Prolia Information
Prolia () Indications And Usage
Prolia () is indicated as a treatment to increase bone mass in men at high risk for fracture receiving androgen deprivation therapy for nonmetastatic prostate cancer. In these patients Prolia () also reduced the incidence of vertebral fractures .
Prolia () is indicated as a treatment to increase bone mass in women at high risk for fracture receiving adjuvant aromatase inhibitor therapy for breast cancer .
Prolia () Dosage And Administration
Prolia () should be administered by a healthcare professional.
The recommended dose of Prolia () is 60 mg administered as a single subcutaneous injection once every 6 months. Administer Prolia () via subcutaneous injection in the upper arm, the upper thigh, or the abdomen. All patients should receive calcium 1000 mg daily and at least 400 IU vitamin D daily .
If a dose of Prolia () 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.
Visually inspect Prolia () for particulate matter and discoloration prior to administration whenever solution and container permit. Prolia () is a clear, colorless to pale yellow solution that may contain trace amounts of translucent to white proteinaceous particles. Do not use if the solution is discolored or cloudy or if the solution contains many particles or foreign particulate matter.
Prior to administration, Prolia () may be removed from the refrigerator and brought to room temperature (up to 25°C/77°F) by standing in the original container. This generally takes 15 to 30 minutes. Do not warm Prolia () in any other way
DO NOT
Activate the green safety guard (slide over the needle) the injection.
The grey needle cap on the single-use prefilled syringe contains dry natural rubber (a derivative of latex); people sensitive to latex should not handle the cap.
DO NOT
With the
Hold the prefilled syringe by the clear plastic finger grip with one hand. Then, with the other hand, grasp the green safety guard by its base and gently slide it towards the needle until the green safety guard locks securely in place and/or you hear a “click.” grip the green safety guard too firmly – it will move easily if you hold and slide it gently.
Immediately dispose of the syringe and needle cap in the nearest sharps container. put the needle cap back on the used syringe.
For administration of Prolia () from the single-use vial, use a 27-gauge needle to withdraw and inject the 1 mL dose. Do not re-enter the vial. Discard vial and any liquid remaining in the vial.
Prolia () Warnings And Precautions
Prolia () contains the same active ingredient (denosumab) found in Xgeva. Patients receiving Prolia () should not receive Xgeva.
Hypocalcemia may be exacerbated by the use of Prolia () . Pre-existing hypocalcemia must be corrected prior to initiating therapy with Prolia () . In patients predisposed to hypocalcemia and disturbances of mineral metabolism (e.g. history of hypoparathyroidism, thyroid surgery, parathyroid surgery, malabsorption syndromes, excision of small intestine, severe renal impairment [creatinine clearance (CrCL)
Hypocalcemia following Prolia () administration is a significant risk in patients with severe renal impairment [CrCL
Adequately supplement all patients with calcium and vitamin D .
In a clinical trial of over 7800 women with postmenopausal osteoporosis, 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 subjects. The incidence of opportunistic infections was balanced between placebo and Prolia () groups, and the overall incidence of infections was 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. Consider the benefit-risk profile in such patients before treating with Prolia () . In patients who develop serious infections while on Prolia () , prescribers should assess the need for continued Prolia () therapy.
Osteonecrosis of the jaw (ONJ), which can occur spontaneously, is generally associated with tooth extraction and/or local infection with delayed healing. ONJ has been reported in patients receiving denosumab . A routine oral exam should be performed by the prescriber prior to initiation of Prolia () treatment. A dental examination with appropriate preventive dentistry should be considered prior to treatment with Prolia () in patients with risk factors for ONJ such as invasive dental procedures (e.g. tooth extraction, dental implants, oral surgery), diagnosis of cancer, concomitant therapies (e.g. chemotherapy, corticosteroids), poor oral hygiene, and co-morbid disorders (e.g. periodontal and/or other pre-existing dental disease, anemia, coagulopathy, infection, ill-fitting dentures). Good oral hygiene practices should be maintained during treatment with Prolia () .
For patients requiring invasive dental procedures, clinical judgment of the treating physician and/or oral surgeon should guide the management plan of each patient based on individual benefit-risk assessment.
Patients who are suspected of having or who develop ONJ while on Prolia () should receive care by a dentist or an oral surgeon. In these patients, extensive dental surgery to treat ONJ may exacerbate the condition. Discontinuation of Prolia () therapy should be considered based on individual benefit-risk assessment.
Prolia () Adverse Reactions
The following serious adverse reactions are discussed below and also elsewhere in the labeling:
The most common adverse reactions reported with Prolia () in patients with postmenopausal osteoporosis are back pain, pain in extremity, musculoskeletal pain, hypercholesterolemia, and cystitis.
The most common (per patient incidence ≥ 10%) adverse reactions reported with Prolia () 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 Prolia () are back pain and constipation.
The Prolia () Postmarketing Active Safety Surveillance Program is available to collect information from prescribers on specific adverse events. Please see www.Prolia () safety.com or call 1-800-772-6436 for more information about this program.
Prolia () Drug Interactions
No drug-drug interaction studies have been conducted with Prolia () .
Prolia () Use In Specific Populations
Pregnancy Category C
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”), 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. Patients or their physicians should call 1-800-77-AMGEN (1-800-772-6436) to enroll.
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
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 .
Prolia () is not recommended in pediatric patients. The safety and effectiveness of Prolia () in pediatric patients have not been established.
Treatment with Prolia () may impair bone growth in children with open growth plates and may inhibit eruption of dentition. In neonatal rats, inhibition of RANKL (the target of Prolia () therapy) with a construct of osteoprotegerin bound to Fc (OPG-Fc) at doses ≤ 10 mg/kg was associated with inhibition of bone growth and tooth eruption. Adolescent primates dosed with denosumab at 10 and 50 times (10 and 50 mg/kg dose) higher than the recommended human dose of 60 mg administered once every 6 months, based on body weight (mg/kg), had abnormal growth plates .
No dose adjustment is necessary in patients with renal impairment.
In clinical studies, patients with severe renal impairment (CrCL
Prolia () Overdosage
There is no experience with overdosage with Prolia () .
Prolia () Description
Prolia () (denosumab) is a human IgG2 monoclonal antibody with affinity and specificity for human RANKL (receptor activator of nuclear factor kappa-B ligand). Denosumab has an approximate molecular weight of 147 kDa and is produced in genetically engineered mammalian (Chinese hamster ovary) cells.
Prolia () is a sterile, preservative-free, clear, colorless to pale yellow solution.
Each 1 mL single-use prefilled syringe of Prolia () contains 60 mg denosumab (60 mg/mL solution), 4.7% sorbitol, 17 mM acetate, 0.01% polysorbate 20, Water for Injection (USP), and sodium hydroxide to a pH of 5.2.
Each 1 mL single-use vial of Prolia () contains 60 mg denosumab (60 mg/mL solution), 4.7% sorbitol, 17 mM acetate, Water for Injection (USP), and sodium hydroxide to a pH of 5.2.
Prolia () Clinical Pharmacology
In clinical studies, treatment with 60 mg of Prolia () resulted in reduction in the bone resorption marker serum type 1 C-telopeptide (CTX) by approximately 85% by 3 days, with maximal reductions occurring by 1 month. CTX levels were below the limit of assay quantitation (0.049 ng/mL) in 39% to 68% of subjects 1 to 3 months after dosing of Prolia () . At the end of each dosing interval, CTX reductions were partially attenuated from a maximal reduction of ≥ 87% to ≥ 45% (range: 45% to 80%), as serum denosumab levels diminished, reflecting the reversibility of the effects of Prolia () on bone remodeling. These effects were sustained with continued treatment. Upon reinitiation, the degree of inhibition of CTX by Prolia () was similar to that observed in patients initiating Prolia () treatment.
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 () . After discontinuation of Prolia () therapy, markers of bone resorption increased to levels 40% to 60% above pretreatment values but returned to baseline levels within 12 months.
In a study conducted in healthy male and female volunteers (n = 73, age range: 18 to 64 years) following a single subcutaneously administered Prolia () dose of 60 mg after fasting (at least for 12 hours), the mean maximum denosumab concentration (C) was 6.75 mcg/mL (standard deviation [SD] = 1.89 mcg/mL). The median time to maximum denosumab concentration (T) was 10 days (range: 3 to 21 days). After C, serum denosumab concentrations declined over a period of 4 to 5 months with a mean half-life of 25.4 days (SD = 8.5 days; n = 46). The mean area-under-the-concentration-time curve up to 16 weeks (AUC) of denosumab was 316 mcg•day/mL (SD = 101 mcg•day/mL).
No accumulation or change in denosumab pharmacokinetics with time was observed upon multiple dosing of 60 mg subcutaneously administered once every 6 months.
Prolia () pharmacokinetics were not affected by the formation of binding antibodies.
A population pharmacokinetic analysis was performed to evaluate the effects of demographic characteristics. This analysis showed no notable differences in pharmacokinetics with age (in postmenopausal women), race, or body weight (36 to 140 kg).
Drug Interactions
No drug-drug interaction studies have been conducted with Prolia () .
Specific Populations
Gender:
Age:
Race:
Renal Impairment:
Hepatic Impairment:
Prolia () Nonclinical Toxicology
Carcinogenicity
The carcinogenic potential of denosumab has not been evaluated in long-term animal studies.
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).
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 .
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 .
Prolia () Clinical Studies
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 vertebral fracture at baseline. Women were randomized to receive subcutaneous 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
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).
Effect on Nonvertebral Fractures
Treatment with Prolia () resulted in a significant reduction in the incidence of nonvertebral fractures (Table 3).
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.
After Prolia () discontinuation, BMD returned to approximately baseline levels within 12 months.
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.
The efficacy and safety of Prolia () in the treatment of bone loss in men with nonmetastatic prostate cancer receiving androgen deprivation therapy (ADT) were demonstrated in a 3‑year, randomized (1:1), double-blind, placebo-controlled, multinational study. Men less than 70 years of age had either a BMD T‑score at the lumbar spine, total hip, or femoral neck between ‑1.0 and -4.0, or a history of an osteoporotic fracture. The mean baseline lumbar spine BMD T-score was -0.4, and 22% of men had a vertebral fracture at baseline. The 1468 men enrolled ranged in age from 48 to 97 years (median 76 years). Men were randomized to receive subcutaneous injections of either placebo (n = 734) or Prolia () 60 mg (n = 734) once every 6 months for a total of 6 doses. Randomization was stratified by age ( 6 months). Seventy-nine percent of patients received ADT for more than 6 months at study entry. All men received at least 1000 mg calcium and 400 IU vitamin D supplementation daily.
Effect on Bone Mineral Density (BMD)
The primary efficacy variable was percent change in lumbar spine BMD from baseline to month 24. An additional key secondary efficacy variable was the incidence of new vertebral fracture through month 36 diagnosed based on x-ray evaluation by two independent radiologists. Lumbar spine BMD was higher at 2 years in Prolia () -treated patients as compared to placebo-treated patients [-1.0% placebo, +5.6% Prolia () ; treatment difference 6.7% (95% CI: 6.2, 7.1); p
With approximately 62% of patients followed for 3 years, treatment differences in BMD at 3 years were 7.9% (-1.2% placebo, +6.8% Prolia () ) at the lumbar spine, 5.7% (-2.6% placebo, +3.2% Prolia () ) at the total hip, and 4.9% (-1.8% placebo, +3.0% Prolia () ) at the femoral neck. Consistent effects on BMD were observed at the lumbar spine in relevant subgroups defined by baseline age, BMD, and baseline history of vertebral fracture.
Effect on Vertebral Fractures
Prolia () significantly reduced the incidence of new vertebral fractures at 3 years (p = 0.0125), as shown in Table 4.
The efficacy and safety of Prolia () in the treatment of bone loss in women receiving adjuvant aromatase inhibitor (AI) therapy for breast cancer was assessed in a 2‑year, randomized (1:1), double-blind, placebo-controlled, multinational study. Women had baseline BMD T-scores between ‑1.0 to ‑2.5 at the lumbar spine, total hip, or femoral neck, and had not experienced fracture after age 25. The mean baseline lumbar spine BMD T-score was -1.1, and 2.0% of women had a vertebral fracture at baseline. The 252 women enrolled ranged in age from 35 to 84 years (median 59 years). Women were randomized to receive subcutaneous injections of either placebo (n = 125) or Prolia () 60 mg (n = 127) once every 6 months for a total of 4 doses. Randomization was stratified by duration of adjuvant AI therapy at trial entry (≤ 6 months vs. > 6 months). Sixty-two percent of patients received adjuvant AI therapy for more than 6 months at study entry. All women received at least 1000 mg calcium and 400 IU vitamin D supplementation daily.
Effect on Bone Mineral Density (BMD)
The primary efficacy variable was percent change in lumbar spine BMD from baseline to month 12. Lumbar spine BMD was higher at 12 months in Prolia () -treated patients as compared to placebo-treated patients [-0.7% placebo, +4.8% Prolia () ; treatment difference 5.5% (95% CI: 4.8, 6.3); p
With approximately 81% of patients followed for 2 years, treatment differences in BMD at 2 years were 7.6% (-1.4% placebo, +6.2% Prolia () ) at the lumbar spine, 4.7 % (-1.0% placebo, +3.8% Prolia () ) at the total hip, and 3.6% (-0.8% placebo, +2.8% Prolia () ) at the femoral neck.
Prolia () How Supplied/storage And Handling
Prolia () is supplied in a single-use prefilled syringe with a safety guard or in a single-use vial. The grey needle cap on the single-use prefilled syringe contains dry natural rubber (a derivative of latex).
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 () .
Prolia () Patient Counseling Information
Prolia ()
Prolia () Medication Guide
Read the Medication Guide that comes with Prolia () before you start taking it and each time you get a refill. There may be new information. This Medication Guide does not take the place of talking with your doctor about your medical condition or treatment. Talk to your doctor if you have any questions about Prolia () .
Prolia () is a prescription medicine used to:
Prolia () is not recommended for use in children.
Do not take Prolia () if you have been told by your doctor that your blood calcium level is too low.
Know the medicines you take. Keep a list of medicines with you to show to your doctor or pharmacist when you get a new medicine.
Prolia () may cause serious side effects.
The most common side effects of Prolia () in women who are being treated for osteoporosis after menopause are:
The most common side effects of Prolia () in patients receiving certain treatments for prostate or breast cancer are:
Tell your doctor if you have any side effect that bothers you or that does not go away.
These are not all the possible side effects of Prolia () . For more information, ask your doctor or pharmacist.
Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.
Do not give Prolia () to other people even if they have the same symptoms that you have. It may harm them.
This Medication Guide summarizes the most important information about Prolia () . If you would like more information, talk with your doctor. You can ask your doctor or pharmacist for information about Prolia () that is written for health professionals.
For more information, go to www.Prolia () .com or call Amgen at 1-800-772-6436.
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Amgen Manufacturing Limited, a subsidiary of Amgen Inc.One Amgen Center Drive Thousand Oaks, California 91320-1799
This Medication Guide has been approved by the U.S. Food and Drug Administration.
1xxxxxx - v3Revised: 09/2011
Prolia () Package Label - Principal Display Panel - Prefilled Syringe, Mg
1 x 60 mg Single Use Prefilled Syringe
NDC 55513-710-01
AMGEN
Prolia ()
(denosumab)
60 mg/mL
60 mg/mL Injection – For Subcutaneous Use Only.
Single Use Prefilled Syringe. Discard unused portion.
Sterile Solution – No Preservative.
Rx Only
Refrigerate at 2° to 8°C (36° to 46°F). Do not freeze. Avoid excessive shaking. Protect from direct light and heat.
This Product Contains Dry Natural Rubber.
Manufactured by: Amgen Manufacturing Ltd., a subsidiary of Amgen Inc. Thousand Oaks, CA 91320-1799
