Pralia

Treatment of osteoporosis in postmenopausal women and in men at increased risk of fractures. In postmenopausal women Pralia 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, Pralia significantly reduces the risk of vertebral fractures.

Multiple Myeloma And Bone Metastasis From Solid Tumors

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

Giant Cell Tumor Of Bone

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

Hypercalcemia Of Malignancy

Pralia is indicated for the treatment of hypercalcemia of malignancy refractory to bisphosphonate therapy.

Multiple Myeloma And Bone Metastasis From Solid Tumors

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

Giant Cell Tumor Of Bone

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.

Hypercalcemia Of Malignancy

Xgeva is indicated for the treatment of hypercalcemia of malignancy refractory to bisphosphonate therapy.

Posology

The recommended dose of Pralia is 60 mg administered as a single subcutaneous injection once every 6 months into the thigh, abdomen or upper arm.

Patients must be adequately supplemented with calcium and vitamin D.

Patients treated with Pralia should be given the package leaflet and the patient reminder card.

The optimal total duration of antiresorptive treatment for osteoporosis (including both denosumab and bisphosphonates) has not been established. The need for continued treatment should be re-evaluated periodically based on the benefits and potential risks of denosumab on an individual patient basis, particularly after 5 or more years of use.

Renal impairment

).

Hepatic impairment

The safety and efficacy of denosumab have not been studied in patients with hepatic impairment.

Elderly (age > 65)

No dose adjustment is required in elderly patients.

Paediatric population

Pralia is not recommended in paediatric patients (age < 18) as the safety and efficacy of Pralia in these patients have not been established. Inhibition of RANK/RANK ligand (RANKL) in animal studies has been coupled to inhibition of bone growth and lack of tooth eruption.

Method of administration

For subcutaneous use.

Administration should be performed by an individual who has been adequately trained in injection techniques.

Important Administration Instructions

Pralia is intended for subcutaneous route only and should not be administered intravenously, intramuscularly, or intradermally.

Multiple Myeloma And Bone Metastasis From Solid Tumors

The recommended dose of Pralia is 120 mg administered as a subcutaneous injection every 4 weeks in the upper arm, upper thigh, or abdomen.

Administer calcium and vitamin D as necessary to treat or prevent hypocalcemia.

Giant Cell Tumor Of Bone

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

Administer calcium and vitamin D as necessary to treat or prevent hypocalcemia.

Hypercalcemia Of Malignancy

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

Preparation And Administration

Visually inspect Pralia for particulate matter and discoloration prior to administration. Pralia is a clear, colorless to pale yellow solution that may contain trace amounts of translucent to white proteinaceous particles. Do not use if the solution is discolored or cloudy or if the solution contains many particles or foreign particulate matter.

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

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

Important Administration Instructions

Xgeva is intended for subcutaneous route only and should not be administered intravenously, intramuscularly, or intradermally.

Multiple Myeloma And Bone Metastasis From Solid Tumors

The recommended dose of Xgeva is 120 mg administered as a subcutaneous injection every 4 weeks in the upper arm, upper thigh, or abdomen.

Administer calcium and vitamin D as necessary to treat or prevent hypocalcemia.

Giant Cell Tumor Of Bone

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

Administer calcium and vitamin D as necessary to treat or prevent hypocalcemia.

Hypercalcemia Of Malignancy

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

Preparation And Administration

Visually inspect Xgeva for particulate matter and discoloration prior to administration. Xgeva is a clear, colorless to pale yellow solution that may contain trace amounts of translucent to white proteinaceous particles. Do not use if the solution is discolored or cloudy or if the solution contains many particles or foreign particulate matter.

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

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

Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.

Hypocalcaemia.

Hypocalcemia

Pre-existing hypocalcemia must be corrected prior to initiating therapy with Pralia.

Hypersenstivity

Pralia is contraindicated in patients with known clinically significant hypersensitivity to Pralia.

Hypocalcemia

Pre-existing hypocalcemia must be corrected prior to initiating therapy with Xgeva.

Hypersenstivity

Xgeva is contraindicated in patients with known clinically significant hypersensitivity to Xgeva.

Calcium and Vitamin D supplementation

Adequate intake of calcium and vitamin D is important in all patients.

Precautions for use

Hypocalcaemia

It is important to identify patients at risk for hypocalcaemia. Hypocalcaemia must be corrected by adequate intake of calcium and vitamin D before initiating therapy. Clinical monitoring of calcium levels is recommended before each dose and, in patients predisposed to hypocalcaemia within two weeks after the initial dose. If any patient presents with suspected symptoms of hypocalcaemia during treatment calcium levels should be measured. Patients should be encouraged to report symptoms indicative of hypocalcaemia.

In the post-marketing setting, severe symptomatic hypocalcaemia has been reported , with most cases occurring in the first weeks of initiating therapy, but it can occur later.

Skin infections

Patients receiving Pralia may develop skin infections (predominantly cellulitis) leading to hospitalisation. Patients should be advised to seek prompt medical attention if they develop signs or symptoms of cellulitis.

Osteonecrosis of the Jaw (ONJ)

ONJ has been reported rarely in patients receiving Pralia for osteoporosis.

The start of treatment/new treatment course should be delayed in patients with unhealed open soft tissue lesions in the mouth. A dental examination with preventive dentistry and an individual benefit-risk assessment is recommended prior to treatment with denosumab in patients with concomitant risk factors.

The following risk factors should be considered when evaluating a patient's risk of developing ONJ:

- potency of the medicinal product that inhibits bone resorption (higher risk for highly potent compounds), route of administration (higher risk for parenteral administration) and cumulative dose of bone resorption therapy.

- cancer, co-morbid conditions (e.g. anaemia, coagulopathies, infection), smoking.

- concomitant therapies: corticosteroids, chemotherapy, angiogenesis inhibitors, radiotherapy to head and neck.

- poor oral hygiene, periodontal disease, poorly fitting dentures, history of dental disease, invasive dental procedures e.g. tooth extractions.

All patients should be encouraged to maintain good oral hygiene, receive routine dental check-ups, and immediately report any oral symptoms such as dental mobility, pain or swelling or non-healing of sores or discharge during treatment with denosumab. While on treatment, invasive dental procedures should be performed only after careful consideration and be avoided in close proximity to Pralia administration.

The management plan of the patients who develop ONJ should be set up in close collaboration between the treating physician and a dentist or oral surgeon with expertise in ONJ. Temporary interruption of treatment should be considered until the condition resolves and contributing risk factors are mitigated where possible.

Osteonecrosis of the external auditory canal

Osteonecrosis of the external auditory canal has been reported with denosumab. Possible risk factors for osteonecrosis of the external auditory canal include steroid use and chemotherapy and/or local risk factors such as infection or trauma. The possibility of osteonecrosis of the external auditory canal should be considered in patients receiving denosumab who present with ear symptoms including chronic ear infections.

Atypical fractures of the femur

Atypical femoral fractures have been reported in patients receiving denosumab. Atypical femoral fractures may occur with little or no trauma in the subtrochanteric and diaphyseal regions of the femur. Specific radiographic findings characterise these events. Atypical femoral fractures have also been reported in patients with certain co-morbid conditions (e.g. vitamin D deficiency, rheumatoid arthritis, hypophosphatasia) and with use of certain pharmaceutical agents (e.g. bisphosphonates, glucocorticoids, proton pump inhibitors). These events have also occurred without antiresorptive therapy. Similar fractures reported in association with bisphosphonates are often bilateral; therefore the contralateral femur should be examined in denosumab-treated patients who have sustained a femoral shaft fracture. Discontinuation of Pralia therapy in patients suspected to have an atypical femur fracture should be considered pending evaluation of the patient based on an individual benefit-risk assessment. During denosumab treatment, patients should be advised to report new or unusual thigh, hip, or groin pain. Patients presenting with such symptoms should be evaluated for an incomplete femoral fracture.

Long-term antiresorptive treatment

Long-term antiresorptive treatment (including both denosumab and bisphosphonates) may contribute to an increased risk for adverse outcomes such as osteonecrosis of the jaw and atypical femur fractures due to significant suppression of bone remodelling.

Concomitant treatment with other denosumab-containing medicinal products

Patients being treated with Pralia should not be treated concomitantly with other denosumab-containing medicinal products (for prevention of skeletal related events in adults with bone metastases from solid tumours).

Renal impairment

Patients with severe renal impairment (creatinine clearance < 30 mL/min) or receiving dialysis are at greater risk of developing hypocalcaemia. The risks of developing hypocalcaemia and accompanying parathyroid hormone elevations increase with increasing degree of renal impairment. Adequate intake of calcium, vitamin D and regular monitoring of calcium is especially important in these patients, see above.

Dry natural rubber

The needle cover of the pre-filled syringe contains dry natural rubber (a derivative of latex), which may cause allergic reactions.

Warnings for excipients

This medicinal product contains sorbitol. Patients with rare hereditary problems of fructose intolerance should not take this medicinal product.

This medicinal product contains less than 1 mmol sodium (23 mg) per 60 mg i.e. essentially 'sodium-free'.

WARNINGS

Included as part of the PRECAUTIONS section.

PRECAUTIONS

Drug Products With Same Active Ingredient

Pralia includes the same active ingredient (denosumab) found in Prolia. Patients receiving Pralia should not take Prolia.

Hypersensitivity

Clinically significant hypersensitivity including anaphylaxis has been reported with use of Pralia. Reactions may include hypotension, dyspnea, upper airway edema, lip swelling, rash, pruritus, and urticaria. If an anaphylactic or other clinically significant allergic reaction occurs, initiate appropriate therapy and discontinue Pralia therapy permanently.

Hypocalcemia

Pralia can cause severe symptomatic hypocalcemia, and fatal cases have been reported. Correct pre-existing hypocalcemia prior to Pralia treatment. Monitor calcium levels, throughout Pralia therapy, especially in the first weeks of initiating therapy, and administer calcium, magnesium, and vitamin D as necessary. Monitor levels more frequently when Pralia is administered with other drugs that can also lower calcium levels. Advise patientsto contact a healthcare provider for symptoms of hypocalcemia.

An increased risk of hypocalcemia has been observed in clinical trials of patients with increasing renal dysfunction, most commonly with severe dysfunction (creatinine clearance less than 30 mL/minute and/or on dialysis), and with inadequate/no calcium supplementation. Monitor calcium levels and calcium and vitamin D intake.

Osteonecrosis Of The Jaw (ONJ)

Osteonecrosis of the jaw (ONJ) has been reported in patients receiving Pralia, manifesting as jaw pain, osteomyelitis, osteitis, bone erosion, tooth or periodontal infection, toothache, gingival ulceration, or gingival erosion. Persistent pain or slow healing of the mouth or jaw after dental surgery may also be manifestations of ONJ. In clinical trialsin patients with cancer, the incidence of ONJ was higher with longer duration of exposure. Seventy-nine percent of patients with ONJ had a history of tooth extraction, poor oral hygiene, or use of a dental appliance as a predisposing factor. Other risk factors for the development of ONJ include immunosuppressive therapy, treatment with angiogenesis inhibitors, systemic corticosteroids, diabetes, and gingival infections. Similarly, for Pralia patients with multiple myeloma that developed ONJ, 58% had a history of invasive dental procedures as a predisposing factor.

Perform an oral examination and appropriate preventive dentistry prior to the initiation of Pralia and periodically during Pralia therapy. Advise patients regarding oral hygiene practices. Avoid invasive dental procedures during treatment with Pralia. Consider temporary discontinuation of Pralia therapy if an invasive dental procedure must be performed. There are no data available to suggest the optimal duration of treatment interruption.

Patients who are suspected of having or who develop ONJ while on Pralia should receive care by a dentist or an oral surgeon. In these patients, extensive dental surgery to treat ONJ may exacerbate the condition. Clinical judgment of the treating healthcare provider should guide the management plan of each patient based on individual risk/benefit assessment.

Atypical Subtrochanteric And Diaphyseal Femoral Fracture

Atypical femoral fracture has been reported with Pralia. 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.

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 Pralia 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 beevaluated to ruleout an incomplete femur fracture. Patient presenting with an atypical femur fracture should also be assessed for symptoms and signs of fracture in the contralateral limb. Interruption of Pralia therapy should be considered, pending a risk/benefit assessment, on an individual basis.

Hypercalcemia Following Treatment Discontinuation In Patients With Growing Skeletons

Clinically significant hypercalcemia has been reported in Pralia-treated patients with growing skeletons weeks to months following treatment discontinuation. Monitor patients for signs and symptoms of hypercalcemia and treat appropriately.

Embryo-Fetal Toxicity

Based on data from animalstudies and its mechanism of action, Pralia can cause fetal harm when administered to a pregnant woman. In animal reproduction studies, administration of denosumab to cynomolgus monkeys throughout pregnancy at a dose 25-fold higher than the recommended human dose of Praliabased on body weight resulted in increased fetal loss, stillbirths, and postnatal mortality, along with evidence of absent peripherallymph nodes, abnormal bone growth and decreased neonatal growth.

Verify the pregnancy status of females of reproductive potential prior to the initiation of Pralia. Advise pregnant women and females of reproductive potential that exposure to Pralia during pregnancy or within 5 months prior to conception can result in fetal harm. Advise females of reproductive potential to use effective contraception during therapy, and for at least 5 months after the last dose of Pralia.

Nonclinical Toxicology

Carcinogenesis, Mutagenesis, Impairment Of Fertility

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

Denosumab had no effect on female fertility or male reproductive organs in monkeys at doses that were 6.5-to 25-fold higher than the recommended human dose of 120 mg subcutaneously administered once every 4 weeks, based on body weight (mg/kg).

Use In Specific Populations

Pregnancy

Risk Summary

Based on findings in animals and its mechanism of action, Pralia can cause fetal harm when administered to a pregnant woman. 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 Pralia 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 Pralia 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 6months 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 minimalto 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. Maternalmammary gland development was normal. There was no fetal NOAEL (no observable adverse effect level) established for this study because only one dose of 50mg/kg was evaluated. Mammary gland histopathology at6 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 impairmentof dentition and bone growth. Pregnant RANKL knockout mice showed altered maturation of the maternal mammary gland, leading to impaired lactation.

Lactation

Risk Summary

There is no information regarding the presence of Pralia (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. Consider the developmental and health benefits of breastfeeding along with the mother's clinical need for Pralia treatment and any potential adverse effects on the breastfed child from Pralia or from the underlying maternal condition.

Females And Males Of Reproductive Potential

Based on findings in animals and its mechanism of action, Pralia can cause fetal harm when administered to a pregnant woman.

Pregnancy Testing

Verifythepregnancystatusoffemalesofreproductivepotentialpriortoinitiating Praliatreatment.

Contraception

Females

Advise females of reproductive potential to use effective contraception during therapy, and for at least 5 months after the last dose of Pralia.

Pediatric Use

The safety and efficacy of Pralia have not been established in pediatric patients except in skeletally mature adolescents with giant cell tumor of bone. Pralia is recommended only for treatment of skeletally mature adolescents with giant cell tumor of bone.

Pralia was studied in an open-label trial that enrolled a subset of 10 adolescent patients (aged 13-17years) with giant cell tumor of bone who had reached skeletal maturity, defined by at least 1 mature long bone(e.g., closed epiphysealgrowth plate of the humerus),and had a body weight≥ 45 kg. A total of two of six(33%) evaluable adolescent patients had an objective response by retrospective independent assessment of radiographic response according to modified Response Evaluation Criteriain Solid Tumors (RECIST1.1) criteria. The adverse reaction profile and efficacy results appeared to be similar in skeletally mature adolescents and adults.

Treatment with Pralia 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 Pralia 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 doses5 and 25times (10 and 50 mg/kg dose) higher than the recommended human dose of 120 mg administered once every 4weeks, 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.

Geriatric Use

Of the total number of patients in clinical studies that received Pralia (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 2009482 that received Pralia, 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.

Renal Impairment

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 requiringdialysis)received asingle60mg subcutaneous dose of denosumab. In a second study, patients (N = 32) with severe renal dysfunction (creatinine clearance less than 30mL/minuteand/or on dialysis)were given two 120mg 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.

WARNINGS

Included as part of the PRECAUTIONS section.

PRECAUTIONS

Drug Products With Same Active Ingredient

Xgeva includes the same active ingredient (denosumab) found in Prolia. Patients receiving Xgeva should not take Prolia.

Hypersensitivity

Clinically significant hypersensitivity including anaphylaxis has been reported with use of Xgeva. Reactions may include hypotension, dyspnea, upper airway edema, lip swelling, rash, pruritus, and urticaria. If an anaphylactic or other clinically significant allergic reaction occurs, initiate appropriate therapy and discontinue Xgeva therapy permanently.

Hypocalcemia

Xgeva can cause severe symptomatic hypocalcemia, and fatal cases have been reported. Correct pre-existing hypocalcemia prior to Xgeva treatment. Monitor calcium levels, throughout Xgeva therapy, especially in the first weeks of initiating therapy, and administer calcium, magnesium, and vitamin D as necessary. Monitor levels more frequently when Xgeva is administered with other drugs that can also lower calcium levels. Advise patientsto contact a healthcare provider for symptoms of hypocalcemia.

An increased risk of hypocalcemia has been observed in clinical trials of patients with increasing renal dysfunction, most commonly with severe dysfunction (creatinine clearance less than 30 mL/minute and/or on dialysis), and with inadequate/no calcium supplementation. Monitor calcium levels and calcium and vitamin D intake.

Osteonecrosis Of The Jaw (ONJ)

Osteonecrosis of the jaw (ONJ) has been reported in patients receiving Xgeva, manifesting as jaw pain, osteomyelitis, osteitis, bone erosion, tooth or periodontal infection, toothache, gingival ulceration, or gingival erosion. Persistent pain or slow healing of the mouth or jaw after dental surgery may also be manifestations of ONJ. In clinical trialsin patients with cancer, the incidence of ONJ was higher with longer duration of exposure. Seventy-nine percent of patients with ONJ had a history of tooth extraction, poor oral hygiene, or use of a dental appliance as a predisposing factor. Other risk factors for the development of ONJ include immunosuppressive therapy, treatment with angiogenesis inhibitors, systemic corticosteroids, diabetes, and gingival infections. Similarly, for Xgeva patients with multiple myeloma that developed ONJ, 58% had a history of invasive dental procedures as a predisposing factor.

Perform an oral examination and appropriate preventive dentistry prior to the initiation of Xgeva and periodically during Xgeva therapy. Advise patients regarding oral hygiene practices. Avoid invasive dental procedures during treatment with Xgeva. Consider temporary discontinuation of Xgeva therapy if an invasive dental procedure must be performed. There are no data available to suggest the optimal duration of treatment interruption.

Patients who are suspected of having or who develop ONJ while on Xgeva should receive care by a dentist or an oral surgeon. In these patients, extensive dental surgery to treat ONJ may exacerbate the condition. Clinical judgment of the treating healthcare provider should guide the management plan of each patient based on individual risk/benefit assessment.

Atypical Subtrochanteric And Diaphyseal Femoral Fracture

Atypical femoral fracture has been reported with Xgeva. 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.

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 Xgeva 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 beevaluated to ruleout an incomplete femur fracture. Patient presenting with an atypical femur fracture should also be assessed for symptoms and signs of fracture in the contralateral limb. Interruption of Xgeva therapy should be considered, pending a risk/benefit assessment, on an individual basis.

Hypercalcemia Following Treatment Discontinuation In Patients With Growing Skeletons

Clinically significant hypercalcemia has been reported in Xgeva-treated patients with growing skeletons weeks to months following treatment discontinuation. Monitor patients for signs and symptoms of hypercalcemia and treat appropriately.

Embryo-Fetal Toxicity

Based on data from animalstudies and its mechanism of action, Xgeva can cause fetal harm when administered to a pregnant woman. In animal reproduction studies, administration of denosumab to cynomolgus monkeys throughout pregnancy at a dose 25-fold higher than the recommended human dose of Xgevabased on body weight resulted in increased fetal loss, stillbirths, and postnatal mortality, along with evidence of absent peripherallymph nodes, abnormal bone growth and decreased neonatal growth.

Verify the pregnancy status of females of reproductive potential prior to the initiation of Xgeva. Advise pregnant women and females of reproductive potential that exposure to Xgeva during pregnancy or within 5 months prior to conception can result in fetal harm. Advise females of reproductive potential to use effective contraception during therapy, and for at least 5 months after the last dose of Xgeva.

Nonclinical Toxicology

Carcinogenesis, Mutagenesis, Impairment Of Fertility

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

Denosumab had no effect on female fertility or male reproductive organs in monkeys at doses that were 6.5-to 25-fold higher than the recommended human dose of 120 mg subcutaneously administered once every 4 weeks, based on body weight (mg/kg).

Use In Specific Populations

Pregnancy

Risk Summary

Based on findings in animals and its mechanism of action, Xgeva can cause fetal harm when administered to a pregnant woman. 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 6months 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 minimalto 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. Maternalmammary gland development was normal. There was no fetal NOAEL (no observable adverse effect level) established for this study because only one dose of 50mg/kg was evaluated. Mammary gland histopathology at6 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 impairmentof dentition and bone growth. Pregnant RANKL knockout mice showed altered maturation of the maternal mammary gland, leading to impaired lactation.

Lactation

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. 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.

Females And Males Of Reproductive Potential

Based on findings in animals and its mechanism of action, Xgeva can cause fetal harm when administered to a pregnant woman.

Pregnancy Testing

Verifythepregnancystatusoffemalesofreproductivepotentialpriortoinitiating Xgevatreatment.

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.

Pediatric Use

The safety and efficacy of Xgeva have not been established in pediatric patients except in skeletally mature adolescents with giant cell tumor of bone. Xgeva is recommended only for treatment of skeletally mature adolescents with giant cell tumor of bone.

Xgeva was studied in an open-label trial that enrolled a subset of 10 adolescent patients (aged 13-17years) with giant cell tumor of bone who had reached skeletal maturity, defined by at least 1 mature long bone(e.g., closed epiphysealgrowth plate of the humerus),and had a body weight≥ 45 kg. A total of two of six(33%) evaluable adolescent patients had an objective response by retrospective independent assessment of radiographic response according to modified Response Evaluation Criteriain Solid Tumors (RECIST1.1) criteria. The adverse reaction profile and efficacy results appeared to be similar in skeletally mature adolescents and adults.

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 doses5 and 25times (10 and 50 mg/kg dose) higher than the recommended human dose of 120 mg administered once every 4weeks, 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.

Geriatric Use

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 2009482 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.

Renal Impairment

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 requiringdialysis)received asingle60mg subcutaneous dose of denosumab. In a second study, patients (N = 32) with severe renal dysfunction (creatinine clearance less than 30mL/minuteand/or on dialysis)were given two 120mg 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.

Summary of the safety profile

The most common side effects with Pralia (seen in more than one patient in ten) are musculoskeletal pain and pain in the extremity.8 - description of selected adverse reactions) have been observed in patients taking Pralia.

Tabulated list of adverse reactions

The data in Table 1 below describe adverse reactions reported from Phase II and III clinical trials in patients with osteoporosis and breast or prostate cancer patients receiving hormone ablation; and/or spontaneous reporting.

The following convention has been used for the classification of the adverse reactions (see table 1): very common (> 1/10), common (> 1/100 to < 1/10), uncommon (> 1/1,000 to < 1/100), rare (> 1/10,000 to < 1/1,000) and very rare (< 1/10,000). Within each frequency grouping and system organ class, adverse reactions are presented in order of decreasing seriousness.

Table 1 Adverse reactions reported in patients with osteoporosis and breast or prostate cancer patients receiving hormone ablation

¹ See section Description of selected adverse reactions

²

In a pooled analysis of data from all phase II and phase III placebo-controlled studies, Influenza-like illness was reported with a crude incidence rate of 1.2% for denosumab and 0.7% for placebo. Although this imbalance was identified via a pooled analysis, it was not identified via a stratified analysis.

Description of selected adverse reactions

Hypocalcaemia

In two phase III placebo-controlled clinical trials in postmenopausal women with osteoporosis, approximately 0.05% (2 out of 4,050) of patients had declines of serum calcium levels (less than 1.88 mmol/l) following Pralia administration. Declines of serum calcium levels (less than 1.88 mmol/l) were not reported in either the two phase III placebo-controlled clinical trials in patients receiving hormone ablation or the phase III placebo-controlled clinical trial in men with osteoporosis.

In the post-marketing setting, rare cases of severe symptomatic hypocalcaemia have been reported predominantly in patients at increased risk of hypocalcaemia receiving Pralia, with most cases occurring in the first weeks of initiating therapy. Examples of the clinical manifestations of severe symptomatic hypocalcaemia have included QT interval prolongation, tetany, seizures and altered mental status. Symptoms of hypocalcaemia in denosumab clinical studies included paraesthesias or muscle stiffness, twitching, spasms and muscle cramps.

Skin infections

In phase III placebo-controlled clinical trials, the overall incidence of skin infections was similar in the placebo and the Pralia groups: in postmenopausal women with osteoporosis (placebo [1.2%, 50 out of 4,041] versus Pralia [1.5%, 59 out of 4,050]); in men with osteoporosis (placebo [0.8%, 1 out of 120] versus Pralia [0%, 0 out of 120]); in breast or prostate cancer patients receiving hormone ablation (placebo [1.7%, 14 out of 845] versus Pralia [1.4%, 12 out of 860]). Skin infections leading to hospitalisation were reported in 0.1% (3 out of 4,041) of postmenopausal women with osteoporosis receiving placebo versus 0.4% (16 out of 4,050) of women receiving Pralia. These cases were predominantly cellulitis. Skin infections reported as serious adverse reactions were similar in the placebo (0.6%, 5 out of 845) and the Pralia (0.6%, 5 out of 860) groups in the breast and prostate cancer studies.

Osteonecrosis of the jaw

ONJ has been reported rarely, in 16 patients, in clinical trials in osteoporosis and in breast or prostate cancer patients receiving hormone ablation including a total of 23,148 patients. Thirteen of these ONJ cases occurred in postmenopausal women with osteoporosis during the phase III clinical trial extension following treatment with Pralia for up to 10 years. Incidence of ONJ was 0.04% at 3 years, 0.06% at 5 years and 0.44% at 10 years of Pralia treatment. The risk of ONJ increased with duration of exposure to Pralia.

Atypical fractures of the femur

In the osteoporosis clinical trial program, atypical femoral fractures were reported rarely in patients treated with Pralia.

Diverticulitis

In a single phase III placebo-controlled clinical trial in patients with prostate cancer receiving ADT an imbalance in diverticulitis adverse events was observed (1.2% denosumab, 0% placebo). The incidence of diverticulitis was comparable between treatment groups in postmenopausal women or men with osteoporosis and in women undergoing aromatase inhibitor therapy for non-metastatic breast cancer.

Drug-related hypersensitivity reactions

In the post-marketing setting, rare events of drug-related hypersensitivity, including rash, urticaria, facial swelling, erythema, and anaphylactic reactions have been reported in patients receiving Pralia.

Musculoskeletal pain

Musculoskeletal pain, including severe cases, has been reported in patients receiving Pralia in the post-marketing setting. In clinical trials, musculoskeletal pain was very common in both denosumab and placebo groups. Musculoskeletal pain leading to discontinuation of study treatment was uncommon.

Other special populations

Renal impairment

In clinical studies, patients with severe renal impairment (creatinine clearance < 30 mL/min) or receiving dialysis were at greater risk of developing hypocalcaemia in the absence of calcium supplementation. Adequate intake of calcium and vitamin D is important in patients with severe renal impairment or receiving dialysis.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via:

United Kingdom

Yellow Card Scheme

Website: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store

Ireland

HPRA Pharmacovigilance

Earlsfort Terrace

IRL - Dublin 2

Tel: +353 1 6764971

Fax: +353 1 6762517

Website: www.hpra.ie

e-mail: [email protected]

The following adverse reactions are discussed below and elsewhere in the labeling:

• Hypersensitivity
• Hypocalcemia
• Osteonecrosis of the Jaw
• Atypical Subtrochanteric and Diaphyseal Femoral Fracture
• Hypercalcemia following treatment discontinuation in patients with growing skeletons

Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

Bone Metastasis From Solid Tumors

The safety of Pralia was evaluated in three randomized, double-blind, double-dummy trials in which a total of 2841patients with bone metastasis from prostate cancer, breast cancer, or other solid tumors, or lytic bony lesions from multiple myeloma received at least one dose of Pralia. In Studies 20050136, 20050244, and 20050103, patients were randomized to receive either 120 mg of Pralia every 4 weeks as a subcutaneous injection or 4mg (dose adjusted for reduced renal function) of zoledronic acid every 4 weeks by intravenous (IV) infusion. Entry criteria included serum calcium (corrected) from 8 to 11.5mg/dL (2 to 2.9mmol/L) and creatinine clearance 30mL/min or greater. Patients who had received IV bisphosphonates were excluded, as were patients with prior history of ONJ or osteomyelitis of the jaw, an active dentalor jaw condition requiring oral surgery, non-healed dental/oral surgery, or any planned invasive dental procedure. During the study, serum chemistries including calcium and phosphorus were monitored every 4 weeks. Calcium and vitamin D supplementation was recommended but not required.

The median duration of exposure to Pralia was 12months (range: 0.1 -41) and median duration on-study was 13months (range: 0.1 -41). Of patients who received Pralia, 46% were female. Eighty-five percent were White, 5% Hispanic/Latino, 6% Asian, and 3% Black. The median age was 63 years (range: 18 -93). Seventy-five percent of patients who received Pralia received concomitant chemotherapy.

The most common adverse reactions in patients (incidence greater than or equal to 25%) were fatigue/asthenia, hypophosphatemia, and nausea (see Table 1). The most common serious adverse reaction was dyspnea. Themost common adverse reactions resulting in discontinuation of Pralia were osteonecrosis and hypocalcemia.

Table 1: Selected^a Adverse Reactions of Any Severity (Studies 20050136, 20050244, and 20050103)

Severe Mineral/Electrolyte Abnormalities

• Severe hypocalcemia (corrected serum calcium less than 7mg/dL or less than 1.75mmol/L) occurred in 3.1% of patients treated with Pralia and 1.3% of patients treated with zoledronic acid. Of patients who experienced severe hypocalcemia, 33% experienced 2 or more episodes of severe hypocalcemia and 16% experienced 3 or more episodes.
• Severe hypophosphatemia (serum phosphorus less than 2 mg/dL or less than 0.6 mmol/L) occurred in 15.4% of patients treated with Pralia and 7.4% of patients treated with zoledronic acid.

Osteonecrosis Of The Jaw (ONJ)

In the primary treatment phases of Studies 20050136, 20050244, and 20050103, ONJ was confirmed in 1.8% of patients in the Pralia group (median exposure of 12.0 months; range: 0.1-40.5) and 1.3% of patients in the zoledronic acid group. The trials in patients with breast (Study 20050136) or prostate (Study 20050103) cancer included an Pralia open label extension treatment phase where patients were offered Pralia 120mg once every 4weeks (median overall exposure of 14.9months; range: 0.1-67.2). The patient-year adjusted incidence (number of events per 100 patient years) of confirmed ONJ was 1.1% during the first year of treatment, 3.7% in the second year, and 4.6% per year thereafter. The median time to ONJ was 20.6months (range: 4-53).

In a placebo-controlled clinical trial with an extension treatment phase evaluating Pralia for the prevention of bone metastases in patients with non-metastatic prostate cancer (a patient population for which Pralia is not indicated), with longer treatment exposure of up to 7 years, the patient-year adjusted incidence (number of events per 100 patient years) of confirmed ONJ was 1.1% during the first year of treatment, 3.0% in the second year, and 7.1% per year thereafter.

Atypical Subtrochanteric And Diaphyseal Fracture

Atypical femoral fracture has been reported with Pralia.

Multiple Myeloma

The safety of Pralia was evaluated in an international, randomized (1:1), double-blind, active-controlled trial of patients with newly diagnosed multiple myeloma with treatment through disease progression. In this trial, patients received 120 mg Pralia every 4 weeks as a subcutaneous injection (n=850) or4mg (dose adjusted for renal function) of zoledronic acid intravenously (IV) every 4 weeks by IV infusion (n=852). Entry criteria included serum calcium (corrected) from 8 to 11.5mg/dL (2 to 2.9mmol/L) and creatinine clearance 30mL/min or greater. Patients who had received IV bisphosphonates were excluded, as were patients with prior history of ONJ or osteomyelitis of the jaw, an active dentalor jaw condition requiring oralsurgery, non-healed dental/oral surgery, or any planned invasive dental procedure. During the study, serum chemistries including calcium and phosphorus were monitored every 4 weeks. Calcium and vitamin D supplementation was recommended but not required.

The median duration of exposure to Pralia was 16 months (range: 1 -50) and median duration on-study was 17 months (range: 0.0 -49). Of patients who received Pralia, 46% were female, 83% percent were White, 13% Asian, 3% Black or African American, and 4% Hispanic/Latino. The median age of the patients randomized to Pralia was 63years (range: 29 -91) and allpatients who received Pralia received concomitant anti-myeloma chemotherapy.

The adverse reaction profile of Pralia in patients with multiple myeloma, Study 2009482, was similar to that observed in Studies 20050136, 20050244, and 20050103. The most common adverse reactions (incidence ≥ 10%) were diarrhea (34%), nausea (32%), anemia (22%), back pain (21%), thrombocytopenia (19%), peripheral edema (17%), hypocalcemia (16%), upper respiratory tract infection (15%), rash (14%), and headache (11%). The most common serious adverse reaction (incidence ≥ 5%) was pneumonia (8%). The most common adverse reaction resulting in discontinuation of Pralia (≥ 1.0%) was osteonecrosis of the jaw.

Hypocalcemia And Hypophosphatemia

Severe hypocalcemia (corrected serum calcium less than 7mg/dL or less than 1.75mmol/L) and severe hypophosphatemia (serum phosphorus less than 2mg/dL or less than 0.6mmol/L) occurred in 2% and 21% patients treated with Pralia, respectively.

Osteonecrosis Of The Jaw (ONJ)

In the primary treatment phase of Study 2009482, ONJ was confirmed in 4.1% of patients in the Pralia group (median exposure of 16 months; range: 1 -50) and 2.8% of patients in the zoledronic acid group (median 15 months, range: 1 -45 months). At the completion of the double-blind treatment phase of Study 2009482, the patient-year adjusted incidence (number of events per 100 patient years) of confirmed ONJ in the Pralia group (median exposure of 19.4 months; range 1 -52)was 2.0%during the first year of treatment,5.0%in the second year, and 4.5%per year thereafter. The median time to ONJ was18.7 months (range: 1 -44).

Giant Cell Tumor Of Bone

The safety of Pralia was evaluated in two single arm trials (Study 20062004 and Study 20040215) in which a total of 304 adult or skeletally mature adolescent patients with giant cell tumor of bone received at least 1 dose of Pralia. Patients received 120 mg Pralia subcutaneously every 4 weeks with additional 120 mg doses on Days 8 and 15 of the first month of therapy. Patients receiving concurrent bisphosphonate therapy were excluded from enrollment in both studies. Patients with prior history of ONJ or osteomyelitis of the jaw, an active dental or jaw condition requiring oral surgery, non-healed dental/oral surgery, or any planned invasive dental procedure were excluded from enrollment in Study 20040215. During the trial, serum chemistries including calcium and phosphorus were monitored every 4 weeks. Calcium and vitamin D supplementation was recommended but not required.

Of the 304 patients who received Pralia, 145 patients were treated with Pralia for ≥ 1 year, 44 patients for ≥ 2 years, and 15 patients for ≥ 3 years. The median number of doses received was 14(range:1to60doses) and the median number of months on study was 11 (range: 0 to 54months). Fifty-eight percent of the enrolled patients were women and 80% were White. The median age was 33years (range: 13 to 83 years); a total of 10patients were skeletally mature adolescents (13 to 17years of age).

The adverse reaction profile of Pralia in patients with giant cell tumor of bone was similar to that reported in Studies 20050136, 20050244, and 20050103. The most common adverse reactions in patients (incidence ≥ 10%) were arthralgia, headache, nausea, back pain, fatigue, and pain in extremity. The most common serious adverse reactions were osteonecrosis of the jaw and osteomyelitis (incidence of 0.7%). The most common adverse reactions resulting in discontinuation of Pralia were osteonecrosis of the jaw (incidence of 0.7%), and tooth abscess or tooth infection (incidence of 0.7%). The adverse reaction profile appeared similar in skeletally mature adolescents and adults.

Hypocalcemia And Hypophosphatemia

• Moderate hypocalcemia (corrected serum calcium less than 8 to 7 mg/dL or less than 2 to 1.75 mmol/L) occurred in 2.6% of patients treated with Pralia.
• Severe hypophosphatemia (serum phosphorus less than 2 to 1 mg/dL or less than 0.6 to 0.3 mmol/L) occurred in 29 patients (9.5%).

Osteonecrosis Of The Jaw (ONJ)

In Study 20062004 and Study 20040215, ONJ was confirmed in 4 of 304 (1.3%) patients who received Pralia. Themediantime to ONJ was 16months (range: 13 to 20months).

Hypercalcemia Of Malignancy

Pralia was evaluated in an open-label, single-arm trial (Study 20070315) in which 33 patients with hypercalcemia of malignancy (with or without bone metastases) refractory to treatment with intravenous bisphosphonate therapy were enrolled.

The adverse reaction profile of Pralia in patients with hypercalcemia of malignancy was similar to that reported in Studies20050136, 20050244, 20050103, 20062004, and 20040215. Adverse reactions occurring in greater than 20% of patients were nausea (30%), dyspnea (27%), decreased appetite (24%), headache (24%), peripheral edema (24%), vomiting (24%), anemia (21%), constipation (21%), and diarrhea (21%). The following adverse reactions of Grade 3 or greater severity related to study therapy were reported on study: fatigue (3%) and infection (6%). Grade 3 laboratory abnormalities included hypomagnesemia (3%), hypokalemia (3%), and hypophosphatemia (76%) of patients. No deaths on study were related to Pralia therapy.

Postmarketing Experience

The following adverse reactions have been identified during postapproval use of Pralia. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

• Hypocalcemia: Severe symptomatic hypocalcemia, including fatal cases.
• Hypersensitivity, including anaphylactic reactions.
• Musculoskeletalpain, including severe musculoskeletal pain. Positive re-challenge has been reported.

Immunogenicity

As with all therapeutic proteins, there is potential for immunogenicity. The detection of antibody formation is highly dependent on the sensitivity and specificity of the assay. Additionally, the observed incidence of antibody (including neutralizing antibody) positivity in an assay may be influenced by several factors including assay methodology, sample handling, timing of sample collection, concomitant medications, and underlying disease. For these reasons, comparison of the incidence of antibodies to denosumab in the studies described below with the incidence of antibodies to other studies or to other products may be misleading.

Using an electrochemiluminescent bridging immunoassay, less than 1% (7/2758) of patients with osseous metastases treated with denosumab doses ranging from 30-180 mg every 4 weeks or every 12 weeks for up to 3 years tested positive for binding antibodies. None of the 304 patients with giant cell tumor of bone in Study 20062004 and Study 20040215 tested positive for binding antibodies. In multiple myeloma patients in Study 20090482, 1 out of 199 patients with a post baseline result, tested positive for binding antibodies. No patient with positive binding antibodies tested positive for neutralizing antibodies as assessed using a chemiluminescent cell-based in vitro biological assay. There was no evidence of altered pharmacokinetic profile, toxicity profile, or clinical response associated with binding antibody development.

The following adverse reactions are discussed below and elsewhere in the labeling:

• Hypersensitivity
• Hypocalcemia
• Osteonecrosis of the Jaw
• Atypical Subtrochanteric and Diaphyseal Femoral Fracture
• Hypercalcemia following treatment discontinuation in patients with growing skeletons

Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

Bone Metastasis From Solid Tumors

The safety of Xgeva was evaluated in three randomized, double-blind, double-dummy trials in which a total of 2841patients with bone metastasis from prostate cancer, breast cancer, or other solid tumors, or lytic bony lesions from multiple myeloma received at least one dose of Xgeva. In Studies 20050136, 20050244, and 20050103, patients were randomized to receive either 120 mg of Xgeva every 4 weeks as a subcutaneous injection or 4mg (dose adjusted for reduced renal function) of zoledronic acid every 4 weeks by intravenous (IV) infusion. Entry criteria included serum calcium (corrected) from 8 to 11.5mg/dL (2 to 2.9mmol/L) and creatinine clearance 30mL/min or greater. Patients who had received IV bisphosphonates were excluded, as were patients with prior history of ONJ or osteomyelitis of the jaw, an active dentalor jaw condition requiring oral surgery, non-healed dental/oral surgery, or any planned invasive dental procedure. During the study, serum chemistries including calcium and phosphorus were monitored every 4 weeks. Calcium and vitamin D supplementation was recommended but not required.

The median duration of exposure to Xgeva was 12months (range: 0.1 -41) and median duration on-study was 13months (range: 0.1 -41). Of patients who received Xgeva, 46% were female. Eighty-five percent were White, 5% Hispanic/Latino, 6% Asian, and 3% Black. The median age was 63 years (range: 18 -93). Seventy-five percent of patients who received Xgeva received concomitant chemotherapy.

The most common adverse reactions in patients (incidence greater than or equal to 25%) were fatigue/asthenia, hypophosphatemia, and nausea (see Table 1). The most common serious adverse reaction was dyspnea. Themost common adverse reactions resulting in discontinuation of Xgeva were osteonecrosis and hypocalcemia.

Table 1: Selected^a Adverse Reactions of Any Severity (Studies 20050136, 20050244, and 20050103)

Severe Mineral/Electrolyte Abnormalities

• Severe hypocalcemia (corrected serum calcium less than 7mg/dL or less than 1.75mmol/L) occurred in 3.1% of patients treated with Xgeva and 1.3% of patients treated with zoledronic acid. Of patients who experienced severe hypocalcemia, 33% experienced 2 or more episodes of severe hypocalcemia and 16% experienced 3 or more episodes.
• Severe hypophosphatemia (serum phosphorus less than 2 mg/dL or less than 0.6 mmol/L) occurred in 15.4% of patients treated with Xgeva and 7.4% of patients treated with zoledronic acid.

Osteonecrosis Of The Jaw (ONJ)

In the primary treatment phases of Studies 20050136, 20050244, and 20050103, ONJ was confirmed in 1.8% of patients in the Xgeva group (median exposure of 12.0 months; range: 0.1-40.5) and 1.3% of patients in the zoledronic acid group. The trials in patients with breast (Study 20050136) or prostate (Study 20050103) cancer included an Xgeva open label extension treatment phase where patients were offered Xgeva 120mg once every 4weeks (median overall exposure of 14.9months; range: 0.1-67.2). The patient-year adjusted incidence (number of events per 100 patient years) of confirmed ONJ was 1.1% during the first year of treatment, 3.7% in the second year, and 4.6% per year thereafter. The median time to ONJ was 20.6months (range: 4-53).

In a placebo-controlled clinical trial with an extension treatment phase evaluating Xgeva for the prevention of bone metastases in patients with non-metastatic prostate cancer (a patient population for which Xgeva is not indicated), with longer treatment exposure of up to 7 years, the patient-year adjusted incidence (number of events per 100 patient years) of confirmed ONJ was 1.1% during the first year of treatment, 3.0% in the second year, and 7.1% per year thereafter.

Atypical Subtrochanteric And Diaphyseal Fracture

Atypical femoral fracture has been reported with Xgeva.

Multiple Myeloma

The safety of Xgeva was evaluated in an international, randomized (1:1), double-blind, active-controlled trial of patients with newly diagnosed multiple myeloma with treatment through disease progression. In this trial, patients received 120 mg Xgeva every 4 weeks as a subcutaneous injection (n=850) or4mg (dose adjusted for renal function) of zoledronic acid intravenously (IV) every 4 weeks by IV infusion (n=852). Entry criteria included serum calcium (corrected) from 8 to 11.5mg/dL (2 to 2.9mmol/L) and creatinine clearance 30mL/min or greater. Patients who had received IV bisphosphonates were excluded, as were patients with prior history of ONJ or osteomyelitis of the jaw, an active dentalor jaw condition requiring oralsurgery, non-healed dental/oral surgery, or any planned invasive dental procedure. During the study, serum chemistries including calcium and phosphorus were monitored every 4 weeks. Calcium and vitamin D supplementation was recommended but not required.

The median duration of exposure to Xgeva was 16 months (range: 1 -50) and median duration on-study was 17 months (range: 0.0 -49). Of patients who received Xgeva, 46% were female, 83% percent were White, 13% Asian, 3% Black or African American, and 4% Hispanic/Latino. The median age of the patients randomized to Xgeva was 63years (range: 29 -91) and allpatients who received Xgeva received concomitant anti-myeloma chemotherapy.

The adverse reaction profile of Xgeva in patients with multiple myeloma, Study 2009482, was similar to that observed in Studies 20050136, 20050244, and 20050103. The most common adverse reactions (incidence ≥ 10%) were diarrhea (34%), nausea (32%), anemia (22%), back pain (21%), thrombocytopenia (19%), peripheral edema (17%), hypocalcemia (16%), upper respiratory tract infection (15%), rash (14%), and headache (11%). The most common serious adverse reaction (incidence ≥ 5%) was pneumonia (8%). The most common adverse reaction resulting in discontinuation of Xgeva (≥ 1.0%) was osteonecrosis of the jaw.

Hypocalcemia And Hypophosphatemia

Severe hypocalcemia (corrected serum calcium less than 7mg/dL or less than 1.75mmol/L) and severe hypophosphatemia (serum phosphorus less than 2mg/dL or less than 0.6mmol/L) occurred in 2% and 21% patients treated with Xgeva, respectively.

Osteonecrosis Of The Jaw (ONJ)

In the primary treatment phase of Study 2009482, ONJ was confirmed in 4.1% of patients in the Xgeva group (median exposure of 16 months; range: 1 -50) and 2.8% of patients in the zoledronic acid group (median 15 months, range: 1 -45 months). At the completion of the double-blind treatment phase of Study 2009482, the patient-year adjusted incidence (number of events per 100 patient years) of confirmed ONJ in the Xgeva group (median exposure of 19.4 months; range 1 -52)was 2.0%during the first year of treatment,5.0%in the second year, and 4.5%per year thereafter. The median time to ONJ was18.7 months (range: 1 -44).

Giant Cell Tumor Of Bone

The safety of Xgeva was evaluated in two single arm trials (Study 20062004 and Study 20040215) in which a total of 304 adult or skeletally mature adolescent patients with giant cell tumor of bone received at least 1 dose of Xgeva. Patients received 120 mg Xgeva subcutaneously every 4 weeks with additional 120 mg doses on Days 8 and 15 of the first month of therapy. Patients receiving concurrent bisphosphonate therapy were excluded from enrollment in both studies. Patients with prior history of ONJ or osteomyelitis of the jaw, an active dental or jaw condition requiring oral surgery, non-healed dental/oral surgery, or any planned invasive dental procedure were excluded from enrollment in Study 20040215. During the trial, serum chemistries including calcium and phosphorus were monitored every 4 weeks. Calcium and vitamin D supplementation was recommended but not required.

Of the 304 patients who received Xgeva, 145 patients were treated with Xgeva for ≥ 1 year, 44 patients for ≥ 2 years, and 15 patients for ≥ 3 years. The median number of doses received was 14(range:1to60doses) and the median number of months on study was 11 (range: 0 to 54months). Fifty-eight percent of the enrolled patients were women and 80% were White. The median age was 33years (range: 13 to 83 years); a total of 10patients were skeletally mature adolescents (13 to 17years of age).

The adverse reaction profile of Xgeva in patients with giant cell tumor of bone was similar to that reported in Studies 20050136, 20050244, and 20050103. The most common adverse reactions in patients (incidence ≥ 10%) were arthralgia, headache, nausea, back pain, fatigue, and pain in extremity. The most common serious adverse reactions were osteonecrosis of the jaw and osteomyelitis (incidence of 0.7%). The most common adverse reactions resulting in discontinuation of Xgeva were osteonecrosis of the jaw (incidence of 0.7%), and tooth abscess or tooth infection (incidence of 0.7%). The adverse reaction profile appeared similar in skeletally mature adolescents and adults.

Hypocalcemia And Hypophosphatemia

• Moderate hypocalcemia (corrected serum calcium less than 8 to 7 mg/dL or less than 2 to 1.75 mmol/L) occurred in 2.6% of patients treated with Xgeva.
• Severe hypophosphatemia (serum phosphorus less than 2 to 1 mg/dL or less than 0.6 to 0.3 mmol/L) occurred in 29 patients (9.5%).

Osteonecrosis Of The Jaw (ONJ)

In Study 20062004 and Study 20040215, ONJ was confirmed in 4 of 304 (1.3%) patients who received Xgeva. Themediantime to ONJ was 16months (range: 13 to 20months).

Hypercalcemia Of Malignancy

Xgeva was evaluated in an open-label, single-arm trial (Study 20070315) in which 33 patients with hypercalcemia of malignancy (with or without bone metastases) refractory to treatment with intravenous bisphosphonate therapy were enrolled.

The adverse reaction profile of Xgeva in patients with hypercalcemia of malignancy was similar to that reported in Studies20050136, 20050244, 20050103, 20062004, and 20040215. Adverse reactions occurring in greater than 20% of patients were nausea (30%), dyspnea (27%), decreased appetite (24%), headache (24%), peripheral edema (24%), vomiting (24%), anemia (21%), constipation (21%), and diarrhea (21%). The following adverse reactions of Grade 3 or greater severity related to study therapy were reported on study: fatigue (3%) and infection (6%). Grade 3 laboratory abnormalities included hypomagnesemia (3%), hypokalemia (3%), and hypophosphatemia (76%) of patients. No deaths on study were related to Xgeva therapy.

Postmarketing Experience

The following adverse reactions have been identified during postapproval use of Xgeva. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

• Hypocalcemia: Severe symptomatic hypocalcemia, including fatal cases.
• Hypersensitivity, including anaphylactic reactions.
• Musculoskeletalpain, including severe musculoskeletal pain. Positive re-challenge has been reported.

Immunogenicity

As with all therapeutic proteins, there is potential for immunogenicity. The detection of antibody formation is highly dependent on the sensitivity and specificity of the assay. Additionally, the observed incidence of antibody (including neutralizing antibody) positivity in an assay may be influenced by several factors including assay methodology, sample handling, timing of sample collection, concomitant medications, and underlying disease. For these reasons, comparison of the incidence of antibodies to denosumab in the studies described below with the incidence of antibodies to other studies or to other products may be misleading.

Using an electrochemiluminescent bridging immunoassay, less than 1% (7/2758) of patients with osseous metastases treated with denosumab doses ranging from 30-180 mg every 4 weeks or every 12 weeks for up to 3 years tested positive for binding antibodies. None of the 304 patients with giant cell tumor of bone in Study 20062004 and Study 20040215 tested positive for binding antibodies. In multiple myeloma patients in Study 20090482, 1 out of 199 patients with a post baseline result, tested positive for binding antibodies. No patient with positive binding antibodies tested positive for neutralizing antibodies as assessed using a chemiluminescent cell-based in vitro biological assay. There was no evidence of altered pharmacokinetic profile, toxicity profile, or clinical response associated with binding antibody development.

There is no experience with overdose in clinical studies. Denosumab has been administered in clinical studies using doses up to 180 mg every 4 weeks (cumulative doses up to 1,080 mg over 6 months), and no additional adverse reactions were observed.

There is no experience with overdosage of Pralia.

There is no experience with overdosage of Xgeva.

Pharmacotherapeutic group: Drugs for the treatment of bone diseases - Other drugs affecting bone structure and mineralisation, ATC code: M05BX04

Mechanism of action

Denosumab is a human monoclonal antibody (IgG2) that targets and binds with high affinity and specificity to RANKL, preventing activation of its receptor, RANK, on the surface of osteoclast precursors and osteoclasts. Prevention of the RANKL/RANK interaction inhibits osteoclast formation, function and survival, thereby decreasing bone resorption in cortical and trabecular bone.

Pharmacodynamic effects

Pralia treatment rapidly reduced the rate of bone turnover, reaching a nadir for the bone resorption marker serum type 1 C-telopeptides (CTX) (85% reduction) by 3 days, with reductions maintained over the dosing interval. At the end of each dosing interval, CTX reductions were partially attenuated from maximal reduction of > 87% to approximately > 45% (range 45-80%), reflecting the reversibility of Pralia's effects on bone remodelling once serum levels diminish. These effects were sustained with continued treatment. Bone turnover markers generally reached pre-treatment levels within 9 months after the last dose. Upon re-initiation, reductions in CTX by denosumab were similar to those observed in patients initiating primary denosumab treatment.

Immunogenicity

In clinical studies, neutralising antibodies have not been observed for denosumab. Using a sensitive immunoassay < 1% of patients treated with denosumab for up to 5 years tested positive for non neutralising binding antibodies with no evidence of altered pharmacokinetics, toxicity, or clinical response.

Clinical efficacy and safety in postmenopausal women with osteoporosis

Efficacy and safety of Pralia administered once every 6 months for 3 years were investigated in postmenopausal women (7,808 women aged 60-91 years, of which 23.6% had prevalent vertebral fractures) with baseline bone mineral density (BMD) T-scores at the lumbar spine or total hip between -2.5 and -4.0 and a mean absolute 10-year fracture probability of 18.60% (deciles: 7.9-32.4%) for major osteoporotic fracture and 7.22% (deciles: 1.4-14.9%) for hip fracture. Women with other diseases or on therapies that may affect bone were excluded from this study. Women received calcium (at least 1,000 mg) and vitamin D (at least 400 IU) supplementation daily.

Effect on vertebral fractures

Pralia significantly reduced the risk of new vertebral fractures at 1, 2 and 3 years (p < 0.0001) (see table 2).

Table 2 The effect of Pralia on the risk of new vertebral fractures

*p < 0.0001, **p < 0.0001 - exploratory analysis

Effect on hip fractures

Pralia demonstrated a 40% relative reduction (0.5% absolute risk reduction) in the risk of hip fracture over 3 years (p < 0.05). The incidence of hip fracture was 1.2% in the placebo group compared to 0.7% in the Pralia group at 3 years.

In a post-hoc analysis in women > 75 years, a 62% relative risk reduction was observed with Pralia (1.4% absolute risk reduction, p < 0.01).

Effect on all clinical fractures

Pralia significantly reduced fractures across all fracture types/groups (see table 3).

Table 3 The effect of Pralia on the risk of clinical fractures over 3 years

*p ≤ 0.05; **p = 0.0106 (secondary endpoint included in multiplicity adjustment), ***p ≤ 0.0001

⁺ Event rates based on Kaplan-Meier estimates at 3 years.

¹ Includes clinical vertebral fractures and non-vertebral fractures.

² Excludes those of the vertebrae, skull, facial, mandible, metacarpus, and finger and toe phalanges.

³ Includes pelvis, distal femur, proximal tibia, ribs, proximal humerus, forearm, and hip.

⁴ Includes clinical vertebral, hip, forearm, and humerus fractures, as defined by the WHO.

In women with baseline femoral neck BMD ≤ -2.5, Pralia reduced the risk of non-vertebral fracture (35% relative risk reduction, 4.1% absolute risk reduction, p < 0.001, exploratory analysis).

The reduction in the incidence of new vertebral fractures, hip fractures and non-vertebral fractures by Pralia over 3 years were consistent regardless of the 10-year baseline fracture risk.

Effect on bone mineral density

Pralia significantly increased BMD at all clinical sites measured, versus placebo at 1, 2 and 3 years. Pralia increased BMD by 9.2% at the lumbar spine, 6.0% at the total hip, 4.8% at the femoral neck, 7.9% at the hip trochanter, 3.5% at the distal 1/3 radius and 4.1% at the total body over 3 years (all p < 0.0001).

In clinical studies examining the effects of discontinuation of Pralia, BMD returned to approximately pre-treatment levels and remained above placebo within 18 months of the last dose. These data indicate that continued treatment with Pralia is required to maintain the effect of the medicinal product. Re-initiation of Pralia resulted in gains in BMD similar to those when Pralia was first administered.

Open-label extension study in the treatment of postmenopausal osteoporosis

A total of 4,550 women (2,343 Pralia & 2,207 placebo) who missed no more than one dose of investigational product in the pivotal study described above and completed the month 36 study visit agreed to enrol in a 7-year, multinational, multicentre, open-label, single-arm extension study to evaluate the long-term safety and efficacy of Pralia. All women in the extension study were to receive Pralia 60 mg every 6 months, as well as daily calcium (at least 1 g) and vitamin D (at least 400 IU). A total of 2,626 subjects (58% of the women included in the extension study i.e. 34% of the women included in the pivotal study) completed the extension study.

In patients treated with Pralia for up to 10 years, BMD increased from the pivotal study baseline by 21.7% at the lumbar spine, 9.2% at the total hip, 9.0% at the femoral neck, 13.0% at the trochanter and 2.8% at the distal 1/3 radius. The mean lumbar spine BMD T-score at the end of the study was -1.3 in patients treated for 10 years.

Fracture incidence was evaluated as a safety endpoint but efficacy in fracture prevention cannot be estimated due to high number of discontinuations and open-label design The cumulative incidence of new vertebral and non-vertebral fractures were approximately 6.8% and 13.1% respectively, in patients who remained on denosumab treatment for 10 years (n = 1,278). Patients who did not complete the study for any reason had higher on-treatment fracture rates.

Thirteen adjudicated cases of osteonecrosis of the jaw (ONJ) and two adjudicated cases of atypical fractures of the femur occurred during the extension study.

Clinical efficacy and safety in men with osteoporosis

Efficacy and safety of Pralia once every 6 months for 1 year were investigated in 242 men aged 31-84 years. Subjects with an eGFR < 30 mL/min/1.73 m² were excluded from the study. All men received calcium (at least 1,000 mg) and vitamin D (at least 800 IU) supplementation daily.

The primary efficacy variable was percent change in lumbar spine BMD, fracture efficacy was not evaluated. Pralia significantly increased BMD at all clinical sites measured, relative to placebo at 12 months: 4.8% at lumbar spine, 2.0% at total hip, 2.2% at femoral neck, 2.3% at hip trochanter, and 0.9% at distal 1/3 radius (all p < 0.05). Pralia increased lumbar spine BMD from baseline in 94.7% of men at 1 year. Significant increases in BMD at lumbar spine, total hip, femoral neck and hip trochanter were observed by 6 months (p < 0.0001).

Bone histology in postmenopausal women and men with osteoporosis

Bone histology was evaluated in 62 postmenopausal women with osteoporosis or with low bone mass who were either naïve to osteoporosis therapies or had transitioned from previous alendronate therapy following 1-3 years treatment with Pralia. Fifty nine women participated in the bone biopsy sub-study at month 24 (n = 41) and/or month 84 (n = 22) of the extension study in postmenopausal women with osteoporosis. Bone histology was also evaluated in 17 men with osteoporosis following 1 year treatment with Pralia. Bone biopsy results showed bone of normal architecture and quality with no evidence of mineralisation defects, woven bone or marrow fibrosis. Histomorphometry findings in the extension study in postmenopausal women with osteoporosis showed that the antiresorptive effects of Pralia, as measured by activation frequency and bone formation rates, were maintained over time.

Clinical efficacy and safety in patients with bone loss associated with androgen deprivation

Efficacy and safety of Pralia once every 6 months for 3 years were investigated in men with histologically confirmed non-metastatic prostate cancer receiving ADT (1,468 men aged 48-97 years) who were at increased risk of fracture (defined as > 70 years, or < 70 years with a BMD T-score at the lumbar spine, total hip, or femoral neck < -1.0 or a history of an osteoporotic fracture.) All men received calcium (at least 1,000 mg) and vitamin D (at least 400 IU) supplementation daily.

Pralia significantly increased BMD at all clinical sites measured, relative to treatment with placebo at 3 years: 7.9% at the lumbar spine, 5.7% at the total hip, 4.9% at the femoral neck, 6.9% at the hip trochanter, 6.9% at the distal 1/3 radius and 4.7% at the total body (all p < 0.0001). In a prospectively planned exploratory analysis, significant increases in BMD were observed at the lumbar spine, total hip, femoral neck and the hip trochanter 1 month after the initial dose.

Pralia demonstrated a significant relative risk reduction of new vertebral fractures: 85% (1.6% absolute risk reduction) at 1 year, 69% (2.2% absolute risk reduction) at 2 years and 62% (2.4% absolute risk reduction) at 3 years (all p < 0.01).

Clinical efficacy and safety in patients with bone loss associated with adjuvant aromatase inhibitor therapy

Efficacy and safety of Pralia once every 6 months for 2 years was investigated in women with non-metastatic breast cancer (252 women aged 35-84 years) and baseline BMD T-scores between -1.0 to -2.5 at the lumbar spine, total hip or femoral neck. All women received calcium (at least 1,000 mg) and vitamin D (at least 400 IU) supplementation daily.

The primary efficacy variable was percent change in lumbar spine BMD, fracture efficacy was not evaluated. Pralia significantly increased BMD at all clinical sites measured, relative to treatment with placebo at 2 years: 7.6% at lumbar spine, 4.7% at total hip, 3.6% at femoral neck, 5.9% at hip trochanter, 6.1% at distal 1/3 radius and 4.2% at total body (all p < 0.0001).

Paediatric population

The European Medicines Agency has waived the obligation to submit the results of studies with Pralia in all subsets of the paediatric population in the treatment of bone loss associated with sex hormone ablative therapy, and in subsets of the paediatric population below the age of 2 in the treatment of osteoporosis.

In patients with breast cancer and bone metastases, the median reduction in uNTx/Cr was 82% within 1 week following initiation of Pralia 120 mg administered subcutaneously. In Studies 20050136, 20050244, and 20050103, the median reduction in uNTx/Cr from baseline to Month 3 was approximately 80% in 2075 Pralia-treated patients.

In a phase 3 study of patients with newly diagnosed multiple myeloma who received SC doses of Pralia 120 mg every 4 weeks (Q4W), median reductions in uNTx/Cr of approximately 75% were observed by week 5. Reductions in bone turnover markers were maintained, with median reductions of 74% to 79% for uNTx/Cr from weeks 9 to 49 of continued 120 mg Q4W dosing.

In patients with breast cancer and bone metastases, the median reduction in uNTx/Cr was 82% within 1 week following initiation of Xgeva 120 mg administered subcutaneously. In Studies 20050136, 20050244, and 20050103, the median reduction in uNTx/Cr from baseline to Month 3 was approximately 80% in 2075 Xgeva-treated patients.

In a phase 3 study of patients with newly diagnosed multiple myeloma who received SC doses of Xgeva 120 mg every 4 weeks (Q4W), median reductions in uNTx/Cr of approximately 75% were observed by week 5. Reductions in bone turnover markers were maintained, with median reductions of 74% to 79% for uNTx/Cr from weeks 9 to 49 of continued 120 mg Q4W dosing.