Jubereq

Description for Jubereq

Denosumab-desu is a human IgG2 monoclonal antibody that binds to human RANKL. Denosumab-desu has an approximate molecular weight of 147 kDa and is produced in genetically engineered mammalian (Chinese hamster ovary) cells.

Jubereq (denosumab-desu) injection is a sterile, preservative-free, clear, colorless to pale yellow solution for subcutaneous use.

Each single-dose vial contains 1.7 mL solution of 120 mg denosumab-desu, 1.84 mg glacial acetic acid, 0.17 mg polysorbate 20, 78.2 mg sorbitol, Water for Injection, and sodium hydroxide to adjust to a pH of 5.2.

ADVERSE REACTIONS

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

• Hypersensitivity [see Warnings and Precautions (5.2)]
• Hypocalcemia [see Warnings and Precautions (5.3) and Use in Specific Populations (8.6)]
• Osteonecrosis of the Jaw [see Warnings and Precautions (5.4)]
• Atypical Subtrochanteric and Diaphyseal Femoral Fracture [see Warnings and Precautions (5.5)]
• Hypercalcemia following treatment discontinuation in patients with giant cell tumor of bone and in patients with growing skeletons [see Warnings and Precautions (5.6) and Use in Specific Populations (8.4)]
• Multiple vertebral fractures (MVF) following treatment discontinuation [see Warnings and Precautions (5.7)]

Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

Bone Metastasis from Solid Tumors

The safety of denosumab was evaluated in three randomized, double-blind, double-dummy trials [see Clinical Trials (14.1)] in which a total of 2841 patients with bone metastasis from prostate cancer, breast cancer, or other solid tumors, or lytic bony lesions from multiple myeloma received at least one dose of denosumab. In Studies 20050136, 20050244, and 20050103, patients were randomized to receive either 120 mg of denosumab every 4 weeks as a subcutaneous injection or 4 mg (dose adjusted for reduced renal function) of zoledronic acid every 4 weeks by intravenous (IV) infusion. Entry criteria included serum calcium (corrected) from 8 to 11.5 mg/dL (2 to 2.9 mmol/L) and creatinine clearance 30 mL/min or greater. Patients who had received IV bisphosphonates were excluded, as were patients with prior history of ONJ or osteomyelitis of the jaw, an active dental or jaw condition requiring oral surgery, non-healed dental/oral surgery, or any planned invasive dental procedure. During the study, serum chemistries including calcium and phosphorus were monitored every 4 weeks. Calcium and vitamin D supplementation was recommended but not required.

The median duration of exposure to denosumab was 12 months (range: 0.1-41) and median duration on- study was 13 months (range: 0.1-41). Of patients who received denosumab, 46% were female. Eighty- five percent were White, 5% Hispanic/Latino, 6% Asian, and 3% Black. The median age was 63 years (range: 18-93). Seventy-five percent of patients who received denosumab received concomitant chemotherapy.

The most common adverse reactions in patients (incidence greater than or equal to 25%) were fatigue/asthenia, hypophosphatemia, and nausea (see Table 1). The most common serious adverse reaction was dyspnea. The most common adverse reactions resulting in discontinuation of denosumab were osteonecrosis and hypocalcemia.

Table 1: Selected^a Adverse Reactions of Any Severity (Studies 20050136, 20050244, and 20050103)

Body System	Denosumab n = 2841 %	Zoledronic Acid n = 2836 %
GASTROINTESTINAL
Nausea	31	32
Diarrhea	20	19
GENERAL
Fatigue/Asthenia	45	46
INVESTIGATIONS
Hypocalcemiab	18	9
Hypophosphatemiab	32	20
NEUROLOGICAL
Headache	13	14
RESPIRATORY
Dyspnea	21	18
Cough	15	15
a Adverse reactions reported in at least 10% of patients receiving denosumab in Studies 20050136, 20050244, and 20050103, and meeting one of the following criteria: At least 1% greater incidence in denosumab-treated patients, or Between-group difference (either direction) of less than 1% and more than 5% greater incidence in patients treated with zoledronic acid compared to placebo (US Prescribing Information for zoledronic acid) b Laboratory-derived and below the central laboratory lower limit of normal [8.3 -8.5 mg/dL (2.075 -2.125 mmol/L) for calcium and 2.2 -2.8 mg/dL (0.71 -0.9 mmol/L) for phosphorus]

Severe Mineral/Electrolyte Abnormalities

• Severe hypocalcemia (corrected serum calcium less than 7 mg/dL or less than 1.75 mmol/L) occurred in 3.1% of patients treated with denosumab and 1.3% of patients treated with zoledronic acid. Of patients who experienced severe hypocalcemia, 33% experienced 2 or more episodes of severe hypocalcemia and 16% experienced 3 or more episodes [see Warnings and Precautions (5.3) and Use in Specific Populations (8.6)].
• Severe hypophosphatemia (serum phosphorus less than 2 mg/dL or less than 6 mmol/L) occurred in 15% of patients treated with denosumab and 7% of patients treated with zoledronic acid.

Osteonecrosis of the Jaw (ONJ)

In the primary treatment phases of Studies 20050136, 20050244, and 20050103, ONJ was confirmed in 1.8% of patients in the denosumab group (median exposure of 12.0 months; range: 0.1-41) and 1.3% of patients in the zoledronic acid group. The trials in patients with breast (Study 20050136) or prostate (Study 20050103) cancer included an open-label extension treatment phase where patients were offered denosumab 120 mg once every 4 weeks (median overall exposure of 14.9 months; range: 0.1-67.2). The patient-year adjusted incidence (number of events per 100 patient years) of confirmed ONJ was 1.1% during the first year of treatment, 3.7% in the second year, and 4.6% per year thereafter. The median time to ONJ was 20.6 months (range: 4-53) [see Warnings and Precautions (5.4)].

In a placebo-controlled clinical trial with an extension treatment phase evaluating denosumab for the prevention of bone metastases in patients with non-metastatic prostate cancer (a patient population for which denosumab is not indicated), with longer treatment exposure of up to 7 years, the patient-year adjusted incidence (number of events per 100 patient years) of confirmed ONJ was 1.1% during the first year of treatment, 3% in the second year, and 7% per year thereafter.

Atypical Subtrochanteric and Diaphyseal Fracture

In the clinical trial program, atypical femoral fracture has been reported in patients treated with denosumab and the risk increased with longer duration of treatment. Events have occurred during treatment and after treatment was discontinued [see Warnings and Precautions (5.5)].

Multiple Myeloma

The safety of denosumab was evaluated in an international, randomized (1:1), double-blind, active- controlled trial of patients with newly diagnosed multiple myeloma with treatment through disease progression [see Clinical Trials (14.2)]. In this trial, patients received 120 mg denosumab every 4 weeks as a subcutaneous injection (n = 850) or 4 mg (dose adjusted for renal function) of zoledronic acid intravenously (IV) every 4 weeks by IV infusion (n = 852). Entry criteria included serum calcium (corrected) from 8 to 11.5 mg/dL (2 to 2.9 mmol/L) and creatinine clearance 30 mL/min or greater.

Patients who had received IV bisphosphonates were excluded, as were patients with prior history of ONJ or osteomyelitis of the jaw, an active dental or jaw condition requiring oral surgery, non-healed dental/oral surgery, or any planned invasive dental procedure. During the study, serum chemistries including calcium and phosphorus were monitored every 4 weeks. Calcium and vitamin D supplementation was recommended but not required.

The median duration of exposure to denosumab was 16 months (range: 1-50) and median duration on- study was 17 months (range: 0-49). Of patients who received denosumab, 46% were female, 83% percent were White, 13% Asian, 3% Black or African American, and 4% Hispanic/Latino. The median age of the patients randomized to denosumab was 63 years (range: 29-91) and all patients who received denosumab received concomitant anti-myeloma chemotherapy.

The adverse reaction profile of denosumab in patients with multiple myeloma, Study 20090482, was similar to that observed in Studies 20050136, 20050244, and 20050103. The most common adverse reactions (incidence ≥ 10%) were diarrhea (34%), nausea (32%), anemia (22%), back pain (21%), thrombocytopenia (19%), peripheral edema (17%), hypocalcemia (16%), upper respiratory tract infection (15%), rash (14%), and headache (11%). The most common serious adverse reaction (incidence ≥ 5%) was pneumonia (8%). The most common adverse reaction resulting in discontinuation of denosumab (≥ 1%) was osteonecrosis of the jaw.

Hypocalcemia and Hypophosphatemia

Severe hypocalcemia (corrected serum calcium less than 7 mg/dL or less than 1.75 mmol/L) and severe hypophosphatemia (serum phosphorus less than 2 mg/dL or less than 0.6 mmol/L) occurred in 2% and 21% patients treated with denosumab, respectively.

Osteonecrosis of the Jaw (ONJ)

In the primary treatment phase of Study 20090482, ONJ was confirmed in 4.1% of patients in the denosumab group (median exposure of 16 months; range: 1-50) and 2.8% of patients in the zoledronic acid group (median 15 months, range: 1-45 months). At the completion of the double-blind treatment phase of Study 20090482, the patient-year adjusted incidence (number of events per 100 patient years) of confirmed ONJ in the denosumab group (median exposure of 19.4 months; range 1-52) was 2% during the first year of treatment, 5% in the second year, and 4.5% per year thereafter. The median time to ONJ was 18.7 months (range: 1-44) [see Warnings and Precautions (5.4)].

Giant Cell Tumor of Bone

The safety of denosumab was evaluated in two single-arm trials (Study 20062004 and Study 20040215) [see Clinical Trials (14.3)] in which a total of 548 adult or skeletally mature adolescent patients with giant cell tumor of bone received at least 1 dose of denosumab. Patients received 120 mg denosumab subcutaneously every 4 weeks with additional 120 mg doses on Days 8 and 15 of the first month of therapy. Patients receiving concurrent bisphosphonate therapy were excluded from enrollment in both studies. Patients with prior history of ONJ or osteomyelitis of the jaw, an active dental or jaw condition requiring oral surgery, non-healed dental/oral surgery, or any planned invasive dental procedure were excluded from enrollment in Study 20040215. During the trial, serum chemistries including calcium and phosphorus were monitored every 4 weeks. Calcium and vitamin D supplementation was recommended but not required.

Of the 548 patients who received denosumab, 467 patients were treated with denosumab for ≥ 1 year, 323 patients for ≥ 2 years, and 255 patients for ≥ 3 years. The median number of doses received was 33 (range: 4-138 doses) and the median number of months on-study was 60 (range: 0-140 months). Fifty- seven percent of the enrolled patients were women and 82% were White. The median age was 33 years (range: 13-83 years); a total of 19 patients were skeletally mature adolescents (12 to <17 years of age).

The common adverse reaction profile of denosumab in patients with giant cell tumor of bone was generally similar to that reported in Studies 20050136, 20050244, and 20050103. The most common adverse reactions in patients (incidence ≥ 10%) were arthralgia, back pain, pain in extremity, fatigue, headache, nausea, nasopharyngitis, musculoskeletal pain, toothache, vomiting, hypophosphatemia, constipation, diarrhea, and cough. The most frequent serious adverse reactions were osteonecrosis of the jaw (3.6%), bone giant cell tumor (1.5%), anemia (1.1%), pneumonia (0.9%), and back pain (0.9%). The most frequent adverse reactions resulting in discontinuation of denosumab was osteonecrosis of the jaw (incidence of 3.6%). The adverse reaction profile appeared similar in skeletally mature adolescents and adults.

Hypocalcemia and Hypophosphatemia

• Moderate to severe hypocalcemia (corrected serum calcium less than 8 mg/dL or less than 2 mmol/L) occurred in 5% of patients treated with denosumab.
• Severe hypophosphatemia (serum phosphorus less than 2 to 1 mg/dL or less than 6 to 0.3 mmol/L) occurred in 20% of patients treated with denosumab.

Osteonecrosis of the Jaw (ONJ)

In the pooled analysis of Study 20062004 and Study 20040215, ONJ was confirmed in 7% of patients who received denosumab (median number of doses received: 33; range: 4-138 doses).

Study 20140114 (NCT03301857) was a 5-year long term follow-up study for patients (n=85) who completed Study 20062004. In Study 20062004 and Study 20140114 combined, ONJ was confirmed in 7% of patients who received denosumab (median time on trial 62.2 months (range 0 – 173). The combined patient-year adjusted incidence (number of events per 100 patient years) of confirmed ONJ was 0.2% during the first year of treatment, 1.5% in the second year, 1.8% in the third year, 2.1% in the fourth year, 1.4% in the fifth year, and 1.5% thereafter [see Warnings and Precautions (5.4)].

Atypical Subtrochanteric and Diaphyseal Fracture

In the pooled analysis of Study 20062004 and Study 20040215, atypical femoral fracture was observed in 0.9% of patients who received denosumab (median number of doses received: 33; range: 4-138 doses).

In Study 20062004 and Study 20140114, the combined incidence of confirmed atypical femoral fracture was 1.3% of patients who received denosumab [see Warnings and Precautions (5.5)].

Hypercalcemia Following Treatment Discontinuation

In the pooled safety population, 0.7% of patients experienced serious adverse events of hypercalcemia > 30 days following treatment discontinuation that was recurrent in some patients [see Warnings and Precautions (5.6)].

Hypercalcemia of Malignancy

Denosumab was evaluated in an open-label, single-arm trial (Study 20070315) in which 33 patients with hypercalcemia of malignancy (with or without bone metastases) refractory to treatment with intravenous bisphosphonate therapy were enrolled [see Clinical Trials (14.4)].

The adverse reaction profile of denosumab in patients with hypercalcemia of malignancy was similar to that reported in Studies 20050136, 20050244, 20050103, 20062004, and 20040215. Adverse reactions occurring in greater than 20% of patients were nausea (30%), dyspnea (27%), decreased appetite (24%), headache (24%), peripheral edema (24%), vomiting (24%), anemia (21%), constipation (21%), and diarrhea (21%). The following adverse reactions of Grade 3 or greater severity related to study therapy were reported on-study: fatigue (3%) and infection (6%). Grade 3 laboratory abnormalities included hypomagnesemia (3%), hypokalemia (3%), and hypophosphatemia (76%) of patients. No deaths on-study were related to denosumab therapy.

Postmarketing Experience

The following adverse reactions have been identified during post-approval use of denosumab products. Because these 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.

• Hypocalcemia: Severe symptomatic hypocalcemia, including fatal cases [see Contraindications (4.1) and Warnings and Precautions (5.3)].
• Hypercalcemia: Severe symptomatic hypercalcemia following treatment discontinuation can occur [see Adverse Reactions (6) and Warnings and Precautions (5.6)].
• Hypersensitivity, including anaphylactic reactions [see Contraindications (4.2) and Warnings and Precautions (5.2)].
• Musculoskeletal pain, including severe musculoskeletal Positive re-challenge has been reported.
• Lichenoid drug eruptions (e.g., lichen planus-like reactions).
• Alopecia.

Drug Interactions for Jubereq

No information provided.

Warnings for Jubereq

Included as part of the PRECAUTIONS section.

Precautions for Jubereq

Drug Products with Same Active Ingredient

Patients receiving Jubereq should not receive other denosumab products concomitantly.

Hypersensitivity

Clinically significant hypersensitivity including anaphylaxis has been reported with use of denosumab products. Reactions may include hypotension, dyspnea, upper airway edema, lip swelling, rash, pruritus, and urticaria. If an anaphylactic or other clinically significant allergic reaction occurs, initiate appropriate therapy and discontinue Jubereq therapy permanently [see Contraindications (4.2) and Adverse Reactions (6.2)].

Hypocalcemia

Denosumab products can cause severe symptomatic hypocalcemia, and fatal cases have been reported. Correct pre-existing hypocalcemia prior to Jubereq treatment. Monitor calcium levels, throughout Jubereq therapy, especially in the first weeks of initiating therapy, and administer calcium, magnesium, and vitamin D as necessary. Concomitant use of calcimimetics and other drugs that can lower calcium levels may worsen hypocalcemia risk and serum calcium should be closely monitored. Advise patients to contact a healthcare provider for symptoms of hypocalcemia [see Contraindications (4.1), Adverse Reactions (6.1, 6.2), and Patient Counseling Information (17)].

An increased risk of hypocalcemia has been observed in clinical trials of patients with increasing renal dysfunction, most commonly with severe dysfunction (creatinine clearance less than 30 mL/min and/or on dialysis), and with inadequate/no calcium supplementation. Monitor calcium levels and calcium and vitamin D intake [see Adverse Reactions (6.1), Use in Specific Populations (8.6), and Clinical Pharmacology (12.3)].

Osteonecrosis of the Jaw (ONJ)

Osteonecrosis of the jaw (ONJ) has been reported in patients receiving denosumab products, manifesting as jaw pain, osteomyelitis, osteitis, bone erosion, tooth or periodontal infection, toothache, gingival ulceration, or gingival erosion. Persistent pain or slow healing of the mouth or jaw after dental surgery may also be manifestations of ONJ. In clinical trials in patients with cancer, the incidence of ONJ was higher with longer duration of exposure [see Adverse Reactions (6.1)]. Seventy-nine percent of patients with ONJ had a history of tooth extraction, poor oral hygiene, or use of a dental appliance as a predisposing factor. Other risk factors for the development of ONJ include immunosuppressive therapy, treatment with angiogenesis inhibitors, systemic corticosteroids, diabetes, and gingival infections.

Similarly, for denosumab-treated patients with multiple myeloma that developed ONJ, 58% had a history of invasive dental procedures as a predisposing factor.

Perform an oral examination and appropriate preventive dentistry prior to the initiation of Jubereq and periodically during Jubereq therapy. Advise patients regarding oral hygiene practices. Avoid invasive dental procedures during treatment with Jubereq. Consider temporary discontinuation of Jubereq therapy if an invasive dental procedure must be performed. There are no data available to suggest the optimal duration of treatment interruption.

Patients who are suspected of having or who develop ONJ while on Jubereq should receive care by a dentist or an oral surgeon. In these patients, extensive dental surgery to treat ONJ may exacerbate the condition. Clinical judgment of the treating healthcare provider should guide the management plan of each patient based on individual risk/benefit assessment.

Atypical Subtrochanteric and Diaphyseal Femoral Fracture

Atypical femoral fracture has been reported with denosumab products [see Adverse Reactions (6.1)]. These fractures can occur anywhere in the femoral shaft from just below the lesser trochanter to above the supracondylar flare and are transverse or short oblique in orientation without evidence of comminution.

Atypical femoral fractures most commonly occur with minimal or no trauma to the affected area. They may be bilateral and many patients report prodromal pain in the affected area, usually presenting as dull, aching thigh pain, weeks to months before a complete fracture occurs. A number of reports note that patients were also receiving treatment with glucocorticoids (e.g. prednisone) at the time of fracture.

During Jubereq 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 suspected of having an atypical fracture and should be evaluated to rule out an incomplete femur fracture. Patient presenting with an atypical femur fracture should also be assessed for symptoms and signs of fracture in the contralateral limb. Interruption of Jubereq therapy should be considered, pending a risk/benefit assessment, on an individual basis.

Hypercalcemia Following Treatment Discontinuation in Patients with Giant Cell Tumor of Bone and in Patients with Growing Skeletons

Clinically significant hypercalcemia requiring hospitalization and complicated by acute renal injury has been reported in denosumab product-treated patients with giant cell tumor of bone and patients with growing skeletons. Hypercalcemia has been reported within the first year after treatment discontinuation. After treatment is discontinued, monitor patients for signs and symptoms of hypercalcemia, assess serum calcium periodically, reevaluate the patient’s calcium and vitamin D supplementation requirements and manage patients as clinically appropriate [see Adverse Reactions (6) and Use in Specific Populations (8.4)].

Multiple Vertebral Fractures (MVF) Following Treatment Discontinuation

Multiple vertebral fractures (MVF) have been reported following discontinuation of treatment with denosumab products. Patients at higher risk for MVF include those with risk factors for or a history of osteoporosis or prior fractures.

When Jubereq treatment is discontinued, evaluate the individual patient’s risk for vertebral fractures [see Patient Counseling Information (17)].

Embryo-Fetal Toxicity

Based on data from animal studies and its mechanism of action, denosumab products can cause fetal harm when administered to a pregnant woman. In animal reproduction studies, administration of denosumab to cynomolgus monkeys throughout pregnancy at a dose 25-fold higher than the recommended human dose of denosumab based on body weight resulted in increased fetal loss, stillbirths, and postnatal mortality, along with evidence of absent peripheral lymph nodes, abnormal bone growth and decreased neonatal growth.

Verify the pregnancy status of females of reproductive potential prior to the initiation of Jubereq. Advise pregnant women and females of reproductive potential that exposure to Jubereq during pregnancy or within 5 months prior to conception can result in fetal harm. Advise females of reproductive potential to use effective contraception during therapy, and for at least 5 months after the last dose of Jubereq [see Use in Specific Populations (8.1, 8.3) and Clinical Pharmacology (12.1)].

NONCLINICAL TOXICOLOGY

Carcinogenesis, Mutagenesis, Impairment of Fertility

Carcinogenesis

The carcinogenic potential of denosumab products has not been evaluated in long-term animal studies.

Mutagenesis

The genotoxic potential of denosumab products has not been evaluated.

Impairment of Fertility

Denosumab had no effect on female fertility or male reproductive organs in monkeys at doses that were 6.5- to 25-fold higher than the recommended human dose of 120 mg subcutaneously administered once every 4 weeks, based on body weight (mg/kg).

OVERDOSES

There is no experience with overdosage of denosumab products.

Contraindications for Jubereq

Hypocalcemia

Pre-existing hypocalcemia must be corrected prior to initiating therapy with Jubereq [see Warnings and Precautions (5.3)].

Hypersensitivity

Jubereq is contraindicated in patients with known clinically significant hypersensitivity to denosumab products [see Warnings and Precautions (5.2) and Adverse Reactions (6.2)].

Clinical Pharmacology for Jubereq

Mechanism Of Action

Denosumab products bind to RANKL, a transmembrane or soluble protein essential for the formation, function, and survival of osteoclasts, the cells responsible for bone resorption, thereby modulating calcium release from bone. Increased osteoclast activity, stimulated by RANKL, is a mediator of bone pathology in solid tumors with osseous metastases. Similarly, giant cell tumors of bone consist of stromal cells expressing RANKL and osteoclast-like giant cells expressing RANK receptor, and signaling through the RANK receptor contributes to osteolysis and tumor growth. Denosumab products prevent RANKL from activating its receptor, RANK, on the surface of osteoclasts, their precursors, and osteoclast-like giant cells.

Pharmacodynamics

In patients with breast cancer and bone metastases, the median reduction in uNTx/Cr was 82% within 1 week following initiation of denosumab 120 mg administered subcutaneously. In Studies 20050136, 20050244, and 20050103, the median reduction in uNTx/Cr from baseline to Month 3 was approximately 80% in 2075 denosumab-treated patients.

In a phase 3 study of patients with newly diagnosed multiple myeloma who received subcutaneous doses of denosumab 120 mg every 4 weeks (Q4W), median reductions in uNTx/Cr of approximately 75% were observed by Week 5. Reductions in bone turnover markers were maintained, with median reductions of 74% to 79% for uNTx/Cr from weeks 9 to 49 of continued 120 mg Q4W dosing.

In adult and skeletally mature adolescent patients with giant cell tumor of bone who received subcutaneous doses of denosumab 120 mg Q4W with a 120 mg loading dose on Days 8 and 15, median reductions in uNTx/Cr from baseline were 84% at Week 13 and 82% at Week 25.

Pharmacokinetics

Following subcutaneous administration, bioavailability was 62%. Denosumab displayed nonlinear pharmacokinetics at doses below 60 mg, but approximately dose-proportional increases in exposure at higher doses.

With multiple subcutaneous doses of 120 mg once every 4 weeks, up to 2.8-fold accumulation in serum denosumab concentrations was observed and steady-state was achieved by 6 months. A mean (± standard deviation) serum steady-state trough concentration of 20.5 (± 13.5) mcg/mL was achieved by 6 months. The mean elimination half-life was 28 days.

In patients with newly diagnosed multiple myeloma who received 120 mg every 4 weeks, denosumab concentrations appear to reach steady-state by Month 6. In patients with giant cell tumor of bone, after administration of subcutaneous doses of 120 mg once every 4 weeks with additional 120 mg doses on Days 8 and 15 of the first month of therapy, mean (± standard deviation) serum trough concentrations on Day 8, 15, and one month after the first dose were 19.0 (± 24.1), 31.6 (± 27.3), 36.4 (± 20.6) mcg/mL, respectively. Steady-state was achieved in 3 months after initiation of treatment with a mean serum trough concentration of 23.4 (± 12.1) mcg/mL.

Special Populations

Body Weight: A population pharmacokinetic analysis was performed to evaluate the effects of demographic characteristics. Denosumab clearance and volume of distribution were proportional to body weight. The steady-state exposure following repeat subcutaneous administration of 120 mg every 4 weeks to 45 kg and 120 kg subjects were, respectively, 48% higher and 46% lower than exposure of the typical 66 kg subject.

Age, Gender and Race: The pharmacokinetics of denosumab was not affected by age, gender, and race.

Pediatrics: In skeletally-mature adolescent patients (12 to 16 years of age) with giant cell tumor of bone (GCTB) who received 120 mg every 4 weeks with a 120 mg loading dose on Days 8 and 15, the pharmacokinetics of denosumab were comparable to those observed in adult patients with GCTB.

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

Renal Impairment: In clinical trials of 87 patients with varying degrees of renal dysfunction, including patients on dialysis, the degree of renal impairment had no effect on the pharmacokinetics and pharmacodynamics of denosumab [see Use in Specific Populations (8.6)].

Drug Interactions

No formal drug-drug interaction trials have been conducted with denosumab. There was no evidence that various anticancer treatments affected denosumab systemic exposure and pharmacodynamic effect.

Serum denosumab concentrations at 1 and 3 months and reductions in the bone turnover marker uNTx/Cr (urinary N-terminal telopeptide corrected for creatinine) at 3 months were similar in patients with and without prior intravenous bisphosphonate therapy and were not altered by concomitant chemotherapy and/or hormone therapy.

Immunogenicity

The observed incidence of anti-drug antibodies is highly dependent on the sensitivity and specificity of the assay. Differences in assay methods preclude meaningful comparisons of the incidence of anti-drug antibodies in the studies described below with the incidence of anti-drug antibodies in other studies, including those of denosumab or of other denosumab products.

Using an electrochemiluminescent bridging immunoassay, less than 1% (55 out of 8113) of patients treated with denosumab 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. There was no identified clinically significant effect of anti-drug antibodies on pharmacokinetics, pharmacodynamics, safety, or effectiveness of denosumab.

Animal Toxicology and/or Pharmacology

Denosumab products are inhibitors of osteoclastic bone resorption via inhibition of RANKL.

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, OPG-Fc and RANK-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.

Patient Information for Jubereq

Drug Products with Same Active Ingredient

Advise patients that if they receive Jubereq, they should not receive other denosumab products concomitantly [see Warnings and Precautions (5.1)].

Hypersensitivity

Advise patients to seek prompt medical attention if signs or symptoms of hypersensitivity reactions occur. Advise patients who have had signs or symptoms of systemic hypersensitivity reactions that they should not receive denosumab products [see Warnings and Precautions (5.2) and Contraindications (4.2)].

Hypocalcemia

Adequately supplement patients with calcium and vitamin D and instruct them on the importance of maintaining serum calcium levels while receiving Jubereq [see Warnings and Precautions (5.3) and Use in Specific Populations (8.6)]. Advise patients to seek prompt medical attention if they develop signs or symptoms of hypocalcemia.

Osteonecrosis of the Jaw

Advise patients to maintain good oral hygiene during treatment with Jubereq and to inform their dentist prior to dental procedures that they are receiving Jubereq. Patients should avoid invasive dental procedures during treatment with Jubereq and inform their healthcare provider 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)].

Atypical Subtrochanteric and Diaphyseal Femoral Fracture

Advise patients to report new or unusual thigh, hip, or groin pain [see Warnings and Precautions (5.5)].

Hypercalcemia Following Treatment Discontinuation in Patients with Giant Cell Tumor of Bone and in  Patients with Growing Skeletons

Advise patients to report nausea, vomiting, headache, and decreased alertness following treatment discontinuation [see Warnings and Precautions (5.6) and Use in Specific Populations (8.4)].

Multiple Vertebral Fractures (MVF) Following Treatment Discontinuation

Advise patients that after treatment with Jubereq is stopped there may be an increased risk of having broken bones in the spine especially in patients who have had a fracture or who have had osteoporosis. Advise patients not to interrupt Jubereq therapy without their physician’s advice [see Warnings and Precautions (5.7)].

Embryo-Fetal Toxicity

Advise females of reproductive potential that Jubereq can cause harm to a fetus and to inform their healthcare provider of a known or suspected pregnancy [see Warnings and Precautions (5.8) and Use in Specific Populations (8.1, 8.3)].

Advise females of reproductive potential to use effective contraception during treatment and for at least 5 months after the last dose of Jubereq [see Use in Specific Populations (8.3)].

Jubereq (denosumab-desu)

Manufactured by:
Accord BioPharma Inc.
8041 Arco Corporate Drive,
Suite 200, Raleigh, NC, USA 27617
U.S. License No. 2105