Denosumab - Uses, Dosage, Side Effects, Interaction - Rxharun

Denosumab – Uses, Dosage, Side Effects, Interaction

Denosumab is a RANK ligand (RANKL) inhibitor used for the management of osteoporosis in patients at high risk for bone fractures. Denosumab is a novel, fully human IgG2 monoclonal antibody specific to receptor activator of nuclear factor kappa-B ligand (RANKL), suppresses bone resorption markers in patients with a variety of metastatic tumors and is being investigated in multiple clinical trials for the prevention and treatment of bone metastases. Chemically, it consists of 2 heavy and 2 light chains. Each light chain consists of 215 amino acids. Each heavy chain consists of 448 amino acids with 4 intramolecular disulfides. FDA approved on June 1, 2010.

Denosumab is a bone anti-resorptive drug used to treat osteoporosis and other bone-related disorders. FDA-approved indications include prevention of skeletal-related events (e.g., bone pain and fractures) secondary to multiple myeloma or bone metastases from solid tumors, giant cell tumors of the bone, hypercalcemia of malignancy, osteoporosis in postmenopausal women with osteoporosis at high risk for fracture as well as men with osteoporosis at high risk of fracture, glucocorticoid-induced osteoporosis, and bone loss. This activity reviews the mechanism of action, adverse event profile, toxicity, dosing, pharmacodynamics, and monitoring of denosumab pertinent for interprofessional team members when denosumab therapy is appropriate to achieve optimal patient outcomes.

Mechanism of action

Denosumab is designed to target RANKL (RANK ligand), a protein that acts as the primary signal to promote bone removal/resorption. In many bone loss conditions, RANKL overwhelms the body’s natural defense against bone destruction. Denosumab 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.

In clinical studies, treatment with 60 mg of Prolia resulted in a reduction in the bone resorption marker serum type 1 C-telopeptide (CTX) by approximately 85% by 3 days. 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 Prolia.

Indications

  • Prolia is indicated for the treatment of postmenopausal women with osteoporosis at high risk for fracture. It reduces the incidence of vertebral, nonvertebral, and hip fractures. Prolia is also indicated as a treatment to increase bone mass in women at high risk for fracture receiving adjuvant aromatase inhibitor therapy for breast cancer. It can also be used in men with osteoporosis at high risk for fracture or in men receiving androgen deprivation therapy for nonmetastatic prostate cancer to increase bone mass. Xgeva is indicated for the prevention of skeletal-related events in patients with bone metastases from solid tumors.
  • Bone Fractures
  • Bone Loss
  • Bone pain
  • Spinal Cord Compression
  • Bone destruction
  • Giant cell tumor of the bone
  • High risk of fracture Osteoporosis
  • Refractory Hypercalcemia of malignancy
  • Postmenopausal women
  • Men with osteoporosis
  • Men and women receiving daily glucocorticoids
  • Men receiving androgen deprivation therapy for nonmetastatic prostate cancer
  • Women receiving adjuvant aromatase inhibitor therapy for breast cancer

Use in Cancer

Denosumab is approved to treat:

Denosumab is approved to prevent:

  • Broken bones and other bone problems are caused by multiple myeloma or by solid tumors that have metastasized (spread) to the bone. This use is approved for the Xgeva brand of denosumab. Denosumab is also approved to increase bone mass in adults who have a high risk of breaking bones. It is used in the following types of cancer:

These uses are approved for the Prolia brand of denosumab. Denosumab is also being studied in the treatment of other conditions and types of cancer.

FDA-approved Indications

  • Prevention of skeletal-related events (e.g., bone pain and fractures) secondary to multiple myeloma or bone metastases from solid tumors. Used in conjunction with treatments for primary malignancy
  • Giant cell tumor of the bone. Indicated in adults and skeletally mature adolescents with an unresectable tumor or when surgical resection would likely cause severe morbidity.
  • Hypercalcemia of malignancy. This drug is indicated when hypercalcemia is refractory to bisphosphonate therapy.
  • Osteoporosis. Indicated as therapy for postmenopausal women with osteoporosis at high risk for fracture. Indications also include the treatment of men with osteoporosis at high risk of fracture. A high risk for fracture is defined as those with multiple risk factors for fracture, a known history of an osteoporotic fracture,  or those who have failed prior osteoporosis treatment (e.g., bisphosphonates).
  • Glucocorticoid-induced osteoporosis. Indicated for treatment in patients of both sexes at high risk for fracture who are initiating or continuing systemic glucocorticoids at a dose greater than or equal to 7.5 mg of prednisone daily for an expected duration of at least six months.
  • Bone loss. Indicated for treating androgen deprivation-induced bone loss and aromatase inhibitor-induced bone loss. The goal of therapy is to increase bone mass in men with prostate cancer receiving androgen deprivation therapy. In women, the treatment goal is to increase bone mass when receiving aromatase inhibitor therapy for breast cancer.

Contraindications

  • Anemia or
  • Blood clotting problems or
  • Cancer or
  • Dental disease, history of or
  • Dental implants, history of or
  • Dentures that do not fit well or
  • Diabetes or
  • Fractures, history of or
  • Gum disease or
  • Hypoparathyroidism (underactive parathyroid gland), history of or
  • Kidney problems, are severe and may require dialysis or
  • Malabsorption syndrome (trouble absorbing food), history of or
  • Mouth surgery, history of or
  • Parathyroid surgery, history of or
  • Thyroid surgery, history of or
  • Tooth extraction, history of—May cause side effects to become worse.
  • Ear infection or
  • Eczema (skin problem) or
  • Endocarditis (heart infection) or
  • Skin infections or
  • Skin rashes or
  • Stomach infection or
  • Urinary tract infection—Use with caution. This may make these conditions worse.
  • Hypocalcemia (low calcium in the blood)—Should not be given to patients with this condition.

Dosage

Strengths: 60 mg/mL; 120 mg/1.7 mL

Osteoporosis

  • 60 mg subcutaneously once every 6 months
  • Patients should be adequately supplemented with calcium and vitamin D, suggested as calcium 1000 mg/day and at least 400 IU vitamin D per day
  • Postmenopausal women at high risk for fracture include those with a history of osteoporotic fracture, or multiple risk factors for fracture; this drug reduces the incidence of vertebral, nonvertebral, and hip fractures.
  • Men with osteoporosis are at high risk for fracture including those with a history of osteoporotic fracture or multiple risk factors for fracture.
  • Men and women initiating or continuing systemic glucocorticoids at a prednisone equivalent dose of 7.5 mg or greater for 6 months or longer are at high risk of fracture, especially with a history of osteoporotic fracture or multiple risk factors for fracture.
  • Men at high risk for fracture receiving androgen deprivation therapy for nonmetastatic prostate cancer have shown a reduced incidence of vertebral fractures with this drug.

Giant Cell Tumor of Bone

  • First Month: 120 mg subcutaneously on day 1, day 8, and day 15
  • Maintenance dose: 120 mg subcutaneously every 4 week
  • Calcium and vitamin D should be administered to treat or prevent hypocalcemia.
  • For the treatment of patients with giant cell tumor of bone that is unresectable or where surgical resection is likely to result in severe morbidity

Osteolytic Bone Metastases of Solid Tumors

  •  120 mg subcutaneously every 4 weeks
  • Calcium and vitamin D should be administered to treat or prevent hypocalcemia.
  • For the prevention of skeletal-related events in patients with multiple myeloma and in patients with bone metastases from solid tumors

Hypercalcemia of Malignancy

  • First Month: 120 mg subcutaneously on day 1, day 8, and day 15
  • Maintenance dose: 120 mg subcutaneously every 4 weeks
  • For the treatment of hypercalcemia of malignancy refractory to bisphosphonate therapy.

Pediatric Dose for Giant Cell Tumor of Bone

13 years or older and having reached skeletal maturity:

  • First Month: 120 mg subcutaneously on day 1, day 8, and day 15
  • Maintenance dose: 120 mg subcutaneously every 4 weeks
  • Calcium and vitamin D should be administered to treat or prevent hypocalcemia.
  • In clinical trials, skeletal maturity was defined by at least 1 mature long bone (e.g., closed epiphyseal growth plate of the humerus) and a body weight of 45 kg or more.
  • For the treatment of skeletally mature adolescents with giant cell tumor of bone that is unresectable or where surgical resection is likely to result in severe morbidity.

Administration advice:

  • For subcutaneous administration only; do not administer IV, IM, or intradermally
  • Subcutaneous administration should be in the upper arm, upper thigh, or abdomen
  • This drug should be administered by a healthcare professional
  • Patients should receive 1 dose subcutaneously every 6 months
  • Patients should be receiving calcium 1000 mg/day and at least 400 IU vitamin D daily
  • Individuals sensitive to latex should not handle the gray needle cap as it contains dry natural rubber (a derivative of latex)
  • Missed dose: Administer as soon as convenient, thereafter, schedule injections 6 months from the date of the last injection

Side Effects

The Most Common

  • red, dry, or itchy skin
  • oozing or crusty blisters on the skin
  • peeling skin
  • back pain
  • pain in your arms
  • swelling of arms or legs
  • muscle or joint pain
  • nausea
  • diarrhea
  • constipation
  • abdominal pain
  • headache
  • muscle stiffness, twitching, cramps, or spasms
  • numbness or tingling in your fingers, toes, or around your mouth
  • hives, rash, itching, difficulty breathing or swallowing, swelling of the face, eyes, throat, tongue or lips,
  • fever or chills
  • redness, tenderness, swelling or warmth of area of skin
  • fever, cough, shortness of breath
  • ear drainage or severe ear pain
  • frequent or urgent need to urinate, burning feeling when you urinate
  • severe abdominal pain
  • painful or swollen gums, loosening of the teeth, numbness or heavy feeling in the jaw, poor healing of the jaw
  • unusual bleeding or bruising
  • nausea, vomiting, headache, and decreased alertness after stopping denosumab and for up to 1 year afterward

More Common

  • Back pain
  • blistering, crusting, irritation, itching, or reddening of the skin
  • bloody or cloudy urine
  • cracked, dry, or scaly skin
  • difficult, burning, or painful urination
  • frequent urge to urinate
  • muscle or bone pain
  • pain in the arms or legs
  • rash
  • skin rash, encrusted, scaly, and oozing
  • swelling
  • Arm or jaw pain
  • bloating or swelling of the face, arms, hands, lower legs, or feet
  • body aches or pain
  • chest pain or discomfort
  • chest tightness or heaviness
  • chills
  • confusion
  • congestion
  • cough
  • difficulty with breathing
  • difficulty with moving
  • dryness or soreness of the throat
  • ear congestion
  • fast or irregular heartbeat
  • fever
  • headache
  • hoarseness
  • joint pain
  • loss of voice
  • muscle cramps in the hands, arms, feet, legs, or face
  • muscle stiffness
  • numbness and tingling around the mouth, fingertips, hands, or feet
  • pain in the lower back, bottom, upper leg, or hips
  • painful blisters on the trunk of the body
  • pale skin
  • rapid weight gain
  • runny or stuffy nose
  • seizures
  • sneezing
  • stomach cramps
  • swollen joints
  • tender, swollen glands in the neck
  • tremor
  • trouble swallowing
  • troubled breathing with exertion
  • unusual bleeding or bruising
  • unusual tiredness or weakness
  • unusual weight gain or loss
  • voice changes

Rare

  • Blood in the stool
  • change in bowel habits
  • clear or bloody discharge from the nipple
  • constipation
  • darkened urine
  • difficulty with eating
  • dimpling of the breast skin
  • indigestion
  • inverted nipple
  • itching, pain, redness, swelling, tenderness, or warmth on the skin
  • loss of appetite
  • lower back or side pain
  • lump in the breast or under the arm
  • lump or swelling in the abdomen or stomach
  • nausea
  • pains in the stomach, side, or abdomen, possibly radiating to the back
  • persistent crusting or scaling of the nipple
  • raised, firm, and bright red patches of the skin on the arm or leg
  • redness or swelling of the breast
  • sore on the skin of the breast that does not heal
  • stomach discomfort
  • unexplained weight loss
  • vomiting
  • yellow eyes or skin
  • Heavy feeling in the jaw
  • loose teeth
  • pain, swelling, or numbness in the mouth or jaw

Drug interaction

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Pregnancy and Lactation

FDA Pregnancy Category C

Pregnancy

There are no adequate and well-controlled studies of Prolia in pregnant women. In genetically engineered mice in which RANK ligand (RANKL) was turned off by gene removal (a “knockout mouse”), the absence of RANKL (the target of denosumab) caused fetal lymph node agenesis and led to postnatal impairment of dentition and bone growth. Pregnant RANKL knockout mice also showed altered maturation of the maternal mammary gland, leading to impaired lactation postpartum. Prolia should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Women who become pregnant during Prolia treatment are encouraged to enroll in Amgen’s Pregnancy Surveillance Program. In an embryofetal developmental study, cynomolgus monkeys received subcutaneous denosumab weekly
during organogenesis at doses up to 13-fold higher than the recommended human dose of 60 mg administered once every 6 months based on body weight (mg/kg). No evidence of maternal toxicity or fetal harm was observed. However, this study only assessed fetal toxicity during a period equivalent to the first trimester, and fetal lymph nodes were not examined. Monoclonal antibodies are transported
across the placenta in a linear fashion as pregnancy progresses, with the largest amount transferred during the third trimester. Potential adverse developmental effects resulting from exposures during the second and third trimesters have not been assessed in animals

Lactation

It is not known whether Prolia is excreted into human milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from Prolia, 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 Prolia 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

How should this medicine be used?

Denosumab injection comes as a solution (liquid) to be injected subcutaneously (under the skin) in your upper arm, upper thigh, or stomach area. It is usually injected by a doctor or nurse in a medical office or clinic. Denosumab injection (Prolia) is usually given once every 6 months. When denosumab injection (Xgeva) is used to reduce the risk of fractures from multiple myeloma, or cancer that has spread to the bones, it is usually given once every 4 weeks. When denosumab injection (Xgeva) is used to treat giant cell tumor of bone, or high calcium levels caused by cancer, it is usually given every 7 days for the first three doses (on day 1, day 8, and day 15) and then once every 4 weeks starting 2 weeks after the first three doses.

Your doctor will tell you to take supplements of calcium and vitamin D while you are being treated with denosumab injection. Take these supplements exactly as directed.

When denosumab injection (Prolia) is used to treat osteoporosis or bone loss, your doctor or pharmacist will give you the manufacturer’s patient information sheet (Medication Guide) when you begin treatment with denosumab injection and each time you refill your prescription. Read the information carefully and ask your doctor or pharmacist if you have any questions. You can also visit the Food and Drug Administration (FDA) website (http://www.fda.gov/Drugs/DrugSafety/ucm085729.htm) or the manufacturer’s website to obtain the Medication Guide.

What special precautions should I follow?

Before receiving a denosumab injection,

  • tell your doctor and pharmacist if you are allergic to denosumab (Prolia, Xgeva), any other medications, latex, or any of the ingredients in denosumab injection. Ask your pharmacist or check the Medication Guide for a list of the ingredients.
  • you should know that denosumab injection is available under the brand names Prolia and Xgeva. You should not receive more than one product containing denosumab at the same time. Be sure to tell your doctor if you are being treated with either of these medications.
  • tell your doctor and pharmacist what other prescription and nonprescription medications, vitamins, nutritional supplements, and herbal products you are taking or plan to take. Be sure to mention any of the following: angiogenesis inhibitors such as axitinib (Inlyta), bevacizumab (Avastin), everolimus (Afinitor, Zortress), pazopanib (Votrient), sorafenib (Nexavar), or sunitinib (Sutent); bisphosphonates such as alendronate (Binosto, Fosamax), etidronate, ibandronate (Boniva), pamidronate, risedronate (Actonel, Atelvia), zoledronic acid (Reclast); cancer chemotherapy medications; medications that suppress the immune system such as azathioprine (Azasan, Imuran), cyclosporine (Gengraf, Neoral, Sandimmune), methotrexate (Otrexup, Rasuvo, Trexall, Xatmep), sirolimus (Rapamune), and tacrolimus (Astagraf XL, Envarsus, Prograf); steroids such as dexamethasone, methylprednisolone (A-Methapred, Depo-Medrol, Medrol, Solu-Medrol), and prednisone (Rayos); or medications used to lower your calcium levels, such as cinacalcet (Sensipar). Your doctor may need to change the doses of your medications or monitor you carefully for side effects.
  • tell your doctor if you have or have ever had a low level of calcium in your blood. Your doctor will probably check the level of calcium in your blood before you begin treatment and will probably tell you not to receive denosumab injection if the level is too low.
  • tell your doctor if you are receiving dialysis treatments or if you have or have ever had anemia (a condition in which the red blood cells do not bring enough oxygen to all the parts of the body); cancer; any type of infection, especially in your mouth; problems with your mouth, teeth, gums, or dentures; dental or oral surgery (teeth removed, dental implants); any condition that stops your blood from clotting normally; any condition that decreases the functioning of your immune system; surgery on your thyroid gland or parathyroid gland (a small gland in the neck); surgery to remove part of your small intestine; problems with your stomach or intestine that make it difficult for your body to absorb nutrients; polymyalgia rheumatic (disorder that causes muscle pain and weakness); diabetes, or parathyroid or kidney disease.
  • tell your doctor if you are pregnant, plan to become pregnant, or are breastfeeding. You will need to have a negative pregnancy test before starting treatment with a denosumab injection. You should not become pregnant while you are receiving a denosumab injection. You should use a reliable method of birth control to prevent pregnancy while you are receiving a denosumab injection and for at least 5 months after your final treatment. If you become pregnant while receiving a denosumab injection, or within 5 months of your treatment, call your doctor immediately. Denosumab may harm the fetus.
  • you should know that denosumab injection may cause osteonecrosis of the jaw (ONJ, a serious condition of the jaw bone), especially if you have dental surgery or treatment while you are receiving this medication. A dentist should examine your teeth and perform any needed treatments, including cleaning or fixing ill-fitted dentures, before you start to receive a denosumab injection. Be sure to brush your teeth and clean your mouth properly while you are receiving a denosumab injection. Talk to your doctor before having any dental treatments while you are receiving this medication.

References

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