Denosumab

Treatment of osteoporosis in postmenopausal women and in men at increased risk of fractures. In postmenopausal women Kefdensis significantly reduces the risk of vertebral, non-vertebral and hip fractures. 1). In men with prostate cancer receiving hormone ablation, Kefdensis significantly reduces the risk of vertebral fractures.

1).

Posology The recommended dose is 60 mg denosumab administered as a single subcutaneous injection once every 6 months into the thigh, abdomen or upper arm. 4). Patients treated with Kefdensis should be given the package leaflet and they should be provided with the patient reminder card.

The optimal total duration of antiresorptive treatment for osteoporosis (including both denosumab and bisphosphonates) has not been established. 4). Elderly (age ≥ 65) No dose adjustment is required in elderly patients. 4 for recommendations relating to monitoring of calcium).

No data is available in patients with long-term systemic glucocorticoid therapy and severe renal impairment (Glomerular filtration rate, GFR < 30 mL/min). 2). 3). 2. Method of administration For subcutaneous use. Administration should be performed by an individual who has been adequately trained in injection techniques.

6.

Summary of the safety profile The most common side effects with denosumab (seen in more than one patient in ten) are musculoskeletal pain and pain in the extremity. 8 - description of selected adverse reactions) have been observed in patients taking denosumab.

Tabulated list of adverse reactions The data in table 1 below describe adverse reactions reported from phase II and III clinical trials in patients with osteoporosis and breast or prostate cancer patients receiving hormone ablation; and/or spontaneous reporting.

The following convention has been used for the classification of the adverse reactions (see table 1): very common (≥ 1/10), common (≥ 1/100 to < 1/10), uncommon (≥ 1/1 000 to < 1/100), rare (≥ 1/10 000 to < 1/1 000), very rare (< 1/10 000) and not known (cannot be estimated from the available data).

Within each frequency grouping and system organ class, adverse reactions are presented in order of decreasing seriousness. Table 1. Adverse reactions reported in patients with osteoporosis and breast or prostate cancer patients receiving hormone ablation MedDRA system organ class Frequency category Adverse reactions Common Urinary tract infection Common Upper respiratory tract infection Uncommon Diverticulitis1 Uncommon Cellulitis1 Infections and infestations Uncommon Ear infection Rare Drug hypersensitivity1 Immune system disorders Rare Anaphylactic reaction1 Metabolism and nutrition disorders Rare Hypocalcaemia1 Nervous system disorders Common Sciatica Common ConstipationGastrointestinal disorders Common Abdominal discomfort Common Rash Common Eczema Common Alopecia Uncommon Lichenoid drug eruptions1 Skin and subcutaneous tissue disorders Very rare Hypersensitivity vasculitis Very common Pain in extremity Very common Musculoskeletal pain1 Rare Osteonecrosis of the jaw1 Rare Atypical femoral fractures1 Musculoskeletal and connective tissue disorders Not Known Osteonecrosis of the external auditory canal2 1 See section Description of selected adverse reactions.

4. 7% for placebo. Although this imbalance was identified via a pooled analysis, it was not identified via a stratified analysis. 88 mmol/L) following denosumab administration. 88 mmol/L) were not reported in either the two phase III placebo-controlled clinical trials in patients receiving hormone ablation or the phase III placebo-controlled clinical trial in men with osteoporosis.

In the post-marketing setting, rare cases of severe symptomatic hypocalcaemia resulting in hospitalisation, life-threatening events, and fatal cases have been reported, predominantly in patients at increased risk of hypocalcaemia receiving denosumab, with most cases occurring in the first weeks of initiating therapy.

4). Symptoms of hypocalcaemia in denosumab clinical studies included paraesthesias or muscle stiffness, twitching, spasms and muscle cramps. 4%, 12 out of 860]). 4% (16 out of 4 050) of women receiving denosumab. These cases were predominantly cellulitis.

6%, 5 out of 860) groups in the breast and prostate cancer studies. 4). Thirteen of these ONJ cases occurred in postmenopausal women with osteoporosis during the phase III clinical trial extension following treatment with denosumab for up to 10 years.

44% at 10 years of denosumab treatment. The risk of ONJ increased with duration of exposure to denosumab. The risk of ONJ has also been assessed in a retrospective cohort study among 76 192 postmenopausal women newly initiating treatment with denosumab.

65) among patients using denosumab up to 5 years of follow-up. 4). 2% denosumab, 0% placebo). The incidence of […]

1. 4).

1). Treatment of adults and skeletally mature adolescents with giant cell tumour of bone that is unresectable or where surgical resection is likely to result in severe morbidity.

Jubereq should be administered under the responsibility of a healthcare professional. 4). Patients treated with Jubereq should be given the package leaflet and the patient reminder card. Prevention of skeletal related events in adults with advanced malignancies involving bone The recommended dose is 120 mg administered as a single subcutaneous injection once every 4 weeks into the thigh, abdomen or upper arm.

Giant cell tumour of bone 3 The recommended dose of Jubereq is 120 mg administered as a single subcutaneous injection once every 4 weeks into the thigh, abdomen or upper arm with additional 120 mg doses on days 8 and 15 of treatment of the first month of therapy.

Patients in the phase II study who underwent complete resection of giant cell tumour of bone did receive an additional 6 months of treatment following the surgery as per study protocol. Patients with giant cell tumour of bone should be evaluated at regular intervals to determine whether they continue to benefit from treatment.

In patients whose disease is controlled by denosumab, the effect of interruption or cessation of treatment has not been evaluated, however limited data in these patients does not indicate a rebound effect upon cessation of treatment.

2). 2). 2). Paediatric population The safety and efficacy of denosumab have not been established in paediatric patients (age < 18) other than skeletally mature adolescents (aged 12-17 years) with giant cell tumour of bone. 4). Treatment of skeletally mature adolescents with giant cell tumour of bone that is unresectable or where surgical resection is likely to result in severe morbidity: the posology is the same as in adults.

3). Method of administration For subcutaneous use. 7 mL vial should only be performed by a healthcare professional. 6.

Summary of the safety profile Overall safety profile is consistent in all approved indications for denosumab. 7 Hypocalcaemia has very commonly been reported following denosumab administration, mostly within the first 2 weeks. 8 - description of selected adverse reactions).

The decreases in serum calcium were generally appropriately managed by calcium and vitamin D supplementation. The most common adverse reactions with denosumab are musculoskeletal pain. 8 - description of selected adverse reactions) have been commonly observed in patients taking denosumab.

Tabulated list of adverse reactions The following convention has been used for the classification of the adverse reactions based on incidence rates in four phase III, two phase II clinical studies and post-marketing experience (see table 1): very common (≥ 1/10), common (≥ 1/100 to < 1/10), uncommon (≥ 1/1,000 to < 1/100), rare (≥ 1/10,000 to < 1/1,000), very rare (< 1/10,000) and not known (cannot be estimated from the available data.

Within each frequency grouping and system organ class, adverse reactions are presented in order of decreasing seriousness. Table 1. 4 4 Class effect Description of selected adverse reactions Hypocalcaemia A higher incidence of hypocalcaemia among subjects treated with denosumab compared to zoledronic acid has been observed in SRE prevention clinical trials.

The highest incidence of hypocalcaemia was observed in a phase III trial in patients with multiple myeloma. 4% of patients treated with zoledronic acid. 6% of patients treated with zoledronic acid. 1% of patients treated with zoledronic acid.

0% of patients treated with zoledronic acid. 2% of patients treated with zoledronic acid. 4). 7% of patients. None of the adverse events was considered serious. In the post-marketing setting, severe symptomatic hypocalcaemia (including fatal cases) has been reported, with most cases occurring in the first weeks of initiating therapy.

4). Symptoms of hypocalcaemia in clinical studies included paraesthesias or muscle stiffness, twitching, spasms and muscle cramps. Osteonecrosis of the jaw (ONJ) In clinical trials, the incidence of ONJ was higher with longer duration of exposure; ONJ has also been diagnosed after stopping treatment with denosumab with the majority of cases occurring within 5 months after the last dose.

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 the clinical trials.

A higher incidence of ONJ among subjects treated with denosumab compared to zoledronic acid has been observed in SRE prevention clinical trials. The highest incidence of ONJ was observed in a phase III trial in patients with multiple myeloma.

2% of patients treated with zoledronic acid. 5 thereafter. 7 months (range: 1 - 44). 3% of patients treated with zoledronic […]

1. 4). Unhealed lesions from dental or oral surgery.

3 Pediatrics 03/2022 XX/XXXX TABLE OF CONTENTS Sections or subsections that are not applicable at the time of authorization are not listed. RECENT MAJOR LABEL CHANGES .........................................................................................

2 TABLE OF CONTENTS ............................................................................................................... 2 PART I: HEALTH PROFESSIONAL INFORMATION .................................................................

4 1 INDICATIONS ..................................................................................................................... 1 Pediatrics ....................................................................................................................

2 Geriatrics .................................................................................................................... 5 2 CONTRAINDICATIONS ......................................................................................................

5 4 DOSAGE AND ADMINISTRATION .................................................................................... 1 Dosing Considerations ...............................................................................................

2 Recommended Dose and Dosage Adjustment .......................................................... 3 Reconstitution ............................................................................................................. 4 Administration .............................................................................................................

5 Missed Dose ............................................................................................................... 6 5 OVERDOSAGE ...................................................................................................................

6 6 DOSAGE FORMS, STRENGTHS, COMPOSITION AND PACKAGING ............................ 6 7 WARNINGS AND PRECAUTIONS ..................................................................................... 1 Special Populations ..................................................................................................

1 Pregnant Women ..................................................................................................... 2 Breast-feeding ..........................................................................................................

3 Pediatrics .................................................................................................................. 4 Geriatrics ..................................................................................................................

12 PROLIA (denosumab injection) Page 3 of 81 8 ADVERSE REACTIONS ................................................................................................... 1 Adverse Reaction Overview .....................................................................................

2 Clinical Trial Adverse Reactions ............................................................................... 3 Less Common Clinical Trial Adverse Reactions (< 1%) ........................................... 4 Abnormal Laboratory Findings: Hematologic, Clinical Chemistry and Other Quantitative Data ......................................................................................................

5 Postmarket Adverse Reactions ................................................................................ 45 9 DRUG INTERACTIONS ....................................................................................................

1 Serious Drug Interactions ......................................................................................... 2 Drug interactions Overview ......................................................................................

3 Drug-Behavioural Interactions .................................................................................. 4 Drug-Drug Interactions .............................................................................................

5 Drug-Food Interactions ............................................................................................. 6 Drug-Herb Interactions .............................................................................................

7 Drug-Laboratory Test Interactions ............................................................................ 46 10 CLINICAL PHARMACOLOGY .......................................................................................... 1 Mechanism of Action ................................................................................................

2 Pharmacodynamics .................................................................................................. 3 Pharmacokinetics .....................................................................................................

48 11 STORAGE, STABILITY AND DISPOSAL ........................................................................ 50 12 SPECIAL HANDLING INSTRUCTIONS ........................................................................... 50 PART II: SCIENTIFIC INFORMATION ......................................................................................

51 13 PHARMACEUTICAL INFORMATION .............................................................................. 51 14 CLINICAL TRIALS […]

3 Pediatrics 03/2022 XX/XXXX TABLE OF CONTENTS Sections or subsections that are not applicable at the time of authorization are not listed. RECENT MAJOR LABEL CHANGES .........................................................................................

2 TABLE OF CONTENTS ............................................................................................................... 2 PART I: HEALTH PROFESSIONAL INFORMATION .................................................................

4 1 INDICATIONS ..................................................................................................................... 1 Pediatrics ....................................................................................................................

2 Geriatrics .................................................................................................................... 5 2 CONTRAINDICATIONS ......................................................................................................

5 4 DOSAGE AND ADMINISTRATION .................................................................................... 1 Dosing Considerations ...............................................................................................

2 Recommended Dose and Dosage Adjustment .......................................................... 3 Reconstitution ............................................................................................................. 4 Administration .............................................................................................................

5 Missed Dose ............................................................................................................... 6 5 OVERDOSAGE ...................................................................................................................

6

, Postmarket Adverse Drug Reactions). • Hypocalcemia (see 7 WARNINGS AND PRECAUTIONS, Endocrine and Metabolism, Hypocalcemia) • Female patients who are pregnant or who are trying to become pregnant. PROLIA may cause fetal harm when administered to a pregnant woman.

In women of reproductive potential, pregnancy testing should be performed prior to initiating treatment with PROLIA. 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.

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 7 WARNINGS AND PRECAUTIONS, Special Populations, Pregnant Women).

1 Dosing Considerations PROLIA is intended for use under the guidance and supervision of physicians who have fully familiarized themselves with the efficacy/safety profile of PROLIA. After an initial training in proper subcutaneous injection technique, patients may self-inject PROLIA if a physician determines that is appropriate and with medical follow-up as necessary.

Patients should be informed that serious hypersensitivity reactions including anaphylaxis have been reported with PROLIA injections. Pregnancy must be ruled out prior to administration of PROLIA. Perform pregnancy testing in all women of reproductive potential prior to administration of PROLIA.

Based on findings in animals, PROLIA may cause fetal harm when administered to pregnant women (see 2 CONTRAINDICATIONS, 7 WARNINGS AND PRECAUTIONS and 16 NON-CLINICAL TOXICOLOGY, Animal Toxicology). PROLIA (denosumab injection) Page 6 of 81 Patients must be adequately supplemented with calcium and vitamin D at the recommended dosesa.

2 Recommended Dose and Dosage Adjustment Health Canada has not authorized an indication for pediatric use (see 7 WARNINGS AND PRECAUTIONS, Special Populations, Pediatrics). The recommended dose of PROLIA (denosumab) is a single SC injection of 60 mg, once every 6 months.

4 Administration Administration of PROLIA should be performed by an individual who has been adequately trained in injection techniques. The prefilled syringe is not made with natural rubber latex. Parenteral drug products should be inspected visually for particulate matter and discolouration prior to administration, whenever solution and container permit.

PROLIA is a clear, colourless to slightly yellow solution that may contain trace amounts of translucent to white proteinaceous particles. Do not use if the solution is cloudy. Prior to administration, PROLIA may be allowed to reach room temperature (up to 25C) in the original container.

Administer PROLIA via SC injection in the upper arm, the upper thigh, or the abdomen. 5 Missed Dose If a dose is missed, it should be given as soon as convenient. The next dose should be scheduled 6 months from the date of the previous injection.

5 OVERDOSAGE There is no experience with overdosage with PROLIA. For management of a suspected drug overdose, contact your regional poison control centre. 6 DOSAGE FORMS, STRENGTHS, COMPOSITION AND PACKAGING To help ensure the traceability of biologic products, including biosimilars, health professionals should recognize the importance of recording both the brand name and the non-proprietary (active ingredient) name as well as other product-specific identifiers such as the Drug Identification Number (DIN) and the batch/lot number of the product supplied.

a2010 clinical practice guidelines for the diagnosis and management of osteoporosis in Canada: summary PROLIA (denosumab injection) Page 7 of 81 Route of Administration Dosage Form / Strength/Composition Non-medicinal Ingredients Subcutaneous Solution for injection / 60 mg denosumab in 1 mL solution in a single use prefilled syringe (PFS) Acetate, polysorbate 20, sodium hydroxide, sorbitol, and water for injection (USP).

2. PROLIA is supplied in a single use prefilled syringe with a safety guard. The prefilled syringe is not made with natural rubber latex. 2. PROLIA is supplied in a dispensing pack containing one prefilled syringe. 7 WARNINGS AND PRECAUTIONS General Adequate intake of calcium and vitamin D is important in all patients.

PROLIA contains the same active ingredient as found in XGEVA® (denosumab). Patients being treated with PROLIA should not be treated concomitantly with XGEVA. Endocrine and Metabolism Hypercalcemia in Pediatric Patients with Osteogenesis Imperfecta PROLIA is not indicated for use in pediatric patients.

In clinical trials, hypercalcemia has been reported in pediatric patients with osteogenesis imperfecta treated with denosumab. Some cases required hospitalization [see Special Populations, Pediatrics]. Hypocalcemia Hypocalcemia must be corrected by adequate intake of calcium and vitamin D prior to initiating therapy with PROLIA.

Other disorders affecting mineral metabolism (such as vitamin D deficiency) should be treated. Clinical monitoring of calcium levels is recommended before each dose and, in patients predisposed to hypocalcemia within two weeks after the initial dose (see Monitoring and Laboratory Tests).

Patients are advised to report to their physicians any symptoms of hypocalcemia, such as paresthesias or muscle spasms, twitching and muscle cramps (8 ADVERSE REACTIONS, Hypocalcemia). Calcium levels should be measured if any patient presents with suspected symptoms of hypocalcemia during treatment.

PROLIA (denosumab injection) Page 8 of 81 In the postmarket setting, severe symptomatic […]

• PROLIA is contraindicated in patients who are hypersensitive to this drug or to any ingredient in the formulation, including any non-medicinal ingredient, or component of the container. For a complete listing, see 6 DOSAGE FORMS, STRENGTHS, COMPOSITION AND PACKAGING.

Anaphylactic reactions have been reported (see 7 WARNINGS AND PRECAUTIONS, Hypersensitivity and 8 ADVERSE REACTIONS, Postmarket Adverse Drug Reactions). • Hypocalcemia (see 7 WARNINGS AND PRECAUTIONS, Endocrine and Metabolism, Hypocalcemia) • Female patients who are pregnant or who are trying to become pregnant.

PROLIA may cause fetal harm when administered to a pregnant woman. In women of reproductive potential, pregnancy testing should be performed prior to initiating treatment with PROLIA. 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.

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 7 WARNINGS AND PRECAUTIONS, Special Populations, Pregnant Women).

1 Treatment of Postmenopausal Women with Osteoporosis at High Risk for Fracture Stoboclo 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.

1) ] . 2) ] . 5 mg or greater of prednisone and expected to remain on glucocorticoids for at least 6 months. 3) ] . 4 Treatment of Bone Loss in Men Receiving Androgen Deprivation Therapy for Prostate Cancer Stoboclo is indicated as a treatment to increase bone mass in men at high risk for fracture receiving androgen deprivation therapy (ADT) for nonmetastatic prostate cancer.

4) ] . 5) ] .

2 DOSAGE AND ADMINISTRATION Pregnancy must be ruled out prior to administration of Stoboclo. 1 ) Before initiating Stoboclo in patients with advanced chronic kidney disease, including dialysis patients, evaluate for the presence of chronic kidney disease mineral and bone disorder with intact parathyroid hormone, serum calcium, 25(OH) vitamin D, and 1,25(OH) 2 vitamin D.

6 ) Stoboclo should be administered by a healthcare provider. 3 ) Administer 60 mg every 6 months as a subcutaneous injection in the upper arm, upper thigh, or abdomen. 3 ) Instruct patients to take calcium 1000 mg daily and at least 400 IU vitamin D daily.

1 Pregnancy Testing Prior to Initiation of Stoboclo Pregnancy must be ruled out prior to administration of Stoboclo. Perform pregnancy testing in all females of reproductive potential prior to administration of Stoboclo. 3 )] . 73 m 2 ], including dialysis-dependent patients, evaluate for the presence of chronic kidney disease mineral and bone disorder (CKD-MBD) with intact parathyroid hormone (iPTH), serum calcium, 25(OH) vitamin D, and 1,25 (OH) 2 vitamin D prior to decisions regarding Stoboclo treatment.

1) ] . 3 Recommended Dosage Stoboclo should be administered by a healthcare provider. The recommended dose of Stoboclo is 60 mg administered as a single subcutaneous injection once every 6 months. Administer Stoboclo via subcutaneous injection in the upper arm, the upper thigh, or the abdomen.

1) ] . If a dose of Stoboclo 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. 4 Preparation and Administration Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration whenever solution and container permit.

Stoboclo is a clear, colorless to pale yellow solution. Do not use if the solution is discolored or cloudy or if the solution contains particles or foreign particulate matter. Prior to administration, Stoboclo may be removed from the refrigerator and brought to room temperature up to 25°C (77°F) by standing in the original carton.

This generally takes 15 to 30 minutes. Do not warm Stoboclo in any other way [see How Supplied/Storage and Handling (16) ] .

Instructions for Administration of Prefilled Syringe with Safety Guard IMPORTANT:

To reduce the risk of accidental needle stick injury, each prefilled syringe has a safety guard that is automatically activated to cover the needle after you have given the injection. Do not pull back on the plunger rod at any time.

Step 1:

Remove the Needle Cap Dispose of the needle cap right away in the nearest sharps disposal container. DO NOT re-cap the prefilled syringe.

Image Image Step 2:

Administer Subcutaneous Injection Choose an appropriate injection site. The recommended injection sites for Stoboclo include: the outer area of the upper arms OR the upper legs (thighs) OR around the stomach area (abdomen). Inject all of the liquid by using your thumb to push the plunger rod all the way down.

If the plunger rod is not fully pressed, the safety guard will not extend to cover the needle when it is removed.

Image Image Step 3:

Remove the prefilled syringe from the injection site After the prefilled syringe is empty, slowly remove the needle by lifting your thumb from the plunger rod until the needle is completely covered by the safety guard. Do not rub the injection site.

Immediately dispose of the prefilled syringe in the nearest sharps disposal container. Image

8) ] The most common adverse reactions reported with denosumab products in patients with postmenopausal osteoporosis are back pain, pain in extremity, musculoskeletal pain, hypercholesterolemia, and cystitis. The most common adverse reactions reported with denosumab products in men with osteoporosis are back pain, arthralgia, and nasopharyngitis.

The most common adverse reactions reported with denosumab products in patients with glucocorticoid-induced osteoporosis are back pain, hypertension, bronchitis, and headache. The most common (per patient incidence ≥ 10%) adverse reactions reported with denosumab products 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 denosumab products in patients with postmenopausal osteoporosis are back pain and constipation.

Postmenopausal osteoporosis:

Most common adverse reactions (> 5% and more common than placebo) were: back pain, pain in extremity, hypercholesterolemia, musculoskeletal pain, and cystitis. Pancreatitis has been reported in clinical trials. 1 ) Male osteoporosis: Most common adverse reactions (> 5% and more common than placebo) were: back pain, arthralgia, and nasopharyngitis.

1 ) Glucocorticoid-induced osteoporosis: Most common adverse reactions (> 3% and more common than active-control group) were: back pain, hypertension, bronchitis, and headache. 1 ) Bone loss due to hormone ablation for cancer: Most common adverse reactions (≥ 10% and more common than placebo) were: arthralgia and back pain.

Pain in extremity and musculoskeletal pain have also been reported in clinical trials. 1 ) To report SUSPECTED ADVERSE REACTIONS, contact CELLTRION USA, Inc. gov/medwatch . 1 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 denosumab 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 denosumab 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.

8% (n = 70) in the denosumab group. 0% in the denosumab group. 4% for the placebo and denosumab groups, respectively. The most common adverse reactions reported with denosumab in patients with postmenopausal osteoporosis are back pain, pain in extremity, musculoskeletal pain, hypercholesterolemia, and cystitis.

Adverse reactions reported in ≥ 2% of postmenopausal women with osteoporosis and more frequently in the denosumab-treated women than in the placebo-treated women are shown in the table below. Table 1. 7% women in the denosumab group.

The nadir in serum calcium level occurred at approximately day 10 after denosumab 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.

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. 5% in subjects with creatinine clearance < 30 mL/min vs. 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 denosumab products may increase the risk of infection. 2% in both placebo and denosumab treatment groups. 0% in the denosumab groups. 7% placebo vs. 5% placebo vs. 0% placebo vs. 1% denosumab) were reported.

Endocarditis was reported in no placebo patients and 3 patients receiving denosumab. 1% placebo vs. 4% denosumab). The incidence of opportunistic infections was similar to that reported with placebo. 0001). 8) ] . 4) ] . Atypical Subtrochanteric and Diaphyseal Femoral Fractures In the osteoporosis clinical trial program, atypical femoral fractures were reported in patients treated with denosumab.

5) ] . Multiple Vertebral Fractures (MVF) Following Treatment Discontinuation In the osteoporosis clinical trial program, multiple vertebral fractures were reported in patients after discontinuation of denosumab. In the phase 3 trial in women with postmenopausal osteoporosis, 6% of women who discontinued denosumab and remained in the study developed new vertebral fractures, and 3% of women who discontinued denosumab and remained in the study developed multiple new vertebral fractures.

The mean time to onset of multiple vertebral fractures was 17 months (range: 7-43 months) after the last injection of denosumab. 6) ] . 2%) in the denosumab groups. Of these reports, 1 patient in the placebo group and all 8 patients in the denosumab group had serious events, including one death in the denosumab group.

Several patients had a prior history of pancreatitis. The time from product administration to event occurrence was variable. 8% in the denosumab groups. 7% placebo vs. 2% placebo vs. 6% placebo vs. 9% denosumab) were reported. A causal relationship to drug exposure has not been established.

Treatment to Increase Bone Mass in Men with Osteoporosis The safety of denosumab 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 denosumab 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. 8% (n = 1) in the denosumab group. 3% in the denosumab group. 5% for the placebo and denosumab groups, respectively. 7% placebo vs.

8% placebo vs. 8% placebo vs. 7% denosumab). 8%) in the placebo group and no patients in the denosumab group. 2%) in the denosumab group. Osteonecrosis of the Jaw No cases of ONJ were reported. 8%) in the denosumab group. 3%) patients (3 prostate cancers, 1 basal cell carcinoma) in the denosumab group.

5 mg/day oral prednisone (or equivalent). A total of 384 patients were exposed to 5 mg oral daily bisphosphonate (active-control) and 394 patients were exposed to denosumab administered once every 6 months as a 60 mg subcutaneous dose.

All patients were instructed to take at least 1000 mg of calcium and 800 IU of vitamin D supplementation per day. 5% (n = 6) in the denosumab group. The incidence of serious adverse events was 17% in the active-control group and 16% in the denosumab group.

8% for the active-control and denosumab groups, respectively. Adverse reactions reported in ≥ 2% of patients with glucocorticoid-induced osteoporosis and more frequently with denosumab than in the active-control-treated patients are shown in the table below.

Table 2. 8) Polymyalgia rheumatica Events of worsening of underlying polymyalgia rheumatica. 3) Osteonecrosis of the Jaw No cases of ONJ were reported. Atypical Subtrochanteric and Diaphyseal Femoral Fractures Atypical femoral fractures were reported in 1 patient treated with denosumab.

5) ] . 3%) in the denosumab group. 8%) in the denosumab 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 denosumab 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 denosumab 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.

6% in the denosumab group. 0% for the placebo and denosumab groups, respectively. The safety of denosumab 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 denosumab 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.

7% in the denosumab group. 8% for the placebo and denosumab groups, respectively. 0% placebo vs. 5% placebo vs. 5% denosumab). 7% placebo vs. 8% placebo vs. 0% denosumab) have also been reported in clinical trials. 2% placebo vs. 7% denosumab).

4% vs. 0%) at the month 1 visit. 2 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.

g. ANCA positive vasculitis, leukocytoclastic vasculitis) Drug reaction with eosinophilia and systemic symptoms (DRESS) syndrome

1) ] .

Pregnant women:

Denosumab products may cause fetal harm when administered to a pregnant woman. 1) ] .

Patients with hypersensitivity to denosumab products:

Stoboclo is contraindicated in patients with a history of systemic hypersensitivity to any component of the product. 2) ] . 3 )