Prolia

• Patients with advanced chronic kidney disease (eGFR < 30 mL/min/1.73 m²), including dialysis-dependent patients, are at greater risk of severe hypocalcemia following Prolia administration. Severe hypocalcemia resulting in hospitalization, life-threatening events and fatal cases have been reported

  [see

  5.1 Severe Hypocalcemia and Mineral Metabolism Changes

  Prolia can cause severe hypocalcemia and fatal cases have been reported. Pre-existing hypocalcemia must be corrected prior to initiating therapy with Prolia. Adequately supplement all patients with calcium and vitamin D

  [see Dosage and Administration (2.1), Contraindications (4), and Adverse Reactions (6.1)]

  .

  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 Prolia 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 [i.e., eGFR < 30 mL/min/1.73 m²] including dialysis-dependent patients are at greater risk for severe hypocalcemia following Prolia 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)₂vitamin D prior to decisions regarding Prolia 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 Prolia 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 Prolia in these patients should be supervised by a healthcare provider who is experienced in diagnosis and management of CKD-MBD.

  ]

  .
• The presence of chronic kidney disease-mineral bone disorder (CKD-MBD) markedly increases the risk of hypocalcemia in these patients

  [see

  5.1 Severe Hypocalcemia and Mineral Metabolism Changes

  Prolia can cause severe hypocalcemia and fatal cases have been reported. Pre-existing hypocalcemia must be corrected prior to initiating therapy with Prolia. Adequately supplement all patients with calcium and vitamin D

  [see Dosage and Administration (2.1), Contraindications (4), and Adverse Reactions (6.1)]

  .

  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 Prolia 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 [i.e., eGFR < 30 mL/min/1.73 m²] including dialysis-dependent patients are at greater risk for severe hypocalcemia following Prolia 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)₂vitamin D prior to decisions regarding Prolia 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 Prolia 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 Prolia in these patients should be supervised by a healthcare provider who is experienced in diagnosis and management of CKD-MBD.

  ]

  .
• Prior to initiating Prolia in patients with advanced chronic kidney disease, evaluate for the presence of CKD-MBD. Treatment with Prolia in these patients should be supervised by a healthcare provider with expertise in the diagnosis and management of CKD-MBD

  [see

  2.2 Laboratory Testing in Patients with Advanced Chronic Kidney Disease Prior to Initiation of Prolia

  In patients with advanced chronic kidney disease [i.e., estimated glomerular filtration rate (eGFR) < 30 mL/min/1.73 m²], 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)₂vitamin D prior to decisions regarding Prolia 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

  [see Warnings and Precautions (5.1)]

  .

  and

  5.1 Severe Hypocalcemia and Mineral Metabolism Changes

  Prolia can cause severe hypocalcemia and fatal cases have been reported. Pre-existing hypocalcemia must be corrected prior to initiating therapy with Prolia. Adequately supplement all patients with calcium and vitamin D

  [see Dosage and Administration (2.1), Contraindications (4), and Adverse Reactions (6.1)]

  .

  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 Prolia 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 [i.e., eGFR < 30 mL/min/1.73 m²] including dialysis-dependent patients are at greater risk for severe hypocalcemia following Prolia 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)₂vitamin D prior to decisions regarding Prolia 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 Prolia 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 Prolia in these patients should be supervised by a healthcare provider who is experienced in diagnosis and management of CKD-MBD.

  ].

Prolia is a RANK ligand (RANKL) inhibitor indicated for treatment:

• of postmenopausal women with osteoporosis at high risk for fracture (
  1.1 Treatment of Postmenopausal Women with Osteoporosis at High Risk for Fracture

  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)]

  .
  )
• to increase bone mass in men with osteoporosis at high risk for fracture (
  1.2 Treatment to Increase Bone Mass in Men with Osteoporosis

  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)]

  .
  )
• of glucocorticoid-induced osteoporosis in men and women at high risk for fracture (
  1.3 Treatment of Glucocorticoid-Induced Osteoporosis

  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)]

  .
  )
• to increase bone mass in men at high risk for fracture receiving androgen deprivation therapy for nonmetastatic prostate cancer (
  1.4 Treatment of Bone Loss in Men Receiving Androgen Deprivation Therapy for Prostate Cancer

  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)]

  .
  )
• to increase bone mass in women at high risk for fracture receiving adjuvant aromatase inhibitor therapy for breast cancer (
  1.5 Treatment of Bone Loss in Women Receiving Adjuvant Aromatase Inhibitor Therapy for Breast Cancer

  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)]

  .
  )

• Pregnancy must be ruled out prior to administration of Prolia. (
  2.1 Pregnancy Testing Prior to Initiation of Prolia

  Pregnancy must be ruled out prior to administration of Prolia. Perform pregnancy testing in all females of reproductive potential prior to administration of Prolia. Based on findings in animals, Prolia can cause fetal harm when administered to pregnant women

  [see Use in Specific Populations (8.1, 8.3)]

  .
  )
• Before initiating Prolia 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. (
  2.2 Laboratory Testing in Patients with Advanced Chronic Kidney Disease Prior to Initiation of Prolia

  In patients with advanced chronic kidney disease [i.e., estimated glomerular filtration rate (eGFR) < 30 mL/min/1.73 m²], 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)₂vitamin D prior to decisions regarding Prolia 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

  [see Warnings and Precautions (5.1)]

  .
  ,
  5.1 Severe Hypocalcemia and Mineral Metabolism Changes

  Prolia can cause severe hypocalcemia and fatal cases have been reported. Pre-existing hypocalcemia must be corrected prior to initiating therapy with Prolia. Adequately supplement all patients with calcium and vitamin D

  [see Dosage and Administration (2.1), Contraindications (4), and Adverse Reactions (6.1)]

  .

  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 Prolia 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 [i.e., eGFR < 30 mL/min/1.73 m²] including dialysis-dependent patients are at greater risk for severe hypocalcemia following Prolia 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)₂vitamin D prior to decisions regarding Prolia 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 Prolia 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 Prolia in these patients should be supervised by a healthcare provider who is experienced in diagnosis and management of CKD-MBD.
  ,
  8.6 Renal Impairment

  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)]

  .
  )
• Prolia should be administered by a healthcare provider. (
  2.3 Recommended Dosage

  Prolia should be administered by a healthcare provider.

  The recommended dose of Prolia is 60 mg administered as a single subcutaneous injection once every 6 months. Administer Prolia 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

  [see Warnings and Precautions (5.1)]

  .

  If a dose of Prolia 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.
  )
• Administer 60 mg every 6 months as a subcutaneous injection in the upper arm, upper thigh, or abdomen. (
  2.3 Recommended Dosage

  Prolia should be administered by a healthcare provider.

  The recommended dose of Prolia is 60 mg administered as a single subcutaneous injection once every 6 months. Administer Prolia 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

  [see Warnings and Precautions (5.1)]

  .

  If a dose of Prolia 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.
  )
• Instruct patients to take calcium 1000 mg daily and at least 400 IU vitamin D daily. (
  2.3 Recommended Dosage

  Prolia should be administered by a healthcare provider.

  The recommended dose of Prolia is 60 mg administered as a single subcutaneous injection once every 6 months. Administer Prolia 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

  [see Warnings and Precautions (5.1)]

  .

  If a dose of Prolia 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.
  )

• Injection: 60 mg/mL clear, colorless to pale yellow solution in a single-dose prefilled syringe.

• Pregnant women and females of reproductive potential: Prolia may cause fetal harm when administered to pregnant women. Advise females of reproductive potential to use effective contraception during therapy, and for at least 5 months after the last dose of Prolia. (
  8.1 Pregnancy

  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 C_maxof 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)]

  .
  ,
  8.3 Females and Males of Reproductive Potential

  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)]

  .
  )
• Pediatric patients: Prolia is not approved for use in pediatric patients. (
  8.4 Pediatric Use

  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 demonstrated.

  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.

  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 5 to 17 years, evaluating change from baseline in lumbar spine BMD Z-score.

  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)]

  .
  )
• Renal impairment: No dose adjustment is necessary in patients with renal impairment. Patients with advanced chronic kidney disease (eGFR < 30 mL/min/1.73 m²), including dialysis-dependent patients, are at greater risk of severe hypocalcemia. The presence of underlying chronic kidney disease-mineral bone disorder markedly increases the risk of hypocalcemia. (
  5.1 Severe Hypocalcemia and Mineral Metabolism Changes

  Prolia can cause severe hypocalcemia and fatal cases have been reported. Pre-existing hypocalcemia must be corrected prior to initiating therapy with Prolia. Adequately supplement all patients with calcium and vitamin D

  [see Dosage and Administration (2.1), Contraindications (4), and Adverse Reactions (6.1)]

  .

  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 Prolia 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 [i.e., eGFR < 30 mL/min/1.73 m²] including dialysis-dependent patients are at greater risk for severe hypocalcemia following Prolia 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)₂vitamin D prior to decisions regarding Prolia 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 Prolia 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 Prolia in these patients should be supervised by a healthcare provider who is experienced in diagnosis and management of CKD-MBD.
  ,
  8.6 Renal Impairment

  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)]

  .
  )