Osenvelt Drug Information

Multiple Myeloma and Bone Metastasis from Solid Tumors Osenvelt is indicated for

the prevention of skeletal-related events in patients with multiple myeloma and in patients with bone metastases from solid tumors.

Giant Cell Tumor of Bone Osenvelt is indicated for the treatment of

adults and skeletally mature adolescents with giant cell tumor of bone that is unresectable or where surgical resection is likely to result in severe morbidity .

Hypercalcemia of Malignancy Osenvelt is indicated for the treatment of hypercalcemia of

malignancy refractory to bisphosphonate therapy.

Important

Administration Instructions Osenvelt should be administered by a healthcare provider. Osenvelt is intended for subcutaneous route only and should not be administered intravenously, intramuscularly, or intradermally.

Multiple Myeloma and Bone Metastasis from Solid Tumors

The recommended dose of Osenvelt is 120 mg administered as a subcutaneous injection every 4 weeks in the upper arm, upper thigh, or abdomen. Administer calcium and vitamin D as necessary to treat or prevent hypocalcemia.

Giant Cell Tumor of Bone

The recommended dose of Osenvelt is 120 mg administered every 4 weeks with additional 120 mg doses on Days 8 and 15 of the first month of therapy. Administer subcutaneously in the upper arm, upper thigh, or abdomen. Administer calcium and vitamin D as necessary to treat or prevent hypocalcemia.

Hypercalcemia of Malignancy

The recommended dose of Osenvelt is 120 mg administered every 4 weeks with additional 120 mg doses on Days 8 and 15 of the first month of therapy. Administer subcutaneously in the upper arm, upper thigh, or abdomen.

Preparation and

Administration Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration. Osenvelt is a clear, colorless to pale yellow solution. Do not use if the solution is discolored or cloudy or if the solution contains particles or foreign particulate matter.

Prior to administration, Osenvelt may be removed from the refrigerator and brought to room temperature up to 25°C (77°F) by standing in the original carton. This generally takes 15 to 30 minutes. Do not warm Osenvelt in any other way.

Use a 27-gauge needle to withdraw and inject the entire contents of the vial. Do not re-enter the vial. Discard vial after single-dose or entry.

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 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 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) 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 Hypocalcemia Laboratory-derived and below the central laboratory lower limit of normal 18 9 Hypophosphatemia 32 20 NEUROLOGICAL Headache 13 14 RESPIRATORY Dyspnea 21 18 Cough 15 15 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 . Severe hypophosphatemia (serum phosphorus less than 2 mg/dL or less than 0.6 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 a denosumab 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) . 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. 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 . 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% 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) . Giant Cell Tumor of Bone The safety of denosumab was evaluated in two single-arm trials (Study 20062004 and Study 20040215) 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 0.6 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 . 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 . 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 . 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 . 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 . Hypercalcemia: Severe symptomatic hypercalcemia following treatment discontinuation can occur . Hypersensitivity, including anaphylactic reactions . Musculoskeletal pain, including severe musculoskeletal pain.

Positive re-challenge has been reported. Lichenoid drug eruptions (e.g., lichen planus-like reactions). Alopecia.

Pregnancy Risk Summary Based on findings in animals and its mechanism of action, denosumab products can cause fetal harm when administered to a pregnant woman . There are insufficient data with denosumab products use in pregnant women to inform any drug associated risks for adverse developmental outcomes. In utero denosumab exposure from cynomolgus monkeys dosed monthly with denosumab 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; and absent lymph nodes, abnormal bone growth, and decreased neonatal growth . Apprise pregnant women of the potential risk to the fetus. The background rate of major birth defects and miscarriage is unknown for the indicated population.

In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively. Data Animal Data The effects of denosumab on prenatal development have been studied in both cynomolgus monkeys and genetically engineered mice in which RANK ligand (RANKL) expression was turned off by gene removal (a "knockout mouse"). In cynomolgus monkeys dosed subcutaneously with denosumab throughout pregnancy starting at gestational day 20 and at a pharmacologically active dose 25-fold higher than the recommended human dose of denosumab based on body weight, there was increased fetal loss during gestation, stillbirths, and postnatal mortality. Other findings in offspring included absence of axillary, inguinal, mandibular, and mesenteric lymph nodes; abnormal bone growth, reduced bone strength, reduced hematopoiesis, dental dysplasia, and tooth malalignment; and decreased neonatal growth.

At birth out to one month of age, infants had measurable blood levels of denosumab (22-621% of maternal levels). Following a recovery period from birth out to 6 months of age, the effects on bone quality and strength returned to normal; there were no adverse effects on tooth eruption, though dental dysplasia was still apparent; axillary and inguinal lymph nodes remained absent, while mandibular and mesenteric lymph nodes were present, though small; and minimal to moderate mineralization in multiple tissues was seen in one recovery animal. There was no evidence of maternal harm prior to labor; adverse maternal effects occurred infrequently during labor. Maternal mammary gland development was normal.

There was no fetal NOAEL (no observable adverse effect level) established for this study because only one dose of 50 mg/kg was evaluated. Mammary gland histopathology at 6 months of age was normal in female offspring exposed to denosumab in utero ; however, development and lactation have not been fully evaluated. In RANKL knockout mice, absence of RANKL (the target of denosumab) also caused fetal lymph node agenesis and led to postnatal impairment of dentition and bone growth.

Pregnant RANKL knockout mice showed altered maturation of the maternal mammary gland, leading to impaired lactation.

Pediatric Use The safety and efficacy of Osenvelt have not been established in pediatric patients except in skeletally mature adolescents (aged 12-16 years) with giant cell tumor of bone. Osenvelt is recommended only for treatment of skeletally mature adolescents (aged 12-16 years) with giant cell tumor of bone. Clinically significant hypercalcemia after treatment discontinuation has been reported in pediatric patients with growing skeletons who received denosumab products for giant cell tumor of bone or for unapproved indications.

Denosumab was studied in an open-label trial that enrolled a subset of 19 adolescent patients (aged 12-16 years) with giant cell tumor of bone who had reached skeletal maturity, defined by at least 1 mature long bone (e.g., closed epiphyseal growth plate of the humerus), and had a body weight ≥ 45 kg. A total of one of five (20%) evaluable adolescent patients had an objective response by retrospective independent assessment of radiographic response according to modified Response Evaluation Criteria in Solid Tumors (RECIST 1.1). The adverse reaction profile and efficacy results appeared to be similar in skeletally mature adolescents and adults . Animal Data Treatment with denosumab products 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 denosumab 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 treated with denosumab at doses 5 and 25 times (10 and 50 mg/kg dose) higher than the recommended human dose of 120 mg administered once every 4 weeks, based on body weight (mg/kg), had abnormal growth plates, considered to be consistent with the pharmacological activity of denosumab. Cynomolgus monkeys exposed in utero to denosumab exhibited bone abnormalities, reduced hematopoiesis, tooth malalignment, decreased neonatal growth, and an absence of axillary, inguinal, mandibular, and mesenteric lymph nodes. Some bone abnormalities recovered once exposure was ceased following birth; however, axillary and inguinal lymph nodes remained absent 6 months post-birth.

Hypersensitivity Osenvelt is contraindicated in patients with known clinically significant hypersensitivity to

denosumab products .

There is no experience with overdosage of denosumab products.