Conexxence Drug Information
Generic name: DENOSUMAB
RANK Ligand Inhibitor [EPC]
Uses of Conexxence
Treatment of Postmenopausal Women with Osteoporosis at High Risk for Fracture Conexxence
is indicated for the treatment of postmenopausal women with osteoporosis at high risk for fracture, defined as a history of osteoporotic fracture, or multiple risk factors for fracture; or patients who have failed or are intolerant to other available osteoporosis therapy. In postmenopausal women with osteoporosis, denosumab reduces the incidence of vertebral, nonvertebral, and hip fractures.
Treatment to Increase Bone Mass in Men with Osteoporosis Conexxence is indicated
for treatment to increase bone mass in men with osteoporosis at high risk for fracture, defined as a history of osteoporotic fracture, or multiple risk factors for fracture; or patients who have failed or are intolerant to other available osteoporosis therapy.
Treatment of Glucocorticoid-Induced Osteoporosis Conexxence is indicated for the treatment of glucocorticoid-induced
osteoporosis in men and women at high risk of fracture who are either initiating or continuing systemic glucocorticoids in a daily dosage equivalent to 7.5 mg or greater of prednisone and expected to remain on glucocorticoids for at least 6 months. High risk of fracture is defined as a history of osteoporotic fracture, multiple risk factors for fracture, or patients who have failed or are intolerant to other available osteoporosis therapy .
Treatment of Bone Loss in Men Receiving Androgen Deprivation Therapy for Prostate
Cancer Conexxence is indicated as a treatment to increase bone mass in men at high risk for fracture receiving androgen deprivation therapy (ADT) for nonmetastatic prostate cancer. In these patients denosumab also reduced the incidence of vertebral fractures .
Treatment of Bone Loss in Women Receiving Adjuvant Aromatase Inhibitor Therapy for
Breast Cancer Conexxence is indicated as a treatment to increase bone mass in women at high risk for fracture receiving adjuvant aromatase inhibitor therapy for breast cancer .
Dosage & Administration of Conexxence
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Side Effects of Conexxence
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 denosumab 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 denosumab 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 denosumab group. The incidence of nonfatal serious adverse events was 24.2% in the placebo group and 25.0% in the denosumab group.
The percentage of patients who withdrew from the study due to adverse events was 2.1% and 2.4% for the placebo and denosumab groups, respectively. The most common adverse reactions reported with denosumab in patients with postmenopausal osteoporosis are back pain, pain in extremity, musculoskeletal pain, hypercholesterolemia, and cystitis. Adverse reactions reported in ≥ 2% of postmenopausal women with osteoporosis and more frequently in the denosumab-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 Preferred Term Denosumab (N = 3886) n (%) Placebo (N = 3876) n (%) Back pain Pain in extremity Musculoskeletal pain Hypercholesterolemia Cystitis Vertigo Upper respiratory tract infection Edema peripheral Sciatica Bone pain Abdominal pain upper Anemia Insomnia Myalgia Angina pectoris Rash Pharyngitis Asthenia Pruritus Flatulence Spinal osteoarthritis Gastroesophageal reflux disease Herpes zoster 1347 453 297 280 228 195 190 189 178 142 129 129 126 114 101 96 91 90 87 84 82 80 79 1340 430 291 236 225 187 167 155 149 117 111 107 122 94 87 79 78 73 82 53 64 66 72 Hypocalcemia 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 denosumab group. The nadir in serum calcium level occurred at approximately day 10 after denosumab 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 denosumab dosing was -5.5% in subjects with creatinine clearance < 30 mL/min vs. -3.1% in subjects with creatinine clearance ≥ 30 mL/min. Serious Infections 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 denosumab products 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 denosumab treatment groups. However, the incidence of nonfatal serious infections was 3.3% in the placebo and 4.0% in the denosumab groups. Hospitalizations due to serious infections in the abdomen (0.7% placebo vs. 0.9% denosumab), urinary tract (0.5% placebo vs. 0.7% denosumab), and ear (0.0% placebo vs. 0.1% denosumab) were reported.
Endocarditis was reported in no placebo patients and 3 patients receiving denosumab. Skin infections, including erysipelas and cellulitis, leading to hospitalization were reported more frequently in patients treated with denosumab (< 0.1% placebo vs. 0.4% denosumab). The incidence of opportunistic infections was similar to that reported with placebo. Dermatologic Adverse Reactions A significantly higher number of patients treated with denosumab 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 denosumab groups (p < 0.0001). Most of these events were not specific to the injection site.
Osteonecrosis of the Jaw ONJ has been reported in the osteoporosis clinical trial program in patients treated with denosumab. Atypical Subtrochanteric and Diaphyseal Femoral Fractures In the osteoporosis clinical trial program, atypical femoral fractures were reported in patients treated with denosumab. The duration of denosumab exposure to time of atypical femoral fracture diagnosis was as early as 2½ years . Multiple Vertebral Fractures (MVF) Following Treatment Discontinuation In the osteoporosis clinical trial program, multiple vertebral fractures were reported in patients after discontinuation of denosumab.
In the phase 3 trial in women with postmenopausal osteoporosis, 6% of women who discontinued denosumab and remained in the study developed new vertebral fractures, and 3% of women who discontinued denosumab 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 denosumab. Prior vertebral fracture was a predictor of multiple vertebral fractures after discontinuation . Pancreatitis Pancreatitis was reported in 4 patients (0.1%) in the placebo and 8 patients (0.2%) in the denosumab groups.
Of these reports, 1 patient in the placebo group and all 8 patients in the denosumab group had serious events, including one death in the denosumab group. Several patients had a prior history of pancreatitis. The time from product administration to event occurrence was variable.
New Malignancies The overall incidence of new malignancies was 4.3% in the placebo and 4.8% in the denosumab groups. New malignancies related to the breast (0.7% placebo vs. 0.9% denosumab), reproductive system (0.2% placebo vs. 0.5% denosumab), and gastrointestinal system (0.6% placebo vs. 0.9% denosumab) were reported. A causal relationship to drug exposure has not been established.
Treatment to Increase Bone Mass in Men with Osteoporosis The safety of denosumab 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 denosumab 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 denosumab group. The incidence of nonfatal serious adverse events was 7.5% in the placebo group and 8.3% in the denosumab group. The percentage of patients who withdrew from the study due to adverse events was 0% and 2.5% for the placebo and denosumab groups, respectively.
Adverse reactions reported in ≥ 5% of men with osteoporosis and more frequently with denosumab than in the placebo-treated patients were: back pain (6.7% placebo vs. 8.3% denosumab), arthralgia (5.8% placebo vs. 6.7% denosumab), and nasopharyngitis (5.8% placebo vs. 6.7% denosumab). Serious Infections Serious infection was reported in 1 patient (0.8%) in the placebo group and no patients in the denosumab group. Dermatologic Adverse Reactions 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 denosumab group. Osteonecrosis of the Jaw No cases of ONJ were reported.
Pancreatitis Pancreatitis was reported in 1 patient (0.8%) in the placebo group and 1 patient (0.8%) in the denosumab group. New Malignancies 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 denosumab group. Treatment of Glucocorticoid-Induced Osteoporosis The safety of denosumab in the treatment of glucocorticoid-induced osteoporosis was assessed in the 1-year, primary analysis of a 2-year randomized, multicenter, double-blind, parallel-group, active-controlled study of 795 patients (30% men and 70% women) aged 20 to 94 (mean age of 63 years) treated with greater than or equal to 7.5 mg/day oral prednisone (or equivalent). A total of 384 patients were exposed to 5 mg oral daily bisphosphonate (active-control) and 394 patients were exposed to denosumab administered once every 6 months as a 60 mg subcutaneous dose.
All patients 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 0.5% (n = 2) in the active-control group and 1.5% (n = 6) in the denosumab group. The incidence of serious adverse events was 17% in the active-control group and 16% in the denosumab group.
The percentage of patients who withdrew from the study due to adverse events was 3.6% and 3.8% for the active-control and denosumab groups, respectively. Adverse reactions reported in ≥ 2% of patients with glucocorticoid-induced osteoporosis and more frequently with denosumab than in the active-control-treated patients are shown in the table below. Table 2. Adverse Reactions Occurring in ≥ 2% of Patients with Glucocorticoid-induced Osteoporosis and More Frequently with Denosumab than in Active-Control-treated Patients *Events of worsening of underlying polymyalgia rheumatica.
Preferred Term Denosumab (N=394) n (%) Oral Daily Bisphosphonate (Active-Control) (N=384) n (%) Back pain 18 17 Hypertension 15 13 Bronchitis 15 11 Headache 14 7 Dyspepsia 12 10 Urinary tract infection 12 8 Abdominal pain upper 12 7 Upper respiratory tract infection 11 10 Constipation 11 6 Vomiting 10 6 Dizziness 9 8 Fall 8 7 Polymyalgia rheumatica* 8 1 Osteonecrosis of the Jaw No cases of ONJ were reported. Atypical Subtrochanteric and Diaphyseal Femoral Fractures Atypical femoral fractures were reported in 1 patient treated with denosumab. The duration of denosumab exposure to time of atypical femoral fracture diagnosis was at 8.0 months . Serious Infections Serious infection was reported in 15 patients (3.9%) in the active-control group and 17 patients (4.3%) in the denosumab group.
Dermatologic Adverse Reactions Epidermal and dermal adverse events (such as dermatitis, eczema, and rashes) were reported in 16 patients (4.2%) in the active-control group and 15 patients (3.8%) in the denosumab group. Treatment of Bone Loss in Patients Receiving Androgen Deprivation Therapy for Prostate Cancer or Adjuvant Aromatase Inhibitor Therapy for Breast Cancer The safety of denosumab 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 denosumab 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 denosumab group. The percentage of patients who withdrew from the study due to adverse events was 6.1% and 7.0% for the placebo and denosumab groups, respectively.
The safety of denosumab 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 denosumab 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 denosumab group. The percentage of patients who withdrew from the study due to adverse events was 4.2% and 0.8% for the placebo and denosumab groups, respectively. Adverse reactions reported in ≥ 10% of denosumab -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% denosumab) and back pain (10.5% placebo vs. 11.5% denosumab). Pain in extremity (7.7% placebo vs. 9.9% denosumab) and musculoskeletal pain (3.8% placebo vs. 6.0% denosumab) have also been reported in clinical trials.
Additionally, in denosumab-treated men with nonmetastatic prostate cancer receiving ADT, a greater incidence of cataracts was observed (1.2% placebo vs. 4.7% denosumab). Hypocalcemia (serum calcium < 8.4 mg/dL) was reported only in denosumab -treated patients (2.4% vs. 0.0%) 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 denosumab products: Drug-related hypersensitivity reactions: anaphylaxis, rash, urticaria, facial swelling, and erythema Hypocalcemia: severe symptomatic hypocalcemia resulting in hospitalization, life-threatening events, and fatal cases 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 treatment discontinuation Cutaneous and mucosal lichenoid drug eruptions (e.g. lichen planus-like reactions) Alopecia Vasculitis (e.g. ANCA positive vasculitis, leukocytoclastic vasculitis) Drug reaction with eosinophilia and systemic symptoms (DRESS) syndrome
Warnings & Cautions for Conexxence
Severe Hypocalcemia and Mineral Metabolism Changes Denosumab products can cause severe hypocalcemia
and fatal cases have been reported. Pre-existing hypocalcemia must be corrected prior to initiating therapy with Conexxence. Adequately supplement all patients with calcium and vitamin D. In patients without advanced chronic kidney disease who are predisposed to hypocalcemia and disturbances of mineral metabolism (e.g. history of hypoparathyroidism, thyroid surgery, parathyroid surgery, malabsorption syndromes, excision of small intestine, treatment with other calcium-lowering drugs), assess serum calcium and mineral levels (phosphorus and magnesium) 10 to14 days after Conexxence injection.
In some postmarketing cases, hypocalcemia persisted for weeks or months and required frequent monitoring and intravenous and/or oral calcium replacement, with or without vitamin D. Patients with Advanced Chronic Kidney Disease Patients with advanced chronic kidney disease including dialysis-dependent patients are at greater risk for severe hypocalcemia following denosumab products administration. Severe hypocalcemia resulting in hospitalization, life-threatening events and fatal cases have been reported. The presence of underlying chronic kidney disease-mineral bone disorder (CKD-MBD, renal osteodystrophy) markedly increases the risk of hypocalcemia.
Concomitant use of calcimimetic drugs may also worsen hypocalcemia risk. To minimize the risk of hypocalcemia in patients with advanced chronic kidney disease, evaluate for the presence of chronic kidney disease mineral and bone disorder with intact parathyroid hormone (iPTH), serum calcium, 25(OH) vitamin D, and 1,25(OH) 2 vitamin D prior to decisions regarding Conexxence 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.
Monitor serum calcium weekly for the first month after Conexxence administration and monthly thereafter. Instruct all patients with advanced chronic kidney disease, including those who are dialysis-dependent, about the symptoms of hypocalcemia and the importance of maintaining serum calcium levels with adequate calcium and activated vitamin D supplementation. Treatment with Conexxence in these patients should be supervised by a healthcare provider who is experienced in diagnosis and management of CKD-MBD.
Drug Products with Same Active Ingredient Patients receiving Conexxence should not receive
other denosumab products concomitantly.
Hypersensitivity Clinically significant hypersensitivity including anaphylaxis has been reported with denosumab products.
Symptoms have included hypotension, dyspnea, throat tightness, facial and upper airway edema, pruritus, and urticaria. If an anaphylactic or other clinically significant allergic reaction occurs, initiate appropriate therapy and discontinue further use of Conexxence .
Osteonecrosis of the Jaw Osteonecrosis of the jaw (ONJ), which can occur
spontaneously, is generally associated with tooth extraction and/or local infection with delayed healing. ONJ has been reported in patients receiving denosumab products. A routine oral exam should be performed by the prescriber prior to initiation of Conexxence treatment.
A dental examination with appropriate preventive dentistry is recommended prior to treatment with Conexxence in patients with risk factors for ONJ such as invasive dental procedures (e.g. tooth extraction, dental implants, oral surgery), diagnosis of cancer, concomitant therapies (e.g. chemotherapy, corticosteroids, angiogenesis inhibitors), poor oral hygiene, and comorbid disorders (e.g. periodontal and/or other pre-existing dental disease, anemia, coagulopathy, infection, ill-fitting dentures). Good oral hygiene practices should be maintained during treatment with Conexxence. Concomitant administration of drugs associated with ONJ may increase the risk of developing ONJ. The risk of ONJ may increase with duration of exposure to denosumab products. For patients requiring invasive dental procedures, clinical judgment of the treating physician and/or oral surgeon should guide the management plan of each patient based on individual benefit-risk assessment.
Patients who are suspected of having or who develop ONJ while on Conexxence should receive care by a dentist or an oral surgeon. In these patients, extensive dental surgery to treat ONJ may exacerbate the condition. Discontinuation of Conexxence therapy should be considered based on individual benefit-risk assessment.
Atypical Subtrochanteric and Diaphyseal Femoral Fractures Atypical low energy or low trauma
fractures of the shaft have been reported in patients receiving denosumab products . 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. Causality has not been established as these fractures also occur in osteoporotic patients who have not been treated with antiresorptive agents. 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 Conexxence 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. Patients presenting with an atypical femur fracture should also be assessed for symptoms and signs of fracture in the contralateral limb. Interruption of Conexxence therapy should be considered, pending a benefit-risk assessment, on an individual basis.
Multiple Vertebral Fractures (MVF) Following Discontinuation of Treatment Following discontinuation of denosumab
treatment, fracture risk increases, including the risk of multiple vertebral fractures. Treatment with denosumab results in significant suppression of bone turnover and cessation of denosumab treatment results in increased bone turnover above pretreatment values 9 months after the last dose of denosumab. Bone turnover then returns to pretreatment values 24 months after the last dose of denosumab.
In addition, bone mineral density (BMD) returns to pretreatment values within 18 months after the last injection. New vertebral fractures occurred as early as 7 months (on average 19 months) after the last dose of denosumab. Prior vertebral fracture was a predictor of multiple vertebral fractures after denosumab discontinuation.
Evaluate an individual's benefit-risk before initiating treatment with Conexxence. If Conexxence treatment is discontinued, patients should be transitioned to an alternative antiresorptive therapy .
Serious Infections
In a clinical trial of over 7800 women with postmenopausal osteoporosis, serious infections leading to hospitalization were reported more frequently in the denosumab group than in the placebo group . Serious skin infections, as well as infections of the abdomen, urinary tract, and ear, were more frequent in patients treated with denosumab. Endocarditis was also reported more frequently in denosumab-treated patients. The incidence of opportunistic infections was similar between placebo and denosumab groups, and the overall incidence of infections was similar between the treatment groups.
Advise patients to seek prompt medical attention if they develop signs or symptoms of severe infection, including cellulitis. Patients on concomitant immunosuppressant agents or with impaired immune systems may be at increased risk for serious infections. Consider the benefit-risk profile in such patients before treating with Conexxence.
In patients who develop serious infections while on Conexxence, prescribers should assess the need for continued Conexxence therapy.
Dermatologic Adverse Reactions
In a large clinical trial of over 7800 women with postmenopausal osteoporosis, epidermal and dermal adverse events such as dermatitis, eczema, and rashes occurred at a significantly higher rate in the denosumab group compared to the placebo group. Most of these events were not specific to the injection site . Consider discontinuing Conexxence if severe symptoms develop.
Musculoskeletal Pain
In postmarketing experience, severe and occasionally incapacitating bone, joint, and/or muscle pain has been reported in patients taking denosumab products . The time to onset of symptoms varied from one day to several months after starting denosumab products. Consider discontinuing use if severe symptoms develop . 5.10 Suppression of Bone Turnover In clinical trials in women with postmenopausal osteoporosis, treatment with denosumab resulted in significant suppression of bone remodeling as evidenced by markers of bone turnover and bone histomorphometry . The significance of these findings and the effect of long-term treatment with denosumab products are unknown. The long-term consequences of the degree of suppression of bone remodeling observed with denosumab may contribute to adverse outcomes such as osteonecrosis of the jaw, atypical fractures, and delayed fracture healing.
Monitor patients for these consequences. 5.11 Hypercalcemia in Pediatric Patients with Osteogenesis Imperfecta Conexxence is not approved for use in pediatric patients. Hypercalcemia has been reported in pediatric patients with osteogenesis imperfecta treated with denosumab products. Some cases required hospitalization .
Pregnancy Safety for Conexxence
Pregnancy Risk Summary Conexxence 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 . 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 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. Pregnant 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).
Pediatric Use of Conexxence
Pediatric Use The safety and effectiveness of Conexxence have not been established in pediatric patients. In one multicenter, open-label study with denosumab conducted in 153 pediatric patients with osteogenesis imperfecta, aged 2 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. Based on results from animal studies, denosumab may negatively affect long-bone growth and dentition in pediatric patients below the age of 4 years. Juvenile Animal Toxicity Data 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 10 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 .
Contraindications for Conexxence
- Conexxence is contraindicated in: Patients with hypocalcemia: Pre-existing hypocalcemia must be corrected prior to initiating therapy with Conexxence .
- 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 Conexxence .
- Patients with hypersensitivity to denosumab products: Conexxence is contraindicated in patients with a history of systemic hypersensitivity to any component of the product. Reactions have included anaphylaxis, facial swelling, and urticaria . Hypocalcemia Pregnancy Known hypersensitivity to denosumab products
Clinical Studies of Conexxence
Treatment of Postmenopausal Women with Osteoporosis
The efficacy and safety of denosumab 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 denosumab 60 mg (N = 3902) once every 6 months.
All women received at least 1000 mg calcium and 400 IU vitamin D supplementation daily. The primary efficacy variable was the incidence of new morphometric (radiologically-diagnosed) vertebral fractures at 3 years. Vertebral fractures were diagnosed based on lateral spine radiographs (T4-L4) using a semiquantitative scoring method.
Secondary efficacy variables included the incidence of hip fracture and nonvertebral fracture, assessed at 3 years. Effect on Vertebral Fractures Denosumab significantly reduced the incidence of new morphometric vertebral fractures at 1, 2, and 3 years (p < 0.0001), as shown in Table 3. The incidence of new vertebral fractures at year 3 was 7.2% in the placebo-treated women compared to 2.3% for the denosumab-treated women. The absolute risk reduction was 4.8% and relative risk reduction was 68% for new morphometric vertebral fractures at year 3. Table 3. The Effect of Denosumab on the Incidence of New Vertebral Fractures in Postmenopausal Women + Event rates based on crude rates in each interval. * Absolute risk reduction and relative risk reduction based on Mantel-Haenszel method adjusting for age group variable.
Proportion of Women with Fracture (%) + Absolute Risk Reduction (%) * (95% CI) Relative Risk Reduction (%) * (95% CI) Placebo N = 3691 (%) Denosumab N = 3702 (%) 0-1 Year 2.2 0.9 1.4 61 0-2 Years 5.0 1.4 3.5 71 0-3 Years 7.2 2.3 4.8 68 Denosumab was effective in reducing the risk for new morphometric vertebral fractures regardless of age, baseline rate of bone turnover, baseline BMD, baseline history of fracture, or prior use of a drug for osteoporosis. Effect on Hip Fractures The incidence of hip fracture was 1.2% for placebo-treated women compared to 0.7% for denosumab-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 N = number of subjects randomized Figure Effect on Nonvertebral Fractures Treatment with denosumab resulted in a significant reduction in the incidence of nonvertebral fractures ( Table 4 ). Table 4. The Effect of Denosumab on the Incidence of Nonvertebral Fractures at Year 3 + Event rates based on Kaplan-Meier estimates at 3 years. 1 Excluding those of the vertebrae (cervical, thoracic, and lumbar), skull, facial, mandible, metacarpus, and finger and toe phalanges. * p-value = 0.01. Proportion of Women with Fracture (%) + Absolute Risk Reduction (%) (95% CI) Relative Risk Reduction (%) (95% CI) Placebo N = 3906 (%) Denosumab N = 3902 (%) Nonvertebral fracture 1 8.0 6.5 1.5 20 * Effect on Bone Mineral Density (BMD) Treatment with denosumab 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 denosumab discontinuation, BMD returned to approximately baseline levels within 12 months. Bone Histology and Histomorphometry A total of 115 transiliac crest bone biopsy specimens were obtained from 92 postmenopausal women with osteoporosis at either month 24 and/or month 36 (53 specimens in denosumab 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 denosumab. 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 denosumab, 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 denosumab 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 denosumab 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 denosumab 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. Effect on Bone Mineral Density (BMD) 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 denosumab significantly increased BMD at 1-year. The treatment differences in BMD at 1-year were 4.8% (+0.9% placebo, +5.7% denosumab; (95% CI: 4.0, 5.6); p < 0.0001) at the lumbar spine, 2.0% (+0.3% placebo, +2.4% denosumab) at the total hip, and 2.2% (0.0% placebo, +2.1% denosumab) 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.
Bone Histology and Histomorphometry A total of 29 transiliac crest bone biopsy specimens were obtained from men with osteoporosis at 12 months (17 specimens in denosumab group, 12 specimens in placebo group). Of the biopsies obtained, 29 (100%) were adequate for qualitative histology and, in denosumab 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 denosumab. 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 denosumab, 6% had no tetracycline label present at the month 12 biopsy, while 100% of placebo-treated patients had double label present. When compared to placebo, treatment with denosumab resulted in markedly reduced bone formation rates. However, the long-term consequences of this degree of suppression of bone remodeling are unknown.
Treatment of Glucocorticoid-Induced Osteoporosis
The efficacy and safety of denosumab in the treatment of patients with glucocorticoid-induced osteoporosis was assessed in the 12-month primary analysis of a 2-year, randomized, multicenter, double-blind, parallel-group, active-controlled study (NCT 01575873) of 795 patients (70% women and 30% men) aged 20 to 94 years (mean age of 63 years) treated with greater than or equal to 7.5 mg/day oral prednisone (or equivalent) for < 3 months prior to study enrollment and planning to continue treatment for a total of at least 6 months (glucocorticoid-initiating subpopulation; n = 290) or ≥ 3 months prior to study enrollment and planning to continue treatment for a total of at least 6 months (glucocorticoid-continuing subpopulation, n = 505). Enrolled patients < 50 years of age were required to have a history of osteoporotic fracture. Enrolled patients ≥ 50 years of age who were in the glucocorticoid-continuing subpopulation were required to have a baseline BMD T-score of ≤ -2.0 at the lumbar spine, total hip, or femoral neck; or a BMD T-score ≤ -1.0 at the lumbar spine, total hip, or femoral neck and a history of osteoporotic fracture. Patients were randomized (1:1) to receive either an oral daily bisphosphonate (active-control, risedronate 5 mg once daily) (n = 397) or denosumab 60 mg subcutaneously once every 6 months (n = 398) for one year.
Randomization was stratified by gender within each subpopulation. Patients received at least 1000 mg calcium and 800 IU vitamin D supplementation daily. Effect on Bone Mineral Density (BMD) In the glucocorticoid-initiating subpopulation, denosumab significantly increased lumbar spine BMD compared to the active-control at one year (Active-control 0.8%, denosumab 3.8%) with a treatment difference of 2.9% (p < 0.001). In the glucocorticoid-continuing subpopulation, denosumab significantly increased lumbar spine BMD compared to active-control at one year (Active-control 2.3%, denosumab 4.4%) with a treatment difference of 2.2% (p < 0.001). Consistent effects on lumbar spine BMD were observed regardless of gender; race; geographic region; menopausal status; and baseline age, lumbar spine BMD T-score, and glucocorticoid dose within each subpopulation.
Bone Histology Bone biopsy specimens were obtained from 17 patients (11 in the active-control treatment group and 6 in the denosumab treatment group) at Month 12. Of the biopsies obtained, 17 (100%) were adequate for qualitative histology. Qualitative assessments showed bone of normal architecture and quality without mineralization defects or bone marrow abnormality. 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 active-control, 100% of biopsies had tetracycline label. In patients treated with denosumab, 1 (33%) had tetracycline label and 2 (67%) had no tetracycline label present at the 12 - month biopsy. Evaluation of full quantitative histomorphometry including bone remodeling rates was not possible in the glucocorticoid-induced osteoporosis population treated with denosumab.
The long-term consequences of this degree of suppression of bone remodeling in glucocorticoid-treated patients is unknown.
Treatment of Bone Loss in Men with Prostate Cancer
The efficacy and safety of denosumab 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 denosumab 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.
Effect on Bone Mineral Density (BMD) The primary efficacy variable was percent change in lumbar spine BMD from baseline to month 24. An additional key secondary efficacy variable was the incidence of new vertebral fracture through month 36 diagnosed based on x-ray evaluation by two independent radiologists. Lumbar spine BMD was higher at 2 years in denosumab -treated patients as compared to placebo-treated patients. With approximately 62% of patients followed for 3 years, treatment differences in BMD at 3 years were 7.9% (-1.2% placebo, +6.8% denosumab) at the lumbar spine, 5.7% (-2.6% placebo, +3.2% denosumab) at the total hip, and 4.9% (-1.8% placebo, +3.0% denosumab) at the femoral neck.
Consistent effects on BMD were observed at the lumbar spine in relevant subgroups defined by baseline age, BMD, and baseline history of vertebral fracture. Effect on Vertebral Fractures Denosumab significantly reduced the incidence of new vertebral fractures at 3 years (p = 0.0125), as shown in Table 5. Table 5. The Effect of Denosumab on the Incidence of New Vertebral Fractures in Men with Nonmetastatic Prostate Cancer + Event rates based on crude rates in each interval. * Absolute risk reduction and relative risk reduction based on Mantel-Haenszel method adjusting for age group and ADT duration variables. Proportion of Men with Fracture (%) + Absolute Risk Reduction (%) * (95% CI) Relative Risk Reduction (%) * (95% CI) Placebo N = 673 (%) Denosumab N = 679 (%) 0-1 Year 1.9 0.3 1.6 85 0-2 Years 3.3 1.0 2.2 69 0-3 Years 3.9 1.5 2.4 62
Treatment of Bone Loss in Women with Breast Cancer
The efficacy and safety of denosumab 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 denosumab 60 mg (n = 127) once every 6 months for a total of 4 doses.
Randomization was stratified by duration of adjuvant AI therapy at trial entry (≤ 6 months vs. > 6 months). Sixty-two percent of patients received adjuvant AI therapy for more than 6 months at study entry. All women received at least 1000 mg calcium and 400 IU vitamin D supplementation daily. Effect on Bone Mineral Density (BMD) The primary efficacy variable was percent change in lumbar spine BMD from baseline to month 12. Lumbar spine BMD was higher at 12 months in denosumab -treated patients as compared to placebo-treated patients.
With approximately 81% of patients followed for 2 years, treatment differences in BMD at 2 years were 7.6% (-1.4% placebo, +6.2% denosumab) at the lumbar spine, 4.7 % (-1.0% placebo, +3.8% denosumab) at the total hip, and 3.6% (-0.8% placebo, +2.8% denosumab) at the femoral neck.
Drug information sourced from the FDA. This content is for informational purposes only and does not constitute medical advice. Consult a healthcare professional before making any medication decisions.
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