Denosumab

Dosage Forms & Strengths

subcutaneous injection

• Prolia: 60mg/mL (1mL prefilled syringe or 1mL vial)
• Xgeva: 70mg/mL (120mg/1.7mL vial)

Osteoporosis

Treatment of men and postmenopausal women with osteoporosis who are at high risk for fracture; treatment to increase bone mass in men at high risk for fracture who are receiving androgen deprivation therapy for nonmetastatic prostate cancer; treatment to increase bone mass in women at high risk for fracture who are receiving adjuvant aromatase inhibitor therapy for breast cancer

Prolia: 60 mg SC every 6 months

Supplement with calcium 1000 mg/day and vitamin D 400 IU/day

Aromatase Inhibitor Induced Bone Loss

Women with breast cancer: 60 mg (Prolia) SC every 6 months

Androgen Deprivation Induced Bone Loss

Men with prostate cancer: 60 mg (Prolia) SC every 6 months

Skeletal-Related Events

Prevention of skeletal-related events (SREs; eg, bone fractures and pain) in patients with bone metastases from solid tumors

Xgeva: 120 mg (1.7 mL) SC every 4 weeks

Giant Cell Tumor

Treatment of adults and skeletally mature adolescents with giant cell tumor of bone in whom surgical resection is impossible or is likely to result in severe morbidity

Xgeva: 120 mg SC every 4 weeks with additional 120 mg on days 8 and 15 during first month of therapy

Hypercalcemia of Malignancy

Indicated for treatment of hypercalcemia of malignancy refractory to bisphosphonate therapy

Xgeva: 120 mg SC q4wk

Give 2 additional 120 mg doses during the first month of therapy on Days 8 and 15

Administration

Must be administered by healthcare professional

Administer SC in upper arm, upper thigh, or abdomen; do NOT administer intradermally, IM, or IV

Administer calcium and vitamin D as needed to treat or prevent hypocalcemia

Avoid vigorous shaking of vial/syringe

Storage

• Store refrigerated at 2-8°C (36-46°F)
• Once removed from refrigerator, preparation must be used within 14 days

Dosage Forms & Strengths

subcutaneous injection

• Xgeva: 70mg/mL (120mg/1.7mL vial)

Giant Cell Tumor

Treatment of skeletally mature adolescents with giant cell tumor of bone in whom surgical resection is impossible or is likely to result in severe morbidity

Xgeva: 120 mg SC every 4 weeks, with additional 120 mg on days 8 and 15 during first month of therapy

Administration

Must be administered by healthcare professional

Administer SC in upper arm, upper thigh, or abdomen; do NOT administer intradermally, IM, or IV

Administer calcium and vitamin D as needed to treat or prevent hypocalcemia

Avoid vigorous shaking of vial/syringe

Storage

• Store refrigerated at 2-8°C (36-46°F)
• Once removed from refrigerator, preparation must be used within 14 days

Pregnancy

Prolia is contraindicated for use in pregnant women because it may cause harm to fetus; 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 50-fold higher than the recommended human dose based on body weight resulted in increased fetal loss, stillbirths, and postnatal mortality, and absent lymph nodes, abnormal bone growth, and decreased neonatal growth

Lactation

There is no information regarding presence of denosumab in human milk, effects on breastfed infant, or effects on milk production; denosumab was detected in maternal milk of cynomolgus monkeys up to 1 month after last dose of denosumab (less than or equal to 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 maternal mammary gland, leading to impaired lactation

Pregnancy Categories

A:Generally acceptable. Controlled studies in pregnant women show no evidence of fetal risk.

B:May be acceptable. Either animal studies show no risk but human studies not available or animal studies showed minor risks and human studies done and showed no risk.

C:Use with caution if benefits outweigh risks. Animal studies show risk and human studies not available or neither animal nor human studies done.

D:Use in LIFE-THREATENING emergencies when no safer drug available. Positive evidence of human fetal risk.

X:Do not use in pregnancy. Risks involved outweigh potential benefits. Safer alternatives exist.

NA:Information not available.

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

• Hypocalcemia [see WARNINGS AND PRECAUTIONS]
• Osteonecrosis of the Jaw [see WARNINGS AND PRECAUTIONS]
• Hypercalcemia following treatment discontinuation in patients with growing skeletons [see WARNINGS AND PRECAUTIONS]

The most common adverse reactions in patients (per-patient incidence greater than or equal to 25%) were fatigue/asthenia, hypophosphatemia, and nausea (see Table 1). The most common serious adverse reaction was dyspnea. The most common adverse reactions resulting in discontinuation of Xgeva were osteonecrosis and hypocalcemia.

Clinical Trials Experience

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

Bone Metastasis From Solid Tumors

The safety of Xgeva was evaluated in three randomized, double-blind, double-dummy trials [see Clinical Studies] in which a total of 2841 patients with bone metastasis from prostate cancer, breast cancer, or other solid tumors, or lytic bony lesions from multiple myeloma received at least one dose of Xgeva. In Trials 1, 2, and 3, patients were randomized to receive either 120 mg of Xgeva every 4 weeks as a subcutaneous injection or 4 mg (dose adjusted for reduced renal function) of zoledronic acid every 4 weeks by intravenous (IV) infusion. Entry criteria included serum calcium (corrected) from 8 to 11.5 mg/dL (2 to 2.9 mmol/L) and creatinine clearance 30 mL/min or greater. Patients who had received IV bisphosphonates were excluded, as were patients with prior history of ONJ or osteomyelitis of the jaw, an active dental or jaw condition requiring oral surgery, non-healed dental/oral surgery, or any planned invasive dental procedure. During the study, serum chemistries including calcium and phosphorus were monitored every 4 weeks. Calcium and vitamin D supplementation was recommended but not required.

The median duration of exposure to Xgeva was 12 months (range: 0.1 - 41) and median duration on-study was 13 months (range: 0.1 - 41). Of patients who received Xgeva, 46% were female. Eighty-five percent were White, 5% Hispanic/Latino, 6% Asian, and 3% Black. The median age was 63 years (range: 18 - 93). Seventy-five percent of patients who received Xgeva received concomitant chemotherapy.

Table 1. Per-patient Incidence of Selecteda Adverse Reactions of Any Severity (Trials 1, 2, and 3)

• Severe hypocalcemia (corrected serum calcium less than 7 mg/dL or less than 1.75 mmol/L) occurred in 3.1% of patients treated with Xgeva and 1.3% of patients treated with zoledronic acid. Of patients who experienced severe hypocalcemia, 33% experienced 2 or more episodes of severe hypocalcemia and 16% experienced 3 or more episodes [see WARNINGS AND PRECAUTIONS and Use In Specific Populations].
• Severe hypophosphatemia (serum phosphorus less than 2 mg/dL or less than 0.6 mmol/L) occurred in 15.4% of patients treated with Xgeva and 7.4% of patients treated with zoledronic acid.

In the primary treatment phases of Trials 1, 2, and 3, ONJ was confirmed in 1.8% of patients in the Xgeva group (median exposure of 12.0 months; range 0.1-40.5) and 1.3% of patients in the zoledronic acid group. The trials in patients with breast (Trial 1) or prostate (Trial 3) cancer included an Xgeva open label extension treatment phase where patients were offered Xgeva 120 mg once every 4 weeks (median overall exposure of 14.9 months; range 0.1-67.2). The patient-year adjusted incidence of confirmed ONJ was 1.1% during the first year of treatment, 3.7% in the second year, and 4.6% per year thereafter. The median time to ONJ was 20.6 months (range: 4-53) [see WARNINGS AND PRECAUTIONS].

In a placebo-controlled clinical trial with an extension treatment phase evaluating Xgeva for the prevention of bone metastases in patients with non-metastatic prostate cancer (a patient population for which Xgeva is not indicated), with longer treatment exposure of up to 7 years, the patient-year adjusted incidence of confirmed ONJ was 1.1% during the first year of treatment, 3.0% in the second year, and 7.1% per year thereafter.

Atypical femoral fracture has been reported with Xgeva [see WARNINGS AND PRECAUTIONS].

Giant Cell Tumor Of Bone

The safety of Xgeva was evaluated in two single arm trials (Trials 4 and 5) [see Clinical Studies] in which a total of 304 adult or skeletally mature adolescent patients with giant cell tumor of bone received at least 1 dose of Xgeva. Patients received 120 mg Xgeva subcutaneously every 4 weeks with additional 120 mg doses on Days 8 and 15 of the first month of therapy. Patients receiving concurrent bisphosphonate therapy were excluded from enrollment in both studies. Patients with prior history of ONJ or osteomyelitis of the jaw, an active dental or jaw condition requiring oral surgery, non-healed dental/oral surgery, or any planned invasive dental procedure were excluded from enrollment in Trial 5. During the trial, serum chemistries including calcium and phosphorus were monitored every 4 weeks. Calcium and vitamin D supplementation was recommended but not required.

Of the 304 patients who received Xgeva, 145 patients were treated with Xgeva for ≥ 1 year, 44 patients for ≥ 2 years, and 15 patients for ≥ 3 years. The median number of doses received was 14 (range: 1 to 60 doses) and the median number of months on study was 11 (range: 0 to 54 months). Fifty-eight percent of the enrolled patients were women and 80% were White. The median age was 33 years (range: 13 to 83 years); a total of 10 patients were skeletally mature adolescents (13 to 17 years of age).

The adverse reaction profile of Xgeva in patients with giant cell tumor of bone was similar to that reported in Trials 1, 2, and 3. The most common adverse reactions in patients (per-patient incidence ≥ 10%) were arthralgia, headache, nausea, back pain, fatigue, and pain in extremity. The most common serious adverse reactions were osteonecrosis of the jaw and osteomyelitis (per-patient incidence of 0.7%). The most common adverse reactions resulting in discontinuation of Xgeva were osteonecrosis of the jaw (per-patient incidence of 0.7%), and tooth abscess or tooth infection (per-patient incidence of 0.7%). The adverse reaction profile appeared similar in skeletally mature adolescents and adults.

• Moderate hypocalcemia (corrected serum calcium less than 8 to 7 mg/dL or less than 2 to 1.75 mmol/L) occurred in 2.6% of patients treated with Xgeva.
• Severe hypophosphatemia (serum phosphorus less than 2 to 1 mg/dL or less than 0.6 to 0.3 mmol/L) occurred in 29 patients (9.5%).

In Trials 4 and 5, ONJ was confirmed in 4 of 304 (1.3%) patients who received Xgeva. The median time to ONJ was 16 months (range: 13 to 20 months) [see WARNINGS AND PRECAUTIONS].

Hypercalcemia Of Malignancy

Xgeva was evaluated in an open-label, single-arm trial (Trial 6) in which 33 patients with hypercalcemia of malignancy (with or without bone metastases) refractory to treatment with intravenous bisphosphonate therapy were enrolled [see Clinical Studies].

The adverse reaction profile of Xgeva in patients with hypercalcemia of malignancy was similar to that reported in Trials 1, 2, 3, 4, and 5. Adverse reactions occurring in greater than 20% of patients were nausea (30%), dyspnea (27%), decreased appetite (24%), headache (24%), peripheral edema (24%), vomiting (24%), anemia (21%), constipation (21%), and diarrhea (21%). The following adverse reactions of Grade 3 or greater severity related to study therapy were reported on study: fatigue (3%) and infection (6%). Grade 3 laboratory abnormalities included hypomagnesemia (3%), hypokalemia (3%), and hypophosphatemia (76%) of patients. No deaths on study were related to Xgeva therapy.

Postmarketing Experience

The following adverse reactions have been identified during postapproval use of Xgeva. Because these 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.

• Hypocalcemia: Severe symptomatic hypocalcemia, including fatal cases [see CONTRAINDICATIONS and WARNINGS AND PRECAUTIONS.
• Hypersensitivity, including anaphylactic reactions [see CONTRAINDICATIONS and WARNINGS AND PRECAUTIONS].
• Musculoskeletal pain, including severe musculoskeletal pain. Positive rechallenge has been reported.

Immunogenicity

As with all therapeutic proteins, there is potential for immunogenicity. Using an electrochemiluminescent bridging immunoassay, less than 1% (7/2758) of patients with osseous metastases treated with denosumab doses ranging from 30-180 mg every 4 weeks or every 12 weeks for up to 3 years and none of the 304 patients with giant cell tumor of bone in Trials 4 and 5 tested positive for binding antibodies. No patient with positive binding antibodies tested positive for neutralizing antibodies as assessed using a chemiluminescent cell-based in vitro biological assay. There was no evidence of altered pharmacokinetic profile, toxicity profile, or clinical response 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.

Denosumab is part of the drug class:

• Other drugs affecting bone structure and mineralization

Serious side effects have been reported with denosumab. See the "Drug Precautions" section.

Common side effects of denosumab include the following:

• red, dry, itchy skin
• back pain
• nausea
• headache
• pain in arms or legs
• joint pain
• muscle pain
• fatigue
• increase in cholesterol
• urinary tract infections

This is not a complete list of denosumab side effects. Ask your doctor or pharmacist for more information.

Tell your doctor if you have any side effect that bothers you or that does not go away.

Call your doctor for medical advice about side effects. You may report side effects to the FDA at 1-800-FDA-1088.

Denosumab is injected under the skin of your stomach, upper thigh, or upper arm. A healthcare provider will give you this injection.

Prolia is usually given once every 6 months.

Your doctor may have you take extra calcium and vitamin D while you are being treated with denosumab. Take only the amount of calcium and vitamin D that your doctor has prescribed.

If you need to have any dental work (especially surgery), tell the dentist ahead of time that you are receiving denosumab.

Pay special attention to your dental hygiene. Brush and floss your teeth regularly while receiving this medication. You may need to have a dental exam before you begin treatment with Prolia. Follow your doctor's instructions.

Your risk of bone fractures can increase when you stop using Prolia. Do not stop using this medicine without first talking to your doctor.

If you keep this medicine at home, store it in the original container in a refrigerator. Protect from light and do not freeze.

You may take the medicine out of the refrigerator and allow it to reach room temperature before the injection is given. Do not heat the medicine before using.

Do not shake the prefilled syringe or you may ruin the medicine. Do not use the medicine if it looks cloudy or has particles in it. Call your pharmacist for a new prescription.

Each prefilled syringe of this medicine is for one use only. Throw away after one use, even if there is still some medicine left in it after injecting your dose.

After you have taken Prolia out of the refrigerator, you may keep it at room temperature for up to 14 days. Store in the original container away from heat and light.

Use a disposable needle and syringe only once. Follow any state or local laws about throwing away used needles and syringes. Use a puncture-proof "sharps" disposal container (ask your pharmacist where to get one and how to throw it away). Keep this container out of the reach of children and pets.

Do not share this medicine with another person, even if they have the same symptoms you have.

Other drugs may interact with denosumab, including prescription and over-the-counter medicines, vitamins, and herbal products. Tell each of your health care providers about all medicines you use now and any medicine you start or stop using.

Bone resorption inhibitor; fully human monoclonal antibody specific for receptor activator of nuclear factor kappa-B ligand (RANKL); RANKL inhibitor.1 2 10 25

• Denosumab (Prolia) medication guide must be provided to the patient each time the drug is administered; importance of reading the medication guide prior to initiating therapy and prior to each subsequent dose.1 8 16 (See REMS.)

• Importance of receiving adequate calcium and vitamin D supplementation during denosumab therapy, and importance of seeking medical attention if signs or symptoms of hypocalcemia develop (e.g., spasms, twitches, muscle cramps, numbness or tingling in fingers, toes, or near mouth).1 2 16

• Advise patients to seek prompt medical attention if they develop symptoms of hypersensitivity (e.g., rash, urticaria, pruritus, lip swelling, shortness of breath, hypotension, respiratory tract edema).1 2 Advise such patients they should not receive further doses of denosumab.1 2

• Advise patients to seek prompt medical attention if they develop signs or symptoms of infection, including cellulitis (e.g., fever, chills, severe abdominal pain, frequent or urgent need to urinate or burning feeling when urinating, skin that is red, swollen, hot, or tender to touch).1 16

• Advise patients to seek prompt medical attention if they develop signs or symptoms of dermatologic reactions (e.g., redness, itching, rash, dry skin, blisters that ooze or crust, peeling skin).1 16

• Importance of maintaining good oral hygiene during denosumab treatment; importance of informing dentist about denosumab treatment prior to dental procedures.1 2 Advise patients to inform clinician or dentist if persistent pain and/or slow healing of mouth or jaw occurs after dental surgery or if symptoms of ONJ (pain, numbness, swelling of or drainage from the jaw, mouth, or teeth) occur at any time.1 2

• Advise patients to report new or unusual thigh, hip, or groin pain since these may be symptoms of atypical femoral fracture.1 2

• Advise patients that denosumab is commercially available as Prolia and Xgeva; patients should not receive concomitant treatment with both drugs.1 2 16

• Importance of informing clinician about latex allergy.1 (See Latex Sensitivity under Cautions.)

• Inform patients receiving denosumab (Prolia) for treatment of osteoporosis or bone loss associated with androgen deprivation or aromatase inhibitor therapy that if a dose is missed, the dose should be given as soon as convenient and subsequent dose should be scheduled for 6 months from date of last dose.1

• Importance of women informing clinicians if they are or plan to become pregnant or plan to breast-feed.1 2 Advise male patients with pregnant partners about potential fetal exposure to denosumab during unprotected sex.1 Advise female patients with reproductive potential to use highly effective contraception during and for at least 5 months after last dose of denosumab (Xgeva).2 (See Fetal/Neonatal Morbidity and Mortality under Cautions.)

• Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs, as well as any concomitant illnesses.1 2

• Importance of informing patients of other important precautionary information.1 2 (See Cautions.)

(den OH sue mab)

• Bone-Modifying Agent
• Monoclonal Antibody

Denosumab is a monoclonal antibody with affinity for nuclear factor-kappa ligand (RANKL). Osteoblasts secrete RANKL; RANKL activates osteoclast precursors and subsequent osteolysis which promotes release of bone-derived growth factors, such as insulin-like growth factor-1 (IGF1) and transforming growth factor-beta (TGF-beta), and increases serum calcium levels. Denosumab binds to RANKL, blocks the interaction between RANKL and RANK (a receptor located on osteoclast surfaces), and prevents osteoclast formation, leading to decreased bone resorption and increased bone mass in osteoporosis. In solid tumors with bony metastases, RANKL inhibition decreases osteoclastic activity leading to decreased skeletal related events and tumor-induced bone destruction. In giant cell tumors of the bone (which express RANK and RANKL), denosumab inhibits tumor growth by preventing RANKL from activating its receptor (RANK) on the osteoclast surface, osteoclast precursors, and osteoclast-like giant cells.

Bone metastases from solid tumors (Xgeva): Prevention of skeletal-related events (eg, fracture, spinal cord compression, bone pain requiring surgery/radiation therapy) in patients with bone metastases from solid tumors.

Limitation of use: Denosumab is NOT indicated for prevention of skeletal-related events in patients with multiple myeloma

Giant cell tumor of bone (Xgeva): Treatment of giant cell tumor of bone (in adults and skeletally mature adolescents) that is unresectable or where surgical resection is likely to result in severe morbidity.

Hypercalcemia of malignancy (Xgeva): Treatment of hypercalcemia of malignancy refractory to bisphosphonate therapy

Osteoporosis/bone loss (Prolia): Treatment of osteoporosis in postmenopausal women at high risk of fracture; treatment of osteoporosis (to increase bone mass) in men at high risk of fracture; treatment of bone loss in men receiving androgen-deprivation therapy (ADT) for nonmetastatic prostate cancer; treatment of bone loss in women receiving aromatase inhibitor (AI) therapy for breast cancer

There are no dosage adjustments provided in the manufacturer's labeling (has not been studied).

Use of Prolia is contraindicated in pregnant women. Based on data from animal reproduction studies and the mechanism of action, denosumab may cause fetal harm if administered to a pregnant woman. In females of reproductive potential, pregnancy status should be verified prior to treatment initiation. Denosumab is a human IgG monoclonal antibody; fetal exposure to monoclonal antibodies is expected to increase as pregnancy progresses. Women of reproductive potential should be advised to use effective contraception during denosumab treatment and for at least 5 months following the last dose. Studies of denosumab when used for osteoporosis/bone loss in men demonstrated that denosumab is present in the semen in low concentrations (~2% of serum exposure) and therefore unlikely that a female partner or fetus would be exposed during unprotected sex to pharmacologically relevant denosumab concentrations via seminal fluid; however, exposure from seminal fluid of men receiving denosumab for other indications and higher doses is unknown and; therefore, their pregnant partners should be counseled regarding this potential risk.

Women exposed to denosumab during pregnancy should contact the Amgen Pregnancy Surveillance Program (800-772-6436).

Prolia(R): 60 mg subcutaneously once every 6 months

Comments:
-If a dose is missed, the injection should be administered as soon as possible. Thereafter, injections should be scheduled every 6 months from the date of the last injection.
-This drug should be injected into the upper arm, upper thigh, or abdomen.

Uses:
-Treatment of postmenopausal women with osteoporosis at high risk for fracture
-Treatment to increase bone mass in men with osteoporosis
-Treatment of bone loss in men receiving androgen deprivation therapy for prostate cancer
-Treatment of bone loss in women receiving adjuvant aromatase inhibitor therapy for breast cancer

Xgeva(R): 120 mg subcutaneously every 4 weeks with additional 120 mg doses on Days 8 and 15 of the first month of therapy

Comment:
-This drug should be injected into the upper arm, upper thigh, or abdomen.

Use: Treatment of hypercalcemia of malignancy refractory to bisphosphonate therapy