Drug Formulary information is intended for use by healthcare professionals. It is not intended to be medical advice. Some of the information, including information about funding for cancer drugs, does not apply to all patients. Cancer treatment plans are unique to each patient. If you are a patient, please speak with your healthcare team to understand how this information applies to you.
denosumab
Denosumab is a fully human IgG2 monoclonal antibody, which targets the human receptor activator of nuclear factor kappa-B ligand (RANKL). Denosumab inhibits osteoclast formation, function, survival, and thus reduces bone resorption.
Drug exposure is approximately dose-proportional for doses of 60mg or higher. Steady state is reached on or after 6 doses of 120mg q4 weeks. Pharmacokinetics do not change with age, weight, race, time or multiple dosing.
| Bioavailability | SC: 62% |
Volume of distribution and clearance were observed to be proportional to body weight.
Likely via immunoglobulin clearance pathways and not metabolized or eliminated hepatically
Clearance is believed to occur via the reticuloendothelial system.
| Urine | Not likely |
| Feces | Not likely |
| Half-life | 28 days (mean half-life, 120mg q4 week dosing) |
- for reducing the risk of developing skeletal-related events in patients with multiple myeloma and in patients with bone metastases from breast cancer, prostate cancer, non-small cell lung cancer, and other solid tumours
- for the treatment of hypercalcemia of malignancy refractory to intravenous bisphosphonate
- treatment of adults and skeletally mature adolescents with giant cell tumour of bone (GCTB) that is unresectable or where surgical resection is likely to result in severe morbidity
Emetogenic Potential:
Extravasation Potential: None
The following side effects are listed irrespective of causality from randomized controlled trials of 120 mg in cancer patients with bone metastases, usually in combination with systemic anticancer therapy.
| ORGAN SITE | SIDE EFFECT* (%) | ONSET** | |||
|---|---|---|---|---|---|
| Cardiovascular | Arrhythmia (2%) | E | |||
| Arterial thromboembolism (<1%) | E | ||||
| Cardiotoxicity (2%) | D | ||||
| Hypertension (5%) | E | ||||
| Hypotension (3%) | E | ||||
| Venous thromboembolism (2%) | E | ||||
| Dental | Pain (4%) | E | |||
| Dermatological | Hand-foot syndrome (4%) | E | |||
| Nail disorder (2%) | E | ||||
| Rash (7%) | E | ||||
| Gastrointestinal | Abdominal pain (10%) | E | |||
| Anorexia, weight loss (23%) | E | ||||
| Constipation (21%) | E | ||||
| Diarrhea (20%) | E | ||||
| Dyspepsia (5%) | E | ||||
| Mucositis (5%) | E | ||||
| Nausea, vomiting (31%) | I | ||||
| General | Fatigue (27%) | E | |||
| Fever (14%) | I E | ||||
| Hematological | Anemia (27%) | E | |||
| Myelosuppression (10%) | E | ||||
| Hepatobiliary | Hepatic failure (<1%) | D | |||
| ↑ LFTs (3%) | E | ||||
| Hypersensitivity | Hypersensitivity (rare) | I | |||
| Infection | Infection (8%) (including cellulitis) | E | |||
| Metabolic / Endocrine | Abnormal electrolyte(s) (5%) (not including calcium, PO4 changes) | E | |||
| ↓ Ca (10%) (severe 3%) | E D | ||||
| ↑ Ca (rarely severe, observed after treatment ends in patients with GCTB or growing skeletons) | E | ||||
| Hyperglycemia (4%) | E | ||||
| Hypoglycemia (1%) | E | ||||
| ↓ PO4 (15%) (severe) | E | ||||
| Musculoskeletal | Fracture (6%) (including atypical femoral fractures and multiple post-treatment vertebral fractures) | D | |||
| Musculoskeletal pain (25%) (may be severe) | E | ||||
| Osteonecrosis of jaw (2%) | D | ||||
| Neoplastic | Secondary malignancy (1%) | D L | |||
| Nervous System | Anxiety (7%) | E | |||
| Cognitive disturbance (3%) | E | ||||
| Depression (7%) | E | ||||
| Dizziness (8%) | E | ||||
| Dysgeusia (4%) | E | ||||
| Headache (13%) | E | ||||
| Paresthesia (6%) | E | ||||
| Ophthalmic | Eye disorders (2% - lacrimation, conjunctivitis, blurred vision) | E | |||
| Renal | Creatinine increased (4%) | E | |||
| Renal failure (3%) | E | ||||
| Respiratory | Cough, dyspnea (21%) | E | |||
* "Incidence" may refer to an absolute value or the higher value from a reported range.
"Rare"
may refer to events with < 1% incidence, reported in post-marketing, phase 1 studies,
isolated data or anecdotal
reports.
Dose-limiting side effects are underlined.
** I = immediate (onset in hours to days)
E = early (days to weeks)
D = delayed (weeks to months)
L = late (months to years)
The most common side effects for denosumab in bone metastases include nausea/vomiting, fatigue and hypophosphatemia.
Denosumab may cause severe hypocalcemia (fatal in rare cases). The risk is increased with renal impairment and may be accompanied by elevated parathyroid hormone levels. Patients (except those with hypercalcemia) should receive calcium, vitamin D and magnesium supplements (as indicated) while on denosumab treatment. (See Dosing section).
Worsening hypercalcemia has been reported when denosumab is used to treat hypercalcemia and has also been reported in patients with GCTB or growing skeletons, weeks to months following denosumab discontinuation.
Atypical fractures of the femur (subtrochanteric or diaphyseal) have been reported. They are often bilateral, occur with minimal or no trauma, with symptoms including thigh or groin pain. Imaging features of stress features may be seen weeks to months before presentation with a completed femoral fracture. These fractures have also been reported in patients with certain conditions such as vitamin D deficiency, rheumatoid arthritis, hypophosphatasia and with/without use of certain medications (e.g. antiresorptive therapy, glucocorticoids, proton pump inhibitors).
Multiple vertebral fractures following denosumab discontinuation were reported in post-marketing. These were not due to bone metastases and particularly occurred in patients with risk factors such as osteoporosis or prior fractures.
Binding antibodies to denosumab have been reported in < 1% of patients who had up to 3 years of treatment, but neutralizing antibodies have not been reported. The clinical relevance is limited.
A higher rate of cellulitis has been observed in patients on denosumab.
(Continued on next page)
Osteonecrosis of the jaw (ONJ) is a common cause of denosumab discontinuation in clinical trials. The incidence of ONJ was observed to be higher with longer duration of exposure (1% with <12 months versus 4% in the second year, and 5% per year thereafter). Median onset in prostate or breast cancer patients was 20.6 months. Poor oral hygiene, invasive dental procedures, treatment with anti-angiogenic drugs, local gum or oral infection were risk factors for ONJ. Other risk factors include infections, older age, concomitant treatments (e.g., chemotherapy, corticosteroids, head and neck radiotherapy), smoking and previous bisphosphonate treatment. ONJ has also been reported after the end of treatment, with a majority of cases occurring 5 months after the last dose. Dental evaluation is recommended prior to starting treatment and during therapy, but invasive dental procedures should be avoided during treatment.
Refer to protocol by which patient is being treated. Pre-existing hypocalcemia must be corrected prior to starting treatment. Patients being treated with denosumab should not be treated concomitantly with bisphosphonates.
All patients, except those with hypercalcemia, should receive the following supplementation:
- at least 500mg of calcium daily
- at least 400 IU of vitamin D daily
Myeloma and bone metastases from cancer:
Subcutaneous: 120 mg every 4 weeks
Hypercalcemia of malignancy and Giant cell tumour of bone:
Subcutaneous: 120 mg Days 1, 8 and 15 of month 1 (loading dose), THEN
| Toxicity | Action |
| Grade 3 or 4 drug-related toxicity | Consider holding or discontinuing |
| Osteonecrosis of the jaw | Follow guidelines for management. Consider holding or discontinuing treatment. Refer patient to dentist or oral surgeon. |
| Hypocalcemia | Treat appropriately. Consider holding or discontinuing treatment if severe. |
| Anaphylaxis or significant hypersensitivity | Treat appropriately. Discontinue denosumab permanently. |
No studies have been conducted in patients with hepatic impairment.
No dose adjustment is required with renal impairment. Patients with renal impairment are at increased risk of severe life threatening hypocalcemia and require increased monitoring (refer to monitoring section)
No adjustment required. No overall differences in safety and efficacy.
May impair bone growth and tooth eruption in pediatric patients. Safety and efficacy have not been established and therefore not indicated in pediatric patients, except in skeletally mature adolescents (aged 13-17 years) with giant cell tumour of bone. Severe hypercalcemia has been reported in patients with growing skeletons, weeks to months following denosumab discontinuation
- Inject subcutaneously in the upper arm, upper thigh, or the abdomen.
- Should not be administered intravenously, intramuscularly or intradermally
- Use a 27-gauge needle to withdraw or inject the drug. Avoid vigorous shaking of the drug.
- Denosumab should appear clear, colourless to slightly yellow. It may contain trace amounts of translucent or white proteinaceous particles. Do not use if the solution is discoloured, cloudy, contains many particles or foreign matter.
- If a dose is missed, it may be given as soon as possible and the subsequent injection should be scheduled q4 weeks from the most recent injection date.
- Keep refrigerated in the original carton between 2-8°C. Protect from direct light
- Before use, the drug vial (in its original container) can be brought to room temperature (usually takes 15-30 minutes). Do not warm the drug by other methods. Once removed from the refrigerator, it must be stored at room temperature (≤ 25°C) and used within 30 days.
- Patients who have a hypersensitivity to this drug or any of its components
- Do not use Xgeva® with Prolia®, as both products contain the same active ingredient, denosumab.
- Pre-existing hypocalcemia must be corrected before starting denosumab treatment. Risk of hypocalcemia is greater in patients with moderate to severe renal impairment. Patients, except those with hypercalcemia, should receive adequate calcium and vitamin D supplementation (see Dosing section).
- Patients being treated with denosumab should not be treated concomitantly with bisphosphonates
- Risk-benefit should be assessed for patients with risk factors for ONJ before starting treatment.
Other Drug Properties:
-
Carcinogenicity:
No
-
Immunosuppressive:
No
-
Genotoxicity:
Unlikely
-
Fertility effects:
No
-
Lactation:
Not recommended
Denosumab may impair lactation. Although it is unknown whether denosumab excretes into breast milk, mammary gland development and lactation were impaired in animals lacking RANKL. Women who are nursing during denosumab treatment are encouraged to enroll in the manufacturer’s Lactation Surveillance Program. -
Fetotoxicity:
Yes
Denosumab is not recommended for use in pregnancy; impaired bone or teeth development have been observed in young animals. Adequate contraception should be used by both sexes during treatment, at for at least 5 months after the last denosumab dose. Women who become pregnant during denosumab treatment are encouraged to enroll in the manufacturer's Pregnancy Surveillance Program.
No formal drug-drug interaction studies have been documented.
| AGENT | EFFECT | MECHANISM | MANAGEMENT |
|---|---|---|---|
| Drugs that may cause hypocalcemia (e.g. anticonvulsants - phenytoin, phenobarbital; foscarnet) | ↑ risk of hypocalcemia | Additive | Caution; monitor calcium levels closely |
Treating physicians may decide to monitor more or less frequently for individual patients but should always consider recommendations from the product monograph.
| Monitor Type | Monitor Frequency |
|---|---|
Calcium, phosphate, magnesium |
No hypercalcemia: baseline, within 2 weeks of the first dose, and as clinically indicated. Hypercalcemia: baseline, before each dose and as clinically indicated. Additional monitoring with renal dysfunction, symptoms of hypercalcemia, and after denosumab discontinuation especially in patients with growing skeletons. |
Dental examination with appropriate preventative dentistry should be considered prior to treatment. Regular dental check-ups. Avoid invasive dental surgeries while on treatment. |
Baseline and regular |
Clinical toxicity assessment for fatigue, musculoskeletal effects, hypocalcemia, ONJ, cough/dyspnea |
At each visit |
Vertebral fractures |
Evaluate patient’s risk after treatment discontinuation |
Grade toxicity using the current NCI-CTCAE (Common Terminology Criteria for Adverse Events) version
Exceptional Access Program (EAP Website)
- denosumab - Bony metastases in hormone refractory prostate cancer, with specific criteria ()
- Denosumab - Hormone Refractory Prostate Cancer
McEvoy GK, editor. AHFS Drug Information 2011. Bethesda, Maryland: American Society of Health-System Pharmacists; 2011. Denosumab; p. 2676-8, and Foscarnet; p. 873.
Muir VJ, Scott LJ. Denosumab: in cancer treatment-induced bone loss. BioDrugs 2010; 24(6): 379-86.
DILANTIN® (phenytoin) product monograph. Pfizer Canada Inc.; 29 July 2010.
PROLIA® (denosumab) product monograph. Amgen Inc. (US); September 2011.
XGEVA® (denosumab) product monograph. Amgen Canada Inc.; April 2018.
July 2018 updated adverse effects (multiple vertebrae fractures, severe hypercalcemia), monitoring section, added dosing for giant cell tumour of bone
Refer to the New Drug Funding Program or Ontario Public Drug Programs websites for the most up-to-date public funding information.
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