5 INDICATIONS

Prolia® 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. In postmenopausal women with osteoporosis, Prolia® reduces the incidence of vertebral, See More

For the treatment of postmenopausal women with osteoporosis at high risk for fracture

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PIVOTAL PHASE 3 FRACTURE TRIAL

Prolia® was studied over 3 years in the pivotal phase 3 fracture trial1,2

There were 7,808 women in a multicenter, international, randomized, double-blind, placebo-controlled trial. In the pivotal phase 3 fracture trial, 70% of patients had no prior osteoporosis therapy.2,3,*

The primary endpoint was incidence of new vertebral fractures at 3 years, and secondary endpoints were time to first nonvertebral and hip fracture.1,2

*See pivotal study for patient characteristics.

See more pivotal study design details

Pivotal study design details

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Multicenter, international, randomized, double-blind, placebo-controlled clinical trial. Patients were postmenopausal women between 60 and 91 years of age with a BMD T-score between -2.5 and -4.0 at the lumbar spine or total hip. 7,808 patients were randomized to receive Prolia® 60 mg (n = 3,902) or placebo (n = 3,906) subcutaneously (SC) every 6 months (Q6M). All patients were supplemented with daily calcium and vitamin D.

Find out how Prolia® significantly reduced fracture risk at key sites at 3 years1,2

Prolia® is proven to significantly reduce fracture risk at vertebral, hip, and nonvertebral sites at 3 years1,2

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Verterbral Fracture Relative Risk Reduction vs Placebo1,2,*

Primary Endpoint: Incidence of new vertebral fractures at 3 years

*Includes 7,393 patients with a baseline and at least one post-baseline radiograph.1,2

†Relative risk reduction.

‡Absolute risk reduction.

Primary Endpoint: Incidence of new vertebral fractures at 3 years

Secondary Endpoints: Time to first nonvertebral and hip fracture1,2

Prolia® reduced the incidence of new vertebral fracture in patients with or without a baseline vertebral fracture1,2

In the pivotal phase 3 fracture trial, 1 in 4 patients had a baseline vertebral fracture2

No overall differences in the efficacy and safety of Prolia® were observed between younger patients and patients aged 75 or older1

Of the total number of patients in clinical studies of Prolia®, 9,943 (76%) were 65 years old, and 3,576 (27%) were 75 years old1

*Includes 7,393 patients with a baseline and at least one post-baseline radiograph.1,2

†Relative risk reduction.

‡Absolute risk reduction.

§Secondary endpoints were time to first nonvertebral and hip fracture, assessed at 3 years.

**Composite measurement excluding pathological fractures and those associated with severe trauma, fractures of the vertebrae, skull, face, mandible, metacarpals, fingers, and toes.1,2

Important Safety Information

Clinically significant hypersensitivity including anaphylaxis has been reported with Prolia®. If an anaphylactic or other clinically significant allergic reaction occurs, initiate appropriate therapy and discontinue Prolia®.

See how Prolia® significantly increased BMD at key sites at 3 years1

Prolia® significantly increased BMD at key sites at 3 years1

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Significant Increase in Total Hip BMD at 3 Years1,3

 

Significant Increase in Lumbar Spine BMD at 3 Years1,3

 

Significant Increase in Femoral Neck BMD at 3 Years1,3

 
  • Prolia® increased bone mass and strength in both cortical and trabecular bone1
  • Prolia® patient bone biopsies showed normal bone architecture and quality1,†

*p< 0.0001, when compared to placebo.

†53 bone biopsy specimens taken from transiliac crest.1

Find out how many patients achieved clinically meaningful BMD gains (>3%) with Prolia®4,†

With Prolia®, more patients achieved clinically meaningful* BMD gains (>3%) at 36 months4,†

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Percentage of patients achieving clinically meaningful* BMD gains vs placebo


Lumbar Spine

 

Total Hip

 

*“Clinically meaningful” defined as achieving BMD gains that were beyond least significant change, which is 3% in this substudy. Least significant change is the smallest change in BMD that, when equaled or exceeded, allows the physician to conclude that there has been a real biological change in BMD least significant change.4

†BMD assessments were performed at baseline and at 36 months for the lumbar spine and total hip in all patients in the pivotal phase 3 fracture trial. A subset of patients (n=441) assessments were performed more frequently and at additional sites.4

‡In the Prolia® group, 5% of patients experienced no change (or a decrease) in BMD from baseline at the lumbar spine (compared to 47% in the placebo group). N-values included subjects with baseline and > 1 post baseline measurement; missing data were imputed by last observation carried forward.4

§In the Prolia® group, 8% of patients experienced no change (or a decrease) in BMD from baseline at the total hip (compared to 65% in the placebo group). N-values included subjects with baseline and > 1 post baseline measurement; missing data were imputed by last observation carried forward.4

Results of a prespecified, last observation carried forward analysis including Prolia®-treated patients (lumbar spine: n = 3203; total hip: n = 3624) with a baseline and at least one post-baseline measurement.

Learn about safety reported in the pivotal phase 3 fracture trial1

Safety reported in the pivotal phase 3 fracture trial

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The following most common adverse reactions were reported in >5% of postmenopausal women with osteoporosis and more frequently in the Prolia®-treated women than in the placebo-treated patients.1


Most Common Adverse Reactions

Placebo
(n = 3,876) n (%)		 Prolia®
(n = 3,886) n (%)
Back pain 1,340 (34.6) 1,347 (34.7)
Pain in extremity 430 (11.1) 453 (11.7)
Musculoskeletal pain 291 (7.5) 297 (7.6)
Hypercholesterolemia 236 (6.1) 280 (7.2)
Cystitis 225 (5.8) 228 (5.9)
Vertigo 187 (4.8) 195 (5.0)
Upper respiratory tract infection 167 (4.3) 190 (4.9)
Edema, peripheral 155 (4.0) 189 (4.9)
Sciatica 149 (3.8) 178 (4.6)
Pneumonia 150 (3.9) 152 (3.9)
Bone pain 117 (3.0) 142 (3.7)
Abdominal pain, upper 111 (2.9) 129 (3.3)
Anemia 107 (2.8) 129 (3.3)
Insomnia 122 (3.1) 126 (3.2)
Myalgia 94 (2.4) 114 (2.9)
Angina pectoris 87 (2.2) 101 (2.6)
Rash 79 (2.0) 96 (2.5)
Pharyngitis 78 (2.0) 91 (2.3)
Asthenia 73 (1.9) 90 (2.3)
Pruritus 82 (2.1) 87 (2.2)
Flatulence 53 (1.4) 84 (2.2)
Spinal osteoarthritis 64 (1.7)) 82 (2.1)
Gastroesophageal reflux disease 66 (1.7) 80 (2.1)
Atrial fibrillation 77 (2.0) 79 (2.0)
Herpes zoster 72 (1.9) 79 (2.0)

OPEN-LABEL EXTENSION STUDY


Long-term use of Prolia® has been studied for up to 10 years in the pivotal phase 3 fracture trial and open-label extension5-7

Study of Prolia® continued in a 7-year, international, multicenter, open-label, single-arm extension.5

The primary endpoint was safety and tolerability up to 10 years, and secondary endpoints included percent changes from baseline in BMD at lumbar spine and total hip, and vertebral and nonvertebral fracture incidence during 10 years of Prolia® administration.5



Consider open-label extension study limitations when interpreting results. The open-label extension study is not blinded, not controlled, and includes inherent self-selection bias. A total of 351 patients (7.7%) had adverse events that led to discontinuation of Prolia® and 277 patients (6.1%) had adverse events that led to discontinuation of the study.5

SC= subcutaneously, Q6M= every 6 months.

*At year 3, n-values represent patients who began the open-label extension study. At years 6 and 10, n-values represent patients who completed those respective years of the open-label extension study.5-7

See more extension study design details

Safety continued to be studied as the primary endpoint of the open-label extension study5

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Study Design

  • 7-year, international, multicenter, open-label, single-arm extension study
  • All patients received Prolia® (denosumab) 60 mg SC Q6M, daily calcium, and vitamin D

Primary Endpoint

  • Safety and tolerability of up to 10 years of Prolia® administration

Secondary Endpoints

  • Percent change from baseline in bone mineral density (BMD) during 10 years of Prolia® administration
  • Incidence of vertebral and nonvertebral fractures during 10 years of Prolia® administration

Key Inclusion Criteria

  • Must have completed the pivotal phase 3 fracture trial (received denosumab or placebo)
  • Missed no more than 1 dose of investigational product
  • Not receiving any other osteoporosis medications

Review the incidence of adverse events over 10 years of study6,7

Prolia® safety profile reflects data through 10 years6,7

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Exposure-adjusted Subject Incidence of AEs (Rates per 100 Subject-years)6,7

PIVOTAL PHASE 3 FRACTURE TRIAL6
Years 1-3 Rate

Placebo
(n = 3883)		 Prolia®
(n = 3879)
All AEs 156.1 154.3
Infections 30.7 29.3
Malignancies 1.6 1.8
Eczema 0.6 1.1
Hypocalcemia < 0.1 0.0
Serious AEs 10.4 10.6
Infections 1.3 1.5
Cellulitis or Erysipelas < 0.1 0.1

OPEN-LABEL EXTENSION STUDY7
Years 4-10 Rate

Cross-over Prolia® (n = 2206) Continued Prolia® (n = 2343)
All AEs 96.8 97.0
Infections 20.7 19.9
Malignancies 2.0 2.0
Eczema 0.9 0.9
Hypocalcemia < 0.1 < 0.1
Serious AEs 10.1 10.3
Infections 1.4 1.5
Cellulitis or Erysipelas < 0.1 < 0.1

Atypical Femoral Fracture From Open-label Extension Study5,8

  • 0.8 per 10,000 subject-years*

Osteonecrosis of the Jaw From Open-label Extension Study5,8

  • 5.2 per 10,000 subject-years*
  • There were 13 adjudicated cases of ONJ from the OLE study: 12 among women who participated in an oral procedure and event (OPE) survey; 1 additional case in a woman who did not complete the survey*,†
  • If a dental procedure (including extractions and implant surgery) is required, clinical judgment of the treating physician and/or oral surgeon should guide the management plan of each patient based on individual benefit-risk assessment
  • Advise patients to maintain good oral hygiene during treatment with Prolia® and to inform their dentist prior to dental procedures that they are receiving Prolia®. Patients should inform their physician or dentist if they experience persistent pain and/or slow healing of the mouth or jaw after dental surgery1

*Exposure-adjusted subject incidence during the open-label extension study (years 4-10); rates include both the continued and cross-over groups.

†Of the 4,550 patients enrolled in 7-yr extension study, 3,591 subjects participated in self-reporting invasive OPEs through an oral event questionnaire administered every 6 months beginning in year 3 of OLE through the end of the study. OPEs included dental implants, tooth extraction, natural tooth loss, scaling or root planing and jaw surgery.9 OPEs may be underestimated due to limited capture of events in medical charts and possible recall bias in patients with the events that occurred in the first 2.5 years of the extension study.9

Amgen continues to monitor ONJ through post-marketing pharmacovigilance activities.

Learn about how Prolia® continued to increase BMD at 10 years5,7

Prolia® continued to increase lumbar spine and total hip BMD at 10 years in the open-label extension study5,8,*

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Lumbar Spine BMD at 10 Years3,5,8


BMD data results are not meant to imply fracture efficacy and should not be extrapolated to predict differences in fracture efficacy.

  • At 10 years, Prolia® patient bone biopsies (n = 22) showed normal bone architecture and quality10

Data are least-squares means (95% confidence interval).

*BMD measured as a secondary endpoint.

†p < 0.05 compared with pivotal phase 3 fracture trial baseline.

‡Represents subjects from BMD substudy of pivotal phase 3 fracture trial.

§p < 0.05 compared with both pivotal phase 3 fracture trial and open-label extension study baselines.

**The n-values represent number of subjects with observed BMD data. For baseline and year 3, these values represent observed BMD data during the pivotal phase 3 trial. In the open-label extension study, subjects were required to have 1 BMD measurement at baseline and at least 1 BMD measurement post baseline to be included in the analysis. As such, the number of subjects measured in the open-label extension study is greater than the number of subjects measured in the first 3 years.

Total Hip BMD at 10 Years3,5,8


BMD data results are not meant to imply fracture efficacy and should not be extrapolated to predict differences in fracture efficacy.

  • At 10 years, Prolia® patient bone biopsies (n = 22) showed normal bone architecture and quality10

Data are least-squares means (95% confidence interval).

*BMD measured as a secondary endpoint.

†p < 0.05 compared with pivotal phase 3 fracture trial baseline.

‡Represents subjects from BMD substudy of pivotal phase 3 fracture trial.

§p < 0.05 compared with both pivotal phase 3 fracture trial and open-label extension study baselines.

**The n-values represent number of subjects with observed BMD data. For baseline and year 3, these values represent observed BMD data during the pivotal phase 3 trial. In the open-label extension study, subjects were required to have 1 BMD measurement at baseline and at least 1 BMD measurement post baseline to be included in the analysis. As such, the number of subjects measured in the open-label extension study is greater than the number of subjects measured in the first 3 years.

Find out about the incidence of fracture with continued Prolia® through 10 years5,8

Incidence of fractures with Prolia® through 10 years in the open-label extension study5,8

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Evaluation of New Vertebral Fractures in Pivotal and Open-label Extension Study (Years 4-10)5,8,*


N = number of enrolled subjects in the study at the beginning of each period.

*Lateral radiographs (lumbar and thoracic) were not obtained at year 4, year 7, and year 9 (year 1, year 4, and year 6 of the open-label extension study). The data presented for years 4 and 5, years 7 and 8, and years 9 and 10 represent the respective annualized fracture incidence.7

Evaluation of Hip Fractures in Pivotal and Open-label Extension Study (Years 4-10)5,8,*


N = number of enrolled subjects in the study at the beginning of each period.

*Percentages for hip fractures are Kaplan-Meier estimates.5

IMPORTANT SAFETY INFORMATION

SEVERE HYPOCALCEMIA IN PATIENTS WITH ADVANCED KIDNEY DISEASE:

Patients with advanced chronic kidney disease are at greater risk of severe hypocalcemia following Prolia administration. Severe hypocalcemia resulting in hospitalization, life-threatening events and fatal cases have been reported. The presence of chronic kidney disease-mineral bone disorder (CKD-MBD) markedly increases the risk of hypocalcemia. Prior to initiating Prolia in patients with advanced chronic kidney disease, evaluate for the presence of CKD-MBD. Treatment with Prolia in these patients should be supervised by a healthcare provider with expertise in the diagnosis and management of CKD-MBD.

Contraindications: Prolia® is contraindicated in patients with hypocalcemia. Pre-existing hypocalcemia must be corrected prior to initiating Prolia®. Prolia® is contraindicated in women who are pregnant and may cause fetal harm. In women of reproductive potential, pregnancy testing should be performed prior to initiating treatment with Prolia®. Prolia® is contraindicated in patients with a history of systemic hypersensitivity to any component of the product. Reactions have included anaphylaxis, facial swelling and urticaria.

Severe Hypocalcemia and Mineral Metabolism Changes: Prolia can cause severe hypocalcemia and fatal cases have been reported. Pre existing hypocalcemia must be corrected prior to initiating therapy with Prolia. Adequately supplement all patients with calcium and vitamin D.

In patients without advanced chronic kidney disease who are predisposed to hypocalcemia and disturbances of mineral metabolism (e.g. treatment with other calcium lowering drugs), assess serum calcium and mineral levels (phosphorus and magnesium) 10 to14 days after Prolia injection.

Same Active Ingredient: Prolia® contains the same active ingredient (denosumab) found in XGEVA®. Patients receiving Prolia® should not receive XGEVA®.

Hypersensitivity: Clinically significant hypersensitivity including anaphylaxis has been reported with Prolia®. Symptoms have included hypotension, dyspnea, throat tightness, facial and upper airway edema, pruritus and urticaria. If an anaphylactic or other clinically significant allergic reaction occurs, initiate appropriate therapy and discontinue further use of Prolia®.

Osteonecrosis of the Jaw (ONJ): ONJ, which can occur spontaneously, is generally associated with tooth extraction and/or local infection with delayed healing, and has been reported in patients receiving Prolia®. An oral exam should be performed by the prescriber prior to initiation of Prolia®. A dental examination with appropriate preventive dentistry is recommended prior to treatment in patients with risk factors for ONJ such as invasive dental procedures, diagnosis of cancer, concomitant therapies (e.g., chemotherapy, corticosteroids, angiogenesis inhibitors), poor oral hygiene, and co-morbid disorders. Good oral hygiene practices should be maintained during treatment with Prolia®. The risk of ONJ may increase with duration of exposure to Prolia®.

For patients requiring invasive dental procedures, clinical judgment should guide the management plan of each patient. Patients who are suspected of having or who develop ONJ should receive care by a dentist or an oral surgeon. Extensive dental surgery to treat ONJ may exacerbate the condition. Discontinuation of Prolia® should be considered based on individual benefit-risk assessment.

Atypical Femoral Fractures: Atypical low-energy, or low trauma fractures of the shaft have been reported in patients receiving Prolia®. Causality has not been established as these fractures also occur in osteoporotic patients who have not been treated with antiresorptive agents.

During Prolia® treatment, patients should be advised to report new or unusual thigh, hip, or groin pain. Any patient who presents with thigh or groin pain should be evaluated to rule out an incomplete femur fracture. Interruption of Prolia® therapy should be considered, pending a risk/benefit assessment, on an individual basis.

Multiple Vertebral Fractures (MVF) Following Discontinuation of Prolia® Treatment: Following discontinuation of Prolia® treatment, fracture risk increases, including the risk of multiple vertebral fractures. New vertebral fractures occurred as early as 7 months (on average 19 months) after the last dose of Prolia®. Prior vertebral fracture was a predictor of multiple vertebral fractures after Prolia® discontinuation. Evaluate an individual’s benefit/risk before initiating treatment with Prolia®. If Prolia® treatment is discontinued, consider transitioning to an alternative antiresorptive therapy.

Serious Infections: In a clinical trial (N=7808), serious infections leading to hospitalization were reported more frequently in the Prolia® group than in the placebo group. Serious skin infections, as well as infections of the abdomen, urinary tract and ear were more frequent in patients treated with Prolia®.

Endocarditis was also reported more frequently in Prolia®-treated patients. The incidence of opportunistic infections and the overall incidence of infections were similar between the treatment groups. Advise patients to seek prompt medical attention if they develop signs or symptoms of severe infection, including cellulitis.

Patients on concomitant immunosuppressant agents or with impaired immune systems may be at increased risk for serious infections. In patients who develop serious infections while on Prolia®, prescribers should assess the need for continued Prolia® therapy.

Dermatologic Adverse Reactions: In the same clinical trial in women with postmenopausal osteoporosis, epidermal and dermal adverse events such as dermatitis, eczema and rashes occurred at a significantly higher rate with Prolia® compared to placebo. Most of these events were not specific to the injection site. Consider discontinuing Prolia® if severe symptoms develop.

Musculoskeletal Pain: Severe and occasionally incapacitating bone, joint, and/or muscle pain has been reported in patients taking Prolia®. Consider discontinuing use if severe symptoms develop.

Suppression of Bone Turnover: Prolia® resulted in significant suppression of bone remodeling as evidenced by markers of bone turnover and bone histomorphometry. The significance of these findings and the effect of long-term treatment are unknown. Monitor patients for consequences, including ONJ, atypical fractures, and delayed fracture healing.

Adverse Reactions: The most common adverse reactions (>5% and more common than placebo) in women with postmenopausal osteoporosis are back pain, pain in extremity, musculoskeletal pain, hypercholesterolemia, and cystitis. The most common adverse reactions (>5% and more common than placebo) in men with osteoporosis are back pain, arthralgia, and nasopharyngitis. Pancreatitis has been reported with Prolia®.

In women with postmenopausal osteoporosis, the overall incidence of new malignancies was 4.3% in the placebo group and 4.8% in the Prolia® group. In men with osteoporosis, new malignancies were reported in no patients in the placebo group and 4 (3.3%) patients in the Prolia® group. A causal relationship to drug exposure has not been established.

The most common adverse reactions (>3% and more common than active-control group) in patients with glucocorticoid-induced osteoporosis are back pain, hypertension, bronchitis, and headache.

The most common (per patient incidence 10%) adverse reactions reported with Prolia® in patients with bone loss receiving ADT for prostate cancer or adjuvant AI therapy for breast cancer are arthralgia and back pain. Pain in extremity and musculoskeletal pain have also been reported in clinical trials. Additionally, in Prolia®-treated men with nonmetastatic prostate cancer receiving ADT, a greater incidence of cataracts was observed.

Denosumab is a human monoclonal antibody. As with all therapeutic proteins, there is potential for immunogenicity.

Please see Prolia® full Prescribing Information, including Medication Guide.

IMPORTANT SAFETY INFORMATION
SEVERE HYPOCALCEMIA IN PATIENTS WITH ADVANCED KIDNEY DISEASE: Patients with advanced chronic kidney disease are at greater risk of severe hypocalcemia following Prolia administration. Severe hypocalcemia resulting in hospitalization, life-threatening events and fatal cases have been reported. The presence of chronic kidney disease-mineral bone disorder (CKD-MBD) markedly increases the risk of hypocalcemia. Prior to initiating
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References: 1. Prolia® (denosumab) prescribing information, Amgen. 2. Cummings SR, San Martin J, McClung MR, et al. Denosumab for prevention of fractures in postmenopausal women with osteoporosis. N Engl J Med. 2009;361(8):756-765. 3. Data on file, Amgen. 2008. 4. Bolognese MA, Teglbjaerg CS, Zanchetta JR, et al. Denosumab significantly increases DXA BMD at both trabecular and cortical sites: results from the FREEDOM study. J Clin Densitom. 2003;16:147-153. 5. Bone HG, Wagman RB, Brandi ML, et al. 10 years of denosumab treatment in postmenopausal women with osteoporosis: results from the phase 3 randomized FREEDOM trial and open-label extension. Lancet Diabetes Endocrinol. 2017;5:513-523. 6. Bone HG, Chapurlat R, Brandi ML, et al. The effect of three or six years of denosumab exposure in women with postmenopausal osteoporosis: results from the FREEDOM extension. J Clin Endocrinol Metab. 2013;98(11):4483-4492. 7. Bone HG, Brandi ML, Brown JP, et al. Ten years of denosumab treatment in postmenopausal women with osteoporosis: results from the FREEDOM extension trial. Presented at: American Society of Bone and Mineral Research; October 9-12, 2015; Seattle, WA. 8. Data on file, Amgen. 2015. 9. Watts NB, Grbic JT, Binkley N, et al. Evaluation of invasive oral procedures and events in women with postmenopausal osteoporosis treated for up to 10 years with denosumab: results from the phase 3 FREEDOM open-label extension. Presented at: American Society of Bone and Mineral Research; October 9-12, 2015; Seattle, WA. 10. Dempster DW. Effect of 10 years of denosumab treatment on bone histology and histomorphometry in the FREEDOM extension study. Paper presented at: American Society for Bone and Mineral Research (ASBMR) 2016 Annual Meeting; September 16-19, 2016; Atlanta, GA. Abstract 1005.