denosumab

Denosumab is a medication used to reduce bone loss in patients at high risk for bone fractures due to postmenopausal osteoporosis, cancers or other conditions.

Denosumab is a lab-made human monoclonal immunoglobulin G2 (IgG2) antibody that specifically blocks the activity of the primary signaling protein involved in the resorption of bone tissue, preventing bone loss. 

Resorption is a natural process by which old bone tissue is broken down by cells known as osteoclasts, before new bone cells grow from osteoblasts. Osteoclasts break down the bone tissue and release calcium and other minerals from the bone into the blood. Many bone loss conditions are caused when the bone loss from osteoclast activity is more rapid than the rate of new bone tissue growth from osteoblasts.

Denosumab is a RANKL inhibitor, a monoclonal antibody that specifically binds to and inhibits receptor activator of nuclear factor kappa-B ligand (RANKL), a protein essential for the formation, function, and survival of osteoclasts. Denosumab prevents RANKL from binding to RANK receptors in the osteoclasts and activating the bone resorption process. This reduces the loss of bone and increases bone mass in patients at high risk for bone loss.

Denosumab is available in two brands, Prolia and Xgeva, and the two brands have different dosage strengths and are used for different indications. The uses of denosumab include:

Adults:

• Treatment of osteoporosis in the following conditions:
  • Postmenopausal women at high risk of fracture
  • Men at high risk of fracture
  • Men receiving androgen-deprivation therapy for nonmetastatic prostate cancer
  • Women receiving aromatase inhibitor therapy for breast cancer
  • Glucocorticoid-induced osteoporosis in men and women at high risk of fracture
• Prevention of skeletal-related events in patients with bone metastases from solid tumors
• Prevention of skeletal-related events in patients with multiple myeloma
• Treatment of hypercalcemia of malignancy refractory to bisphosphonate therapy
• Treatment of giant cell tumor of bone in adults and skeletally mature adolescents
• Treatment of bone destruction caused by rheumatoid arthritis (off-label)

• Do not administer to patients with hypersensitivity to any component in the denosumab formulation.
• Do not use denosumab to treat patients with pre-existing low blood calcium levels (hypocalcemia).
• Do not use denosumab to treat pregnant women:
  • Verify pregnancy status in women of pregnancy potential before initiating denosumab therapy.
  • Advise women of pregnancy potential to use effective contraception while on therapy and for at least 5 months following the last dose of denosumab.
  •  If denosumab is used during pregnancy or if the patient becomes pregnant while on denosumab therapy, apprise the patient of the potential hazard to the fetus.
• Two brands of denosumab are available, Prolia and Xgeva, and the two have different dosage strengths and are used for different indications. Do not interchange the brands or use concurrently.
• Serious hypersensitivity reactions have been reported. If hypersensitivity reactions develop, institute appropriate treatment and discontinue denosumab permanently.
• Denosumab can cause severe, symptomatic hypocalcemia:
  • Patients with a history of hypoparathyroidism, thyroid surgery, parathyroid surgery, malabsorption syndromes, excision of small intestine, or severe kidney function impairment are at a higher risk for hypocalcemia.
  • Correct pre-existing hypocalcemia before initiating denosumab and monitor levels of calcium and other minerals including magnesium and phosphorous.
  • Administer calcium, magnesium, and vitamin D as necessary and advise patients to report if they develop symptoms of hypocalcemia.
• Death of bone tissue in the jaw, or osteonecrosis of the jaw (ONJ), has been reported with denosumab therapy. Patients with high-risk factors for ONJ, such as invasive dental procedures, dental disease, poor oral hygiene, or cancer diagnosis, should have a dental examination and preventive dentistry before initiation of denosumab therapy.
• Atypical low-trauma femoral shaft fractures have been reported in patients receiving denosumab. Advise patients to report unusual hip, thigh, or groin pain and evaluate for femoral fracture. Consider interruption of therapy until a risk/benefit assessment can be made.
• Severe and occasionally incapacitating bone, joint, and/or muscle pain has been reported in some patients taking denosumab. Consider discontinuing therapy if the patient develops severe symptoms.
• Fracture risk, including multiple vertebral fractures, increases with discontinuation of denosumab. Consider alternative antiresorptive therapy if denosumab is discontinued.
• Denosumab therapy for postmenopausal osteoporosis resulted in significant suppression of bone remodeling. Long-term consequences of bone remodeling suppression may contribute to adverse outcomes such as osteonecrosis of the jaw, atypical fractures, and delayed fracture healing.
• Denosumab can cause skin reactions in some patients. Consider discontinuing the drug in case severe symptoms develop.
• Serious infections including skin, ear, abdomen, urinary tract, and heart’s inner lining (endocarditis), leading to hospitalization have been reported in clinical trials. Advise patients to seek medical care immediately if they develop signs of infection.

Common side effects of denosumab include:

Prolia

• Back pain
• Pain in the extremities
• Musculoskeletal pain
• Sciatica
• Bone pain
• Joint pain (arthralgia)
• Spinal osteoarthritis
• Muscle pain (myalgia)
• Weakness (asthenia)
• Upper respiratory tract infection
• Pneumonia
• Bladder infection and inflammation (cystitis)
• Upper abdominal pain
• Gastroesophageal reflux disease (GERD)
• Flatulence
• Throat inflammation (pharyngitis)
• Vertigo
• Insomnia
• Peripheral swelling (edema)
• Low red blood cell count (anemia)
• Chest pain related to coronary artery disease (angina)
• Rapid and irregular heart rhythm in the atria (atrial fibrillation)
• Rash
• Itching (pruritus)
• Herpes zoster
• Pancreas inflammation (pancreatitis)

Xgeva

• Fatigue
• Weakness (asthenia)
• Low blood phosphate levels (hypophosphatemia)
• Low blood calcium levels (hypocalcemia)
• Nausea
• Diarrhea
• Shortness of breath (dyspnea)
• Cough
• Headache

Serious side effects of denosumab include:

Prolia

• Serious abdominal infection requiring hospitalization
• Serious urinary tract infection requiring hospitalization
• Serious ear infection requiring hospitalization
• Serious infections resulting in death

Less common side effects of denosumab include:

Prolia

• Severe symptomatic hypocalcemia
• Severe musculoskeletal pain
• Multiple vertebral fractures after discontinuation of the drug
• Elevated parathyroid hormone in patients with severe renal impairment or on dialysis
• Blood vessel inflammation (vasculitis)
• Hair loss (alopecia)
• Hypersensitivity reactions including:
  • Rash
  • Hives (urticaria)
  • Redness (erythema)
  • Facial swelling
  • Severe allergic reaction (anaphylaxis)
• Drug reaction with eosinophilia and systemic symptoms (DRESS) syndrome

Xgeva

• Severe symptomatic hypocalcemia including fatality
• High blood calcium levels (hypercalcemia) following treatment discontinuation in patients with giant cell tumor of bone and patients with growing skeletons
• Musculoskeletal pain
• Atypical femur shaft fractures (subtrochanteric and diaphyseal fractures)
• Lichen planus-like (lichenoid) drug reactions
• Hypersensitivity reactions including anaphylactic reactions
• Recurrence of adverse effect after restarting drug (positive rechallenge)

Call your doctor immediately if you experience any of the following symptoms or serious side effects while using this drug:

• Serious heart symptoms include fast or pounding heartbeats, fluttering in your chest, shortness of breath, and sudden dizziness;
• Severe headache, confusion, slurred speech, severe weakness, vomiting, loss of coordination, feeling unsteady;
• Severe nervous system reaction with very stiff muscles, high fever, sweating, confusion, fast or uneven heartbeats, tremors, and feeling like you might pass out; or
• Serious eye symptoms include blurred vision, tunnel vision, eye pain or swelling, or seeing halos around lights.

This is not a complete list of all side effects or adverse reactions that may occur from the use of this drug. Call your doctor for medical advice about serious side effects or adverse reactions. You may also report side effects or health problems to the FDA at 1-800-FDA-1088.

Injectable Solution

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

Adult:

Osteoporosis

• Prolia only
• Indicated for postmenopausal women with osteoporosis at high risk for fracture (defined as history of osteoporotic fracture, or multiple risk factors for fracture; or patients who have failed or are intolerant to other available osteoporosis therapy)
• Indicated for treatment to increase bone mass in men with osteoporosis at high risk for fracture
• 60 mg subcutaneously (SC) every 6 months

Aromatase Inhibitor Induced Bone Loss

• Prolia only
• Indicated as a treatment to increase bone mass in women at high risk for fracture receiving adjuvant aromatase inhibitor therapy for breast cancer
• 60 mg SC every 6 months

Androgen Deprivation Induced Bone Loss

• Prolia only
• Indicated as a treatment to increase bone mass in men at high risk for fracture receiving androgen deprivation therapy for nonmetastatic prostate cancer
• 60 mg SC every 6 months

Glucocorticoid Induced Osteoporosis

• Prolia only
• Indicated for glucocorticoid-induced osteoporosis in men and women at high risk of fracture who are either initiating or continuing systemic glucocorticoids equivalent to 7.5 mg/day or more of prednisone and are expected to remain on glucocorticoids for at least 6 months
• 60 mg SC every 6 months

Skeletal-Related Events

• Xgeva only
• Prevention of skeletal-related events (SREs; e.g., bone fractures and pain) in patients with multiple myeloma and patients with bone metastases from solid tumors
• 120 mg SC every 4 weeks
• Administer calcium and vitamin D as necessary to treat or prevent hypocalcemia

Giant Cell Tumor

• Xgeva only
• 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
• 120 mg SC every 4 weeks
• Give 2 additional 120 mg doses during the first month of therapy on Days 8 and 15

Hypercalcemia of Malignancy

• Xgeva only
• Indicated for the treatment of hypercalcemia of malignancy refractory to bisphosphonate therapy
• 120 mg SC every 4 weeks
• Give 2 additional 120 mg doses during the first month of therapy on Days 8 and 15

Dosage Modifications

Hepatic impairment

• Safety and efficacy not evaluated

Renal impairment

• Mild-to-severe: No dosage adjustment necessary
• Severe (creatinine clearance (CrCl below 30 mL/min) or receiving dialysis: In clinical trial, patients were at greater risk of developing hypocalcemia

Dosing Considerations

• Prolia
• Patients receiving Prolia should not receive Xgeva
• All patients should receive calcium 1000 mg/day and at least 400 IU vitamin D daily

Pediatric:

Giant Cell Tumor

• Xgeva only
• 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
• Skeletal maturity is defined by at least 1 mature long bone (e.g., closed epiphyseal growth plate of the humerus)
• Children below 13 years or weight below 45 kg: Safety and efficacy not established
• Children 13-17 years (45 kg or above): 120 mg SC every 4 weeks; give 2 additional 120 mg doses during the first month of therapy on Days 8 and 15

Inform your doctor of all medications you are currently taking, who can advise you on any possible drug interactions. Never begin taking, suddenly discontinue, or change the dosage of any medication without your doctor’s recommendation.

• Denosumab has no known severe interactions with other drugs.
• Serious interactions of denosumab include:
  • axicabtagene ciloleucel
  • brexucabtagene autoleucel
  • ciltacabtagene autoleucel
  • idecabtagene vicleucel
  • influenza virus vaccine quadrivalent, adjuvanted
  • influenza virus vaccine trivalent, adjuvanted
  • lisocabtagene maraleucel
  • palifermin
  • tisagenlecleucel
• Denosumab has moderate interactions with at least 109 different drugs.
• Denosumab has no known mild interactions with other drugs.

The drug interactions listed above are not all of the possible interactions or adverse effects. For more information on drug interactions, visit the RxList Drug Interaction Checker.

It is important to always tell your doctor, pharmacist, or health care provider of all prescription and over-the-counter medications you use, as well as the dosage for each, and keep a list of the information. Check with your doctor or health care provider if you have any questions about the medication.

• There are no adequate and well-controlled studies on denosumab use in pregnant women. Animal studies indicate denosumab can cause fetal harm, including fetal loss and stillbirth, as well as absent lymph nodes, abnormal bone growth and reduced growth in the newborn, and neonatal mortality.
• Pregnancy status should be verified in women of pregnancy potential before initiating denosumab. Do not administer denosumab to pregnant women.
• Women of reproductive potential should use effective contraception during denosumab therapy and for at least 5 months after discontinuation.
• Inform your physician immediately if you become pregnant or suspect pregnancy while on denosumab therapy.
• Animal studies indicate denosumab use during pregnancy may impair mammary gland development and postpartum milk production.
• It is not known if denosumab is present in breast milk, however, many drugs are excreted in breast milk. The decision should be made to discontinue nursing or denosumab, taking into account the importance of the drug to the mother, because of the potential for serious adverse effects in the breastfed infant.
• Women who become pregnant during denosumab 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.

• While on denosumab therapy, contact your physician immediately if you:
  • Develop symptoms of low blood calcium levels such as muscle spasms, cramps, seizures, tingling and numbness around the mouth, face, hands, and feet
  • Experience unusual hip, thigh or groin pain
  • Experience severe skin reaction
  • Develop signs and symptoms of infection