DENO

Denosumab is a novel, fully human IgG2 monoclonal antibody specific to receptor activator of nuclear factor kappa-B ligand (RANKL), suppresses bone resorption via inhibiting RANK-mediated activation of osteoclasts.

It is the first and currently the only RANKL inhibitor approved to prevent osteoclast-mediated bone loss.

Chemically, it consists of 2 heavy and 2 light chains, with each light chain consisting of 215 amino acids and each heavy chain consisting of 448 amino acids with 4 intramolecular disulfides.

Denosumab was approved by the FDA approved on June for the treatment of osteoporosis in postmenopausal women.

It further received additional indication approval to increase bone mass in men at high risk for fracture receiving androgen deprivation therapy for non-metastatic prostate cancer and women at high risk for fracture receiving adjuvant aromatase inhibitor therapy for breast cancer in September and in men with osteoporosis at high risk for fracture in September 2012.

An Denosumab biosimilar, Jubbonti, was approved for Health Canada in February 2024. 9.

Two denosumab biosimilars—Wyost® (denosumab-bbdz) 11 and Jubbonti® (denosumab-bbdz) 10 —were approved by the FDA in March for all indications of the reference products Xgeva® and Prolia®; Both biosimilars also received marketing authorization in the EU in May 2024. 12 13.

Denosumab under the brand name

Prolia is indicated as a treatment for osteoporosis in menopausal women or men and glucocorticoid-induced osteoporosis in men and women at high risk of fracture.

It is also used to increase bone mass in men at high risk for fractures receiving androgen deprivation therapy for nonmetastatic prostate cancer or women at high risk for fractures receiving adjuvant aromatase inhibitor therapy for breast cancer.

Xgeva is indicated to prevent skeletal-related events in patients with multiple myeloma and in patients with bone metastases from solid tumors and to treat giant cell tumors of bone in adults and skeletally mature adolescents and hypercalcemia of malignancy refractory to bisphosphonate therapy.

In clinical studies, treatment with 60 mg of denosumab resulted in a 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 1-3 months after dosing of denosumab.

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 denosumab on bone remodelling.

These effects were sustained with continued treatment.

Upon reinitiation, the degree of inhibition of CTX by denosumab was similar to that observed in patients initiating denosumab 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 ) were observed starting 1 month after the first dose of denosumab.

After discontinuation of denosumab therapy, markers of bone resorption increased to levels 40% to 60% above pretreatment values but returned to baseline levels within 12 months.

In patients with breast cancer and bone metastases, the median reduction in urinary N-terminal telopeptide corrected for creatinine (uNTx/Cr) was 82% within 1 week following initiation of denosumab 120 mg administered Subcutaneous.

In Studies 20050136, 20050244, and 20050103, the median reduction in uNTx/Cr from baseline to Month 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 9-49 of continued 120 mg Q4W dosing.

In a study conducted in healthy male and female volunteers (n = 73, age range: 18-64 years) following a single Subcutaneous administered denosumab dose of 60 mg after fasting (at least for 12 hours), the mean maximum denosumab concentration (C max ) was 6.75 mcg/mL (standard deviation = 1.89 mcg/mL).

The median time to maximum denosumab concentration (T max ) was 10 days (range: 3-21 days).

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 Subcutaneous administered once every 6 months. 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) C max 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) T max values in the serum and seminal fluid samples were 8.0 and 21 days, respectively.

Among the subjects, the highest denosumab concentration in the 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).

In patients with newly diagnosed multiple myeloma who received 120 mg every 4 weeks, denosumab concentrations appear to reach a 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 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.

The central volume of distribution and volume of distribution at steady-state were calculated to be 2.49 L/66 kg and 3.5-7 L respectively.

No information is available on the metabolism of denosumab.

As an antibody, denosumab is likely cleared by the reticuloendothelial system with minimal renal filtration and excretion.

C max, serum denosumab concentrations declined over a period of 4-5 months with a mean half-life of 25.4 days (SD = 8.5 days; n = 46).

No information is available on the clearance of denosumab.

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Denosumab is contraindicated for use in pregnant women because it may cause harm to a fetus.

There are insufficient data with denosumab 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 50-fold higher than the recommended human dose based on body weight resulted in increased fetal loss, stillbirths, and postnatal mortality, and absent lymph nodes abnormal bone growth, and decreased neonatal growth.

In clinical trials, hypercalcemia has been reported in pediatric patients with osteogenesis imperfect treated with denosumab products, including Prolia.

Some cases required hospitalization and were complicated by acute renal injury.

Based on results from animal studies, denosumab may negatively affect long-bone growth and dentition in pediatric patients below the age of 4 years.

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

Denosumab had no effect on female fertility or male reproductive organs in monkeys at doses that were 13.

• to 50-fold higher than the recommended human dose of 60 mg Subcutaneous administered once every 6 months, based on body weight (mg/kg).

Stoboclo is contraindicated in

Patients with hypocalcemia: Pre-existing hypocalcemia must be corrected prior to initiating therapy with Stoboclo.

Pregnant women

Denosumab products may cause fetal harm when administered to a pregnant woman.

In women of reproductive potential, pregnancy testing should be performed prior to initiating treatment with Stoboclo.

Patients with hypersensitivity to denosumab products

Stoboclo is contraindicated in patients with a history of systemic hypersensitivity to any component of the product.

Reactions have included anaphylaxis, facial swelling, and urticaria.

Known hypersensitivity to denosumab products.

Pregnancy must be ruled out prior to administration of Stoboclo.

Before initiating

Stoboclo in patients with advanced chronic kidney disease, including dialysis patients, evaluate for the presence of chronic kidney disease mineral and bone disorder with intact parathyroid hormone, serum calcium, 25(OH) vitamin D, and 1,25(OH) 2 vitamin D. Stoboclo should be administered by a healthcare provider.

Administer 60 mg every 6 months as a subcutaneous injection in the upper arm, upper thigh, or abdomen.

Instruct patients to take calcium 1000 mg daily and at least 400 IU vitamin D daily. 2.1 Pregnancy Testing Prior to Initiation of Stoboclo Pregnancy must be ruled out prior to administration of Stoboclo.

Perform pregnancy testing in all females of reproductive potential prior to administration of Stoboclo.

Based on findings in animals, denosumab products can cause fetal harm when administered to pregnant women. 2.2 Laboratory Testing in Patients with Advanced Chronic Kidney Disease Prior to Initiation of Stoboclo In patients with advanced chronic kidney disease [i.e., estimated glomerular filtration rate (eGFR) < 30 mL/min/1.73 m 2 ], including dialysis-dependent patients, evaluate for the presence of chronic kidney disease mineral and bone disorder (CKD-MBD) with intact parathyroid hormone (iPTH), serum calcium, 25(OH) vitamin D, and 1,25 (OH) 2 vitamin D prior to decisions regarding Stoboclo treatment.

Consider also assessing bone turnover status (serum markers of bone turnover or bone biopsy) to evaluate the underlying bone disease that may be present. 2.3 Recommended Dosage Stoboclo should be administered by a healthcare provider.

The recommended dose of

Stoboclo is 60 mg administered as a single subcutaneous injection once every 6 months.

Stoboclo via subcutaneous injection in the upper arm, the upper thigh, or the abdomen.

All patients should receive calcium 1000 mg daily and at least 400 IU vitamin D daily.

If a dose of

Stoboclo is missed, administer the injection as soon as the patient is available.

Thereafter, schedule injections every 6 months from the date of the last injection. 2.4 Preparation and Administration Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration whenever solution and container permit.

Stoboclo 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, Stoboclo 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 to 30 minutes.

Do not warm

Stoboclo in any other way.

Instructions for Administration of Prefilled Syringe with Safety Guard IMPORTANT: To reduce the risk of accidental needle stick injury, each prefilled syringe has a safety guard that is automatically activated to cover the needle after you have given the injection.

Do not pull back on the plunger rod at any time.

Step 1: Remove the Needle Cap Dispose of the needle cap right away in the nearest sharps disposal container.

DO NOT re-cap the prefilled syringe.

Step 2: Administer Subcutaneous Injection Choose an appropriate injection site.

The recommended injection sites for

Stoboclo include: the outer area of the upper arms OR the upper legs (thighs) OR around the stomach area (abdomen).

Inject all of the liquid by using your thumb to push the plunger rod all the way down.

If the plunger rod is not fully pressed, the safety guard will not extend to cover the needle when it is removed.

Step 3: Remove the prefilled syringe from the injection site After the prefilled syringe is empty, slowly remove the needle by lifting your thumb from the plunger rod until the needle is completely covered by the safety guard.

Do not rub the injection site.

Immediately dispose of the prefilled syringe in the nearest sharps disposal container.

Stoboclo (denosumab-bmwo) injection is a clear, colorless to pale yellow solution supplied in a single-dose prefilled syringe with a safety guard.

The prefilled syringe is not made with natural rubber latex. 60 mg/mL in a single-dose prefilled syringe 1 per carton NDC 72606-037-01 Storage and Handling Store Stoboclo refrigerated at 2°C to 8°C (36°F to 46°F) in the original carton to protect from light.

Do not freeze.

Prior to administration, Stoboclo may be allowed to reach room temperature up to 25°C (77°F) in the original carton.

Stoboclo may be stored at temperatures up to a maximum 25°C (77°F) for a single period of up to 63 days but not exceeding the original expiry date.

If necessary, the product may be returned to the refrigerator once within 63 days and provided this does not exceed the original expiry date.

It must be used after subsequent removal from refrigeration.

Stoboclo if not used or returned to refrigerator within the 63 days.

Do not use

Stoboclo after the expiry date printed on the label.

Stoboclo from direct light and heat.

Avoid vigorous shaking of

Stoboclo refrigerated at 2°C to 8°C (36°F to 46°F) in the original carton to protect from light.

Do not freeze.

Prior to administration, Stoboclo may be allowed to reach room temperature up to 25°C (77°F) in the original carton.

Stoboclo may be stored at temperatures up to a maximum 25°C (77°F) for a single period of up to 63 days but not exceeding the original expiry date.

If necessary, the product may be returned to the refrigerator once within 63 days and provided this does not exceed the original expiry date.

It must be used after subsequent removal from refrigeration.

Stoboclo if not used or returned to refrigerator within the 63 days.

Do not use

Stoboclo after the expiry date printed on the label.

Stoboclo from direct light and heat.

Avoid vigorous shaking of

Stoboclo is contraindicated for use in pregnant women because it may cause harm to a fetus.

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 50-fold higher than the recommended human dose based on body weight resulted in increased fetal loss, stillbirths, and postnatal mortality, and absent lymph nodes, abnormal bone growth, and decreased neonatal growth.

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 and at a pharmacologically active dose 50-fold higher than the recommended human dose 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 1 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.

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

The no effect dose for denosumab product-induced teratogenicity is unknown.

However, a C max of 22.9 ng/mL was identified in cynomolgus monkeys as a level in which no biologic effects (NOEL) of denosumab were observed (no inhibition of RANKL) .

The safety and effectiveness of

Stoboclo have not been established in pediatric patients.

In one multicenter, open-label study with denosumab conducted in 153 pediatric patients with osteogenesis imperfecta, aged to 17 years, evaluating fracture risk reduction, efficacy was not demonstrated.

Hypercalcemia has been reported in pediatric patients with osteogenesis imperfecta treated with denosumab products.

Some cases required hospitalization and were complicated by acute renal injury.

Clinical studies in pediatric patients with osteogenesis imperfecta were terminated early due to the occurrence of life-threatening events and hospitalizations due to hypercalcemia.

Safety and effectiveness were not demonstrated for the treatment of glucocorticoid-induced osteoporosis in one multicenter, randomized, double-blind, placebo-controlled, parallel-group study conducted in 24 pediatric patients with glucocorticoid-induced osteoporosis, aged to 17 years, evaluating change from baseline in lumbar spine BMD Z-score.

Based on results from animal studies, denosumab may negatively affect long-bone growth and dentition in pediatric patients below the age of 4 years.

Treatment with denosumab products may impair long-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 and 50 times (10 and 50 mg/kg dose) higher than the recommended human dose of 60 mg administered every 6 months, 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, an absence of axillary, inguinal, mandibular, and mesenteric lymph nodes, reduced hematopoiesis, tooth malalignment, and decreased neonatal growth.

Some bone abnormalities recovered once exposure was ceased following birth; however, axillary, and inguinal lymph nodes remained absent 6 months post-birth.

Of the total number of patients in clinical studies of denosumab, 9943 patients (76%) were ≥ 65 years old, while 3576 (27%) were ≥ 75 years old.

Of the patients in the osteoporosis study in men, 133 patients (55%) were ≥ 65 years old, while 39 patients (16%) were ≥ 75 years old.

Of the patients in the glucocorticoid-induced osteoporosis study, 355 patients (47%) were ≥ 65 years old, while 132 patients (17%) were ≥ 75 years old.

No overall differences in safety or efficacy were observed between these patients and younger patients, and other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out.