Denosumab Injection

This medication may be prescribed for other uses; ask your doctor or pharmacist for more information.

Keep all appointments with your doctor and the laboratory. Your doctor will order certain tests to be sure it is safe for you to receive denosumab injection and to check your body's response to denosumab injection.

Do not let anyone else use your medication. Ask your pharmacist any questions you have about refilling your prescription.

It is important for you to keep a written list of all of the prescription and nonprescription (over-the-counter) medicines you are taking, as well as any products such as vitamins, minerals, or other dietary supplements. You should bring this list with you each time you visit a doctor or if you are admitted to a hospital. It is also important information to carry with you in case of emergencies.

There is no experience with overdosage with Prolia.

Mechanism Of Action

Prolia binds to RANKL, a transmembrane or soluble protein essential for the formation, function, and survival of osteoclasts, the cells responsible for bone resorption. Prolia prevents RANKL from activating its receptor, RANK, on the surface of osteoclasts and their precursors. Prevention of the RANKL/RANK interaction inhibits osteoclast formation, function, and survival, thereby decreasing bone resorption and increasing bone mass and strength in both cortical and trabecular bone.

Pharmacodynamics

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 patients 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.

Pharmacokinetics

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 (Cmax) was 6.75 mcg/mL (standard deviation [SD] = 1.89 mcg/mL). The median time to maximum denosumab concentration (Tmax) was 10 days (range: 3 to 21 days). After Cmax, 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 (AUC0-16 weeks) 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).

Serum and seminal fluid concentrations of denosumab were measured in 12 healthy male volunteers (age range: 43-65 years). After a single 60 mg subcutaneous administration of denosumab, the mean (± SD) Cmax values in the serum and seminal fluid samples were 6170 (± 2070) and 100 (± 81.9) ng/mL, respectively, resulting in a maximum seminal fluid concentration of approximately 2% of serum levels. The median (range) Tmax values in the serum and seminal fluid samples were 8.0 (7.9 to 21) and 21 (8.0 to 49) days, respectively. Among the subjects, the highest denosumab concentration in seminal fluid was 301 ng/mL at 22 days post-dose. On the first day of measurement (10 days post-dose), nine of eleven subjects had quantifiable concentrations in semen. On the last day of measurement (106 days post-dose), five subjects still had quantifiable concentrations of denosumab in seminal fluid, with a mean (± SD) seminal fluid concentration of 21.1 (± 36.5) ng/mL across all subjects (n = 12).

Drug Interactions

In a study of 17 postmenopausal women with osteoporosis, midazolam (2 mg oral) was administered 2 weeks after a single dose of denosumab (60 mg subcutaneous injection), which approximates the T max of denosumab. Denosumab did not affect the pharmacokinetics of midazolam, which is metabolized by cytochrome P450 3A4 (CYP3A4). This indicates that denosumab should not alter the pharmacokinetics of drugs metabolized by CYP3A4 in postmenopausal women with osteoporosis.

Specific Populations

Gender: Mean serum denosumab concentration-time profiles observed in a study conducted in healthy men ≥ 50 years were similar to those observed in a study conducted in postmenopausal women using the same dose regimen.

Age: The pharmacokinetics of denosumab were not affected by age across all populations studied whose ages ranged from 28 to 87 years.

Race: The pharmacokinetics of denosumab were not affected by race.

Renal Impairment: In a study of 55 patients with varying degrees of renal function, including patients on dialysis, the degree of renal impairment had no effect on the pharmacokinetics of denosumab; thus, dose adjustment for renal impairment is not necessary.

Hepatic Impairment: No clinical studies have been conducted to evaluate the effect of hepatic impairment on the pharmacokinetics of denosumab.

Animal Toxicology And/Or Pharmacology

Denosumab 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.

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.

Clinical Studies

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 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.

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 in Postmenopausal Women

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.

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).

Figure 1: Cumulative Incidence of Hip Fractures Over 3 Years

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

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.

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 patients 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.

Treatment To Increase Bone Mass In Men With Osteoporosis

The efficacy and safety of Prolia in the treatment to increase bone mass in men with osteoporosis was demonstrated in a 1-year, randomized, double-blind, placebo-controlled trial. Enrolled men had a baseline BMD T-score between -2.0 and -3.5 at the lumbar spine or femoral neck. Men with a BMD T-score between -1.0 and -3.5 at the lumbar spine or femoral neck were also enrolled if there was a history of prior fragility fracture. Men with other diseases (such as rheumatoid arthritis, osteogenesis imperfecta, and Paget's disease) or on therapies that may affect bone were excluded from this study. The 242 men enrolled in the study ranged in age from 31 to 84 years with a mean age of 65 years. Men were randomized to receive SC injections of either placebo (n = 121) or Prolia 60 mg (n = 121) once every 6 months. All men received at least 1000 mg calcium and at least 800 IU vitamin D supplementation daily.

The primary efficacy variable was percent change in lumbar spine BMD from baseline to 1 year. Secondary efficacy variables included percent change in total hip, and femoral neck BMD from baseline to 1 year.

Treatment with Prolia significantly increased BMD at 1 year. The treatment differences in BMD at 1 year were 4.8% (+0.9% placebo, +5.7% Prolia; (95% CI: 4.0, 5.6); p < 0.0001) at the lumbar spine, 2.0% (+0.3% placebo, +2.4% Prolia) at the total hip, and 2.2% (0.0% placebo, +2.1% Prolia) at femoral neck. Consistent effects on BMD were observed at the lumbar spine regardless of baseline age, race, BMD, testosterone concentrations, and level of bone turnover.

A total of 29 transiliac crest bone biopsy specimens were obtained from men with osteoporosis at 12 months (17 specimens in Prolia group, 12 specimens in placebo group). Of the biopsies obtained, 29 (100%) were adequate for qualitative histology and, in Prolia patients, 6 (35%) 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 patients treated with Prolia, 6% had no tetracycline label present at the month 12 biopsy, while 100% of placebo pa-treated tients had double label present. When compared to placebo, treatment with Prolia resulted in markedly reduced bone formation rates. However, the long-term consequences of this degree of suppression of bone remodeling are unknown.

Treatment Of Bone Loss In Men With Prostate Cancer

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 ( < 70 years vs. ≥ 70 years) and duration of ADT at trial entry ( ≤ 6 months vs. > 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.

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 < 0.0001].

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.

Prolia significantly reduced the incidence of new vertebral fractures at 3 years (p = 0.0125), as shown in Table 4.

Table 4: The Effect of Prolia on the Incidence of New Vertebral Fractures in Men with Nonmetastatic Prostate Cancer

Treatment Of Bone Loss In Women With Breast Cancer

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.

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 < 0.0001].

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®
(PRÓ-lee-a)
(denosumab) Injection, For Subcutaneous Use

What is the most important information I should know about Prolia?

If you receive Prolia, you should not receive XGEVA®. Prolia contains the same medicine as Xgeva (denosumab).

Prolia can cause serious side effects including:

• Serious allergic reactions. Serious allergic reactions have happened in people who take Prolia. Call your doctor or go to your nearest emergency room right away if you have any symptoms of a serious allergic reaction. Symptoms of a serious allergic reaction may include:
  • low blood pressure (hypotension)
  • trouble breathing
  • throat tightness
  • swelling of your face, lips, or tongue
  • rash
  • itching
  • hives
• Low calcium levels in your blood (hypocalcemia). Prolia may lower the calcium levels in your blood. If you have low blood calcium before you start receiving Prolia, it may get worse during treatment. Your low blood calcium must be treated before you receive Prolia. Most people with low blood calcium levels do not have symptoms, but some people may have symptoms. Call your doctor right away if you have symptoms of low blood calcium such as:
  • spasms, twitches, or cramps in your muscles
  • numbness or tingling in your fingers, toes, or around your mouth

Your doctor may prescribe calcium and vitamin D to help prevent low calcium levels in your blood while you take Prolia. Take calcium and vitamin D as your doctor tells you to.

• Severe jaw bone problems (osteonecrosis). Severe jaw bone problems may happen when you take Prolia. Your doctor should examine your mouth before you start Prolia. Your doctor may tell you to see your dentist before you start Prolia. It is important for you to practice good mouth care during treatment with Prolia. Ask your doctor or dentist about good mouth care if you have any questions.
• Unusual thigh bone fractures. Some people have developed unusual fractures in their thigh bone. Symptoms of a fracture include new or unusual pain in your hip, groin, or thigh.
• Increased risk of broken bones, including broken bones in the spine, after stopping Prolia. After your treatment with Prolia is stopped, your risk for breaking bones, including bones in your spine, is increased. Your risk for having more than 1 broken bone in your spine is increased if you have already had a broken bone in your spine. Do not stop taking Prolia without first talking with your doctor. If your Prolia treatment is stopped, talk to your doctor about other medicine that you can take.
• Serious infections. Serious infections in your skin, lower stomach area (abdomen), bladder, or ear may happen if you take Prolia. Inflammation of the inner lining of the heart (endocarditis) due to an infection also may happen more often in people who take Prolia. You may need to go to the hospital for treatment if you develop an infection. Prolia is a medicine that may affect the ability of your body to fight infections. People who have a weakened immune system or take medicines that affect the immune system may have an increased risk for developing serious infections. Call your doctor right away if you have any of the following symptoms of infection:
  • fever or chills
  • skin that looks red or swollen and is hot or tender to touch
  • fever, shortness of breath, cough that will not go away
  • severe abdominal pain
  • frequent or urgent need to urinate or burning feeling when you urinate
• Skin problems. Skin problems such as inflammation of your skin (dermatitis), rash, and eczema may happen if you take Prolia. Call your doctor if you have any of the following symptoms of skin problems that do not go away or get worse:
  • redness
  • itching
  • small bumps or patches (rash)
  • your skin is dry or feels like leather
  • blisters that ooze or become crusty
  • skin peeling
• Bone, joint, or muscle pain. Some people who take Prolia develop severe bone, joint, or muscle pain.

Call your doctor right away if you have any of these side effects.

What is Prolia?

Prolia is a prescription medicine used to:

• Treat osteoporosis (thinning and weakening of bone) in women after menopause (“change of life”) who:
  • are at high risk for fracture (broken bone)
  • cannot use another osteoporosis medicine or other osteoporosis medicines did not work well
• Increase bone mass in men with osteoporosis who are at high risk for fracture.
• Treat bone loss in men who are at high risk for fracture receiving certain treatments for prostate cancer that has not spread to other parts of the body.
• Treat bone loss in women who are at high risk for fracture receiving certain treatments for breast cancer that has not spread to other parts of the body.

It is not known if Prolia is safe and effective in children.

Do not take Prolia if you:

• have been told by your doctor that your blood calcium level is too low.
• are pregnant or plan to become pregnant.
• are allergic to denosumab or any of the ingredients in Prolia. See the end of this leaflet for a complete list of ingredients in Prolia.

Before taking Prolia, tell your doctor about all of your medical conditions, including if you:

• are taking a medicine called Xgeva (denosumab). Xgeva contains the same medicine as Prolia.
• have low blood calcium.
• cannot take daily calcium and vitamin D.
• had parathyroid or thyroid surgery (glands located in your neck).
• have been told you have trouble absorbing minerals in your stomach or intestines (malabsorption syndrome).
• have kidney problems or are on kidney dialysis.
• plan to have dental surgery or teeth removed.
• are pregnant or plan to become pregnant. Prolia may harm your unborn baby. Tell your doctor right away if you become pregnant while taking Prolia.
• are breastfeeding or plan to breastfeed. It is not known if Prolia passes into your breast milk. You and your doctor should decide if you will take Prolia or breastfeed. You should not do both.

Tell your doctor about all the medicines you take, including prescription and over-the-counter medicines, vitamins, and herbal supplements.

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.

How will I receive Prolia?

• Prolia is an injection that will be given to you by a healthcare professional. Prolia is injected under your skin (subcutaneous).
• You will receive Prolia 1 time every 6 months.
• You should take calcium and vitamin D as your doctor tells you to while you receive Prolia.
• If you miss a dose of Prolia, you should receive your injection as soon as you can.
• Take good care of your teeth and gums while you receive Prolia. Brush and floss your teeth regularly.
• Tell your dentist that you are receiving Prolia before you have dental work.

What are the possible side effects of Prolia?

Prolia may cause serious side effects.

• See “What is the most important information I should know about Prolia?”
• It is not known if the use of Prolia over a long period of time may cause slow healing of broken bones.

The most common side effects of Prolia in women who are being treated for osteoporosis after menopause are:

• back pain
• pain in your arms and legs
• high cholesterol
• muscle pain
• bladder infection

The most common side effects of Prolia in men with osteoporosis are:

• back pain
• joint pain
• common cold (runny nose or sore throat)

The most common side effects of Prolia in patients receiving certain treatments for prostate or breast cancer are:

• joint pain
• back pain
• pain in your arms and legs
• muscle pain

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. Call your doctor for medical advice about side effects.

You may report side effects to FDA at 1-800-FDA-1088.

How should I store Prolia if I need to pick it up from a pharmacy?

• Keep Prolia in a refrigerator at 36°F to 46°F (2°C to 8°C) in the original carton.
• Do not freeze Prolia.
• When you remove Prolia from the refrigerator, Prolia must be kept at room temperature [up to 77°F (25°C)] in the original carton and must be used within 14 days.
• Do not keep Prolia at temperatures above 77°F (25°C). Warm temperatures will affect how Prolia works.
• Do not shake Prolia.
• Keep Prolia in the original carton to protect from light.

Keep Prolia and all medicines out of the reach of children.

General information about the safe and effective use of Prolia.

Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. Do not use Prolia for a condition for which it was not prescribed. Do not give Prolia to other people, even if they have the same symptoms that you have. It may harm them. You can ask your doctor or pharmacist for information about Prolia that is written for health professionals.

What are the ingredients in Prolia?

Active ingredient: denosumab

Inactive ingredients: sorbitol, acetate, polysorbate 20, Water for Injection (USP), and sodium hydroxide

Prolia can harm an unborn baby or cause birth defects. Do not use if you are pregnant.

This medication guide provides information about the Prolia brand of denosumab. Xgeva is another brand of denosumab used to prevent bone fractures and other skeletal conditions in people with tumors that have spread to the bone.

You should not receive denosumab if you are allergic to it, or if you have low levels of calcium in your blood (hypocalcemia).

Before you receive this medication, tell your doctor if you have kidney disease (or if you are on dialysis), a weak immune system, a history of hypoparathyroidism or thyroid surgery, a history of intestinal surgery, a condition that makes it hard for your body to absorb nutrients from food, or if you are allergic to latex.

Serious infections may occur during treatment with Prolia. Call your doctor right away if you have signs of infection such as: severe skin irritation; swelling or redness anywhere on your body; pain or burning when you urinate; severe stomach pain; ear pain, trouble hearing; cough, feeling short of breath; purple or red spots under your skin; or fever, chills, night sweats, flu symptoms, or weight loss.

Some people using denosumab have developed bone loss in the jaw, also called osteonecrosis of the jaw. Symptoms may include jaw pain, swelling, numbness, loose teeth, gum infection, or slow healing after injury or surgery involving the gums. You may be more likely to develop osteonecrosis of the jaw if you have cancer or have been treated with chemotherapy, radiation, or steroids. Other conditions associated with osteonecrosis of the jaw include blood clotting disorders, anemia (low red blood cells), and a pre-existing dental problem.

If you need to have any dental work (especially surgery), tell the dentist ahead of time that you are receiving denosumab. You may need to stop using the medicine for a short time.

Follow your doctor's instructions about any restrictions on food, beverages, or activity.

The following serious adverse reactions are discussed below and also elsewhere in the labeling:

• Hypocalcemia [see WARNINGS AND PRECAUTIONS]
• Serious Infections [see WARNINGS AND PRECAUTIONS]
• Dermatologic Adverse Reactions [see WARNINGS AND PRECAUTIONS]
• Osteonecrosis of the Jaw [see WARNINGS AND PRECAUTIONS]
• Atypical Subtrochanteric and Diaphyseal Femoral Fractures [see WARNINGS AND PRECAUTIONS]
• Multiple Vertebral Fractures (MVF) Following Discontinuation of Prolia Treatment [see WARNINGS AND PRECAUTIONS]

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 adverse reactions reported with Prolia in men with osteoporosis are back pain, arthralgia, and nasopharyngitis.

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 in patients with postmenopausal osteoporosis are back pain and constipation.

To report Adverse Reactions with Prolia®, please call Amgen Medical Information at 1-800-772-6436, email medinfo@amgen.com, or report the event at FDA MedWatch.

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 Prolia 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 Prolia 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.

The incidence of all-cause mortality was 2.3% (n = 90) in the placebo group and 1.8% (n = 70) in the Prolia group. The incidence of nonfatal serious adverse events was 24.2% in the placebo group and 25.0% in the Prolia group. The percentage of patients who withdrew from the study due to adverse events was 2.1% and 2.4% for the placebo and Prolia groups, respectively.

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

Table 1: Adverse Reactions Occurring in ≥ 2% of Patients with Osteoporosis and More Frequently than in Placebo-treated Patients

Decreases in serum calcium levels to less than 8.5 mg/dL at any visit were reported in 0.4% women in the placebo group and 1.7% women in the Prolia group. The nadir in serum calcium level occurs at approximately day 10 after Prolia 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. In a study of 55 subjects with varying degrees of renal function, serum calcium levels < 7.5 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. In a study of 4550 postmenopausal women with osteoporosis, the mean change from baseline in serum calcium level 10 days after Prolia dosing was -5.5% in subjects with creatinine clearance < 30 mL/min vs. -3.1% in subjects with creatinine clearance ≥ 30 mL/min.

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 Prolia may increase the risk of infection.

In the clinical study of 7808 postmenopausal women with osteoporosis, the incidence of infections resulting in death was 0.2% in both placebo and Prolia treatment groups. However, the incidence of nonfatal serious infections was 3.3% in the placebo and 4.0% in the Prolia groups. Hospitalizations due to serious infections in the abdomen (0.7% placebo vs. 0.9% Prolia), urinary tract (0.5% placebo vs. 0.7% Prolia), and ear (0.0% placebo vs. 0.1% Prolia) were reported. Endocarditis was reported in no placebo patients and 3 patients receiving Prolia.

Skin infections, including erysipelas and cellulitis, leading to hospitalization were reported more frequently in patients treated with Prolia ( < 0.1% placebo vs. 0.4% Prolia).

The incidence of opportunistic infections was similar to that reported with placebo.

A significantly higher number of patients treated with Prolia developed epidermal and dermal adverse events (such as dermatitis, eczema, and rashes), with these events reported in 8.2% of the placebo and 10.8% of the Prolia groups (p < 0.0001). Most of these events were not specific to the injection site [see WARNINGS AND PRECAUTIONS].

ONJ has been reported in the osteoporosis clinical trial program in patients treated with Prolia [see WARNINGS AND PRECAUTIONS].

In the osteoporosis clinical trial program, atypical femoral fractures were reported in patients treated with Prolia. The duration of Prolia exposure to time of atypical femoral fracture diagnosis was as early as 2½ years [see WARNINGS AND PRECAUTIONS].

In the osteoporosis clinical trial program, multiple vertebral fractures were reported in patients after discontinuation of Prolia. In the phase 3 trial in women with postmenopausal osteoporosis, 6% of women who discontinued Prolia and remained in the study developed new vertebral fractures, and 3% of women who discontinued Prolia 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 Prolia. Prior vertebral fracture was a predictor of multiple vertebral fractures after discontinuation [see WARNINGS AND PRECAUTIONS].

Pancreatitis was reported in 4 patients (0.1%) in the placebo and 8 patients (0.2%) in the Prolia groups. Of these reports, 1 patient in the placebo group and all 8 patients in the Prolia group had serious events, including one death in the Prolia group. Several patients had a prior history of pancreatitis. The time from product administration to event occurrence was variable.

The overall incidence of new malignancies was 4.3% in the placebo and 4.8% in the Prolia groups. New malignancies related to the breast (0.7% placebo vs. 0.9% Prolia), reproductive system (0.2% placebo vs. 0.5% Prolia), and gastrointestinal system (0.6% placebo vs. 0.9% Prolia) were reported. A causal relationship to drug exposure has not been established.

Treatment To Increase Bone Mass In Men With Osteoporosis

The safety of Prolia 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 Prolia 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.

The incidence of all-cause mortality was 0.8% (n = 1) in the placebo group and 0.8% (n = 1) in the Prolia group. The incidence of nonfatal serious adverse events was 7.5% in the placebo group and 8.3% in the Prolia group. The percentage of patients who withdrew from the study due to adverse events was 0% and 2.5% for the placebo and Prolia groups, respectively.

Adverse reactions reported in ≥ 5% of men with osteoporosis and more frequently with Prolia than in the placebo-treated patients were: back pain (6.7% placebo vs. 8.3% Prolia), arthralgia (5.8% placebo vs. 6.7% Prolia), and nasopharyngitis (5.8% placebo vs. 6.7% Prolia).

Serious infection was reported in 1 patient (0.8%) in the placebo group and no patients in the Prolia group.

Epidermal and dermal adverse events (such as dermatitis, eczema, and rashes) were reported in 4 patients (3.3%) in the placebo group and 5 patients (4.2%) in the Prolia group.

No cases of ONJ were reported.

Pancreatitis was reported in 1 patient (0.8%) in the placebo group and 1 patient (0.8%) in the Prolia group.

New malignancies were reported in no patients in the placebo group and 4 (3.3%) patients (3 prostate cancers, 1 basal cell carcinoma) in the Prolia group.

The safety of Prolia 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 Prolia 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.

The incidence of serious adverse events was 30.6% in the placebo group and 34.6% in the Prolia group. The percentage of patients who withdrew from the study due to adverse events was 6.1% and 7.0% for the placebo and Prolia groups, respectively.

The safety of Prolia 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 Prolia 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.

The incidence of serious adverse events was 9.2% in the placebo group and 14.7% in the Prolia group. The percentage of patients who withdrew from the study due to adverse events was 4.2% and 0.8% for the placebo and Prolia groups, respectively.

Adverse reactions reported in ≥ 10% of Prolia-treated patients receiving ADT for prostate cancer or adjuvant AI therapy for breast cancer, and more frequently than in the placebo-treated patients were: arthralgia (13.0% placebo vs. 14.3% Prolia) and back pain (10.5% placebo vs. 11.5% Prolia). Pain in extremity (7.7% placebo vs. 9.9% Prolia) and musculoskeletal pain (3.8% placebo vs. 6.0% Prolia) 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 (1.2% placebo vs. 4.7% Prolia). Hypocalcemia (serum calcium < 8.4 mg/dL) was reported only in Prolia-treated patients (2.4% vs. 0%) at the month 1 visit.

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.

The following adverse reactions have been identified during post approval use of Prolia:

• Drug-related hypersensitivity reactions: anaphylaxis, rash, urticaria, facial swelling, and erythema
• Hypocalcemia: severe symptomatic hypocalcemia
• Musculoskeletal pain, including severe cases
• Parathyroid Hormone (PTH): Marked elevation in serum PTH in patients with severe renal impairment (creatinine clearance < 30 mL/min) or receiving dialysis.
• Multiple vertebral fractures following discontinuation of Prolia

Immunogenicity

Denosumab is a human monoclonal antibody. As with all therapeutic proteins, there is potential for immunogenicity. Using an electrochemiluminescent bridging immunoassay, less than 1% (55 out of 8113) of patients treated with Prolia for up to 5 years tested positive for binding antibodies (including pre-existing, transient, and developing antibodies). None of the patients tested positive for neutralizing antibodies, as was assessed using a chemiluminescent cell-based in vitro biological assay. No evidence of altered pharmacokinetic profile, toxicity profile, or clinical response was associated with binding antibody development.

The incidence of antibody formation is highly dependent on the sensitivity and specificity of the assay. Additionally, the observed incidence of a positive antibody (including neutralizing antibody) test result may be influenced by several factors, including assay methodology, sample handling, timing of sample collection, concomitant medications, and underlying disease. For these reasons, comparison of antibodies to denosumab with the incidence of antibodies to other products may be misleading.

Read the entire FDA prescribing information for Prolia (Denosumab Injection)