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side effects and safety 

Prolia® side effects and safety 

Frequency of Prolia® side effects  


Very common denosumab side effects (may affect more than 1 in 10 patients)

  • Pain in extremity
  • Musculoskeletal pain

Common denosumab side effects (may affect up to 1 in 10 pATIENTS)

  • Urinary tract infection
  • Upper respiratory tract infection
  • Sciatica
  • Cataracts
  • Constipation
  • Abdominal discomfort 
  • Rash 
  • Eczema

Uncommon denosumab side effects (may affect up to 1 in 100 patients) 

  • Diverticulitis
  • Cellulitis
  • Ear infection

Rare denosumab side effects (May affect up to 1 in 1000 pATIENTS)

  • Drug hypersensitivity / allergic reactions
  • Anaphylactic reaction
  • Hypocalcaemia
  • Osteonecrosis of the jaw
  • Atypical femoral fractures 

Description of selected Prolia® side effects

Hypocalcemia

It is important to identify patients at risk for hypocalcemia. Hypocalcemia 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 hypocalcemia within two weeks after the initial dose. If any patient presents with suspected symptoms of hypocalcemia during treatment calcium levels should be measured. Patients should be encouraged to report symptoms indicative of hypocalcemia. 

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.

Renal impairment

Patients with severe renal impairment (creatinine clearance < 30 ml/min) or receiving dialysis are at greater risk of developing hypocalcemia. The risks of developing hypocalcemia 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. 

Osteonecrosis of the Jaw 

ONJ has been reported rarely in clinical studies and in the post marketing setting in patients receiving denosumab at a dose of 60 mg every 6 months for osteoporosis. ONJ has been reported commonly in clinical studies in patients with advanced cancer treated with denosumab at the studied dose of 120 mg administered monthly.

Known risk factors for ONJ include previous treatment with bisphosphonates, older age, poor oral hygiene, invasive dental procedures (e.g. tooth extractions, dental implants, oral surgery), andco-morbid disorders (e.g. pre-existing dental disease, anaemia, coagulopathy, infection), smoking, a diagnosis of cancer with bone lesions, concomitant therapies (e.g., chemotherapy, antiangiogenicbiologics, corticosteroids, radiotherapy to head and neck).

It is important to evaluate patients for risk factors for ONJ before starting treatment. A dental examination with appropriate preventive dentistry is recommended prior to treatment with Prolia® in patients with concomitant risk factors.

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 during treatment with Prolia®

While on treatment, patients should avoid invasive dental procedures if possible. For patients who develop ONJ while on Prolia® therapy, dental surgery may exacerbate the condition. The management plan of the individual 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.

Atypical fractures of the femur

Atypical femoral fractures have been reported in patients receiving Prolia®.Atypical femoral fractures may occur with little or no trauma in the subtrochanteric and diaphyseal regions of the femur. Specific radiographic findings characterize these events. 

Atypical femoral fractures have also been reported in patients with certain comorbid conditions (e.g. vitamin D deficiency, rheumatoidarthritis, 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 Prolia®- treated patients who have sustained a femoral shaft fracture. 

Discontinuation of Prolia® 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 Prolia® 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.

Skin Infections

Patients receiving denosumab may develop skin infections leading to hospitalization, predominantly cellulitis. Prompt medical attention should be sought if patients experience symptoms of cellulitis.

Drug-related hypersensitivity

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 Prolia®. In addition, it should be noted that the needle cover of the prefilled syringe contains dry natural rubber (a derivative of latex), which may cause allergic reactions.


all patients on prolia® (denosumab) therapy should maintain good oral hygiene, go for regular dental check-ups and report any symptoms on onj promPtly


Prolia® (denosumab) safety information

More than 13,000 patients have been exposed to denosumab in over 30 clinical studies, with more than 1,540 patients treated for 8 years in FREEDOM Extension study (Refer to Prolia® SmPC for detailed safety information). 


More than 13,000 patients have been exposed to denosumab in over 30 clinical studies


Fertility, pregnancy and breastfeeding

Fertility 

No data are available on the effect of denosumab on human fertility but animal studies do not indicate direct or indirect harmful effects with respect to fertility.

Pregnancy 

There are no adequate data from the use of Prolia® in pregnant women. Reproductive toxicity was shown in a study of cynomolgus monkeys, dosed throughout pregnancy with denosumab at AUC exposures 119-fold higher than the human dose.

Prolia® is not recommended for use in pregnant women.

Women who become pregnant during Prolia® treatment are encouraged to enrol in Amgen’s pregnancy surveillance programme. Contact details are provided in section 6 of the package leaflet – Information for the user.

Breast-feeding 

It is unknown whether denosumab is excreted in human milk. In genetically engineered mice in which RANKL has been turned off by gene removal (a “knockout mouse”), studies suggest absence of RANKL during pregnancy may interfere with maturation of the mammary gland leading to impaired lactation post-partum.  A decision on whether to abstain from breast-feeding or to abstain from therapy with Prolia® should be made, taking into account the benefit of breast-feeding to the newborn/infant and the benefit of Prolia® therapy to the woman.

Women who are breast-feeding during Prolia® treatment are encouraged to enrol in Amgen’s lactation surveillance program. Contact details are provided in section 6 of the package leaflet – Information for the user.

Safety in special populations

Renal impairment

In a study of 55 patients with varying degrees of renal function, including patients on dialysis, the degree of renal impairment had no effect on the pharmacokinetics of denosumab.

Hepatic impairment

Patients with hepatic impairment have not been studied. 

Pediatric population

Prolia® is not recommended in pediatric patients (age < 18) as the safety and efficacy of Prolia® in these patients have not been established.

Ability to drive and use machines 

Prolia® has no or negligible influence on the ability to drive and use machines. 

Overdose

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.