And Strengths

  • 1 mL of a 60 mg/mL solution in a single-use prefilled syringe
  • 1 mL of a 60 mg/mL solution in a single-use vial

Storage And Handling

Xgeva is supplied in a single-use prefilled syringe with a safety guard or in a single-use vial. The grey needle cap on the single-use prefilled syringe contains dry natural rubber (a derivative of latex).

60 mg/1 mL in a single-use prefilled syringe 1 per carton NDC 55513-710-01
60 mg/1 mL in a single-use vial 1 per carton NDC 55513-720-01

Store Xgeva in a refrigerator at 2°C to 8°C (36°F to 46°F) in the original carton. Do not freeze. Prior to administration, Xgeva may be allowed to reach room temperature (up to 25°C/77°F) in the original container. Once removed from the refrigerator, Xgeva must not be exposed to temperatures above 25°C/77°F and must be used within 14 days. If not used within the 14 days, Xgeva should be discarded. Do not use Xgeva after the expiry date printed on the label. Protect Xgeva from direct light and heat.

Avoid vigorous shaking of Xgeva.

Manufactured by: Amgen Inc. One Amgen Center Drive Thousand Oaks, California 91320-1799. Revised: Aug 2016

Side Effects & Drug Interactions

SIDE EFFECTS

The following serious adverse reactions are discussed below and also elsewhere in the labeling:

The most common adverse reactions reported with Xgeva in patients with postmenopausal osteoporosis are back pain, pain in extremity, musculoskeletal pain, hypercholesterolemia, and cystitis.

The most common adverse reactions reported with Xgeva in men with osteoporosis are back pain, arthralgia, and nasopharyngitis.

The most common (per patient incidence ≥ 10%) adverse reactions reported with Xgeva in patients with bone loss receiving androgen deprivation therapy for prostate cancer or adjuvant aromatase inhibitor therapy for breast cancer are arthralgia and back pain. Pain in extremity and musculoskeletal pain have also been reported in clinical trials.

The most common adverse reactions leading to discontinuation of Xgeva in patients with postmenopausal osteoporosis are back pain and constipation.

The Xgeva Postmarketing Active Safety Surveillance Program is available to collect information from prescribers on specific adverse events. Please see www.proliasafety.com or call 1-800-772-6436 for more information about this program.

Clinical Trials Experience

Because clinical studies are conducted under widely varying conditions, adverse reaction rates observed in the clinical studies of a drug cannot be directly compared to rates in the clinical studies of another drug and may not reflect the rates observed in clinical practice.

Treatment Of Postmenopausal Women With Osteoporosis

The safety of Xgeva in the treatment of postmenopausal osteoporosis was assessed in a 3-year, randomized, double-blind, placebo-controlled, multinational study of 7808 postmenopausal women aged 60 to 91 years. A total of 3876 women were exposed to placebo and 3886 women were exposed to Xgeva administered subcutaneously once every 6 months as a single 60 mg dose. All women were instructed to take at least 1000 mg of calcium and 400 IU of vitamin D supplementation per day.

The incidence of all-cause mortality was 2.3% (n = 90) in the placebo group and 1.8% (n = 70) in the Xgeva group. The incidence of nonfatal serious adverse events was 24.2% in the placebo group and 25.0% in the Xgeva group. The percentage of patients who withdrew from the study due to adverse events was 2.1% and 2.4% for the placebo and Xgeva groups, respectively.

Adverse reactions reported in ≥ 2% of postmenopausal women with osteoporosis and more frequently in the Xgeva-treated women than in the placebo-treated women are shown in the table below.

Table 1: Adverse Reactions Occurring in ≥ 2% of Patients with Osteoporosis and More Frequently than in Placebo-treated Patients

SYSTEM ORGAN CLASS
Preferred Term
Xgeva
(N = 3886)
n (%)
Placebo
(N = 3876)
n (%)
BLOOD AND LYMPHATIC SYSTEM DISORDERS
  Anemia 129 (3.3) 107 (2.8)
CARDIAC DISORDERS
  Angina pectoris 101 (2.6) 87 (2.2)
  Atrial fibrillation 79 (2.0) 77 (2.0)
EAR AND LABYRINTH DISORDERS
  Vertigo 195 (5.0) 187 (4.8)
GASTROINTESTINAL DISORDERS
  Abdominal pain upper 129 (3.3) 111 (2.9)
  Flatulence 84 (2.2) 53 (1.4)
  Gastroesophageal reflux disease 80 (2.1) 66 (1.7)
GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS
  Edema peripheral 189 (4.9) 155 (4.0)
  Asthenia 90 (2.3) 73 (1.9)
INFECTIONS AND INFESTATIONS
  Cystitis  228 (5.9) 225 (5.8)
  Upper respiratory tract infection 190 (4.9) 167 (4.3)
  Pneumonia 152 (3.9) 150 (3.9)
  Pharyngitis 91 (2.3) 78 (2.0)
  Herpes zoster 79 (2.0) 72 (1.9)
METABOLISM AND NUTRITION DISORDERS
  Hypercholesterolemia 280 (7.2) 236 (6.1)
MUSCULOSKELETAL AND CONNECTIVE TISSUE DISORDERS
  Back pain 1347 (34.7) 1340 (34.6)
  Pain in extremity 453 (11.7) 430 (11.1)
  Musculoskeletal pain 297 (7.6) 291 (7.5)
  Bone pain 142 (3.7) 117 (3.0)
  Myalgia 114 (2.9) 94 (2.4)
  Spinal osteoarthritis 82 (2.1) 64 (1.7)
NERVOUS SYSTEM DISORDERS
  Sciatica 178 (4.6) 149 (3.8)
PSYCHIATRIC DISORDERS
  Insomnia 126 (3.2) 122 (3.1)
SKIN AND SUBCUTANEOUS TISSUE DISORDERS
  Rash 96 (2.5) 79 (2.0)
  Pruritus 87 (2.2) 82 (2.1)

Hypocalcemia

Decreases in serum calcium levels to less than 8.5 mg/dL at any visit were reported in 0.4% women in the placebo group and 1.7% women in the Xgeva group. The nadir in serum calcium level occurs at approximately day 10 after Xgeva dosing in subjects with normal renal function.

In clinical studies, subjects with impaired renal function were more likely to have greater reductions in serum calcium levels compared to subjects with normal renal function. In a study of 55 subjects with varying degrees of renal function, serum calcium levels < 7.5 mg/dL or symptomatic hypocalcemia were observed in 5 subjects. These included no subjects in the normal renal function group, 10% of subjects in the creatinine clearance 50 to 80 mL/min group, 29% of subjects in the creatinine clearance < 30 mL/min group, and 29% of subjects in the hemodialysis group. These subjects did not receive calcium and vitamin D supplementation. In a study of 4550 postmenopausal women with osteoporosis, the mean change from baseline in serum calcium level 10 days after Xgeva dosing was -5.5% in subjects with creatinine clearance < 30 mL/min vs. -3.1% in subjects with creatinine clearance ≥ 30 mL/min.

Serious Infections

Receptor activator of nuclear factor kappa-B ligand (RANKL) is expressed on activated T and B lymphocytes and in lymph nodes. Therefore, a RANKL inhibitor such as Xgeva may increase the risk of infection.

In the clinical study of 7808 postmenopausal women with osteoporosis, the incidence of infections resulting in death was 0.2% in both placebo and Xgeva treatment groups. However, the incidence of nonfatal serious infections was 3.3% in the placebo and 4.0% in the Xgeva groups. Hospitalizations due to serious infections in the abdomen (0.7% placebo vs. 0.9% Xgeva), urinary tract (0.5% placebo vs. 0.7% Xgeva), and ear (0.0% placebo vs. 0.1% Xgeva) were reported. Endocarditis was reported in no placebo patients and 3 patients receiving Xgeva.

Skin infections, including erysipelas and cellulitis, leading to hospitalization were reported more frequently in patients treated with Xgeva ( < 0.1% placebo vs. 0.4% Xgeva).

The incidence of opportunistic infections was similar to that reported with placebo.

Dermatologic Reactions

A significantly higher number of patients treated with Xgeva developed epidermal and dermal adverse events (such as dermatitis, eczema, and rashes), with these events reported in 8.2% of the placebo and 10.8% of the Xgeva groups (p < 0.0001). Most of these events were not specific to the injection site [see WARNINGS AND PRECAUTIONS].

Osteonecrosis Of The Jaw

ONJ has been reported in the osteoporosis clinical trial program in patients treated with Xgeva [see WARNINGS AND PRECAUTIONS].

Atypical Subtrochanteric And Diaphyseal Fractures

In the osteoporosis clinical trial program, atypical femoral fractures were reported in patients treated with Xgeva. The duration of Xgeva exposure to time of atypical femoral fracture diagnosis was as early as 2½ years [see WARNINGS AND PRECAUTIONS].

Pancreatitis

Pancreatitis was reported in 4 patients (0.1%) in the placebo and 8 patients (0.2%) in the Xgeva groups. Of these reports, 1 patient in the placebo group and all 8 patients in the Xgeva group had serious events, including one death in the Xgeva group. Several patients had a prior history of pancreatitis. The time from product administration to event occurrence was variable.

New Malignancies

The overall incidence of new malignancies was 4.3% in the placebo and 4.8% in the Xgeva groups. New malignancies related to the breast (0.7% placebo vs. 0.9% Xgeva), reproductive system (0.2% placebo vs. 0.5% Xgeva), and gastrointestinal system (0.6% placebo vs. 0.9% Xgeva) were reported. A causal relationship to drug exposure has not been established.

Treatment to Increase Bone Mass in Men with Osteoporosis

The safety of Xgeva in the treatment of men with osteoporosis was assessed in a 1-year randomized, double-blind, placebo-controlled study. A total of 120 men were exposed to placebo and 120 men were exposed to Xgeva administered subcutaneously once every 6 months as a single 60 mg dose. All men were instructed to take at least 1000 mg of calcium and 800 IU of vitamin D supplementation per day.

The incidence of all-cause mortality was 0.8% (n = 1) in the placebo group and 0.8% (n = 1) in the Xgeva group. The incidence of nonfatal serious adverse events was 7.5% in the placebo group and 8.3% in the Xgeva group. The percentage of patients who withdrew from the study due to adverse events was 0% and 2.5% for the placebo and Xgeva groups, respectively.

Adverse reactions reported in ≥ 5% of men with osteoporosis and more frequently with Xgeva than in the placebo-treated patients were: back pain (6.7% placebo vs. 8.3% Xgeva), arthralgia (5.8% placebo vs. 6.7% Xgeva), and nasopharyngitis (5.8% placebo vs. 6.7% Xgeva).

Serious Infections

Serious infection was reported in 1 patient (0.8%) in the placebo group and no patients in the Xgeva group.

Dermatologic Reactions

Epidermal and dermal adverse events (such as dermatitis, eczema, and rashes) were reported in 4 patients (3.3%) in the placebo group and 5 patients (4.2%) in the Xgeva group.

Osteonecrosis Of The Jaw

No cases of ONJ were reported.

Pancreatitis

Pancreatitis was reported in 1 patient (0.8%) in the placebo group and 1 patient (0.8%) in the Xgeva group.

New Malignancies

New malignancies were reported in no patients in the placebo group and 4 (3.3%) patients (3 prostate cancers, 1 basal cell carcinoma) in the Xgeva group.

Treatment of Bone Loss in Patients Receiving Androgen Deprivation Therapy for Prostate Cancer or Adjuvant Aromatase Inhibitor Therapy for Breast Cancer

The safety of Xgeva in the treatment of bone loss in men with nonmetastatic prostate cancer receiving androgen deprivation therapy (ADT) was assessed in a 3-year, randomized, double-blind, placebo-controlled, multinational study of 1468 men aged 48 to 97 years. A total of 725 men were exposed to placebo and 731 men were exposed to Xgeva administered once every 6 months as a single 60 mg subcutaneous dose. All men were instructed to take at least 1000 mg of calcium and 400 IU of vitamin D supplementation per day.

The incidence of serious adverse events was 30.6% in the placebo group and 34.6% in the Xgeva group. The percentage of patients who withdrew from the study due to adverse events was 6.1% and 7.0% for the placebo and Xgeva groups, respectively.

The safety of Xgeva in the treatment of bone loss in women with nonmetastatic breast cancer receiving aromatase inhibitor (AI) therapy was assessed in a 2-year, randomized, double-blind, placebo-controlled, multinational study of 252 postmenopausal women aged 35 to 84 years. A total of 120 women were exposed to placebo and 129 women were exposed to Xgeva administered once every 6 months as a single 60 mg subcutaneous dose. All women were instructed to take at least 1000 mg of calcium and 400 IU of vitamin D supplementation per day.

The incidence of serious adverse events was 9.2% in the placebo group and 14.7% in the Xgeva group. The percentage of patients who withdrew from the study due to adverse events was 4.2% and 0.8% for the placebo and Xgeva groups, respectively.

Adverse reactions reported in ≥ 10% of Xgeva-treated patients receiving ADT for prostate cancer or adjuvant AI therapy for breast cancer, and more frequently than in the placebo-treated patients were: arthralgia (13.0% placebo vs. 14.3% Xgeva) and back pain (10.5% placebo vs. 11.5% Xgeva). Pain in extremity (7.7% placebo vs. 9.9% Xgeva) and musculoskeletal pain (3.8% placebo vs. 6.0% Xgeva) have also been reported in clinical trials. Additionally in Xgeva-treated men with nonmetastatic prostate cancer receiving ADT, a greater incidence of cataracts was observed (1.2% placebo vs. 4.7% Xgeva). Hypocalcemia (serum calcium < 8.4 mg/dL) was reported only in Xgeva-treated patients (2.4% vs. 0%) at the month 1 visit.

Postmarketing Experience

Because postmarketing reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

The following adverse reactions have been identified during post approval use of Xgeva:

  • Drug-related hypersensitivity reactions: anaphylaxis, rash, urticaria, facial swelling, and erythema
  • Hypocalcemia: severe symptomatic hypocalcemia
  • Musculoskeletal pain, including severe cases
  • Parathyroid Hormone (PTH): Marked elevation in serum PTH in patients with severe renal impairment (creatinine clearance < 30 mL/min) or receiving dialysis.

Immunogenicity

Denosumab is a human monoclonal antibody. As with all therapeutic proteins, there is potential for immunogenicity. Using an electrochemiluminescent bridging immunoassay, less than 1% (55 out of 8113) of patients treated with Xgeva for up to 5 years tested positive for binding antibodies (including pre-existing, transient, and developing antibodies). None of the patients tested positive for neutralizing antibodies, as was assessed using a chemiluminescent cell-based in vitro biological assay. No evidence of altered pharmacokinetic profile, toxicity profile, or clinical response was associated with binding antibody development.

The incidence of antibody formation is highly dependent on the sensitivity and specificity of the assay. Additionally, the observed incidence of a positive antibody (including neutralizing antibody) test result may be influenced by several factors, including assay methodology, sample handling, timing of sample collection, concomitant medications, and underlying disease. For these reasons, comparison of antibodies to denosumab with the incidence of antibodies to other products may be misleading.

DRUG INTERACTIONS

In subjects with postmenopausal osteoporosis, Xgeva (60 mg subcutaneous injection) did not affect the pharmacokinetics of midazolam, which is metabolized by cytochrome P450 3A4 (CYP3A4), indicating that it should not affect the pharmacokinetics of drugs metabolized by this enzyme in this population [see CLINICAL PHARMACOLOGY].

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Warnings & Precautions

WARNINGS

Included as part of the PRECAUTIONS section.

PRECAUTIONS

Drug Products With Same Active Ingredient

Xgeva contains the same active ingredient (denosumab) found in Prolia. Patients receiving Xgeva should not receive Prolia.

Hypersensitivity

Clinically significant hypersensitivity including anaphylaxis has been reported with Xgeva. Symptoms have included hypotension, dyspnea, throat tightness, facial and upper airway edema, pruritus, and urticaria. If an anaphylactic or other clinically significant allergic reaction occurs, initiate appropriate therapy and discontinue further use of Xgeva [see CONTRAINDICATIONS, ADVERSE REACTIONS].

Hypocalcemia And Mineral Metabolism

Hypocalcemia may be exacerbated by the use of Xgeva. Pre-existing hypocalcemia must be corrected prior to initiating therapy with Xgeva. In patients predisposed to hypocalcemia and disturbances of mineral metabolism (e.g. history of hypoparathyroidism, thyroid surgery, parathyroid surgery, malabsorption syndromes, excision of small intestine, severe renal impairment [creatinine clearance < 30 mL/min] or receiving dialysis), clinical monitoring of calcium and mineral levels (phosphorus and magnesium) is highly recommended within 14 days of Xgeva injection. In some postmarketing cases, hypocalcemia persisted for weeks or months and required frequent monitoring and intravenous and/or oral calcium replacement, with or without vitamin D.

Hypocalcemia following Xgeva administration is a significant risk in patients with severe renal impairment [creatinine clearance < 30 mL/min] or receiving dialysis. These patients may also develop marked elevations of serum parathyroid hormone (PTH). Instruct all patients with severe renal impairment, including those receiving dialysis, about the symptoms of hypocalcemia and the importance of maintaining calcium levels with adequate calcium and vitamin D supplementation.

Adequately supplement all patients with calcium and vitamin D [see DOSAGE AND ADMINISTRATION, CONTRAINDICATIONS, ADVERSE REACTIONS, and PATIENT INFORMATION].

Osteonecrosis Of The Jaw

Osteonecrosis of the jaw (ONJ), which can occur spontaneously, is generally associated with tooth extraction and/or local infection with delayed healing. ONJ has been reported in patients receiving denosumab [see ADVERSE REACTIONS]. A routine oral exam should be performed by the prescriber prior to initiation of Xgeva treatment. A dental examination with appropriate preventive dentistry is recommended prior to treatment with Xgeva in patients with risk factors for ONJ such as invasive dental procedures (e.g. tooth extraction, dental implants, oral surgery), diagnosis of cancer, concomitant therapies (e.g. chemotherapy, corticosteroids, angiogenesis inhibitors), poor oral hygiene, and co-morbid disorders (e.g. periodontal and/or other pre-existing dental disease, anemia, coagulopathy, infection, ill-fitting dentures). Good oral hygiene practices should be maintained during treatment with Xgeva. Concomitant administration of drugs associated with ONJ may increase the risk of developing ONJ. The risk of ONJ may increase with duration of exposure to Xgeva.

For patients requiring invasive dental procedures, clinical judgment of the treating physician and/or oral surgeon should guide the management plan of each patient based on individual benefit-risk assessment.

Patients who are suspected of having or who develop ONJ while on Xgeva should receive care by a dentist or an oral surgeon. In these patients, extensive dental surgery to treat ONJ may exacerbate the condition. Discontinuation of Xgeva therapy should be considered based on individual benefit-risk assessment.

Atypical Subtrochanteric And Diaphyseal Femoral Fractures

Atypical low-energy or low trauma fractures of the shaft have been reported in patients receiving Xgeva [see ADVERSE REACTIONS]. These fractures can occur anywhere in the femoral shaft from just below the lesser trochanter to above the supracondylar flare and are transverse or short oblique in orientation without evidence of comminution. Causality has not been established as these fractures also occur in osteoporotic patients who have not been treated with anti-resorptive agents.

Atypical femoral fractures most commonly occur with minimal or no trauma to the affected area. They may be bilateral and many patients report prodromal pain in the affected area, usually presenting as dull, aching thigh pain, weeks to months before a complete fracture occurs. A number of reports note that patients were also receiving treatment with glucocorticoids (e.g. prednisone) at the time of fracture.

During Xgeva treatment, patients should be advised to report new or unusual thigh, hip, or groin pain. Any patient who presents with thigh or groin pain should be suspected of having an atypical fracture and should be evaluated to rule out an incomplete femur fracture. Patient presenting with an atypical femur fracture should also be assessed for symptoms and signs of fracture in the contralateral limb. Interruption of Xgeva therapy should be considered, pending a risk/benefit assessment, on an individual basis.

Serious Infections

In a clinical trial of over 7800 women with postmenopausal osteoporosis, serious infections leading to hospitalization were reported more frequently in the Xgeva group than in the placebo group [see ADVERSE REACTIONS]. Serious skin infections, as well as infections of the abdomen, urinary tract, and ear, were more frequent in patients treated with Xgeva. Endocarditis was also reported more frequently in Xgeva-treated patients. The incidence of opportunistic infections was similar between placebo and Xgeva groups, and the overall incidence of infections was similar between the treatment groups. Advise patients to seek prompt medical attention if they develop signs or symptoms of severe infection, including cellulitis.

Patients on concomitant immunosuppressant agents or with impaired immune systems may be at increased risk for serious infections. Consider the benefit-risk profile in such patients before treating with Xgeva. In patients who develop serious infections while on Xgeva, prescribers should assess the need for continued Xgeva therapy.

Dermatologic Adverse Reactions

In a large clinical trial of over 7800 women with postmenopausal osteoporosis, epidermal and dermal adverse events such as dermatitis, eczema, and rashes occurred at a significantly higher rate in the Xgeva group compared to the placebo group. Most of these events were not specific to the injection site [see ADVERSE REACTIONS]. Consider discontinuing Xgeva if severe symptoms develop.

Musculoskeletal Pain

In post-marketing experience, severe and occasionally incapacitating bone, joint, and/or muscle pain has been reported in patients taking Xgeva [see ADVERSE REACTIONS]. The time to onset of symptoms varied from one day to several months after starting Xgeva. Consider discontinuing use if severe symptoms develop [see PATIENT INFORMATION].

Suppression Of Bone Turnover

In clinical trials in women with postmenopausal osteoporosis, treatment with Xgeva resulted in significant suppression of bone remodeling as evidenced by markers of bone turnover and bone histomorphometry [see CLINICAL PHARMACOLOGY and Clinical Studies]. The significance of these findings and the effect of long-term treatment with Xgeva are unknown. The long-term consequences of the degree of suppression of bone remodeling observed with Xgeva may contribute to adverse outcomes such as osteonecrosis of the jaw, atypical fractures, and delayed fracture healing. Monitor patients for these consequences.

Patient Counseling Information

See FDA-approved patient labeling (Medication Guide).

Drug Products With Same Active Ingredient

Advise patients that denosumab is also marketed as Xgeva, and if taking Xgeva, they should not receive Xgeva [see WARNINGS AND PRECAUTIONS].

Hypersensitivity

Advise patients to seek prompt medical attention if signs or symptoms of hypersensitivity reactions occur. Advise patients who have had signs or symptoms of systemic hypersensitivity reactions that they should not receive denosumab (Xgeva or Xgeva) [see WARNINGS AND PRECAUTIONS, CONTRAINDICATIONS].

Hypocalcemia

Adequately supplement patients with calcium and vitamin D and instruct them on the importance of maintaining serum calcium levels while receiving Xgeva [see WARNINGS AND PRECAUTIONS and Use In Specific Populations]. Advise patients to seek prompt medical attention if they develop signs or symptoms of hypocalcemia.

Osteonecrosis Of The Jaw

Advise patients to maintain good oral hygiene during treatment with Xgeva and to inform their dentist prior to dental procedures that they are receiving Xgeva. Patients should inform their physician or dentist if they experience persistent pain and/or slow healing of the mouth or jaw after dental surgery [see WARNINGS AND PRECAUTIONS].

Atypical Subtrochanteric And Diaphyseal Femoral Fractures

Advise patients to report new or unusual thigh, hip, or groin pain [see WARNINGS AND PRECAUTIONS].

Serious Infections

Advise patients to seek prompt medical attention if they develop signs or symptoms of infections, including cellulitis [see WARNINGS AND PRECAUTIONS].

Dermatologic Reactions

Advise patients to seek prompt medical attention if they develop signs or symptoms of dermatological reactions (dermatitis, rashes, and eczema) [see WARNINGS AND PRECAUTIONS].

Musculoskeletal Pain

Inform patients that severe bone, joint, and/or muscle pain have been reported in patients taking Xgeva. Patients should report severe symptoms if they develop [see WARNINGS AND PRECAUTIONS].

Embryo-Fetal Toxicity

Pregnancy Advise patients that Xgeva is contraindicated in women who are pregnant and may cause fetal harm [see CONTRAINDICATIONS, Use In Specific Populations].

Nursing Mothers

Advise patients that because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from Xgeva, a decision should be made whether to discontinue nursing or discontinue the drug, taking into account the importance of the drug to the mother [see Use in Specific Populations].

Schedule Of Administration

If a dose of Xgeva is missed, administer the injection as soon as convenient. Thereafter, schedule injections every 6 months from the date of the last injection.

Nonclinical Toxicology

Carcinogenesis, Mutagenesis, Impairment Of Fertility

Carcinogenicity

The carcinogenic potential of denosumab has not been evaluated in long-term animal studies.

Mutagenicity

The genotoxic potential of denosumab has not been evaluated.

Impairment Of Fertility

Denosumab had no effect on female fertility or male reproductive organs in monkeys at doses that were 13-to 50-fold higher than the recommended human dose of 60 mg subcutaneously administered once every 6 months, based on body weight (mg/kg).

Use In Specific Populations

Pregnancy

Pregnancy Category X

Risk Summary

Xgeva may cause fetal harm when administered to a pregnant woman based on findings in animals. In utero denosumab exposure in cynomolgus monkeys resulted in increased fetal loss, stillbirths, and postnatal mortality, along with evidence of absent lymph nodes, abnormal bone growth and decreased neonatal growth. Xgeva is contraindicated in women who are pregnant. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to a fetus.

Women who become pregnant during Xgeva treatment are encouraged to enroll in Amgen's Pregnancy Surveillance Program. Patients or their physicians should call 1-800-77-AMGEN (1-800-772-6436) to enroll.

Clinical Considerations

The effects of Xgeva on the fetus are likely to be greater during the second and third trimesters of pregnancy. Monoclonal antibodies, such as denosumab, are transported across the placenta in a linear fashion as pregnancy progresses, with the largest amount transferred during the third trimester. If the patient becomes pregnant during Xgeva therapy, treatment should be discontinued and the patient should consult their physician.

Xgeva was present at low concentrations (approximately 2% of serum exposure) in the seminal fluid of male subjects given Xgeva. Following vaginal intercourse, the maximum amount of Xgeva delivered to a female partner would result in exposures approximately 11,000 times lower than the prescribed 60 mg subcutaneous dose.

The no-effect dose for denosumab-induced teratogenicity is unknown. However, a Cmax of 22.9 ng/mL was identified in cynomolgus monkeys as a level in which no biologic effects (NOEL) of denosumab were observed (no inhibition of RANKL). Using the highest seminal fluid concentration measured in men, and assuming 100% vaginal and placental transfer from a 6-mL ejaculate per day, female and fetal exposure via seminal fluid would be up to 0.6 ng/mL per day. Thus, the potential amount of fetal exposure when a man treated with Xgeva has unprotected sexual intercourse with a pregnant partner is at least 38-times lower than the NOEL in monkeys. Therefore, it is unlikely that a female partner or fetus would be exposed to pharmacologically relevant concentrations of denosumab via seminal fluid [see CLINICAL PHARMACOLOGY].

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 at a pharmacologically active dose, 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 1 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.

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 and Nonclinical Toxicology].

Nursing Mothers

It is not known whether Xgeva is excreted into human milk. Measurable concentrations of denosumab were present in the maternal milk of cynomolgus monkeys up to 1 month after the last dose of denosumab ( ≤ 0.5% milk:serum ratio). Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from Xgeva, a decision should be made whether to discontinue nursing or discontinue the drug, taking into account the importance of the drug to the mother.

Maternal exposure to Xgeva during pregnancy may impair mammary gland development and lactation based on animal studies in pregnant mice lacking the RANK/RANKL signaling pathway that have shown altered maturation of the maternal mammary gland, leading to impaired lactation postpartum. However in cynomolgus monkeys treated with denosumab throughout pregnancy, maternal mammary gland development was normal, with no impaired lactation. 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 [see Use in Specific Populations and Nonclinical Toxicology].

Pediatric Use

Xgeva is not recommended in pediatric patients. The safety and effectiveness of Xgeva in pediatric patients have not been established.

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 10 and 50 times (10 and 50 mg/kg dose) higher than the recommended human dose of 60 mg administered every 6 months, 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, an absence of axillary, inguinal, mandibular, and mesenteric lymph nodes, reduced hematopoiesis, tooth malalignment, and decreased neonatal growth. 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].

Geriatric Use

Of the total number of patients in clinical studies of Xgeva, 9943 patients (76%) were ≥ 65 years old, while 3576 (27%) were ≥ 75 years old. Of the patients in the osteoporosis study in men, 133 patients (55%) were ≥ 65 years old, while 39 patients (16%) were ≥ 75 years old. No overall differences in safety or efficacy were observed between these patients and younger patients and other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out.

Renal Impairment

No dose adjustment is necessary in patients with renal impairment.

In clinical studies, patients with severe renal impairment (creatinine clearance < 30 mL/min) or receiving dialysis were at greater risk of developing hypocalcemia. Consider the benefit-risk profile when administering Xgeva to patients with severe renal impairment or receiving dialysis. Clinical monitoring of calcium and mineral levels (phosphorus and magnesium) is highly recommended. Adequate intake of calcium and vitamin D is important in patients with severe renal impairment or receiving dialysis [see WARNINGS AND PRECAUTIONS, ADVERSE REACTIONS, and CLINICAL PHARMACOLOGY].

Hepatic Impairment

No clinical studies have been conducted to evaluate the effect of hepatic impairment on the pharmacokinetics of Xgeva.

Overdosage & Contraindications

OVERDOSE

There is no experience with overdosage with Xgeva.

CONTRAINDICATIONS

Hypocalcemia

Pre-existing hypocalcemia must be corrected prior to initiating therapy with Xgeva [see WARNINGS AND PRECAUTIONS].

Pregnancy

Xgeva may cause fetal harm when administered to a pregnant woman. In utero denosumab exposure in cynomolgus monkeys resulted in increased fetal loss, stillbirths, and postnatal mortality, along with evidence of absent lymph nodes, abnormal bone growth and decreased neonatal growth. Xgeva is contraindicated in women who are pregnant. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to a fetus [see Use in Specific Populations].

Hypersensitivity

Xgeva is contraindicated in patients with a history of systemic hypersensitivity to any component of the product. Reactions have included anaphylaxis, facial swelling and urticaria [see WARNINGS AND PRECAUTIONS, ADVERSE REACTIONS].

Clinical Pharmacology

CLINICAL PHARMACOLOGY

Mechanism Of Action

Xgeva binds to RANKL, a transmembrane or soluble protein essential for the formation, function, and survival of osteoclasts, the cells responsible for bone resorption. Xgeva prevents RANKL from activating its receptor, RANK, on the surface of osteoclasts and their precursors. Prevention of the RANKL/RANK interaction inhibits osteoclast formation, function, and survival, thereby decreasing bone resorption and increasing bone mass and strength in both cortical and trabecular bone.

Pharmacodynamics

In clinical studies, treatment with 60 mg of Xgeva resulted in reduction in the bone resorption marker serum type 1 C-telopeptide (CTX) by approximately 85% by 3 days, with maximal reductions occurring by 1 month. CTX levels were below the limit of assay quantitation (0.049 ng/mL) in 39% to 68% of patients 1 to 3 months after dosing of Xgeva. At the end of each dosing interval, CTX reductions were partially attenuated from a maximal reduction of ≥ 87% to ≥ 45% (range: 45% to 80%), as serum denosumab levels diminished, reflecting the reversibility of the effects of Xgeva on bone remodeling. These effects were sustained with continued treatment. Upon reinitiation, the degree of inhibition of CTX by Xgeva was similar to that observed in patients initiating Xgeva treatment.

Consistent with the physiological coupling of bone formation and resorption in skeletal remodeling, subsequent reductions in bone formation markers (i.e. osteocalcin and procollagen type 1 N-terminal peptide [PlNP]) were observed starting 1 month after the first dose of Xgeva. After discontinuation of Xgeva therapy, markers of bone resorption increased to levels 40% to 60% above pretreatment values but returned to baseline levels within 12 months.

Pharmacokinetics

In a study conducted in healthy male and female volunteers (n = 73, age range: 18 to 64 years) following a single subcutaneously administered Xgeva dose of 60 mg after fasting (at least for 12 hours), the mean maximum denosumab concentration (Cmax) was 6.75 mcg/mL (standard deviation [SD] = 1.89 mcg/mL). The median time to maximum denosumab concentration (Tmax) was 10 days (range: 3 to 21 days). After Cmax, serum denosumab concentrations declined over a period of 4 to 5 months with a mean half-life of 25.4 days (SD = 8.5 days; n = 46). The mean area-under-the-concentration-time curve up to 16 weeks (AUC0-16 weeks) of denosumab was 316 mcg•day/mL (SD = 101 mcg•day/mL).

No accumulation or change in denosumab pharmacokinetics with time was observed upon multiple dosing of 60 mg subcutaneously administered once every 6 months.

Xgeva pharmacokinetics were not affected by the formation of binding antibodies.

A population pharmacokinetic analysis was performed to evaluate the effects of demographic characteristics. This analysis showed no notable differences in pharmacokinetics with age (in postmenopausal women), race, or body weight (36 to 140 kg).

Seminal Fluid Pharmacokinetic Study

Serum and seminal fluid concentrations of denosumab were measured in 12 healthy male volunteers (age range: 43-65 years). After a single 60 mg subcutaneous administration of denosumab, the mean (± SD) Cmax values in the serum and seminal fluid samples were 6170 (± 2070) and 100 (± 81.9) ng/mL, respectively, resulting in a maximum seminal fluid concentration of approximately 2% of serum levels.

The median (range) Tmax values in the serum and seminal fluid samples were 8.0 (7.9 to 21) and 21 (8.0 to 49) days, respectively. Amongst the subjects, the highest denosumab concentration in seminal fluid was 301 ng/mL at 22 days post-dose. On the first day of measurement (10 days post-dose), nine of eleven subjects had quantifiable concentrations in semen. On the last day of measurement (106 days post-dose), five subjects still had quantifiable concentrations of denosumab in seminal fluid, with a mean (± SD) seminal fluid concentration of 21.1 (±36.5) ng/mL across all subjects (n = 12). [see Use in Specific Populations].

Drug Interactions

In a study of 17 postmenopausal women with osteoporosis, midazolam (2 mg oral) was administered two weeks after a single dose of denosumab (60 mg subcutaneous injection), which approximates the Tmax of denosumab. Denosumab did not affect the pharmacokinetics of midazolam, which is metabolized by cytochrome P450 3A4 (CYP3A4). This indicates that denosumab should not alter the pharmacokinetics of drugs metabolized by CYP3A4 in postmenopausal women with osteoporosis.

Specific Populations

Gender: Mean serum denosumab concentration-time profiles observed in a study conducted in healthy men ≥ 50 years were similar to those observed in a study conducted in postmenopausal women using the same dose regimen.

Age: The pharmacokinetics of denosumab were not affected by age across all populations studied whose ages ranged from 28 to 87 years.

Race: The pharmacokinetics of denosumab were not affected by race.

Renal Impairment: In a study of 55 patients with varying degrees of renal function, including patients on dialysis, the degree of renal impairment had no effect on the pharmacokinetics of denosumab; thus, dose adjustment for renal impairment is not necessary.

Hepatic Impairment: No clinical studies have been conducted to evaluate the effect of hepatic impairment on the pharmacokinetics of denosumab.

Animal Toxicology And/Or Pharmacology

Denosumab is an inhibitor of osteoclastic bone resorption via inhibition of RANKL.

In ovariectomized monkeys, once-monthly treatment with denosumab suppressed bone turnover and increased bone mineral density (BMD) and strength of cancellous and cortical bone at doses 50-fold higher than the recommended human dose of 60 mg administered once every 6 months, based on body weight (mg/kg). Bone tissue was normal with no evidence of mineralization defects, accumulation of osteoid, or woven bone.

Because the biological activity of denosumab in animals is specific to nonhuman primates, evaluation of genetically engineered (“knockout”) mice or use of other biological inhibitors of the RANK/RANKL pathway, namely OPG-Fc, provided additional information on the pharmacodynamic properties of denosumab. RANK/RANKL knockout mice exhibited absence of lymph node formation, as well as an absence of lactation due to inhibition of mammary gland maturation (lobulo-alveolar gland development during pregnancy). Neonatal RANK/RANKL knockout mice exhibited reduced bone growth and lack of tooth eruption. A corroborative study in 2-week-old rats given the RANKL inhibitor OPG-Fc also showed reduced bone growth, altered growth plates, and impaired tooth eruption. These changes were partially reversible in this model when dosing with the RANKL inhibitors was discontinued.

Clinical Studies

Postmenopausal Women With Osteoporosis

The efficacy and safety of Xgeva in the treatment of postmenopausal osteoporosis was demonstrated in a 3-year, randomized, double-blind, placebo-controlled trial. Enrolled women had a baseline BMD T-score between -2.5 and -4.0 at either the lumbar spine or total hip. Women with other diseases (such as rheumatoid arthritis, osteogenesis imperfecta, and Paget's disease) or on therapies that affect bone were excluded from this study. The 7808 enrolled women were aged 60 to 91 years with a mean age of 72 years. Overall, the mean baseline lumbar spine BMD T-score was -2.8, and 23% of women had a vertebral fracture at baseline. Women were randomized to receive subcutaneous injections of either placebo (N = 3906) or Xgeva 60 mg (N = 3902) once every 6 months. All women received at least 1000 mg calcium and 400 IU vitamin D supplementation daily.

The primary efficacy variable was the incidence of new morphometric (radiologically-diagnosed) vertebral fractures at 3 years. Vertebral fractures were diagnosed based on lateral spine radiographs (T4-L4) using a semiquantitative scoring method. Secondary efficacy variables included the incidence of hip fracture and nonvertebral fracture, assessed at 3 years.

Effect on Vertebral Fractures

Xgeva significantly reduced the incidence of new morphometric vertebral fractures at 1, 2, and 3 years (p < 0.0001), as shown in Table 2. The incidence of new vertebral fractures at year 3 was 7.2% in the placebo-treated women compared to 2.3% for the Xgeva-treated women. The absolute risk reduction was 4.8% and relative risk reduction was 68% for new morphometric vertebral fractures at year 3.

Table 2: The Effect of Xgeva on the Incidence of New Vertebral Fractures in Postmenopausal Women

  Proportion of Women With Fracture (%)+ Absolute Risk Reduction (%)* (95% CI) Relative Risk Reduction (%)* (95% CI)
Placebo
N = 3691 (%)
Xgeva
N = 3702 (%)
0-1 Year 2.2 0.9 1.4 (0.8, 1.9) 61 (42, 74)
0-2 Years 5.0 1.4 3.5 (2.7, 4.3) 71 (61, 79)
0-3 Years 7.2 2.3 4.8 (3.9, 5.8) 68 (59, 74)
+ Event rates based on crude rates in each interval.
* Absolute risk reduction and relative risk reduction based on Mantel-Haenszel method adjusting for age group variable.

Xgeva was effective in reducing the risk for new morphometric vertebral fractures regardless of age, baseline rate of bone turnover, baseline BMD, baseline history of fracture, or prior use of a drug for osteoporosis.

Effect On Hip Fractures

The incidence of hip fracture was 1.2% for placebo-treated women compared to 0.7% for Xgeva-treated women at year 3. The age-adjusted absolute risk reduction of hip fractures was 0.3% with a relative risk reduction of 40% at 3 years (p = 0.04) (Figure 1).

Figure 1: Cumulative Incidence of Hip Fractures Over 3 Years

Cumulative Incidence of Hip Fractures Over 3 Years - Illustration

Effect On Nonvertebral Fractures

Treatment with Xgeva resulted in a significant reduction in the incidence of nonvertebral fractures (Table 3).

Table 3: The Effect of Xgeva on the Incidence of Nonvertebral Fractures at Year 3

  Proportion of Women With F racture (%)+ Absolute Risk Reduction (%) (95% CI) Relative Risk Reduction (%) (95% CI)
Placebo
N = 3906 (%)
Xgeva
N = 3902 (%)
Nonvertebral fracture1 8.0 6.5 1.5 (0.3, 2.7) 20 (5, 33)*
+ Event rates based on Kaplan-Meier estimates at 3 years.
1 Excluding those of the vertebrae (cervical, thoracic, and lumbar), skull, facial, mandible, metacarpus, and finger and toe phalanges.
* p-value = 0.01.

Effect On Bone Mineral Density (BMD)

Treatment with Xgeva significantly increased BMD at all anatomic sites measured at 3 years. The treatment differences in BMD at 3 years were 8.8% at the lumbar spine, 6.4% at the total hip, and 5.2% at the femoral neck. Consistent effects on BMD were observed at the lumbar spine, regardless of baseline age, race, weight/body mass index (BMI), baseline BMD, and level of bone turnover.

After Xgeva discontinuation, BMD returned to approximately baseline levels within 12 months.

Bone Histology And Histomorphometry

A total of 115 transiliac crest bone biopsy specimens were obtained from 92 postmenopausal women with osteoporosis at either month 24 and/or month 36 (53 specimens in Xgeva group, 62 specimens in placebo group). Of the biopsies obtained, 115 (100%) were adequate for qualitative histology and 7 (6%) were adequate for full quantitative histomorphometry assessment.

Qualitative histology assessments showed normal architecture and quality with no evidence of mineralization defects, woven bone, or marrow fibrosis in patients treated with Xgeva.

The presence of double tetracycline labeling in a biopsy specimen provides an indication of active bone remodeling, while the absence of tetracycline label suggests suppressed bone formation. In patients treated with Xgeva, 35% had no tetracycline label present at the month 24 biopsy and 38% had no tetracycline label present at the month 36 biopsy, while 100% of placebo-treated patients had double label present at both time points. When compared to placebo, treatment with Xgeva resulted in virtually absent activation frequency and markedly reduced bone formation rates. However, the long-term consequences of this degree of suppression of bone remodeling are unknown.

Treatment To Increase Bone Mass In Men With Osteoporosis

The efficacy and safety of Xgeva in the treatment to increase bone mass in men with osteoporosis was demonstrated in a 1-year, randomized, double-blind, placebo-controlled trial. Enrolled men had a baseline BMD T-score between -2.0 and -3.5 at the lumbar spine or femoral neck. Men with a BMD T-score between -1.0 and -3.5 at the lumbar spine or femoral neck were also enrolled if there was a history of prior fragility fracture. Men with other diseases (such as rheumatoid arthritis, osteogenesis imperfecta, and Paget's disease) or on therapies that may affect bone were excluded from this study. The 242 men enrolled in the study ranged in age from 31 to 84 years with a mean age of 65 years. Men were randomized to receive SC injections of either placebo (n = 121) or Xgeva 60 mg (n = 121) once every 6 months. All men received at least 1000 mg calcium and at least 800 IU vitamin D supplementation daily.

Effect On Bone Mineral Density (BMD)

The primary efficacy variable was percent change in lumbar spine BMD from baseline to 1 year. Secondary efficacy variables included percent change in total hip, and femoral neck BMD from baseline to 1 year.

Treatment with Xgeva significantly increased BMD at 1 year. The treatment differences in BMD at 1 year were 4.8% (+0.9% placebo, +5.7% Xgeva; (95% CI: 4.0, 5.6); p < 0.0001) at the lumbar spine, 2.0% (+0.3% placebo, +2.4% Xgeva) at the total hip, and 2.2% (0.0% placebo, +2.1% Xgeva) at femoral neck. Consistent effects on BMD were observed at the lumbar spine regardless of baseline age, race, BMD, testosterone concentrations and level of bone turnover.

Bone Histology And Histomorphometry

A total of 29 transiliac crest bone biopsy specimens were obtained from men with osteoporosis at 12 months (17 specimens in Xgeva group, 12 specimens in placebo group). Of the biopsies obtained, 29 (100%) were adequate for qualitative histology and, in Xgeva patients, 6 (35%) were adequate for full quantitative histomorphometry assessment. Qualitative histology assessments showed normal architecture and quality with no evidence of mineralization defects, woven bone, or marrow fibrosis in patients treated with Xgeva. The presence of double tetracycline labeling in a biopsy specimen provides an indication of active bone remodeling, while the absence of tetracycline label suggests suppressed bone formation. In patients treated with Xgeva, 6% had no tetracycline label present at the month 12 biopsy, while 100% of placebo-treated patients had double label present. When compared to placebo, treatment with Xgeva resulted in markedly reduced bone formation rates. However, the long-term consequences of this degree of suppression of bone remodeling are unknown.

Treatment Of Bone Loss In Men With Prostate Cancer

The efficacy and safety of Xgeva in the treatment of bone loss in men with nonmetastatic prostate cancer receiving androgen deprivation therapy (ADT) were demonstrated in a 3-year, randomized (1:1), double-blind, placebo-controlled, multinational study. Men less than 70 years of age had either a BMD T-score at the lumbar spine, total hip, or femoral neck between -1.0 and -4.0, or a history of an osteoporotic fracture. The mean baseline lumbar spine BMD T-score was -0.4, and 22% of men had a vertebral fracture at baseline. The 1468 men enrolled ranged in age from 48 to 97 years (median 76 years). Men were randomized to receive subcutaneous injections of either placebo (n = 734) or Xgeva 60 mg (n = 734) once every 6 months for a total of 6 doses. Randomization was stratified by age ( < 70 years vs. ≥ 70 years) and duration of ADT at trial entry ( ≤ 6 months vs. > 6 months). Seventy-nine percent of patients received ADT for more than 6 months at study entry. All men received at least 1000 mg calcium and 400 IU vitamin D supplementation daily.

Effect On Bone Mineral Density (BMD)

The primary efficacy variable was percent change in lumbar spine BMD from baseline to month 24. An additional key secondary efficacy variable was the incidence of new vertebral fracture through month 36 diagnosed based on x-ray evaluation by two independent radiologists. Lumbar spine BMD was higher at 2 years in Xgeva-treated patients as compared to placebo-treated patients [-1.0% placebo, +5.6% Xgeva; treatment difference 6.7% (95% CI: 6.2, 7.1); p < 0.0001].

With approximately 62% of patients followed for 3 years, treatment differences in BMD at 3 years were 7.9% (-1.2% placebo, +6.8% Xgeva) at the lumbar spine, 5.7% (-2.6% placebo, +3.2% Xgeva) at the total hip, and 4.9% (-1.8% placebo, +3.0% Xgeva) at the femoral neck. Consistent effects on BMD were observed at the lumbar spine in relevant subgroups defined by baseline age, BMD, and baseline history of vertebral fracture.

Effect On Vertebral Fractures

Xgeva significantly reduced the incidence of new vertebral fractures at 3 years (p = 0.0125), as shown in Table 4.

Table 4: The Effect of Xgeva on the Incidence of New Vertebral Fractures in Men with Nonmetastatic Prostate Cancer

  Proportion of Men With F racture (%)+ Absolute Risk Reduction (%)* (95% CI) Relative Risk Reduction (%)* (95% CI)
Placebo
N = 673 (%)
Xgeva
N = 679 (%)
0-1 Year 1.9 0.3 1.6 (0.5, 2.8) 85 (33, 97)
0-2 Years 3.3 1.0 2.2 (0.7, 3.8) 69 (27, 86)
0-3 Years 3.9 1.5 2.4 (0.7, 4.1) 62 (22, 81)
+ Event rates based on crude rates in each interval.
* Absolute risk reduction and relative risk reduction based on Mantel-Haenszel method adjusting for age group and ADT duration variables.

Treatment Of Bone Loss In Women With Breast Cancer

The efficacy and safety of Xgeva in the treatment of bone loss in women receiving adjuvant aromatase inhibitor (AI) therapy for breast cancer was assessed in a 2-year, randomized (1:1), double-blind, placebo-controlled, multinational study. Women had baseline BMD T-scores between -1.0 to -2.5 at the lumbar spine, total hip, or femoral neck, and had not experienced fracture after age 25. The mean baseline lumbar spine BMD T-score was -1.1, and 2.0% of women had a vertebral fracture at baseline. The 252 women enrolled ranged in age from 35 to 84 years (median 59 years). Women were randomized to receive subcutaneous injections of either placebo (n = 125) or Xgeva 60 mg (n = 127) once every 6 months for a total of 4 doses. Randomization was stratified by duration of adjuvant AI therapy at trial entry ( ≤ 6 months vs. > 6 months). Sixty-two percent of patients received adjuvant AI therapy for more than 6 months at study entry. All women received at least 1000 mg calcium and 400 IU vitamin D supplementation daily.

Effect On Bone Mineral Density (BMD)

The primary efficacy variable was percent change in lumbar spine BMD from baseline to month 12. Lumbar spine BMD was higher at 12 months in Xgeva-treated patients as compared to placebo-treated patients [-0.7% placebo, +4.8% Xgeva; treatment difference 5.5% (95% CI: 4.8, 6.3); p < 0.0001].

With approximately 81% of patients followed for 2 years, treatment differences in BMD at 2 years were 7.6% (-1.4% placebo, +6.2% Xgeva) at the lumbar spine, 4.7 % (-1.0% placebo, +3.8% Xgeva) at the total hip, and 3.6% (-0.8% placebo, +2.8% Xgeva) at the femoral neck.

Medication Guide

PATIENT INFORMATION

No information provided. Please refer to the WARNINGS AND PRECAUTIONS sections.

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