Mutagenicity
The genotoxic potential of denosumab has not been evaluated.
Impairment of Fertility
Denosumab had no effect on female fertility or male reproductive organs in monkeys at doses that were 13- to 50-fold higher than the recommended human dose of 60 mg administered once every 6 months, based on body weight (mg/kg).
12.2 Animal Toxicology and/or Pharmacology
Prolia is an inhibitor of osteoclastic bone resorption via inhibition of RANKL.
In ovariectomized monkeys, once-monthly treatment with denosumab suppressed bone turnover and increased bone mineral density (BMD) and strength of cancellous and cortical bone at doses 50-fold higher than the recommended human dose of 60 mg administered once every 6 months, based on body weight (mg/kg). Bone tissue was normal with no evidence of mineralization defects, accumulation of osteoid, or woven bone.
Adolescent primates treated with denosumab at doses > 10 times (10 and 50 mg/kg dose) higher than the recommended human dose of 60 mg administered once every 6 months, based on mg/kg, had abnormal growth plates, considered to be consistent with the pharmacological activity of denosumab [see Use in Specific Populations (8.4)].
Because the biological activity of denosumab in animals is specific to nonhuman primates, evaluation of genetically engineered (“knockout”) mice or use of other biological inhibitors of the RANK/RANKL pathway, namely OPG-Fc, provided additional information on the pharmacodynamic properties of denosumab. RANK/RANKL knockout mice exhibited absence of lymph node formation, as well as an absence of lactation due to inhibition of mammary gland maturation (lobulo-alveolar gland development during pregnancy). Neonatal RANK/RANKL knockout mice exhibited reduced bone growth and lack of tooth eruption. A corroborative study in 2-week-old rats given the RANKL inhibitor OPG-Fc also showed reduced bone growth, altered growth plates, and impaired tooth eruption. These changes were partially reversible in this model when dosing with the RANKL inhibitors was discontinued [see Use in Specific Populations (8.1, 8.4)].
13 CLINICAL STUDIES
13.1 Postmenopausal Women with Osteoporosis
The efficacy and safety of Prolia in the treatment of postmenopausal osteoporosis was demonstrated in a 3-year, randomized, double-blind, placebo-controlled trial. Enrolled women had a baseline BMD T-score between -2.5 and -4.0 at either the lumbar spine or total hip. Women with other diseases (such as
rheumatoid arthritis, osteogenesis imperfecta, and Paget’s disease) or on therapies that affect bone were excluded from this study. The 7808 enrolled women were aged 60 to 91 years with a mean age of 72 years. Overall, the mean baseline lumbar spine BMD T-score was -2.8 and 23% of women had a
Page 13 vertebral fracture at baseline. Women were randomized to receive SC injections of either placebo (N = 3906) or Prolia 60 mg (N = 3902) once every 6 months. All women received at least 1000 mg calcium and 400 IU vitamin D supplementation daily.
The primary efficacy variable was the incidence of new morphometric (radiologically-diagnosed) vertebral fractures at 3 years. Vertebral fractures were diagnosed based on lateral spine radiographs (T4-L4) using a semiquantitative scoring method. Secondary efficacy variables included the incidence of hip fracture and nonvertebral fracture, assessed at 3 years.
Effect on Vertebral Fractures
Prolia significantly reduced the incidence of new morphometric vertebral fractures at 1, 2, and 3 years (p < 0.0001), as shown in Table 2. The incidence of new vertebral fractures at year 3 was 7.2% in the placebo-treated women compared to 2.3% for the Prolia-treated women. The absolute risk reduction was 4.8% and relative risk reduction was 68% for new morphometric vertebral fractures at year 3.
Table 2. The Effect of Prolia on the Incidence of New Vertebral Fractures
Proportion of Women
With Fracture (%)+ Absolute Risk Reduction
* Absolute risk reduction and relative risk reduction based on Mantel-Haenszel method adjusting for age group variable.
+ Event rates based on crude rates in each interval.
Prolia was effective in reducing the risk for new morphometric vertebral fractures regardless of age, baseline rate of bone turnover, baseline BMD, baseline history of fracture, or prior use of a drug for osteoporosis.
Effect on Hip Fractures
The incidence of hip fracture was 1.2% for placebo-treated women compared to 0.7% for Prolia-treated women at year 3. The age-adjusted absolute risk reduction of hip fractures was 0.3% with a relative risk reduction of 40% at 3 years (p = 0.04) (Figure 1).
Page 14 Figure 1. Cumulative Incidence of Hip Fractures Over 3 Years
N = number of subjects randomized
Effect on Nonvertebral Fractures
Treatment with Prolia resulted in a significant reduction in the incidence of nonvertebral fractures (Table 3).
Table 3. The Effect of Prolia on the Incidence of Nonvertebral Fractures at Year 3 Proportion of Women With
Fracture (%)+ Absolute Risk Reduction (%)
(95% CI)
Relative Risk Reduction (%)
(95% CI) Placebo
N = 3906 (%)
Prolia N = 3902
(%) Nonvertebral
fracture1
8.0 6.5 1.5 (0.3, 2.7) 20 (5, 33)*
* p-value = 0.01.
+ Event rates based on Kaplan-Meier estimates at 3 years.
1 Excluding those of the vertebrae (cervical, thoracic, and lumbar), skull, facial, mandible, metacarpus, and finger and toe phalanges.
Effect on Bone Mineral Density (BMD)
Treatment with Prolia significantly increased BMD at all anatomic sites measured at 3 years. The
treatment differences in BMD at 3 years were 8.8% at the lumbar spine, 6.4% at the total hip, and 5.2% at the femoral neck. Consistent effects on BMD were observed at the lumbar spine, regardless of baseline age, race, weight/body mass index (BMI), baseline BMD, and level of bone turnover.
Page 15 In a placebo-controlled study in 266 Japanese women with postmenopausal osteoporosis, denosumab significantly increased 5.7%,, 6.7% and 7.5% (mean % change from baseline) of BMD at 1 year at the lumbar spine across 3 dose groups (14, 60 and 100 mg subcutaneous once every 6 months) for the 3 denosumab groups as compared to 0.5% for the placebo group, all p < 0.0001. Also, all 3 denosumab dose cohorts had significantly greater increases in BMD of the total hip, and femoral neck at month 12 compared with the placebo cohort (p < 0.05). The extent of increase in BMD at each anatomical site in Japanese women with postmenopausal osteoporosis was generally similar to, or somewhat higher than, that observed in Western women with postmenopausal osteoporosis.
Bone Histology and Histomorphometry
A total of 115 transiliac crest bone biopsy specimens were obtained from 92 postmenopausal women with osteoporosis at either month 24 and/or month 36 (53 specimens in Prolia group, 62 specimens in placebo group). Of the biopsies obtained, 115 (100%) were adequate for qualitative histology and 7 (6%) were adequate for full quantitative histomorphometry assessment.
Qualitative histology assessments showed normal architecture and quality with no evidence of
mineralization defects, woven bone, or marrow fibrosis in patients treated with Prolia. The presence of double tetracycline labeling in a biopsy specimen provides an indication of active bone remodeling, while the absence of tetracycline label suggests suppressed bone formation. In subjects treated with Prolia, 35%
had no tetracycline label present at the month 24 biopsy and 38% had no tetracycline label present at the month 36 biopsy, while 100% of placebo-treated patients had double label present at both time points.
When compared to placebo, treatment with Prolia resulted in virtually absent activation frequency and markedly reduced bone formation rates. However, the long-term consequences of this degree of suppression of bone remodeling are unknown.
14 HOW SUPPLIED/STORAGE AND HANDLING
Prolia is supplied in a use prefilled syringe with a safety guard. The grey needle cap on the single-use prefilled syringe contains dry natural rubber (a derivative of latex).
60 mg/1 mL in a single-use prefilled syringe 1 per carton NDC 55513-710-01
Store Prolia in a refrigerator at 2°C to 8°C (36°F to 46°F) in the original carton. Do not freeze. Prior to administration, Prolia may be allowed to reach room temperature (up to 25°C/77°F) in the original container. Once removed from the refrigerator, Prolia must not be exposed to temperatures above 25°C/77°F and must be used within 14 days. If not used within the 14 days, Prolia should be discarded.
Do not use Prolia after the expiry date printed on the label.
Protect Prolia from direct light and heat.
Avoid vigorous shaking of Prolia.
15 PATIENT COUNSELING INFORMATION See Medication Guide.
15.1 Hypocalcemia
Adequately supplement patients with calcium and vitamin D and instruct them on the importance of maintaining serum calcium levels while receiving Prolia [see Warnings and Precautions (5.1) and Use in
Page 16 Specific Populations (8.6)]. Advise patients to seek prompt medical attention if they develop signs or symptoms of hypocalcemia.
15.2 Serious Infections
Advise patients to seek prompt medical attention if they develop signs or symptoms of infections, including cellulitis [see Warnings and Precautions (5.2)].
15.3 Dermatologic Reactions
Advise patients to seek prompt medical attention if they develop signs or symptoms of dermatological reactions (dermatitis, rashes, and eczema) [see Warnings and Precautions (5.3)].
15.4 Osteonecrosis of the Jaw
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 surgery [see Warnings and Precautions (5.4)].
15.5 Schedule of Administration
If a dose of Prolia is missed, administer the injection as soon as convenient. Thereafter, schedule injections every 6 months from the date of the last injection.
Manufactured by:
Amgen Manufacturing Limited, a subsidiary of Amgen Inc.
One Amgen Center Drive
Thousand Oaks, California 91320-1799
This product, its production, and/or its use may be covered by one or more US Patents, including US Patent Nos. 6,740,522; 7,097,834; 7,364,736; and 7,411,050, as well as other patents or patents pending.
PROLIA is a registered trademark of Amgen Inc., and is being used under license by GlaxoSmithKline.
© 2011 Amgen Inc. All rights reserved.
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