Australia - English - Department of Health (Therapeutic Goods Administration)

amgen australia pty ltd - denosumab, quantity: 120 mg - injection, solution - excipient ingredients: sorbitol; sodium hydroxide; glacial acetic acid; water for injections; polysorbate 20 - prevention of skeletal related events in patients with multiple myeloma and in patients with bone metastases from solid tumours. treatment of giant cell tumour of bone in adults or skeletally mature adolescents that is recurrent, or unresectable, or resectable but associated with severe morbidity. treatment of hypercalcaemia of malignancy that is refractory to intravenous bisphosphonate.

Australia - English - Department of Health (Therapeutic Goods Administration)

amgen australia pty ltd - denosumab, quantity: 60 mg/ml - injection, solution - excipient ingredients: acetate; water for injections; polysorbate 20; sodium hydroxide; sorbitol - the treatment of osteoporosis in postmenopausal women. prolia significantly reduces the risk of vertebral, non-vertebral and hip fractures.,treatment to increase bone mass in men with osteopaenia receiving androgen deprivation therapy for non-metastatic prostate cancer (see clinical trials).,treatment to increase bone mass in men with osteoporosis at increased risk of fracture.,treatment to increase bone mass in women and men at increased risk of fracture due to long-term systemic glucocorticoid therapy.

United States - English - NLM (National Library of Medicine)

amgen inc - denosumab (unii: 4eqz6yo2hi) (denosumab - unii:4eqz6yo2hi) - denosumab 60 mg in 1 ml - prolia 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, prolia reduces the incidence of vertebral, nonvertebral, and hip fractures [see clinical studies (14.1)] . prolia 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 [see clinical studies (14.2)] . prolia 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 [see clinical studies (14.3)] . prolia 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 prolia also reduced the incidence of vertebral fractures [see clinical studies (14.4)] . prolia is indicated as a treatment to increase bone mass in women at high risk for fracture receiving adjuvant aromatase inhibitor therapy for breast cancer [see clinical studies (14.5)] . prolia is contraindicated in: - patients with hypocalcemia: pre-existing hypocalcemia must be corrected prior to initiating therapy with prolia [see warnings and precautions (5.1)] . - pregnant women: prolia 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 prolia [see use in specific populations (8.1)] . - patients with hypersensitivity to prolia: prolia is contraindicated in patients with a history of systemic hypersensitivity to any component of the product. reactions have included anaphylaxis, facial swelling, and urticaria [see warnings and precautions (5.3), adverse reactions (6.2)] . risk summary prolia 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 [see data] . 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 [see use in specific populations (8.2), nonclinical toxicology (13.2)] . the no effect dose for denosumab-induced teratogenicity is unknown. however, a cmax 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) [see clinical pharmacology (12.3)] . risk summary there is no information regarding the presence of denosumab in human milk, the effects on the breastfed infant, or the effects on milk production. denosumab was detected in the maternal milk of cynomolgus monkeys up to 1 month after the last dose of denosumab (≤ 0.5% milk:serum ratio) and maternal mammary gland development was normal, with no impaired lactation. however, pregnant rankl knockout mice showed altered maturation of the maternal mammary gland, leading to impaired lactation [see use in specific populations (8.1), nonclinical toxicology (13.2)] . based on findings in animals, prolia can cause fetal harm when administered to a pregnant woman [see use in specific populations (8.1)] . pregnancy testing verify the pregnancy status of females of reproductive potential prior to initiating prolia treatment. contraception females advise females of reproductive potential to use effective contraception during therapy, and for at least 5 months after the last dose of prolia. males denosumab was present at low concentrations (approximately 2% of serum exposure) in the seminal fluid of male subjects given prolia. following vaginal intercourse, the maximum amount of denosumab delivered to a female partner would result in exposures approximately 11000 times lower than the prescribed 60 mg subcutaneous dose, and at least 38 times lower than the noel in monkeys. therefore, male condom use would not be necessary as it is unlikely that a female partner or fetus would be exposed to pharmacologically relevant concentrations of denosumab via seminal fluid [see clinical pharmacology (12.3)] . the safety and effectiveness of prolia have not been established in pediatric patients. in one multicenter, open-label study conducted in 153 pediatric patients with osteogenesis imperfecta, aged 2 to 17 years, evaluating fracture risk reduction, efficacy was not established. hypercalcemia has been reported in pediatric patients with osteogenesis imperfecta treated with denosumab products, including prolia. some cases required hospitalization and were complicated by acute renal injury [see warnings and precautions (5.11)]. 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, prolia may negatively affect long-bone growth and dentition in pediatric patients below the age of 4 years. juvenile animal toxicity data treatment with prolia 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 prolia 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 [see nonclinical toxicology (13.2)]. 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 [see use in specific populations (8.1)] . of the total number of patients in clinical studies of prolia, 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. no dose adjustment is necessary in patients with renal impairment. severe hypocalcemia resulting in hospitalization, life-threatening events and fatal cases have been reported postmarketing. in clinical studies, patients with advanced chronic kidney disease (i.e., egfr < 30 ml/min/1.73 m2 ), including dialysis-dependent patients, were at greater risk of developing hypocalcemia. 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. consider the benefits and risks to the patient when administering prolia to patients with advanced chronic kidney disease. monitor calcium and mineral levels (phosphorus and magnesium). adequate intake of calcium and vitamin d is important in patients with advanced chronic kidney disease including dialysis-dependent patients [see dosage and administration (2.2),warnings and precautions (5.1), adverse reactions (6.1) and clinical pharmacology (12.3)] .

United States - English - NLM (National Library of Medicine)

amgen inc - denosumab (unii: 4eqz6yo2hi) (denosumab - unii:4eqz6yo2hi) - denosumab 120 mg in 1.7 ml - xgeva is indicated for the prevention of skeletal-related events in patients with multiple myeloma and in patients with bone metastases from solid tumors. xgeva 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 [see clinical trials ( 14.2 )] . xgeva is indicated for the treatment of hypercalcemia of malignancy refractory to bisphosphonate therapy. pre-existing hypocalcemia must be corrected prior to initiating therapy with xgeva [s ee warnings and precautions ( 5.3 )] . xgeva is contraindicated in patients with known clinically significant hypersensitivity to xgeva [see   warnings and precautions ( 5.2 ) and   adverse reactions ( 6.2 )] . risk summary based on findings in animals and its mechanism of action, xgeva can cause fetal harm when administered to a pregnant woman [see clinical pharmacology ( 12.1 )] . 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 25-fold higher than the recommended human dose of xgeva based on body weight resulted in increased fetal loss, stillbirths, and postnatal mortality; and absent lymph nodes, abnormal bone growth, and decreased neonatal growth [ see data ] .   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 xgeva 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 [see use in specific populations ( 8.3 ) and nonclinical toxicology ( 13.2 )] . risk summary there is no information regarding the presence of xgeva (denosumab) in human milk, the effects on the breastfed child, or the effects on milk production. denosumab was detected in the maternal milk of cynomolgus monkeys  up to 1 month after the last dose of denosumab (≤ 0.5% milk:serum ratio) and maternal mammary gland development was normal, with no impaired lactation. however, pregnant rankl knockout mice showed altered maturation of the maternal mammary gland, leading to impaired lactation [see use in specific populations ( 8.1 ) and nonclinical toxicology ( 13.2 )] . consider the developmental and health benefits of breastfeeding along with the mother’s clinical need for xgeva treatment and any potential adverse effects on the breastfed child from xgeva or from the underlying maternal condition. based on findings in animals and its mechanism of action, xgeva can cause fetal harm when administered to a pregnant woman [see use in specific populations ( 8.1 )] . pregnancy testing verify the pregnancy status of females of reproductive potential prior to initiating xgeva treatment. contraception   females advise females of reproductive potential to use effective contraception during therapy, and for at least 5 months after the last dose of xgeva. the safety and efficacy of xgeva have not been established in pediatric patients except in skeletally mature adolescents (aged 12–16 years) with giant cell tumor of bone. xgeva is recommended only for treatment of skeletally mature adolescents (aged 12–16 years) with giant cell tumor of bone [see indications and usage ( 1.2 )] . clinically significant hypercalcemia after treatment discontinuation has been reported in pediatric patients with growing skeletons who received denosumab for giant cell tumor of bone or for unapproved indications [see adverse reactions ( 6.2 ) and warnings and precautions ( 5.6 )]. xgeva 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 [see indications and usage ( 1.2 ) and clinical trials ( 14.3 )]. 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 [see adverse reactions ( 6.1 ) and clinical trials ( 14.3 )] . animal data treatment with xgeva 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 xgeva 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 [see   use in specific populations ( 8.1 ) ] . of the total number of patients in clinical studies that received xgeva (n = 2841) in studies 20050136, 20050244, and 20050103, 1271 (44%) were ≥ 65 years old, while 473 patients (17%) were ≥ 75 years old. of the 859 patients in study 20090482 that received xgeva, 387 patients (45%) were ≥ 65 years old, while 141 patients (16%) were ≥ 75 years old. no overall differences in safety or efficacy were observed between older and younger patients. two clinical trials were conducted in patients without cancer and with varying degrees of renal function. in one study, patients (n = 55) with varying degrees of renal function (ranging from normal through end-stage renal disease requiring dialysis) received a single 60 mg subcutaneous dose of denosumab. in a second study, patients (n = 32) with severe renal dysfunction (creatinine clearance less than 30 ml/min and/or on dialysis) were given two 120 mg subcutaneous doses of denosumab. in both studies, greater risk of developing hypocalcemia was observed with increasing renal impairment, and with inadequate/no calcium supplementation. hypocalcemia was mild to moderate in severity in 96% of patients. monitor calcium levels and calcium and vitamin d intake [see warnings and precautions ( 5.3 ), adverse reactions ( 6.1 ), and clinical pharmacology ( 12.3 )] .

Israel - English - Ministry of Health

amgen europe b.v. - denosumab - solution for injection - denosumab 60 mg / 1 ml - denosumab - denosumab - treatment of osteoporosis in postmenopausal women and in men at increased risk of fractures. in postmenopausal women prolia significantly reduces the risk of vertebral, non vertebral and hip fractures. treatment of bone loss associated with hormone ablation in men with prostate cancer at increased risk of fractures. in men with prostate cancer receiving hormone ablation, prolia significantly reduces the risk of vertebral fractures.treatment of bone loss associated with long-term systemic glucocorticoid therapy of a daily dosage equivalent to 7.5 mg or greater of prednisone and expected to remain on glucocorticoids for at least 3 months, in adult patients at high risk of fracture.

Australia - English - Department of Health (Therapeutic Goods Administration)

amgen australia pty ltd - denosumab, quantity: 60 mg/ml - injection, solution - excipient ingredients: water for injections; sorbitol; acetate; polysorbate 20; sodium hydroxide - the treatment of osteoporosis in postmenopausal women. prolia significantly reduces the risk of vertebral, non-vertebral and hip fractures.,treatment to increase bone mass in men with osteopaenia receiving androgen deprivation therapy for non-metastatic prostate cancer (see clinical trials).,treatment to increase bone mass in men with osteoporosis at increased risk of fracture.,treatment to increase bone mass in women and men at increased risk of fracture due to long-term systemic glucocorticoid therapy.

Israel - English - Ministry of Health

amgen europe b.v. - denosumab - solution for injection - denosumab 120 mg / 1.7 ml - denosumab - denosumab - prevention of skeletal related events (pathological fracture, radiation to bone, spinal cord compression or surgery to bone) in adults with multiple myeloma and in adults with bone metastases from solid tumours.treatment of adult and skeletally mature adolescents with giant cell tumor of bone that is unresectable or where surgical resection is likely to result in severe morbidity.

European Union - English - EMA (European Medicines Agency)

amgen europe b.v. - denosumab - fractures, bone; neoplasm metastasis - drugs for treatment of bone diseases - prevention of skeletal related events (pathological fracture, radiation to bone, spinal cord compression or surgery to bone) in adults with advanced malignancies involving bone (see section 5.1).treatment of adults and skeletally mature adolescents with giant cell tumour of bone that is unresectable or where surgical resection is likely to result in severe morbidity.  

Singapore - English - HSA (Health Sciences Authority)

amgen biotechnology singapore pte ltd - denosumab - injection, solution - 60 mg/ml - denosumab 60 mg/ml

Armenia - English - Դեղերի և բժշկական տեխնոլոգիաների փորձագիտական կենտրոնի գործունեության Հայաստանի Հանրապետությունում

amgen europe b.v. - denosumab - solution for s/c injection - 60mg/ml