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PROLIA (denosumab)

Brief Prescribing Information Please refer to the Summary of Product Characteristics before prescribing PROLIA.Pharmaceutical Form: Pre-filled syringe with automatic needle guard containing 60 mg of denosumab in 1 ml solution for injection for single use only. Indications: Treatment of osteoporosis in postmenopausal women and in men at increased risk of fractures. In postmenopausal women Prolia significantly reduces the risk of vertebral, non-vertebral and hip fractures.Treatment of bone loss associated with hormone ablation in men with prostate cancer at increased risk of fractures. In men with prostate cancer receiving hormone ablation, Prolia significantly reduces the risk of vertebral fractures. Treatment of bone loss associated with long-term systemic glucocorticoid therapy in adult patients at increased risk of fracture Posology and method of administration: Posology; The recommended dose of Prolia 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 Prolia 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: No dose adjustment is required in patients with renal impairment. No Data is available in patients with long-term systemic glucocorticoid therapy and severe renal impairment (GFR < 30 mL/min) 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 : Prolia is not recommended in paediatric patients (age < 18) as the safety and efficacy of Prolia 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. Contraindications. Hypersensitivity to the active substance or to any of the excipients. Hypocalcaemia. Special warnings and precautions for use: 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. Concomitant glucocorticoid treatment is an additional risk factor for hypocalcaemia 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.Skin infections: Patients receiving Prolia 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 Prolia 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 Prolia 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 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 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 Prolia 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). 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 medicine contains 47 mg sorbitol in each mL of solution. The additive effect of concomitantly administered products containing sorbitol (or fructose) and dietary intake of sorbitol (or fructose) should be taken into account.This medicinal product contains less than 1 mmol sodium (23 mg) per 60 mg i.e. essentially ‘sodium free’. Interaction with other medicinal products and other forms of interaction In an interaction study, Prolia did not affect the pharmacokinetics of midazolam, which is metabolized by cytochrome P450 3A4 (CYP3A4). This indicates that Prolia should not alter the pharmacokinetics of medicinal products metabolized by CYP3A4. There are no clinical data on the co-administration of denosumab and hormone replacement therapy (oestrogen), however the potential for a pharmacodynamic interaction is considered to be low. In postmenopausal women with osteoporosis the pharmacokinetics and pharmacodynamics of denosumab were not altered by previous alendronate therapy, based on data from a transition study (alendronate to denosumab). Fertility, pregnancy and lactation: Pregnancy There are no or limited amount of data from the use of denosumab in pregnant women. Studies in animals have shown reproductive toxicity.Prolia is not recommended for use in pregnant women and women of child-bearing potential not using contraception. Women should be advised not to become pregnant during and for at least 5 months after treatment with Prolia. Any effects of Prolia are likely to be greater during the second and third trimesters of pregnancy since monoclonal antibodies are transported across the placenta in a linear fashion as pregnancy progresses, with the largest amount transferred during the third trimester. 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. Fertility: No data are available on the effect of denosumab on human fertility. Animal studies do not indicate direct or indirect harmful effects with respect to fertility. Effects on ability to drive and use machines Prolia has no or negligible influence on the ability to drive and use machines. Undesirable effects: Summary of the safety profile The most common side effects with Prolia (seen in more than one patient in ten) are musculoskeletal pain and pain in the extremity. Uncommon cases of cellulitis, rare cases of hypocalcaemia, hypersensitivity, osteonecrosis of the jaw and atypical femoral fractures, have been observed in patients taking.Prolia Very common (≥ 1/10): Pain in extremity, Musculoskeletal pain. Common (≥ 1/100 to < 1/10): Urinary tract infection, Upper respiratory tract infection, Sciatica, abdominal discomfort, Constipation, Rash, Eczema. Uncommon (≥ 1/1,000 to < 1/100): Diverticulitis, Cellulitis, Ear infection. Rare (≥ 1/10,000 to < 1/1,000) Drug hypersensitivity, Anaphylactic reaction, Osteonecrosis of the jaw, Atypical femoral fractures, Hypocalcaemia. 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. Special precautions for storage: Store in a refrigerator (2°C – 8°C).Do not freeze. Keep the container in the outer carton in order to protect from light. Special precautions for disposal and other handling Before administration, the solution should be inspected. Do not inject the solution if it contains particles, or is cloudy or discoloured. Do not shake. To avoid discomfort at the site of injection, allow the pre-filled syringe to reach room temperature (up to 25°C) before injecting and inject slowly. Inject the entire contents of the pre-filled syringe. Any unused medicinal product or waste material should be disposed of in accordance with local requirements. Legal Category: POM. Administrative information: Marketing Authorisation Holder: Amgen Europe B.V. Minervum 7061 NL-4817 ZK Breda,The Netherlands.product license Number:PROLIA 60 mg/mL pre-filled syringe 17-475-13 date of revision of text: June 2018 Local representive in Saudi Arabia: : Cigalah Group of Companies. Address: Office Number 606&607, 6th floor, Al Akariya Building Number 2, Olaya Street, Riyadh, PIN 11533, Kingdom of Saudi Arabia.Tel: 00966 11 419 1471

Any suspected adverse reactions should be reported immediately to Amgen in accordance with local spontaneous reporting requirements. Amgen Fax: +966-11-2799301 or send to mailbox: and/or National Pharmacovigilance Centre (NPC), Email: , Fax: +966-11-2057662 ,Toll free phone: 8002490000, website: For any questions or require additional information, please contact Amgen Medical Information: